NZ621710B2

NZ621710B2 - Formulations and dosage forms of oxidized phospholipids

Info

Publication number: NZ621710B2
Application number: NZ621710A
Authority: NZ
Inventors: Massoud Bakhshaee; Alyn Mcnaughton; Naamit Sher; Ian Robert Wilding; Victor M Young
Original assignee: Vascular Biogenics Ltd
Priority date: 2011-09-01
Filing date: 2012-08-31
Publication date: 2016-02-02

Abstract

The current disclosure provides pharmaceutical compositions containing an oxidized phospholipid, such as 1-hexadecyl-2-(4'-carboxybutyl)-glycero-3-phosphocholine (VB-201) and a thermosoftening carrier, e.g. a poloxamer. The pharmaceutical compositions may further comprise an anti-adherent agent, such as talc and/or a thixotropic agent. The current disclosure further provides processes for preparing the pharmaceutical compositions. The disclosure further provides capsules containing the pharmaceutical compositions. Uses of such pharmaceutical compositions and capsules in treating inflammatory disorders are also disclosed. h as talc and/or a thixotropic agent. The current disclosure further provides processes for preparing the pharmaceutical compositions. The disclosure further provides capsules containing the pharmaceutical compositions. Uses of such pharmaceutical compositions and capsules in treating inflammatory disorders are also disclosed.

Description

FORMULATIONS AND DOSAGE FORMS OF OXIDIZED PHOSPHOLIPIDS FIELD AND BACKGROUND OF THE INVENTION The present invention, relates to the ﬁeld of cology and more particularly, but not exclusively, to novel oral dosage forms of oxidized phospholipids. ed phospholipids have been previously described as useful in the treatment of medical conditions such as, for example, cardiovascular diseases, cerebrovascular diseases and inﬂammatory diseases and disorders.

International Patent Application No. (Publication No. WO 04/106486), by the present assignee, describes oxidized lipids for prevention and ent of inﬂammation associated with endogenous oxidized lipids. An exemplary such compound is bed and known as CI-201 (l—hexadecyl-2—(4’-carboxybutyl)- glycerophosphocholine), also referred to in the art as VB-201. VB-201 was found to be an orally active drug, useful in the ent of atory disorders such as atherosclerosis, psoriasis, multiple sclerosis, rheumatoid arthritis and inﬂammatory bowel disease.

International Patent Application No. PCT/ILOl/01080 (Publication No. WO 02/41827), by the present assignee, describes oxidized lipids for prevention and treatment of atherosclerosis and related es.

Additional background art includes ational Patent Application Nos.

PCT/IL05/000735 (Publication No. WO 06/006161), PCT/IL02/00005 (Publication No.

WO 02/053092) and PCT/[LOS/OOOOB (Publication No. WO 472), all being also by the present assignee.

All of the above cited publications are incorporated by reference as if fully set forth herein.

Recently, and in View of the promising therapeutic effect of VB—201, clinical studies were conducted in order to evaluate the ty, y and pharrnacokinetic parameters of orally stered VB-201. The obtained results showed that daily dosages of 80 mg VB-201 per day or less are safe, well-tolerated, and effective at inhibiting inﬂammatory processes, that a substantial percentage of VB—201 is absorbed into the bloodstream, and that plasma concentrations of VB-201 are relatively stable when VB-201 is stered once per day, and are described in International Patent Application PCT/1L2011/000008, ﬁled January 5, 2011, which is orated by reference as if fully set forth herein.

In View of the potential therapeutic effects of oxidized phospholipids (e.g., VB— 201), a need arises for industréally and pharrnaceutically able formulations containing oxidized phospholipids, such as VB-201, as the active ingredient.

SUMMARY OF THE INVEE'INTION {$3009} The present disclosure provides pharmaceutical compositions comprising an oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB~219) having a structure as described herein (see, e.g., Formulae (I), (II), and (111)) and a thermosoftening carrier.

These compositions are useful as liquid ﬁll compositions, which can be placed into pharmaceutical receptacles, such as capsules (e.g., hell gelatin capsules). The inventors have discovered that certain oxidized olipids of the present disclosure tend to be adherent (i.e., sticky) and ally copic. These physical properties at about may arise from undergoing a phase transition at relatively low temperature (e.g., -30 °C). As a result, these oxidized phospholipids are difﬁcult to formulate into traditional dosage forms, such as tablets or capsules ﬁlled with liquid compositions. An exemplary oxidized phospholipid is 1-hexadecyl(4’-carboxybutyl)-glycero phosphocholine (VB-201).

Capsules constitute one of the principal dosage forms for pharmaceutical and health food products. The s of producing liquid-ﬁll capsules is lly associated with various difﬁculties. For example, in capsule ﬁll compositions which can be used in conjunction with soft capsules, the active ingredient needs to be in the solubilized state in a solvent mixture. ing an appropriate solution of the pharrnaceutically active substance may be challenging. Often it is not possible to dissolve the pharrnaceutically active substance in a volume of t small enough to produce a capsule of appropriate size from the standpoint of economics and patient acceptance. Furthermore, the solvent, carrier or vehicle itself must have ent solvating power to dissolve the desired amount of the pharrnaceutically active substance to e. a reasonably concentrated solution, while at the same time not hydrolyzing, dissolving or discoloring the capsule shell. Furthermore, the ﬁll composition as a whole must be chemically compatible with the capsule material and avoid degradation of the material once it has been encapsulated, as well as be inert or reduce e chemical interaction with the active ingredient. The biological activity of the active ient must not be signiﬁcantly compromised.

Accordingly, developmental challenges can arise in balancing all of these characteristics while accounting for the chemical nature of the active ingredient.

The inventors have discovered that capsules containing oxidized phospholipids in a liquid carrier are not sufﬁciently stable (e.g., leakage and cracking occurred).

Liquid-ﬁll hard capsule technology was contemplated to overcome the substantial challenges associated with producing a commercially viable oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-2l9) formulation. Hard capsules are typically made from gelatin, hydroxypropylmethyl cellulose (HPMC) or other suitable material and are ﬁlled on purpose-built high speed ﬁlling machines. The capsules may be ﬁlled with materials such as powders, granules, pellets, other capsules, s, semi-solids or thermosetting materials.

It was discovered that liquid-ﬁll hard capsule technology is suitable for the formulation of oxidized phospholipids. Experiments were conducted to ate the oxidized phospholipids into a liquid—ﬁll composition, which ns a thermosoftening carrier. For example, at higher temperature, e.g., above 60 °C, the ceutical composition is sufﬁciently liquid le) for ﬁlling the composition into ceutical receptacles, such as capsules. Upon cooling, the composition ﬁes sufﬁciently to preserve homogeneity and prevent leakage and ng of the receptacle (e.g., capsule). Upon cooling the solidiﬁed ﬁll-composition forms a solid or semi-solid matrix of the capsule.

Surprisingly, the inventors have further uncovered that the homogeneity of the pharmaceutical ition, the ﬁll-composition, and consequently batches of capsules containing the oxidized phospholipid (e.g., , VB-208, VB-221, or VB-219) can be considerably improved by mixing the ed olipid (e.g., VB-201, VB-208, VB- 221, or VB-219) with an dherent agent, e.g., prior to contacting the oxidized phospholipid with the molten thermosoftening carrier. For example, it is surprising that the use of an anti-adherent agent with little or no solubility (e.g., in the molten thermosoftening carrier) increases neity of the ﬁnal formulation because typically, such addition would be expected to decrease homogeneity of a liquid-ﬁll composition (e.g., by sedimentation and/or coagulation).

Hence, in some embodiments, the above pharmaceutical compositions further comprise an anti-adherent agent. For e, homogeneity of the pharmaceutical composition can be further increased by ng or milling the ed phospholipid (e.g., VB-201, VB-208, , or VB-219) with the anti-adherent agent, e.g., to form a powder blend. In some embodiments, the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) is mixed (e.g., milled together with) the anti-adherent agent prior to contacting the ed phospholipid with the softening r. For example, milling the oxidized phospholipid with an anti-adherent agent increases the homogeneity of the solidiﬁed pharmaceutical composition with respect to the spacial distribution of the oxidized phospholipid in the ﬁnal composition.

The inventors have further ered that the addition of a thixotropic agent to the ceutical composition (i.e., liquid-ﬁll composition) further increases the above described homogeneity of the ﬁnal formulation. Thus, in some examples according to any of the above embodiments, the ceutical composition further comprises a thixotropic agent or a gelling agent. For example, adding the thixotropic agent or the gelling agent to the pharmaceutical composition increases the viscosity of the composition and further increases the homogeneity of the pharmaceutical composition, e.g., by ting separation of ingredients before the ition solidiﬁes upon cooling. Thixotropic agents are particularly usefull in the pharmaceutical compositions of the present disclosure, e..g., because they can cause the composition to become “gel- like” when stirring ceases and the composition is allowed to stand prior to ﬁlling and ﬁnal cooling. Thixotropic agents may also allow for a more rapid solidiﬁcation of the composition once the composition has been ﬁlled into the capsule therby improving homogeneity.

According to some embodiments of the present invention there is provided a liquid-ﬁll capsule comprising an oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or ) and a solid or semi-solid , the matrix comprising a thermosoﬁening carrier. According to other embodiments of the present invention there is provided a liquid-ﬁll capsule comprising an oxidized phospholipid (e.g., VB-201, , VB-221, or VB-219) and a solid or olid matrix, the matrix comprising a thermosoﬁening carréer and an anti-adherent agent. According to other embodiments of the present invention there is provided a liquid-ﬁll capsule comprising an oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) and a solid or semi—solid matrix, the matrix comprising a thermosoftening carrier, an anti-adherent agent, and a thixotropic agent.

According to some embodiments of the invention, the capsule comprises a shell material selected from the group consisting of n, pullulan, starch, and hydroxypropyl methyl cellulose (HPMC).

According to some embodiments of the invention, the shell material comprises gelatin.

According to some ments of the present invention there is provided a liquid-ﬁll capsule comprising 1-hexadecyl(4’-carboxybutyl)-glycero—3-phosphocholine (VB-201) and a solid or semi-solid matrix, the matrix comprising a thermosoftening carrier. ing to some embodiments of the invention, the thermosoftening carrier has a melting point in a range from about 40 °C to about 100 °C.

According to some embodiments of the ion, the softening carrier is ed from the group consisting of a polyalkylene glycol, a polyalkylene glycol derivative, and a wax. An oil may be added to the thermosoﬁening carrier.

According to some embodiments of the invention, the polyalkylene glycol is selected from the group consisting of a polyethylene glycol, a polypropylene , and copolymers thereof.

According to some embodiments ofthe invention, the thermosoftening carrier is a poloxamer.

According to some embodiments of the invention, the poloxamer has a lar weight in a range of from about 2000 to about 18000 daltons.

According to some ments of the invention, the poloxamer has a lar weight in a range of from about 7000 to about 10000 s.

According to some embodiments of the invention, the poloxamer comprises from about 40 to about 90 weight percent polyethylene glycol.

According to some embodiments of the ion, the poloxamer is poloxamer 188. m 5 - {992%} According to some embodimente ot‘tne ion, the themiosotiening carrier is a poiyethyiene glycol. {@939} According to some embodiments ot’the invention, the hyiene giycoi has a molecular weight in a range of about i530 to about 8000 daitons, Etitﬁli According to some embodiments of the ion, the poiyethyiene giycoi has a inoiecniar weight ofabont 60%. {(3832} According to Some embodiments of the invention, the anti-adherent ngenE is taic. {£93333} According to some embodiments ofthe invention, a ratio of an amount of the anti~ adherent agent to an amount ofthe “$261 is in a range of from about 3:5 to 5:! (egg from about iz4 to 5:1, from about 1:4 to about i:i, or ﬁbm about 1:3 to about 5: i). {@3343 Accortiing to some etnoodirnents of the invention, a concentration of the anti» adherent agent in the pharmaceutical composition or matrix is in a range of from about 1 to about 30 weight percent” {@357} According to Some embodiments of the invention, the phannaeenticai composition or matrix of the cepsuie further coinprises a. ropic agent and/or a geiiing agent. {8936} According to some embodiments of the invention, the phannacenticai composition or matrix comprises a thixotropic agent. {@3377} According to some embodiments of the invention, the thixotropic agent is ﬁnned silica. {($33} According to some embodiments of the invention, the concentration of the ropic agent in the phannacenticai composition or matrix is in a range of from about 0.25 weight percent to about 10 weight t. {@939} According to some embodiments of the invention, the capsnie comprises from about i rng to about 190 mg VB~20i. {onto} According to some embodiments of the invention, the capsnie comprises from about 29 mg to about 8% mg VB1391.

} According to some embodiments of the ion, the capsnie comprises 20 mg VBQQL {8842} According to some ments of the inventiom the capsnie coniprieee 49 mg V3401. _ 7 _ According to some embodiments of the ion, the capsule comprises 80 mg VB-201. £0044} According to some embodiments of the invention, tlee capsule is a size 0 capsule. [0045} The present disclosure r provides a process for producing a pharmaceutical composition comprising an ed phospholipid (e.g., VBQOT, VBQGEZ, VB—221, or VB-219) and a thermosoftening carrier. The process comprises heating the thermosoftening carrier to a temperature above the melting point of the thermosoftening carrier, and contacting the oxidized olipid with the thermosoftening carrier, to thereby obtain the ceutical composition. The process may further include contacting (e.g., mixing or milling) the oxidized phospholipid with an anti-adherent agent, e. g., prior to contacting the oxidized phospholipid with the softening carrier.

The process may further include admixing the thermosoftening carrier with a thixotropic agent, e.g., prior to contacting the oxidized phospholipid with the thermosot‘tening carrier. [0E46] The present disclosure further provides a process for producing a liquid-ﬁll capsule comprising 1-hexadecyl(4’-carboxybutyl)—glycero—3-phosphocholine (VB- 201), the process comprising ﬁlling a capsule shell with a liquid-ﬁll composition which comprises VB-201 and a thermosoftening r, to thereby e the capsule.

According to some ments of the present disclosure there is provided a process for ing a liquid ﬁll composition which comprises VB-201, the process comprisirsg mixing VB-201 with a therrnosoftening carrier at a temperature above room temperature, to thereby obtain the liquid ﬁll composition.

According to some embodiments of the present invention there is provided a liquid—ﬁll capsule prepared by the abovementioned process for producing a liquid-ﬁll capsule.

According to some embodiments of the invention, the ﬁlling is performed at a temperature above room temperature, and the liquid composition forms a solid or semisolid matrix upon being cooled to room ature.

According to some embodiments of the ion, the process r comprises mixing VB—201 with a carrier to thereby obtain the composition sing VB-201.

According to some embodiments of the invention, the process r comprises mixing VB-201 with an anti-adherent agent prior to the mixing of VB—201 with the carrier.

According to some embodiments of the ion, the dherent agent is mixed with the VB-201 in a ratio in a range of ﬁom about 1:5 to about 5:1 (e.g., from about 1:4 to about 1:1, or from about 1:3 to about 5:1). ing to some embodiments of the invention, a ﬁnal concentration of the anti-adherent agent in the composition is in a range of from 1 to 30 weight percent.

According to some embodiments of the invention, the process further comprises admixing a thixotropic agent and/or a gelling agent with the carrier and the VB-201.

According to some embodiments of the invention, the process further comprises admixing a ropic agent with the carrier and the VB-201.

According to some embodiments of the invention, the process ﬁthher comprises admixing with the liquid ﬁll composition a thixotropic agent and/or a gelling agent.

According to some embodiments of the invention, the process further comprises admixing with the liquid ﬁll composition a thixotropic agent.

According to some embodiments of the ion, the thixotropic agent is added such that a ﬁnal concentration of the thixotropic agent in the composition is in a range of from 0.25 weight percent to 10 weight percent.

According to some embodiments of the invention, the carrier has a melting point in a range of from 40 °C to 100 °C, and the mixing is performed above the melting point.

According to some embodiments of the invention, the capsule is for use in the treatment of an inﬂammatory disease or disorder. [0061} According to some embodiments of the present disclosur there is provided a method of treating an inﬂammatory disease or disorder, the method comprising administering to a subject in need thereof a pharmaceutical ition or a capsule described .

According to some embodiments of the ion, the inﬂammatory disease or er is associated with an endogenous oxidized lipid.

According to some ments of the ion, the inﬂammatory disease or disorder is selected from the group consisting of an idiopathic inﬂammatory disease or er, a chronic inﬂammatory disease or disorder, an acute inﬂammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inﬂammatory malignant disease or disorder, an inﬂammatory transplantation-related e or disorder, an inﬂammatory rative disease or disorder, a disease or WO 33642 disorder associated with a hypersensitivity, an inﬂammatory cardiovascular disease or disorder, an inﬂammatory cerebrovascniar disease or disorder, a peripherai vascniar disease or disorder, an inﬂammatory gianduiar disease or disorder, an inﬂammatory gastrointestinai disease or disorder, an inﬂammatory ous disease or disorder, an inﬂammatory hepatic e or disorder, an inﬂammatory nenroiogieal disease or er, an inﬂammatory musenio—skeietai disease or er, an inﬂammatory renal disease or disorder; an inﬂammatory reproductive disease or disorder, an inﬂammatory systemic disease or er, an inﬂammatory tive tissue disease or disorder, an inﬂammatory tumor, is, an inﬂammatory impiantaelated disease or disorder, an inﬂammatory aging proeess, an immunodeﬁciency e or disorder, a proiiferative disease or disorder and an inﬂammatory pulmonary disease or disorder. {@6364} According to some embodiments of the invention, the e or disorder is seieeted from the group consisting of psoriasis, rheumatoid arthritis, multipie scierosis, inﬂammatory bowel disease, atherosclerosis, and inﬂammation of an artery.

In other embodiments, the present disclosure provides a pharmaceutical. formulation comprising VB—201, wherein the formulation, when orally administered to a human subject at a single oral dose of about 40 mg of VB-201, provides a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL, and a median time to mean maximum plasma concentration (Tmax) of VB— 201 from about 5 hours to about 10 hours.

Unless otherwise deﬁned, all technical and/or scientiﬁc terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of ments of the invention, exemplary s and/or materials are bed below. In case of conﬂict, the patent speciﬁcation, including deﬁnitions, will l. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRiEF DESCRIPTIQN (I)? 1813 DRAWINGS Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With speciﬁc reference now to the drawings in detail? it is stressed that the particulars shown are by way of example and for In this regard, the purposes of rative discussion of embodiments of the invention. description taken with the drawings makes apparent to those skilled in the art how embodiments ofthe invention may be practiced. {0%8] FIGS. 1A and 1B are graphs showing uptake of water by VB-201 at various relative humidities, as ined by gravimetric vapor sorption analysis. presents kinetic data showing both weight percentage uptake (Wt (% db.» and relative humidity (RH (%)) as a function of time. shows the equilibrium values for weight percentage uptake as a function of relative humidity, during sorption (Iso 01 Sorp) and desorption (Iso 01 Desorp); {£3060} is a graph showing the results of isothermal calorimetry of 88 mg ; is a graph showing the results of isothermal calorimetry of 262 mg Lauroglycol FCC; is a graph showing the results of isothermal calorimetry of 88 mg VB-201 mixed with 262 mg Lauroglycol FCC, g power as a function of time; is a differential scanning calorimetry thermograph obtained by heating (solid line) and then cooling (dotted line) VB-20l at a rate of 10 °C per minute ; is a graph showing the weight loss proﬁle of VB-201 obtained upon heating VB-201 at a rate of 10 °C per minute; is a graph g the storage modulus of VB-20l as a on of temperature, using a maximum displacement of 0.05 mm at l, 10 and 30 Hz, and a heating rate of 2 °C per minute; and {0075} is a is a graph g the damping parameter (tan5) of VB-201 as a function of temperature, using a maximum displacement of 0.05 mm at l, 10 and 30 Hz; and a g rate of 2 °C per minute. is a graph showing the plasma concentrations (ng/mL) of VB—201 following a single 40 mg oral dose ofVB-201 administered as formulation 10 of Example 13 and formulation 4 of Example 11 to human subjects.

DESC’RIPTK‘IN {BF IC EMBODIMENTS OF THE I‘ION [$077 The principles and ogaeration 0f the present invention may be better understand with reference to the ﬁgures and accompanying descriptions. 2012/053533 ..]1- {@678} Before explaining at least one embodiment of the invention in detail, it is to be tood that the invention is not limited in its ation to the s set forth in the following description or exempliﬁed by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of ption and should not be regarded as limiting. {@793 The present inventors have put ample efforts into identifying and overcoming many obstacles to ation of oxidized phospholipids, such as VB-201, in a unit dosage form that is convenient for administration, can be produced readily at low cost, and is safe, long-lasting and reliable. The identiﬁcation and solution of several obstacles is described in the Examples section.

{M383} VB-201 (also referred to herein and in the art as CI—201) has shown considerable promise as a therapeutically active agent in s in vitro models and in vivo animal models of inﬂammatory conditions. VB-201 is currently oing Phase II clinical trials for the treatment of various inﬂammatory conditions.

In an attempt to facilitate treatment with VB-201 and other oxidized phospholipids, the present inventors have devised suitable formulations and unit dosage forms for such compounds. ing now to the gs, FIGS. 1A and 1B show that certain oxidized phospholipids, such as , are copic and absorb considerable amounts of water from the surroundings, especially at a relative humidity of 40 % or higher.

{M383} shows isothermal calorimetry data which indicates that VB-201 undergoes a transition when exposed to the surrounding environment. FIGS. 3 and 4 show isothermal calorimetry data which indicates that Lauroglycol FCC (a non—polar solvent) does not undergo such a transition and is capable of ting VB-201 dissolved therein from undergoing such a transition. FIGS. 2-4 conﬁrm the abovementioned ﬁnding that VB-201 is hygroscopic, and suggest that absorption of water by VB-201 can be prevented by providing a non—aqueous environment. {@384} shows dittbrentiai scanning caiorimetry data which indicates that VB—ZGI undergoes a phase transition when heated to above about 25 °C. shows that the observed transition is not associated with removal of a volatile compound from the VB- 201 sample. shows that the storage modulus of VB-201 decreases considerably when VB-201 is heated to about 30 OC. shows that the damping parameter (tan5) ofVB- 201 peaks at about 25 °C when VB-201 is heated, and that the temperature at which the damping parameter peaks is dependent upon the frequency of oscillation.

FIGs. 5-8 te that VB-201 undergoes a phase transition at a temperature range of about 25-30 °C. The data presented in FIGS. 7 and 8 suggest that the transition is a glass transition. These results conﬁrm the visual observation that VB-201 becomes sticky and cohesive at 25-30 °C.

Because certain oxidized olipids of the present disclosure (e.g., VB-201) are sticky and cohesive at room temperature, formulating these substances (e. g., VB-201) into conventional oral solid dosage forms (e.g. tablet or powder blend capsules) was not feasible, i.e., for large-scale production. Accordingly, studies were ted for developing either liquid ﬁll capsules of solubilized drug (which stays liquid) or -ﬁll es ofmolten carrier which becomes solid or semi-solid upon cooling.

As described in the experimental results presented in the Examples section below, an exemplary oxidized phospholipid, VB-201, was stable in a liquid carrier, but such formulation resulted in leakage and cracking of the capsule containing the VB-201 in the liquid carrier. The hygroscopic nature of VB—201 may be responsible for the instability ofthe liquid ation ﬁlled capsule.

As ﬁirther bed herein, the entioned e and cracking was circumvented by encapsulating the oxidized phospholipid (e.g., VB-201) by liquid-ﬁlling with a molten carrier that ﬁes at room temperature to form a solid matrix (thermosoftening carrier). However, the uniformity of VB—201 t in the capsules was not optimal.

Following erable experimentation, the present inventors have uncovered that the stickiness and cohesiveness of certain oxidized phospholipids (e.g. VB-201) result in a decrease of capsule uniformity when the oxidized phospholipid (e.g., ) is mixed with a molten carrier. The stickiness and cohesiveness of the oxidized phospholipid (e.g., VB-201) also make encapsulation of the oxidized phospholipid (e.g., VB—201) by solid—ﬁlling (e.g., using powdered VB-201) a less preferred method of encapsulation. {0091; As r demonstrated in the Examples section, the present inventors have devised novel methodologies for overcoming the stickiness and cohesiveness of oxidized phospholipids (e.g., VB-201), thereby ng for the production of oxidized phOSpholipid (e.g., VB-201) formulations characterized by a high uniformity. In some examples, the improved ations are capsules having a solid or semi—solid matrix.

The matrix reduces water tion by the oxidized phospholipid (e.g., VBQOI}, thereby ting adverse effects of absorption, such as cracking and leakage.

Pharmaceutical itions Hence, the t disclosure provides pharmaceutical compositions (e.g., liquid- ﬁll compositions) comprising an oxidized phospholipid as the active pharmaceutical ingredient (e.g., VB—201, VB-208, , or VB—219) and a thermosoftening careier as bed herein. Oxidized phospholipids and thermosoftening carrier that are useful in the above pharmaceutical compositions are described herein. In one example, the pharmaceutical composition is suitable to be ﬁlled into a pharmaceutical receptacle, such as a capsule (e.g., a liquid-ﬁll hard shell capsule); e.g., upon heating to produce a liquid composition. {0093} In some embodiments, the disclosure provides pharmaceutical compositions (e.g., liquid-ﬁll compositions) sing an oxidized phospholipid as the active pharmaceutical ingredient (e.g., VB-201, VB-208, VB-22l, or ), a thermosoftening r as described herein, and an anti—adherent agent as described herein.

In other embodiments, the disclosure provides pharmaceutical compositions (e.g., liquid-ﬁll compositions) comprising an oxidized phospholipid as the active pharmaceutical ingredient (e.g., VB-201, VB-208, VB-221, or VB—219), a thermosoftening carrier as bed herein, an dherent agent as described herein, and a thixotropic agent as described herein.

Thus, in some embodiments the present disclosure provides a pharmaceutical composition comprising VB—201 and a softening carrier. Exemplary thermosoftening carrier are sed herein. {0095} In other embodiments the present disclosure provides a pharmaceutical composition comprising VB-20l, a thermosoftening carrier, and an anti-adherent agent.

Exemplary thermosoftening carrier and anti-adherent agents are described herein. Any 2012/053533 combination of the disclosed thermosoﬁening carriers and anti—adherent agents is contemplated.

In other embodiments the t sure provides a pharmaceutical composition comprising VB-201, a thermosoﬁening carrier, an anti-adherent agent, and a thixotropic agent. Exemplary thermosoftening carrier, anti-adherent , and thixotropic agents are described herein. Any combination of the sed thermosoftening carriers, anti-adherent agents, and thixotropic agents is contemplated.

In some embodiments the current disclosure provides a pharmaceutical composition comprising: a thermosoﬁening carrier; a thixotropic agent at a concentration from about 0.25 weight percent to about 10 weight percent relative to the combined weight of the thermosoﬁening carrier and the thixotropic agent; an ed phospholipid (e.g., VB-201, VE-208, VB-221, or VB—219), e.g., at a concentration from about 0.1 weight percent to about 25 weight t relative to the total weight of the pharmaceutical composition; and an anti-adherent agent at a weight ratio from about 1:5 to about 5:1 anti-adherent agentoxidized phospholipid (e.g., VB-201, , VB-221, or VB-219).

In some embodiments the current disclosure provides a pharmaceutical composition comprising: a thermosoﬁening carrier; a thixotropic agent at a concentration from about 0.5 weight percent to about 5 weight percent (e.g., from about 1 weight percent to about 3 weight percent) relative to the combined weight of the thermosoﬁening carrier and the thixotropic agent; an oxidized phospholipid (e.g., VB-201, VB-208, VB—221, or VB-219), e.g., at a tration from about 4 weight percent to about 18 weight percent relative to the total weight ofthe ceutical composition; and an anti-adherent agent at a weight ratio from about 1:4 to about 2:1 anti-adherent agentzoxidized phospholipid (e.g., VB—201, VB-208, VB-221, or VB-219).

Liquid-ﬁll Capsules In some embodiments, the present disclosure provides a formulation, e.g., a liquid-fill capsule, comprising a solid or semi-solid , wherein the matrix comprises a thermoscftening r and an oxidized phospholipid as described herein. The liquid- ﬁll capsule may further include an anti-adherent agent as bed herein, and optionally a thixotropic agent as described herein.

According to some embodiments of the present sure there is provided a liquid—ﬁll capsule comprising: a thermosoﬁening carrier (e.g., poloxamer 188); an oxidized phospholipid (e.g., VB-201) from about 1 mg to about 100 mg (e.g., from about 20 mg to about 80 mg); an anti—adherent agent at a weight ratio faom about 1:5 to 5:1 (anti-adherent agentzoxidized olipid (e.g., VB—201); and a thixotropic agent (e.g., fumed silicon dioxide) at a tration relative to the combined weight of the thermosoﬁening carrier and the thixotropic agent from about 0.25 weight percent to about 10 weight t (e.g., 1 weight percent to about 3 weight percent).

According to other embodiments of the present disclosure there is provided a liquid-ﬁll capsule comprising: a thermosoftening carrier (e.g., poloxamer 188); VB-201 from about 1 mg to about 100 mg (e.g., from about 20 mg to about 80 mg); talc at a weight ratio from about 1:5 to 5:1 VB—201); and a thixotropic agent (e.g., fumed silicon dioxide) at a concentration relative to the combined weight of said thermosoftening r and said thixotropic agent from about 0.5 weight percent to about 5 weight percent (e.g., from about 1 weight percent to about 3 weight percent).

According to some embodiments of the present disclosure there is provided a liquid—ﬁll capsule comprising: a thermosoftening carrier selected from a poloxamer (e.g., poloxamer 188) and a polyethylene glycol having a lar weight from about 6000 to about 8000; VB-201 from about 1 mg to about 100 mg (e.g., from about 20 mg to about 80 mg); talc at a weight ratio from about 1:4 to about 1:1 VB-ZOl); and a thixotropic agent (e.g., ﬁlmed silicon dioxide) at a concentration relative to , the combined weight of said therrnosoftening carrier and said thixotropic agent from about 0.5 weight percent to about 5 weight percent (e.g., from about 1 weight percent to about 3 weight percent).

According to some embodiments of the present disclosure there is provided a liquid-ﬁll capsule comprising: a thermosoﬁening r selected from a poloxamer (e.g., poloxamer 188) and a polyethylene glycol having a molecular weight from about 6000 to about 8000; VB—201 from about 20 mg to about 100 mg (e.g., about 20 mg to about 80 mg); talc at a weight ratio from about 1:4 to about 1:1 (talc:VB-201); and a thixotropic agent (e.g., fumed silicon dioxide) at a concentration ve to the combined weight of said softening carrier and said thixotropic agent from about 1 weight percent to about 3 weight percent.

According to some embodiments of the present disclosure there is provided a liquid-ﬁll e comprising from about 400 mg to about 600 mg of a solid or semi-solid matrix, the matrix consisting of: VB-201 from about 20 mg to about 100 mg (e.g., about 20 mg to about 80 mg); An anti-adherent agent (e.g., talc) from about 5 mg to about 100 mg (e.g., from about 10 mg to about 80 mg); a thixotropic agent (e.g., fumed n dioxide) from about 2 mg to about 20 mg (e.g., from about 4 mg to about 12 mg); and the remainder being a thermosoftening carrier. The thermosoftening carrier may be selected, e.g., from a poloxamer (e.g., poloxamer 188) and a polyethylene glycol having a molecular weight from about 6000 to about 8000.

According to some ments there is provided a -ﬁll capsule comprising a capsule shell and a ﬁll composition (matrix), the ﬁll composition comprising: a softening carrier; an oxidized phospholipid at a concentration from about 0.1 weight percent to about 25 weight percent; an anti-adherent agent at a weight ratio from about 1:5 to about 5:1 anti-adherent agentzoxidized phospholipid; and a thixotropic agent at a concentration from about 0.25 weight percent to about 10 weight percent relative to the combined weight of the thermosoftening carrier and the thixotropic agent. ,37_ According to some embodiments there is provided a liquid-ﬁll capsule comprising a e shell and a ﬁll composition (matrix), the ﬁll composition comprising: a thermosoftening carrier; VB—201 at a concentration from about 0.1 weight t to about 25 weight percent; an dherent agent at a weight ratio from about 1:5 to about 5:1 anti-adherent agentzVB-ZO l; and a thixotropic agent at a concentration from about 0.25 weight percent to about weight percent relative to the combined weight of the thermosoﬁening carrier and the thixotropic agent.

According to some embodiments there is provided a liquid—ﬁll capsule comprising a capsule shell and a ﬁll composition (matrix), the ﬁll composition comprising: a thermosoﬁening carrier; VB-201 at a tration from about 4 weight t to about 25 weight percent; an anti-adherent agent at a weight ratio from about 1:4 to about 2:1 dherent agentzVB—ZOI; and a thixotropic agent at a concentration from about 1 weight percent to about 5 weight percent relative to the ed weight of the thermosoftening carrier and the thixotropic agent. {00109} Optionally, the capsule comprises from about 400 mg to about 600 mg of a ﬁll composition comprising the abovementioned ingredients. Optionally, the capsule comprises from about 440 mg to about 600 mg of the ﬁll composition comprising the abovementioned ingredients. Optionally, the e comprises from about 440 mg to about 480 mg of a ﬁll composition comprising the abovementioned ingredients.

Optionally, the capsule comprises about from about 560 mg to about 600 mg of a ﬁll composition comprising the abovementioned ingredients.

In some examples according to any of the above embodiments, the total weight of the thermosoftening carrier and the thixotropic agent (if present) in the capsule is about 400 mg. In some embodiments, such a capsule comprises from about 1 mg to about 100 mg of oxidized olipid (e.g., VB-201, , VB-221, or VB-219).

WO 33642 In some embodiments, the ratio of anti-adherent agent (e.g., talc) to VB-201 is 1:1, such that the capsule comprises, for example, 20 mg each of VB-201 and antiadherent agent, 40 mg each of VB-201 and anti-adherent agent, 80 mg each of VB-201 and anti—adherent agent, or 100 mg each of VB-201 and anti—adherent agent.

In some embodiments the capsule comprises 20 mg of VB—201, 20 mg anti- adherent agent (e.g., talc), and 400 mg of a thermosoﬁening carrier with a thixotropic agent (e.g., 440 mg ﬁll composition per capsule). In other embodiments the capsule comprises 40 mg of VB-201, 40 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a ropic agent (e.g., 480 mg ﬁll ition per capsule). In other embodiments the capsule comprises 80 mg of VB-201, 80 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoﬂening r with a ropic agent (e.g., 560 mg ﬁll composition per capsule), In other embodiments the capsule compréses 100 mg of VB-201, 100 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 600 mg ﬁll composition per capsule).

In other embodiments, the ratio of anti-adherent agent (e.g., tale) to VB-201 is 1:2, such that the capsule comprises, for example, 20 mg VB-201 and 10 mg anti- adherent agent, 40 mg VB-201 and 20 mg dherent agent, 60 mg VB-201 and 30 mg anti-adherent agent, 80 mg VB-201 and 40 mg anti-adherent agent, or 100 mg VB-201 and 50 mg anti-adherent agent.

] In some embodiments the capsule comprises 20 mg of VB—201, 10 mg of an anti- adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 430 mg ﬁll composition per capsule). In other ments the capsule comprises 40 mg of VB-201, 20 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 460 mg ﬁll composition per capsule). In other embodiments the capsule comprises 60 mg of VB-201, 30 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier With a thixotropic agent (e.g., 490 mg ﬁll composition per capsule). In other ments the capsule comprises 80 mg of VB-201, 40 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoﬁening carrier with a thixotropic agent (e.g., 520 mg ﬁll composition per capsule). In other ments the capsule comprises 100 mg of VB-201, 50 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 550 mg ﬁll composition per capsule).

In other embodiments, the ratio of anti-adherent agent (e.g., talc) to VB—201 is 1:4, such that the capsule comprises, for example, 20 mg VB-201 and 5 mg anti-adherent agent, 40 mg VB-201 and 10 mg anti—adherent agent, 60 mg VB-201 and 15 mg anti- adherent agent, 80 mg VB-201 and 20 mg anti-adherent agent, or 100 mg VB-201 and 25 mg anti—adherent agent.

] In some embodiments the capsule comprises 20 mg of VB—201, 5 mg of an anti- adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 425 mg ﬁll composition per capsule). In other mbodiments the e comprises 40 mg of VB-201, 10 mg of an dherent agent (e.g., talc) and 400 mg of a thermosoftening r with a thixotropic agent (e.g., 450 mg ﬁll composition per capsule). In other embodiments the capsule comprises 60 mg of VB-201, 15 mg of an dherent agent (e. g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 475 mg ﬁll composition per e). In other embodiments the capsule comprises 80 mg of VB-201, 20 mg of an anti-adherent agent (e.g., talc) and 400 mg of a softening carrier with a ropic agent (e.g., 500 mg ﬁll composition per capsule). In other embodiments the capsule comprises 100 mg of VB-201, 25 mg of an anti-adherent agent (e.g., talc) and 400 mg of a thermosoftening carrier with a thixotropic agent (e.g., 525 mg ﬁll composition per capsule).

In one example according to any of the above embodiments, the carrier is a poloxamer (e.g., poloxamer 188). Optionally, the carrier is a polyethylene glycol having a molecular weight of about 6000 (e.g., :t10 %).

In embodiments where a capsule comprises about 400 mg of thermosoftening carrier and thixotropic agent, the capsule comprises, for example, 20 mg of , 20 40 mg of mg anti-adherent agent, and a total of 440 mg of ﬁll composition per e; VB-201, 40 mg anti-adherent agent, and 480 mg of ﬁll composition per capsule; or 80 mg of VB-201, 80 mg dherent agent and 560 mg of ﬁll composition per capsule.

Optionally, the carrier is a poloxamer (e.g., poloxamer 188). Optionally, the carrier is a polyethylene glycol having a molecular weight of 6000 (3:10 %). The 400 mg of thermosoftening carrier with thixotropic agent may consist of, for example, 12 mg WO 33642 -29" thixetrepic agent with 388 mg carrier, 19 mg thixett‘ople agent with 396 mg carrier, or 4 mg thixntrepie agent with 396 mg of thennesoﬁening r. ltltllltll The thixetrepie agent is eptienally from about 1 to about 5 weight percent, e.g., from ahnnt l to aheut 3, from, about 2 to about 3, er from aheut 2.5 to about 3 weight percent ropie agent (eg, fumed silica) relative tn the combined weight of the thixotrepie agent and the therniesottening carrier. For example the ﬁll eompesitien may contain 12 mg thlxotreple agent and 388 mg thermosettenlng carrier, it) mg thlxetrepie agent, and 390 mg thermesoitening carrier, 9 mg thixotrepie agent and 35l mg thermesettening carrier, er 3’ mg thixntropie agent and 273 mg thermesottening carrier. in other examples, the fill eempesitien may enntain 9 mg thlxetropie agent and 39l mg thennosnttening r, 3 mg thixotropie agent and 392 mg thennnset‘tening carrier? 7 and 394 mg mg thlxetrople agent and 393 ttlennesottenirtg carrier, 6 mg thixetrngie agent thermesettening carrier, 5 mg thixetropie agent and 395 mg thermosoﬁemng carrier, 4 mg thixetropie agent and 396 mg thennosettening carrier, or 3 mg thixen‘opie agent 397 mg thenneseftening earrien {$0319} in some embodimentsﬁ the thermeseltening carrier is a polyethylene glycol carrier and the fill eempositr‘on comprises aheut 2.5 weight nereent of a thixettepie agent (e.g., fumed silica), for example, 390 mg of a hylene glycol r (tag, PEG 6906) with it) mg thixetrepic agent. in ether embodiments, the till eemposititm eemprises n pelyethylene glycol carrier {e.g., PEG 60639) and about 1 weight t tliixotrepie agent (eg, fumed silica), for examnie, 396 mg carrier with 4 mg thixetrople agent.

EtitllZﬁ'E ln seme embodiments, the thermeseftening earrier is a polexamer (egt, polexamer lSS) and the fill eemposltien comprises aheut 3 weight percent thixotrepie agent (e.g., fumeé silica)? for example, 388 mg carrier with EB mg thixetropie agent. In some embodiments, the softening r is a pelexamer (eg, pelexamer 138) and the fill eempnsition eernprises about l weight percent thixntrepie agent (eg, fumed silica), for example, 396 mg themmsot‘tening carrier and 4 mg repie agent {@1le ing te Senie embediments of the preeent diselesure there is provided a liqnimﬁli eapeule sing: VB~201 at a concentration that ranges item 0.} weight percent to 25 weight percent; 43.3“ an antiwaoherent agent at a weight ratio in a range of from 3:3 to 51i anti—adherent agetitz‘v’B—Zﬁi; a titixotropio agent at a concentration in a range ot‘ftom 0.25 weight percent to 10 weight percent; and the balance being a themiosofteniiig carrier. {@6122} According to some embodiments of the present sure there is provided a iiquid~tiii capsuie eon'iprisiog: from about 20 mg to about 100 mg VB—Zﬁi; mg to about 100 mg of an dhﬁl‘ﬁni agent; 2 mg to about i2 mg ot‘a tiiixottopie agent; and 388 mg to about 3:98 mg ofa themiosoftening carrier. iﬁﬁlZS} According to some embodiments of the present diseiosure there is ed a wﬁii oapsuie comprising: ’20 mg V3201; 29 mg ot‘tm dherent agent; 12 mg of a ropie agent; and 388 mg of a thermosoftening carrier. iiiiiilcii According ”to some embotiimeiitg of the oresem disclosure there is provided a iiqttid~iiii eapsuie comprising: 28 mg Vii—201; mg taie; 12 mg fumed siiiea; and 388 mg of poloxaitier 133. {@9325} According some embodiments of the t, diseiosute there is provided a iiquici~ iii} capsule comprising: 46 mg VBQGI; 40 mg of an aritieiiherent agent; if: mg ofa tiiixotrooie agent; and 388 mg ofa. theonosottetiiiig carrier.

{W126} According some embodiments oi~ the present disciosure there is provided a iiquid~ fiii oapsuie comprising: 43 mg VBQOE; WO 33642 40 mg talc; 12 mg of fumed silicon dioxide; and 388 mg of a poloxamer.

According some embodiments of the t disclosure there is provided a liquid- ﬁll capsule sing: 40 mg VB-201; 40 mg talc; 12 mg fumed silicon dioxide; and 388 mg ofpoloxamer 188.

According some embodiments of the t disclosure there is provided a liquid- ﬁll capsule comprising: 40 mg VB-201; mg of an anti-adherent agent; 4 mg of a thixotropic agent; and 396 mg of a thermosoftening carrier.

According some embodiments ofthe present disclosure there is provided a liquid— ﬁll capsule comprising: 40 mg VB=201; mg talc; 4 mg of fumed silicon dioxide; and 396 mg of a mer.

According some embodiments of the present disclosure there is provided a - ﬁll capsule comprising: 40 mg VB-201; mg talc; 4 mg fumed silicon dioxide; and 396 mg of poloxamer 188.

According some embodiments of the present disclosure there is provided a liquid— ﬁll capsule comprising: 60 mg ; mg of an anti-adherent agent; 4 mg of a thixotropic agent; and -23“ 396 mg of a thermosoftening carrier.

According some embodiments of the present sure there is provided a liquid- ﬁll capsule comprising: 60 mg VB-201; mg talc; 4 mg of fumed silicon dioxide; and 396 mg of a poloxamer.

] According some embodiments of the present disclosure there is provided a liquid- ﬁll capsule comprising: 60 mg VB-201; mg tale; 4 mg fumed silicon e; and 396 mg of poloxan’ger 188.

According to some embodiments of the present invention there is provided a liquid-ﬁll capsule sing: 80 mg VB-201; 80 mg of an anti—adherent agent; 12 mg of a thixotropic agent; and 388 mg of a thermosoﬁening carrier.

According to some embodiments of the present invention there is provided a liquid-ﬁll capsule comprising: 80 mg VB—201; 80 mg talc; 12 mg fumed silica; and 388 mg ofpoloxamer 188.

] According some embodiments ofthe present disclosure there is provided a liquid- ﬁll capsule comprising: 80 mg ; mg of an anti-adherent agent; 4 mg of a thixotropic agent; and 396 mg of a thermosoftening carrien WO 33642 ,24- According some embodiments of the present disclosure there is provided a liquid- ﬁll capsule comprising: 80 mg VB-201; mg talc; 4 mg of fumed silicon dioxide; and 396 mg of a poloxamer.

According some ments of the present disclosure there is provided a liquid- ﬁll capsule comprising: 80 mg VB-201; mg talc; 4 mg fumed silicon dioxide; and 396 mg of mer 188.

In other embodiments the present disclosure provides a capsule comprising VB- 201 and a thermosoftening carrier.

Liquid-Fill Compositions The liquid-ﬁll composition is a pharmaceutical composition of the present disclosure suitable to be ﬁlled into a pharmaceutical receptacle (e.g., -ﬁll capsule).

According to some embodiments of the present disclosure, there is provided a liquid ﬁll composition comprising VB-201, VB—208, VB-219, and/or VB-221 and a thermosoftening carrier, as described herein, and optionally one or more of an herent agent, a thixotropic agent and/or a gelling agent, as described .

Optionally, the liquid ﬁll composition is liquid only at a temperature above room temperature (i.e., above 25 °C). According to other embodiments of the present disclosure, there is provided a liquid ﬁll composition comprising VB-201 and a thermosoﬁening r, as described , and optionally one or more of an anti- adherent agent, a thixotropic agent and/or a gelling agent, as described herein.

Optionally, the liquid—ﬁll ition is liquid only at a ature above room temperature (i.e., above 25 °C).

Amounts, proportions and concentrations of the ingredients of the liquid ﬁll ition are described herein in the context of the pharmaceutical compositions. Also described herein are methods and procedures for mixing the ingredients to obtain the liquid ﬁll composition. 2012/053533 Formulations Providing Pharmacokinetic Parameters In some embodiments, the pharmaceutical composition or the liquid-ﬁll capsule according to any of the embodiments bed herein, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, provides a mean maximum plasma concentration (Cmax) of VB—201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL.

In some embodiments, the pharmaceutical composition or the liquid-ﬁll capsule according to any of the embodiments described herein, when orally administered to a human subject, median e.g., at a single oral dose of about 40 mg of VB-201, provides a time to mean maximum plasma concentration (Tmax) of VB—201 from about 5 hours to about 10 hours (e.g., from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours).

In some ments, the pharmaceutical composition or the -ﬁll capsule ing to any of the embodiments described herein, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, provides a plasma concentration time curve with a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/mL, e.g., from about 50,000 to about 65,000 ng h/mL, or from about 55,000 to about 60,000 ng h/mL.

In some embodiments, the ceutical composition or the -ﬁll capsule according to any of the embodiments described herein, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, provides a mean terminal half-live (ty,) between about 32 and about 42 hours (e.g., between about 35 and about 40 hours, or between about 36 and about 38 hours, or about 37 hours).

In some embodiments, the pharmaceutical composition or the liquid-ﬁll capsule according to any of the embodiments described , when orally stered to a human subject, e.g., at a single oral dose of about 40 mg of VB—201, provides a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL, and a median time to mean maximum plasma concentration (Tmax) of VB-201 from about 5 “25, hours to about 10 hours (e.g., from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours).

] In some embodiments, the pharmaceutical composition or the liquid-ﬁll capsule according to any of the embodiments bed herein, when orally stered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, provides a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL), a median time to mean maximum plasma concentration (Tmax) of VB-201 from about 5 hours to about 10 hours (e.g., féom about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours), and a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/mL (e.g., from about 50,000 to about 65,000 ng h/mL, or from about 55,000 to about 60,000 ng h/mL).

In some embodiments, the pharmaceutical composition or the liquid-ﬁll capsule according to any of the ments described herein, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, provides a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL), a median time to mean maximum plasma concentration (Tmax) of VB-201 from about 5 hours to about 10 hours (e.g., from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours), a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/mL (e.g., from about 50,000 to about 65,000 ng h/mL, or from about 55,000 to about 60,000 ng h/mL), and a mean terminal half-live (ti/2) between about 32 and about 42 hours (e.g., between about 35 and about 40 hours, or between about 36 and about 38 hours, or about 37 hours).

] In some embodiments, the present disclosure provides a VB-201 formulation, wherein the formulation when orally administered to a human subject, e.g., at a single oral dose of about 40 mg of VB-201, es a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL), {003150} in some embodiments, the present disclosure es a Vl3—201 fonnulation, wherein the tonnuiation when orally administered to a human subject e.g,, at a single oral dose of about 40 mg of Vii-20L es a median time to mean m piasma concentration x) of \I’Bv20i {torn about 5 hours to about l0 hours tag, from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours), {00151} In some embodiments, the present disetosure provides a VIE—201 formuiation, n the formulation when orally administered to a human subject, eg, at a single oral dose of about 40 mg of Vii—20L provides a plasma concentration time eurve with a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/m'i, (eg, from about 50,000 to about 65,000 ng lu’niL, or from about 55,000 to about 60,000 ng thnL}. {00152} in some embodiments, the present disclosure provides a VB~201 fonnulation, wherein the ation when orally administered to a human subject, e.g., at a single orai dose of about 40 mg of Vl3«20l, provides a mean terminal halﬁlive (ti/1,) between about 32 and about 42 hours (eﬂg, between about 35 and about 40 hours, or between about 36 and about 38 hours, or about 37 hours}“ {0063} in some embodiments, the present. disclosure provides a formulation, wherein the tbrmuiation when orally ariministereo to a human subject, e.g., at a single oral dose of about 40 mg of VB~20l , provides a mean m plasma concentration (Cum) of VB~ 20l from about i.,000 ng/‘mL to about 1,600 ng/mL tag, from about 1,100 rig/nth to about l,:300 ng/mL, or from about l,200 rig/ml; to about 1,400 fig/URL, or from about l,‘200 rig/mi, to about 1,300 ng/mL), and a median time to mean maximum plasma concentration ('l‘max) of VB—20l from about 5 hours to about 10 hours (e.g., from about 5 hours to about 7.5 hours, or from about ti hours to about 65 hours, E00154} in some embodiments, the present diselosure provides a formulation, wherein the formulation when oraliy administered to a human subject, e.g., at a single oral dose of about 40 mg of V0201, provides a mean maximum plasma. coneentration (Cram) of V8— 201 from about L000 rig/in}; to about 1,600 ; (age, from about l,l00 rig/mil to about 1,500 ng/mL, or from about 1,200 ngme to about L400 , or from about 1,200 rig/mil to about 1,300 rig/mil), a median time to mean maximum piasrna concentration ('i‘max) of V0301 from about 5 hours to about l0 hours tag, from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours), and a plasma concentration time curve with a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/mL (e.g., from about 50,000 to about 65,000 ng h/mL, or from about 55,000 to about 60,000 ng h/mL).

In other embodiments the present disclosure provides a pharmaceutical formulation comprising VB-201, wherein the formulation, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg VB-201, provides a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL (e.g., from about 1,100 ng/mL to about 1,500 ng/mL, or from about 1,200 ng/mL to about 1,400 ng/mL, or from about 1,200 ng/mL to about 1,300 ng/mL), a median time to mean maximum plasma concentration (Tmax) 0f VB-201 from about 5 hours to about 10 hours (e.g., from about 5 hours to about 7.5 hours, or from about 6 hours to about 6.5 hours), a plasma concentration time curve with a mean area under the curve (AUCw) ranging from about 45,000 to about 70,000 ng h/mL (e.g., from about 50,000 to about 65,000 ng h/mL, or from about 55,000 to about 60,000 ng h/mL), and a mean terminal half-live (tr/2) between about 32 and about 42 hours (e.g., between about 35 and about 40 hours, or between about 36 and about 38 hours, or about 37 hours).

In other embodiments the t disclosure provides a pharmaceutical formulation comprising , wherein the formulation, when orally administered to a human subject, e.g., at a single oral dose of about 40 mg VB-201, provides the following mean values for Cmax, Tmax, AUC and ty, with the indicated standard deviations (SD): Cmax ): 1289.74 (SD: ) Tmax (h): 6.00 (mean) (from 5.00-10.00) AUCT (ng-h/mL): 53200 (SD: 12500) AUG... (ng-h/mL): 57500 (SD: 12000) t1/2 (h): 37.4 (SD: 4.98) Cmax (ng/mL): 1298.08 (SD: 230.97) Tmax (h): 6.50 (mean) (from 0) AUCT (ng-h/mL): 55000 (SD: 13900) AUC... (ng-h/mL): 58900 (SD: 14500) 0/. r h): 37.2 (SD: 6.07) 2012/053533 -79,a...

In some examples, according to any of the above embodiments the VB~201 formulation is selected from the liquid-ﬁll capsule formulations described herein (e.g., a liquid-ﬁll capsules ning about 40 mg VB-201). In some examples according to any of the above embodiments, the formulation is selected from formulation 10 of example 13, ation 4 of example 11, and formulation 7 of example 12.

In some embodiments, the above described cokinetic parameters are ed as described in Example 15.

Oxidized Phospholioids ] In some embodiments, the active pharmaceutical ients useful in the formulations, pharmaceutical compositions, liquid-ﬁll compositions, es, and methods of the present disclosure include at least one oxidized phospholipid. The oxidized phospholipid may be characterized by at least a n degree of adhesiveness or stickiness at room temperature (i.e., 25 °C).

In one example according to any of the embodiments described herein, the oxidized phospholipid has a structure according to Formula (I): CH2—0——R1 O>7X1—O—lH Rso ]H,__0_R3 In Formula (I), R1 is Clo-C30 straight or branched alkyl. In some examples, R1 is C12-C3o ht or branched alkyl. In some examples, R1 is C14-C30 straight or ed alkyl. In other examples, R1 is C12-C25 straight or branched alkyl. In other examples, R1 is C12-C20 straight or branched alkyl. In other examples, R1 is C14-C20 straight or branched alkyl. In other examples, R1 is C16-C20 straight or branched alkyl. In other examples, R1 is selected from tetradecyl, pentadecyl, hexadecyl, ecyl, octadecyl, nonadecyl, eicosanyl, cis-9—hexadecenyl, and (2-octyl)dodecyl. In other examples, R1 is a branched Clo—C30 alkyl. In another example, R1 is a branched 0 alkyl. In yet another example, R1 in Formula (IE is hexadecyl (-C16H33).

In Formula (I), R3 is selected from atidylethanolamine, phosphatidylcholine, thiophosphatidylcholine, phosphatitylethanolamine—N-glutaric acid, and phosphatidylserine. In one example, R3 is selected from phosphatidylethanolamine and phosphatidylcholine. In some embodiments R3 is phosphatidylcholine, ~30— R5 in Formula (I) is a member selected from H, a negative charge, and C1-C6 straight or branched alkyl. In some examples, R5 is C1-C4 straight or leranched alkyl. in other examples, R5 is selected from H, a negative charge, , and ethyl. In some examples, R5 is selected from H and a negative charge. In other es, R5 in Formula (I) is H. In yet other examples, R5 in Formula (I) is methyl.

In Formula (I), X1 is C2-C6 alkylene. In some examples, X1 is C3-C6 ne. In other examples, X1 is C3, C4, C5 or C6 alkylene. In other examples, X1 is C; or C5 alkylene. In other examples, X1 in Formula (I) is C4 alkylene (-CHg-CHz-CHZ-CHZ) In some examples, R3 in Formula (I) is phosphatidylcholine and the oxidized phospholipid has a structure according to Formula (II): CH2 o_R1 O$41-0? H _o__ __0[1 CH3 (L xii—CH3 \H, (H) n R1, R and X1 are deﬁned as for Formula (I). In one example in Formula (II), R1 is selected from tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, cishexadecenyl, and (2-octyl)dodecyl. In yet another example, R1 in Formula (L) is hexadecyl (-C16H33). In another example in Formula (11), X1 is C4 or C5 alkylene. In another example X1 in Formula (II) is C4 alkylene (-CHz-CHz-CHz-CHZ- ). In one example in Formula (II), R5 is H, a negative charge or methyl. In another example in a (II), R1 is ed from tetradecyl, pentadecyl, hexadecyl, ecyl, octadecyl, nonadecyl, eicosanyl, hexadecenyl, and (2-octy1)dodecyl, X1 is C4 or C5 alkylene, and R5 is H, a negative charge or methyl.

In other examples, X1 in Formula (II) is C4 ne (-CH2-CH2-CH2-CH2—), and the oxidized phospholipid has a structure according to Formula (III): _ 31 _ CH2 o__R1 o . A m [O—iH ‘kqﬂf \‘xf’f \xvsf 0 $525 le_o_u_o CH3 \°H3 (HI) wherein R1 and R5 are deﬁned as for Formula (I). In one example in Formula (HIE, R1 is selected from tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, cishexadecenyl, and yl)dodecyl. In another example in Formula (III), R5 is H, a ve charge or methyl. In another example in Formula (III), R5 is H or a negative charge. In another example in Formula (III), R1 is selected from tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, cis—9- cenyl, and (2-octyl)dodecyl, and R5 is H, a negative charge or . In yet another example, R1 in Formula (III) is hexadecyl (—C16H33). In yet another example, R1 in Formula (III) is cyl (—C16H33), and R5 is H, a negative charge or methyl.

The structures of Formulae (I), (II), and (III; are meant to include all stereoisomers and mixtures thereof.

In some embodiments, the oxidized phospholipid is VB-201 [l-hexadecy1(4’- carboxybutyl)—glycerophosphocholine] having the formula: €in 0—C16H33 G A, ... {SE-i \kf1.x \vi‘f 5 Q I g a; my; H2 ----------Q ------ WC? 3 . ......CH31‘ {3 \m, In some embodiments, the oxidized phospholipid is VB-208 [1-hexadecyl(4'— methyl"carboxybutyl)-glycero-3 -phosphocholine] having the formula; 2012/053533 _ 32 s CH2 0—C1sH33 O¢Q§§ffx’\\\fﬂ.«»\\¥/ﬂﬂo O J,— xr—cns \CH3 In some embOdimentS’ the oxidized phospholipid is VB-219 [l-eicosanYI-Z-(4L carboxybutyl)—glycero—3 -phosphocholine] having the formula: CH2 0—C20H41 ww"“’x\ 3fo x" a» m i 0 Jr XXI/32m In some embodiments, the oxidized phospholipid is VB-221 [l-(2'-octy1)dodecyl- 2-(4'-carboxybutyl)—glycerophosphocholine] having the formula: C8H17 0H21 CH2 o_CH2 , O—lH \. “an. r\. m” \«f’ “v",_..~' vi 0 H2__o_iJ__o (if Kgdm \2H3 VB-201 according to embodiments of the present invention may be a chiral enantiomer of 1-hexadecyl(4’-carboxybutyl)—glycero—3-phosphocholine, i.e., either the (R)- enantiomer ((R)—1-hexadecyl(4’-carboxybutyl)-sn-glycerophosphocholine) or the (S)- omer ((S)hexadecyl(4’-carboxybutyl)-glycero—3-phosphocholine), or a mixture f (e.g., a racemate). According to exemplary embodiments, VB-201 is (R) - l -hexadecyl(4 ’-carboxybutyl)—sn-glycero-3 -phosphocholine. 1.4, w I In some embodiments, the compositions of the present disclosure include more than one oxidized phospholipid, e.g., two, three, or more oxidized olipids, each independently selected from those described herein.

Ca mules As used herein, the general term "capsule" or "capsules" is intended to encompass any suitable capsular container or case d for oral ingestion, e.g., those adapted for use in conjunction with liquid ﬁll itions. The term "capsule" includes capsules having a shell composed of soft and/or hard materials, such as gelatin, starches, celluloses, cellulose derivatives (e.g., hydroxypropyl methyl cellulose), hydrocolloids, gums, carrageenans, or any other natural or synthetic material which can be used to encapsulate the liquid composition and be ingested by an animal. Optionally, the shell material is gelatin and/or hydroxypropyl methyl cellulose. In optional embodiments, the shell al is gelatin. The term “capsule” is intended to include a variety of capsule shapes and sizes, and is not intended to limit the dosage form to a speciﬁc type or shape.

Any cially ble capsule shells or shell materials are contemplated.

In some embodiments, the capsule is a size 0 capsule. In some ments, the capsule is a size 1 capsule. In some embodiments, the capsule is a size 2 capsule. In some ments, the capsule is a size 3 e. Other capsule sizes are also plated.

The capsule may be formulated, for example, for oral administration or as a suppository. According to exemplary embodiments, the capsule is formulated for oral administration.

A capsule, according to the present embodiments, is therefore composed of a matrix containing therein a pharmaceutically active ingredient (e.g., VB-20l, VB-208, VB-221, or VB-219) and a shell which encapsulates the matrix. {00182} In some embodiments, the capsule is a liquid-ﬁll capsule.

The term “liquid-ﬁll capsule” refers to a capsule that is ﬁlled with a ﬁll composition that is a liquid during the ulation process. It is to be appreciated that the ﬁll ition need not remain a liquid after ulation, and that the term “liquid-ﬁll” therefore does not necessarily indicate that the ﬁnal capsule contains any liquid. In one example, the liquid-ﬁll capsule is a hard-shell capsule (e.g., a hard-shell gelatin capsule), In some embodiments, the liquid-ﬁll capsule which comprises the active pharmaceutical ingredient (e.g., VB-201, VB-208, VB-221, or VB-219) is a lized form within a matrix that ns the active ingredient (e.g., a pharmaceutically acceptable carrier).

] In some ments, the liquid-ﬁll capsule is such that the matrix containing the active pharmaceutical ingredient (e.g., VB-201, Vii-208, VB—221, or VB-219) is a solid or olid.

The phrase “solid or semi-solid matrix” refers herein to a matrix that is a solid or semi-solid at room temperature (e.g., 25 °C). The term “semi—solid” encompasses gels and highly viscous substances, for example, substances characterized by a viscosity of at least about 50,000 centipoise, and optionally at least about 200,000 centipoise.

Typically, the solid or semi-solid matrix is formed from components of the liquid ﬁll composition (e.g., by cooling).

It is to be appreciated that a e sing a solid or semi-solid matrix is resistant to leakage, as a solid or semi—solid matrix will not readily leak from the capsule.

Without being bound by any particular theory, it is also believed that a solid or semi-solid matrix will prevent cracking of the capsule and leakage of the capsule contents by shielding the oxidized phospholipid (e.g., VB-201, VB—208, VB-221, or VB-219) from moisture, thereby preventing the absorption of moisture by the oxidized phospholipid (e.g., VB-201, VB-208, VB-22l, or VB-2l9) from the surroundings (e.g., from the capsule shell) which es ng.

Carreer As used herein, the term "carrier" refers to a substance or mixture of substances, optionally an inert substance, added to facilitate preparation of the capsule and administration of the oxidized phospholipid (e.g., VB—201, VB-208, VB-22l, or ).

In some embodiments, the carrier is a pharmaceutically acceptable r. , the phrase “pharmaceutically acceptable carrier” describes a careier or a t that does not cause signiﬁcant irritation to the subject and does not abrogate the biological activity and properties of the active pharmaceutical ingredient (e.g., , VB-208, VE-221, or VB-2l9). The carrier includes a thermosoftening carrier and may include additional components, such as other excipients, ts, coloring agents, and the like. softening r As used herein, the term osoftening carrier” refers to a carrier which becomes soft (e.g., a ﬂuid) upon heating to a temperature above room temperature. A thermosoftening carrier becomes soft at a temperature which does not damage the active pharmaceutical ient (e.g., by oxidation) or the thermosoftening caréier itself. The softening upon heating may be either characterized by a phase transition (e.g., a solid-toliquid transition), or not characterized by a phase transition (e.g., softening of an amorphous material). The thermosoftening is reversible, such that the softened carrier becomes harder upon being cooled back to room ature. In some embodiments, the thermosoftening r is a mixture oftwo or more agents.

The softening carrier facilitates preparation of a liquid ﬁll composition and ﬁlling of capsules therewith at a temperature at which the thermosoftening carrier is soft, as well as formation of a solid or semi—solid matrix following cooling (e.g., cooling to room temperature). In one example, the thermosoftening carrier is a solid or a olid at a temperature below 35 °C, or below 30 °C (e.g., at room temperature, i.e., 25 °C). In one example, the thermosoftening r is non-hygroscopic. The thermosoftening carrier is a pharmaceutically acceptable carrier.

Optionally, the soﬁening carrier becomes soft at a temperature of no more than about 150 °C, and optionally at a temperature of no more than about 100 °C, or 90 In some embodiments, the softening carrier has a melting point in a range of from about 40 °C to about 100 °C. Optionally, the melting point is in a range of from about 50 °C to about 80 °C. In other examples, the melting point of the thermosoftening carrier is from about 50 °C to about 70 °C, or from about 50 °C to about 60 °C,, and optionally in a range of from about 55 °C to about 65 °C. Accordingly, at such temperatures, the thermosoﬁening carrier undergoes transformation from a hard to a soft material, and vice versa. In one example, the thermosoftening carrier at a temperature above its melting point is sufﬁciently soft for ﬁlling the carrier into a capsule (e.g., into a hard gelatin capsule).

Examples of thermosoftening carriers include waxes, poloxamers (e.g., mer 188), macrogol glycerides, high-molecular weight PEGs (e.g., 0 or PEG 8000), glycerol monooleates or monostearates, hydrogenated or partially hydrogenated glycerides (e.g., hydrogenated palm kernel oil or hydrogenated cotton seed oil)), GeluciresTM, and hard fats such as beeswax. Other exemplary thermosoﬁening carriers e anTM and hexadecane-l-ol.

The therenosoftening carrier may be a polyalkylene . In one example, the polyalkylene glycol has a high molecular weight, e.g., a molecular weight that is sufﬁcient to render the polyalkylene glycol carrier non‘hygroscopic (e.g., a polyalkylene glycol having a molecular weight of at least about 1000 daltons, or at least about 1500 daltons). In one example, the kylene glycol has a molecular weight of at least about 2000 daltons. In another example, the polyalkylene glycol has a molecular weight of at least about 3000 daltons. In another example, the polyalkylene glycol has a molecular weight of at least about 4000 daltons. In another example, the polyalkylene glycol has a molecular weight of at least about 5000 daltons. In another example, the polyalkylene glycol has a molecular weight of at least about 6000 daltons. It is to be understood that a molecular weight in connection with polyalkylene glycols described herein is meant to represent an average molecular weight in accordance with commonly used nomenclature for such compounds. Suitable polyalkylene glycols include, without limitation, polyethylene glycols, polypropylene glycols and copolymers thereof, such as poloxamers (e.g., poloxamers 188, 237, 338 and 407).

In some embodiments, the polyalkylene glycol is a poloxamer. Accordingly, in some ments, the therrnosoftening r is a poloxamer.

Poloxamers are ck polyalkylene glycols, comprising a l polypropylene glycol chain, which is vely hydrophobic, ﬂanked by two polyethylene glycol chains, which are relatively hydrophilic. This combination of hydrophobic and hydrophilic chains provides poloxamers with surfactant properties.

Poloxamers are lly characterized by molecular weight of the polypropylene glycol core of the poloxamer and by the proportion of polyethylene glycol versus opylene glycol. These parameters are commonly described by characterizing a poloxamer with a three-digit number, n the ﬁrst two digits, when multiplied by 100, give the molecular weight (in daltons) of the opylene glycol core, whereas the last digit, when multiplied by 10, gives the percentage of hylene glycol. Thus, for example, poloxamer 188 has a polypropylene glycol core with a molecular weight of 1800 daltons and is 80 % polyethylene glycol (and thus has a total molecular weight of WO 33642 approximately 9000 daltons), whereas poloxamer 407 has a polypropylene glycol core with a molecular weight of 4000 daltons and is 70 % polyethylene glycol (and thus has a total molecular weight of approximately 13000 daltons).

According to some embodiments, the poloxamer has a molecular weight in a range of from about 2000 to about 18000 daltons. ally, the poloxamer has a molecular weight in a range of from about 4000 to 15000 daltons, and optionally from about 6000 to about 12000 daltons. In ary embodiments, the molecular weight of the poloxamer is in a range of from about 7000 to about 10000 daltons. In other examples, the poloxamer has a molecular weight from about 4000 to about 18,000 daltons, from about 6000 to about 18,000 daltons, from about 6000 to about 14,000 daltons, or from about 8000 to about 10,000 s. In one example, the poloxamer has a molecular weight of about 9000 daltons. ing to some embodiments, the polypropylene core of the poloxamer has a molecular weight in a range of from about 1000 to about 5000 s. Optionally the polypropylene core of the poloxamer has a molecular weight in a range of from about 1200 to about 2400 daltons, and optionally from about 1500 to about 2100 daltons. In ary embodiments, the molecular weight of the polypropylene core of the poloxamer is about 1800 daltons.

According to some embodiments, the poloxamer comprises at least about 20 weight percent of polyethylene glycol, optionally at least about 30 weight percent, optionally at least about 40 weight percent, optionally at least about 50 weight percent, optionally at least about 60 weight percent, optionally at least about 70 weight percent, and optionally at least about 80 weight percent of polyethylene glycol.

In some embodiments the tion of polyethylene glycol in the poloxamer is in a range of from 40 to 90 weight percent, optionally from 50 to 90 weight percent, optionally from 60 to 90 weight percent, and optionally from 70 to 90 weight t. In exemplary embodiments the poloxamer comprises about 80 weight percent polyethylene glycol.

Poloxamer 188 is an exemplary mer. Accordingly, in some embodiments, the thermosoﬁening carrier is mer 188.

In some embodiments, the thermosofteningcarrier is a polyethylene glycol.

Optionally, the polyethylene glycol has a molecular weight in a range of from about 1500 to about 10,000 daltons, or about 1500 to about 8000 daltons, optionally from about 4000 to about 8000 daltons, and ally from about 5000 to about 7000 daltons. In exemplary embodiments, the polyethylene glycol has a molecular weight of about 6000 daltons. In one example, the polyethylene glycol has a molecular weight of at least about 2000 s. In another example, the polyethylene glycol has a molecular weight of at least about 3000 daEtoris. In r example, the polyethylene glycol has a molecular weight of at least about 4000 daltons. In another example, the polyethylene glycol has a molecular weight of at least about 5000 s. In another e, the polyethylene glycol has a molecular weight of at least about 6000 daltons.

] In one embodiment, the thermosoftening carrier is selected from PEG6000, poloxamer 188, and combinations thereof.

The phrase "poly(alkylene glycol)" or "polyalkylene glycol", as used herein, formula: encompasses a family of polyether polymers which share the following general -O-[(CR2)m-O-]n-, wherein each R is independently hydrogen or alkyl, m represents the number of carbon atoms in the backbone of the polymer in each ne glycol unit, and n represents the number of repeating units.

] For example, when m = 2 and R is en, the polymer is referred to as a polyethylene glycol. When m = 3 and R is hydrogen, or when m = 2 and one R in each unit is methyl (and the other R groups are hydrogen), the r is referred to as a opylene glycol.

In some embodiments, m is an integer greater than 1 (e.g., m = 2, 3, 4, etc.).

Optionally, m varies among the units of the poly(alkylene glycol) chain. For example, a poly(alkylene glycol) chain may comprise both ethylene glycol and propylene glycol units linked together.

The thermosoﬁening carrier may also be a polyalkylene glycol derivative. The phrase “polyalkylene glycol derivative” refers herein to a polyalkylene glycol as deﬁned herein, of which at least a portion (e.g., 1-50 %) is modiﬁed so as to include moieties other than an alkylene glycol, as deﬁned herein. In some embodiments, a polyalkylene glycol derivative is a polyalkylene glycol d at one or both i thereof so as to include additional moieties. Exemplary polyalkylene glycol derivatives which are suitable for use in the context of embodiments of the invention include, without L13 9- limitation, polyalkylene glycol ides, such as GeluciresTM (e.g., Gelucire 40/01TM) ) and erol polyethylene glycol succinate.

The thermosoftening carrier may also comprise an oil or a combination of one or more oils. Many oils suitable for use as a thermosoﬁening carrier for therapeutic ations are known in the art. Examples include, without limitation, esters of fatty acids, such as triglycerides and diesters of a glycol (e.g., propylene glycol). Other oils may be added to the thermosoftening carrier to decrease/ﬁne tune Viscosity, e.g., fractioned t oil or soybean oil.

As exempliﬁed in the Examples section herein, the use of a thermosoftening carrier in a liquid ﬁll capsule ted cracking and leakage of the capsules, but was associated with non-homogeneity of the liquid ﬁll ition used to ﬁll the capsules.

Anti—Adherent Agent As further described hereinabove and exempliﬁed in the Examples section that follows, the present inventors have surprisingly uncovered that the homogeneity of batches of capsules containing ed olipids (e.g., VB—201, VB-208, VB-221, or ) can be considerably improved by mixing the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB—219) with an anti-adherent agent.

} Hence, according to some embodiments of the invention, the solid or semi-solid matrix ﬁirther comprises an anti-adherent agent.

It is to be appreciated that inclusion of anti-adherent agents in liquid ﬁll compositions of capsules has not been suggested nor practiced heretofore. It is to be further appreciated that typically, when utilizing liquid ﬁll techniques for encapsulation, a problem of adherence does not arise.

As used herein, the phrase “anti-adherent agen ” refers to an agent which reduces the cohesion n particles of a substance (e.g., VB—201, VB-208, VB-221, or VB- 219) and/or an adherence of such particles to a solid surface (e.g., of a container and/or encapsulation machinery). For example, the reduction of cohesion caused by an anti- adherent agent is greater than a reduction of cohesion caused by mere dilution of the substance by addition of an agent.

Optionally, the anti—adherent agent is a material (e.g., a solid, such as a powder) with little or no lity in the other components of the capsule (e.g., the thermosoftening carrier). The anti-adherent agent may act by adhering to the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) e.g., VB-201, VB-208, VB- 221, or VB-219thereby forming, e.g., grains and/or powder particles. As a result, the adherence of the oxidized phospholipid (e.g., VB-201, VB-208, , or VB-219) to other surfaces (e.g., other VB-201 grains and/0r powder particles, surfaces of containers and/or encapsulation machinery) is reduced.

It is to be appreciated that the use of a material with little or no lity to increase homogeneity in a liquid ﬁll composition is novel and surprising, as insoluble materials typically increase inhomogeneity (e.g., by sedimentation, coagulation) in a liquid, and would therefore not be expected to increase homogeneity.

Without being bound to any particular theory, it is suggested that the anti-adherent agent results in the formation of m dispersion of grains and/or powder particles of the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB—2l9) that are adhered to the anti-adherent agent.

Examples of anti-adherent agents include, but are not limited to, talc, magnesium stearate, cellulose (e.g., microcrystalline cellulose), ose derivatives (e.g., hydroxypropyl neethylcellulose (HPMC)), lactose, gelatin, alginates, ium hydroxide, magnesium oxide, clays, attapulgite, bentonite, carrageenan, copovidone, ite, polymethacrylates, sodium docusate, erythritol, povidones, croscarrnellose sodium, dextrates, starches, iron oxide, , silicates (e.g., magnesium aluminium te), corn ﬂour, sugars, m carbonate, magnesium ate, calcium phosphate, calcium e, bicarbonates (e.g., of potassium or sodium), citrate salts (e.g., potassium citrate) and titanium dioxide.

As exempliﬁed in the Examples n, tale is an example for an effective anti- nt agent.

In one example, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-20l, VB-208, , or VB-219), e.g., in the pharmaceutical composition (i.e., liquid-ﬁll composition), is in a range of from about 1:5 to about 5:1 (anti-adherent agent:oxidized olipid). In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB—201, VB—208, VB—221, or VB- 219) is in the range from about 1:4 to about 5:1, from about 1:3 to about 5:1, from about 1:2 to about 5:1, or from about 1:1 to about 5:1. -41, ] In other examples, the weight ratio of the anti—adherent agent to the oxidized phospholipid (e.g., VB-201, VB—208, VB-221, or VB-219) is from about 1:5 to about 4:1, from about 1:5 to about 3:1, from about 1:5 to about 2:1, or from about 1:5 to about 1:1.

In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) is from about 1:4 to about 4:1, from about 1:4 to about 3:1, from about 1:4 to about 2:1, or from about 1:4 to about 121.

In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) is from about 1:3 to about 4:1, from about 1:3 to about 321, from about 1:3 to about 2:1, or from about 1:3 to about 1:1.

In other examples, the weight ratio of the anti—adherent agent to the oxidized phospholipid (e.g., VB—201, VB-208, , or VB-219) is from about 1:2 to about 4:1, from about 1:2 to about 3:1, from about 1:2 to about 2:1, or from about 1:2 to about 1:1, or from about 1:2 to about 1.5:1.

In other examples, the weight ratio of the anti—adherent agent to the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) is in the range from about 1:1 to about 521, from about 1:1 to about 4:1, from about 1:1 to about 3:1, from about 1:1 to about 2:1, or from about 1:1 to about 1.5:1.

In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-201, , VB—22l, or VB-2l9) is about 1:1. In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-201, , VB-221, or VB-219) is about 1:2. In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB—201, VB-208, , or VB-219) is about 1:3. In other examples, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB—201, VB-208, VB-221, or ) is about 1:4. In other es, the weight ratio of the anti-adherent agent to the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) is about 1:5.

Thus, an anti-adherent agent : ed phospholipid (e.g., VB-201, VB-208, VB- 221, or VB-219) ratio can be, for e, about 1:5, 1:4, 1:3, 1:2, 1:1, 1:12, 1:1.4, 1:1.5, 1:1.6,1:1.8,1.2:1,1.4:1,1.5:1,1.6:1,1.8:1, 2:1, 25:], 3:1, 3.5:1, 4:1, 4.5:}, or 5:1. cher ratio values are also contemplated.

In one e according to any of the above embodiments, the anti-adherent agent is talc. In another example according to any of the above embodiments, the anti- adherent agent is tale and the oxidized phaspholipid is VB~20L Fer example, the oxidized pht‘ispheiipid (eg, V8201, VB«203, VBQZI, or VBwa} is milied with an equal amount. of tale (1:1 weight ratio). In another example, the exidized olipid ﬂag, VBJZQI, 3134.203, VB~22‘3, er VBQEQ) is milled with tale. in a talezexidized phospholipid weight ratio of about 1:2, about 3:3, about 1:4, or abeut 1:5. In other examples, the exidized phosphelipid tag, Vii—201, V3203, V8421, or V8219) is milled with tale in a xidized phospholipid weight ratie of about 2:1, about 3:1, or about 4:1.

The inventors have recognized that the weight ratio of the anti-adherent agent to the oxidized phospholipid has an effect on the homogeneity (i.e., a sufﬁcient dose content uniformity), e.g., with respect to the distribution of the oxidized phospholipid in the therrnsoftening caﬁier or the ﬁnal composition, and/or on the long-term stability of the ﬁnal formulation. Hence, in some embodiments, the anti-adherent agent to oxidized olipid (e.g., , VB-208, VB-221, or VB-2l9) weight ratio is about 1:1 or less (e.g., 1:2 or less, or 1:3 or less).

In other embodiments, the dherent agent to oxidized phospholipid (e.g., VB- 201, VB-208, VB-221, or ) weight ratio is about 1:1.l, 1:12, 1:13, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 121.9, or about 1:2. In some embodiments, the anti-adherent agent to oxidized phospholipid (e.g., , VB-208, VB-22l, or VB-219) weight ratio is about 1:2 or less.

In other embodiments, the anti-adherent agent to oxidized olipid (e.g., VB- 201, VB-208, VB—22l, or VB-2l9) ratio is at least about 1:1, at least about 2:1, at least about 3:1, at least about 4:1, or at least about 5:1. For example, in the case of VB-201, a ratio of at least about 1:2 (e.g., at least about 1:1) was associated with satisfactory dose content uniformities.

Optionally, a ratio of an amount of anti-adherent agent to an amount of VB-20l in the capsule is in a range of from 1:3 to 5:1 (anti-adherent agent : ), and optionally from 1:2 to 3:1. Thus, an anti-adherent agent:VB-20l ratio can be, for example, 1:3, 1:2, l:l.5, 1:12, 1:1, 12:1, 15:1, 2:1, 2.5:1, 3:1, 4:1 or 5:1. Other ratio values are also contemplated.

In exemplary embodiments the anti-adherent agent to VB-20l ratio is about 1:1.

Herein, ratios of anti-adherent agent to oxidized phospholipid (e.g., VB-201, VB- 208, VB—221, or VB-219) refer to weight ratios.

In some embodiments, the concentration of the anti-adherent agent in the pharmaceutical composition (i.e., matrix) is in a range of from about 1 to about 50 weight percent, from about 1 to about 40 weight percent, or about 1 to about 30 weight percent, optionally from about 2 to about 25 weight percent, and optionally Eom about 3 to about weight percent. Such percentages of anti—adherent agent may optionally pond to a ratio of anti-adherent agent to oxidised phospholipid (e.g., , VB—208, VB-221, or VB—219) as bed herein. In some embodiments, the concentration of the anti- adherent agent in the ceutical composition (i.e., ) is in a range of from about 2 to about 20 weight percent, from about 2 to about 15 weight percent, from about 2 to about 10 weight percent, or from about 2 to about 5 weight percent. In other embodiments, the concentration of the anti-adherent agent in the pharmaceutical composition (i.e., matrix of the capsule) is in a range of from about 1 to about 20 weight percent, from about 1 to about 10 weight percent, or from about 1 to about 5 weight t. In some embodiments, the concentration of the anti-adherent agent in the pharmaceutical composition (i.e., matrix) is in a range of from about 5 to about 40 weight percent, from about 5 to about 30 weight percent, from about 5 to about 20 weight percent, or from about 5 to about 15 weight percent. In other embodiments, the concentration of the anti—adherent agent in the pharmaceutical composition (i.e., matrix of the capsule) is in a range of from about 7 to about 15 weight percent.

Talc In one example according to any of the above embodiments, the anti—adherent agent is talc. Any pharmaceutical-grade or food-grade talc (e.g., powdered talc) may be used. Exemplary grades of talc, which can be used in the pharmaceutical compositions, liquid-ﬁll compositions, capsules and other are embodiments herein are disclosed in Dawoodbhai et al., "Pharmaceutical and Cosmetic Uses of Talc," Drug Development and rial Pharmacy, 16(16):2409-2429 (1990); and Dawoodbhai et al., "Glidants and ant Properties of l Types of Talcs," Drug pment and Industrial Pharmacy, 13(13):2441-2467 (1987), each of which is incorporated herein by reference in its entirety. In some examples, the talc is powdered talc. In some examples, the talc is of USP grade. In other example, the talc is powdered talc and of USP grade. _ 44 _ Thixotropic Agent In some embodiments, the ceutical ition or the capsule of the present disclosure further includes a thixotropic agent (also referred to herein as a thixotrop), a gelling agent, or a combination thereof. In some embodiments, the pharmaceutical composition or the capsule of the present disclosure further includes a thixotropic agent. As exempliﬁed in the Examples section that follows, inclusion of a thixotropic agent (e.g., fumed silica) in capsules results in capsules having a greater uniformity of oxidized phospholipid (e.g., VB-201, VB-208, , or VB—219) content. t being bound by any particular theory, it is believed that the increase in viscosity of the ﬁll composition, which is caused by the thixotropic agent, prevents separation of ingredients of the ﬁll ition (e.g., VB-ZOI, VB—208, VB—221, or VB- 219 and/or talc) from the carrier before a solid or semi-solid matrix is formed, y increasing homogeneity of the ﬁll ition.

Hence, according to some embodiments, the matrix r comprises an agent which increases the Viscosity of the softening carrier softened by heating (e.g., a molten carrier), such as a thixotropic agent and/or a gelling agent. In one example, the thixotropic agent and/or gelling agent is capable of sing the Viscosity of the pharmaceutical composition (Le, a ﬁll composition) at a temperature at which the ﬁll composition is ed (e.g., at the temperature to which the ﬁll composition is heated prior to ﬁlling into a capsule (e.g., the agent should not decompose at such a temperature).

As used herein, a “gelling agent” refers to an agent which forms a gel when added to a liquid. {$13245} As used herein, a trepie agent” refers to an agent which increases a viscosity Of a Eiquid when added to a iiquid. As known in the art ”thixutropy” is a reversibie behaviour of viscous iiquids (e.gt, geis) that iiquefy when subjected to shear stress such as shaking or stirring, or otherwise disturbed.

A viscous liquid ei‘intaining a thixotropic agent exhibits thixeti‘opy, wherein the ity is reduced under stress (e.g., stirring, heating and/er applicatien of shear forces).

The ingredients in a liquid iiii eompesitien (e.g., carrier, Vii—20L thixetrepie agent, and/er anti—adherent agent) can ibre i::e readily mixed by stirring, as the viseesity is 245., d during stirring, yet the ﬁll composition is relatively resistant to separation of components, as the viscosity increases when stirring ceases. 500247} Examples of thixotropic agents suitable for use in the context of the present embodiments include, but are not limited to, fumed silica able, for example as Aerosils® and Cab-O-Sil® ts), kieselguhr, gums (e.g., n gum, guar gum, locust bean gum, tes), cellulose derivatives (e.g., hydroxypropyl methyl cellulose), starches, polymers (e.g., polyvinyl alcohol, polyacrylates, hydrophobically—modiﬁed polyacrylates), emulsiﬁers, and clay derivatives (e.g., amine treated magnesium aluminum silicate, bentonite colloidal silicic acid, white smectite clays and bleaching earth, attapulgite, mica, synthetic magnesium phyllosilicates (Laponite), layered silicates, modiﬁed smectites, hectorite, and sepiolite. Optionally, the thixotropic agent comprises fumed silica and/or attapulgite.

The tration of the thixotropic agent in the pharmaceutical composition (i.e., liquid-ﬁll composition or matrix of the capsule) unless otherwise indicated is determined relative to the combined weight of the thermosoftening carrier and the thixotropic agent.

For example, at 2.5 weight t of thixotropic agent, the ceutical ition carrier (10/400 = may contain 10 mg ropic agent and 390 mg of a thermosoftening 2.5%).

In some embodiments, the concentration of the thixotropic agent is from about 0.1 weight percent to about 10 weight percent, or from about 0.25 to 10 weight percent, or from about 0.5 weight percent to about 5 weight percent, or from about 0.5 weight percent to about 4 weight percent, or from about 0.5 weight percent to about 3 weight percent, or from about 1 weight percent to about 10 weight percent, or from about 1 weight percent to about 5 weight percent, or from about 1 weight percent to about 4 weight percent, or from about 1 weight percent to about 3 weight percent, optionally from about 2 weight t to about 3 weight percent. {00250} In one example according to any of the above embodiments, the thixotropic agent is a different substance than the thermosoftening agent (i.e., the thixotropic agent is chemically ct from the thermosoftening agent). In another example according to than the anti- any of the above embodiments, the thixotropic agent is a diEErent substance nt agent (i.e., the thixotropic agent is chemically distinct from the anti-adherent agent). In other es according to any of the above embodiments, the thixotropic -46— agent is a different substance than the thermosoﬁening agent and the anti-adherent agent (i.e., the thixotropic agent is chemically distinct Eom both the thermosoftening agent and the anti-adherent agent).

Unit Engage Forms ] The pharmaceutical compositions or ﬁll-compositions of the current disclosure may be used to produce unit dosage forms (e.g., capsules) comprising a certain amount active ingredient. In some embodiments, the current disclosure es a unit dosage form comprising from about 1 mg to about 100 mg of active pharmaceutical ingredient.

The active pharmaceutical ient is selected from oxidized phospholipids described herein and combinations thereof. Hence, in some embodiments, the current disclosure es a unit dosage form comprising from about 1 mg to about 100 mg of ed phospholipid (e.g., VB-201, VB-208, , or VB-221), or from about 10 mg to about 100 mg of oxidized phospholipid, or from about 20 mg to about 100 mg of oxidized phospholipid, or from about 20 mg to about 80 mg of oxidized olipid.

In one example according to any of the above embodiments, the active pharmaceutical ingredient is VB-201. Hence, in some embodiments, the current sure provides a unit dosage form comprising from about 1 mg to about 100 mg of VB-201, or from about 10 mg to about 100 mg of VB-201, or from about 20 mg to about 100 mg ofVB-201, or from about 20 mg to about 80 mg ofVB-201.

In some ments, the unit dosage form is a capsule. Accordingly, in some embodiments, a capsule as described herein comprises from about 1 mg to about 100 mg of oxidized phospholipid (e.g., Vii-201, VB-208, VB-221, or VB-219) per capsule, or about 10 mg to about 100 mg of oxidized phospholipid per capsule, or from about 20 mg to about 100 mg of oxidized phospholipid per capsule, or from about 20 mg to about 80 mg of oxidized phospholipid per capsule. According to some embodiments, a capsule as descrébed herein comprises from about 1 mg to about 100 mg of VB-201 per capsule, or from about 10 mg to about 100 mg of VB-201 per capsule, or from about 20 mg to about 80 mg of VB-201 per capsule. ing to other embodiments of the present disclosure, a e as described herein comprises about 20 mg of ed phospholipid. In some embodiments, a capsule as described herein comprises about 20 mg of VB-201. According to other embodiments, a capsule as descrébed herein comprises about 40 mg of oxidized phospholipid. In some embodiments, a capsule as bed herein comprises about 40 mg ofVB-201.According to other embodiments, a capsule as descrébed herein comprises about 80 mg of oxidized phospholipid. In some embodiments, a capsule as described herein comprises about 80 mg of VB-201 .

According to some embodiments, a e as described herein comprises about 100 mg of oxidized phospholipid. In some embodiments, a capsule as described herein comprises about 100 mg of VB—201.Capsules containing higher amounts of oxidized phospholipids (e.g., VB-201, VB-208, VB-22l, or VB-219), e.g., about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 200 mg are also contemplated. It is noted however that higher amounts of oxidized phospholipid (e.g., VB—201, VB-208, VB—221, or VB-219) may require larger es.

E88256} According to some ments, a capsule as described herein comprises oxidized olipid from about 0.1 weight percent to about 25 weight percent of the total weight of the ﬁll composition or matrix, and optionally from about 1 weight percent to about 25 weight percent. In some embodiments, a capsule comprises oxidized phospholipid from about 2 weight percent to about 23 weight percent of the total weight of the ﬁll composition or matrix. In other embodiments, a capsule comprises oxidized phospholipid from about 4 weight percent to about 18 weight percent of the total weight of the ﬁll composition or matrix.

} In other embodiments, a capsule comprises oxidized phospholipid from about 4 weight percent to about 5 weight percent of the total weight of the ﬁll composition or matrix. In other embodiments, a capsule comprises oxidized phospholipid from about 8 weight percent to about 9 weight percent of the total weight of the ﬁll composition or matrix. In other embodiments, a capsule comprises oxidized olipid from about 14 weight percent to about 17 weight t of the total weight of the ﬁll composition or According to some embodiments, a e as described herein comprises from about 0.1 weight percent to about 25 weight percent of VB-201, and optionally from about 1 weight percent to about 25 weight percent of VB-201 relative to the total weight of the ﬁll composition or matrix. In some embodiments, a capsule ses from about 2 weight percent to about 23 weight percent of VB-201 in the ﬁll ition or matrix.

In other embodiments, a e comprises from about 4 weight percent to about 18 weight percent of VE-201 in the ﬁll composition or matrix. [0E259] In some embodiments, a capsule comprises oxidized phospholipid at a concentration of about 4.5 weight percent of the total weight of the ﬁll ition. in some embodiments, a capsule comprises VB-201 at a concentration of about 4.5 weight t of the total weight ofthe ﬁll composition.

In some embodiments, a capsule compréses oxidized phospholipid at a tration of about 8 weight percent of the total weight of the ﬁll composition. In some embodiments, a capsule comprises VB-201 at a concentration of about 8 weight t of the total weight of the ﬁll composition. In some embodiments, a capsule comprises VB-201 at a concentration of about 9 weight percent of the total weight of the ﬁll composition.

In some embodiments, a capsule comprises oxidized phospholipid at a concentration of about 14 weight percent of the total weight of the ﬁll composition. In some embodiments, a capsule comprises VB-201 at a concentration of about 14 weight percent of the total weight of the ﬁll composition. In some embodiments, a capsule comprises VB-201 at a tration of about 17 weight percent of the total weight of the ﬁll composition. In some embodiments, a e comprises VB-ZOl at a concentration of about 18 weight percent of the total weight of the ﬁll composition.

In some embodiments, a capsule comprises VB-201 at a tration of about 23 weight percent of the total weight of the ﬁll composition.

In some embodiments, a capsule comprises VB-201 at a concentration of about 28 weight percent of the total weight ofthe ﬁll composition.

The pharmaceutical compositions, mpositions or capsule matrices described herein may optionally ﬁlrther include additional chemical components, including, but not limited to, ents, lubricants, buffering agents, antibacterial agents, bulking agents (e.g. mannitol), antioxidants (e.g., ic acid or sodium bisulﬁte), and the like. Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ient. These or other ingredients can be contained in the shell of the capsule.

As exempliﬁed in the es section that follows, the capsules may be coated with a coating (e.g., an enteric coating). Any such coating known in the art is contemplated. Suitable materials for forming a coating include, but are not limited to, Eudragit®, Opadry® (e.g., Opadry ® AMB) and Acryl-Eze®, which may be used alone or in combination to form an enteric coating. ary excipients and techniques for formulation and administration of drugs may be found in “Remington’s Pharmaceutical Sciences” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference in its ty.

Processes As exempliﬁed in the Examples section, the inventors have developed a process for ulation of oxidized phospholipids (e.g., VB-20l, VB-208, VB-221, or VB-219) which provides liquid ﬁll capsules with excellent content uniformity and which do not orate upon e (e.g., by leakage or cracking).

Thus, in some embodiments, the present disclosure provides a process for producing a pharmaceutical composition comprising a thermosoftening carrier and an oxidized phospholipid having a structure according to Formula (I): CH2_0_R1 angst.

Rso [ n R1, R3, R5, and X1 are deﬁned as for Formula (I) herein above. The process comprises heating said thermosoftening carrier to a temperature above the melting point of the thermosoftening carrier, and contacting the oxidized phospholipid with the thennosofteeing carrier, to thereby obtain said pharmaceutical composition. ] ed phospholipids useful in the above process are selected from those described . In some embodiments, the oxidized phospholipid in the above process can have a structure according to Formula (II) or Formula (III) as described hereinabove.

In one example, the oxidized phospholipid is VB-201. [$0270] The softening carrier useful in the above process is selected from those described herein. In some examples according to any of the above embodiments, the thermosoftening carrier has a melting point from about 40 °C to about 100 °C. In other examples according to any of the above embodiments, the thermosoﬁening carrier is ed from a polyalkylene , a polyalkylene glycol derivative, and a wax. In some examples according to any of the above embodiments, the thermosoﬁening carrier is a member selected from polyethylene glycol, polypropylene , and copolymers thereof. In other examples according to any of the above embodiments, the thermosoﬁening carrier is a poloxamer. In other examples according to any of the above embodiments, the poloxamer has a molecular weight from about 2000 to about 18000 daltons. In other examples, the poloxamer has a molecular weight from about 7000 to about 10000 daltons. In other es, the poloxamer comprises from about 40 to about 90 weight percent of polyethylene glycol. In other examples, the poloxamer is poloxamer 188 (i.e., Lutrol F68).

In other examples according to any of the above embodiments, the thennosoftening carrier is polyethylene glycol, e.g., a polyethylene glycol having a molecular weight from about 1500 to about 8000 daltons, or about 6000 daltons.

In some embodiments the above process ﬁthher comprises milling, ng or mixing the oxidized phospholipid (e.g., , VB-208, VB-221, or VB-219) with an anti—adherent agent, e.g., prior to contacting the oxidized phospholipid (e.g., VB-201, VB-208, , or VB-219) with the thermosoﬁening carrier.

The anti-adherent agent useful in the above process can be any anti-adherent agent known in the art and may be selected from those described herein. In some examples according to the above embodiment, the anti-adherent agent is selected from talc, ium stearate, cellulose, cellulose derivatives, lactose, gelatin, alginates, ium hydroxide, magnesium oxide, clays, attapulgite, bentonite, carrageenan, copovidone, hectorite, polymethacrylates, sodium docusate, erythrétol, povidones, croscarmellose sodium, dextrates, starches, iron oxide, kaolin, silicates, corn ﬂour, sugars, calcium ate, magnesium carbonate, calcium phosphate, calcium sulfate, bicarbonates, citrate salts, and titanium dioxide. In some examples according to any of the above embodiments, the anti-adherent agent is talc.

In some examples according to any of the above embodiments, the anti-adherent agent is milled with the ed phospholipid in a weight ratio as described herein (see section "Anti-Adherent ), e.g., from about 1:5 to about 5:1, from about 1:4 to about 2:1, or from about 1:4 to about 1:1. In some es, the ﬁnal concentration of the anti-adherent agent in the pharmaceutical composition is from about 1 to about 30 weight percent. Other ary anti-adherent agentzoxidized phospholipid weight ratios are described herein.

] In some examples ing to any of the above embodiments, the above process further comprises admixing the thermosoftening carrier with a thixotropic agent, a gelling agent, or a combination thereof. In some examples according to any of the above embodiments, the above process further comprises admixing the thermosoftening r with a thixotropic agent; e.g., prior to contacting the thermosoftening r with the oxidized phospholipid. In some examples according to any of the above embodiments, the thixotropic agent is a fumed silicon e (also referred to as fumed silica). In some examples according to any of the above embodiments, the thixotropic agent is l 200.

In some examples according to any of the above embodiments, the concentration of the thixotropic agent (relative to the combined weight of the thermosoftening carrier and the ropic agent) is from about 0.25 weight percent to about 10 weight percent.

Other useful weight percentages are described herein.

In some embodiments, the above process further comprises ﬁlling the pharmaceutical composition into a capsule shell to thereby form a capsule. In some examples, the ﬁlling is med at a temperature above the melting point of the thermosoﬁening carrier and the pharmaceutical composition forms a solid or semi-solid matrix upon cooling below the melting point of the thermosoftening carrier. In some examples, the capsule comprises a shell material selected from the group consisting of gelatin, pullulan, starch, and hydroxypropyl methyl cellulose . In other examples, the shell material is gelatin.

In one example according to any of the above embodiments of the above described process, the ed phospholipid is VB—201.

In some embodiments, the the current disclosure provides a liquid-ﬁll capsule prepared by the above process or any of its embodiments and examplesAccording to other embodiments of the present disclosure there is provided a process of producing a liquid ﬁll composition which comprises an oxidized phospholipid (e.g., VB-201, , , or VB-219), the process comprising contacting (e.g., mixing) the oxidized phospholipid (e.g. VB-201) with a thermosoftening r (e.g., a carrier as described herein) at a temperature above room temperature, as described herein. Optionally, the process r comprises adding an anti-adherent agent. For example, the process may further include mixing (e.g., milling) the oxidized phospholipid with an anti-adherent agent, e. g., prior to contacting the oxidized phospholipid with the thermosoftening carrier.

The process can ﬁthher e adding a thixotropic agent. For example, the process may r include admixing the thermosoftening r with a thixotropic agent, a gelling agent, or a combination thereof, e.g., prior to contacting the oxidized phospholipid (e.g., which has been milled with the anti-adherent agent) with the thermosoftening carrier.

According to some embodiments the present disclosure provides a process of producing a liquid ﬁll capsule comprising an oxidized phospholipid (e.g.,VB—ZOI). In one embodiment, the process comprises ﬁlling a e shell with a liquid ﬁll composition (e.g., a composition as described ) which comprises an oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB-219) and a thermosoftening carrier as described herein (e.g., a polyalkylene glycol described herein). Optionally, the ﬁlling is performed at a temperature above room temperature (e.g., at least 40 °C, at least 50 °C, at least 60 °C), and the liquid ﬁll composition forms a solid or semi-solid matrix upon being cooled to room temperature.

In some examples according to any of the above embodiments, the capsule shell ally comprises gelatin, HPMC, pullulan, starch and/or any shell material described herein.

In some embodiments, the process further comprises ting (e.g., mixing) the oxidized phospholipid (e.g., VB-201, VB—208, VB-221, or ) (e.g., granulated VB- 201 or powdered VB-201) with the thermosoftening carréer to obtain the liquid ﬁll composition. The softening carrier is optionally heated so as to soften the carrier (e.g., by melting) prior to mixing the oxidized phospholipid (e.g., VB-201, VB—208, VB- 221, or VB-219) with the thermosoftening carrier.

] In some embodiments, the process r comprises mixing (e.g., milling or ng) the oxidized phospholipid (e.g., VB-201, VB-208, , or VB-219) with an anti-adherent agent (e.g., an anti—adherent agent as described herein) prior to contacting (e.g., mixing) the ed phospholipid (e.g., VB-201, VB-208, VB—22l, or VB-219) with the thermosoftening carrier. The oxidized phospholipid (e.g., VB-201, VB-208, VB— 221, or VB-219) and the anti-adherent agent may be mixed in any weight ratio described herein, for e in a ratio from about 1:3 to about 5:1 anti-adherent agentzoxidized phospholipid (e.g., , VB-208, VB-221, or VB-219). ally, the oxidized phospholipid (e.g., VB-201, VB—208, VB-221, or VB-219) and the anti—adherent agent are in powder form, and are mixed to form a powder blend, or are milled together to form a powder-blend.

Mixing the the oxidized phospholipid (e.g., VB-201, VB-208, VB-221, or VB- 219) and the anti-adherent agent may be accomplished according to any suitable method known in the art. Optionally, the mixing is performed by a method ed so as to provide a homogeneous mixture (e.g., a homogeneous powder blend). In an ary method, the oxidized phospholipid (e.g. VB-201) and the anti-adherent agent are ground or milled together to form a homogeneous powder blend. In some examples according to any of the above embodiments, the oxidized phospholipid (e.g. VB-201) and the anti- adherent agent are ground or milled using a mill/grinder that is suitable to minimize a potential temperature increase of the material being ground. Suitable machines include bladed grinders, such as those that work on the principle of rapidly rotating blades (e.g., about 9000 rpm at full speed). An exemplary mill is the Fitzpatrick mill. Ideally, the mill is equipped with an output sieve or screen for retaining any oversize remnant of the grinding process. The screen can have various mesh sizes. In some examples according to any of the above ments, the screen has from about 20 mesh to about 80 mesh, or from about 30 mesh to about 80 mesh, or from about 40 mesh to about 80 mesh, or from about 40 mesh to about 60 mesh or about 50 mesh.

The mixture of the ed phospholipid (e.g., VB-201, VB-208, , or VB-219) and the anti-adherent agent is then contacted with or combined with (e.g., added to) the thermosoftening r (e.g., molten carr‘éer) to form a composition at an amount which provides a desired concentration (e.g., a tration described ) of the oxidized phospholipid (e.g., VB—201, VB-208, VB-221, or VB-219) and/or anti-adherent agent in the ﬁll composition.

Alternatively, the anti-adherent agent is combined with (e.g., added to) the thermosoftening carrier so as to form a mixture and then the oxidized phospholipid (e.g., VB-201, VB-208, VB—221, or VB—219) is combined with (e.g., added to) the mixture.

Optionally, a ﬁnal concentration of the anti-adherent agent in the ition is in a range of from about 1 to about 30 weight percent, optionally fifom about 2 to about 25 “54“ weight percent, and optionally from about 3 to about 20 weight percent. Such percentages of anti-adherent agent may ally correspond to a ratio of anti-adherent agent to oxidized phospholipid (e.g., VB-ZOl, VB-208, VB-221, or ) described herein.

According to optional embodiments, the process r comprises adding a thixotropic gel and/or gelling agent (e.g., an agent described ) to the other ingredients of the ﬁll composition, such that the ﬁll composition comprises a thixotropic gel and/or gelling agent. The thixotropic gel and/or gelling agent may be mixed with VB- 201 and/or with the carrier at any stage of the process, for example, prior to mixing of VB-201 with the carrier, concurrently with mixing of VB-201 with the r, and/or subsequently to mixing of VB-201 with the carrier. In an exemplary embodiment, the thixotropic gel and/or gelling agent is added to the r prior to mixing of VB-201 with the carrier.

] Optionally, the thixotropic agent is added to the composition to obtain a ﬁnal concentration of thixotropic agent as described herein, for example, a ﬁnal tration of thixotropic agent in a range of from 0,25 weight percent to 10 weight percent.

The ingredients of the ﬁll composition (e.g., VB-201, carrier, anti-adherent agent, thixotropic gel and/or gelling agent) may be mixed in amounts and proportions, so as to obtain a ﬁll composition suitable for ﬁlling a capsule with any ﬁnal amount and/or concentration of ingredient described herein.

Mixing the ingredients can be performed by utilizing any que known in the art, ing, for example, a high shear mixer, a paddle mixer, a blender, a rébbon blender, a double cone blender, a planetary mixer, a static mixer, and sonication.

According to other embodiments of the current disclosure, there is provided a liquid ﬁll capsule prepared according to the process descrébed herein, for example, using a liquid ﬁll composition as described herein.

Fillin of Ca asules [(313293] Filling ofthe capsules with the ﬁll composition and encapsulating the composition so as to obtain a capsule as bed herein may be performed according to any method known in the art. [@0294] Various designs of hard shell capsules are known in the art, and can be used in embodiments of the present invention. Techniques for ﬁlling capsules of any given design will be known to one of skill in the nt art.

The following describes an exemplary method of obtaining the capsule. Empty capsules are generally ed to the ﬁlling machine in a “prelocked” condition, wherein the capsule body has a cap which is y attached thereto. Generally, a series of rings or sions are provided in the mating surfaces of the cap or body which enable the cap to be loosely attached to the body so that the cap and body are held together during storage but enabling the cap to be d prior to ﬁlling of the capsule. Once the capsule has been ﬁlled, the cap is replaced and forced beyond the ked position into a fully locked position. Alternatively, other types of e ﬁlling machines are designed to accept separate es of capsule bodies and caps.

The capsules are closed at high speed after ﬁlling and, although most have some form of air vent in their cap or body design, this may not be totally effective at normal ﬁlling speeds in eliminating the ng of air or other gas within the capsule, thereby leaving the ﬁlled capsule in a pressurized state (e.g. up to 1 bar) until the pressure equilibrates with the exterior.

During closure of the capsule, the cap is ﬁtted over the body and the body is pushed up until it locks on the cap. The cap is close ﬁtting and normally approximately half the length ofthe body, so it travels for a considerable distance down the capsule body before locking. This has the effect of a piston in ng and pressurizing the capsule.

The excess gas normally escapes through the gap between the cap and the body, and vents may be provided in this region so as to facilitate the escape of excess pressure.

Alternatively, the capsule may utilize a particularly tight locking mechanism rather than vents (e.g., as in Capsugel Licaps® capsules).

In some embodiments, the capsule is banded by applying a band of polymer solution around the junction n cap and body. The polymer solution is optionally a solution of the same polymer as the capsule cap and/or body in a solvent therefor. g is particularly suitable, for example, for providing a smooth capsule surface for coating, which prevents movement between the cap and body of the capsule (which would break the coating).

In cases where the capsule is ﬁlled with a molten liquid which sets to a solid state prior to administration, the ﬁlling is optionally performed under conditions such that the solid state in the capsule in the capsule is in a predetermined shape (e.g., a plug shape). A predetermined shape may enhance the predictability of a e proﬁle for the pharrnaceutically active agent contained therein.

Packaging and Kits ally, the capsules are packaged in a packaging material and identiﬁed for use, in or on the packaging material, for use in the ent of a disease or disorder, e.g., an inﬂammatory disease or disorder.

Capsules according to the present ments may, if desired, be presented in a pack or dispenser device, such as an FDA (the US. Food and Drug Administration) approved kit, which may contain one or more capsules containing the oxidized phospholipid (e.g., VB-201, , VB-22l, or VB-219). The pack or dispenser device may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack.

The pack or dispenser device may be accompanied by instructions for administration.

The pack may also be accompanied by a notice associated with the ner in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reﬂective of approval by the agency of the form of the compositions for human administration. Such notice, for example, may be of labeling approved by the US. Food and Drug Administration for prescription drugs or of an approved product insert. Capsules may also be prepared, placed in an appropriate container, and labeled for treatment of an inﬂammatory disease or disorder, as deﬁned herein.

Methods ofrTreatment M‘Weam.

] According to some embodiments, the pharmaceutical compositions, ﬁll- itions and capsules described herein are for use in the ent of an atory disease or disorder.

The present disclosure further provides a method of ng an inﬂammatory disease or disorder, comprising administering (e.g., orally) to a subject in need thereof a pharmaceutical composition of the present disclosure, i.e., a ceutical composition WO 33642 comprising an oxidized olipid (e.g., , VB-208, VB-219, or VB-22l), a thennosoftening carrier, and optionally an anti—adherent agent as described herein.

The present disclosure further provides a method of treating an inﬂammatory disease or disorder, comprising administering (e.g., orally) to a subject in need thereof a capsule which comprises an ed phospholipid (e.g., VB-201, VB-208, VB-219, or VB-221), as described herein.

According to optional embodiments, the inﬂammatory disease or disorder is an atory disease or disorder associated with an endogenous ed lipid.

As used , the phrase “an endogenous oxidized lipid” refers to one or more oxidized lipids that are present or formed in vivo, as a result of inﬂammatory and other cell- or humoral-mediated processes. Oxidized low-density lipoprotein (oxidized-LDL) is an example of an endogenous oxidized lipid associated with an atory disease or Inﬂammatory diseases or disorders according to exemplary embodiments of the present ion e psoriasis (e.g., plaque psoriasis), rheumatoid arthritis, and atherosclerosis and related conditions, such as vascular inﬂammation, i.e., inﬂammation of an artery (e.g., inﬂammation of a carotid artery and/or inﬂammation of an aorta).

Additional examples of atory diseases or disorders according to exemplary embodiments of the present invention include multiple sclerosis and inﬂammatory bowel disease (e.g., chronic inﬂammatory bowel disease).

Representative inﬂammatory diseases and disorders ing to embodiments of the present invention include, for example, idiopathic inﬂammatory diseases or disorders, chronic inﬂammatory diseases or disorders, acute inﬂammatory diseases or disorders, autoimmune es or disorders, infectious diseases or disorders, inﬂammatory malignant diseases or disorders, inﬂammatory transplantation-related diseases or disorders, inﬂammatory rative diseases or disorders, diseases or disorders associated with a hypersensitivity, inﬂammatory cardiovascular diseases or disorders, inﬂammatory cerebrovascular diseases or disorders, perépheral vascular diseases or disorders, inﬂammatory glandular diseases or disorders, inﬂammatory gastrointestinal diseases or ers, inﬂammatory ous diseases or disorders, inﬂammatory hepatic diseases or disorders, inﬂammatory neurological diseases or disorders, inﬂammatory musculo—skeletal es or disorders, inﬂammatory renal diseases or disorders, atory reproductive diseases or disorders, inﬂammatory systemic diseases or disorders, inﬂammatory connective tissue diseases or disorders, inﬂammatory tumors, necrosis, inﬂammatory implant-related diseases or disorders, inﬂammatory aging ses, immunodeﬁciency es or disorders, proliferative diseases and disorders and inﬂammatory pulmonary diseases or disorders, as is detailed herein below.

NOE-limiting examples of hypersensitivities include Type I hypersensitivity, Type II hypersensitivity, Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody mediated ensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity, delayed type ensitivity, helper T lymphocyte mediated ensitivity, cytotoxic T lymphocyte mediated hypersensitivity, THl lymphocyte mediated hypersensitivity, and TH2 lymphocyte mediated ensitivity.

Non-limiting es of inﬂammatory cardiovascular disease or disorder include occlusive diseases or disorders, atherosclerosis, a cardiac valvular disease, stenosis, restenosis, in-stent—stenosis, myocardial infarction, coronary arterial e, acute coronary syndromes, congestive heart failure, angina pectoris, myocardial ischemia, thrombosis, Wegener’s granulomatosis, Takayasu’s arteritis, Kawasaki syndrome, anti- factor VIII autoimmune disease or disorder, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal izing glomerulonephritis, crescentic glomerulonephritis, antiphospholipid syndrome, antibody induced heart e, ocytopenic purpura, autoimmune hemolytic , c munity, Chagas’ disease or disorder, and anti-helper T lymphocyte autoimmunity.

Stenosis is an ive e of the vasculature, commonly caused by atheromatous plaque and enhanced platelet activity, most critically affecting the coronary vasculature.

Restenosis is the progressive re-occlusion often following reduction of occlusions in stenotic vasculature. In cases where patency of the vasculature requires the mechanical support of a stent, in-stent-stenosis may occur, re-occluding the treated vessel.

Non-limiting examples of cerebrovascular diseases or disorders include , cerebrovascular inﬂammation, cerebral hemorrhage and vertebral arterial insufﬁciency. 2012/053533 Non-limiting examples of peripheral vascular diseases or ers include gangrene, diabetic vasculopathy, ischemic bowel disease, thrombosis, diabetic pathy and diabetic nephropathy. ] miting examples of autoimmune es or disorders include all of the diseases caused by an immune response such as an autoantibody or cell-mediated immunity to an autoantigen and the like. Representative examples are chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, 's disease, le sclerosis, mune diabetes, Hashimoto's disease, psoriasis, primary myxedema, pernicious anemia, myasthenia , chronic active tis autoimmune hemolytic , anemia, idicpatiiic thrcmbocytopenic purpara, uveitis, vasculitides and heparin induced thrombocytopenia, {00317} Nondimiting examples of inﬂammatcry glandular diseases or disorders inciude pancreatic diseases or disorders, Type i diabetes, thyroid diseases or disorders, Graves’ e, ciditis, spontaneous autoimmune thyroiditis, moto’s ditis, thic myxedema, ovarian autoimmunity, autoimmune anti~sperm infertility, autoimmune prostatitis and Type 1 autoimmune poiygianduiar syndrome. {00318} Nondimiting examples of inﬂammatory gastrointestinal diseases or disorders include colitis, iieitis, Crchn’s disease, chronic inﬂammatory intestinal disease, inﬂammatory bowel syndrome, inﬂammatory bowel disease, celiac disease, ulcerative colitis, an ulcer, a skin ulcer, a bed sore, a gastric ulcer, a peptic ulcer, a buccal ulcer, a nasopharyngeal ulcer, an esophageal ulcer, a duodenal ulcer and a gastrointestinal ulcer.

Non-limiting examples of atory cutaneous diseases or disorders e acne, an autoimmune bullous skin disease, pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, contact dermatitis and drug eruption.

Non—limiting examples of inﬂammatory hepatic diseases or disorders include mune hepatitis, hepatic cirrhosis, and biliary cirrhosis.

Non—limiting examples of inﬂammatory neurological diseases or disorders include multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, myasthenia gravis, motor neuropathy, Guillain—Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, progressive cerebellar atrophy, Rasmussen’s encephalitis, amyotrophic lateral sis, Sydeham chorea, Gilles de la Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sis (AML), multiple sclerosis, stroke, an inﬂammatory retinal disease or disorder, an inﬂammatory ocular disease or disorder, optic neuritis, spongiform encephalopathy, migraine, headache, cluster headache, and stiff-man syndrome. miting examples of inﬂammatory tive tissue diseases or disorders include autoimmune myositis, primary Sjogren’s me, smooth muscle autoimmune disease or disorder, myositis, tendinitis, a ligament inﬂammation, itis, a joint inﬂammation, a al inﬂammation, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, a skeletal inﬂammation, an autoimmune ear disease or disorder, and an autoimmune disease or disorder of the inner ear.

Non-limiting examples of inﬂammatory renal es or disorders include autoimmune interstitial nephritis and/or renal cancer.

Non-limiting examples of inﬂammatory reproductive diseases or ers include repeated fetal loss, ovarian cyst, or a menstruation associated disease or er.

Non-limiting es of inﬂammatory ic es or disorders include systemic lupus erythematosus, ic sis, septic shock, toxic shock syndrome, and cachexia.

Non-limiting examples of infectious disease or disorder include chronic infectious diseases or ers, a subacute infectious e or disorder, an acute infectious disease or disorder, a viral disease or disorder, a bacterial e or disorder, a protozoan disease or disorder, a parasitic disease or disorder, a fungal disease or disorder, a mycoplasma disease or disorder, gangrene, sepsis, a prion disease or disorder, inﬂuenza, tuberculosis, malaria, acquired immunodeﬁciency syndrome, and severe acute respiratory syndrome.

Non-limiting examples of inﬂammatory transplantation-related diseases or disorders include graft rejection, chronic graft rejection, subacute graft rejection, acute graft rejection hyperacute graft rejection, and graft versus host disease or disorder.

Exemplary implants include a prosthetic implant, a breast implant, a silicone t, a dental implant, a penile implant, a cardiac implant, an artiﬁcial joint, a bone fracture repair device, a bone replacement implant, a drug delivery implant, a catheter, a pacemaker, an artiﬁcial heart, an artiﬁcial heart valve, a drug release implant, an ode, and a respirator tube. miting examples of inﬂammatory tumors include a malignant tumor, a benign tumor, a solid tumor, a atic tumor and a non-solid tumor.

Non—limiting examples of inﬂammatory pulmonary es or ers e asthma, allergic , emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis and bronchitis.

An example of a proliferative disease or disorder is cancer.

In some examples according to any of the above ments, the pharmaceutical compositions of the present disclosure or the capsules of the present disclosure are administered to the subject concomitantly with another active pharmaceutical agent that is other than an oxidized phospholipid as described herein (co-therapy). For example, the pharmaceutical composition or the capsule of the current disclosure is administered to the subject concomitantly with a statin (i.e., the subject undergoes statin therapy at the time the oxidized phospholipid is administered to the subject). In one embodiment, the statin is administered in a separate dosage form. The oxidized phospholipid can be administered at the same time of the day as the statin or at a ent time of the day.

Other Deﬁnitions As used herein the term “about” refers to i 10 %.

The terms "compréses", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

The term “consisting of” means “including and limited to”.

The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any ment described as “exemplary” is not necessarily to be construed as preferred or ageous over other ments and/or to exclude the incorporation of features from other embodiments.

The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conﬂict. {@8337} As used herein, the singular tbnn "a", "an” and "the" include plural references unless the context clearly dictates ntherwise. For example, the term "a nd” er "at least one compound" may include a. plurality efccrnpnunds, including mixtures thereof.

Etltl338l Threugheut this application, various embodiments of this inventicn may be presented in a range . it sheuld be understood that the description in range fennat is merely fer ience and brevity and sheuld not be censtrued as an intlexible limitation en the scope efthe ion, Accordingly, the descriptinn of a range should he censidered to have speciﬁcally disclosed all the le subranges as well as individual numerical values within that range. For example, description of a range such as from l in 6 should be eensidered to have speciﬁcally diselcsed subranges such as from i to 3, from l to 4, from l in 5, from 2 tn 4, from 2 to b, from 3 in 6 etc, as well as individual numbers within that range, fer example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth ofthe range. {@339} Whenever a numerical range is indicated herein, it is meant to include any cited numeral (ti‘actienai or integral) Within the indicated range. The phrases “ranging/ranges between” a ﬁrst indicate number and a seennd indicate number and “ranging/ranges from” a ﬁrst indicate number “in” a second indicate number are used herein interchangeably and are meant to include the ﬁrst and second indicated numbers and all the iractienal and integral numerals therebetween. {@9349} As used herein the term nr " refers te manners, means, techniques and procedures for accemplishing a given task ineluding, but not limited to, these manners, means techniques and procedures either linewn tn, er readily developed iron”; known manners, means, techniques and procedures by practitioners of the chemical, cnlogical, hielegieal, biochemical and medical arts {(39341} As used herein, the term “treating” includes ahrngating, substantially inhibiting, slewing or reversing the progression (if a cunditicn, substantially ameliorating clinical er aesthetical ms of a condition, or ntially preventing the appearance of clinical or aesthetical symptoms of a condition.

As used herein the term “alkyl” means, unless otherwise , a straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbon . In the context of this ation, e.g., with respect to the variable R1 in Formulae (I), (II), and (III), an alkyl group will typically «63» have from 1 to 30 carbon atoms, for example having from 10 to 30 carbon atoms, from 12 to 30 carbon atoms or from 14 to 30 carbon atoms. Other exemplary alkyl groups have from 14 to 20 carbon atoms. Exemplary alkyl groups include tetradecyl, pentadecyl, hexadecyl, heptadecyl, cyl, nonadecyl, eicosanyl, cis—9-hexadecenyl, and (2- octyl)dodecyl. In other examples, e.g., with respect to the variable R5 in Formulae (I), (II), and (III), the alkyl group is a “lower alkyl” group having from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.

Examples of “lower alkyl” radicals e, but are not limited to, methyl, ethyl, n- propyl, iso-propy], n-butyl, tert—butyl, iso—butyl, tyl, as well as homologs and isomers of, for example, n—pentyl, n-hexyl, n-heptyl and n-octyl. The term “alkyl” es di- and multivalent radicals. For example, the term “alkyl” includes “alkylene” wherever appropriate, e.g., when the formula indicates that the alkyl group is divalent.

The term “alkyl” includes “alkenyl” and “alkynyl” as deﬁned .

The term “alkylene” means a divalent (diradical) alkyl group, wherein alkyl is deﬁned herein. Typically, an “alkylene” group will have from 1 to 30 carbon atoms.

Other exemplary ranges for the number of carbon atoms are those described for “alkyl”.

“Alkylene” is exempliﬁed, but not d, by butylene (-CH2CH2CH2CH2-) .

] The term “alkenyl” refers to a straight or branched chain hydrocarbon l having from 2 to 30 carbon atoms and at least one double bond. Other exemplary ranges for the number of carbon atoms are those described for “alkyl”. A typical “alkenyl” group has from 12 to 30 carbon atoms and at least one double bond. In one embodiment, “alkenyl” groups have from 14 to 30 carbon atoms or from 14 to 20 carbon atoms and at least one double bond. An exemplary “alkenyl” group is cishexadecenyl. Exemplary “lower alkenyl” groups having from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms include Vinyl, 2-propenyl, 1-butenyl, crotyl, 2-(butadienyl), 2,4- ienyl, 3-(1,4-pentadienyl), entenyl, l-pent-3—enyl, l-hex—S-enyl and the like.

The term “alkynyl” refers to a straight or branched chain, unsaturated or polyunsaturated hydrocarbon radical having from 2 to 30 carbon atoms and at least one triple bond. Other ary ranges for the number of carbon atoms are those described for “alkyl”. In the context of this application, an “alkynyl” group typically has from 12 to carbon atoms and at least one triple bond. In some examples of the present disclosure, “alkynyl” groups have from 12 to 20 carbon atoms and at least one triple bond. An 2012/053533 yl” group may additionally include one or more double bonds. Other “alkynyl” groups are “lower alkynyl” groups having from 2 to 10 carbon atoms (e.g., 2 to 6 carbon atoms), which include prop-l-ynyl, prop-Z-ynyl (i.e., propargyl), ethynyl and nyl.

] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be ed in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be ed separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features bed in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.Various embodiments and aspects of the present ion as delineated hereinabove and as claimed in the claims section below ﬁnd experimental support in the following examples.

EXAMPLES Reference is now made to the following examples, which er with the above descriptions illustrate some embodiments of the invention in a non—limiting fashion.

ALS AND METHODS Materials: Acryl-EZE® was obtained from Colorcon; Gelatin was obtained from DG Stoess; Lauroglycol FCC was obtained from Gattefosse; Magnesium stearate was obtained from Procter & Gamble; Opadry® AMB was obtained from Colorcon; 0 was obtained from BASF; Poloxamer 188 (Lutr01® F 68) was obtained from BASF; Size 0 gelatin capsules were obtained from Qualicaps and from Capsugel; Talc (Ph Eur) was ed from Fluka; Tocopherol polyethyleneglycol succinate (TPGS) was obtained from Eastman Chemical C0.; TWEEN 80 was obtained from Riedel—de-Haén; and Vii-20} was obtained from Cordenphamia {previously Genzyme).

Gravimetric vapor on: {08348} Sorption was ed using an p re Sorption Analyser (Hiden Analytical). A sample of VB-201 was carefully placed on the ultra-microbalance of the instrument and dried in a stream (250 standard cubic centimeters per minute) of dry nitrogen (<0.l % relative humidity) until equilibration had been attained. The sample was then exposed to the following water relative humidity proﬁle: 10, 20, 30, 40, 50, 60, 70, 80 and 90 % relative humidity, allowing equilibration to be attained at each step (99.5 % step completion). The study was continued for a period of 3 days. The sorption isotherm was calculated from the equilibrium mass values at each step.

Isothermal calorimetry: Samples of 88 mg VB-20l, 262 mg Lauroglycol FCC, and 88 mg VB-201 combined with 262 mg Lauroglycol FCC were freshly prepared and loaded immediately into a meter (TAM, metric AB, Sweden), and the unit was then allowed to equilibrate at 25 °C for a period of 30 minutes. Data were collected every 15 seconds for a period of 24 hours using the dedicated re package Digitam 4.1. Samples containing 350 mg water were used as the reference. Data is was performed using the graphical software package Origin cal Software Inc., USA). The calorimeter was calibrated using the electrical substitution method and was run with an ampliﬁer range of 300 uW.

Differential scanning calorimetry (DSC): Approximately 5 mg of sample was placed in an aluminum DSC pan and sealed with a pin-hole lid. The sample was loaded into a Pyris l differential scanning calorimeter (Perkin Elmer) held at 10 °C, and then cooled to -20 °C. After equilibration, the sample was heated from —20 °C to 100 °C at a rate of 10 °C per minute, held at 100 °C for 1 minute, and cooled from 100 °C to -20 °C at a rate of 20 °C per minute. During the temperature cycles, the sample was purged with nitrogen at a ﬂow rate of 20 ml per minute to prevent ion. £00351} Prior to analysis, the calorimeter was temperature-calibrated and heat ﬂow- calibrated using an indium reference standard. a66_ Thermogravimetric analysis (TGA): Approximately 5-10 mg of sample was laced in a um pan and loaded into a TGA l Thermogravimetréc er held at ambient temperature. The sample was then heated from 5 °C to 300 °C at rate of 10 °C per minute while monitoring the weight ofthe . Nitrogen was used to purge the sample at a ﬂow rate of 20 ml/minute to prevent oxidation upon g.

Prior to analysis, the instrument was temperature calibrated using an alumel reference standard, and weight calibrated using a 100 mg calibration weight.

Pawdeppaekes‘ c mechanicai anaivsis: Dynamic mechanical analysis (DMA) measures the mechanical properties of a sample as a function of temperature. The solid sample is subjected to an oscillating stress which results in ating strain within the sample. The applied force and the amplitude and phase ofthe resultant displacement are measured.

Most materials behave viscoelastically, such that the oscillating strain lags behind the applied oscillating stress by a phase difference 8. The modulus (the ratio of the force or stress to the deformation or strain) thus has an in-phase component, which corresponds to an elastic response and is deﬁned as the storage modulus, as well as an -phase viscous component, deﬁned as the loss modulus. The ratio of loss modulus to storage modulus equals the damping ter tano, which is proportional to the ratio of dissipated mechanical energy (prémarily as heat) to stored mechanical energy for each cycle.

Powder-pocket DMA allows analysis of powder by holding the powder between to thin plates of steel. Experiments were med using a Perkin Elmer DMA 8000 apparatus. Approximately 50 mg of sample powder was loaded into metal pockets, which were closed to form a thin sandwich of approximately 0.4 mm of powder encased in the pocket. The pocket was then clamped directly into the instrument, one end on end into a rigid frame and the other end attached to a moving driveshaft. The experimental geometry used to determine the force data in the software was a rectangular cross-section in a single cantilever bending using a single frequency deformation mode. The pocket was subjected to a bending oscillatory motion in and out of the plane, forcing horizontal shearing of the powder between the two plates ofthe pocket. -67— The samples were heated from -20 °C to 50 °C at a rate of 2 °C per minute.

Optimized mental conditions were used, namely, a dynamic displacement of 0.05 mm under frequencies of 1 Hz, 10 Hz and 30 Hz. The modulus was then calculated from the measured dynamic displacement amplitude.

The instrument was calibrated for temperature using the melting point of indium (156.6 °C), and for force by placing a known weight of approximately 100 grams on the driveshaft ing to the manufacturer’s instructions.

Overview: VB-201 is synthetically prepared via published procedures (see, e.g., U.S. Patent Application No. 11/650,973), dried from solvents by evaporation under d pressure and oven dried. It is obtained as a waxy solid material which shatters and powders easily at room temperature, 18-22 0C. VB-201 was further characterized as highly hygroscopic.

These physicochemical properties of the API (active pharmaceutical ient) t that conventional oral solid dosage form (e.g. tablet or powder blend e) could not be developed. Accordingly, studies were made for developing either liquid ﬁll capsules of solubilized drug (which stay as liquid) or liquid ﬁll capsules of molten carrier which become solid on cooling.

The following examples be the route for developing suitable oral dosage forms of VB-201 .

EXAMPLE 1 Encapsulation 0f VB-201 in gelatin capsules using a Lauroglycol FCC carrier The solubility of VB-201 in lycol FCC lene glycol laurate) was tested, and was found to be at least 255 mg per gram. VB-201 was also found to be stable in Lauroglycol FCC over the course of 66 days (data not shown). Based on these results, Lauroglycol FCC was considered to be a suitable liquid carrier for .

In order to test the stability of VB-201 in gelatin capsules, size 0 capsules were ﬁlled with 255 mg/gram VB-201 in Lauroglycol FCC and then sealed. Capsules were stored under the following storage conditions; a) ambient relative humidity at 4 °C; b) 65 % ve humidity at room temperature; and c) 75 % relative humidity at 40 °C. -68— As shown in Table 1, VB-201 content in the capsules was reduced, in contrast to the results obtained for VB-201 in lycol FCC in the e of capsules.

In order to determine whether the VB-201 interacted with the gelatin in a way which caused the VB-ZOl to be refractory to the analysis, VB-201 was extracted from n capsules in order to r any VB—201 which interacted with the n.

Capsules were d from storage after 24 days or 59 days.

As shown in Table 1 below, when VB-201 was assayed by extraction of the capsules, no signiﬁcant loss of VB‘201 were observed even after 59 days of storage at 4 °C with ambient relative humidity or at room temperature with 65 % relative humidity.

The VB—201 content of capsules stored at 40 °C with 75 % relative humidity decreased by imately 20 %.

Table 1: Stability of VB-201 in gelatin capsules, as determined by sampling unsealed capsules and by extraction of VB-201 from capsules Initial recovery storaue 4 °C, ambient relative humiditr Room temperature, MIN—mg! . 40 °C, The above results suggest that VB-ZOl cts with the gelatin capsule during storage, but that the VB-201 is recovered when the capsule breaks down. Hence, the VB— 201 would be available for absorption when a capsule breaks down in the gut.

] VB-201 was then encapsulated on a larger scale. VB-201 was dissolved in Lauroglycol FCC at a temperature of approximately 40 °C. The solution was then encapsulated in gelatin capsules at a similarly slightly elevated temperature, using a Bosch 1500L ﬁlling machine. The capsules were then banded with gelatin on a Qualiseal SlOO banding machine. es with 5, 20, 25 and 100 mg VB—201 were prepared.

Placebo capsules containing Lauroglycol FCC Without VB—201 were also prepared.

The capsules were then leak tested under reduced pressure and, where appropriate, transferred for coating with EZE®, a pharmaceutical enteric coat ation, in a Manesty Accelacota g machine. An undercoat of Opadry® AMB, a moisture barrier sub-coat, was applied to prevent moisture migration through the Acryl-EZE® coat, which softens and distorts capsules during dissolution testing.

It was noticed that leaks developed in capsules prior to coating with an enteric coat. The source of the leaks was identiﬁed as ssive cracking of the capsules, which was e of leading to loss of all the VB-201 in the capsule. Cracking was not observed in coated capsules or in uncoated placebo capsules (i.e., without VB-201).

] The above results te that VB-201 may be ulated in liquid-ﬁll n capsules, but that VB-201 causes cracking of uncoated gelatin capsules.

EXAMPLE 2 Hygroscopicity of VB-201 The physical properties of VB-ZOl were examined in order to understand the mechanism whereby VB-201 causes ng of gelatin capsules, as described in Example 1.

The aqueous solubility of VB-201 was determined by suspending VB-201 in aqueous solutions of 0.1 M HCl (pH 1) or in 50 mM phosphate buffers (pH 5 and 7).

After initial hand mixing, the preparations were further mixed by vortexing and bath sonication to try to bring about dissolution of the drug. Optical microscopy was used to examine for the ce of undissolved material. Using this method, it was determined that the solubility of VB-201 at each of the tested pH values is in excess of 225 mg/gram.

Thus, VB-201 is relatively water-soluble.

Absorption of humidity by VB-201 was determined by gravimetréc vapor sorption is, as described in the Materials and Methods section.

As shown in FIGS. 1A and 1B, a slight weight loss was observed when VB-201 was exposed to 0 % relative humidity.

This result indicates that the VB-201 contained some absorbed water.

As further shown in FIGs. 1A and 1B, the VB-ZOl increased slightly (by approximately 3.5 %) in weight as the relative humidity was increased gradualéy to 40 %, foiiowed by a iarge increase (> 31’} %) in weight as the ve humidity was iriereased beyond 49 ‘34:: partieniariy in the range ot‘dﬁ % to 60 9/2; reiative humidity. {@3377} These results suggest that a phase transition occurred in the V3201 at reiative humidities of 4t} % to ﬁt) “/6, with the formation of a hydrated state, or tion of a supersaturated solution. {89373} As thrther shown in F1G. i8, the serption and deserptinn protiies were simiiar in the range of 60 % to 90 % reiative humidity, whereas there was a eensiderahie dii‘ierence etween the profiles (hysteresis) in the range of % tn 60 % relative humidity.

] These resuits suggest that between 60 % and 9G % reiative humidityt the water is simply absorbed into the huik of the structure without eheniieaiiy interacting with the sample sorption), whereas n 0 9A;- and (it) ‘34: reiative humidity, there was sorption and desorptinn of a. more strongly hound water species from the sampie.

Etiti38ti} The above restiits further indicate that VBJEOi is highiy hygroscopic. The VB— 201 is nhysieaiiy stable with regards to hygroscopicity as long as the reiative humidity is maintained heiow 40 %t Reiative humidities greater than 40 ‘Vés resuit in the formation of a supersaturated solution, with possible deiiquescenoe of the FBQGL {89381} As highiy hygrnseopie substances can potentiality ahsorh water from an e environment even when dissnived in a hydrophobic- oii phase (eg, Laurogiyeoi FCC} the hygroscopieity can affect the stahiiity ot‘ a thrrnuiatien and/er eapsnie, especiaiiy if soft geiatin capsuies are used The reiative ty range at which n capsuies are stahie iies between 35 % and 65 %, and V390} is highiy hygroscopic in this range. {@9383} As hearty aii chemieai or physical ses are aceoninanied by a change in heat, Vii—201 and Lanrogiyeoi FCC. (atone and in combination} were aiso examined using isothermai eaiorirnetry, as described in the Materialis and Methods section Preiiminary s are shown in FIGS, 2, 3 and 4. {($333} As shnwn in FIG. '2. i exhibited an endothermic. signai of approximateiy «6 uW over the ﬁrst i. 1. hours. This resnit indicates iiity otVB«ZGi. {($384} As shown in F185. 3 and 4, no significant signai was ohseweti for either Laurngiyeoi FCC ( or for Lauregiyeoi FCC with VBQOE (.

{W335} These resuits indicate that Vii-’20! undergoes a ehahge, but that Laurogiyeoi FCC prevents this change. The resuits are consistent with a mechanism wherein VB-201 s73” absorbs moisture and lycol FCC excludes moisture, thereby limiting absorption by VB-201.

The above s, along with the interaction between VB-201 and gelatin described in Example 1, suggest that the VB—201—associated cracking of gelatin capsules and subsequent leakage, as described in Example 1, is due to the hygroscopic properties ofVB-201.

Encapsulation of VB-201 in gelatin capsules using a solid carrier In order to provide a more stable n capsule containing VB-201, VB-201 was incorporated into a solid excipient having a low melting point, by adding VB-201 to the molten excipient.

The solid formulation was expected to be advantageous because no leakage is possible, the VB-201 is immobilized and therefore prevented from interacting with the gelatin shell wall, and absorption of water by Vi§~201 would be limited.

In order to facilitate HPLC is, the excipient was ed to have little UV absorption and to be water-soluble. The excipient was further selected so as to be FDA- approved. Based on the aforementioned criteria, PEG6000 (polyethylene glycol with a molecular weight of 6000 daltons) and TPGS (tocopherol polyethylene glycol succinate) were selected as suitable excipients, and tested in order to ine which excipient provides the best stability. The melting point of TPGS is about 40 °C, and the melting point of PEG6000 is about 60 °C.

Binary mixes were prepared at 20 % (w/w) VB—201 in TPGS and PEG6000, matching the VB-20l concentration in a 100 mg dosage unit. The excipient was melted in an oil bath and ground VB-201 was incorporated into the mix with high shear .

Both blends ed by visual examination to form a uniform mix. Samples of both ents (without VB-201) and binary mixes were stored in sealed amber glass bottles at 40 °C with 75 % relative humidity or at 5 °C for four weeks. Approximately 500 mg of the mix was also used to ﬁll size 0 gelatin capsules obtained from either of two manufacturers (Shionogi and Capsugel), and the capsules were banded and then stored under the abovementioned conditions.

After one week, capsules ﬁlled with the ased formulation exhibited no cracking or deformation, although leakage was observed and almost all of the capsules were brittle.

However, es ﬁlled with the PEG6000-based formulation exhibited no leakage or embrittlement, even after 4 weeks, in addition to exhibiting no cracking or deformation. Based on this result, PEG6000 was selected as the excipient for subsequent tests.

EXAMPLE 4 Machine encapsulation of VB-201 with a PEG6000 r VB-201 gelatin capsules containing 25 mg or 100 mg VB-201 were prepared on a large scale (12,000-24,000) by machine encapsulation. PEG6000 was melted at 65 °C in a Schweizer mixer, and VB-201 was then orated as a powder that had been produced in a small scale bladed blender under nitrogen. The mix was mixed using paddle stirring and ﬁll speed high shear mixing.

The mix was degassed and transferred to the heated hopper of a Bosch ﬁill scale ﬁlling machine where the formulation was encapsulated at a target temperature of 65 °C.

The es were then banded and coated with an EZE® enteric coating, as described in Example 1.

Additional batches of es with 5, 10 or 25 mg VB-201 were prepared on a r scale (3,400), using procedures similar to those described above. The VB—201 was incorporated into molten PEG6000 in a stainless vessel, mixed by a spatula, and then distributed using a bench scale high shear mixer. The mix was then degassed and encapsulated as described above, but capsules were not banded or coated.

After high shear mixing, the mixes did not appear by visual examination to have any geneity, although it was noticed that they had a “wallpaper paste” consistency. In addition, VB-201 became sticky on oration, and some lumps needed to be dispersed with a spatula before they would pass through the high shear head.

The VB—201 content was assayed in order to test the accuracy and uniformity of the VB—201 content, and the results are summarized in Table 2 below. .1 I _ Table 2: VB-201 t and uniformity of capsules with PEG6000 carrier Batch No. Scale of Targetw VB—201 Uniformlfyof VB-201 content ‘ 5 production VB=201 content (RSD= relative standard ion)3 content 3 (% of tarseté,,, ,,,, new.31 103/029/2 24,000 25 mg 1 106.2 9/10 capsules within 3: 15 % of mean i 1 ca\sule 117.5 % ofmean “mm“~--m444mm¢e+fu-muuuumum-3u~ «n W... “WWW; .....1,Q3/029/3 12,000 100 me [1 10/10 capsules within i15%of‘mean ..... 103/032/2 24,000 25 mg 101.7 9/10 capsules within :t 15 % of mean Wthln i 25 % ofmean 777777777777__1,Q/ ......- W ‘ 103/032/3 13,000 100 mg 104.6 8/10 capsuleswithin i 15 % ofmean 1/ 10 cagsulesoutside i 25 3/9 ofmean3 3%______ VC2434 3,400 Range 80.33 % - 119.79 % oftarget 3 3 RSD—— 11.08 % VV “1393913L1yalue—— 29.4‘8 VC2436 3,400 3 Range 92.70 % - 10879% of target 3 3 RSD= 4.80 % 1 Batch L1 value?» 1304 . .

VC2438 3 3,400 3 Range. 9900 % - 14691 % oftarget RSD-u— 1341 % } As shown in Table 2, the average V3201 content in all of the batches was close to 100 % of the target. However, the uniformity of content in some of the batches was relatively low. As the capsules had uniform weights, the relatively low uniformity indicated that inhomogeneities were present in the mixes.

It was hypothesized that geneities were present in the mixes due to the viscous lumps which were formed when VB-201 was added to molten 0. Bench scale trials were therefore performed in which VB-201 was ground with PEG6000 before being added to PEG6000, in order to ease incorporation of the VB-201 into the PEG6000. [004003 1 part ground VB-201 was combined with 1, 2 or 3 parts ground PEG6000 at room temperature to form a free ﬂowing powder blend. These blends greatly increased the ease of oration of VB-201 into molten PEG6000 and a ratio of 2:1 PEG6000:VB-201 was selected as the best compromise for further trials.

Batches of capsules (3,400 capsules) were then prepared by incorporating the VB- 201/PEG6000 blend into molten PEG6000 in a stainless vessel, mixed by a spatula, and then distributed using a bench scale high shear mixer. The mix was then degassed and encapsulated as described above. es were not coated with an enteric coating.

Incorporation of VB—201 was considerably improved, with no viscous lumps being formed upon incorporation. N0 inhomogeneities were visible after mixing, and the mix was used to ﬁll capsules at 65 °C without any difﬁculty.

The VB-201 content was assayed in order to test the accuracy and mity of the VB-20l t, and the results are summarized in Table 3 below.

Table 3: T’Bnlﬁi content and mity at capsuies prepared T111111 V8201 gmund with PEI-(36000 BatchV11E t T/Ti:201 TfnéfcrmiT‘s;1.1TVBQTTT sentient” i ‘ VB20]; content (RS?)—~ relative standard ‘ cantent (% 0f deviaticn) met? ,,,,,, VE2480 10mg 93.75 TRange: 5749%- 10231% oftarget RSD— 15.06 % Batch L1 value--—38.__63____ VE2482 20 mg Range: 72.55 % — 112.38 % et RSD: 8.95 % .....ﬁatghwliLyalgg:—:;l.§gil.

TTTTTL‘TTETE As shown in Table 3, the average VB-201 content in all of the batches was close to 100 % of the target, but the content mity was poor.

EXAMPLE 5 Hand encapsulation of VB-201 with a PEG6000 carrier In order to improve homogeneity, capsules containing 10 mg VB-201 were prepared without the use of machine , in which material may separate, adhere and/or be ﬁltered out of a mix.

A mix was prepared from a blend containing 1 part VB—201 and 2 parts PEG6000, using the procedures described in Example 4. Capsules were then lled at a temperature of 65 °C using plastic disposable syringes with material taken from the outlet of the high shear head. All capsules were individually ﬁlled to the target weight, with the target VB-201 content being 10 mg. The VB—201 content was assayed in order to test the accuracy and uniformity of the VB-201 content. The average VB-201 content was 89.41 % of the target content (10 mg), and the range of the VB-201 t was from 56.21 % to 102.23 % of the target content. Thus, the average VB-201 content was considerably below target and the results indicate that poor homogeneity is not due to machine ﬁlling per se.

EXAMPLE 6 Eﬂect erature on solubility of VB-201 in PEG6000 In order to further enhance the uniformity of VB-201 capsules, the effect of temperature on VB-201 solubility in PEG6000 was studied, so as to determine whether dissolution/precipitation contribute to poor homogeneity.

Nine pieces of caked, non—ground VB-201 were submerged in molten PEG6000 at 65 °C and stirred slowly using a paddle mixer. The mix was held for approximately two hours at this temperature, examined visually for the dissolution state of the VB-201, and three samples of the liquid PEG6000 were then taken for analysis. The temperature was then raised by 10 °C and the process was repeated. The process was repeated in 10 °C steps until the mix reached a ﬁnal temperature of 105 °C. The entire process lasted 30 hours.

After 30 hours and at a temperature of 105 °C, the PEG6000 had slowly turned lightly yellow (normal for prolonged g of PEG6000 in air), yet there was no signiﬁcant visible dissolution of VB-201 or reduction in size of the VB-20l pieces. After taking the ﬁnal ical samples the VB-201 pieces were removed from the melt, dried from PEG6000, and weighed. The weight recorded (32 grams) indicated that there was no signiﬁcant change from the initial weight (25 grams), when taking into consideration adherence of some PEG6000 to the solid .

After removing the solid VB-201, the PEG6000 was allowed to cool from 105 °C to 65 °C. There was no itation of material from the mix.

Chemical analysis of the PEG6000 samples showed there was no able VB- 201, indicating that the VB-201 concentration was less than approximately 0.5 mg/gram.

The above results indicate that VB—201 has negligible or no solubility in molten 0, and that a dissolution/precipitation ism is not a cause of the le homogeneity which was observed.

It was then observed that at a temperature of 28-30 °C, the solid , before use or l from containment bags, transformed from a brittle solid into a rubbery, stretchy, cohesive material. -76.. {£39434} it was further observed by careful examination aﬁer encapsulation and removal of remaining niixi that the walls of the filling machine hopper and the thweizer mixer showed dirnpling on the surface, The ance of the walls suggested that particles were left on the wall, although no discrete particles were visible, Although the-mix looks almost transparent, it is possible that the relrac‘tive index of P566086 and VBmiLZOl are sufﬁciently similar such that les are not Visible. ltlﬁdlﬁ} in addition, the high shear head was observed to have rims of material let‘t round its exit slots, a phenomenon which does not usually occur, {seats} The above observations indieate that Vii—320i became soft and sticky when added to molten P7866900 due to the elevated temperature (at least :35 SC) of the molten G required, and that the VB~29l was sufﬁciently soft so as to be extruded front the high shear head, rather than being dispersed. The this then behaved in a manner similar to two inriniseihle liquids. Poor homogeneity of the mixes could have been caused by agglomeration, adhesion and/or separation of the Vii—201 in the molten P336006. {illidl’i} The observation that Vii-2m onns from a e solid such as a free ﬂowing powder into a robbery, stretchy, cohesive material at a temperature ofahont 28—39 0C was eonﬁnned by results obtained irorn differential scanning calorimetry and dynamic n’ieehanieal analysis. {@413} Slow scan ential scanning metry was perl‘hrrned for solid VB—20l as described in the Materials and Methods section. liltidlil} As shown in , an endothennie transition occurred when the Vii—201 was heated to about 25 °C. As r shown therein, a corresponding transition ed during g at a. moderately lower temperature, The lower transition temperature during cooling ts supercooling of the V’B»2lll. {asses} ln order to determine whether the observed transition is due to l of a volatile compound, thennogravinietrie analysis was performed as described in the Materials and Methods section: litlliélZlii As shown in FlG. 6, no significant weight loss is observed when Vis~2tll was heated to about 25 “Ct These results indicate that a phase transition of VB-201 occurs when heating to about 25 °C, and that the observed transition is not due to removal of a volatile compound. £00423] Powder-pocket c mechanical is (DMA) of solid V8420} was performed as bed in the Materials and Methods n.

As shown in MG, 7, the e modulus of VB-201 gradually decreases upon heating above 0 °C. The decrease ends ly at about 30 °C. These ﬁndings indicate that the VB—201 gradually soﬁens upon g above 0 °C, as the VB-201 begins to undergo a phase transition, and that the phase transition is complete at about 30 °C.

As shown in the tan?) value of VB-201 lly increases upon heating above 0 °C, and then falls abruptly at temperatures above about 25 °C. As further shown therein, the temperature at which tan5 is maximal increases as the oscillation frequency is increased.

The above results are consistent with a glass transition (Tg) of an amorphous al, which typically appears as a step-like lowering of the storage modulus when the sample is heated through Tg, and as a large peak in tanS. The frequency-dependency of the temperature at which tan5 is maximal indicates that the phase transition is not a crystalline-to-liquid transition, as such transitions are thermodynamically driven and therefore not associated with frequency dependency. However, glass transitions are kinetic and therefore may be frequency—dependent.

The above differential scanning calorimetry and dynamic mechanical analysis results indicate that VB-20l undergoes a phase transition at about 25 °C, conﬁrming the visual observation that VB-20l is ormed into a rubbery, stretchy, cohesive material at temperatures above about 25 °C.

Mixing of VB—20I with addite'ves and a PEG6000 carrier In order to identify a material that would coat the VB-201 granules and prevent them from sticking together in a mix, ground VB-201 was combined at room temperature with various additives before being mixed with molten PEG6000.

The following combinations were : 1) 2.5 grams of ground VB-201 wetted with 1 gram of Lauroglycol FCC; 2) 2.5 grams of ground VB-201 wetted with 1 gram ofTWEEN 80; 3) 2.5 grams of VB-201 ground er with 5 grams of PEG6000, then wetted with 1 gram of lycol FCC; 4) 2.5 grams of VB-201 ground together with 5 grams of PEG6000, then wetted with 1 gram ofTWEEN 80; ) 2.5 grams of VB—201 ground together with 0.3 gram of magnesium stearate; 6) 2.5 grams of VB—201 ground together with 0.3 gram of magnesium stearate and 5 grams of PEG6000; 7) 1 part VB-201 ground together with 3 parts talc and 2 parts PEG2000; 8) 1 part VB—201 ground together with 3 parts tale; 9) 1 part VB-201 ground together with 2 parts talc; ) 1 part VB-201 ground together with 1 part talc; ll) 1 part VB-201 ground er with 0.5 part talc; and 12) 1 part VB—20l ground together with 0.25 part talc.

Addition of Lauroglycol FCC or TWEEN 80 (with or without PEG6000) resulted in a sticky material, whereas addition of magnesium stearate or talc (with or without PEG6000) resulted in a free-ﬂowing powder.

The combined al was then placed in a sealed amber glass jar, and placed in a stability cabinet at 40 °C. Aﬁer 1 hour at 40 °C, all combinations appeared sticky and/or fused, except for combinations including talc, which remained free-ﬂowing even after being stored for several hours (typically overnight) at 40 °C, although the 1 part VB- 201/0.25 part talc mixture agglomerated following 24 hours at 40 °C.

] The es containing lycol FCC, TWEEN 80 or magnesium stearate were added to 50 grams of molten PEG6000 at 65 °C and high shear mixed. The samples were kept at a temperature of 65 °C and degassed, and were then examined visually. In all of the samples, the VB—20l formed a mass at the surface, and lumps were present.

The s were not used further. {00433} In a similar test, all of the talc-containing powders which were free-ﬂowing at 40 °C were incorporated into molten PEG6000 (at 65 °C) using a spatula. High shear mixing was not used, as the powders were readily distributed in the PEG6000 and appeared to form a m mix. All mixes were prepared at a concentration that would incorporate 20 mg of VB-201 in a total mass of 420 mg.

On being held overnight at 65 °C, the talc slowly d into a thick layer on the bottom. The tale was readily redistributed by brief stirring.

There was no sign of VB-201 on the surface of the PEG6000 after standing, granules of VB-201 were not seen on the vessel walls, nor did the mix have a “wallpaper paste” appearance as was seen in previously prepared VB-201/PEG6000 mixes without talc.

The VB-201/talc combination appeared to slowly settle to the bottom of the PEG6000, although VB-201 without talc rises under identical conditions. This indicates that the talc adhering to the VB-201 increases the average density of the VB-201/talc combination to above the y ofPEG6000.

The abovementioned mixes were used to ﬁll es by hand. The content of capsules prepared using the powder with a 1:1 ratio of VB-201/talc was ed. The e t of VB-201 in these capsules was 100.39 % of the target (range: 97.04 — 103.49 %), with a relative standard deviation of 2.38 %.

These results indicate that VB—201 powder mixed with talc, at a ratio of at least 0.5:1 talc to VB-201, facilitates the preparation of capsules with the desired quantity of VB-201 and with high uniformity between capsules.

EXAMPLE 8 Uniformity over time of Vii-201 capsulesprepared with talc and PEG 6000 ] Two 5 kg technical scale batches of VB-201 capsules were prepared using the incorporation of talc described in e 7.

Talc was incorporated at a ratio of 1:0.5 VB-201 to talc by grinding VB-201 with talc. The ground mix was added to molten PEG6000 at 70 °C and mixed using low shear mixing followed by 10 minutes of high shear mixing at low speed (50 on mixer readout) in a temperature controlled 201 Schweizer mixer. The mix was degassed and encapsulated using a Bosch 1500L ﬁlling machine with paddle mixing (moderate speed) in the hoppers.

] In the ﬁrst technical batch ﬁlling continued over 30 minutes with analytical capsule samples being taken at the beginning, middle and end of the run. The ﬁlling machine speed was 30,300 capsules per hour per hopper. For each , ten capsules were ed for VB-201 content and uniformity of ﬁll. The results are shown in Table 4 below: Table 4: VB-201 content arid uniformity of capsules prepared using 1:0.5 ratio of VB-201 to talein PEG6000 (ﬁrst batch) : Relative .1 Range ] content standard (% oftarget) (% of target) deviation l 3 = ' VVVWVWVLVM ,,,,, ““W‘d . \ Beginning ofrun “1‘02.53 3.68 9743- 10863 """" 95 Middle of run 106.86 5.34 2611324 3 EndofruM689il4176243;10138mi; As shown in Table 4, the content and uniformity of the capsules in the batch were relatively good for capsules from the beginning and middle of the run, both uniformity and accuracy of VB-201 content had deteriorated signiﬁcantly by the end ofthe run.

These s suggest that VB—201 separated and began to sink in the hopper, adding additional VB-201 to the middle section and depleting VB—201 from the upper layer in the hopper. The enriched mix in the middle section was used to ﬁll the capsules from the middle of the run, which had a high VB-201 content, and the depleted mix in the upper layer was used to ﬁll the capsules from the end of the run, which had a low VB-201 content.

In order to conﬁrm these results, a second cal batch was prepared with sub- division of the capsules produced in the batch into two sets of three sub-lots, giving six ts in total. In addition, additional ng was provided to determine whether this eliminated or reduced the apparent tion of VB-201.

For each set of three sub-lots, the ﬁlling machine hopper was ﬁlled with half of the mix described above, and capsules were ﬁlled with one sub-lot containing capsules prepared at the beginning, one sub-lot containing capsules prepared at the middle, and one sub-lot containing capsules ed at the end. The remaining mix was retained, while stirring, in the Schweizer mixer.

Once the ﬁrst set of three sub—lots (numbered sub-lots 1—3) was prepared using almost all of the mix in the hopper, the remaining half of the mix was transferred from the mixer to the hopper, and used to prepare a second set of three sub-lots (numbered sub—lots 4-6), using the same process described herein for the ﬁrst set of three ts.

For both sets, Vigorous paddle mixing (maximum practical speed) was applied to the machine hopper. The speed of mixing of the second set was reduced slightly, as the speed used for the ﬁrst set appeared to be so Vigorous as to slightly impede the ﬂow of mix into the ﬁlling pump (weight had to be continually increased as the hopper emptied).

All of the capsules of the batch were ﬁlled after a 70 minute period. However, a signiﬁcant portion of this time period was due to transfer of the second half of the mix into the hopper. The ﬁlling machine speed was then d slightly to 18,000 capsules per hour per hopper. The ﬁnal dregs remaining after the second set of sub-lots was completed were collected and designated as sub-lot 7.

For each sub-lot, ten es were analyzed for VB—201 content and uniformity of ﬁll. The s are shown in Table 5 below: Table 5: VB-201 t and uniformity of es prepared using 120.5 ratio of VB—201 to taic in PEG6000 (second batch) Sample "WVB-zm (“iiE‘iEEEE content 1 standard (% of target) 3 (% of target) s deviation; eleZ 3.36 égig‘if‘i‘dsi‘ii‘é“ hSublot2(midd_le)w“AM105623W1013810932 SEEZiSi‘EYWE"m"[:"Wiwz.96 é—?§i§§7‘i'67‘85‘W §‘“‘§i15:1‘& 4 ung)“W985 Siibiibf'3"(rniddle) TWB LN“...................... M i. ............. i Sub-lot 6 (end) 94.86 17.05 74.91 ~ 131.10 [Sump l25.89 2 “WW As shown in Table 5, the second batch showed a similar trend to that of the ﬁrst batch. ~82~ The ﬁrst two sub-lots from the ﬁrst set (sub-lots l and 2) exhibited a VB-201 content close to the target, with relatively good uniformity, whereas the last t (sub- lot 3) ted decreased VB-201 content with low mity of content.

Similarly, the second set of sub-lots had a high VB—201 content and moderate uniformity of content in the ﬁrst sub-lot (sub lot 4), a middle t that exhibited a VB- 201 content close to the target, with excellent uniformity, and a third sub lot with a decreased VB—201 content and low uniformity of content. However, the second set was inferior to the ﬁrst set, as t 4 ted signiﬁcantly poorer accuracy and uniformity of content than did the corresponding sub-lot 1, and the low content and mity of sub-lot 6 was lower than even that ofthe corresponding sub—lot 3.

] As further shown in Table 5, the last dregs (sub-lot 7) exhibited a very high VB- 201 content.

The above results indicate that the accuracy and uniformity of VB-201 content decreased as a fuection of time spent by the mix in the e hopper (e.g., sub-lots 3 and 6 were inferior to sub-lots l, 2, 4 and 5).

The above results further indicate that the accuracy and uniformity of VB—201 content decreased as a on of time spent by the mix in the mixer (e.g., sub-lot 7 was inferior to sub-lots 4—6, which were inferior as a whole to sub-lots 1-3).

Thus, the above results suggest that the accuracy and uniformity of VB-201 content decrease over time, regardless ofhow the mix is handled during that time.

EXAMPLE 9 Uniform large scale batches of VB—201 capsules prepared with talc and PEG 6000 As the s presented in Example 8 indicate that the accuracy and uniformity of VB-201 content of capsules decrease over time during preparation of capsules, the following encapsulation process was devised in order to meet pharrnacopoeial standards.

Brieﬂy, capsules were ﬁlled rapidly with the talc-containing mix described hereinabove, and each batch of capsules was initially separated into sub-lots which were analyzed.

Only satisfactory sub-lots were retained, and were then combined to provide a batch for e. Using these procedures, capsules with 20 mg VB-201 and 40 mg VB-201 were prepared, VB-201 was ground with an equal weight of talc using a'bladed bench scale grinder. The ground mix was added to molten PEG6000 at 70 °C and mixed, ed and encapsulated as described in Example 8.

A small quantity of mix (suitable for 20 mg or 40 mg dosage units) was used to set the ﬁll weight, the ﬁlling machine was pumped to dryness, and then all of the mix was transferred and the machine run at full speed (30,600 per hour per pump) without stopping until all the material was encapsulated. The product was collected in ten sub- lots of approximately 1000 capsules each. Filling took 21 and 23 minutes respectively for the 20 mg and 40 mg dosage units.

Batch size for both 20 mg and 40 mg dosage units was targeted at 11,400 capsules, with a 5—5.5 kg l mix quantity.

Ten capsule samples from each sub-lot were taken and analyzed for VB-201 content and mity of ﬁll.

The agreed testing criteria were that every second sub-lot would be analyzed until a sub-lot . The sub-lot immediately preceding the failed sub—lot was then tested.

All able sub-lots up to the ﬁrst sub-lot found unacceptable were combined to produce the batch for further release testing. The results of the sub-lot testing are shown in Table 6 below. The batch Ll value was 5.3 for the 20 mg capsules, and 3.7 for the 40 mg capsules (acceptance value was LISIS).

Table 6: VB-201 content and uniformity of capsules in batch sub-lots for target dosage units of 20 mg and 40 mg VB-201 :........................WWSub-lot N VB—ZOI Relative Range AdEépt content standard (% of target) or (% of target) deviation Reject ‘ 81.1 —101.3 1 Bred , ,, 77:2,:129-1 3 Rejec‘ . WIOOEW; i ' 3. .VVVVVVWVWVWW L__cqzabiaed.7“ WWW.“ i a i‘rAcérést __ “We ‘W 1 i v WW2§:§?“;1WQQ;3WLL3iAﬁcei-‘t Accept iiii2§zmwm W2§;Q* 191:8 ‘ ACCQR......§ 26.7 — 102.4 i Accent ‘ 76 '5 —111.2 I} Re§€§£\xxx\u‘l Accept combined J {@463} As shewn in Table 6, the batches prepared as described above yielded a satisfactory product, and cal hatehes ing in the availability (if 7746 capsules with 2% mg VBJZQ} and 8732 capsules with 40 mg VB—ZOi were obtained after all s, waste and quality contmi sampiing.

This s is repeated with similar yield using a two pump operation, to thereby obtain a batch size twice as large with similar product quality.

I ”—4 VI 1 EXAMPLE 10 Encapsulation 0f VB-20I with PEG 6000, talc and a thixotropic agent {00465} As described in Example 8, the quality of a \Eﬁ-ZOl/PEG6000 mix for encapsulation decreases over time, possibly due to separation of . A thixotropic agent was added to the mix in order to improve mix homogeneity by increasing viscosity and thereby slowing tion processes. Fumed silica was used as a thixotropic agent. £00666} Capsules containing 20 mg, 40 mg or 80 mg VB-201 were ed from a mix containing equal amounts of VB-201 and talc in a mixture of molten PEG6000 with 2.5 % Aerosil® 200 fumed silica (“Aerosil 200”).

PEG6000 was heated in a Schweizer mixer at 70 i 2 °C. The fumed silica was added to the molten PEG6000 and incorporated by high shear mixing. The mixture was then degassed. VB-201 and talc were ground at a 1:1 ratio (by weight) until a uniform powder mixture was obtained. The powder mixture was rapidly transferred into the mixer and stirred thoroughly with a spatula to wet and disperse the powder. The mix was then stirred using a paddle mixer, until all the material appeared uniformly distributed, and then with a high shear mixer, until the mix appeared neous. The mix was then degassed.

The mix was then transferred to a hopper of a Bosch 1500L ﬁlling machine for encapsulation. During encapsulation, the mix was kept at a constant temperature of 70 ﬂ: 2 °C. Capsugel size 0 capsules were ﬁlled with the mix. Each capsule contained 10 mg fumed , 390 mg PEG6000, the ted amount of VB-201 (20, 40 or 80 mg) and an equal amount of tale. The following compositions containing the indicated ingredients were thus prepared: Formulation 1: 20 mg VB-201; 20 mg talc; 10 mg Aerosil 200; 390 mg 0.

Formulation 2: 40 mg VB-201; 40 mg talc; 10 mg Aerosil 200; 390 mg PEG6000. ation 3: 80 mg VB-201; 80 mg talc; 10 mg Aerosil 200; 390 mg PEG6000.

One of every two sub-lots was analyzed. For each tested sub-lot, 6 es were taken for analysis. {@0470} The results of the analysis of 40 mg VB-201 capsules are shown in Table 7 below.

Encapsulation lasted approximately 6 hours. 2012/053533 Table 7: VB-201 content (% of target) and relative standard deviation (RSD) in capsules prepared with talc and a thixotropic agent 3 5 “\\\ \\\\\\\\\\\\\\\\\\\W\\\\\\\\\\ “- ‘9‘ 9966 9849 .....99.-.03 9724 98 14 VB-201 : 99.40 99.65 99.28 99.40 97.96 101.43 101.79 g content“Mg i ____________________ 9 RSD §28%i11%[\xxwwvaV‘Wv‘ws-m'x'xx<1<1<1\<1<1x\\\\\\\\\ \ ' \\\\\\\\ -~ - V ~< - - - - ~ v v - - - - ~ ~ - - - - - - - - - ------ 24%[24%§\m. \“ , Overall RSD= 2.5 % \ux‘uaxuuxxmui As shown in Table 7, the average VB-201 content was extremely close to the target amount (99.84 % 0f the target), with high uniformity (RSD = 2.5 %). As further shown n, there was little change in uniformity over the course of the 6 hours of the manufacturing process.

These results indicate that the thixotropic agent was effective for stabilizing the mix for the duration of the encapsulation and for increasing uniformity of the obtained capsules.

EXAMPLE ll Encapsulation 0f VB-201 with poloxamer 188, talc and a thixotropic agent Peroxide impurities in PEG may potentially cause gelatin crosslinking, which may lead to deterioration of the dissolution performance of the ﬁnished product. The use of poloxamers as alternative carriers to PEG was therefore investigated.

] VB-201 was encapsulated using a thermosoﬁening carrier, talc as an dherent agent, and Aerosil® fumed silica as a thixotropic agent, as described in e 10, except that poloxamer 188 1® F 68) was used instead of PEG6000 as the thermosoftening carrier.

{W475} Capsules containing 20 mg, 40 mg or 80 mg VBQQE were prepared from a mix containing equal amounts ofVB~20l and taic in a mixture Of mniten poloxamer 188 with 3 % Aerosil® i200 fumed silica. {93476} The fumed silica was mixed with moiten poloxamer iSSl VB—ZGl and talc Were ground at a 1:1 ratio {by weight) until a uniferm powder mixture was ed. The mix was then eneapsuiated such that each capsule contained 12 mg fumed : 388 mg poloxamer 183, the indicated amount ofVB~§ZGi and an equai amount of "taic. {($477} An exemplary ﬂow diagram for the V3201 drug product manufacturing process is shown below: W“““': i Poloxamer 188 (Excipient) QC i . . . i VB-201 j approval. D1spense fumed SlllCOl’l sieved API ' QC approval Heat Poloxamer 188 to 70°C i2°C. 1'“ 3 ' Once molten, orate Aerosil :3 co-Blended by means ofhigh shear mixing to VB'201 API l achieve a visually uniform e. With talc : E 3 Incorporate blended drug substance/talc i into Poloxamer/Aerosil mixture to form i uniform mix. i Degas mix 1 Liquid ﬁlling machine Fill required quantity into size hard gelatin capsules VWvﬁrﬁrﬁwwwaw«WW........r_r_rﬁ..“““““““eeeeeeeeeeeq The following formulations were thus prepared: Formulation 4: 40 mg VB—201 with 40 mg talc, 12 mg Aerosil 200 and 388 mg Poloxamer 188.

Formulation 5: 20 mg VB-201 with 20 mg talc, 12 mg Aerosil 200 and 388 mg Poloxamer 188.

Formulation 6: 80 mg VB-201 with 80 mg tale, 12 mg Aerosil 200 and 388 mg Poloxamer 188.

] Each of the above compositions were added to a size 0, white gelatin capsule.

The uniformity of 10 capsules containing 40 mg VB—201 was determined ing to Chapter 2.9.40 of the European copoeia.

The 10 individual capsules ned 105.3 %, 102.8 %, 103.1 %, 106.5 %, 102.1 %, 107.9 %, 102.2 %, 103.0 %, 106.1 % and 102.0 %, of the target amount of VB-201.

The mean VB-201 t was 104.08 % of the target amount (RSD = 2.05 %; L1 value = 7.71).

These results indicate high uniformity of the prepared capsules.

EXAMPLE 12 Encapsulation of VB-20I with poloxamer 188, talc and a thixotropic agent VB—201 was encapsulated using poloxamer 188 as a thermosoftening carrier, talc as an anti-adherent agent, and Aerosil® fumed silica as a thixotropic agent, as described in Example 11, except that reduced amounts of talc and Aerosil 200 were used. Capsules containing 40 mg, 60 mg or 80 mg VB-201 were prepared from a mix containing talc and VB-201 in a weight ratio of talczVB-201 of about 1:4 in a mixture of molten Poloxamer 188 with about 1 % ofAerosil® 200 fumed silica.

The following formulations were thus prepared: Formulation 7: 40 mg VB-201 with 10 mg talc, 4 mg Aerosil 200 and 396mg Poloxamer 188.

Formulation 8: 60 mg VB-201 with 15 mg tale, 4 mg Aerosil 200 and 396 mg mer 188.

Formulation 9: 80 mg VB—201 with 20 mg talc, 4 mg Aerosil 200 and 396 mg Poloxamer 188.

] Each of the above compositions were added to a size 0, white gelatin capsule.

WO 33642 - 39 s L 13 Encapsulation of VB-20I with PEG 6000 and talc (without a ropic agent) As described in Example 10, VB-201 was formulated with PEG6000 as the thermosoftening carrier with the difference that a thixotropic agent was not added. The following formulation containing 40 mg VB-201 was prepared from a mix containing equal amounts ofVB-201 and talc in a mixture of molten PEG6000: Formulation 10: 40 mg VB—201; 40 mg talc; 400 mg PEG6000.

The above composition was added to a size 0, white gelatin capsule.

In a similar fashion the following formulations can be prepared: Formulation 11: 20 mg ; 20 mg talc; 400 mg PEG6000. ation 12: 60 mg VB-201; 60 mg talc; 400 mg PEG6000.

Formulation 13: 80 mg VB—201; 80 mg talc; 400 mg PEG6000.

The above compositions can be added to a size 0, white gelatin capsule.

E. 1. 4 Encapsuiatian 0faxidizedpiwsph{)Iénids with pairwamer 188, 11150 and a tiaixatmpic agent Other compounds urally related to VB-201 may be formulated as described herein for VB-201. Exemplary compounds that can be formulated according to the present disclosure are described in international patent application publication W02010/052718, the disclosure of which is incorporated herein by reference in its entirety. For example, the following compounds can be encapsulated using the procedures and formulations described in Examples 10-13 by replacing VB-201 with one or more of these compounds. For example, each of the below analogs can be encapsulated using poloxamer 188 as a thermosoﬁening carrier, talc as an anti-adherent agent, and Aerosil® fumed silica as a thixotropic agent, e.g., as described in Examples 11 and 12: 1 -hexadecyl(4'-methylcarboxybutyl)—glycero—3 —phosphoethanolamine; l-hexadecyl -methy1carboxybutyl)—glycero-3 -phosphocholine (VB-208); decyl(4'-carboxybutyl)-glycero—3—phosphoethanolamine 2); l-hexadecyl (3'—carboxypropyl)-g1ycerophosphoethanolamine (VB-206); -99" l—hexadecyl (3'—carboxypropyl)-glycero-3 -phosphocholine (VB-205); l-hexadecyl(6'-carboxyhexanyl)-glycero—3 -phosphocholine (VB-203); l-dodecyl-2—(4'-carboxybutyl)-glycero-3 ~phosphocholine (VB-209); l—hexadecyl -2—(4'-carboxybutyl)—glycero—3 hoethanolamine-N-glutaric acid (VBéZHD; l -(1 5'-carboxypentadecyl)(4'-carboxybutyl)—glycero-3 -phosphocholine (VB-2 l 3); l—(l boxypentadecyl)(4'-carboxybutyl)-glycero-3 -phosphoethanolamine (VB-2 l 4); 1—octadecyl(4'-carboxybutyl)-glycero-3 hocholine (VB-215); l-octadecyl-Z-(4'-carboxybutyl)-glycero—3 -phosphoethanolamine (VB-2 l 6); l-hexadecy1(2'-carboxyethyl)-glycero-3 -phosphocholine (VB-21 7); xadecyl(4'-carboxybutyl)-glycero-3 -phosphocholine (l-S-VB-201 ); l—S-hexadecyl-2—(4'—carboxybutyl)-glycero-3 -phosphoethanolamine (l—S-VB-202); -9—hexadecenyl)(4'-cart;oxybutyl)-glycerophosphocholine; l-octyl (4'-carboxybutyl)-glycerophosphocholine (VB-207); l-octyl-2—(4'-carboxybutyl)-glycerophosphoethanolamine; sanyl(4'—carboxybutyl)-glycero-3 -phosphocholine (VB-2 l 9) ; l-eicosanyl (4'—carboxybutyl)-glycero—3 -phosphoethanolamine (VB-220); l-(2'-octyl)dodecyl(4'—carboxybutyl)—glycero-3 -phosphocholine (VB-221 ); l-(2'—octyl)dodecyl(4'-carboxybutyl)-glycero-3 -phosphoethanolamine (VB-222); and l -hexadecy1 (4'-carboxybutyl)-glycero—3 -phosphoserine (VB-223).

EXAMPLE 15 Pharmacokinetic (PK) data of VB-201from Formulations 10 and 4 Pharmacokinetic studies were performed using two different VB-201 formulations (formulation 10 of Example 13 and formulation 4 of Example 11). Single oral doses of 40 mg VB-201 were stered to 26 human subjects for each formulation, and the VB-201 plasma concentrations were measured for a period of 144 hours after dosing for each subject.

As shown in the mean plasma concentrations of VB-201, following stration of formulation 10 and formulation 4 to human subjects peaked at similar times (median Tmaxz 6—6.5 h) and at similar concentrations (mean Cmax: l,290—1,298 ng/mL). In the postabsorption / post-distribution phase, plasma trations of VB—201 declined in a similar mono-exponential fashion (not explicitly shown in . The mean terminal half—lives (02) after stration of both formulations were about 37 hours. VB-201 plasma concentrations were above the assay limit of quantiﬁcation for at least 96 hours in all subjects. [004933 Overall, the plasma pharmacokinetics ing from administration of either formulation were remarkably similar in magnitude and in inter-subject variability of the calculated parameter. The relative bioavailability Fr (AUCOO ratio of formulation 4 to formulation 10) and the Cmax ratio of formulation 4 relative to formulation 10 were 103% and 102%, respectively, and both of these PK ter ratios exhibited similar intersubject variabilites (i.e., l6—20%). Results of statistical evaluations for bioequivalency for 40-mg, single, oral doses of VB-201, when administered as formulation 10 and formulation 4 are shown in Table 8 below: Table 8 Sammaw ﬁfths: 90% confidence als {£33 for the geometrit mean ratio: 03' V3820.1 Cm, and AUC parameters “E1 “amen10 3351:26ng Parameter ’cmax,ng/mL . 18.01 1298.08 230.97 17.79 T a h 3 (500 3 ma“ 6.00 3 1000) 3 NA 6.50 (5.009%00) NA _AUCT,ng-h/mL 53200 12500 23.5 55000 13900 3 25.3 iAUC...,,nglr1/mL 57500 12000 20.8 58900 14500 3 24.6 3CL/F, L/h 3 0.725 0.154 21.3 ‘3 0.725 0.205 3 28.3 32,,1/h ~ 0.0185 0.002415 13.3 0.0186 0.00303 3 16.2 311/3111 3 37.4 1 4.98 13.3 3 37.2 6.07 1 16.3 3qu 3 0.997 3 0.00267 0268 3 0.997 0.00515 0.517 3131, % 3 NA NA NA 1 103 16.6 3 16.2 3cmax Ratio % NA NANA 3 102 20.6 3 3 20,1_______ “ Expressed as median and range. b Expressed as harmonic mean and pseudo rd deviation based on jackknife variance.

NA — Not Applicable.

Table 9 presents results of statistical evaluations for ivalency n the formulation 4 and formulation 10 after 40—mg, single, oral doses of . For Cmax, AUCT, and AUCw, the 90% conﬁdence limits for the geometric mean ratios were within the acceptable bioequivalence range of 80% to 125%, indicating that formulation 4 is bioequivalent to Formulation 10. The statistical power of each of these three separate analyses was greater than 99%.

Table 9 Summary of the 90% Conﬁdence Intervals (CI) for the Geometric Mean Ratio (GMR) of VB-201 Cmax and AUC Parameters Geometric 90% CI for Parameter Formulation Least Squares GMR‘a) Mean ‘ 127056"" 1275.14 100.36 94.01 1Q1Q1191566 13 111Q6.66 (a) GeometncMeanRatioofFormulation 4 (test) andFormulation l0 (reference); sed 55“”a percent. (b)p-value for testing difference in natural log—transformed parameter between Formulation B (test) and Formulation A (reference). (c) Expressed as a t.

] Statistical tests for differences between Formulations 10 and 4 were also performed for Tmax (using the Wilcoxon signed rank test) and for the terminal rate constant (AZ, using the paired t—test). There were no formulation-related statistical difé’erences in either ofthese PK parameters as show; in Table 10 below.

Table 10 Statistical ison of VB-201 Terminal Rate nt (la) and Time to Maximum Observed Plasma Concentration (Tmax) Parameter N Formulation 1 etic Mean (Al) SD 0‘1) or Range 1 p——“value orrrMednan T Wa :7 1111/11 1 26 10 0.0185 0.00246 1 I 26 4 0.0186 000303 0.835 1Tmax, h 2610 gOWOO i 26 4 6.50 5.00-9.00 0.747 " Statlstlcal inferencebetween treatments.

Note: X2 was statistically evaluated by a paired t-test and Tmax was statistically evaluated by the Wilcoxon signed rank test with signiﬁcance set at £0.05 for both.

Although the invention has been described in ction with speciﬁc embodiments thereof, it is evident that many alternatives, modiﬁcations and variations “93.

Wilt be apparent to those skiiieti in the art Accordingly, it is intended to enthrace all such aitematives, modifications and variations that fail within the spirit and broad scope of the appended, eieims. {@9497} Ah pnbhcations, patents and patent applications ned in this speciﬁcation are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent er patent ation was specifically and individnaiiy ted to be ineoiporated herein by reference. in addition, citation or identiﬁcation of any reference in this appiieation shat} not be construed as an admission that seen reference is bie as prior art to the present invention. To the extent that section headings are used; they should not be construed as neeessariiy limiting.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition sing an oxidized phospholipid having a structure ing to Formula (I): wherein R1 is C14-C30 ht or branched alkyl; R3 is selected from phosphorylethanolamine, phosphorylcholine, phosphorylethanolamine-N-glutaric acid, and phosphorylserine; R5 is a member selected from H, a negative charge, and C1-C6 straight or branched alkyl; and X1 is C2-C6 alkylene, a thermosoftening carrier, and an anti-adherent agent, wherein the weight ratio of said anti-adherent agent to said oxidized phospholipid is from about 1:5 to about 5:1.

2. The pharmaceutical composition of claim 1, wherein said thermosoftening r has a melting point from about 40 °C to about 100 °C.

3. The pharmaceutical composition of claim 1 or claim 2, wherein said thermosoftening carrier is selected from the group consisting of a kylene glycol, a polyalkylene glycol derivative, a wax, and ations thereof.

4. The pharmaceutical composition of claim 3, wherein said thermosoftening carrier is a poloxamer.

5. The pharmaceutical composition of claim 4, wherein said poloxamer has a molecular weight from about 2000 to about 18000 daltons.

6. The pharmaceutical composition of claim 5, wherein said poloxamer has a molecular weight from about 7000 to 10000 daltons.

7. The ceutical composition of any one of claims 4 to 6, wherein said poloxamer comprises from about 40 to about 90 weight percent polyethylene glycol.

8. The pharmaceutical composition of claim 4, n said poloxamer is poloxamer 188.

9. The ceutical composition of claim 3, wherein said softening carrier is a polyethylene glycol, a polypropylene glycol, or a co-polymer thereof.

10. The pharmaceutical composition of claim 9, wherein said thermosoftening carrier is a polyethylene glycol.

11. The pharmaceutical composition of claim 10, n said polyethylene glycol has a molecular weight from about 2000 to about 8000 daltons.

12. The pharmaceutical composition of claim 11, wherein said hylene glycol has a molecular weight of about 6000 daltons.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein said antiadherent agent is selected from the group consisting of talc, ium stearate, cellulose, cellulose derivatives, lactose, gelatin, alginates, aluminium hydroxide, magnesium oxide, clays, lgite, ite, carrageenan, copovidone, hectorite, polymethacrylates, sodium docusate, erythritol, povidones, croscarmellose sodium, tes, starches, iron oxide, kaolin, silicates, corn flour, sugars, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, bicarbonates, citrate salts, and titanium dioxide.

14. The pharmaceutical composition of claim 13, wherein said anti-adherent agent is talc.

15. The pharmaceutical composition of claim 13 or claim 14, wherein said weight ratio of said anti-adherent agent to said oxidized olipid is from about 1:4 to about 1:1.

16. The pharmaceutical composition of claim 15, wherein said weight ratio of said antiadherent agent to said oxidized phospholipid is about 1:1.

17. The pharmaceutical composition of claim 15, wherein said weight ratio of said antiadherent agent to said oxidized phospholipid is about 1:4.

18. The pharmaceutical composition of any one of claims 14 to 17, wherein a concentration of said anti-adherent agent in said pharmaceutical composition is in a range of from about 1 to about 30 weight percent relative to the total weight of the pharmaceutical composition.

19. The pharmaceutical composition of any one of claims 1 to 18, further comprising a ropic agent, a gelling agent, or a combination thereof.

20. The pharmaceutical composition of any one of claims 1 to 18, further comprising a thixotropic agent.

21. The ceutical composition of claim 20, wherein said thixotropic agent is ed from the group consisting of fumed silica, kieselguhr, gums, ose derivatives, starches, polymers, emulsifiers, and clay tives, lgite, mica, synthetic magnesium phyllosilicates, layered silicates, modified smectites, hectorite, and sepiolite.

22. The pharmaceutical composition of claim 21, wherein said thixotropic agent is a fumed silica.

23. The pharmaceutical composition of any one of claims 19 to 22, wherein the concentration of said thixotropic agent, relative to the combined weight of said thermosoftening carrier and said thixotropic agent, is from about 0.25 weight percent to about 10 weight percent.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein said pharmaceutical composition is a liquid-fill composition.

25. The pharmaceutical composition of any one of claims 1 to 24, n the oxidized phospholipid is 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201).

26. The pharmaceutical composition of any one of claims 1 to 24, wherein the oxidized phospholipid is 1-hexadecy1(4'-methy1carboxybutyl)-glycerophosphocholine (VB-208), 1-eicosanyl(4'-carboxybutyl)-glycerophosphocholine (VB-219), or 1-(2'- octyl)dodecyl(4'-carboxybutyl)-glycerophosphocholine (VB-221).

27. A process for producing a pharmaceutical composition comprising an oxidized phospholipid having a structure according to Formula (I): wherein R1 is C14-C30 straight or ed alkyl; R3 is selected from phosphorylethanolamine, phosphorylcholine, phosphorylethanolamine-N-glutaric acid, and phosphorylserine; R5 is a member selected from H, a negative charge, and C1-C6 straight or branched alkyl; and X1 is C2-C6 alkylene, a thermosoftening carrier, and an anti-adherent agent, n the weight ratio of said herent agent to said oxidized phospholipid is about 1:5 to about 5:1, the process comprising heating said thermosoftening carrier to a temperature above the g point of said thermosoftening r, milling said oxidized phospholipid with the anti-adherent agent, and contacting the oxidized phospholipid and the anti-adherent agent with the thermosoftening carrier, to thereby obtain said pharmaceutical composition.

28. The process of claim 27, wherein said thermosoftening carrier has a melting point from about 40 °C to about 100 °C.

29. The process of claim 27 or claim 28, wherein said thermosoftening carrier is selected from the group consisting of a polyalkylene glycol, a polyalkylene glycol tive, a wax, or a combination f.

30. The process of claim 29, wherein said thermosoftening carrier is a poloxamer.

31. The process of claim 30, wherein said poloxamer has a molecular weight from about 2000 to about 18000 daltons.

32. The process of claim 31, wherein said poloxamer has a molecular weight from about 7000 to about 10000 daltons.

33. The process of claim 30, wherein said poloxamer comprises from about 40 to about 90 weight percent polyethylene glycol.

34. The process of claim 30, wherein said poloxamer is poloxamer 188.

35. The process of claim 27, wherein said softening carrier is a member selected from polyethylene , polypropylene glycol, and copolymers thereof.

36. The process of claim 35, wherein said thermosoftening carrier is polyethylene glycol.

37. The process of claim 36, wherein said polyethylene glycol has a molecular weight from about 2000 to about 8000 daltons.

38. The process of claim 37, n said polyethylene glycol has a molecular weight of about 6000 to about 8000 daltons.

39. The process of any one of claims 27 to 38, wherein said anti-adherent agent is a member ed from talc, magnesium stearate, cellulose, cellulose derivatives, lactose, gelatin, alginates, ium hydroxide, magnesium oxide, clays, attapulgite, bentonite, carrageenan, copovidone, hectorite, polymethacrylates, sodium docusate, erythritol, povidones, croscarmellose sodium, dextrates, starches, iron oxide, , tes, corn flour, sugars, calcium carbonate, magnesium carbonate, m phosphate, calcium sulfate, bicarbonates, citrate salts, and titanium dioxide.

40. The process of claim 39, n said anti-adherent agent is talc.

41. The process of claim 39 or claim 40, wherein said anti-adherent agent is milled with said oxidized phospholipid in a weight ratio of anti-adherent agent:oxidized phospholipid from about 1:4 to about 1:1.

42. The process of claim 41, wherein said anti-adherent agent is milled with said oxidized phospholipid in a weight ratio of about 1:1.

43. The process of claim 41, wherein said anti-adherent agent is milled with said oxidized phospholipid in a weight ratio of about 1:4.

44. The process of any one of claims 39 to 43, wherein a final concentration of said antiadherent agent in said pharmaceutical composition is from about 1 to about 30 weight percent.

45. The process of any one of claims 27 to 44, further comprising admixing said thermosoftening carrier with a thixotropic agent, a gelling agent, or a combination thereof.

46. The process of any one of claims 27 to 44, further comprising admixing said thermosoftening carrier with a thixotropic agent.

47. The process of claim 46, wherein said admixing said thermosoftening carrier with said thixotropic agent occurs prior to ting said thermosoftening carrier with said ed phospholipid.

48. The process of claim 46 or claim 47, wherein said thixotropic agent is selected from the group consisting of a fumed silica, kieselguhr, gums, cellulose derivatives, starches, polymers, emulsifiers, and clay derivatives, attapulgite, mica, synthetic ium phyllosilicates, layered silicates, ed smectites, hectorite, and sepiolite.

49. The process of claim 48, wherein said thixotropic agent is a fumed silica.

50. The s of any one of claims 46 to 49, wherein the concentration of said thixotropic agent, relative to the combined weight of said thermosoftening carrier and said thixotropic agent, is from about 0.25 weight percent to about 10 weight percent.

51. The process of any one of claims 27 to 50 further comprising g the pharmaceutical composition into a capsule shell to thereby form a capsule.

52. The process of claim 51, wherein said filling is performed at a temperature above the melting point of said thermosoftening r, wherein said pharmaceutical ition forms a solid or semi-solid matrix upon cooling below said melting point.

53. The process of claim 51 or claim 52, wherein said capsule comprises a shell material selected from the group consisting of n, pullulan, starch, and hydroxypropyl methyl ose (HPMC).

54. The process of claim 53, wherein said shell material is gelatin.

55. The process of any one of claims 27 to 54, wherein said oxidized olipid is 1- hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201).

56. The s of any one of claims 27 to 54, wherein said oxidized phospholipid is 1- hexadecy1(4'-methy1carboxybutyl)-glycerophosphocholine (VB-208), 1-eicosanyl (4'-carboxybutyl)-glycerophosphocholine (VB-219), or 1-(2'-octyl)dodecyl(4'- carboxybutyl)-glycerophosphocholine (VB-221).

57. A liquid-fill capsule prepared by the process of any one of claims 51 to 56.

58. A liquid-fill capsule comprising an oxidized olipid having a ure according to Formula (I): wherein R1 is C14-C30 straight or branched alkyl; R3 is ed from phosphorylethanolamine, phosphorylcholine, phosphorylethanolamine-N-glutaric acid, and phosphorylserine; R5 is a member selected from H, a negative charge, and C1-C6 ht or branched alkyl; and X1 is C2-C6 alkylene, the liquid-fill capsule further comprising a solid or semi-solid matrix, said matrix comprising a thermosoftening carrier and the anti-adherent agent, wherein the weight ratio of said antiadherent agent to said oxidized phospholipid is about 1:5 to about 5:1.

59. The capsule of claim 58, wherein said thermosoftening carrier has a melting point in a range from about 40 °C to about 100 °C.

60. The capsule of claim 58 or claim 59, wherein said thermosoftening carrier is selected from the group consisting of a polyalkylene glycol, a polyalkylene glycol tive, a wax, and a combination thereof.

61. The capsule of claim 60, wherein said polyalkylene glycol is selected from the group consisting of a hylene glycol, a polypropylene glycol, and copolymers thereof.

62. The capsule of claim 61, wherein said thermosoftening carrier is a poloxamer.

63. The capsule of claim 62, wherein said poloxamer has a molecular weight in a range of from about 2000 to about 18000 daltons.

64. The capsule of claim 63, wherein said poloxamer has a molecular weight in a range of from about 7000 to about 10000 daltons.

65. The capsule of any one of claims 62 to 64, wherein said poloxamer comprises from about 40 to about 90 weight percent of hylene .

66. The capsule of claim 62, wherein said poloxamer is poloxamer 188.

67. The capsule of claim 61, wherein said thermosoftening carrier is a polyethylene glycol.

68. The capsule of claim 67, wherein said polyethylene glycol has a lar weight in a range of from about 2000 to about 8000 s.

69. The capsule of claim 68, wherein said polyethylene glycol has a lar weight of about 6000 daltons to about 8000 daltons.

70. The capsule of any of claims 58 to 69, wherein said capsule comprises a shell material selected from the group consisting of gelatin, pullulan, starch, and hydroxypropyl methyl cellulose (HPMC).

71. The capsule of claim 70, wherein said shell material is gelatin.

72. The capsule of any one of claims 68 to 71, wherein said anti-adherent agent is selected from the group consisting of talc, magnesium stearate, cellulose, ose tives, lactose, gelatin, alginates, aluminium ide, magnesium oxide, clays, attapulgite, bentonite, carrageenan, copovidone, hectorite, thacrylates, sodium docusate, erythritol, povidones, croscarmellose , dextrates, starches, iron oxide, kaolin, silicates, corn flour, sugars, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, bicarbonates, citrate salts, and titanium dioxide.

73. The capsule of claim 72, wherein said anti-adherent agent is talc.

74. The capsule of claim 72 or claim 73, wherein said weight ratio of said anti-adherent agent to said oxidized phospholipid is in a range of from about 1:4 to about 1:1.

75. The capsule of claim 74, wherein said weight ratio of said anti-adherent agent to said oxidized phospholipid is about 1:1.

76. The capsule of claim 74, wherein said weight ratio of said anti-adherent agent to said oxidized phospholipid is about 1:4.

77. The capsule of any one of claims 72 to 76, wherein a concentration of said anti-adherent agent in said matrix is in a range of from about 1 to about 30 weight percent.

78. The e of any one of claims 58 to 77, wherein said matrix further ses a thixotropic agent, a gelling agent, or a combination thereof.

79. The capsule of any one of claims 58 to 77, wherein said matrix further comprises a thixotropic agent.

80. The capsule of claim 79, wherein said thixotropic agent is selected from the group consisting of a fumed silica, kieselguhr, gums, cellulose derivatives, starches, polymers, fiers, and clay derivatives, lgite, mica, synthetic magnesium phyllosilicates, layered silicates, modified smectites, hectorite, and sepiolite.

81. The capsule of claim 80, wherein said thixotropic agent is a fumed silica.

82. The capsule of any one of claims 79 to 81, wherein the concentration of said thixotropic agent, relative to the combined weight of said thermosoftening carrier and said thixotropic agent, is from about 0.25 weight percent to about 10 weight percent percent.

83. The capsule of any one of claims 58 to 82, comprising from about 1 mg to about 100 mg of ed phospholipid.

84. The e of any one of claims 58 to 83, wherein said oxidized phospholipid is 1- hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201).

85. The capsule of any one of claims 58 to 83, wherein said oxidized phospholipid is 1- hexadecy1(4'-methy1carboxybutyl)-glycerophosphocholine (VB-208), 1-eicosanyl (4'-carboxybutyl)-glycerophosphocholine 9), or 1-(2'-octyl)dodecyl(4'- carboxybutyl)-glycerophosphocholine (VB-221).

86. The capsule of claim 84, comprising from about 20 mg to about 80 mg VB-201.

87. The capsule of claim 84, comprising 40 mg VB-201.

88. The capsule of claim 84, comprising 60 mg VB-201.

89. The capsule of claim 84, comprising 80 mg VB-201.

90. The capsule of any one of claims 58 to 89, being a size 0 capsule.

91. A liquid-fill capsule comprising: a thermosoftening carrier; 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201) from about 1 mg to about 100 mg; an anti-adherent agent at a weight ratio from about 1:5 to 5:1 (anti-adherent agent:VB- 201); and a thixotropic agent at a concentration relative to the combined weight of said thermosoftening r and said thixotropic agent from about 0.25 weight percent to about 10 weight percent.

92. The liquid-fill capsule of claim 91 comprising: a thermosoftening carrier; VB-201 from about 1 mg to about 100 mg; talc at a weight ratio from about 1:5 to 5:1 VB-201); and a thixotropic agent at a concentration relative to the combined weight of said thermosoftening carrier and said thixotropic agent from about 0.5 weight t to about 5 weight t.

93. The liquid-fill capsule of claim 92 comprising: a softening carrier selected from a poloxamer and a polyethylene glycol having a molecular weight from about 6000 to about 8000; VB-201 from about 20 mg to about 100 mg; talc at a weight ratio from about 1:4 to about 1:1 (talc:VB-201); and a thixotropic agent at a tration relative to the ed weight of said thermosoftening carrier and said thixotropic agent from about 0.5 weight percent to about 5 weight percent.

94. The liquid-fill capsule of any one of claims 91 to 93, wherein said thermosoftening carrier is poloxamer 188.

95. The liquid-fill capsule of any one of claims 91 to 94, wherein said thixotropic agent is fumed silicon dioxide.

96. The liquid-fill capsule of claim 58 comprising: 20 mg decyl(4’-carboxybutyl)-glycerophosphocholine (VB-201); 20 mg of an dherent agent; 12 mg of a thixotropic agent; and 388 mg of a thermosoftening carrier.

97. The liquid-fill capsule of claim 96 comprising: 20 mg VB-201; 20 mg talc; 12 mg fumed silica; and 388 mg of poloxamer 188.

98. The -fill capsule of claim 58 comprising: 40 mg 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201); 40 mg of an anti-adherent agent; 12 mg of a thixotropic agent; and 388 mg of a thermosoftening carrier.

99. The liquid-fill e of claim 98 comprising: 40 mg VB-201; 40 mg talc; 12 mg of fumed silicon dioxide; and 388 mg of a poloxamer 188.

100. The liquid-fill capsule of claim 58 comprising: 40 mg 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201); 10 mg of an anti-adherent agent; 4 mg of a thixotropic agent; and 396 mg of a thermosoftening agent.

101. The liquid-fill capsule of claim 100 comprising: 40 mg VB-201; 10 mg talc; 4 mg fumed silicon dioxide; and 396 mg of poloxamer 188.

102. The liquid-fill capsule of claim 58 comprising: 80 mg 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201); 80 mg of an anti-adherent agent; 12 mg of a thixotropic agent; and 388 mg of a thermosoftening carrier.

103. The liquid-fill capsule of claim 102 comprising: 80 mg VB-201; 80 mg talc; 12 mg fumed silica; and 388 mg of poloxamer 188.

104. The liquid-fill capsule of claim 58 comprising: 80 mg 1-hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201); 20 mg of an anti-adherent agent; 4 mg of a thixotropic agent; and 396 mg of a thermosoftening agent.

105. The liquid-fill e of claim 104 comprising: 80 mg VB-201; 20 mg talc; 4 mg fumed silicon dioxide; and 396 mg of mer 188.

106. The pharmaceutical composition of any one of claims 1 to 26, or the liquid-fill e of any one of claims 58 to 105, for use in the treatment of an inflammatory disease or disorder.

107. Use of the pharmaceutical composition of any one of claims 1 to 26, or the liquid-fill e of any of claims 58 to 105 in the manufacture of a ment for treating an inflammatory disease or disorder to a subject in need thereof.

108. The use of claim 107, n said inflammatory disease or disorder is associated with an endogenous oxidized lipid.

109. The use of claim 107, wherein said inflammatory disease or disorder is selected from the group consisting of an idiopathic inflammatory e or disorder, a chronic matory e or disorder, an acute matory disease or disorder, an autoimmune disease or disorder, an infectious e or disorder, an matory ant disease or er, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or er, a peripheral ar disease or disorder, an inflammatory glandular disease or disorder, an matory gastrointestinal disease or disorder, an inflammatory cutaneous disease or disorder, an matory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculo-skeletal disease or disorder, an inflammatory renal e or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, an inflammatory tumor, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunodeficiency disease or disorder, a proliferative disease or disorder and an matory pulmonary disease or disorder.

110. The use of claim 109, wherein said disease or disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, and vascular inflammation.

111. The pharmaceutical composition according to any one of claims 1 to 26, or the liquidfill capsule according to any one of claims 58 to 105, wherein the oxidized olipid is 1- hexadecyl(4’-carboxybutyl)-glycerophosphocholine (VB-201), and wherein the pharmaceutical composition or liquid-fill capsule is formulated for oral administration to a human subject, and to provide a mean maximum plasma concentration (Cmax) of VB-201 from about 1,000 ng/mL to about 1,600 ng/mL.

112. The pharmaceutical composition, or the liquid-fill capsule of claim 111, formulated to provide a median time to mean maximum plasma concentration (Tmax) of VB-201 from about 5 hours (h) to about 10 h.

113. The pharmaceutical composition, or the liquid-fill capsule of claim 111 or claim 112, formulated to provide a plasma concentration time curve with a mean area under the curve (AUC∞) g from about 45,000 to about 70,000 ng h/mL.

114. The pharmaceutical composition, or the -fill capsule of any one of claims 111 to 113, formulated to provide a mean terminal half-live (t½) between about 32 and about 42 hours. Vascular Biogenics Ltd. By the patent attorneys for the applicant CULLENS