AU759001B2

AU759001B2 - Soluble form osmotic dose delivery system

Info

Publication number: AU759001B2
Application number: AU66492/00A
Authority: AU
Inventors: Beth A Burnside; Richard A. Couch; Henry H. Flanner; Edward M. Rudnic; Sandra E. Wassink
Original assignee: Shire Laboratories Inc
Current assignee: Supernus Pharmaceuticals Inc
Priority date: 1996-10-25
Filing date: 2000-10-13
Publication date: 2003-04-03
Anticipated expiration: 2017-10-22
Also published as: AU6649200A

Description

S&F Ref: 458296D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

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Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Shire Laboratories, Inc.

1550 East Gude Drive Rockville Maryland 20850 United States of America Edward M Rudnic, Beth A Burnside, Henry H Flanner, Sandra E Wassink, Richard A Couch Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Soluble Form Osmotic Dose Delivery System 4

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9 The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c SOLUBLE FORM OSMOTIC DOSE DELIVERY SYSTEM The present invention relates to the field of osmotic pharmaceutical dose.

delivery systems and preparations, particularly preparations which can be "administered orally.

Theeuwes et al., U.S. Patent No. 3,916,899, discloses a drug delivery preparation that is said to release the pharmaceutical agent through openings in the wall of the tablet or capsule by the osmotic pressure differential that is set up between the concentration of pharmaceutical agent in the tablet or capsule interior and the exterior fluid environment of the patient when the medicament is taken orally. See, also, Theeuwes et al., U.S. Patent No. 3,845,770 which discloses another preparation for osmotic pressure differential delivery of a pharmaceutical agent. In this original type of approach the interior of the tablet had a hydrophobic core surrounded by a hydrophilic layer within the tablet wall. As such, water entering the tablet remained in the hydrophilic layer and so very little drug was 1- actually released.

It has been believed that this approach did not deliver the pharmaceutical agent as completely or efficiently as had previously been thought. Therefore, a different approach to releasing the pharmaceutical agent was developed. In this approach the interior of the tablet or capsule is characteristically of two layers, one containing the pharmaceutical agent (again to be released through openings in the wall of the tablet or capsule) and the other being a layer of material that sivells when coming into contact with water. These materials that swell or expand to an equilibrium state when exposed to water or other biological fluids are referred to as S"osmopolymers". This volume expansion is used to physically force the pharmaceutical agent out through openings which have been formed in the wall, shell or coating during manufacture. The pharmaceutical agent is primarily released as insoluble particles, which therefore have limited bioavailability. This has commonly been referred to as the "push/pull" approach. See, for example, U.S. Patent Nos.

5,422,123; 4,783,337; 4,765,989; 4,612,008; and 4,327,725. The patent literature has taught that this approach was necessary to deliver adequate doses, at controlled rates and for extended times, of a broad variety of drugs. Other "osmotic delivery systems have also been described. See, for example, U.S. Patent Nos. 4,609,374; 4,036,228; 4,992,278; 4,160,020; and 4,615,698. The osmopolymers used in these 3 types of systems are components whose functions are to swell when they interact with water and aqueous fluids. This swelling effect is defined in these patents as a property of embibing fluid so is to expand to a very high degree, usually exhibiting a 2 to 50 fold volume increase.

Summary of the Invention In arriving at the present invention it has been discovered that it is possible to efficiently deliver therapeutically effective doses, at controlled rates and for extended times, of a broad variety of drugs without the need for polymers that swell or expand within the tablet wall so as to phy sically force the medicament particles out into their intended environment of use. As used herein the term "swell", i.e.

that property which the present invention has been able to avoid, is used so as to have the same definition as in the patents described above. Further, the invention makes it possible to deliver agents which have limited aqueous solubility.

In accordance with the preferred invention, there is provided an osmotic delivery system, preferably in the form of a tablet, which dispenses a therapeutic agent having a limited solubility in water or physiological environments without the 3 use of osmopolymers or swelling agents to deliver the therapeutic agents. Further in accordance with the present invention, the therapeutic agent is incorporated into a composition which is capable of solubilizing the therapeutic agent whereby the therapeutic agent is delivered in a predominantly solubilized form.

In a preferred embodiment, the invention has combined appropriate solubilizing agents and, throughout the composition containing the solubilizing and pharmaceutical agent(s), a "wicking" agent which provides enhanced flow channels for the pharmaceutical agent which has been made predominantly into its solubilized form by the solubilizing agent(s) while still within the tablet or capsule. Thus, the drug is delivered io out through passages in the coating wall by true osmosis predominantly in its solubilized form, rather than by physical force on a particulate form.

According to a first embodiment of the present invention there is provided an osmotic pharmaceutical delivery system comprising a semipermeable wall that :maintains its integrity during pharmaceutical delivery and which has at least one passage :i0 15s therethrough; and a composition within said wall, which composition comprises a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutical agent; (iii) at least one non-swelling osmotic agent and (iv) a nonswelling wicking agent dispersed throughout the composition, said composition being free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered 00 through the passageway by osmosis rather than by another force.

o00°o According to a second embodiment of the present invention there is provided an 000 osmotic pharmaceutical delivery system comprising a semipermeable wall that .i 25 maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; and a composition within said wall, which composition comprises a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutical agent; and (iii) at least one non-swelling osmotic agent, said composition being free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis rather than by another force.

[R:\LIBVV]02995.doc:sxc According to a third embodiment of the present invention there is provided a method of preparing an osmotic pharmaceutical delivery system, comprising: adding water to a composition comprising a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of said pharmaceutical agent; and (iii) at least one non-swelling osmotic agent, wherein said composition is free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis rather than by another force, to provide said composition as a wet granulation mass; drying said wet granulation mass to provide dry granules including components and (iii) hereinabove; compressing said granules into at least one tablet; and coating each of said at least one tablet(s) with a semipermeable wall that :maintains its integrity during pharmaceutical delivery; and 15 providing at least one passage through said semipermeable wall.

Preferred non-swelling solubilizing agents include agents that inhibit crystal formation of the pharmaceutical or otherwise acts by complexation therewith; (ii) a high HLB (hydrophilic-lipophilic balance) micelle-forming surfactant, particularly non-ionic and/or anionic surfactants; (iii) citrate esters; and combinations thereof, particularly combinations of complexation agents with anionic surfactants. Preferred non-swelling osmotic agents include sugars with ten or fewer rings, preferably five or fewer rings and most preferably two rings. Examples include fructose, lactose, xylitol and sorbitol.

P ein ll *Preferred wicking agents include colloidal .o0.

0.

silicon dioxide and polyvinyl pyrrolidone and sodium lauryl sulfate can also function as wicking agents.

Brief Description of the Drawings The invention will now be further described by reference to a brief description of each of the accompanying drawings. The brief description and the drawings are in no way a limitation of the invention.

Figure 1A schematically illustrates the elementary osmotic dose delivery system of the prior art.

Figure 1B schematically illustrates the osmotic dose delivery system of the prior art.

Figure 2 schematically illustrates the osmotic dose delivery system of the \C present invention.

Figure 3 diagramatically shows the percent of nifedipine released by dosage forms of the invention containing formulations 1G (30 mg); 1C (30 mg); as shown on Table 1 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Figure 4 diagramatically shows the percent of nifedipine released by dosage forms of the invention containing formulations 2B (47 mg); 2C (47 mg); and 2D (47 mg) as shown on Table 2 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Figure 5 diagramatically shows the percent of nifedipine released by dosage forms of the invention containing formulations 3C (30 mg); 3H (30 mg); as shown on Table 3 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

2-S Figure 6 diagramatically shows the percent of nifedipine released by forms of the invention containing formulations 4H (30 mg); 4C (90 mg); as shown on Table 4 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Figure 7 diagramatically shows the percent of nifedipine released by forms of the invention containing formulations 5G (60 mg); 5H (60 mg); as shown on Table 5 as compared to Procardia XL®(Pfizer, Inc.; 60 mg).

Figure 8 diagramatically shows the percent of nifedipine released by forms of the invention containing formulations 6E (60 mg); 6F (60 mg); as shown on Table 6 as compared to Procardia XL®(Pfizer, Inc., New York; 60 mg).

Figure 9 diagramatically shows the percent of nifedipine released by forms of the invention containing formulation 6F (60 mg) with a 1% ethylcellulose seal coat as shown on Table 6 as compared to Procardia XL®(Pfizer, Inc., New York; mg).

Detailed Description of Preferred Embodiments The invention will now be described in more detail with respect to numerous \C embodiments and examples in support thereof.

The semipermeable wall of the elementry osmotic delivery system is composed of a polymeric material cast or sprayed onto the tablet to give a 2 15 coating weight. One example of a polymeric material includes, but is not limited to, cellulose acetate. The use of such polymeric material requires plasticizers for \S increased flexibility, durability, and stability. In the case of cellulose acetate, examples of suitable plasticizers are triethyl citrate (TEC), propylene glycol (PG), a mixture of TEC and PG in ratios ranging from 25% TEC plus 75% PG to TEC plus 25 PG, Tween 80 or other polyoxyethylene sorbitan esters, triacetin, diethyl phthalate, polyethylene glycol, mineral oil, tributyl sebacate, and glycerol.

2-0 The plasticizers are included as a weight ratio of cellulose acetate suitable for creating a semipermeable wall to achieve retainment of the bioactive substance while permitting water permeation to the core of the tablet.

The semi-permeable wall of the tablet can contain at least one passageway communicating the contents of the core with the exterior of the device, delivering the beneficial drug through the passageways from the elementary osmotic device.

The size of an individual passageway can range from 100 microns to 1000 microns, more preferred 300 to 900 microns, most preferred 500 to 850 microns. One or multiple passageways can be present to communicate the contents with the exterior of the tablet.

A wicking agent, defined as any material with the ability to draw water into the porous network of a delivery device is included in the core of this type of tablet S- formulation. A wicking agent can do this with or without swelling, but those used in the present invention are non-swelling wicking agents. Some materials can both wick water and swell, others can function as wicking agents only. The wicking agents are characterized by having the ability to undergo physisorption with water.

Physisorption is defined as a form of adsorption in which the solvent molecules can I\ loosely adhere to surfaces of the wicking agent via van der Waals interaction between the surface of the wicking agent and the adsorbed molecule. In the case of a drug delivery device, the adsorbed molecule is primarily water or other biological fluid which is mainly composed of water. A wicking agent that attracts water willultimately have a volume that is essentially composed of the volume of wicking agent and the volume of water attracted to it. A material that swells will have a volume that is esentially composed of the volume of wicking/swelling agent, the volume of water attracted to it, and an additional volume created by steric and molecular S forces.

The wicking agent included in the formulations described in this invention 20 creates channels or pores in the core of the tablet. This facilitates the channeling of water molecules through the core of the tablet by physisorption. The function of the wicking agent is to carry water to surfaces inside the core of the tablet, thereby creating channels or a network of increased surface area. For the purposes of this invention, these wicking agents do not swell to any appreciable degree. For ZS bioactive agents with low solubility in water, the wicking agent aids in the delivery of partially solubilized bioactive agent through the passageway in the semipermeable coating. Materials suitable for acting as wicking agents include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinyl pyrrolidone, m-pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene. Materials particularly suitable for the purpose of this invention include the non-swellable wicking agent, examples of which are sodium lauryl sulfate, colloidal silicon dioxide, and low molecular weight polyvinylpyrrolidone.

Preferred non-swelling solubilizing agents include agents that inhibit crystal formation of the pharmaceutical or otherwise acts by complexation therewith; (ii) a high HLB (hydrophilic-lipophilic balance) micelle-forming surfactant, particularly anionic surfactants; (iii) citrate esters; and combinations thereof, particularly combinations of complexation agents with anionic surfactants. Examples of the agents that inhibit crystal formation of the pharmaceutical or otherwise acts by complexation therewith include polyvinylpyrrolidone, polyethyleneglycol VO (particularly PEG 8 0 0 0 3 and 6 cyclodextrins and other modified cyclodextrins.

Examples of the high HLB, micelle-forming surfactants include non-ionic and/or anionic surfactants, such as Tween 20, Tween 60 or Tween 80; polyoxyethylene or polyethylene-containing surfactants, or other long chain anionic surfactants, particularly sodium lauryl sulfate. Examples of citrate ester derivatives that are preferred are the alkyl esters, particularly triethyl citrate. Combinations of these types of non-swelling solubilizing agents are especially effective. Preferred among such types of combinations are combinations of complexation agents and anionic surfactants. Particularly preferred examples of such combinations are polyvinylpyrrolidone with sodium lauryl sulfate and polyethyleneglycol with sodium lauryl sulfate.

Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium, stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, and hydrogenated vegetable oil.

These lubricants should be present in amounts from 0.1-10% with a preferred range of 0.3-3.0% Preferred lubricants for tableting include but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, stearic acid, glycerol behenate, sodium lauryl sulfate, polyethylene glycol and hydrogenated vegetable oil.

Particularly preferred lubricants are those which are soluble in water or gastric fluids or are readily emulsified. Combinations of lubricants are especially effective.

Lubricant combinations which are preferred are a small amount of hydrophobic lubricant with a larger amount of soluble or emulsifiable lubricant. The rate of use for lubricants extends from 0.25 to 10.0% with a preferred range of 1 to 4%.

The delivery system of the invention can be used to provide controlled release of any of a broad variety of therapeutically active agents. Examples include the following: cough suppressants, such as dextromethorphan hydrobromide and codeine; antihistamines such as chlorpheniramine maleate, brompheniramine maleate, loratidine, astemizole, diclofenac sodium and terfenadine; decongestants such as pseudoephedrine and phenylephrine; antihypertensives such as nifedipine, verapamil, IO enalapril and salts thereof, metoprolol, metoprolol succinate, metoprolol fumarate, metoprolol tartarate; calcium channel blockers such as verapamil, diltiazam, nifedipine, nimodipine, felodipine, nicardipine, isradipine and amlodipine; antidiabetic agents such as glipizide and ibromectin; proton pump inhibitors such asomeprazole; H2 receptor antagonists such as cimetidine, ranitidine, famotidine, \S nizatidine; carbamazepine; anti-Parkinson agents such as selegiline, carbidopa/levodopa, pergolide, bromocriptine, amantadine, trihexyphenidyl HC1; antiviral agents including antiherpesvirus agents such as acyclovir, famciclovir, foscarnet, ganciclovir; antiretroviral agents such as didanosine, stavudine, zalcitabine, zidovudine; and others such as amantadine, interferon alpha, ribavirin, ZO rimantadine; and other therapeutic agents such as cimetidine, propiomazine, phenytoin, tacrine, propiazam, proplazam. The system of the present invention is particularly applicable to therapeutic agents which are insoluble or poorly soluble in water or aqueous environments at physiological pH.

In a preferred embodiment the system of the present invention is employed 2~ for dispensing nifedipine. In such a preferred embodiment, the composition is free of agents which prevents solubilization of the nifedipine such as the Group I and Group II metals and salts thereof. In such compositions preferred osmotic agents are sugars.

Example 1 Nifedipine Granulation/Tableting/Coating (TEC) or another suitable wetting agent is added to enough water to produce a good dispersion which will atomize and pump well. Add between 50 to 100% of the PEG 8000. Next add between 50 to 100% of the nifedipine to the dispersion.

Finally add between 25 to 75% of the Cab-o-Sil® to the binder dispersion. Mix for minutes before spraying. Also, other ingredients can be added to or removed from the dispersion as necessary. A dispersion is also not necessary, the binder may be a solution of PVP, PEG, surgar or other binder. The solution may be aqueous \G or organic. In some cases, a hot melt method of granulating may be preferred. In this case, the binder may be a molten wax, wax mixture or other material.

Charge a fluid bed bowl with osmagents (xylitol, sorbitol lactose, fructose, inositol, etc.). Add between 50 to 100% of the SLS, add the remaining PEG 8000; and add between 50-100% of the PVP K-25, add all or the remaining amount of Nitedipine and other ingredients as required.

Spray the dispersion onto the powder bed with a spray rate of 20-50 g/min which will produce granules of an adequate size for tableting. (Spray rate will vary with batch size.) Inlet air flow rate and temperature are adjusted to keep powder bed from over-granulating or becoming overly wet. (Typical range 100-250 CMH and ZO 40-60*C, depending on batch size.) Discharge granulation and add remaining sodium lauryl sulfate (SLS), polyvinyl pyrrolidone (PVP K-25), osmagents, polyethylene glycol (PEG), nifedipine and Cab-o-Sil® (colloidal silicon dioxide; Cabot Corporation) and mix in a V-blender or appropriate mixer for 2-5 minutes or as necessary. Add suitable lubricant such 2S as Magnesium Stearate (approximately and blend 2-5 minutes or as necessary.

Discharge final blend from mixer and tablet on suitable tablet press. Coat tablets in pan coater or fluid bed dryer with spray rate of 30-100 g/min or higher (depending on batch size). The coating solution is prepared by dissolving cellulose Acetate, NF (National Formulary) in Acetone or other suitable solvent then adding 25-45 plasticizers such as TEC or PG or mixture thereof.

Process may also be done by direct compression, high shear granulation, dry compression or slugging.

In some cases it may be desirable to modify the solubility characteristics of the osmagents, solubilizers, granulation or other ingredient to achieve a desired release profile.

One method for modifying the release profile is to use a hydrophobic coating method. Initially, all ingredients could be granulated together with a 0-20% PVP LU K 25 or PEG 8000 or other binder aqueous or organic solution to ensure that drug, sugars, and solubilizers are evenly distributed throughout the granules. Following this procedure, a coating agent such as hydrogenated castor oil, hydrogenated vegetable oil, type I, ethyl cellulose, glyceryl monostearate, Gelucire® or carnauba wax at 1-20% of the total formulation weight could be applied to 5-50% of the total granulation. The coating agent may be applied in a fluid bed by top spray, wurtser column coating, or rotor application; a pan coater equipped with a screen for coating granules may also be utilized. The hydrophobic agent could be applied in a melted state or dissolved in a suitable solvent in which it would be sprayed onto the granules. Both parts of the granulation, immediate and sustained release, could then 2-0 be blended thoroughly by using a V-Blender before tableting.

Alternatively, the method presented above may be applied to a component or combination of components of the formulation. One or more of the osmagents may be granulated alone or in combination with other osmagents, solubilizers or other components of the core. These granules may then be coated alone or in combination ZG with any other component of the core with the materials and methods described above. The coated granules can then be added to the rest of formulation by dry blending, or they may actually be granulated with the remainder of the formulation.

Alternatiavely, a hydrophobic granulation method may be utilized. In this method powdered wax is mixed together with the portion of the granulation to be coated (in the same percentage ranges already stated). Non-powdered wax may be utilized by milling the wax to a fine particle size. Wax mixtures may be formed by melting the wax, adding the desired component, allowing the mixture to congeal and then screening or milling the wax mixture to a fine particle size. The powdered wax or wax mixture is then added to the fluid bed with the portion of the granulation to be coated. The materials are granulated by increasing and controlling the inlet temperatures of the fluid bed (inlet temperature 60-80 0 C, outlet temperature 1C 60 0 to cause the melting/congealing steps involved in the granulation process.

in other instances a jacketed device could be used to granulate. Here, however, the temperature ranges would apply to the substance used in heating and cooling the device, such as steam, hot oil or water.

For sustained release agents which are not waxes, the granulation process can 000* be carried out utilizing standard granulation techniques such as aqueous moist o~oo granulation or solvent granulation (in the same percentage ranges already stated).

0 The sustained release agent may be dissolved or suspended in the granulating fluid or it may be dispersed with the powders to be granulated. The granules are formed 0 and dried and finally added to the remainder of the formulation.

2060 Again, the above granulation techniques may be applied to a portion of the 0 entire formulation or any component or mixture of components in the formulation.

0* The sustained release granules may then be combined with the remainder of the formulation by techniques previously discussed.

Finally, a matrix technique may be utilized. This technique involves adding 27z> a powdered wax at 5-30% of the total formulation weight, such as hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, GelucireD, PEG 8000 or any other non-swellable matrix forming agent known to one skilled in the art to the formulation. The wax may be granulated with any component or combination of components of the formulation with a 0-20% PVP K25 or PEG 8000 or other binder SL solution, or a roller compaction or slugging method may be used in the formation -12of the granules. The granules are then added to the remainder of the formulation using the methods stated earlier.

The modified release osmagents, solubilizers or granulation may then be tableted after addition of a suitable lubricant. A single layer tablet would have all components of the formulation blended together and compressed. One or more holes may be provided to give the proper release. One or more holes may be provided on the tablet. It may be beneficial for a tablet to have a hole on both sides of the tablet so that the optimum release rate is achieved. One or more holes may be provided to achieve the desired release characteristics.

\C It is possible that any of the previously discussed excipients in combination with the tablet core may lower the melting point. The temperatures that the tablet should be exposed to in an aqueous color coating process may be extreme enough 60°C) to partially melt the core and change the physico-chemical behavior of the tablet in dissolution or stability. To avoid this change, a solvent-based color coat was formulated at Shire Laboratories Inc., consisting of a 1:1 mixture of hydroxypropyl cellulose and HPMC, and 1% of a colored aluminum lake dispersed in a 70:30 IPA:Water solution. Because the color coat is solvent-based, the temperature that the tablets will be exposed to in the coating process is significantly lower (-35-40 0

C).

A one to two hour delay before the onset of dissolution may be beneficial.

In order to provide this lag time a seal coat may be added to the tablet. The seal coat should provide a water impermeable barrier for no longer than two hours.

Some polymers which would providethis type of coating include ethylcellulose, shellac, Eudragit RS. Other ingredients may be added to the polymers in order to 2 modify the coating to achieve the desired lag time. A 1-10% weight gain should be applied to the tablets. The coating is applied as an aqueous or organic solvent solution or dispersion. The coating is typically applied in a coating pan or fluid bed equipped with a wurster column.

-13- 9 *9 *9 Examp~le 2 Nifedipine Forulations The following are examples of formulations Of the single, homogeneous composition within the tablet wall of the dosage form of the invention.

Table 1 1ncretaens IA 1B IC ID IE IF IG I Fructose 43.5 21.5 49.6 44.5 37.2 20.5 18.5 Lactose 315 17 18 17 17 17 32 17 17 Sodbiol 43.5 21 21 19 PVPK2S 15 15 15 12.7 15 12.5 15 to PEG8000 10 10 10 (50) 8.5 10 (50) 8.4 10 (50) 20 (1041 (4.20) TEC I 1' 1' 1.7* 1* 0.84' I' SLS 3 3 3 3 3 1.95 3 3 (1.25') Cab-o-Sil* 2.0 1.0 1 0.92 1 1.1 1 5) 5) (0.30) (0.42) 5) Nifedipine 8' 8' 6.80 6.7 go 8' Mg Stc 0.5 0.5 0.5 0.5 0.5 0.5 0.5 3 K Sorbate 3 TOWa 100 100 100 100 100 100 100 100 Indicates in dzSPerSi1 Table 2 Ingredients 2A 2 C2D

ZE

Fructose Lactose 315 Sorbitol 15.5 15.5 5.5 23.25 12.5 XylIuoI 23.25 23.25 23.25 15.5 Mannitol PVPK-12PF 35 35 35 35 PEG8000 10(5) 10* 20(10') 10(5) 10(5) SiS 5 5 5 5 Cab-o-SiI' 1(0.50) 1(0.5) 1(0. Nifedipine 8.25' 8.250 8.25 8.25' TEC I'IsI'1 Mg Sta-tc I

II

TotaW0 100 100 100 100 Inatcates in dispersion Table 3 [ngredients I 3A 3B 3C 3D 3E 3F 3G 3IT Fructose 21.5 20.5 19.5 16.5 18.5 17.5 17.5 16.5 Lactose 15 17 17 17 17 17 17 17 14.5 Sorbicol 23 21 23 21 21 20 20 18.5 15 15 15 15 iS 15 15 PEG8000 10 10 10 10 tO0(5-) 10 10 10 TEC I '1 SLS 3 3 5 5 3555 Cab-o-Sil 1(0.50) 1(0.50) Nifedipine 8* 8* 8' 80 8' 8* 80 8' Mg Stearatc 0.5 0.5 0.5 0.5 0.5 0.5 0.5 K Sorbate 3

EL-

Inositol 100 ToWa 100 100 100 t00 100 100 100 100 indicates in d!sprsion Polyethylene glycol castor oil derivative (other suitable derivatives of castor oil are disclosed by the International Cosmetic Ingredient Dictionary (5th Cosmetic Fragrance and Toiletry Association. Washington. D.C. (1993), e.g. at pages 479-481) Table 4

C

a a aCt h~rde~ A 45 4C :AD 4E AG 411: Fructose 13 13 4.5 17.5 18.5 15.25 15.675 15.675 Lactose 315 10.5 10.5 4 17 17.5 30 16.15 16.15 Sorbitol 16 16 6 20 22 19.95 19.95 35 15 35 15 15 15 14.25 14.25 PEG8000 10 35 35 10 10 10 9.5(4.75*) 9.5(4.75*) TEC I1* 1* 1* 6 0.95* 0.95* SLS 5 5 5 5 5 5 5 Cab-o-Sil 1.0 1.0 1.0 1.0 1 .975 .975 5* (0.475*) 475) Nifedipine 8* 8 8 8 8 8.25 7.6* 7.6* Mg Stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 K Sorbate 4.75 4.75 Glycerol Cremophor

EL

Inositol Calcium Sulfate Total 100 100 100 100 100 100 100 100 Indicates in dispersion Table AnrdensS 5C 5SE S SG: SH Xylitol 15.5 5 32.5 31.5 24.0 16.9 Sorbitol 15.0 5 15.5 15.5 15 18.75 Fructose 7.5 17.5 Lactose PEG 8000 10 10 20 10 10(5* PVP K-25 35 35 15 15 35 35 50 35(5*) TEC 1 1 1 1.0 1* 1* 1* Cab-o-SiIg 1.0 1 1 1 2 Nifedipine 17 25 25 50.0 10 10 10.1 8.25 Mg Stearate, 0.5 0.5 0.5 0.5 1 1 1 1 S LS 5.0 5 5 3 5 5 K Sorbate 3 Total 100 100 100 100 100 100 100 100 Indicates in dfpersion p a.

p Table 6 Nifedipine Formulations 6A 6B 6C 61) 6E 6F 6G 6H Xylitol 27.5 27.5 25.5 30.8 28.5 32.5 34.5 25.5 Sorbitol 25 25 26 28.5 29 30 30 26 SLS 5 5 4.5 4.8 5 5 5 PVP K25 15(3*) 15(3*) 13.5 14.2 15(3*) 15(3*) 5 13.5 Nifedipine 15 15 18 14.2 20 15 17.5 18 Stearic 1 11 1 1 1 1 2 1 Acid Mag. 1 1 1 1 1 1 0.5 1 Stearate Cab-o-sil* 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Glycerol Behenate Stearic Acid (Binder) Stearic 10 Acid Coated Xylitol Stearic Acid Coated 6E -19- Example 3 Comparative Percentage of Nifedipine Release This example reports experiments which compared the percentage of nifedipine released by certain of the above formulations in dose delivery forms of the invention as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Materials and Methods Dose delivery forms of the invention are placed in a Vankel Dissolution Apparatus containing simulated gastric fluid without enzymes and dissoluted for 20 to 24 hours.

Samples of the dissolution media are taken periodically and analyzed by high performance liquid chromatography for nifedipine concentration. The calculated percent release is plotted .versus time. Dose delivery forms of the invention and procardia XL tablets are tested in the same manner to produce effective comparisons.

Results Figure 3 diagramatically shows the percent of nifedipine released by dosage forms of the invention containing formulations 1G (30 mg); 1C (30 mg); as shown on Table 1 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Figure 6 diagramatically shows the percent of nifedipine released by forms of the invention containing formulations 4H (30 mg); 4C (90 mg); as shown on Table 4 as compared to Procardia XL®(Pfizer, Inc.; 30 mg).

Figure 9 diagramatically shows the percent of nifedipine released by forms of the invention containing formulation 6F (60 mg) with a 1% ethylcellulose seal coat as shown on Table 6 as compared to Procardia XL®(Pfizer, Inc., New York; 60 mg).

S *o o* -21-

Claims

1. An osmotic pharmaceutical delivery system comprising a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; and a composition within said wall, which composition comprises a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutical agent; (iii) at least one non-swelling osmotic agent and (iv) a non-swelling wicking agent dispersed throughout the composition, said composition being free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis rather than by another force.

2. The pharmaceutical delivery system of claim 1 wherein said at least one non- swelling solubilizing agent is selected from the group consisting of agents that inhibit crystal formation of the pharmaceutical; (ii) a surfactant; (iii) citrate esters; and (iv) 15 combinations thereof.

3. The pharmaceutical delivery system of claim 2 wherein said non-swelling solubilizing agent comprising the combination of at least one agent that inhibits crystal formation of the pharmaceutical with at least one surfactant.

4. The pharmaceutical delivery system of any one of claims 1 to 3 wherein said semipermeable wall comprises cellulose acetate and triethyl citrate.

5. The pharmaceutical delivery system of claim 1 wherein said at least one solubilizing agent is selected from the group consisting of sodium lauryl sulfate and a low molecular weight polyvinylpyrrolidone, and combinations thereof. The pharmaceutical delivery system of claim 5 wherein said at least one S: 25 solubilizing agent is a combination of sodium lauryl sulfate and a low molecular weight polyvinylpyrrolidone.

7. The pharmaceutical delivery system of any one of claims 1 to 6 wherein the osmotic agent is selected from the group consisting of xylitol and mannitol.

8. The pharmaceutical delivery system of any one of claims 1 to 7 wherein the pharmaceutical agent has limited aqueous solubility at physiological pH.

9. The pharmaceutical delivery system of claim 8 wherein the pharmaceutical agent is nifedipine. 23 The pharmaceutical delivery system of any one of claims 1 to 9 wherein the composition within said wall further comprises a lubricant.

11. The pharmaceutical delivery system of claim 1 wherein the pharmaceutical agent is nifedipine; (ii) the at least one non-swelling solubilizing agent is polyvinylpyrrolidone; and (iii) the at least one non-swelling osmotic agent comprises at least one sugar.

12. The pharmaceutical delivery system of claim 11 wherein the at least one non- swelling solubilizing agent is a low molecular weight polyvinylpyrrolidone.

13. The pharmaceutical delivery system of claim 11 which further comprises a high hydrophilic-lipophilic balance micelle-forming surfactant as a non-swelling solubilizing agent.

14. The pharmaceutical delivery system of claim 13 wherein the surfactant is sodium lauryl sulfate.

15. The pharmaceutical delivery system of any one of claims 11 to 14, wherein 15 the at least one sugar is xylitol.

16. An osmotic pharmaceutical delivery system comprising a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; and a composition within said wall, which composition comprises a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutical agent; and (iii) at least one non-swelling osmotic agent, said composition being free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis rather than by another force. 25 17. The pharmaceutical delivery system of any one of claims 1 to 16 wherein the pharmaceutical agent is released through said at least one passage.

18. The pharmaceutical delivery system of any one of claims 1 to 17 wherein the wall has a plurality of passages therethrough.

19. The pharmaceutical delivery system of claim 1 wherein the non-swelling solubilizing agent is selected from the group consisting of agents that inhibit crystal formation of the pharmaceutical or otherwise act by complexation therewith; (ii) a high HLB (hydrophilic-lipophilic balance) micelle-forming surfactant, (iii) citrate esters; and I R4 ombinations thereof. ,\lBW]02995.doc:sxc An osmotic pharmaceutical delivery system comprising a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; and a composition within said wall, which composition comprises a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutical agent; (iii) at least one non-swelling osmotic agent and (iv) a non-swelling wicking agent dispersed throughout the composition, said composition being free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis rather than by another force, the system being substantially as hereinbefore described with reference to Figure 2.

21. An osmotic pharmaceutical delivery system according to claim 1 or 16 wherein the pharmacological agent is nifedipine, substantially as hereinbefore described with reference to Example 1 or Example 2. 15 22. A method of preparing an osmotic pharmaceutical delivery system, comprising: oooQ adding water to a composition comprising a pharmaceutical agent that has a limited solubility in water or physiological environments; (ii) at least one non-swelling solubilizing agent which enhances the solubility of said pharmaceutical agent; and (iii) at least one non-swelling osmotic agent, wherein said composition is free of an agent that provides a physical force other than by osmotic pressure for delivering the pharmaceutical agent whereby the pharmaceutical agent is delivered through the passageway by osmosis .°oooo rather than by another force, to provide said composition as a wet granulation mass; drying said wet granulation mass to provide dry granules including S 25 components and (iii) hereinabove; compressing said granules into at least one tablet; and coating each of said at least one tablet(s) with a semipermeable wall that maintains its integrity during pharmaceutical delivery; and providing at least one passage through said semipermeable wall.

23. The method of claim 22 wherein said at least one non-swelling solubilizing agent is selected from the group consisting of agents that inhibit crystal formation of the pharmaceutical; (ii) a surfactant; (iii) citrate esters; and (iv) combinations thereof. [R:\LIVVBW]02995.doc:sxc

24. The method of claim 23 wherein said non-swelling solubilizing agent comprises the combination of at least one agent that inhibits crystal formation of the pharmaceutical with at least one surfactant. The method of claim 22 wherein said semipermeable wall comprises cellulose acetate and triethyl citrate.

26. The method of claim 22 wherein said at least one solubilizing agent is selected from the group consisting of sodium lauryl sulfate and a low molecular weight polyvinylpyrrolidone, and combinations thereof.

27. The method of claim 22 wherein the pharmaceutical agent has limited 0o aqueous solubility at physiological pH.

28. The method of claim 27 wherein the pharmaceutical agent is nifedipine.

29. The method of claim 22 wherein the composition within said wall further comprises a lubricant.

30. The method of claim 22 wherein the at least one non-swelling osmotic agent 15 is a sugar. *o *31. The method of claim 30 wherein the sugar has no more than ten rings.

32. The method of claim 31 wherein the sugar has no more than five rings.

33. The method of claim 32 wherein the sugar is selected from the group consisting of monosaccharides, disaccharides, and trisaccharides.

34. The method of claim 32 wherein the sugar is selected from the group consisting of fructose, lactose, xylitol, inositol, and sorbitol. The method of claim 22 wherein said pharmaceutical agent is glipizide.

36. The method of claim 35 wherein the pharmaceutical agent is glipizide; (ii) the at least one non-swelling solubilizing agent is sodium lauryl sulfate; and (iii) the at 25 least one non-swelling osmotic agent comprises at least one sugar.

37. A method of preparing an osmotic pharmaceutical delivery system according to claim 1 or 16 substantially as hereinbefore described with reference to Example 1 or Example 2. Dated 22 January, 2003 Shire Laboratories, Inc. Patent Attorneys for the Applicant/Nominated Person RZV SPRUSON FERGUSON