WO2025262119A1 - Solid pharmaceutical compositions - Google Patents

Abstract

In summary, a solid composition comprising a polymer and a liquid, wherein the liquid comprises a pharmaceutical compound or a salt thereof and one or more further components is described. A solid dosage form comprising such a composition, and a method of preparing the composition are also described.

Description

Solid Pharmaceutical Compositions

Field of the Invention

The present invention relates to a solid composition comprising a polymer and a pharmaceutical compound-containing liquid; a solid dosage form comprising such a composition, and a method of preparing such a composition. In particular, the invention relates to a powder comprising a polymer and a pharmaceutical compound-containing liquid.

Background of the Invention

Advancements in drug discovery often lead to new drug molecules with increased lipophilicity, poor solubility or stability, making their delivery to the target site challenging. Suboptimal physicochemical characteristics follow, giving rise to variable pharmacokinetic profiles and necessitating intricate formulation strategies. The majority of marketed drug molecules belong to class II, III, or IV, according to the Biopharmaceutical Classification System (BCS). In all these cases the Active Pharmaceutical Ingredients (APIs) have suboptimal bioavailability when administered orally. Conventional formulation techniques cannot always overcome solubility and permeability limitations to achieve a therapeutic effect within reasonable dose ranges. Numerous formulation approaches have been developed to improve oral bioavailability, including formation of amorphous and self-emulsifying solid dispersions, advanced crystal engineering, co-processed APIs, polymer nanocarrier based systems, liquisolid technologies, and lipid-based delivery systems.

Ionic liquids (ILs), a class of organic salts made solely of ions with melting points below 100 °C, are the subject of intense investigation for the past three decades. ILs typically are asymmetric molecules, with bulky ions and delocalised charge, which renders the formation of ordered crystal structures very difficult. Thus, ILs have an unusually low melting point because of their low lattice enthalpy. API-ILs form when an ionisable API is paired with a non-toxic, inert counterion or with a pharmaceutically active counterion (dual functional API-ILs). By virtue of being liquids, API-ILs evade issues related to the solid state, and exhibit increased solubility, due to high ionicity and lack of significant crystal lattice energy that needs to be overcome via dissolution. It has also been proposed that ILs form ion-pairs in aqueous environments, instead of ions dissociating and dissolving independently, which increases the API's membrane permeability.

Despite their advantages, ionic liquids exist as highly viscous liquids or waxes, which complicates their handling, processing, and formulation. To overcome these limitations, API-ILs have been immobilized in materials like ionogels, mesoporous silica, and as amorphous solid dispersions (ASDs).

Deep eutectic solvents (DESs) are a class of compounds broadly related to ILs that are currently defined as mixtures of Lewis or Bnansted acidic hydrogen bond donors (HBDs) and basic hydrogen bond acceptors (HBAs) that may or may not be ionised. In the context of drug delivery DESs can be used in a number of ways. For example, DESs can be used as an adjuvant solvent to improve API bioavailability where the API is dissolved in a DES and then administered orally. Such systems can include DESs based on naturally occurring components (NaDES), Additionally, formulations comprised of DES may include additional auxiliary components such as polymeric precipitation inhibitors, or non-ionic lipidic surfactants An alternative strategy approach for increasing bioavailability involves forming a DES from the API molecule directly with a eutectic constituent(s) at various molar ratios. APIs maybe used in this way as their free acid or base form or also as salts. Collectively these are referred to as therapeutic deep eutectic solvents, or THEDES.

Lipid-based formulations (LBFs) are self-emulsifying drug delivery systems (SEDDS) commonly used in the pharmaceutical industry to improve the bioavailability of BCS Class II and IV drugs and to improve the apparent aqueous solubility of BCS Class II and IV drugs. The key constituents found within lipid-based formulations (LBFs) are glycerides (mono, di and tri - glycerides), surfactants and cosolvents. They promote the in vivo drug dispersion and solubilisation, and thereby increase the oral bioavailability while reducing the impact of food on the API’s bioavailability. LBFs trigger the bile-mediated absorption which improves gastrointestinal (Gl) fluids' solubilisation capacity and induce lymphatic transport instead of transport through the portal vein, bypassing the first-pass metabolism in the liver. Moreover, they offer prolonged residence time in the Gl tract which provides more time for drug dissolution and absorption across intestinal epithelium membranes. Additionally, they can improve drug stability by protecting it from degradation within the acidic environments of the stomach. LBFs bypass the traditional dissolution processes and facilitate solubilisation of both the API and lipid digestion products within bile salt micelles. As a result, the API is efficiently molecularly dispersed, existing in rapid equilibrium with its free form, which ultimately facilitates optimal absorption. By adopting this approach, LBFs harness natural fat digestion processes while leveraging on the inherent solubilising abilities of mixed micelles composed of bile salts and lecithin. Such design principles contribute towards improving oral bioavailability for challenging APIs.

LBFs are usually in liquid or semiliquid form and are used as liquid-filled hard gelatine capsules or lipid multi-particulate finished dosage forms. Their commercial success has been limited thus far due to low drug loading, poor in vitro - in vivo correlation (IVIVC), limited stability and portability of liquid formulations, predisposition for API crystallisation and precipitation in vivo, and expensive manufacturing and distribution processes.

Summary of the Invention

It is one aim of the present invention, amongst others, to provide a solid dosage form that addresses at least one disadvantage of the prior art, whether identified here or elsewhere, or to provide an alternative to existing solid dosage forms. For instance, it may be an aim of the present invention to provide a solid dosage form which has high bioavailability.

According to aspects of the present invention, there is provided a composition, a solid dosage form, and a method as set forth in the appended claims. Other features of the invention will be apparent from the dependent claims, and the description which follows.

According to a first aspect of the present invention, there is provided a solid composition comprising a polymer and a liquid, wherein the liquid comprises a pharmaceutical compound or a salt thereof and one or more further components.

The inventors have found that it is possible to formulate pharmaceutical compounds in liquids in solid compositions (such as powders) by combining the liquid with a polymer. These compositions may have the advantage of bioavailability associated with liquids.

The compositions of the present invention are solid compositions at room temperature. By the term “solid composition” we mean a composition that can be handled and formulated as a solid. Such solid compositions include two-phase compositions, for example that may comprise some liquid, but which can be handled and formulated as a solid. Such solid compositions offer advantages in use of ease of handling and administration as typically associated with solid compositions.

The solid composition may be in any suitable solid form. Suitably, the solid composition is in a solid form obtainable by spray drying. Preferably, the solid composition is in the form of a powder.

Any suitable polymer may be included in the compositions of the present invention.

Suitable polymers may be selected from a polysaccharide, a polysaccharide derivative, a polyvinyl ester (such as polyvinyl acetate), an aliphatic polyester (such a poly(glycolic acid) and copolymers thereof), a polyester (such as polycaprolactone), shellac, a (meth)acrylic acid based polymer, and mixtures thereof. Examples of suitable copolymers of poly(glycolic acid) include, for example, poly(lactic-co- glycolic acid, poly(glycolide-co-caprolactone) and poly (glycolide-co-trimethylene carbonate).

Examples of suitable polysaccharides include maltodextrin and sodium alginate. Preferably, the polysaccharide comprises maltodextrin.

Examples of suitable polysaccharide derivatives include cellulose derivatives, such as a cellulose ester (such as cellulose acetate, cellulose acetate phthalate, and cellulose acetate butyrate,) or cellulose ether (such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxylpropyl cellulose, and carboxymethyl cellulose). Suitably, the cellulose derivative is selected from cellulose acetate, ethyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof. Preferably, the cellulose derivative is selected from cellulose acetate, ethyl cellulose and a mixture of ethyl cellulose and hydroxypropyl methyl cellulose. Mixtures of ethyl cellulose and hydroxypropyl methyl cellulose suitably comprise ethyl cellulose and hydroxypropyl methyl cellulose in a ratio of from 90:10 to 10:90 by weight, for example 75:25 or 50:50 by weight.

Examples of suitable (meth)acrylic acid based polymers include poly(meth)acrylate, (meth)acrylic acid copolymers, ammonio methacrylate, ammonio methacrylate copolymer type A, ammonio methacrylate copolymer type B, methacrylic acid copolymer type A, methacrylic acid copolymer type B, methacrylic acid copolymer type C, amino dimethyl methacrylate copolymers and amino diethyl methacrylate copolymers.

As used herein and as conventional in the art, use of “(meth)acrylate”, and like terms, refers to both methacrylate and acrylate.

Suitably, the polymer comprises a polysaccharide, a cellulose derivative, a (meth)acrylic acid based polymer, or a mixture thereof. Preferably, the polymer comprises a cellulose derivative.

Suitable ethyl celluloses include, for example, Ethocel Standard 10 Premium and Ethocel Standard 4 Premium (from Dow Wolff Cellulosics GmbH., Bomlitz, Germany).

Suitable maltodextrins include, for example, Glucidex 6D and Glucidex 19D (from Roquette Freres, Lestrem, France).

A suitable methacrylic acid copolymer is, for example, Eudragit L100 (from Evonik Industries, Essen, Germany). In some embodiments, the polymer is selected from maltodextrin, cellulose acetate, ethyl cellulose, hydroxypropyl methyl cellulose, a (meth)acrylic acid copolymer, and mixtures thereof.

In some embodiments the polymer is immiscible with the liquid at room temperature. By this we mean that the polymer has sufficiently low solubility in the liquid that the polymer and the liquid exist as two phases within the composition. In such embodiments the polymer suitably encapsulates the liquid, for instance by forming a matrix, solid phase support or surround in which the liquid is held. The inventors have surprisingly found that the dissolution properties of an liquid in such a system are not significantly affected by the polymer, even where the polymer itself does not fully dissolve in the dissolution medium. This is advantageous as it allows the composition to be formulated without negatively affecting the performance of the liquid. These embodiments also allow the inclusion of polymers having lower glass transition temperatures than if the polymer and liquid were intimately mixed, since the liquid does not cause depression of the glass transition temperature of the polymer.

Suitable polymers that are selected as being immiscible with the liquid at room temperature will, of course, depend on the particular liquid being used. Typically, examples of suitable polymers that are immiscible with the liquid at room temperature may be selected from a polysaccharide derivative, a polyvinyl ester (such as polyvinyl acetate), an aliphatic polyester (such as poly(glycolic acid) and copolymers thereof), a polyester (such as polycaprolactone), shellac, a (meth)acrylic acid based polymer, and mixtures thereof.

In other embodiments the polymer is miscible with the liquid at room temperature. By this we mean that the polymer has sufficiently high solubility in the liquid that the polymer and the liquid form a single continuous phase within the composition. In such embodiments the polymer and the liquid typically form a single phase solid dispersion or solid solution. Compositions comprising the polymer and the liquid in a single phase may be particularly suitable for preparing a solid dosage form by a compression-based technique, such as roller compaction granulation or direct compression.

Suitable polymers that are selected as being miscible with the liquid at room temperature will, of course, depend on the particular liquid being used. Typically, suitable polymers that are miscible with the liquid at room temperature include polysaccharides.

The polymer may have a glass transition temperature (T_g) of greater than 80 °C, suitably greater than 100 °C, for example greater than 150 °C. The polymer may have a glass transition temperature (T_g) of greater than 80 °C, suitably greater than 100 °C, for example greater than 150 °C, and may be miscible with the liquid at room temperature.

The polymer may have a glass transition temperature (T_g) of less than 80 °C, suitably less than 60 °C, for example less than 20 °C.

The polymer may have a glass transition temperature (T_g) of less than 80 °C, suitably less than 60 °C, for example less than 20 °C, and may be immiscible with the liquid at room temperature.

The polymer may be substantially insoluble in water at room temperature, by which we mean that no more than 1 g of the polymer will dissolve in 1 ,000 ml of water. The polymer may be substantially insoluble in water at 37 °C. A suitable example of a polymer which is substantially insoluble in water at room temperature is ethyl cellulose.

Alternatively, the polymer may be soluble in water at room temperature, by which we mean that 1 g of the polymer will dissolve in in 30 ml or less of water. The polymer may be soluble in water at 37 °C. A suitable example of a polymer which is soluble in water at room temperature is maltodextrin.

By the term “room temperature” we mean a temperature of from 15 to 30 °C, suitably from 20 to 25 °C, for example about 20 °C.

The solid composition according to the first aspect comprises a liquid. The liquid comprises a pharmaceutical compound or a salt thereof and one or more further components. The liquid is suitably liquid at room temperature. The solid composition is suitably formed from the polymer and the liquid.

Any suitable pharmaceutical compound or a salt thereof may be included in the compositions of the present invention. Examples thereof include aspirin, ibuprofen, ranitidine hydrochloride, and ritonavir. Salts of pharmaceutical compounds are suitably pharmaceutically acceptable salts.

The one or more further components in the liquid may comprise a pharmaceutical compound or a salt thereof as defined herein.

By the term “pharmaceutical compound” we mean a chemical compound that has pharmaceutical activity, for example so as to be effective to treat or prevent a disease or symptom in a warm-blooded animal such as a human. The pharmaceutical compound may alternatively be defined as an active pharmaceutical ingredient (API). The pharmaceutical compound orthe salt thereof may be an ionic liquid. By the term “ionic liquid” we mean a salt (i.e. a salt of the pharmaceutical compound) that melts below 100 °C. The ionic liquid may have a melting point of less than 100 °C, suitably less than 40 °C, for example less than 25 °C. Suitably, the ionic liquid is liquid at room temperature. The ionic liquid may be liquid at 37 °C. The ionic liquid may be alternatively defined as a molten salt or a lipophilic salt. The ionic liquid may be an oligomeric ionic liquid, in which the anions and cations are not in a 1 :1 stoichiometric ratio.

The ionic liquid is a salt of a pharmaceutical compound having an ionisable group. Suitable ionisable groups include carboxylic acid groups, hydroxyl groups, and amine groups.

Examples of suitable pharmaceutical compounds having an ionisable group include chlorpromazine and metformin.

The ionic liquid comprises an ion of the pharmaceutical compound and a counterion. Suitably, the counterion is pharmaceutically acceptable. In embodiments where the ion of the pharmaceutical compound is a cation, the counterion is an anion. In embodiments where the ion of the pharmaceutical compound is an anion, the counterion is a cation. The counterion may be an organic ion. The counterion may comprise at least 4, suitably at least 5, for example at least 6 carbon atoms. In some embodiments the counterion is selected from 1-butyl-3-methyl imidazolium, choline, saccharin, and docusate. In some embodiments, the counterion may be the ion of another pharmaceutical compound. In such embodiments the ionic liquid comprises the ions of two or more different pharmaceutical compounds.

Methods of forming ionic liquids will be known to those skilled in the art. Such methods include acid-base neutralisation or the reaction of two or more salts. For example, the ionic liquid may be formed by reacting together a first salt and a second salt, wherein the first salt comprises the ion of the pharmaceutical compound, and the second salt comprises the counterion of the ionic liquid. For example, the first salt and the second salt comprise inorganic ions (such as sodium and chloride) that combine to form an inorganic salt. This inorganic salt can then be separated from the ionic liquid.

Examples of suitable ionic liquids include chlorpromazine docusate and metformin docusate.

In some embodiments, the pharmaceutical compound or the salt thereof is not an ionic liquid. In such embodiments, the pharmaceutical compound or the salt thereof may have a melting point of at least 25 °C, suitably at least 40 °C, for example at least 100 °C. The pharmaceutical compound or the salt thereof may be solid at room temperature. The pharmaceutical compound or the salt thereof may be solid at 37 °C.

The pharmaceutical compound or the salt thereof may be soluble in aqueous media over a pH range of 1 to 6.8 at 37±1 °C. A single therapeutic dose of the pharmaceutical compound or the salt thereof may not be completely soluble in 250 mL or less of aqueous media over a pH range of 1 to 6.8 at 37±1 °C. The pharmaceutical compound or the salt thereof may have high solubility as per the Biopharmaceutics Classification System. For example, the pharmaceutical compound or the salt thereof may be classified as Class 1 or Class 3 according to the Biopharmaceutics Classification System.

Alternatively, the pharmaceutical compound or the salt thereof may be insoluble in aqueous media over a pH range of 1 to 6.8 at 37±1 °C. A single therapeutic dose of the free acid or free base of the pharmaceutical compound may not be completely soluble in 250 mL or less of aqueous media over a pH range of 1 to 6.8 at 37±1 °C. The pharmaceutical compound or the salt thereof may have low solubility as per the Biopharmaceutics Classification System. For example, the pharmaceutical compound or the salt thereof may be classified as Class 2 or Class 4 according to the Biopharmaceutics Classification System.

The pharmaceutical compound or the salt thereof may have low permeability as per the Biopharmaceutics Classification System. For example, the pharmaceutical compound or the salt thereof may be classified as Class 3 or Class 4 according to the Biopharmaceutics Classification System.

The weight ratio of the liquid to the polymer in the solid composition may be from 10:90 to 90:10, suitably from 25:75 to 90:10, for example from 40:60 to 90:10.

Suitably, the solid composition comprises water in an amount of less than 10 wt%, suitably less than 5 wt%, for example less than 1 wt% based on the total weight of the solid composition. The solid composition may be substantially free of water. By “substantially free” we mean that water, if present, is only present in trace amounts (i.e. less than 0.1 wt%, preferably less than 0.01 wt% based on the total weight of the solid composition). In some embodiments, the solid composition is completely free of water.

The solid composition may comprise the liquid and the polymer in separate phases, for example at room temperature. In this embodiment the liquid is suitably encapsulated by the polymer, which may be in the form of a matrix, solid phase support or surround. It may be determined that the solid composition comprises the liquid and the polymer in separate phases by the presence of one or more transition temperatures (such as a glass transition temperature or a melting point) in a differential scanning calorimetry (DSC) thermogram within ±5 °C of transition temperatures of the liquid and/or the polymer in the absence of the other.

Alternatively, the solid composition may comprise the liquid and the polymer in a single phase, for example as a single phase solid dispersion or solid solution. The single phase solid dispersion or solid solution may have a glass transition temperature of at least 60 °C, suitably at least 80 °C, for example at least 100 °C. The glass transition temperature of the dispersion is typically in between the melting point or glass transition temperature of the liquid and the glass transition temperature of the polymer.

The liquid is suitably non-volatile. The liquid suitably has a boiling point of at least 100 °C, such as at least 150 °C. Suitably at least 50 wt% of the components in the liquid (i.e. the pharmaceutical compound or the salt thereof and the one or more further components) based on the total weight of the liquid have a boiling point of at least 100 °C, such as at least 150 °C. Preferably at least 75 wt% of the components in the liquid have a boiling point of at least 100 °C, such as at least 150 °C. In some embodiments, at least 90 wt% of the components in the liquid have a boiling point of at least 100 °C, such as at least 150 °C.

The one or more further components in the liquid suitably comprises a liquid carrier. By “liquid carrier” we mean a substance which, even in the absence of the pharmaceutical compound or the salt thereof, is liquid at room temperature.

The pharmaceutical compound or the salt thereof is suitably in solution with the liquid carrier. The pharmaceutical compound or the salt thereof may be a solid prior to dissolution in the liquid carrier. Alternatively, the pharmaceutical compound or the salt thereof may be a liquid prior to mixing with the liquid carrier. In some embodiments, the composition comprises the salt of the pharmaceutical compound, and the salt is an ionic liquid.

The liquid carrier may comprise a lipid-based formulation, a deep eutectic solvent, or an ionic liquid.

The liquid carrier may comprise a lipid-based formulation. The lipid-based formulation suitably comprises a lipid. Suitable lipids include glycerides of fatty acids, such as monoglycerides, diglycerides and triglycerides of fatty acids, preferably monoglycerides, diglycerides and triglycerides of C12 to C22 fatty acids. Preferably, the lipid comprises glycerides of unsaturated fatty acids, such as monoglycerides, diglycerides and triglycerides of unsaturated C12 to C22 fatty acids, preferably monoglycerides, diglycerides and triglycerides of oleic acid. The lipid-based formulation may comprise the lipid in an amount of from 10 to 100 wt%, suitably from 20 to 75 wt%, such as from 25 to 40 wt%, for example 30 wt% based on the total weight of the lipid-based formulation.

The lipid-based formulation may comprise a surfactant. The surfactant is suitably a non-ionic surfactant. The surfactant is suitably water-dispersible. The surfactant may comprise one or more carboxylic acid esters. The carboxylic acid esters are suitably formed from a polyol and a carboxylic acid. Suitable polyols include polyalkylene glycols (such as polyethylene glycol), glycerol, and mixtures thereof. Suitably carboxylic acids include saturated C4 to C14 carboxylic acids, preferably saturated Ce to C12 carboxylic acids such as caprylic acid and capric acid. In some embodiments, the surfactant comprises monoglycerides, diglycerides and triglycerides of caprylic acid and capric acid and polyethylene glycol monoesters and diesters of caprylic acid and capric acid. The lipid-based formulation may comprise the surfactant in an amount of from 0 to 90 wt%, suitably from 20 to 80 wt%, such as from 40 to 70 wt%, for example 60 wt% based on the total weight of the lipid-based formulation.

The lipid-based formulation may comprise a cosolvent. The cosolvent is suitably water-miscible. The cosolvent may comprise an alcohol, suitably an alkanol such as ethanol. The lipid-based formulation may comprise the cosolvent in an amount of from 0 to 40 wt%, suitably from 3 to 25 wt%, such as from 5 to 15 wt%, for example 10 wt% based on the total weight of the lipid-based formulation.

The lipid-based formulation suitably comprises a lipid, a surfactant and a cosolvent.

The lipid-based formulation may comprise: a lipid in an amount of from 20 to 75 wt%, such as from 25 to 40 wt%, for example 30 wt% based on the total weight of the lipid-based formulation; a surfactant in an amount of from 20 to 80 wt%, such as from 40 to 70 wt%, for example 60 wt% based on the total weight of the lipid-based formulation; and a cosolvent in an amount of from 3 to 25 wt%, such as from 5 to 15 wt%, for example 10 wt% based on the total weight of the lipid-based formulation

In some embodiments, the liquid carrier is a lipid-based formulation and the pharmaceutical compound or the salt thereof is an ionic liquid.

The liquid carrier may comprise a deep eutectic solvent. By “deep eutectic solvent” we mean a mixture of eutectic constituents, wherein the melting point of the mixture is lower than the melting point of any of the pure eutectic constituents. Deep eutectic solvents typically comprise mixtures of Lewis or Bnansted acidic hydrogen bond donors (HBDs) and basic hydrogen bond acceptors (HBAs) that may or may not be ionised. Suitably, the deep eutectic solvent is liquid at room temperature. Suitably, one or more of the pure eutectic constituents are solid at room temperature.

Suitable deep eutectic solvents will be known to those skilled in the art. The deep eutectic solvent is preferably pharmaceutically acceptable. The deep eutectic solvent suitably comprises a mixture of organic compounds and/or salts of organic compounds.

The deep eutectic solvent may comprise an amine compound (such as a secondary or tertiary amine compound), a quaternary ammonium compound, an amide compound, a carboxylic acid (such as a polycarboxylic acid), a polyol, or mixtures thereof. The deep eutectic solvent may comprise components selected from choline, choline chloride, betaine, nicotinamide, malic acid, propylene glycol, citric acid, glycerol, acetamide, fructose, glucose, lactic acid, geranic acid and mixtures thereof.

The molar ratio of each eutectic constituent to each other eutectic constituent in the deep eutectic solvent is suitably from 1 :2 to 1 :4, for example 1 :2, 1 :3 or 1 :4.

Examples of suitable deep eutectic solvents include: choline chloride and propylene glycol (suitably in a molar ratio of 1 :3); betaine and citric acid (suitably in a molar ratio of 1 :1); nicotinamide and propylene glycol (suitably in a molar ratio of 1 :4); malic acid and propylene glycol (suitably in a molar ratio of 1 :2); triethyl citrate, malic acid and propylene glycol (suitably in a molar ratio of 1 :2:4); malic acid and glycerol (suitably in a molar ratio of 1 :2), and choline and geranic acid (suitably in a molar ratio of 1 :2).

In some embodiments, the liquid carrier is a deep eutectic solvent and the pharmaceutical compound or the salt thereof is not an ionic liquid.

The liquid carrier may comprise an ionic liquid. The ionic liquid suitably does not comprise the pharmaceutical compound or the salt thereof. The ionic liquid may have a melting point of less than 100 °C, suitably less than 40 °C, for example less than 25 °C. Suitably, the ionic liquid is liquid at room temperature. The ionic liquid may be liquid at 37 °C.

The ionic liquid may comprise an oligomeric ionic liquid, such the choline salt of geranic acid (CAGE).

The liquid may be a deep eutectic solvent, wherein the deep eutectic solvent comprises the pharmaceutical compound or the salt thereof as a eutectic constituent. In such an embodiment, the liquid suitably does not comprise a liquid carrier as defined above. The deep eutectic solvent suitably comprises one or more further eutectic constituents (corresponding to the “one or more further components” defined in relation to the solid composition of the first aspect). The one or more further eutectic constituents may comprise a pharmaceutical compound or a salt thereof. The one or more further eutectic constituents may comprise a non-pharmaceutical compound or a salt thereof (which is preferably pharmaceutically acceptable).

Suitable eutectic constituents include amine compounds (such as secondary or tertiary amine compounds), quaternary ammonium compounds, amide compounds, carboxylic acids (such as polycarboxylic acids), polyols, or mixtures thereof. Suitable pharmaceutical compounds or salts thereof that may be used as eutectic constituents include ibuprofen, aspirin, ranitidine hydrochloride, ritonavir, itraconazole hydrochloride, propranolol hydrochloride, sodium cefazolin, disodium fosfomycin and mixtures thereof. Suitable non-pharmaceutical compounds or salts thereof that may be used as eutectic constituents include choline, choline chloride, betaine, nicotinamide, malic acid, propylene glycol, citric acid, glycerol, acetamide, fructose, glucose, lactic acid, geranic acid and mixtures thereof.

The molar ratio of each eutectic constituent to each other eutectic constituent in the deep eutectic solvent is suitably from 1 :2 to 1 :4, for example 1 :2, 1 :3 or 1 :4.

Examples of suitable deep eutectic solvents comprising a pharmaceutical compound or a salt thereof as a eutectic constituent include: choline chloride and aspirin (suitably in a molar ratio of 2:1); ranitidine hydrochloride and aspirin (suitably in a molar ratio of 2:1); ranitidine hydrochloride and glycerol (suitably in a molar ratio of 2:1); ritonavir and malic acid (suitably in a molar ratio of 1 :1); and ritonavir, malic acid and glycerol (suitably in a molar ratio of 1 :1 :2).

In some embodiments, the deep eutectic solvent itself has a pharmaceutical effect, such as choline and geranic acid in a molar ratio of 1 :2.

In some preferred embodiments, the solid composition of the first aspect comprises a polymer and a liquid, wherein the liquid comprises a pharmaceutical compound or a salt thereof and one or more further components, wherein the one or more further components suitably comprises a liquid carrier or one or more eutectic constituents. Preferably, the solid composition is substantially free or completely free of water.

According to a second aspect of the present invention, there is provided a solid dosage form comprising the solid composition of the first aspect. Preferably, the solid dosage form is an oral solid dosage form.

The suitable features and advantages of the solid composition in the second aspect are as defined in relation to the first aspect. The solid dosage form may be in the form of a tablet, capsule, caplet, cachet, lozenge, film, granulate, beads, or powder.

The solid dosage form may comprise the solid composition of the first aspect in the form of a loose powder or in a compacted form (e.g. compacted from a loose powder). For example, the solid dosage form may be a tablet comprising the composition of the first aspect in a compacted form.

The solid dosage form may be in the form of beads coated with the solid composition of the first aspect. The core of the beads may be physiologically inert. The core of the beads may be biodegradable.

The solid dosage form may be an immediate release dosage form or a modified release dosage form. In embodiments where the composition of the first aspect comprises the liquid and the polymer in separate phases, the solid dosage form is suitably an immediate release dosage form. The modified release dosage form may suitably comprise an enteric coating. Suitably the enteric coating prevents the solid dosage form from disintegrating or dissolving at a pH of less than 3, for example less than 2.

The solid dosage form may comprise conventional pharmaceutical carriers or excipients known in the art. The solid dosage form may comprise conventional additional components, such as, for example, one or more glidants, disintegrants, binders, coating agents, colouring agents, sweetening agents, flavouring agents and/or preservative agents.

According to a third aspect of the present invention, there is provided a method of preparing the solid composition of the first aspect, comprising the steps of:

(a) forming a solution comprising a polymer, a liquid, and a solvent, wherein the liquid comprises a pharmaceutical compound or salt thereof and one or more further components;

(b) removing the solvent from the solution to form a solid composition according to the first aspect.

The suitable features and advantages of the liquid, the pharmaceutical compound or the salt thereof, the one or more further components, and the polymer of this third aspect are as defined in relation to the first aspect.

The inventors have found that liquids comprising pharmaceutical compounds or salts can be incorporated into a solid composition by removing the solvent from a solution comprising the liquid and a polymer. This is advantageous because it results in compositions having good bioavailability of the pharmaceutical compound. The method of the invention may further provide high loadings of the pharmaceutical compound in the composition, such as loadings of 50 wt% or higher.

The solvent may comprise an organic solvent, an aqueous solvent, or a mixture thereof. Suitable organic solvents include hydrocarbons (such as alkanes, alkenes, and aromatic compounds), alcohols, ethers, esters, ketones, and amides. The solvent may comprise an alcohol, such as methanol, ethanol, and/or propanol, preferably methanol. The solvent may have a boiling point of from 30 to 100 °C, suitably from 40 to 90 °C, for example from 50 to 80 °C.

The solvent is different from the liquid. The liquid does not comprise the solvent.

The concentration of the polymer in the solution in step (a) may be from 1 to 50% w/v, suitably from 1 to 30% w/v, for example from 1 to 10% w/v.

Step (b) of the method of the third aspect suitably comprises removing the solvent from the solution, suitably rapidly removing the solvent from the solution. Step (b) suitably comprises removing the solvent by vaporisation of the solvent.

Step (b) may comprise removing the solvent from the solution by spray drying, spray coating (such as by fluidised bed processing), electrospinning, electrospraying, or solvent casting the solution.

Suitably, step (b) comprises spray drying or spray coating the solution.

Spray drying the solution suitably results in the formation of a powder.

Spray coating may comprise fluidised bed processing. Fluidised bed processing suitably involves the use of a fluidised bed to suspend particles in air while spraying the solution onto said particles.

Spray coating the solution suitably comprises spraying the solution onto beads. This suitably results in the formation of coated beads. The core of the beads may be physiologically inert. The core of the beads may be biodegradable.

Spray coating the solution may comprise spraying the solution onto a powder. This suitably results in the formation of granules. The powder onto which the solution is sprayed may be physiologically inert. Alternatively, powder onto which the solution is sprayed may be formed by spray drying the same solution. Preferably, step (b) comprises spray drying the solution.

Brief Description of the Drawings

Figure 1 shows reversible heat flow mDSC thermograms of Examples 11 and 12 compared to the corresponding liquid and polymer for the second heating cycle. The exotherm is in the upward direction.

Figure 2 shows reversible heat flow mDSC thermograms of Examples 16, 17, 22, and 23 compared to the corresponding liquid and polymer for the second heating cycle. The exotherm is in the upward direction.

Figure 3 shows reversible heat flow mDSC thermograms of Examples 24 and 25 compared to the corresponding liquid and polymer for the second heating cycle. The exotherm is in the upward direction.

Figure 4 shows the dissolution profile over time of Example 5 in phosphate buffer compared to crystalline aspirin.

Figure 5 shows the dissolution profile over time of Examples 7 and 9 in phosphate buffer compared to crystalline ranitidine hydrochloride

Figure 6 shows reversible heat flow mDSC thermograms of (A) cellulose acetate, (B) the LBF used in Examples 30 to 36, (C) Chlor Doc, (D) Example 30, (E) Example 31 , (F) Example 32, and (G) Example 33. The exotherm is in the upward direction.

Figure 7 shows reversible heat flow mDSC thermograms of (A) ethyl cellulose, (B) the LBF used in Examples 30 to 36, (C) Chlor Doc, and (D) Example 34. The exotherm is in the upward direction.

Figure 8 shows reversible heat flow mDSC thermograms of (A) cellulose acetate, (B) the LBF used in Examples 30 to 36, (C) Met Doc, and (D) Example 35. The exotherm is in the upward direction.

Figure 9 shows reversible heat flow mDSC thermograms of (A) ethyl cellulose, (B) the LBF used in Examples 30 to 36, (C) Met Doc, and (D) Example 36. The exotherm is in the upward direction. Figure 10 shows the dissolution profile over time of (A) Chlor Doc, (B) an API-IL solution containing 80 wt% Chlor Doc and 20 wt% LBF used in Examples 30 to 36, (C) chlorpromazine free base, (D) Chlor HCI, (E) Example 33, (F) Example 34, (G) a spray-dried powder formed from 60 wt% Chlor Doc and 40 wt% cellulose acetate, and (H) a spray-dried powder formed from 60 wt% Chlor Doc and 40 wt% ethyl cellulose in FaSSIF.

Figure 11 shows the dissolution profile over time of (A) Met Doc, (B) Met Doc (60% w/w) in LBF, and (C) Met HCI in phosphate buffer.

Figure 12 shows the dissolution profile overtime of (A) Example 35, (B) Example 36, (C) a spray- dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate, and (D) a spray-dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose in phosphate buffer.

Figure 13 shows the dissolution profile over time of (A) Met Doc, (B) Met Doc (60% w/w) in LBF, and (C) Met HCI in FaSSIF.

Figure 14 shows the dissolution profile overtime of (A) Example 35, (B) Example 36, (C) a spray- dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate, and (D) a spray-dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose in FaSSIF.

Examples

Examples 1 to 27

Spray Encapsulation

For Examples 1 to 27 the components (minus the encapsulation polymer system) were dissolved in methanol before the polymer was slowly added to the solution. The solutions were then all sprayed in the following way to obtain white powders:

Spray drying was performed on a Buchi B-290 Mini spray dryer in combination with the B-295 inert loop and two-fluid nozzle with a 1 .5 mm cap and a 0.7 mm tip. Solutions were spray-dried using the following process parameters: 667 L tr¹ atomising nitrogen flow, 35 m³ tr¹ nitrogen drying gas, 6 mL min^-1 solution feed rate, and 80 °C inlet temperature giving an outlet air temperature of 46 °C. As the greatest contribution to solution viscosity is due to the polymer content, all solutions were prepared using a polymer concentration of 2.5% (w/v).

The composition of the powders prepared are shown in Table 1. Table 1

*Not claimed

Asp: Aspirin

Bet: Betaine

ChoCI: Choline chloride

Cit: Citric acid

EC: Ethyl cellulose (Ethocel Standard 10 Premium (EC10) obtained from Dow Wolff Cellulosics GmbH., Bomlitz, Germany)

GIOH: Glycerol

HPMC: Hydroxypropyl methyl cellulose

Ibu: Ibuprofen

Mai: Malic acid

Nic: Nicotinamide

ProGly: Propylene glycol

RanHCI: Ranitidine hydrochloride

Rit: Ritonavir

TEC: Triethyl citrate

Modulated Differential Scanning Calorimetry (mDSC)

Modulated differential scanning calorimetry (mDSC) was used to determine the physical properties of the liquids, polymers, and powders based on how they behaved when put through heating and cooling cycles. In addition to solid-liquid state phase transformations, solid-solid state phase transformations (such glass transition and crystallisation) were determined from how the heat flow (y axis) varied as a function of temperature. Ordinarily, a powder having a single liquid-polymer phase was expected to exhibit a single glass transition at a point between that of the pure components. The presence of two glass transitions was strong evidence of a phase separated system.

All mDSC measurements were performed on a QA-200 TA instrument (TA instruments, Elstree, United Kingdom) calorimeter using nitrogen as the purge gas. Samples of spray dried powder (3-5 mg) were placed in closed standard aluminium pans, while a similar mass of the neat eutectic liquid was placed in a sealed hermetic pan with one pin hole (n = 3). All samples were run in triplicate and the machine was calibrated using indium as a standard. Samples were equilibrated at 20 °C and held isothermally for 5 min. The temperature was then ramped to 1 10 °C at a rate of 5 °C min^-1 with a modulation of 0.8 °C every 60 seconds and held there for 10 min in order to remove any residual moisture. The modulation was maintained for the reminder of the experiment. The sample was then cooled to -50 °C at 5 °C min^-1 and again held there for 10 min before finally being ramped to 250 °C at 5 °C min^-1.

Figures 1 to 3 show reversible heat flow mDSC thermograms of Examples 11 , 12, 16, 17, 22, 23, 24, and 25 compared to the corresponding liquid and polymer for the second heating cycle of the above described method. The exotherm is in the upward direction, and glass transitions are indicated by arrows.

Figure 1 shows that Examples 11 and 12 had single glass transitions in the range of -50 to 200 °C. The glass transition was the same as the pure EC10, providing a strong indication of a phase separated system. The glass transition of CAGE is below -50 °C and therefore is not shown in Figure 1 .

Figures 2 and 3 show two glass transitions in the thermograms of Examples 16, 17, 22, 23, 24, and 25, corresponding to the glass transitions of the liquid and the polymer. This was strong evidence of a phase separated system.

Dissolution

Dissolution studies were performed using a USP Apparatus 2 with an Agilent 708-DS paddle apparatus. The mass of powder corresponding to the equivalent of 50 mg of API was added to 500 mL of phosphate buffer (pH 6.8) equilibrated at 37 °C stirred at 50 rpm. For the tests using ranitidine, dissolution was studied over 1 .5 hours, whilst aspirin dissolution was tracked over 2 hours with a final sample at 24 hours. Samples were taken and replaced with fresh media at 5 min, 15 min, 30 min, then every 30 min for the remainder of the experiment. The first 1 mL of each 3 mL sample was filtered and discarded before the remaining sample was filtered through a 0.45 pm nylon filter into a vial which was analysed by UV-vis spectroscopy using a Shimadzu PharmaSpec 1700 spectrometer. All experiments were carried out in triplicate. A sample of the powder was assayed in triplicate by completely dissolving 0.1 g of powder in 100 mL of DSMO and finding the API content by UV. The dissolution results were plotted as percent dissolved of the average API content versus time.

Figures 4 and 5 show the dissolution profiles of Example 5 compared to crystalline aspirin and Examples 7 and 10 compared to crystalline ranitidine hydrochloride.

Examples 30 to 36

Synthesis of chlorpromazine docusate (Chlor Doc)

Chlorpromazine docusate (Chlor Doc) was synthesized by a metathesis reaction. Equimolar amounts of chlorpromazine hydrochloride (20.00 g, 56.29 mmol, 1 equiv.) and sodium docusate (25.03 g, 56.29 mmol, 1 equiv.) were dissolved separately in 50 mL of methanol. The solutions were then slowly combined and stirred at room temperature for four hours. The mixture was then filtered through a sintered glass funnel (POR 4) under vacuum and the solvent removed under reduced pressure. The resulting ionic liquid was then washed with acetone and filtered with 0.45 pm PTFE syringe filters to remove salt (NaCI). This process was repeated until no more precipitation was observed. Then the produced viscous orange API-IL was dried under vacuum at 40 °C (40.66 g, 97.69%). The formation of Chlor Doc was verified by ¹H and ¹³C Nuclear Magnetic Resonance (NMR) using a Varian VnmrS 400 MHz spectrometer and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR).

Synthesis of chlorpromazine free base

Chlorpromazine base (Chlor) was obtained from its hydrochloride form (Chlor HCI). 2.26 g of Chlor-HCI was dissolved in 50 mL of deionised water at a temperature of 40 °C with continuous stirring. A saturated aqueous NaHCCh solution was added to the Chlor-HCI solution until the pH reached 9, while constantly stirring at 300 rpm with a magnetic stirrer. The resultant mixture was left to stir overnight at room temperature and a yellowish slurry of chlorpromazine free base formed in the bottom of the flask. 50 mL of dichloromethane (DCM) was added to the mixture resulting in instant dissolution of the yellow slurry. The two phases were separated, and the DCM layer was washed with water to eliminate any remaining water-soluble residues. The solvent was evaporated under vacuum producing Chlor as a brown liquid that was dried further at 40 °C for 24 h in a vacuum oven (1.997 g, 98.5%). The formation of chlorpromazine free base was verified by ¹H and ¹³C Nuclear Magnetic Resonance (NMR) using a Varian VnmrS 400 MHz spectrometer.

Synthesis of metformin docusate (Met Doc) Metformin docusate (Met Doc) was synthesized by a metathesis reaction. Metformin hydrochloride (Met HCI) (8.06 g, 48.67 mmol, 1 equiv.) was dissolved in 100 mL deionized water and sodium docusate (21 .64 g, 48.67 mmol, 1 equiv.) was dissolved in 100 mL dichloromethane (DCM). The solutions were combined and stirred at room temperature for 4 h. The DCM layer was separated and concentrated under vacuum. Acetonitrile (20 mL) was added to the resulting viscous product to remove traces of salt (NaCI) and unreacted sodium docusate, and the mixture was stirred for 4 hours. This step was repeated until no further precipitation was observed. The mixture was filtered with 0.22 pm PTFE syringe filters and the solvent was removed under vacuum, to produce a clear viscous liquid. The formation of the product was verified with ¹H and ¹³C Nuclear Magnetic Resonance (NMR) using a Varian VnmrS 400 MHz spectrometer and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR). HPLC quantification revealed that approximately 20 % w/w excess of docusate anion remained in the final product even after multiple washes with acetonitrile.

Preparation of lipid-based formulation (LBF)

A LBF was prepared containing the long chain lipid Peceol™ (30% w/w, obtained from Gattefosse, France), the surfactant and permeation enhancer Labrasol ALF® (60% w/w, obtained from Gattefosse, France), and ethanol as the cosolvent (10% w/w). All excipients were mixed in a glass vial and thoroughly vortexed to ensure complete blending of all components. The Chlor Doc or Met Doc was mixed with the LBF vehicle to the desired concentrations and API concentrations in the resulting solutions were confirmed by HPLC. Attempts to dissolve the commercially available chlorpromazine hydrochloride, the synthesised chlorpromazine free base, or the commercially available metformin hydrochloride within this lipid vehicle were unsuccessful even at API concentrations lower than <2% w/w.

Spray encapsulation

Spray drying was performed on a Buchi B-290 Mini spray dryer in combination with the B-295 inert loop and two-fluid nozzle with a 1 .5 mm cap and a 0.7 mm tip. Solutions were spray-dried using the following process parameters: 667 L tr¹ atomising nitrogen flow, 35 m³ tr¹ nitrogen drying gas, 6 mL min^-1 solution feed rate, and 80 °C inlet temperature giving an outlet air temperature of 43 °C. All spray dried solutions had a fixed polymer concentration of 4% (w/v) in acetone.

The API-IL solutions (containing the API-IL and the LBF), were solidified by spray drying with ethylcellulose or cellulose acetate to obtain white powders. The composition of the powders prepared are shown in Table 2.

Table 2

CA: Cellulose acetate

EC: Ethyl cellulose (Ethocel Standard 10 Premium (EC10) obtained from Dow Wolff Cellulosics

GmbH., Bomlitz, Germany)

Modulated differential scanning calorimetry (mDSC)

The mDSC experiments were conducted using a QA-200 instrument (TA Instruments, United Kingdom). The calorimeter was calibrated with indium and purged with nitrogen. Sealed hermetic pans with one pin hole containing 1-10 mg of sample were used and all experiments were performed in triplicate. To avoid T_g depression due to traces of water, a drying cycle was included as part of the mDSC method for API-IL and LBF containing formulation. This method involved initially heating to 20 °C and holding isothermally for 5 min. The temperature was then ramped to 110 °C at a rate of 5 °C min^-1 with a modulation of 0.8 °C every 60 seconds and held there for 10 min to remove any residual moisture. Next, the sample was cooled to -75°C at 5 °C min^-1 and again held there for 10 min before finally being ramped to 200 or 250 °C at 5 °C min^-1 with a modulation of 0.8 °C every 60 seconds. For crystalline samples initially the pans were heated to 20 °C and held isothermally for 5 min. The temperature was then ramped to 250 °C at a rate of 5 °C min^-1 with a modulation of 0.8 °C every 60 seconds.

Figure 6 shows the reversible heat flow mDSC thermograms of (A) cellulose acetate, (B) the LBF used in Examples 30 to 36, (C) Chlor Doc, (D) Example 30, (E) Example 31 , (F) Example 32, and (G) Example 33. The exotherm is in the upward direction, and glass transitions are indicated by arrows.

Figure 7 shows the reversible heat flow mDSC thermograms of (A) ethyl cellulose, (B) the LBF used in Examples 30 to 36, (C) Chlor Doc, and (D) Example 34. The exotherm is in the upward direction, and glass transitions are indicated by arrows.

Figure 8 shows the reversible heat flow mDSC thermograms of (A) cellulose acetate, (B) the LBF used in Examples 30 to 36, (C) Met Doc, and (D) Example 35. The exotherm is in the upward direction, and glass transitions are indicated by arrows.

Figure 9 shows the reversible heat flow mDSC thermograms of (A) ethyl cellulose, (B) the LBF used in Examples 30 to 36, (C) Met Doc, and (D) Example 36. The exotherm is in the upward direction, and glass transitions are indicated by arrows.

Dissolution

Dissolution studies were conducted using a USP Apparatus 2 equipped with an Agilent 708-DS paddle apparatus (Agilent Technologies, Ireland). The mass of powder corresponding to the equivalent of 100 mg of the chlorpromazine ion or 50 mg of metformin was added to 500 mL of medium, equilibrated at 37 °C, and stirred at a speed of 50 rpm. The experiments used two different types of media; phosphate buffer (PB) and fasted state simulated intestinal fluid (FaSSIF). 0.2M phosphate buffer was prepared and degassed according to the United States Pharmacopeia (USP). 6.8 g of potassium phosphate monobasic were added to 112 ml of a 0.2M NaOH solution and the volume was made up to 1 L of deionized water. The pH of the buffer was 6.80±0.02. The dissolution experiments were also conducted using biorelevant media under conditions simulating the pre-prandial small intestine using FaSSIF, prepared according to the manufacturer’s instructions. FaSSIF was left at room temperature for 2 h prior to further usage. The dissolution was observed for a duration of 4 hours, and samples were collected at designated time intervals (5, 10, 15, 20...240 minutes). Each sample consisted of approximately 3 mL and was replaced with fresh medium at a temperature of 37°C. To minimize any disturbance to the hydrodynamics in the vessel, the sampling probe was introduced only during the moment of sampling. Samples were filtered into a high-performance liquid chromatography (HPLC) vial using Chromafil RC syringe filters 0.45 pm, (Macherey-Nagel Labquip, Ireland) and the first two millilitres were discarded. API-IL content was quantified using HPLC analysis. Filtrates containing chlorpromazine were diluted with methanol prior to HPLC analysis. All experiments were carried out in triplicate. Additionally, a separate triplicate analysis involved dissolving approximately 0.05 grams of the powder in 50 mL of acetone. The API-IL content present in this solution was then determined via HPLC analysis. The results were plotted as percent released of the average API content versus time.

Figure 10 shows the dissolution profile in FaSSIF of (A) Chlor Doc, (B) an API-IL solution containing 80 wt% Chlor Doc and 20 wt% LBF used in Examples 30 to 36, (C) chlorpromazine free base, (D) Chlor HCI, (E) Example 33, (F) Example 34, (G) a spray-dried powder formed from 60 wt% Chlor Doc and 40 wt% cellulose acetate, and (H) a spray-dried powder formed from 60 wt% Chlor Doc and 40 wt% ethyl cellulose.

FaSSIF replicates the physiological conditions of the Gl tract under fasted state, which aids in studying accurately the behavior of lipophilic APIs. Among the four spray encapsulated formulations evaluated in FaSSIF, those containing LBF vehicle (E and F in Figure 10) outperformed those without it (G and H in Figure 10) by 20% on average. This could be attributed to the fact that the LBF vehicle can improve the aqueous solubility of poorly water-soluble APIs, by enhancing the dispersion of lipophilic API-iLs in mixed micelles composed of LBF, bile salts and phospholipids (ingredients of FaSSIF).

The liquid Chlor Doc and the liquid Chlor Doc solution containing LBF vehicle were introduced into hard gelatin capsules to be tested. These liquid formulations performed poorly when compared to the solidified formulations. This could be explained by the small size of the particles in the solid formulations, which elute the API-IL from smaller particles allowing the media to disperse it more effectively. After the gelatin dissolved, it was observed that the liquid formulations settled at the bottom of the tank resembling a concentrated gel-like mass. This indicated strongly that the solidification and elution of the liquid phase formulations played a significant role in mediating their release by dispersing them directly into discontinuous nano or micro size droplets that can easily remain dispersed following release from the insoluble polymer carriers. The efficacy of the solid spray encapsulated products also surpassed that of the free base in FaSSIF.

The dissolution performance of the commercially available chlorpromazine hydrochloride was deemed to be optimal, as expected since the hydrochloride form of the API is classified as a BCS Class III. The release reached 100% after 10 min but then dropped to 90% due to precipitation observed in the dissolution tank. Similar behavior was not observed with the API- IL products. This highlights one advantage of the solid formulations prepared: their ability to prevent precipitation and potentially present the API in a more thermodynamically stable form, due to the stabilizing presence of the surfactants docusate and Labrasol ALF®. The spray encapsulated formulations exhibited slower rates of API release, rendering them suitable candidates for controlled-release formulations. Another potential advantage of the solidified Chlor Doc powders containing LBF (Examples 33 and 34) is that they can be absorbed through the lymphatic system upon dispersion in the Gl tract, thereby bypassing the first-pass metabolism — a crucial constraint affecting chlorpromazine’s bioavailability. The ability to prevent API precipitation and the possibility of engaging with chylomicrons makes the solidified API-IL powders containing LBF an advantageous approach for enhancing chlorpromazine bioavailability.

Figure 11 shows the dissolution profile in phosphate buffer of (A) Met Doc, (B) Met Doc (60% w/w) in LBF, and (C) Met HCI.

Figure 12 shows the dissolution profile in phosphate buffer of (A) Example 35, (B) Example 36, (C) a spray-dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate, and (D) a spray-dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose.

Figure 13 shows the dissolution profile in FaSSIF of (A) Met Doc, (B) Met Doc (60% w/w) in LBF, and (C) Met HCI.

Figure 14 shows the dissolution profile in FaSSIF of (A) Example 35, (B) Example 36, (C) a spray-dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate, and (D) a spray- dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose.

All samples tested performed similarly in the two media tested. Metformin hydrochloride and Example 36 exhibited an immediate drug release, achieving complete dissolution within just 10 minutes. The other solidified formulations as well as the liquid Met Doc containing LBF at 40% w/w exhibited a slower release rate, with a gradual increase of API release over time. Example 35 and the spray-dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose along with the liquid API-IL containing LBF achieved 90% release on average after 90 minutes, whereas the spray-dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate attained the same release after three hours. The release of the liquid Met Doc was incomplete in PB, achieving 31.5% release. In FaSSIF, the liquid API-IL performed poorly with 35.8% release. The liquid forms were loaded into hard gelatin capsules and were inserted in the dissolution vessel with metal sinkers. Once gelatine dissolved, a dense, highly viscous substance accumulated at the lower part of the dissolution vessel in both media. After completion of the four-hour dispersion tests, the accumulated mass readily dispersed with increased stirring at speeds of 75 and 100 rpm.

The presence of LBF appears to have a positive effect on the release kinetics of the drug. This observation is supported by comparing Example 35, which contains LBF and showed a faster release profile and higher level of drug release, with the spray-dried powder formed from 60 wt% Met Doc and 40 wt% cellulose acetate (same polymer but without LBF). Similarly, Example 36 (with LBF) exhibited better results compared to the spray-dried powder formed from 60 wt% Met Doc and 40 wt% ethyl cellulose (same polymer but without LBF). Additionally, when Met Doc solution was used as a liquid formulation, there was incomplete API-release; however, when LBF was included, the API-release increased threefold. These findings suggest that LBF may enhance self-emulsification and facilitate the release of the API.

The liquid API-IL loaded with LBF performed similarly to the solidified formulations. However, there are significant advantages associated with the use of solid forms. Solidification aids in enhancing stability, facilitating processing and storage operations, as well as allowing for further formulation into alternative dosage forms. Solidification is by far the preferred mode of pharmaceutical manufacturing and this spray-encapsulation technique can increase the stability of metastable API-ILs and decrease their crystallization propensity.

Ex vivo evaluation of membrane permeability

Ex vivo studies were carried out in accordance with UCD Animal Research Ethics Committee Protocol # 14-28 and 23-05. Animals purchased from UCD Biomedical Facility or Charles River UK were housed in a pathogen-free environment with controlled conditions of humidity and temperature under a 12:12 h light/dark cycle with access to laboratory chow and filtered water ad lib. In summary, male rats weighing between 250 and 400 grams were euthanized through stunning followed by cervical dislocation. A midline laparotomy was then performed to remove the colon which was subsequently placed in oxygenated Krebs-Henseleit buffer (KH). The circular and longitudinal muscle layers of the colon were stripped using a size #5 watchmaker forceps, after which the tissue was mounted in pre-equilibrated Ussing chambers with a circular diameter of 0.63 cm² (WPI, UK). The tissue was constantly exposed to a mixture of O2/CO2 (95/5%) and the chambers’ temperature was maintained at 37 °C via a glass water jacket, connected to a heated recirculating water bath. To track tissue viability during the experiment, Voltage Clamp system was used to record the electrical parameters.

The parent API metformin hydrochloride, the API-IL, and the spray encapsulated products were tested. Test agents were added to the apical side of colonic mucosae at amounts corresponding to 0.1 mg/mL of metformin for 120 min flux periods. Samples were collected from the basolateral receiver side every 20 min for 120 min followed by replacement with fresh KH. To assay the permeated API, the samples were tested via HPLC. The apparent permeability (P_app) coefficients of all tested materials were calculated according to Equation 1. n dQ 1 a^pp = — dt - 1 C_o Equation 1 where dQ/dt is the transport rate, A is the surface area (0.63 cm²), and Co is the initial concentration in the donor compartment.

The enhancement ratio (ER) was calculated by dividing the P_app values of the formulations by that of the API and can be obtained using Equation 2.

The outcomes of the experiments regarding apparent permeability (Papp) of the Met Doc formulations are summarized in Table 3. Each P_app value represents the mean ± SD (n=3). The results were analyzed by unpaired student’s t test relative to control, ns: not significant, *P < 0.05, **P < 0.01.

Table 3

Table 3 showcases that the performance of the four spray-encapsulated formulations containing Met Doc was found to be superior compared to metformin hydrochloride. The statistical analysis further confirms a significant increase in the permeability of the API for Examples 35 and 36 across the cell membrane, compared to its commercially available form. The Papp of metformin hydrochloride was measured to be 1 ,98x10^-6 cm s^-1, whereas the spray- dried formulations exhibited a range from 4.69 to 12.5 10^-6 cm s^-1. Among these formulations, the highest enhancement in P_app was observed with Example 35, which increased the apparent permeability of the metformin by approximately 6.3 times. When comparing the performance of formulations with and without LBF, it was observed that the inclusion of LBF (Examples 35 and 36) resulted in superior outcomes compared to their counterparts lacking LBF.

An increase in P_app compared to the commercially available API could potentially lead to a corresponding enhancement in drug absorption, reduction of daily dose, fewer ADRs and better patient compliance. Decreasing the dosage of the API could also result in a decrease of metformin found in water sources, thereby introducing an environmental benefit.

The example embodiments described above may provide solid compositions comprising pharmaceutical compound-containing liquids, which are easy to handle and have good solubility and/or bioavailability of the pharmaceutical compound. Many pharmaceutical compounds have poor solubility or bioavailability in their most stable crystalline forms. Non-crystalline forms of pharmaceutical compounds may lack long term stability and/or be in a form which is inconvenient for oral administration. These problems may be addressed by example embodiments as described herein.

In summary, a solid composition comprising a polymer and a liquid, wherein the liquid comprises a pharmaceutical compound or a salt thereof and one or more further components is described. A solid dosage form comprising such a composition, and a method of preparing the composition are also described. The compositions of the invention have the advantages of bioavailability and ease of handling.

Although a few preferred embodiments have been shown and described, it will be appreciated by those skilled in the art that various changes and modifications might be made without departing from the scope of the invention, as defined in the appended claims.

Throughout this specification, the term “comprising” or “comprises” means including the component(s) specified but not to the exclusion of the presence of other components. The term “consisting essentially of’ or “consists essentially of’ means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention. Typically, when referring to compositions, a composition consisting essentially of a set of components will comprise less than 5% by weight, typically less than 3% by weight, more typically less than 1 % by weight of non-specified components. The term “consisting of’ or “consists of’ means including the components specified but excluding addition of other components.

Whenever appropriate, depending upon the context, the use of the term “comprises” or “comprising” may also be taken to encompass or include the meaning “consists essentially of’ or “consisting essentially of’, and may also be taken to include the meaning “consists of’ or “consisting of’.

For the avoidance of doubt, where amounts of components in a composition are described in wt%, this means the weight percentage of the specified component in relation to the whole composition referred to. For example, “wherein the composition comprises solvents in an amount of less than 10 wt%” means that less than 10 wt% of the composition is provided by solvents.

The optional features set out herein may be used either individually or in combination with each other where appropriate and particularly in the combinations as set out in the accompanying claims. The optional features for each aspect or exemplary embodiment of the invention as set out herein are also to be read as applicable to any other aspect or exemplary embodiments of the invention, where appropriate. In other words, the skilled person reading this specification should consider the optional features for each exemplary embodiment of the invention as interchangeable and combinable between different exemplary embodiments.

Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

Claims

1. A solid composition comprising a polymer and a liquid, wherein the liquid comprises a pharmaceutical compound or a salt thereof and one or more further components.

2. The composition of claim 1 , wherein the composition is in the form of a powder.

3. The composition of claim 1 or 2, wherein the polymer is immiscible with the liquid at room temperature.

4. The composition of any preceding claim, wherein the polymer is selected from a polysaccharide, a polysaccharide derivative, a polyvinyl ester (such as polyvinyl acetate), an aliphatic polyester (such a poly(glycolic acid) and copolymers thereof), a polyester (such as polycaprolactone), shellac, a (meth)acrylic acid based polymer, and mixtures thereof, preferably is selected from a polysaccharide, a cellulose derivative, a (meth)acrylic acid based polymer, and mixtures thereof.

5. The composition of any preceding claim, wherein the pharmaceutical compound or the salt thereof is not an ionic liquid.

6. The composition of any one of claims 1 to 4, wherein the composition comprises the salt of the pharmaceutical compound, and the salt is an ionic liquid.

7. The composition of any preceding claim, wherein the one or more further components comprises a liquid carrier.

8. The composition of claim 7, wherein the pharmaceutical compound or the salt thereof is in solution with the liquid carrier.

9. The composition of claim 7 or 8, wherein the liquid carrier comprises a lipid-based formulation, a deep eutectic solvent, or an ionic liquid.

10. The composition of any of claims 1 to 5, wherein the liquid is a deep eutectic solvent, wherein the deep eutectic solvent comprises the pharmaceutical compound or the salt thereof as a eutectic constituent.

11. The composition of any preceding claim, wherein the pharmaceutical compound or the salt thereof has low permeability as per the Biopharmaceutics Classification System.

12. The composition of any preceding claim, wherein the weight ratio of the liquid to the polymer is from 40:60 to 90:10.

13. A solid dosage form comprising the composition of any preceding claim.

14. The solid dosage form of claim 13, which is an oral solid dosage form.

15. A method of preparing the composition of any one of claims 1 to 12, comprising the steps of:

(a) forming a solution comprising a polymer, a liquid, and a solvent, wherein the liquid comprises a pharmaceutical compound or salt thereof and one or more further components;

(b) removing the solvent from the solution to form a solid composition according to any one of claims 1 to 12.

16. The method of claim 15, wherein step (b) comprises removing the solvent from the solution by spray drying, spray coating (such as by fluidised bed processing), electrospinning, electrospraying, or solvent casting the solution (preferably by spray drying).