WO2024014959A2

WO2024014959A2 - Micelle-generating formulations with improved hydrophobicity

Info

Publication number: WO2024014959A2
Application number: PCT/NL2023/050384
Authority: WO
Inventors: Christian DEGELING; Michel VAN DE GRAAFF
Original assignee: Seranovo Holding B.V.
Priority date: 2022-07-15
Filing date: 2023-07-17
Publication date: 2024-01-18
Also published as: WO2024014959A3

Abstract

The invention is directed to a pharmaceutical composition comprising a) more than 1 wt% of an active pharmaceutical ingredient (API); b) 5% to 75 wt% of one or more pharmaceutically acceptable surfactants; c) 0.6 to 75 wt% of one or more hydrophobicity modifiers, or a pharmaceutically acceptable salt thereof; and d) an optional solubilizer; based on the total weight of the pharmaceutical composition.

Description

Title: Micelle-generating formulations with improved hydrophobicity

The invention is in the field of pharmaceutical compositions for enhanced bioavailability. In particular, the invention is directed to a pharmaceutical composition and formulation for active pharmaceutical ingredients that are hydrophobic, i.e. exhibit a water solubility at pH 7 of less than 0.1 mg/ml.

The number of drugs that are classified as Biopharmaceutics Classification System (BCS) class II and IV compounds has increased over the past years. BCS class II and IV are used for drugs that are considered to have low aqueous solubility. In the pharmaceutical industry, it remains challenging to solubilize these poorly water-soluble APIs and to improve their bioavailability. Complex formulations are therefore often required to effectively absorb the API in the gastrointestinal (GI) tract. The terms “API”, “drug”, “active ingredient” may be used interchangeably herein.

Bioavailability of the API relates i.a. to the solubility, membrane permeability and enzymatic degradation of the active ingredient in the patient. Bioavailability may be measured as the area under a curve of the plasma concentration of a drug over a certain time. The bioavailability may be denoted as a percentage and depends i.a. on the half-life of the drug. As most of the APIs are poorly soluble in water, processing these ingredients in dosage forms typically requires the use of less polar solvents such as dimethylsulfoxide, alcohols, acetone, ethyl acetate, chloroform and the like. These solvents present problems including toxicity and danger of explosion.

Several alternative methods have been proposed to enhance the solubility of APIs and their bioavailability. Examples thereof include physical modifications such as solid dispersions, self-emulsifying drug delivery systems (SEDDS) and chemical modifications such as salt formation. Salt formation is a tool to obtain solid-state forms as the ionic interactions in a crystal lattice may be beneficial to crystal lattice stabilization. The ion-ion interactions, moreover, typically contribute strongly to the lattice enthalpy. However, disadvantageously, salts tend to form hydrates as the ions within the salt interact strongly with water and the stability may accordingly be easily compromised. In addition, not all APIs can be formulated into salts.

Solid dispersions are typically dispersions of a drug in an amorphous polymer matrix. The matrix may further comprise i.a. a surfactant. Solid dispersions can be manufactured through a variety of processes including melt extrusion, spray drying and co -precipitation. Several reviews on solid dispersions are Huang and Dai (Acta Pharmaceutica Sinica B, 4, 2014, 18-25), Chivate et al. (Current Pharma Research, 2, 2012, 659-667) and Zhang et al. (Pharmaceutics, 3, 2018, 142). However, disadvantages of solid dispersions include complex manufacturing, the physical instability of the product and a consequent decrease in dissolution rate over time.

SEDDS are typically isotropic mixtures of one or more hydrophilic solvents and co-solvents or surfactants that may form oil-in-water micro emulsions in aqueous media, as for instance detailed by Khedekar and Mittal (International Journal of Pharmaceutical Sciences and Research, 4(12), 2013, 4494-4507). A particular type of SEDDS are super saturable SEDDS which comprise polymeric precipitation inhibitors to stabilize the drug in a supersaturated state. Drawbacks of SEDDS are their low drug loading capacity and limited options for viable dosage forms. Moreover, they are only effective for lipophilic APIs having a logP of more than 5.

It is an object of the present invention to provide a pharmaceutical composition that at least in part overcomes the above- mentioned drawbacks. In particular, it is an object of the present invention to provide a pharmaceutical composition wherein one or more hydrophobic APIs are formulated with a high drug load, in a single phase, which disperses in water yielding a high apparent solubility for timeframes that are biorelevant.

The present inventors surprisingly found that the above object can be met by formulating an active pharmaceutical ingredient (herein abbreviated as API) in a composition comprising one or more pharmaceutically acceptable surfactants (also referred to as the surfactant) and one or more hydrophobicity modifiers (also referred to as the modifier). Surprisingly, the combination of the surfactant and the modifier leads to an improved apparent solubility of the API following dissolution of the API after administration, or more generally, following dissolution in a biorelevant aqueous medium.

Accordingly, the present invention is particularly directed to a pharmaceutical composition comprising: a) more than 1 wt% of an active pharmaceutical ingredient; b) up to 2-75 wt%, preferably 5-75 wt% of a pharmaceutically acceptable surfactants; c) up to 0.6-75 wt% of a hydrophobicity modifier or pharmaceutically acceptable salts thereof; and d) an optional solubilizer; each based on the total weight of the pharmaceutical composition.

The present inventors realized that a composition comprising the surfactant and the modifier may create a micellar solution, with e.g. nanosized micelles, within a short amount of time (e.g. minutes) of contact with an aqueous environment and that the hydrophobic API can be accommodated in the micelles, resulting in a higher apparent solubility of the API upon dissolution in biorelevant media.

The term ‘API’ as used herein includes one or more active pharmaceutical ingredients, ‘API salts’, and combinations thereof. The API preferably comprises a BCS class II or IV API. These API classes are considered to have low water solubility and administration to a patient can be a challenge. Typically, the API has a water solubility of less than 0.1 mg/mL at pH 7. The water solubility may depend on the acidity/basicity of the API. The API may for example have an aqueous solubility of not more than 0.1 mg/mL at pH 6.8 when it is a weakly basic compound, of no more than 0.1 mg/mL at pH 1.2 when it is a weakly acidic compound. In the case of physiological pH of 1.0 to 8.0 for neutral or non-ionizable compounds the aqueous solubility may be no more than 0.1 mg/mL. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. If it does not dissolve in 250 ml at each of the aforementioned conditions, it is generally considered poorly water-soluble. An extensive list of possible APIs is mentioned in Pharmacopeia. The dosage for therapeutically effective amounts for a given API is typically known to a person skilled in the art. The term “aqueous environment” used herein generally relates to gastrointestinal fluid at pH 4.5 to 8.0 or to the stomach at pH 1.0 to 3.0 in vivo or an aqueous test medium in vitro. Advantageously, the amount of API in the pharmaceutical composition may be more than 2.5 wt%, preferably 2.5 to 50 wt% based on the total weight of the pharmaceutical composition.

The components of the composition are typically selected for being safe for oral administration, for example they may be on the generally recognized as safe (GRAS) list for oral administration. The GRAS list is established by the Food and Drug Administration (FDA) of the United States.

The solubilizer is optionally present in the composition of the invention. If sufficient solubilizer is present, the composition is typically liquid or semi-liquid, i.e. not solid, at 1 bar pressure and 20 °C. If, however, the solubilizer is absent or only a small amount of solubilizer is present, the composition can be solid such as an amorphous solid dispersion (ASD). Thus, the solubilizer can suitably be selected to achieve the desired physical properties of the composition.

If a solubilizer is present, it is preferably present in an amount of at least 20 wt%, based on the total weight of the composition. More preferably, it is present in an amount of 20-95 wt%, even more preferably 35-65 wt% of a solubilizer, based on the total weight of the pharmaceutical composition.

In particular embodiments, the solubilizer comprises a co-solvent, a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent.

The co-solvent can be any pharmaceutically acceptable conventional solvent and/or combination thereof. Examples of suitable cosolvents include one or more glycols, such as propylene glycol (PEG), dipropylene glycol, butylene glycol, glycerol, glycofurol (also known as tetraglycol), 1,2-hexanediol, 1,2-butanediol, W-methyl-2 -pyrrolidone, dimethyl acetamide, ethyl lactate, propylene carbonate, diethyl malate, triethyl citrate, pyrrolidines, polyglycerol, transcutol (also known as ethyl diglycol), water, dimethyl isosorbide and combination thereof.

In cases where the drug loading enhancement from incorporation of the co-solvent is not sufficiently high, the solubilizer may comprise a deep eutectic solvent (DES). DESs are liquids with a melting point that is lower than the melting points of its constituents. DESs can be used as solvents for APIs, as for example described in WO 2020/085904 (which is incorporated herein in its entirety) wherein a DES is described based on a combination of a glycol with a polymer solubilizer component.

In embodiments wherein the solubilizer is present, the pharmaceutical composition preferably comprises: a) 2-30 wt% of the API; b) 2-25 wt% of the surfactant; c) 1-75 wt% of the modifier or pharmaceutically acceptable salts thereof; d) 20-95 wt% of the solubilizer; each wt% being based on the total weight of the pharmaceutical composition.

The surfactant can be ionic, non-ionic or a mixture thereof. Further, it can be neutral, cationic, anionic or a mixture thereof. Examples of suitable surfactants include those from the group consisting of sodium dodecyl sulfate, poloxamers, polysorbates, D-a-tocopheryl polyethylene glycol succinate, PEG mono- and/or diesters with Cs-Cis fatty acids, polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil, polyoxyethylated 12-hydroxystearic acid, bile salts, sodium taurocholate, glycocholic acid, tauroursodeoxycholic acid, other conjugates of cholic acid, phospholipids, egg-derived phosphatidylcholine, soy-derived phosphatidylcholine. In some embodiments, tauroursodeoxycholic acid is particularly preferred.

The amphiphilic character of the surfactant can be expressed by a hydrophilic-lipophilic balance (HLB). The HLB is typically determined by the balance of the size and strength of the hydrophilic and lipophilic moieties of a molecule. Herein the HLB is based on Griffin’s method that ranges from 0 (completely hydrophobic) to 20 (completely hydrophilic). The HLB may accordingly be used to predict the surfactant properties of a molecule. Typically, molecules with a HLB above 10 are considered water- soluble and below 10 are considered lipid-soluble. Molecules with a HLB value from approximately 16 to 18 may be used as hydrotrope. A preferred surfactant mixture for use in the present invention has a HLB value between 12-18, preferably between 13-18. The preferred surfactant is accordingly hydrophilic and can be considered water-soluble.

The one or more non-ionic surfactants (herein also referred to in ‘non-ionic surfactant’, ‘non-ionic surfactants’) that are suitable for the present invention preferably comprises one or more polyethylene glycol (PEG) mono- and/or diesters with fatty acids and further optionally one or more mono, di- and/or triglycerides. Glycerides typically comprise a mono- di or tri-ester of glycerol (propane- 1, 2, 3-triol) with fatty acids. The one or more mono, di- and/or triglycerides are typically present as a glyceride fraction and preferably non-covalently mixed, such as blended, with the PEG mono- and/or diesters with fatty acids. Longer PEG chains may be used to increase the melting point, while shorter PEG chains are typically employed to lower the melting point. Further, the non-ionic surfactant may include one or more polyethoxylated sorbitan esters, such as commercially available Tween® 20, 60 or 80, polyethoxylated (hydrogenated) castor oil (e.g. Kolliphor® EL) and/or polyoxyethylated 12-hydroxystearic acid (e.g. Kolliphor® HS15). The non-ionic surfactants may alternatively or additionally include other polyethoxylated-based materials such as e.g. the commercially available Kolliphor® RH 40.

When the surfactant comprises a non-ionic surfactant, the non- ionic surfactant preferably comprises PEG32 mono- and/or diesters with Cs- Ci8 fatty acids, poly ethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil or polyoxyethylated 12-hydroxystearic acid. Os-Cis is used herein to indicate that the fatty acid comprises a carbon chain of 8 to 18 carbon atoms. The number average molecular weight of PEG32 is typically around 1500 g/mol.

In embodiments of the present invention, the non-ionic surfactant comprises one or more polyoxylglycerides. Polyoxylglycerides are mixtures of monoesters, diesters, and triesters of glycerol, and monoesters and diesters of polyethylene glycols (PEG); see also Rowe et al., Handbook of Pharmaceutical Excipients, 6^th Edition, p. 557 et seq. Certain polyoxylglycerides are known and commercially available as Gelucire®. Certain Gelucire® mixtures such as Gelucire® 48/16 however lack the esters of glycerol that are usually present in polyoxylglycerides. Polyoxylglycerides suitable for the present invention can be prepared by partial alcoholysis of glycerides with PEG. Accordingly, in a typical embodiment, the ester(s) of glycerol and the ester(s) of PEG in the non-ionic surfactant may be based on the same fatty acid(s), e.g. one or more of C₈-C is fatty acids.

The amount of surfactant in the pharmaceutical composition may be 5 to 75 wt%, preferably 5 to 50 wt%, more preferably 5 to 40 wt%, most preferably 5 to 25 wt% based on the total weight of the pharmaceutical composition.

It was found that the presence of the modifier within the formulation improves the apparent solubility of the API after dispersion of the formulation in aqueous media. Without wishing to be bound by theory, the inventors believe that the surfactant(s) within the formulation selfassemble into micellar structures, the interior of which has an increased solubilization capacity for the API when compared to the external aqueous medium. Surprisingly, it was found that hydrophobic modifiers were able to significantly further increase the apparent solubility of the API with orders of magnitude when used in conjunction with surfactants, even when these modifiers themselves do not have a high solubilization capacity for the API when neat. Again, without wishing to be bound by theory, it is believed that the synergy between the one or more surfactants and modifiers arises from ternary interactions, and only when dispersed in aqueous media.

The modifiers according to the present invention are thus used to improve the apparent solubility of the API in a biorelevant aqueous medium, e.g. after administration of the composition.

The hydrophobic modifier is defined here as an aromatic small molecule with a molecular weight of 100-400 g/mol and an aqueous solubility of <50 mg/mL at 25 °C at pH 7. Examples include thymol, carvacrol, vanillin, cinnamic acid, gallic acid, methyl salicylate, benzyl alcohol and curcumin. The amount of modifier in the pharmaceutical composition may be 2.5 to 75 wt%, preferably 2.5 to 25 wt% based on the total weight of the pharmaceutical composition.

The modifier is typically a small molecule. Preferably, it is non- polymeric. Moreover, it preferably does not comprise lipids such as fatty acids, mono-, di- or triglycerides, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and/or polyketides.

The modifier is preferably selected from the group consisting of vanillin, carvacrol, thymol, cinnamaldehyde, methyl salicylate, propyl gallate, benzyl alcohol, benzoic acid, methyl 4-hydroxybenzoate, ethyl 4- hydroxybenzoate, propyl 4-hydroxybenzoate, benzyl 4-hydroxybenzoate, curcumin, propenyl guaethol, gallic acid, ferulic acid, and combinations thereof, more preferably from the group consisting of benzyl alcohol, vanillin and thymol, and combinations thereof.

It was found that modifiers that comprise a benzene moiety, in particular a phenol, benzyl alcohol and/or benzoate moiety are particularly preferred for the present invention. In some embodiments, thymol is most preferred.

The present inventors found that a composition comprising thymol and tauroursodeoxycholic acid was particularly suitable to solubilize APIs at high concentrations. For instance, a composition comprising thymol and tauroursodeoxycholic acid is able to solubilize a variety of weakly basic active pharmaceutical ingredients at high concentrations (e.g. more than 100 mg/mL). Further, it may be appreciated that upon dispersing a composition comprising thymol, tauroursodeoxycholic acid and an API into biorelevant media, a high apparent solubility can be measured and crystallization typically does not occur within biorelevant timeframes e.g., 2 hours after dispersion. Accordingly, a pharmaceutical composition comprising the API, the modifier and the surfactant, wherein the modifier comprises thymol and the surfactant comprise tauroursodeoxycholic acid is an embodiment that is most preferred.

The composition of the invention may be solid, semi-solid or liquid at ambient temperature and pressure (i.e. 20 °C and 1 bar). The surfactant and the modifier are separately typically solid or semi-solid at ambient temperature and pressure. A solid or semi-solid composition may further be particularly compatible for further processing.

The composition can be used in a medical treatment comprising enteral, preferably oral administration. The composition can also be used in a medical treatment comprising injectable administration. Oral enteral administration is typically preferred due to the ease of administration resulting in an overall increased patient compliance. More preferably the medical treatment comprises oral administration of capsules or tablets comprising the pharmaceutical composition.

The injectable administration may comprise subcutaneous, intramuscular, and intravenous injections, as well as less common injections such as intraperitoneal, intraosseous, intracardiac, intraarticular, and intracavernous injections. The present invention can particularly suitably be used for treatments comprising intravenous injections.

The composition is typically a single-phase composition. By providing a single physical phase instead of a multiphase system such as an emulsion, the stability of the composition is improved.

As described herein-above, the solubilizer may comprise a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API.

Typical constituents of the DES for the present invention are selected from the group consisting of organic acids, phenolic compounds, terpenoids, fatty acids, organic bases, sugars or sweeteners, glycols, amino acids, quaternary ammonium compounds such as choline compounds, and derivatives of these classes. In addition, the DES may comprise one or more esters and/or lactones of organic acids such as diethyl malate, triethyl citrate, ethyl lactate. These latter compounds can serve as a polymer solubilizing component in the DES. Specific examples of such polymer solubilizing components include one or more dicarboxylic acids and/or esters of dicarboxylic acids such as mono-methyl adipate. Further examples of components that may accordingly be present in the DES include or more esters, ethers and carbonates of diols and/or triols, such as glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, DL- 1,2 -isoprop ylideneglycerol, dipropylene glycol methyl ether acetate, propylene glycol methyl ether acetate, dipropylene glycol methyl ether, l-methoxy-2 -prop anol, diethylene glycol monoethyl ether.

In embodiments, the solubilizer may comprise a pharmaceutically acceptable eutectic constituent that is capable of forming a eutectic mixture with the API. Examples wherein an API and a pharmaceutically acceptable eutectic constituent form a eutectic mixture are described in the Dutch patent application NL2025092 and in WO2021/034192, which are both incorporated herein in their entirety.

The pharmaceutically acceptable eutectic constituent typically has the ability to create hydrogen bonds with the API or other constituents in the formulation e.g. typically hydroxyl groups are present. These intermolecular forces can facilitate the increased solubility of the API in the formulation and thereby increase the physical stability of the formulation.

The pharmaceutically acceptable eutectic constituent preferably comprises one or more carboxylic acids, phenolic compounds, terpenoids, organic bases, sugars, sweeteners, glycols, amino acids, quaternary ammonium compounds, derivative of these classes and/or combinations thereof.

Preferably, the pharmaceutically acceptable eutectic constituent comprises one or more organic acids that may include, but are not limited to, malic acid, citric acid, lactic acid, fumaric acid, tartaric acid, ascorbic acid, pimelic acid, gluconic acid, acetic acid and/or derivatives thereof such as nicotinamide.

The pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more phenolic compounds that may include, but are not limited to, thymol, carvacrol, tyramine hydrochloride, tocopherol, butyl paraben and vanillin.

Additionally or alternatively, the pharmaceutically acceptable eutectic constituent may further comprise one or more terpenoids, which may be one of, but not limited to, terpineol, menthol and perillyl alcohol.

The organic bases that the pharmaceutically acceptable eutectic constituent may additionally or alternatively comprise may include, but are not limited to, N-methyl-D-glucamine, tromethamine and guanine.

In another embodiment the pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more sugars or sweeteners, that may include, but are not limited to, sucrose, glucose, fructose, lactose, maltose, xylose, sucrose, inositol, xylitol, saccharin, sucralose, aspartame, acesulfame potassium and ribitol, as well as their phosphates.

Additionally or alternatively, the pharmaceutically acceptable eutectic constituent may comprise one or more amino acids, these include, but are not limited to, cysteine, tyrosine, lysine, serine, glutamine, alanine and leucine.

The pharmaceutically acceptable eutectic constituent may further or alternatively comprise one or more quaternary ammonium compounds that include, but are not limited to, choline chloride, thiamine mononitrate and carnitine.

More generally, host-guest chemistry may be applicable, wherein the pharmaceutically acceptable eutectic constituent may be considered as host and the API as guest. Host-guest chemistry is a term typically used for supramolecular complexes in which two or more molecules or ions are held together by forces other than fully covalent bonds. These non-covalent interactions may include ionic bonding, hydrogen bonds, Van der Waals forces or hydrophobic interactions. The host usually comprises a void, core, cavity or a pocket, these terms are herein used interchangeably. The core relates to a suitable shape for a second molecule to position into. Molecules comprising such cores include, but are not limited to, cyclo dextrins, cucurbiturils, calixarenes, catenanes, cryptands, crown ethers and pillararenes. Preferably, the exterior of the pharmaceutically acceptable eutectic constituent is hydrophilic and the core is hydrophobic. The hydrophobic core is generally capable of forming hydrophobic interactions with the API.

The composition according to the present invention can be regarded as a preconcentrate when the solubilizer is substantially present or as a solid when the solubilizer is substantially absent (vide supra). As a preconcentrate and solid constitution, the concentration of the components of the composition is generally very high. In embodiments, the composition may be provided in a formulation wherein it is dispersed or dissolved in an aqueous liquid such as a glucose or sodium chloride solution for intravenous administration. Such formulations may for instance be used in clinical settings. Accordingly, an aspect of the invention is directed to an aqueous formulation comprising up to 20 wt% of the pharmaceutical composition and 80 wt% or more of an aqueous solvent.

The composition may be produced by a method comprising forming a homogeneous solution comprising the relative amounts of the one or more surfactants, API, modifier and optional solubilizer. This method may entail mixing and liquifying all components to form the homogeneous solution, or if the surfactant is liquid, the liquification may be omitted and the API and modifier can be directly added to the surfactant. The order in which the components are added is typically not relevant, which may be advantageous for ease of production. If the homogenous solution is at an elevated temperature (i.e. above ambient temperature, approximately 20 °C), it may be let to cool down to ambient temperatures to obtain the composition.

In a particular preferred embodiment, the pharmaceutical composition comprises a) 2.5 to 50 wt% of the API; b) 5 to 50 wt% of the pharmaceutically acceptable surfactant; c) 5 to 75 wt% of the hydrophobicity modifier, or a pharmaceutically acceptable salt thereof; and d) preferably no solubilizer.

In a further preferred embodiment, the pharmaceutical composition comprises a) more than 2.5 wt% of the API; b) 5 to 40 wt% of the pharmaceutically acceptable surfactant; c) 2.5 to 25 wt% of the hydrophobicity modifier, or a pharmaceutically acceptable salt thereof; and d) 20 to 80 wt% of the solubilizer.

In a yet further preferred embodiment, the pharmaceutical composition comprises a) more than 2.5 wt% of the API; b) 5 to 25 wt% of the pharmaceutically acceptable surfactant; c) 2.5 to 25 wt% of the hydrophobicity modifier, or a pharmaceutically acceptable salt thereof; and d) 20 to 80 wt% of the solubilizer.

For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described.

The invention may further be illustrated by the following nonlimiting examples. Example 1

A 1% sodium dodecyl sulfate (SDS) solution in Fasted State Simulated Gastric Fluid (FaSSGF , Biorelevant, pH 1.6) was prepared and heated to 37°C. Either an excess amount of only itraconazole (purchased from Sigma- Aldrich) or an excess amount of a 1:1 molar ratio of itraconazole and propyl 4-hydroxybenzoate sodium (i.e. the hydrophobic modifier) were added to 5 mL of the 1% SDS-FaSSGF solution. This mixture was left to stir at 37°C for 10 hours after which a sample was taken, centrifuged for 5 minutes at 21,000 RCF and the API concentration was measured in the supernatant using UV-Vis spectroscopy. The crystalline solubility was increased by 1.5-fold in the presence of the hydrophobic modifier.

Table 1 Crystalline solubility in the presence or absence of a hydrophobic modifier

Example 2

A 4% Kolliphor RH40 solution in FaSSGF (Biorelevant, pH 1.6) was prepared and heated to 37°C. Either an excess amount of only itraconazole (purchased from Sigma- Aldrich) or an excess amount of a 1:1 molar ratio of itraconazole and the hydrophobic modifier were added to 5 mL of the 4% Kolliphor RH40-FaSSGF solution. This mixture was left to stir at 37°C for 10 hours after which a sample was taken, centrifuged for 5 minutes at 21,000 RCF and the API concentration was measured in the supernatant using UV-Vis spectroscopy. The crystalline solubility was increased by 1.9-fold to 2.6-fold in the presence of the hydrophobic modifier.

Table 2 Crystalline solubility in the presence or absence of a hydrophobic modifier

Example 3

An isotropic mixture of 25% sodium tauroursodeoxycholate (surfactant), 25% progesterone (API), 42.5% thymol (hydrophobic modifier), 5% water and 2.5% SDS (surfactant) was prepared. This progesterone formulation was dispersed in 37°C 5 mL FaSSGF (Biorelevant, pH 1.6) with a target concentration of the API at 1 mg/mL. After 30 minutes of agitation, an equivolumair amount of FaSSIF (Biorelevant, doubly concentrated, pH 7.5) was added to the dissolution beaker. Samples were taken at 10 (FaSSGF), 30 (FaSSGF), 45 (FaSSIF), 60 (FaSSIF) and 90 (FaSSIF) minutes. Samples were centrifuged for 5 minutes at 21,000 RCF and the API concentration was measured in the supernatant using UV-Vis spectroscopy. Crystalline solubility of progesterone was simultaneously measured in the FaSSGF buffer as well as the 1:1 mixture of FaSSGF:doubly concentrated FaSSIF. A comparison is made to the crystalline solubility as a measure of formulation performance as the hydrophobic modifier serves as a co-solvent as well, such that a formulation without the modifier is impossible to synthesize and make a comparison to. The results are included in Table 3.

Table 3 Performance of a formulation with a hydrophobic modifier as cosolvent

Example 4

A solution was prepared by dissolving SDS in FaSSGF (Biorelevant pH 1.6) at a concentration of 0.25 mg/mL. From this solution, five different mixtures were obtained by adding one of the following surfactants at 2 mg/mL: Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80), Kolliphor HS 15, Kolliphor RH 40, or Lipoid P LPC 80. Each of these mixtures thus contains SDS at 0.25 mg/mL and only one of the above-listed surfactants at 2 mg/mL. Additionally, the solutions were split in two in which in one a hydrophobic modifier preconcentrate (10 mg/mL vanillin in ethanol) is added at a final concentration of 0.25 mg/mL. Finally, an excess amount of 1-2 mg of Nilotinib (purchased from LC Laboratories) is added to each of the solutions. Nilotinib has a logP of 4.9 and a melting point of 230- 242 °C. After 16 hours of agitation by means of vortexing at 1500 RPM at 25°C using a Eppendorf Thermomixer C, samples were centrifuged for 10 minutes at 1,000 RCF and the API concentration was quantified in the supernatant using UV-Vis spectroscopy, using the base solution without API as background subtraction.

A significant increase in Nilotinib concentration is observed when the small molecule vanillin is present in the aqueous solution, this effect is observed with various surfactants. The results are depicted in Table 4.

Table 4 Crystalline solubility of Nilotinib in the presence or absence of a hydrophobic modifier

Example 5

A solution was prepared by dissolving SDS in FaSSGF (Biorelevant pH1.6) at a concentration of 0.25 mg/mL. From this solution, eight different mixtures were obtained by adding one of the following surfactants at 2 mg/mL: Kolliphor EL, Labrasol, Kolliphor HS 15, Kolliphor RH 40, Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80), TPGS or Lipoid P LPC 80. Each of these mixtures thus contains SDS at 0.25 mg/mL and only one of the above-listed surfactants at 2 mg/mL. Additionally, the solutions were split in two in which in one a hydrophobic modifier preconcentrate (10 mg/mL thymol, vanillin or carvacrol in ethanol) is added at a final concentration of 0.25 mg/mL. Finally, an excess amount of 1-2 mg of Fenofibrate (purchased from LC Laboratories) is added to each of the solutions. Fenofibrate has a logP of 5.2 and a melting point of 79-82 °C. After 16 hours of agitation by means of vortexing at 1500 RPM at 25°C using a Eppendorf Thermomixer C, samples were centrifuged for 10 minutes at 1,000 RCF and the API concentration was quantified in the supernatant using UV-Vis spectroscopy, using the base solution without API as background subtraction.

A significant increase in Fenofibrate concentration is observed when the hydrophobic modifier thymol, vanillin or carvacrol is present in the aqueous solution, this effect is observed with various different co-surfactants. The results are depicted in Table 5. Table 5 Crystalline solubility of Feno fibrate in the presence or absence of a hydrophobic modifier

Claims

1. A pharmaceutical composition comprising a) more than 1 wt% of an active pharmaceutical ingredient (API); b) 2 to 75 wt% of a pharmaceutically acceptable surfactant; c) 0.6 to 75 wt% of a hydrophobicity modifier, which is an aromatic small molecule with a molecular weight of 100 to 400 g/mol and an aqueous solubility of less than 50 mg/mL at 20 °C at pH 7, or a pharmaceutically acceptable salt thereof; and d) an optional solubilizer; based on the total weight of the pharmaceutical composition.

2. Pharmaceutical composition according to claim 1, comprising a) more than 2.5 wt%, preferably 2.5 to 50 wt% of an active pharmaceutical ingredient (API); b) 5 to 75 wt%, preferably 5 to 50 wt%, more preferably 5 to 40 wt%, most preferably 5 to 25 wt% of a pharmaceutically acceptable surfactant; c) 2.5 to 75 wt%, preferably 2.5 to 25 wt% of a hydrophobicity modifier or a pharmaceutically acceptable salt thereof; and d) an optional solubilizer; based on the total weight of the pharmaceutical composition.

3. Pharmaceutical composition according to claim 1, comprising a) 5 to 30 wt% of the API; b) 2 to 25 wt% of the one or more pharmaceutically acceptable surfactants; c) 1 to 15 wt% of the hydrophobicity modifiers or pharmaceutically acceptable salts thereof; d) 20 to 92 wt%, preferably 20 to 80 wt% of a solubilizer; based on the total weight of the pharmaceutical composition.

4. Pharmaceutical composition according to any of the previous claims, wherein the API has a water solubility of less than 0.1 mg/mL at pH 7.

5. Pharmaceutical composition according to any of the previous claims, wherein the API comprises a BCS class II or IV API.

6. Pharmaceutical composition according to any of the previous claims, wherein the one or more hydrophobicity modifiers have a water solubility of less than 50 mg/mL at pH 7.

7. Pharmaceutical composition according to any of the previous claims, wherein the hydrophobicity modifier is selected from the group consisting of vanillin, carvacrol, thymol, cinnamaldehyde, methyl salicylate, propyl gallate, benzyl alcohol, benzoic acid, methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, benzyl 4-hydroxybenzoate, curcumin, propenyl guaethol, gallic acid, ferulic acid, preferably from the group consisting of benzyl alcohol, vanillin and thymol and combinations thereof.

8. Pharmaceutical composition according to any of the previous claims, wherein the hydrophobicity modifier is free from lipids such as fatty acids, mono-di- or triglycerides, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids and/or polyketides.

9. Pharmaceutical composition according to the previous claims, wherein the solubilizer comprises a co-solvent, a deep eutectic solvent (DES) and/or a pharmaceutically acceptable eutectic constituent.

10. Pharmaceutical composition according to any of the previous claims, wherein the solubilizer comprises a pharmaceutically acceptable co- solvent selected from the group consisting of PEG, propylene glycol, dipropylene glycol, butylene glycol, glycerol, glycofurol (tetraglycol), 1,2- hexanediol, 1,2-butanediol, N-methyl-2 -pyrrolidone, dimethyl acetamide, ethyl lactate, propylene carbonate, diethyl malate, triethyl citrate, pyrrolidines, polyglycerol, transcutol, water, dimethyl isosorbide and combination thereof.

11. Pharmaceutical composition according to any of the previous claims, wherein the surfactant comprises a pharmaceutically acceptable surfactant selected from the group consisting of sodium dodecyl sulfate, poloxamers, polysorbates, D-a-tocopheryl polyethylene glycol, PEG mono- and/or diesters with Os-Cis fatty acids, polyethoxylated sorbitan esters, polyethoxylated (hydrogenated) castor oil, polyoxyethylated 12- hydroxystearic acid, bile salts, sodium taurocholate, glycocholic acid, tauroursodeoxycholic acid other conjugates of cholic acid, phospholipids, egg-derived phosphatidylcholine, soy-derived phosphatidylcholine and combinations thereof.

12. Pharmaceutical composition according to any of the previous claims, wherein said composition is liquid or semi-solid at 20 °C and 1 bar.

13. Pharmaceutical composition according to any of claims 1-8, wherein said composition is solid at 20 °C and 1 bar.

14. Pharmaceutical composition according to any of the previous claims, wherein said composition is in a single phase.

15. Pharmaceutical composition according to any of the previous claims, wherein the hydrophobicity modifier comprise at least thymol, and the one or more pharmaceutically acceptable surfactants comprise at least tauroursodeoxycholic acid.

16. Aqueous formulation, comprising up to 5 wt% of the pharmaceutical composition according to any of the previous claims and 95 wt% or more of an aqueous solvent.

17. Pharmaceutical composition or aqueous intravenous formulation according to any of the previous claims for use in a medical treatment comprising enteral administration or injectable administration, preferably oral enteral administration, more preferably comprising oral administration of capsules comprising the pharmaceutical composition.