WO2026041873A1 - Compositions for systemic administration - Google Patents

Abstract

A composition suitable for administration via the gastrointestinal tract or the respiratory tract, wherein the composition comprises a deep eutectic mixture, a wax and a biologically active agent.

Description

COMPOSITIONS FOR SYSTEMIC ADMINISTRATION

Field of the Invention

The present invention relates to compositions comprising a deep eutectic solvent (DES), a wax and a biologically active agent. The present invention also relates to a method of preparing the compositions.

Background of the Invention

The formulation of medicaments is a common issue in pharmaceutical development, being pivotal in relation to several aspects of a drug’s utility.

A common challenge with many drugs is their poor absorption due to inadequate solubility, necessitating large doses. Additionally, many medications degrade rapidly in the aqueous and/or acidic environments present in the human body and/or require frequent administration due to short half-life. These issues make the maintenance of consistent drug levels within the body difficult, meaning that efficacy can be compromised, the risk of side effects can increase, and patient adherence can be reduced.

Current methods to enhance drug solubility and stability include the use of salts, solid dispersions, polymeric coatings, nanoparticle carriers, liposomal encapsulations, cocrystals, and cyclodextrin complexes. Salt formation, as with erythromycin succinate, often face issues with drug compatibility and variable absorption. Solid dispersions can be costly and prone to physical instability. Polymeric coatings, such as enteric coatings for omeprazole, can be challenging to apply uniformly. Nanoparticle carriers and liposomal encapsulations are often expensive and difficult to scale up. Current formulations for inhalation by dry powder inhaler use lactose as carrier with a weight ratio, reaching >90% in some case to facilitate inhalation. Co-crystals require suitable co-formers and can be complex to develop. Cyclodextrin complexation improves solubility for certain drugs, but not all drugs are compatible, and the method can be costly.

These approaches, while effective to varying degrees, often encounter scalability, cost, and/or biocompatibility challenges. Summary of the Invention

According to a first aspect the present invention provides a composition for administration via the gastrointestinal tract or the respiratory tract, wherein the composition comprises a deep eutectic mixture, a wax and a biologically active agent.

Compositions of the invention have been found to provide several significant and surprising benefits.

The Examples show that compositions of the invention can enhance the stability, and therefore efficacy, of biologically active agents. In particular, the Examples show that compositions of the invention are able to prevent drug degradation in water or in acidic environments, such as stomach acid.

The Examples show that compositions of the invention can achieve controlled release kinetics, enhancing the therapeutic efficacy of a given amount of the biologically active agent.

The compositions of the invention can comprise two or more biologically active agents. Conventional suppositories tend to be difficult to formulate with two or more biologically active agents, especially where they have significantly different hydrophobicities such as glycerol and cocoa butter.

Furthermore, compositions of the invention can achieve a higher loading of the drug compared to previously available powder-based formulations, such as for inhalation. In particular, as the composition of the invention forms a powder, the composition itself can be administered directly to a subject by inhalation without requiring, or requiring less of, carriers such as lactose.

The composition of the first aspect is also beneficial in that it can be prepared with no, or only a small amount of, water. This prevents the degradation of water-sensitive biologically active agents, such as flucioxacillin.

The formulation of the composition of the invention with biologically active agents has been shown to maintain the activity of the biologically active agents. For example, the antibacterial activity of each of ciprofloxacin and erythromycin were maintained in compositions of the invention, and these were successfully used to treat colonies of Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii .

Deep eutectic solvents (DESs) provide low toxicity and high biocompatibility, and can be more environmentally benign than conventional solvents and/or carriers. DESs can facilitate absorption of compounds in the gut as the particle controllably breaks down in the subject’s aqueous environment.

The compositions of the invention show particular benefits in relation to oral administration, rectal administration, and/or administration by inhalation.

The Examples show that compositions of the invention can be formulated as a powder. In particular, the composition can be formulated as particles that are substantially spherical. Spherical particles are known to facilitate inhalation deep into the lungs. This allows the composition to be formulated for inhalation and/or other modes of administration, and for pulmonary and/or topical respiratory delivery.

Investigations have shown that powdered compositions of the invention can be used to achieve predominant deposition in the upper respiratory tract (e.g., oropharyngeal region). This may be suitable for local treatment strategies, such as topical drug action in the nasal or oropharyngeal cavity.

Powdered compositions of the invention may have particularly beneficial particle morphology, avoiding irregular or collapsed particle morphology, where they comprise a surfactant, such as Brij 97 (CAS 9004-98-2, a form of Polyoxyethylene 10 oleoyl ether), in addition to the wax (e.g. beeswax).

Formulation of the compositions of the invention as a powder can be successfully achieved with antibiotics such as ciprofloxacin and erythromycin. It has been shown that at least ciprofloxacin (a type of quinolone antibiotic agent) remains chemically stable in compositions of the invention, avoiding the formation of degradation products, chemical modification, and significant interaction with excipients. Formulation of the compositions of the invention as a powder exhibit minimal evidence of agglomeration, allowing the compositions to remain free-flowing for administration by inhalation.

The Examples show that the powder can be melted and formed (e.g. by pouring into a mould) to provide a solid single unit, for example for rectal administration, for example as a suppository. Solid single units comprising the composition of the invention provide enhanced dissolution of biologically active agents compared to conventional suppositories. The solid single unit may have a desired shape and/or mass.

Compositions of the invention can control the release of the biologically active agent, for example achieving release over a period of 6 hours or more. This can minimise the number and/or severity of side effects associated with the biologically active agent being administered in an immediate release formulation causing spikes in the concentration of the biologically active agent.

W02020028471A1 discloses substantially liquid formulations comprising a deep eutectic solvent for the oral delivery of pharmaceutical agents, such as aspirin. However, there is no clear and unambiguous disclosure of such a formulation that is solid and/or that further includes a surfactant and/or that further includes a wax.

Compared to the liquid formulations of W02020028471A1, the solid formulations of the present invention can use spray chilling to provide spherical particles preferably around 2-20pm in diameter. These solid formulations are stable, non-aqueous, and have defined DES and wax phases. Manufacture of the solid formulations of the present invention can be scalable, can be solvent-free, and can avoid post-formulation drying. The solid formulations of the invention can be directly suitable for oral administration, rectal administration and/or administration by inhalation, and have been shown to have stability in acidic conditions, provide controlled release, have improved biocompatibility, and provide high drug loading without carriers such as lactose.

Formulation of the present invention as a solid allows for particular benefits to be achieved in terms of the administration by inhalation and/or the gastrointestinal tract; for example for ease of administration, for administration as a suppository and/or to achieve controlled release of the biologically active agent. Compared to liquid formulations, solid formulations such as those of the present invention are typically easier to manufacture (e.g. due to existing solid formulation manufacturing and distribution infrastructure), more stable (e.g. improved physical stability, such as lowering the risk of phase separation), able to be up-scaled, easier to be provided as controlled release formulations, easier to handle (e.g. accurately dose), easier to package, more convenient for patients (including increased compliance with treatment regimens), access to alternative dosage forms (e.g. capsules, powders, suppositories, compositions for inhalers), reduced microbial contamination risk, and are able to be used with coatings for taste and/or odour reduction/masking.

According to a second aspect the present invention provides an article that is a solid single unit or a powder, wherein the article comprises a composition of the first aspect.

According to a third aspect the present invention provides a composition of the first aspect (e.g. an article of the second aspect) for use as a medicament.

Compositions of the invention can be formulated in a facile manner, enabling scalability and lower production costs compared to more complex delivery systems.

The present invention integrates special solvents with waxy materials to form tiny particles that shield sensitive drugs, improve solubility and regulate their release within the body.

According to a fourth aspect, the claimed invention provides a method of preparing a composition, the method comprising the steps of: a) providing a melted wax; b) mixing the melted wax with a deep eutectic solvent (DES) and a biologically active agent to provide a mixture; and c) cooling the mixture in the desired form to provide the composition in a solid form.

It will be understood that the mixture is liquid when heated. Cooling the mixture provides the composition in a solid form, such as a powder or a solid single unit. Preferably step c) comprises spray chilling the mixture to provide a powder and/or providing the mixture to one or more moulds and allowing the mixture to cool to provide one or more solid single units. The use of a DES with a wax to make an emulsion (without use of water) and ultimately forming solid powder. Mixing a DES with a solid will not provide the desired composition because DES components are immiscible with waxes and will phase separate.

It is important to note that the method of the claimed invention uses spray chilling rather than spray drying. There is no need for volatile solvents in the preparation of the composition of the invention. The composition can be prepared simply by cooling the mixture in the desired form. Therefore, any volatile solvents (e.g. water and/or organic solvents) can be detrimental. The presence of volatile solvents can require higher temperatures to be used to remove the solvents, potentially causing issues with the stability of the formulation or compounds therein.

The method prepares emulsions of DES with a wax and uses spray chilling to form a molten emulsion which solidifies inside the collecting chamber. The resulting composition is a fine powder of the emulsion. The wax can dissolve many hydrophobic drugs, while the DES can dissolve hydrophilic drugs. The skilled person can vary the ratio of DES to wax according to the intended use and drug in question.

Detailed Description of the Invention

DES

It will be appreciated that terms such as “eutectic mixture”, “eutectic solvent” and “deep eutectic solvent” are typically used interchangeably. These terms as used herein may refer to a homogeneous mixture that has a melting point lower than those of the constituents. Preferably, there are two constituents; however, occasionally there may be more, such as three, four or five constituents. The eutectic mixtures comprise a mixture of organic compounds including a hydrogen-bond acceptor and a hydrogen bond donor. Preferably the eutectic mixture comprises a hydrogen bond acceptor and a hydrogen bond donor.

The eutectic mixture may comprise two or more, such as three or more hydrogen-bond acceptors. The eutectic mixture may comprise two or more, such as three or more hydrogen-bond donors. Examples of hydrogen bond acceptors include quaternary ammonium salt (such as tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, N,N-diethyl-2-hydroxy ethanamidium chloride, N-benzyl-2-hydroxy-N,N- dimethyl ethanamidium chloride, 2-acetyl-N,N,N -trimethyl ethanamidium chloride and choline salts (such as choline chloride and acetylcholine)); amines (such as dimethylurea, urea and thiourea); amides (such as lidocaine); polyols (such as glycerol and sorbitol); carboxylic acids (such as acetic acid, propionic acid, butyric acid, valeric acid, caprolic acid, oxalic acid, malic acid and benzoic acid ascetic acid, ascorbic acid, carbonic acid, citric acid, formic acid, glycolic acid, glutaric acid, lactic acid, maleic acid, malonic acid, salicylic acid); phosphonium salts (such as methyltriphenylphosphonium bromide); alcohols (such as menthol, thymol, and chloroxylenol); and betaine. Examples of hydrogen bond acceptors include choline chloride, N,N-diethyl-2-hydroxy ethanamidium chloride, tetramethylammonium chloride, methyltriphenylphosphonium bromide, tetrabutylammonium chloride, N- benzyl-2-hydroxy-N,N-dimethyl ethanamidium chloride, tetraethylammonium chloride, and 2-acetyl-N,N,N-trimethyl ethanamidium chloride. Choline salts, especially choline chloride, are preferred hydrogen bond acceptors. Preferably the hydrogen bond acceptor is a quaternary ammonium salt (such as a choline salt), an amine (such as urea), and/or glutaric acid.

Examples of hydrogen bond donors are alcohols (such as phenol, menthol, thymol, chloroxylenol dodecanol, polyols (such as glycerol and sorbitol); sugars (such as fructose, glucose, sucrose, xylose) and diols (such as ethylene glycol, 1,2-propanediol, 1,4-butanediol, resorcinol)); amino acids (such as arginine, glycine, lysine, proline and serine); amines (such as dimethylurea, urea, thiourea); amides (such as acetamide, benzamide, niacinamide); nitrogen containing heterocyclic compounds (such as imidazole); and carboxylic acids (such as acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, oxalic acid, malic acid and benzoic acid ascetic acid, ascorbic acid, carbonic acid, citric acid, formic acid, glycolic acid, glutaric acid, lactic acid, maleic acid, malonic acid, salicylic acid). Examples of hydrogen bond donors include urea, thiourea, acetamide, benzamide, glycerol, imidazole, malonic acid and glucose. Glycolic acid, glutaric acid, acetic acid, glycerol and urea are preferred hydrogen bond donors. Urea is a preferred hydrogen bond donor. Various deep eutectic solvents (DESs) were demonstrated using urea combined with environmentally benign and biocompatible substances such as glycolic acid, glycerol, and choline chloride. It will be appreciated that the hydrogen bond donor should be different from the hydrogen bond acceptor.

Some specific embodiments of eutectic mixtures useful for the instant invention are the following: phenol/menthol; phenol/choline chloride; phenol/choline chloride/urea; choline chloride/urea; betaine hydrochloride or choline chloride/urea; resorcinol/choline chloride; BHT/choline chloride; chloroxylenol/choline chloride/menthol; choline chloride/citric acid monohydrate; choline chloride/arginine/urea; choline chloride/niacinamide/urea; camphor/menthol; camphor/menthol/lauryl alcohol; camphor/glycerine mono laurate/menthol; terbinafine hydrochloride/lidocaine; urea/glycolic acid; urea/glycerol; choline chloride/glutaric acid; choline chloride/acetic acid; choline chloride/glycerol; glutaric acid/glycerol.

For each pair of hydrogen bond donors/hydrogen bond acceptors, the skilled person will be aware that the appropriate ratio will differ depending on the freezing point depression to be achieved. For example, in the case of choline chloride/urea, the eutectic point is achieved at a choline chloride: urea ratio of 1 :2, such as a molar ratio. The eutectic formed between choline chloride and urea is preferred in the compositions of the invention, and ratios of between 1 :3 and 1 : 1, such as a molar ratio may be successfully employed.

The molar amount of hydrogen bond donor, relative to the molar amount of hydrogen bond acceptor, may be 10% or more, such as 20% or more, preferably 30% or more, or 50% or more, such as 80% or more, or 90% or more, or 100% or more, such as 150% or more, or 200% or more. The molar amount of hydrogen bond donor, relative to the molar amount of hydrogen bond acceptor, may be 1000% or less, such as 800% or less, such as 500% or less, preferably 300% or less, or 200% or less, such as 150% or less, or 120% or less, for example 100% or less. The molar amount of hydrogen bond donor, relative to the molar amount of hydrogen bond acceptor, may be from 10% to 1000%, such as from 30% to 300%, or from 50% to 200%.

The composition may comprise the eutectic mixture in an amount, by weight, relative to the total weight of the composition, of 1% or more, such as 2% or more, preferably 5% or more, or 8% or more, such as 10% or more, or 15% or more, such as 18% or more, or 20% or more. The composition may comprise the eutectic mixture in an amount, by weight, relative to the total weight of the composition, of 80% or less, or 70% or less, preferably 60% or less, or 50% or less, such as 45% or less, or 40% or less, for instance 35% or less, or 30% or less, such as 25% or less. The composition may comprise the eutectic mixture in an amount, by weight, relative to the total weight of the composition, of from 1 to 80%, such as from 5 to 60%, or from 8 to 40%.

Wax

A wax may be a nonpolar substance that is substantially immiscible with water and that has a melting point above 20°C (e.g. above 30°C). The wax may be a hydrocarbon. The wax may contain carbon atoms, hydrogen atoms, and optionally oxygen atoms.

Suitable waxes may be animal, vegetable, or petrochemical in nature. Preferably, the wax is a naturally occurring wax, and may be vegetable in nature.

The wax may be made of hydrocarbons (e.g. alkanes, alkenes) optionally substituted with one or more alcohol, carboxylic acid and/or ester groups. Waxes may be fatty acids, fatty acid esters, fatty acid diesters, and/or sterol esters.

The wax may be beeswax, spermaceti, lanolin, carnauba wax, candelilla wax, ouricury wax, paraffin wax, microcrystalline wax, montan wax, synthetic waxes (e.g. polyethylene wax, polypropylene wax, polyethylene glycol wax), tallow, soy wax (hydrogenated soybean oil), Chinese wax, shellac, bayberry wax, castor wax, esparto wax, Japan wax, rice bran wax, tallow tree wax, ceresin wax, ozocerite and/or peat wax. Preferably the wax is selected from the list consisting of carnauba wax, beeswax, paraffin wax, candelilla wax, microcrystalline wax, shellac wax, synthetic waxes (e.g., polyethylene glycol wax), rice bran wax, and montan wax.

The wax may comprise an ester, such as myricyl palmitate, cetyl palmitate and/or myricyl cerotate. The wax may comprise a wax acid, such as a fatty acid (alkanoic acid) containing 22 or more carbon atoms, for example behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, lacceroic acid, and/or geddic acid.

Preferably the wax is carnauba wax. The wax may have a melting point of 30°C or higher, such as 40°C or higher, preferably 50°C or higher, such as 60°C or higher, or 70°C or higher. The wax may have a melting point of 200°C or lower, such as 150°C or lower, for example 120°C or lower, preferably 100°C or lower, such as 90°C or lower, or 80°C or lower. The melting point of the wax may be from 30 to 200°C, such as from 50 to 100°C.

The composition may comprise the wax in an amount, by weight, relative to the total weight of the composition, of 1% or more, such as 2% or more, preferably 5% or more, 10% or more, or 20% or more, for example 30% or more, or 40% or more, especially 45% or more, or 50% or more. The composition may comprise the wax in an amount, by weight, relative to the total weight of the composition, of 95% or less, preferably 90% or less, or 85% or less, such as 80% or less, or 70% or less, such as 60% or less, such as 55% or less. The composition may comprise the wax in an amount, by weight, relative to the total weight of the composition, of from 1 to 95%, such as from 5 to 90%, or from 8 to 85%, preferably from 30 to 70%.

Biologically active agent

The composition of the invention comprises a biologically active agent. It will be appreciated that a wide variety of biologically active agents can be used in the composition of the invention. More polar active agents may remain in the DES phase, whereas less polar active agents may remain in the wax phase.

The compositions of the invention have been found to have particularly benefits in terms of administration to the lungs. Diseases and conditions benefitting from administration to the lungs, and therefore finding benefit with the present invention may include respiratory viral infections, respiratory fungal infections, allergic reactions (e.g. allergic rhinitis, anaphylaxis), asthma, bronchitis, emphysema, chronic rhinosinusitis, cystic fibrosis-associated airway disease, chronic obstructive pulmonary disease (COPD, and symptoms and exacerbations thereof), and tuberculosis.

The biologically active agent may be a medicament and/or a cosmetic active ingredient. A medicament may be considered a pharmaceutical active agent.

There is one or more active agents present in the composition, such as two or more active agents. The biologically active agent may be an antimicrobial agent, such as an antifungal, antibacterial and/or antiviral agent. Preferably the biologically active agent is an antifungal and/or antibacterial agent.

The anti-fungal agent may be a phenolic anti-fungal agent, such as griseofulvin or haloprogin. Griseofulvin is a particularly preferred antifungal agent. Griseofulvin is particularly useful in the treatment of dermatophytosis.

The antibiotic may be a penicillin (such as phenoxymethylpenicillin, flucioxacillin, amoxycillin), a quinolone (e.g. a fluoroquinolone, such as ciprofloxacin) or a macrolide antibiotic (e.g. erythromycin). Preferably the antibiotic is flucloxacillin, ciprofloxacin or erythromycin.

The biologically active agent may be a xanthine, such as a methylxanthine, for example caffeine, aminophylline, IBMX (3-isobutyl-l-methylxanthine), paraxanthine, pentoxifylline, theobromine, theophylline, and/or 7-methylxanthine.

The biologically active agent may be a salt, solvate and/or prodrug (e.g. ester) of one of the compounds mentioned herein, for example a pharmaceutically acceptable salt, solvate and/or prodrug (e.g. ester) of one of the compounds mentioned herein.

The composition may comprise the biologically active agent in an amount, by weight, relative to the total weight of the composition, of 0.001 wt% or more, such as 0.01 wt% or more, preferably 0.1 wt% or more, for example 0.2 wt% or more, or 0.5 wt% or more, or 1 wt% or more, more preferably 2 wt% or more, such as 3 wt% or more, or 4 wt% or more. The composition may comprise the biologically active agent in an amount, by weight, relative to the total weight of the composition, of 30 wt% or less, such as 20 wt% or less, or 15 wt% or less, or 10 wt% or less, such as 8 wt% or less, or 6 wt% or less, for example 5 wt% or less. The composition may comprise the biologically active agent in an amount, by weight, relative to the total weight of the composition, of from 0.001 to 30 wt%, such as from 0.1 to 10 wt%. Surfactant

The compositions of the invention preferably comprise a surfactant. This helps the DES and the wax to form a stable emulsion, rather than separating. However, during the preparation of the composition of the invention, the mixture only needs to remain as an emulsion for a relatively short time before the mixture is spray chilled and the structure of the composition is more set.

Anionic, cationic and/or non-ionic surfactants can be suitable. Non-ionic surfactants are preferred. While it is appreciated that some waxes, especially fatty acid and/or fatty ester based waxes, can act as surfactants, it will be understood that the surfactant should be different from the wax.

Preferably the surfactant is a polyoxyethylene hydrocarbon ether, such as those available under the trade name Brij . Preferably the polyoxyethylene hydrocarbon ether is a polyoxyalkene hydrocarbon ether: wherein p is from 10 to 30, such as from 14 to 22, e.g. from 16 to 20, especially 18; m is from 0 to 2, especially 1; and n is from 4 to 30, such as from 4 to 20, or from 6 to 14, for example from 8 to 12, especially 10.

Preferably polyoxyalkene hydrocarbon ether is polyoxyethylene (10) oleyl ether (Brij® 010).

The surfactant may be a fatty acid ester of ethoxylated sorbitan, for example having the general structure (I): wherein x, y, z and w are independently selected integers (e.g. from 1 to 10), and R is a hydrocarbon, especially CH3-(CH2)7“CH=CH-(CH2)7“. x+y+z+w may be 20.

Such examples of polyethoxylated sorbitan monooleate include those available under the trade name Span, such as Span 80 (CAS 1338-43-8) or Span 20 (CAS 1338-39-2).

The surfactant may be polyethoxylated sorbitan monooleate polysorbate 80 (II):

The surfactant may be a polyoxyethylene ether, such as Brij 97 (CAS 9004-98-2) having the formula Ci8H35-O-(CH2CH2)_xH, where x is about 10 on average (mean), such as from 8 to 12.

The surfactant may be a block copolymer, such as an ethylene oxide and propylene oxide block copolymer. For example, those available under the trade name Pluronic, such as Pluronic L-611 (CAS 9003-11-6).

Examples of other suitable surfactants include cetearyl alcohol, stearic acid, lauryl alcohol, and glyceryl behenate.

The composition may comprise the surfactant in an amount, by weight, relative to the total weight of the composition, of 0.1% or more, or 1% or more, preferably 2% or more, or 5% or more, or 8% or more, such as 10% or more, or 15% or more, such as 20% or more, for example 25% or more. The composition may comprise the surfactant in an amount, by weight, relative to the total weight of the composition, of 80% or less, or 60% or less, or 50% or less, preferably 40% or less, for instance 35% or less, or 30% or less, such as 25% or less, or 20% or less. The composition may comprise the surfactant in an amount, by weight, relative to the total weight of the composition, of from 0.1 to 80%, such as from 2 to 40%, or from 8 to 40%.

Composition

The mixture of the melted wax with the DES and the biologically active agent may be an emulsion. The composition of the invention may be termed a solid emulsion.

“Emulsion” as used herein may refer to a colloidal mixture of two or more phases (e.g. liquid-liquid or solid-solid) that are immiscible. Emulsions typically comprise a dispersed and continuous phase; the dispersed phase is dispersed in the continuous phase. It may be that either the eutectic mixture forms the continuous phase and the wax forms the dispersed phase, or alternatively the wax forms the continuous phase and the eutectic mixture the dispersed phase.

Preferably, the emulsions used in the compositions of the invention, particularly following cooling and in the solid form, are stable, and resist flocculation, coalescence, creaming, and sedimentation or other forms of instability for extended periods, such as more than one day, more than one week, more than two weeks, more than one month, or more than one year.

The composition may contain the eutectic mixture in an amount, relative to the amount of wax, by weight, of 1% or more, such as 2% or more, or 5% or more, preferably 10% or more, or 20% or more, such as 30% or more, or 35% or more, for example 40% or more. The composition may contain the eutectic mixture in an amount, relative to the amount of wax, by weight, of 400% or less, such as 200% or less, preferably 100% or less, or 80% or less, or 60% or less. The composition may contain the eutectic mixture in an amount, relative to the amount of wax, by weight, of from 1 to 400%, such as from 10 to 100%.

Preferably, the composition contains little or no water, i.e. it is essentially nonaqueous. Preferably, the amount of water is 5wt% or less, more preferably 1% or less, most preferably 0.1wt% or less. Sensitivity to water may depend on the biologically active agent being used in the composition. The composition may contain water in an amount of 10 wt% or less, such as 5 wt% or less, or 2 wt% or less, preferably 1 wt% or less, for example 0.1 wt% or less, or 0.001 wt% or less, for example wherein there is no water in the composition. Most preferably the composition contains no water, although it will be understood that traces of water may not significantly affect the function of the composition.

Preferably the composition comprises less than 20wt% of a volatile organic solvent, for example wherein the composition comprises no volatile organic solvent. More preferably any amount of volatile organic solvent is 10wt% or less, such as 5 wt% or less, or 2 wt% or less, for example 1 wt% or less. The amount of any given volatile organic solvent may be less than 20wt%, or there may be none of a given volatile organic solvent (e.g. ethanol and/or ethyl acetate). The total combined amount of volatile organic solvents is less than 20wt%, or there may be no volatile organic solvent in the composition. Preferably the volatile organic solvent is ethanol and/or ethyl acetate. The volatile organic solvent may be acetone, ethyl acetate, and/or ethanol, or the like. The volatile organic solvent may be an alcohol (for example methanol, ethanol, propanol (e.g. isopropanol, n-propanol), butanol (e.g. tert-butanol)) and/or a polar aprotic solvent (such as ethyl acetate, acetone, acetonitrile). The volatile organic solvent may include a nonpolar solvent, such as a nonpolar hydrocarbon solvent (such as pentane, cyclopentane, hexane, cyclohexane, heptane, benzene and toluene); a nonpolar ether solvent (such as diethyl ether, 1,4-dioxane, methyl tert-butyl ether, glyme, and tetrahydrofuran); a polar aprotic solvent (such as ethyl acetate, acetone and acetonitrile); a polar protic solvent (such as alcohols, for example methanol, ethanol, propanol (e.g. isopropanol, n-propanol), butanol (e.g. tert-butanol)), and a carboxylic acid (such as acetic acid and formic acid). The volatile organic solvent(s) may be pharmaceutically acceptable (e.g. ethanol). The volatile organic solvent(s) may be those having a boiling point of 150°C or less, such as 120°C or less, such as 105°C or less, or 100°C or less, for example 90°C or less, or 85°C or less, such as 80°C or less (at atmospheric pressure, lOlkPa).

The composition may comprise 50 wt% of a volatile organic solvent (e.g. ethanol and/or ethyl acetate) or less, such as 40 wt% or less, or 30 wt% or less, or 25 wt% or less. The composition preferably comprises 20 wt% of a volatile organic solvent (e.g. ethanol and/or ethyl acetate) or less, such as 18 wt% or less, or 15 wt% or less, or 14 wt% or less, for example 12 wt% or less, or 10 wt% or less, for example 5 wt% or less, or 4 wt% or less, such as 3 wt% or less, or 2 wt% or less, such as 1 wt% or less or 0.1 wt% or less. Preferably the composition includes no volatile organic solvent (e.g. ethanol and/or ethyl acetate). However, it will be understood that trace or low amounts of volatile organic solvents may still allow the composition to be effective. The composition may comprise a volatile organic solvent (e.g. ethanol and/or ethyl acetate) in an amount of from 0.0001 to 50 wt%, preferably from 0.0001 to 20 wt%, or from 0.01 to 20 wt%, such as from 0.01% to 10%.

Article

The second aspect provides an article that is a solid single unit or a powder, wherein the article comprises a composition of the first aspect.

The solid single unit may be a tablet, lozenge, or suppository. Suppositories have a torpedo or bullet-like shape to facilitate administration. Preferably the article is elongate (i.e. longer than its diameter) with a substantially circular cross-section throughout its length, where one end of the length is more pointed and the other end of the length is flat.

The powder may have an average (mean, e.g. number average) particle size (diameter) of 100pm or less, such as 80 pm or less, or 50 pm or less, for example 40 pm or less, or 30 pm or less, such as 25 pm or less, or 20 pm or less, such as 15 pm or less, or 10 pm or less. The average particle size of the powder may be 0.1 pm or more, such as 0.2 pm or more, or 0.5 pm or more, or 1.0 pm or more, such as 1.5 pm or more, or 2.0 pm or more, such as 5.0 pm or more. The average particle size of the powder may be from 0.1 to 100pm, such as from 1.0 to 40pm, or from 2.0 to 20pm. Particle size may be determined dynamic light scattering, for example using a Zetasizer Nano-ZS (Malvern, UK).

Methods of treatment

The compositions of the current invention may be for administration via the gastrointestinal tract or the respiratory tract. Administration via the gastrointestinal tract is preferably oral or rectal. Administration via the respiratory tract is preferably by inhalation. Compositions of the current invention may be for administration to a mucous membrane (such as the conjunctiva, nasal mucosa, olfactory mucosa, oral mucosa, penile mucosa, vaginal mucosa, frenulum of the tongue and/or anal canal). Compositions of the invention may suitably be provided in a suitable form for administration. For example, the composition may be provided as an oral preparation (e.g. tablet, lozenge, capsule, powder, granules, suspension) or a rectal preparation (e.g. suppository). The composition may be provided as a preparation for inhalation (e.g. as a powder), for example in an inhaler.

In certain preferred embodiments, the compositions of the current invention have the advantage of containing high concentrations of low-solubility or hard-to formulate drugs such as griseofulvin. Such concentrated compositions may be of particular benefit in treatment of chronic diseases because the high concentrations can 1) increase the effective concentration of drug in the affected area and/or 2) improve retention of the drug at or near the affected area.

The compositions of the invention may be used effectively to treat diseases and disorders in humans or in other animals, such as cats, dogs, horses, cattle, sheep, goats, pigs, and birds. In human and in veterinary patients, the compositions of the invention may be used, depending on the particular animal treated, to treat conditions involving nails, hooves, horns, or beaks.

Frequency of treatment and duration of therapy will vary depending on several factors, including the condition that is being treated, the identity and concentration of the biologically active agent in the composition, and constituents of the composition other than the biologically active agent. Typically, the frequency of treatment will be three times daily or less often, preferably once daily. The composition may be for administration at a regular interval of three times a day or less frequently, such as twice a day or less frequently, for example daily or less frequently, or every two days or less frequently. The composition may be for administration at a regular interval of from three times a day to biweekly, such as from two times a day to every two days.

Optional additives

The composition may optionally comprise one or more additives. For example an antioxidant may be included in the composition, depending on the stability of the wax used, to improve the stability of the wax against oxygenation. The composition may comprise additives in an amount of 40 wt% or less, such as 30 wt% or less, or 20 wt% or less, preferably 10 wt% or less, such as 5 wt% or less. The composition may comprise additives in an amount of 0.01 wt% or more, such as 0.1 wt% or more. The composition may comprise additives in an amount of from 0.01 wt% to 40 wt%, such as from 0.01 wt% to 10 wt%.

As the formulations are solid, preferably there is a minimal amount of additives other than the DES, wax and biologically active agent.

Method of preparation

The fourth aspect provides a method of preparing a composition, the method comprising the steps of: a) providing a melted wax; b) mixing the melted wax with a deep eutectic solvent (DES) and a biologically active agent to provide a mixture; and c) cooling the mixture in the desired form to provide the composition in a solid form.

The wax may be melted by heating the wax near to (e.g. up to 20°C below, or up to 10°C below) or above its melting point. It will be appreciated that the melting point of a wax depends on its purity. Carnauba wax has a reported melting point of 82-86°C but a sample was found to begin to melt and be used successfully at 75°C. Therefore, the wax may be at or heated to a temperature of 30°C or higher, such as 40°C or higher, preferably 50°C or higher, such as 60°C or higher, or 70°C or higher. Preferably the lowest possible temperature is used to reduce degradation of the wax, for example by oxidation. This may not apply to waxes more stable against oxidation. The temperature may be 200°C or lower, such as 150°C or lower, for example 120°C or lower, preferably 100°C or lower, such as 90°C or lower, or 80°C or lower. The temperature may be from 30 to 200°C, such as from 50 to 100°C.

The eutectic mixture may be formed by combining (e.g. mixing) at least one hydrogen bond donor and at least one hydrogen bond acceptor. The at least one hydrogen bond donor and at least one hydrogen bond acceptor may be heated, until a homogenous clear liquid is obtained. This may require heating. The skilled person would understand that the eutectic mixture would need to be heated to a suitable temperature which is lower than the melting points of either component of the eutectic mixture. For example, the eutectic mixture may be heated to 50°C or higher, or 60°C or higher, 70°C or higher, for example from 50 to 80°C. Agitation may be used to provide the eutectic mixture. Such agitation may be continuous, or intermittent throughout the step of forming a eutectic mixture. Preferably, such agitation is continuous throughout the step of forming the eutectic mixture.

The wax, DES and biologically active agent may be combined in any order or all together. Optionally a surfactant is added at this stage. These components may be mixed by any suitable agitation technique, such as stirring (e.g. using an impeller and/or stirrer bar), sonication or inversion.

Preferably the wax, DES, biologically active agent and optional surfactant are combined until a homogenous mixture is provided. Preferably the homogenous mixture is an emulsion, for example containing bubbles of the DES in the wax and/or bubbles of the wax in the DES. Preferably the wax, DES, biologically active agent and optional surfactant are maintained at a temperature as stated above until the homogeneous mixture is provided. Preferably the mixture is maintained at a temperature as stated above until the mixture is cooled.

The mixture may be cooled at a rate of 5°C per minute or more, such as 10°C per minute or more, or 20°C per minute or more, preferably 30°C per minute or more, such as 50°C per minute or more, or 100°C per minute or more. Rapid cooling allows the structure of the mixture to be maintained.

Spray chilling the mixture provides the composition as particles, such as a powder.

The mixture may be cooled in one or more moulds, providing solid articles that may be used as a suppository.

Such conditions may be considered environmentally benign, as the composition may be formed at relatively low temperatures or requiring the use of harsh reagents.

The present disclosure includes the subject-matter of the following clauses:

1. A composition suitable for administration via the gastrointestinal tract or the respiratory tract, wherein the composition comprises a deep eutectic mixture, a wax and a biologically active agent.

2. The composition of clause 1, wherein the composition further comprises a surfactant. 3. The composition of clause 2, wherein the surfactant is polyoxyethylene (10) oleyl ether.

4. The composition of clause 2 or clause 3, wherein the composition comprises the surfactant in an amount of from 8% to 40% by weight.

5. The composition of any preceding clause, wherein the composition contains 1 wt% or less, for example no, water.

6. The composition of any preceding clause, wherein the composition comprises 20wt% or less, for example no, volatile organic solvent.

7. The composition of any preceding clause, wherein the wax is selected from the list consisting of: carnauba wax, beeswax, paraffin wax, candelilla wax, microcrystalline wax, shellac wax, polyethylene glycol wax, rice bran wax, and montan wax.

8. The composition of any preceding clause, wherein the composition comprises the wax in an amount, relative to the total weight of the composition, of from 30 to 70% by weight.

9. The composition of any preceding clause, wherein the deep eutectic solvent is glycerol/urea.

10. The composition of any preceding clause, wherein the composition comprises the eutectic mixture in an amount, relative to the total weight of the composition, of from 8 to 40% by weight.

11. The composition of any preceding clause, wherein the biologically active agent is selected from the list consisting of: a phenolic anti-fungal agent, a penicillin, and a xanthine.

12. The composition of clause 11, wherein the biologically active agent is selected from the list consisting of: griseofulvin, flucioxacillin and theophylline.

13. The composition of any preceding clause, wherein the composition comprises the biologically active agent in an amount, relative to the total weight of the composition, of from 0.1 to 20% by weight.

14. The composition of clause 3, wherein: the composition comprises the surfactant in an amount of from 8% to 40% by weight; the wax is selected from the list consisting of: carnauba wax, beeswax, paraffin wax, candelilla wax, microcrystalline wax, shellac wax, polyethylene glycol wax, rice bran wax, and montan wax; the composition comprises the wax in an amount, relative to the total weight of the composition, of from 30 to 70% by weight; the deep eutectic solvent is glycerol/urea; and the composition comprises the eutectic mixture in an amount, relative to the total weight of the composition, of from 8 to 40% by weight. 15. The composition of clause 14, wherein the biologically active agent is selected from the list consisting of: griseofulvin, flucioxacillin and theophylline.

16. The composition of clause 15, wherein the composition: contains 1 wt% or less, for example no, water; and comprises 20wt% or less, for example no, volatile organic solvent.

17. An article that is a solid single unit or a powder, wherein the article comprises a composition of any one of clauses 1 to 16.

18. The article of clause 17, wherein the article is a solid single unit that has a torpedo or bullet-like shape, and is for use as a suppository.

19. The article of clause 17, wherein the article is a powder that has an average particle size of 30 pm or less.

20. A composition of any one of clauses 1 to 16 or an article of any one of clauses 17 to 19 for use as a medicament.

21. The composition or the article of clause 20, wherein the composition or the article is for use in a method of treatment, wherein the method comprises administering the composition or the article via the gastrointestinal tract or the respiratory tract.

22. A method of preparing a composition, the method comprising the steps of: a) providing a melted wax; b) mixing the melted wax with a deep eutectic solvent and a biologically active agent to provide a mixture; and c) cooling the mixture in the desired form to provide the composition in a solid form.

23. The method of clause 22, wherein step c) comprises: i) spray chilling the mixture to provide a powder; or ii) providing the mixture to one or more moulds and allowing the mixture to cool to provide one or more solid single units.

Examples

Preparation of compositions of the invention

Figure 1 of the accompanying drawings shows a schematic representation of a procedure to prepare compositions of the invention.

A deep eutectic solvent is prepared by mixing suitable reagents (e.g. urea and glycolic acid) in appropriate ratios, as is well known in the art. A wax, such as carnauba wax, is heated to a temperature of 75 °C, at which temperature it started to melt. The heated wax (50 parts by weight), the deep eutectic solvent (glycolic acid/ urea, 20 parts by weight), the biologically active agent (amount as necessary, usually the biologically active agent makes up 1, 5, or 10 wt% of the total composition depending on the application and the solubility of the drug) and Brij® 010 surfactant (30 parts by weight) were combined and mixed using mechanical stirring (stirrer bar) with heating (e.g. 70°C). The resulting mixture was spray chilled to provide solid particles comprising the wax, DES and surfactant as a powder.

The spray chiller used was an accessory attached to a spray dryer (Buchi B290 (Switzerland) equipped with a spray chilling accessory). It allows the melting of the components via the internal heater, which prevents the solidification of the components prior to and during injection to the nozzle during the drying process. In essence, this acts like a water or oil bath where the temperature of the bath is maintained by the circulating oil or water. The process starts as soon as the mixture is molten and homogenous, and the process of drying happens very fast to give yield to the solid particles which are collected in the cyclone. The process doesn’t perform any drying process, hence the drying chamber in the spray dryer is kept at room temperature. The temperature difference between the chiller and the drying chamber causes immediate solidification of the molten droplets. The particles are carried forward via the action of the chamber nitrogen gas and collected in the cyclone.

Example 1 - Griseofulvin absorption in vivo

A composition of the invention was prepared with griseofulvin, a treatment for fungal infections. Griseofulvin is practically insoluble in water and has a logP of 2.18. Its absorption in vivo is variable, increasing to 25-70% when administered with a fatty meal.

The particles were prepared using an emulsion of with a deep eutectic solvent (urea and glycolic acid), formed at elevated temperatures and solidified at room temperature. The emulsion, maintained at 70°C, was spray chilled to form solid particles.

Figure 2 of the accompanying drawings shows a scanning electron micrograph of the particles. The particles were spherical and had diameters of 2-20pm.

Griseofulvin

The samples were suspended in saline for administration. Specifically, 200pg of solid material was suspended in 200 pL of saline.

Administration

Male CD-I mice were administered Drug. Mice were administered at a lOml/kg dose volume through oral gavage (PO) using a metal gavage. Mice were restrained and dosed 5 minutes apart to allow for sampling at future timepoints.

Blood sampling

Mice were put into a hotbox 10 minutes prior to sampling to allow vasodilation of the veins. Mice were removed from the hotbox once the 10 minutes were completed and placed into a restrainer. The tail was primed, and the right tail vein was isolated, a small cut/nick was made with a scalpel blade to allow for a slow blood flow upon the tail surface. 25pl of blood was collected with a Capillary Piston Pipette, and transferred to an Eppendorf containing 50pl Saline + Ipl HepSaline. The contents was mixed thoroughly within the pipette and left on ice ready for plasma collection.

Results

Figure 3 of the accompanying drawings shows the mean concentration-time curve for the composition of the invention compared with the antifungal drug (griseofulvin) (n=3). The area under curve (AUC) and the maximum concentration (Cmax) for the sample of the invention were both higher than for the drug alone. Male CD-I mice were orally administered (10 ml/kg) using a metal gavage. Blood was sampled after 10 minutes in a hotbox for vasodilation. The right tail vein was nicked, and 25 pL of blood was collected with a capillary piston pipette into 50 pL saline + 1 pL HepSaline. In vivo studies with griseofulvin showed that the composition of the invention produces stable, spherical particles, significantly improving drug bioavailability and stability. Preliminary data indicate higher peak concentrations and greater overall drug exposure with the formulation of the invention.

Mass spec data

The MS data from the composition of the invention, extracted from HPLC samples following in vivo experiments, reveals several key peaks indicative of the drug and its components. Major peaks observed include m/z 353.0794 (the molecular ion of the drug, C17H18O6C1), with additional peaks at m/z 215.0112, 285.0531, 372.0526, 337.0940, 218.2119, 445.2757, and 681.4142. The base peak intensity around 3.96E6 suggests a complex mixture typical of a formulation sample. The retention times (RT 7.55-7.66 minutes) confirm the presence of the drug and the other components of the composition of the invention, highlighting the stability and complexity of the composition in a biological system.

Extracted from an HPLC sample following an in vivo experiment to assess drug stability, likely represents the drug alone. The spectrum shows a high base peak intensity of 3.28E7, indicating a pure sample. Major peaks observed include m/z 353.0792 (the molecular ion of the drug, C17H18O6C1), m/z 215.0111, m/z 285.0530, and m/z 549.0872, with the peak at m/z 353.0792 being the most prominent. The retention time (RT 7.55-7.66 minutes) and the relative abundances of the peaks suggest a stable and pure drug sample with minimal interference, providing a reliable baseline for comparison with the composition of the invention.

This confirms the integrity of griseofulvin in the composition of the invention.

Example 2 - Modified release of theophylline

A composition of the invention was prepared with theophylline, a treatment for asthma and COPD. Theophylline has a logP of 0.05. Theophylline has a short half-life of 6-12 hours, depending on age and disease state. Therefore, frequent dosing and/or modified release formulations are typically required. The particles were prepared using an emulsion of with a deep eutectic solvent (urea and glycolic acid), formed at elevated temperatures and solidified at room temperature. The emulsion, maintained at 70°C, was spray chilled to form solid particles.

Theophylline

The particles of the invention containing theophylline, and theophylline itself, were suspended (e.g. dissolved) in water at 37°C. The mixture was agitated using a Copley dissolution apparatus. The concentration of theophylline in solution was monitored by HPLC (Agilent 1100) over the course of 24 hours.

Figure 4 of the accompanying drawings shows the results of this study. Theophylline itself was almost fully dissolved after the first timepoint, taken after 30 minutes. By contrast, at the same time, 14% of the drug from the composition of the invention had been released. After 3 hours, 99% of theophylline itself was released and 34% of the theophylline from the composition of the invention was released. After 6 hours, 100% of theophylline itself was released and 67% of the theophylline from the composition of the invention was released.

This shows that the composition of the invention can be used to modify or control the release of a biologically active compound over a period of 6 hours or more. This can be particularly beneficial for biologically active compounds with a low half-life, such as theophylline.

Example 3 - Enhanced stability of flucioxacillin

A composition of the invention was prepared with flucioxacillin, an antibiotic for bacterial infections such as staphylococcal infections. Flucioxacillin has a logP of 3.22. Flucioxacillin has a short half-life of 0.75-1 hour in water, which is even lower in acidic conditions as are found in the human stomach. Therefore, frequent dosing and/or modified release formulations are typically required to ensure that the drug passes through the stomach without degrading. The particles were prepared using an emulsion of with a deep eutectic solvent (urea and glycolic acid), formed at elevated temperatures and solidified at room temperature. The emulsion, maintained at 70°C, was spray chilled to form solid particles.

Flucioxacillin

The composition of the invention was placed in acidic water (pH 2) at 37°C and agitated using a Stuart rotary mixer. The proportion of flucloxacillin still present was monitored by HPLC (Agilent 1 100) over time. This was repeated with flucloxacillin itself.

Figure 5 of the accompanying drawings shows the results of this study. The composition of the invention maintained more than 40% intact after 30 min, while flucloxacillin itself completed degraded within same time interval.

The composition of the invention was placed in water at 37°C and the proportion of flucloxacillin still present was monitored by HPLC (Agilent 1 100) over time. This was repeated with flucloxacillin itself.

No degradation of the flucloxacillin was observed for the composition of the invention in water.

Example 4 - Formation of suppositories

A powder prepared by the general procedure above was heated to a temperature of 75- 80°C. The powder started to agglomerate and become increasingly cohesive. The warm composition was placed into metal moulds and allowed to cool to room temperature for Ih. The composition was released from the moulds to provide a firm solid article that was of a size and shape to be used as a suppository.

Figure 6 of the accompanying drawings shows the suppository formed by this Example. Example 5 - Formulations for inhalation

Preparation of sustainable ciprofloxacin-loaded particles

Preparation of deep eutectic solvent (DES): an equal molar ratio of urea and glycolic acid was placed into a glass jar which was immersed in a water bath, heated to 60 °C, and stirred until a homogenous liquid was obtained. Subsequently, the collected “U/GA” DES was stored in a sealed jar at ambient temperature.

A drug-loaded emulsion based on DES and beeswax in the presence of a surfactant (Brij 97) and the antibacterial drug (ciprofloxacin) was used as a model to demonstrate the process. Preparation of DESOLVE particles: 10g of DES (U/GA) was mixed with 750 mg of ciprofloxacin (2.5% w/w of the total formulation) under continuous stirring at 60°C until a completely homogenous dispersion of the drug in the DES was achieved. After that, 5g of Brij 97 was added under continuous stirring at 60°C.

Subsequently, the DES/drug/Brij 97 mixture was added dropwise to melted Beeswax (15 g) under continuous stirring at 90 °C until a clear and homogeneous solution was obtained. The resulting emulsion was then fed into a BUCHI Mini Spray Dryer B-290. The outlet temperature was set to 100 °C to ensure smooth flow of the emulsion through the spray-chilling nozzle. The aspiration rate was set to 100%, with a nitrogen gas flow of 50 L/h. All collected powders were stored in a desiccator at room temperature.

FTIR characterisation of samples for inhalation

The chemical structure of ciprofloxacin, and of the prepared DESOLVE powder was elucidated with FTIR spectroscopy to assess potential interactions or degradation during formulation. The FTIR spectra were recorded using a 100 FTIR spectrometer (Perkin Elmer, UK) over 16 scans within the wavelength range of 4000-650

The analysis revealed strong spectral concordance between the two samples, with all major characteristic absorption bands of ciprofloxacin being retained in the DESOLVE spectrum.

Key functional group vibrations were observed at consistent wavenumbers in both spectra. The strong band around 1700 cm ¹ corresponds to the C=O stretching vibration of the carboxylic acid and ketone groups, a signature feature of the fluoroquinolone core. The region around 1610-1580 cm ¹ shows bands attributable to aromatic C=C stretching, indicating preservation of the quinolone ring system. In addition, bands in the 1250-1020 cm ¹ region are consistent with C-F stretching, characteristic of the fluorine-substituted aromatic ring in ciprofloxacin. A broad absorption near 3400 cm '. associated with O-H and N-H stretching, also appears in both spectra, confirming the retention of hydrogen-bonding groups.

Importantly, no new peaks were observed in the DESOLVE spectrum that would suggest degradation products, chemical modification, or significant interaction with excipients. The absence of peak shifts or significant intensity changes further supports that the ciprofloxacin structure remains intact. This spectral similarity strongly suggests that the formulation process does not compromise the molecular integrity of ciprofloxacin. Therefore, the FTIR data confirm that ciprofloxacin is chemically stable in the DESOLVE matrix, retaining its original functional groups and structural features.

SEM characterisation of samples for inhalation

The surface morphology of the powders was elucidated by SEM at 15 kV and different magnification ranges from 100X to 10000X.

The micrograph reveals spherical, well-defined particles with a relatively narrow size distribution and minimal evidence of agglomeration. The smooth and dense particle surfaces indicate successful spray drying and encapsulation of the drug within the emulsion matrix. Notably, the absence of irregular or collapsed particles suggests effective stabilisation by the Brij 97 surfactant and the structural support provided by the beeswax. The observed particle sizes appear consistent with the aerodynamic findings from ACI testing. The morphological uniformity observed supports the efficiency of the emulsion formulation and atomization during spray drying, leading to reproducible microparticles suitable for pulmonary or topical respiratory delivery. The DES system comprising urea and glycolic acid may have contributed to the smooth, non-porous morphology due to its plasticising and hygroscopic properties, enhancing flowability and minimising surface crystallisation. The micrographs were similar in appearance to those shown by Figure 2.

In vitro drug release profile of samples for inhalation

The in vitro release rate of ciprofloxacin was determined by the dialysis bag method. 50 mg of powder was weighed in a dialysis bag and immersed in 25 mb of SLF (pH 7) under slow continuous stirring at 37°C within time intervals of 0.5h and 24h. After a each time period, 1 mL of supernatant was centrifuged at 5000 rpm for 2 minutes using an Eppendorf 5452 MiniSpin Micro Centrifuge, Germany, and then filtered using a 0.22pm filter syringe. The same volume of fresh SLF was added to replace the amount withdrawn after each sampling. The concentration of the released drug was measured by HPLC at 278 nm. The cumulative percentage of the released drug was calculated in agreement with a calibration curve. HPLC was performed on a C18 analytical column (Avantor® ACE®, 75 x 4.6 mm) at a flow rate of 1 mL/min and the injection volume was 20 pL. The mobile phase is composed of a 95:5 (v/v) mixture of acidified HPLC water (using 0.1% trifluoroacetic acid) and acetonitrile. The peaks were identified by the UV detector at 278 nm, and the calibration curve showed linear behaviour (R² = 0.9979) across the concentration range of 10-100 pg/mL and was fitted to the linear equation of A = 144.3*X - 769.9.

Figure 7 of the accompanying drawings shows the results of this study. It was found that the ciprofloxacin was released in a controlled manner over more than 6 hours.

Aerosol performance of samples for inhalation

The aerosolisation performance of the DESOLVE particles was evaluated using an Andersen Cascade Impactor (ACI; Copley Scientific, Nottingham, UK), providing key metrics for assessing respirable drug delivery efficiency. To improve powder flowability, spray-chilled ciprofloxacin-loaded powders were mixed with lactose at a 1 : 1 weight ratio. A total of 30 mg of the powder-lactose blend was filled into HPMC capsules, which were then loaded into an RS01 dry powder inhaler (DPI) device for testing. The ACI setup included an induction port connected to a flow meter, which was used to confirm and maintain a flow rate of 60 L/min. After adjusting the desired flow rate, the DPI device was attached to the induction port, and the dose was released. The ACI consisted of eight stages (Stage 0 to Stage 7) with aerodynamic cut-off diameters of 8.6, 6.5, 4.4, 3.3, 2.0, 1.1, 0.54, and 0.25 pm, respectively. For each test run, powder aerosolisation time was set to 4 seconds to ensure complete deposition of particles onto the ACI plates. Each stage plate was subsequently rinsed with 10 mL of simulated lung fluid, and the collected samples were filtered using a 0.22 pm syringe filter. The ciprofloxacin concentration in each stage was quantified by HPLC at 278 nm. All measurements were performed in triplicate, and results were reported as mean values. The Mass Median Aerodynamic Diameter (MMAD) was determined to be 6.46 un, with a Geometric Standard Deviation (GSD) of 1.32, indicating a moderately narrow particle size distribution. An MMAD above 5 pm typically suggests predominant deposition in the upper respiratory tract (e.g., oropharyngeal region), which may be suitable for local treatment strategies such as topical drug action in the nasal or oropharyngeal cavity rather than deep lung delivery.

The Emitted Dose (ED) was measured at 202.28 mg, reflecting the total amount of formulation discharged from the device. Of this, the Fine Particle Dose (FPD) — representing particles under 5 pm capable of reaching the lower airways — was 59.64 mg, corresponding to a Fine Particle Fraction (FPF) of 29.48%. This level of FPF is within the expected range for formulations intended for targeted regional deposition rather than systemic delivery via the deep lung. The Coarse Particle Fraction (CPF) was 70.52%, supporting the interpretation that the formulation is primarily deposited in the upper respiratory tract.

These findings suggest that DESOLVE generates an aerosol with aerodynamic properties aligned with localised drug delivery that can be seen in some lung infections. The relatively low GSD indicates a controlled particle dispersion, while the modest FPF is consistent with a design focus on retention in the upper airways rather than alveolar penetration. Together with the FTIR data confirming structural integrity, the ACI results indicate that DESOLVE effectively preserves ciprofloxacin’s stability while delivering it in a particle size range suited for targeted mucosal deposition.

Table 1: Aerosolisation parameters obtained using ACI Microbiological assessment

The antibacterial effects of DESOLVE particles comprising either ciprofloxacin (“DESOLVE CFX”) or erythromycin (“DESOLVE Eryth”) were assessed. Four bacterial isolates were used in this study. Two clinical isolates, Staphylococcus aureus and Klebsiella pneumoniae, were collected from microbiology laboratories at different hospitals in Amman, Jordan. The other two isolates were standard reference strains: Pseudomonas aeruginosa (ATCC 27853) and Acinetobacter baumannii (ATCC 19606), both acquired from the American Type Culture Collection (ATCC). All isolates were sub-cultured and maintained at the microbiology laboratory of the Pharmaceutical and Drug Research Center (PDRC), Al-Ahliyya Amman University. They were cultured on Mueller Hinton Agar (MHA) (Oxoid, UK) and incubated under ambient air conditions at 37°C.

To evaluate the antimicrobial activity of the slow-release DESOLVE formulations, a small amount of each formulation (ciprofloxacin- or erythromycin-loaded) was applied directly onto MHA plates previously inoculated with the bacterial suspensions. No solvents were used, preserving the structural integrity of the formulations and allowing for gradual drug diffusion. This method was chosen to better reflect the intended controlled-release behaviour of DESOLVE in practical use, for example when administered by inhalation. Plates were incubated at 37 °C for 18-24 hours before assessing inhibition zones.

Figure 8 of the accompanying drawings shows representative plates for Klebsiella pneumoniae (treated with DESOLVE CFX), Pseudomonas aeruginosa (treated with DESOLVE CFX), Acinetobacter baumannii (treated with DESOLVE CFX), and Staphylococcus aureus (treated with DESOLVE Eryth).

All plates showed circles around the formulations, indicating that the ciprofloxacin and the erythromycin maintained their antibacterial effects following formulation in DESOLVE particles.

Claims

1. A composition suitable for administration via the gastrointestinal tract or the respiratory tract, wherein the composition comprises a deep eutectic mixture, a wax and a biologically active agent.

2. The composition of claim 1, wherein the composition further comprises a surfactant.

3. The composition of claim 2, wherein the surfactant is polyoxyethylene (10) oleyl ether.

4. The composition of claim 2 or claim 3, wherein the composition comprises the surfactant in an amount of from 8% to 40% by weight.

5. The composition of any preceding claim, wherein the composition contains 1 wt% or less, for example no, water.

6. The composition of any preceding claim, wherein the composition comprises 20wt% or less, for example no, volatile organic solvent.

7. The composition of any preceding claim, wherein the wax is selected from the list consisting of: carnauba wax, beeswax, paraffin wax, candelilla wax, microcrystalline wax, shellac wax, polyethylene glycol wax, rice bran wax, and montan wax.

8. The composition of any preceding claim, wherein the composition comprises the wax in an amount, relative to the total weight of the composition, of from 30 to 70% by weight.

9. The composition of any preceding claim, wherein the deep eutectic solvent is glycerol/urea.

10. The composition of any preceding claim, wherein the composition comprises the eutectic mixture in an amount, relative to the total weight of the composition, of from 8 to 40% by weight.

1 1. The composition of any preceding claim, wherein the biologically active agent is selected from the list consisting of: a phenolic anti-fungal agent, a penicillin, a quinolone, a macrolide antibiotic, and a xanthine.

12. The composition of claim 1 1, wherein the biologically active agent is selected from the list consisting of: erythromycin, ciprofloxacin, griseofulvin, flucioxacillin and theophylline.

13. The composition of any preceding claim, wherein the composition comprises the biologically active agent in an amount, relative to the total weight of the composition, of from 0.1 to 20% by weight.

14. The composition of claim 3, wherein:

- the composition comprises the surfactant in an amount of from 8% to 40% by weight;

- the wax is selected from the list consisting of: carnauba wax, beeswax, paraffin wax, candelilla wax, microcrystalline wax, shellac wax, polyethylene glycol wax, rice bran wax, and montan wax;

- the composition comprises the wax in an amount, relative to the total weight of the composition, of from 30 to 70% by weight;

- the deep eutectic solvent is glycerol/urea; and

- the composition comprises the eutectic mixture in an amount, relative to the total weight of the composition, of from 8 to 40% by weight.

15. The composition of claim 14, wherein the biologically active agent is selected from the list consisting of: erythromycin, ciprofloxacin, griseofulvin, flucioxacillin and theophylline.

16. The composition of claim 15, wherein the composition:

- contains 1 wt% or less, for example no, water; and

- comprises 20wt% or less, for example no, volatile organic solvent.

17. An article that is a solid single unit or a powder, wherein the article comprises a composition of any one of claims 1 to 16.

18. The article of claim 17, wherein the article is a solid single unit that has a torpedo or bullet-like shape, and is for use as a suppository.

19. The article of claim 17, wherein the article is a powder that has an average particle size of 30 pm or less.

20. A composition of any one of claims 1 to 16 or an article of any one of claims 17 to 19 for use as a medicament.

21 . The composition or the article of claim 20, wherein the composition or the article is for use in a method of treatment, wherein the method comprises administering the composition or the article via the gastrointestinal tract or the respiratory tract.

22. The composition or the article of claim 21, wherein the method comprises administering the composition or the article via the respiratory tract.

23. A method of preparing a composition, the method comprising the steps of: a) providing a melted wax; b) mixing the melted wax with a deep eutectic solvent and a biologically active agent to provide a mixture; and c) cooling the mixture in the desired form to provide the composition in a solid form.

24. The method of claim 23, wherein step c) comprises: i) spray chilling the mixture to provide a powder; or ii) providing the mixture to one or more moulds and allowing the mixture to cool to provide one or more solid single units.