Cocrystals of posaconazole, and methods of making and using the same

Abstract

To provide, generally, cocrystals of posaconazole and a coformer.SOLUTION: The disclosure further relates to pharmaceutical compositions comprising the cocrystals, to methods of making the cocrystals, and methods of treating or preventing fungal, yeast or dermatophyte infections using the cocrystals.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Statement of government support This invention was made with government support under GM107146 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0002] Cocrystals have emerged as a useful solubility-enhancing technology. Solid-state forms of drugs that improve solubility include pharmaceutical materials such as salts, polymorphs, and amorphous systems. Cocrystals are distinct in that they are composed of two or more neutral molecular components in a crystal lattice with a well-defined stoichiometry, formed through noncovalent interactions, and the components are solid at room temperature. The ability of cocrystals to confer solubility benefits to poorly water-soluble drugs allows them to address absorption and bioavailability issues. In addition to improving their solubility, cocrystals can also modulate pH-dependent solubility, altering the pH of the microenvironment and improving low and unstable bioavailability.

[0003] Posaconazole (PSZ) is a weak dibasic drug belonging to class II of the Biopharmaceutical Classification System (BCS) and is a 3H-1,2,4-triazol-3-one, 4-[4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-yl-methyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-(1-ethyl- 2-hydroxypropyl]-2,4-dihydro-, [3R-[3α(1S*,2S*),5α]]-; or 4-[p-[4-[p[[3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl]methoxy]phenyl]-1-piperazinyl]phenyl]-1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-Δ 2 It has the IUPAC name -1,2,4-triazolin-5-one and the following structure: [ka]

[0004] PSZ is characterized by low water solubility of <1 μg / mL and high lipophilicity, LogP 4.6. PSZ also has a large positive food effect and a high pH dependence of solubility, resulting in low and unstable bioavailability (with an absorption rate of <30%), in addition to daily doses of PSZ that are over 1000 times higher than can be dissolved in a luminal volume of 250 mL.

[0005] PSZ is an extended-spectrum triazole antifungal agent for the prevention and treatment of invasive yeast and mold infections. Current oral formulations include suspensions and sustained-release tablets. Although the development of tablets has reduced interpatient variability, therapeutic drug monitoring has shown that existing oral formulations do not reach pharmacological targets as effectively as intravenous administration, commonly resulting in inadequate treatment.

[0006] A need exists for salts and cocrystals of PSZ that can be formulated as suspensions and solid dosage forms with improved and less variable bioavailability, good aqueous solubility, solubility, stability, and properties suitable for pharmaceutical processing. Summary of the Invention

[0007] Provided herein is a co-crystal comprising posaconazole and a coformer.

[0008] In various embodiments, the coformer comprises a functional group selected from the group consisting of carboxyl, hydroxyl, carbonyl, amine, amide, nitro, and any combination thereof. In various embodiments, the coformer comprises phenol, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 5-nitroisophthalic acid, adipic acid, arginine, aspartic acid, benzoic acid, caffeine, cholic acid, cinnamic acid, citric acid, fumaric acid, glutamic acid, glutaric acid, hippuric acid, m-nitrobenzoic acid, maleic acid, malic acid, malonic acid, mandelic acid, methionine, methylparaben, nicotinic acid, nicotinamide, oxalic acid, phthalic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, saccharin, suberic acid, succinic acid, d-tartaric acid, l-tartaric acid, DL-tartaric acid, theophylline, tryptophan, o-toluic acid, vanillin, or mixtures thereof.

[0009] In various embodiments, the coformer comprises 4-aminobenzoic acid (4ABA). In various embodiments, posaconazole and 4ABA are present in a molar ratio of posaconazole:4ABA of 1:4 to 4:1. In various embodiments, the molar ratio of posaconazole:4ABA is 2:3. In various embodiments, the cocrystal is characterized by an X-ray powder diffraction (XRPD) pattern using Cu Kα radiation containing peaks at 5.8, 10.3, 11.5, 18.9, 19.3, 21.7, and 22.4±0.2 degrees 2θ. In various embodiments, the cocrystal is further characterized by XRPD pattern peaks at 12.9, 13.3, 20.1, 25.0, 25.3, and 26.3±0.2 degrees 2θ using Cu Kα radiation. In various embodiments, the cocrystal has an XRPD pattern substantially as shown in FIG. 3. In various embodiments, the co-crystal has an endothermic transition, as measured by differential scanning calorimetry (DSC), of 154.1±0.6° C. In various embodiments, the co-crystal has a Raman spectrum substantially as shown in FIG.

[0010] The present disclosure further provides methods of making the co-crystals provided herein. In various embodiments, the methods include combining posaconazole and a coformer in a solvent to form a co-crystal and isolating the co-crystal. In various embodiments, the combining is carried out at 0°C to 40°C. In various embodiments, the combining is carried out at 20°C to 40°C. In various embodiments, the solvent includes acetonitrile, methanol, acetone, ethyl acetate, ethanol, 1-propanol, 2-propanol, chloroform, or a mixture thereof. In various embodiments, the solvent includes acetonitrile, methanol, or ethyl acetate. In various embodiments, the solvent includes acetonitrile.

[0011] Also provided is a pharmaceutical composition comprising a cocrystal according to the present disclosure and a pharmaceutically acceptable carrier. In various embodiments, the composition is in the form of a tablet, capsule, or suspension.

[0012] Also provided are methods of preventing or treating a fungal, yeast, or dermatophyte infection in a subject in need thereof. In various embodiments, the method comprises administering to the subject an effective amount of a cocrystal or composition according to the present disclosure. In various embodiments, the subject is a mammal. In various embodiments, the mammal is a human. In various embodiments, the administering is via oral administration of the cocrystal or composition.

[0013] Further aspects and advantages will be apparent to those skilled in the art from a consideration of the following detailed description. While the following description includes specific embodiments, it should be understood that this disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. [Brief explanation of the drawings]

[0014] [Figure 1]Figure 1(a) shows the structure of a posaconazole-4-aminobenzoic acid (PSZ-4ABA) cocrystal with a 2:3 stoichiometry, and (b) shows the asymmetric stacking of two posaconazole molecules in the PSZ-4ABA cocrystal. [Figure 2] 1 shows X-ray powder diffraction (XRPD) spectra of the cocrystal (PSZ-4ABA), drug (PSZ), and coformer (4ABA) according to the present disclosure. [Figure 3] 1 shows the powder X-ray diffraction spectrum of a co-crystal (PSZ-4ABA) according to the present disclosure. [Figure 4] 1 shows differential scanning calorimetry (DSC) thermograms of a cocrystal (PSZ-4ABA), drug (PSZ), and coformer (4ABA) according to the present disclosure. [Figure 5] 1 shows Raman spectra of the cocrystal (PSZ-4ABA), drug (PSZ), and coformer (4ABA) according to the present disclosure. [Figure 6] 1 shows the Raman spectrum of a co-crystal (PSZ-4ABA) according to the present disclosure. [Figure 7] 1 is a graph of drug concentration over time during dissolution of a cocrystal (PSZ-4ABA) and drug (PSZ) in a biorelevant medium according to the present disclosure. [Figure 8] Graph of drug (PSZ) and coformer (4ABA) concentrations at the eutectic point of the cocrystal and drug, and the corresponding cocrystal (PSZ-4ABA) Keu values in buffer and biorelevant media. DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein are cocrystals comprising posaconazole and a coformer. The cocrystals of the present disclosure are distinct from crystals of the drug alone ("drug crystals") or solvated drug crystals (e.g., those that include a solvent in the crystal structure). Drug crystal solvates may contain solvents such as water, methanol, and dioxane. Cocrystals and solvates are crystals that contain both the drug (posaconazole) and another component (the coformer or solvent, respectively), but the coformer is solid at room temperature, whereas the solvent in the solvate is not.

[0016] Advantageously, the cocrystals of the present disclosure exhibit significantly improved biopharmaceutical properties, such as increased solubility and dissolution at biologically relevant pH levels, compared to the drug as crystal alone (e.g., without the coformer). Furthermore, the cocrystals of the present disclosure are capable of achieving dissolved concentrations in biologically relevant media that can be up to 16-fold higher than the drug crystal alone. These advantages can result in improved biopharmaceutical properties, such as reduced instability, absorption, pH, and food independence, and improved bioavailability.

[0017] As noted above, the coformer is a solid at room temperature. In embodiments, the coformer comprises a functional group selected from the group consisting of carboxyl, hydroxyl, carbonyl, amine, amide, nitro, and any combination thereof. Examples of suitable coformers include, but are not limited to, phenol, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 5-nitroisophthalic acid, adipic acid, arginine, aspartic acid, benzoic acid, caffeine, cholic acid, cinnamic acid, citric acid, fumaric acid, glutamic acid, glutaric acid, hippuric acid, m-nitrobenzoic acid, maleic acid, malic acid, malonic acid, mandelic acid, methionine, methylparaben, nicotinic acid, nicotinamide, oxalic acid, phthalic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, saccharin, suberic acid, succinic acid, d-tartaric acid, l-tartaric acid, DL-tartaric acid, theophylline, tryptophan, o-toluic acid, vanillin, or mixtures thereof. In an embodiment, the coformer is 4-aminobenzoic acid. In an embodiment, the coformer is 4-hydroxybenzoic acid. In an embodiment, the coformer is malic acid.

[0018] Posaconazole and coformer can be present in the cocrystal in any suitable molar ratio, hi embodiments, posaconazole and coformer can be present in a molar ratio of posaconazole to coformer of 1:10 to 10:1, 1:8 to 8:1, 1:4 to 4:1, or 1:2 to 2:1, e.g., 1:10, 1:8, 2:9, 1:5, 2:5, 2:3, 3:2, 5:2, 5:1, 9:2, 8:1, or 10:1.

[0019] Cocrystals 4-Aminobenzoic acid (4ABA) cocrystal In embodiments, the coformer comprises 4-aminobenzoic acid (4ABA). In embodiments, posaconazole and 4ABA may be present in the cocrystal in a molar ratio of posaconazole to 4ABA of 1:4 to 4:1, 1:3 to 3:1, or 1:2 to 2:1, e.g., 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, or 4:1. In embodiments, the molar ratio of posaconazole to 4ABA in the cocrystal is 2:3.

[0020] The 4ABA cocrystal may be characterized by an X-ray powder diffraction pattern (XRPD), obtained as described in the Examples, having peaks at about 5.8, 10.3, 11.5, 18.9, 19.3, 21.7, and 22.4±0.2 degrees 2θ using Cu Kα radiation. The 4ABA cocrystal may further, optionally, be characterized by an XRPD pattern having peaks at 12.9, 13.3, 20.1, 25.0, 25.3, and 26.3±0.2 degrees 2θ using Cu Kα radiation. The 4ABA cocrystal may further, optionally, be characterized by an XRPD pattern having peaks as shown in Figure 3, as described in the Examples. In some embodiments, the 4ABA cocrystal has an XRPD pattern substantially as shown in Figure 3, where "substantially" means that the reported peaks may vary by about ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on several factors such as sample preparation and instrument geometry, but that the peak positions are relatively insensitive to experimental details.

[0021] Differential scanning calorimetry (DSC) thermograms of 4ABA cocrystals can be obtained as described in the Examples. The DSC curve exhibits an endothermic transition at about 154.1±0.6°C. Thus, in some embodiments, 4ABA cocrystals can be characterized by a DSC thermogram with a melting endotherm with an onset in the range of about 149°C to about 159°C. For example, in embodiments, 4ABA cocrystals are characterized by a DSC as shown in Figure 4.

[0022] The 4ABA cocrystal can also be characterized by Raman spectroscopy. For example, the 4ABA cocrystal exhibits Raman peaks at 832, 1173, 1242, and 1686 cm. -1 In embodiments, the 4ABA cocrystal may be characterized by a Raman spectrum substantially as shown in Figure 6, where "substantially" means that the reported peak is at or near 2 cm. -1 This means that it may vary.

[0023] Methods for making cocrystals Also provided herein are methods of making the co-crystals described herein. In embodiments, the methods include combining posaconazole (PSZ) and a coformer in a solvent to form a co-crystal, and isolating the co-crystal.

[0024] In embodiments, the blending is carried out at 0°C to 40°C, 0°C to 20°C, 20°C to 40°C, 25°C to 35°C, or 30°C to 40°C, e.g., 0, 4, 10, 20, 22, 25, 27, 30, 32, 35, 37, or 40°C.

[0025] In general, the process for making the co-crystal can be carried out in any solvent system in which both the PSZ and the coformer are sufficiently soluble. Examples of suitable solvents include, but are not limited to, acetonitrile, methanol, acetone, ethyl acetate, ethanol, 1-propanol, 2-propanol, chloroform, and mixtures thereof. In an embodiment, the solvent comprises acetonitrile.

[0026] Successful co-crystal formation may depend on factors such as the choice of coformer, the solvent and temperature at which the PSZ and coformer are mixed, the initial concentrations of the PSZ and coformer, the pH, the rate of mixing of the reactants, the rate of cooling, and / or the rate of evaporation, among others.

[0027] In embodiments where the co-crystal is a 4ABA co-crystal and the solvent comprises acetonitrile, methanol, or ethyl acetate, PSZ may be present at a concentration that is at least 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 times the solubility of PSZ in acetonitrile, methanol, or ethyl acetate, and may be present at a concentration that is 0.5 to 1.0 times the solubility of 4ABA.

[0028] Co-crystals can be formed using many processes, including reaction crystallization, slurrying the co-crystal component mixture, solvent evaporation, solvent adsorption, cooling, co-milling the co-crystal reactants with or without solvent (liquid-assisted milling), thermally induced hot-melt extrusion, spray drying, wet granulation, dry granulation, solvent freezing, mechanochemical methods such as crystallization in supercritical fluids such as CO. Co-crystal formation, purity, composition, and stoichiometry can depend on the solvent, salts, buffer components, additives such as sugars, polymers, surfactants, pH, temperature, pressure, mass, concentration, rate of addition of the co-crystal components, rate of cooling, and rate of evaporation. The selection of these parameters is well within the purview of one of ordinary skill in the art, given the guidance provided in the examples below.

[0029] Pharmaceutical Compositions, Dosages, and Routes of Administration Also provided herein is a pharmaceutical composition comprising a cocrystal described herein and a pharmaceutically acceptable carrier. In embodiments, the carrier comprises an excipient.

[0030] The phrase "pharmaceutically acceptable" is used herein to refer to ligands, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The compositions described herein can be formulated for any dosage form. In embodiments, the composition is for oral administration. In embodiments, the composition is in the form of a capsule or tablet, e.g., an immediate-release or extended-release tablet. In embodiments, the composition is an oral suspension. In embodiments, the composition is for intravenous injection.

[0031] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the phrase "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are compatible with pharmaceutical administration. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS); (4) polymers such as polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate (PVP / VA); and (5) sodium lauryl sulfate, polysorbate (Tween), polyoxyethylene stearate (Myri), polyoxyethylene alkyl ether (Brij), polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactame systems. (6) surfactants such as graft copolymers (Soluplus), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), (7) gelatin, (8) excipients such as cocoa butter and suppository wax, (9) lipids such as Captex, Capmul, and Cremophore, (10) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (11) glycols such as propylene glycol, (12) glycerins such as propylene glycol, (13) glycerins such as propylene glycol, (14) glycerins such as propylene glycol, (15) glycerins such as propylene glycol, (16) glycerins such as propylene glycol, (17) glycerins such as propylene glycol, (18) glycerins such as propylene glycol, (19) glycerins such as propylene glycol, (20) glycerins such as propylene glycol, (21) glycerins such as propylene glycol, (22) glycerins such as propylene glycol, (23) glycerins such as propylene glycol, (24) glycerins such as propylene glycol, (25) glycerins such as propylene glycol, (26) glycerins such as propylene glycol, (27) glycerins such as propylene glycol, (28) glycerins such as propylene glycol, (29) glycerins such as propylene glycol, (30) glycerins such as propylene glycol, (31) glycerins such as propylene glycol, (32) glycerins such as propylene glycol, (33) glycerins such as propylene glycol, (34) glycerins such as propylene glycol, (35) glycerins such as propylene glycol, (36) glycerins such as propylene glycol, (37) glycerins such as propylene glycol, (38) glycerins (2) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (13) esters such as ethyl oleate and ethyl laurate, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are non-pyrogenic, i.e., do not cause a significant increase in body temperature when administered to a patient.

[0032] Wetting agents, drug solubilizers, emulsifiers such as sodium lauryl sulfate, lubricants such as Tween, Brij, Myri, Solubplus, and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, preservatives, and antioxidants may also be present in the composition as excipients.

[0033] Precipitation inhibitors or cocrystal stabilizers, such as surfactants, lipids, complexing agents, and polymers, that prevent or delay the conversion of cocrystals to drug during processing, storage, and dissolution may also be present in the formulation. Cocrystals are generally more soluble than the parent drug and are therefore predisposed to conversion to less soluble forms of the drug; therefore, formulations may include excipients to stabilize the cocrystals and / or delay their conversion to other less soluble forms.

[0034] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0035] Pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include an isotonicity adjusting agent, such as sugar, in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0036] The compositions prepared as described herein can be administered in various forms, as is well known in the art, depending on the disorder to be treated and the age, condition, and weight of the patient.For example, when the compositions are administered orally, they can be formulated as tablets, capsules, granules, powders, or suspensions; when administered parenterally, they can be formulated as injections (intravenous, intramuscular, or subcutaneous), drip infusion preparations, or suppositories.These preparations can be prepared by conventional means in combination with the methods described herein, and if necessary, the active ingredient can be mixed with any conventional additives or excipients, such as binders, disintegrants, lubricants, colligants, solubilizers, suspension aids, emulsifiers, or coating agents.In some embodiments, the composition is an oral composition.In some cases, the oral composition is a tablet, capsule, or suspension.

[0037] The pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0038] Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein can be varied to obtain a "therapeutically effective amount," that is, an amount of the active ingredient that is effective, for a particular patient, composition, and mode of administration, to achieve the desired therapeutic response without being toxic to the patient.

[0039] The concentration of the compounds provided herein in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound administered, the pharmacokinetic characteristics of the cocrystal used, and the route of administration. Typical dose ranges can include about 0.01 to about 50 mg / kg body weight per day given in one to four divided doses. The dosage will be a therapeutically effective amount, depending on several factors, including the patient's overall health, as well as the cocrystal formulation and route of administration.

[0040] How to use The cocrystals or pharmaceutical compositions described herein can be used to treat or prevent fungal, yeast, and / or dermatophyte infections. For example, the cocrystals can be used to treat or prevent blastomycosis, aspergillosis, histoplasmosis, onychomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, mucormycosis, dermatophyte, and / or candidiasis infections. In some cases, the treatment is for oropharyngeal candidiasis or oropharyngeal candidiasis that is resistant to itraconazole and / or fluconazole.

[0041] In embodiments, the method may include administering an effective amount of a cocrystal or pharmaceutical composition described herein to a subject in need of prevention or treatment. In embodiments, the subject is a mammal. For example, in embodiments, the subject is a human.

[0042] The amount of cocrystal of the pharmaceutical composition administered to a subject will depend on the nature of the disease or disorder (e.g., acute or chronic), as well as the type of disease or disorder, and the route of administration. The dose, frequency of administration, or both may also vary depending on the patient's age, weight, response, past medical history, and consideration of whether the patient is taking other drugs or medications concurrently or concomitantly. Suitable administration regimens are well within the purview of one of ordinary skill in the art, for example, by considering such factors by following dosages and administration regimens reported in the literature and known in the art.

[0043] "Treatment" or "treating" includes one or more of the following: a) inhibiting a disease or disorder, b) delaying or preventing the onset of clinical symptoms of a disease or disorder, and / or c) alleviating a disease or disorder, causing regression of clinical symptoms. This term encompasses both complete and partial reduction of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, a cocrystal described herein, or a pharmaceutical composition described herein, may prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder. "Prevention," i.e., causing clinical symptoms of a disease or disorder not to develop, includes prophylactic administration of a cocrystal or composition described herein to a subject (i.e., an animal, preferably a mammal, most preferably a human) believed to be in need of prophylactic treatment, such as, for example, chronic mucocutaneous candidiasis. In some cases, the prophylactic treatment is for the prevention of invasive Aspergillus or Candida infections.

[0044] In jurisdictions that prohibit patents on methods performed on the human body, the meaning of "administering" a composition to a human subject shall be limited to formulating a controlled substance that the human subject would self-administer by any means (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with any statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patents on methods performed on the human body, "administering" a composition includes both the method and the aforementioned activities performed on the human body.

[0045] While this disclosure is to be read in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, and not limit, the scope of the disclosure, as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [Example]

[0046] The following examples are offered for illustrative purposes and are not intended to limit the scope of the present disclosure.

[0047] Example 1 - Preparation and Evaluation of PSZ-4ABA Cocrystals material Posaconazole was purchased from BOC Sciences (Shirley, NY) and used as received. 4-Aminobenzoic acid, acetic acid, anhydrous sodium acetate, dipotassium hydrogen phosphate, trifluoroacetic acid, and sodium chloride were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Sodium hydroxide was purchased from JT Baker Chemical Company (Phillipsburg, NJ). HPLC-grade methanol, sodium dihydrogen phosphate, and hydrochloric acid were purchased from Fisher Scientific (Fair Lawn, NJ). FaSSIF / FeSSIF products were purchased from Biorelevant.com Ltd (London, UK).

[0048] cocrystal synthesis The PSZ-4ABA cocrystal was prepared by reactive crystallization in acetonitrile at room temperature. 350 mg of drug (equivalent to three times the drug solubility) was added to the coformer solution (approximately 0.17 M) and magnetically stirred for 2 hours. The suspension was filtered through a 0.45 μm pore membrane, and the solid phase was characterized by PXRD, DSC, and Raman spectroscopy.

[0049] Single crystals of PSZ-4ABA were obtained by slow evaporation from acetonitrile. 6.4 mg of PSZ and 71.4 mg of 4ABA were dissolved in 2 mL of acetonitrile. The solution was filtered, transferred to a glass vial, covered with punctured Parafilm®, and allowed to evaporate at 4 °C. Single crystals were obtained, separated from the solution by 48 h, and characterized by Raman spectroscopy and single crystal X-ray diffraction (SCXRD).

[0050] cocrystal analysis Single Crystal X-ray Diffraction (SCXRD) Crystals suitable for SCXRD characterization were mounted in a cryoloop with Fomblin protective oil. Data were collected on a Bruker AXS-KAPPA APEXII diffractometer using graphite-monochromated radiation at 167(2)K (Mo Kα, λ=0.71073 Å). The X-ray generator was operated at 50 kV and 30 mA, and data collection was monitored by the APEX2 program. All data were corrected for Lorentzian, polarization, and absorption effects using the SAINT and SADABS programs. The structure was solved by intrinsic phasing methods using SHELXT-2014 integrated into the Bruker diffractometer interface. F 2 For refinement using full-matrix least-squares in the SHELXL-2017 / 1 program package, included in the WINGX-version 2014.1 package, all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were inserted at ideal positions, except for those belonging to amine groups and chiral carbons, and hydrogen atoms riding on parent carbon atoms were refined, which could be positioned from the electron density map and refined freely. Graphical representations were created using Mercury version 3.10.3.

[0051] The SCXRD spectra, shown in Figure 1, indicated that the cocrystal had a 2:3 PSZ:4ABA stoichiometry. As shown in Figure 1(a), the largest conformational changes involved fragments I and II, located at the left and right ends of the PSZ molecule. The torsion angles involved in these fragments in one molecule were symmetrical to the corresponding torsion angles in the other molecule. Most notably, (i) the plane defined by the a and c phenyl rings forms an angle of 27.33° with the plane supporting the piperazine b ring in the PSZ A molecule and 23.77° in the PSZ B molecule; (ii) the angle between the plane of the two phenyls and the plane of the triazole d group is very different in PSZ A (18.76°) and PSZ B (42.67°). While not intending to be bound by theory, it is believed that these differences may be related to the distinct hydrogen-bonding patterns formed by the PSZ A / 4ABA and PSZB / 4ABA pairs.

[0052] As shown in Figure 1(b), the two molecules of PSZ in the cocrystal asymmetric unit were not superimposable.

[0053] The two PSZ compounds in the cocrystal interacted through OH···N, OH···O, NH···O, and NH···N hydrogen bonds. It was found that the PSZ A molecule interacted with 4ABA through three hydrogen bonds, while the PSZ B molecule interacted with 4ABA through only two hydrogen bonds. Therefore, without intending to be bound by theory, the PSZ A molecule was more compressed in the crystal compaction than its PSZ B counterpart, which explains the conformational differences between the two molecules.

[0054] Powder X-ray diffraction (PXRD) Diffractograms were obtained using a Rigaku MiniFlex diffractometer (Danvers, MA) equipped with a Kα copper radiation (λ = 1.5418 Å) operated at a current of 15 mA and a voltage of 30 kV. Measurements were performed over the range 2° to 40° 2θ at a scan rate of 2.5° / min at room temperature.

[0055] The PXRD spectra of PSZ-4ABA, PSZ, and 4ABA are shown in Figure 2. Figure 3 shows the PXRD spectrum of PSZ-4ABA alone. The spectrum of the PSZ-4ABA cocrystal exhibited a unique pattern compared to PSZ alone and 4ABA alone. In addition, the peaks observed in the experimental pattern corresponded to the simulated pattern calculated by Mercury using the SCXRD data of the 2:3 PSZ-4ABA cocrystal, demonstrating the formation of a pure crystalline phase of the PSZ-4ABA cocrystal.

[0056] Differential scanning calorimetry (DSC) DSC analyses were performed using a TA Instrument (Neward, Del.). Samples weighing approximately 1.5 mg were heated at a rate of 10° C. / min under a nitrogen gas atmosphere (50 mL / min). Standard aluminum sample pans were used for all measurements.

[0057] DSC thermograms showing the thermal behavior of the PSZ-4ABA cocrystal compared to the individual cocrystal components are shown in Figure 4. The DSC thermogram of the cocrystal is clearly different from that of the individual components. A single endothermic event corresponding to the melting point of the cocrystal was observed at 154.1 ± 0.6 °C, which is lower than the melting points of PSZ (168.2 ± 0.5 °C) and 4ABA (188.3 ± 0.6 °C). The drug PSZ exhibits two endothermic events, a nematic-like phase transition at 134 ± 1 °C and the melting point of the drug at 168.2 ± 0.5 °C, as described in the literature.

[0058] Raman spectroscopy Raman spectra of the cocrystal powder and single crystals were collected with a WITec alpha300R confocal Raman imaging microscope (Ulm, Germany) equipped with a 50x air objective (Zeiss EC EPIPLAN, NA = 0.75) and a 532 nm solid-state excitation laser (intensity range 0-55 mW adjustable with the attenuator dial). The spectra are shown in Figure 5 and Figure 6.

[0059] The Raman spectrum of the PSZ-4ABA cocrystal, compared to the individual cocrystal components, shows a peak at 1686 cm -1 It shows new characteristic bands at 832, 1173, and 1242 cm -1 showed some band shifts.

[0060] Determination of solubility and solubility Blank FaSSIF (phosphate buffer, pH 6.50) was prepared at room temperature by dissolving 0.683 g of NaOH (pellets), 7.902 g of NaH2PO4·H2O, and 12.372 g of NaCl in 2 L of purified deionized (DI) water. The pH was adjusted to 6.50 (±0.04) with 1 M NaOH and 1 M HCl solutions. Blank FeSSIF (acetate buffer, pH 5.00) was prepared at room temperature by dissolving 8.089 g of NaOH (pellets), 16.4 mL of acetic acid, and 23.748 g of NaCl in 2 L of purified DI water. The pH was adjusted to 5.00 (±0.03) with 1 M NaOH and 1 M HCl solutions. FaSSIF and FeSSIF media were prepared by dissolving the appropriate amount of FaSSIF / FeSSIF powder in blank media according to the manufacturer's instructions, then stored at room temperature and used within 48 hours. Blank FaSSGF (pH 1.60 buffer) was prepared at room temperature by dissolving 1.999 g of sodium chloride in 1 L of DI water. The pH was adjusted to 1.60 (±0.05) with 2 M HCl solution.

[0061] Dissolution studies of the drug or cocrystal were performed using an overhead stirrer with a glass propeller at 150 rpm for 3 hours. Based on a 300 mg dose in 250 mL, 36 mg of PSZ drug or 46.6 mg of PSZ-4ABA cocrystal (molar equivalent of PSZ) was added to 30 mL of dissolution medium. Dissolution studies were performed in FaSSIF and FeSSIF containing sieved drug and cocrystal fractions in the particle size range of 106–125 μm. Dissolution experiments were performed in a water bath at 25.0 (±0.5) °C. The initial and final pH of the solution was measured. 0.5 mL aliquots were withdrawn by syringe at time points up to 180 minutes. Solution samples were filtered through syringe filters with 0.45 μm pore size PvDF membranes. Solution concentrations of the drug and coformer were analyzed using a Waters HPLC with a photodiode array UV detector. Waters Atlantis C with dimensions of 5 μm and 250 × 4.6 mm 18A column was used for the separation. A gradient method using methanol and water containing 0.1% trifluoroacetic acid was run with the flow rate set at 1 mL / min. The injection volume for PSZ solubility in blank media was 60 μL, and all other solubility and dissolution studies had an injection volume of 20 μL. The wavelengths used for the analytes were 159 nm for PSZ and 287 nm for 4ABA.

[0062] The solubility behavior of the cocrystal and drug is shown in Figure 7 and summarized in Table 1 below. The results showed that the cocrystal had superior dissolution properties compared to the drug crystal. The cocrystal produced drug concentrations that were 16-fold (FaSSIF) and 8-fold (FeSSIF) higher than the drug solubility, and even after 3 hours, the drug concentration was still 3-fold higher than the drug solubility. Cocrystal solubility was measured as a function of the maximum concentration of dissolved drug over time (C ) as a result of the interaction between cocrystal solubility and drug precipitation. max ) resulted in a significant increase in drug solution concentration. Cocrystal solubility increases drug solution concentration, while drug precipitation decreases drug solution concentration. As summarized in Table 1, the superior solubility, dissolution, and drug exposure levels of the cocrystals are demonstrated by the cocrystals' larger area under the dissolution curve (AUC). [Table 1]

[0063] Cocrystal solubility in both media resulted in supersaturation levels compared to PSZ, which persisted for 3 hours. The supersaturation levels at 3 hours were 2.6-2.7 in both FaSSIF and FeSSIF. Furthermore, the cocrystal AUC was 4.1-fold higher than that in FaSSIF and 13-fold higher than that in FeSSIF. RAUC, which represents the increase in drug exposure due to cocrystals, is directly proportional to cocrystal solubility and inversely proportional to drug precipitation or phase separation. These findings suggest that PSZ-4ABA cocrystals have the potential to increase drug exposure in vivo compared to PSZ crystals.

[0064] Example 2 - Evaluation of PSZ-4ABA Cocrystal Co-crystals were prepared according to Example 1 and further evaluated.

[0065] The cocrystal eutectic constant (K) is well recognized as an important stability and solubility index. eu ) to K eu =[coformer] eu / [drugs] eu The eutectic point, where the drug and cocrystal solid phases are in equilibrium with the solution, was determined from measurements of the coformer and drug concentrations according to [1]. Excess PSZ (approximately 200 mg) and 150 mg of PSZ-4ABA were suspended in 3 mL of blank FaSSGF, blank FaSSIF, blank FeSSIF, FaSSIF, or FeSSIF media. Biorelevant media included FaSSIF and FeSSIF. Blank media was a buffered solution of biorelevant media without lecithin and bile salts. The suspension was kept in a water bath at 25.0 ± 0.1 °C and magnetically stirred for up to 72–96 h. Sample solutions were filtered through 0.45 μm cellulose acetate filters and analyzed by HPLC. pH was measured, and the equilibrated solids were characterized by DSC and PXRD.

[0066] K eu is proportional to the cocrystal solubility advantage over the drug (SA = S cc / S 薬物 ), in the case of 2:3, the cocrystal is obtained by

number

[0067] Table 3 below shows the eutectic drug ([PSZ] eu ) and coformer ([4ABA] eu ) concentration, pH 初期 , pH at equilibrium (pH eq ), and the eutectic constants in the solid phase at equilibrium, as well as in buffers and biorelevant media. [Table 2]

[0068] K eu The relationship between K and cocrystal solubility is eu =1.5(S cc / S 薬物 ) 5 / 3 The results in Figure 8 show that K eu >1.5, so the cocrystal solubility (S cc ) is higher than that of the drug. Therefore, the cocrystal may be supersaturated with the drug and potentially undergo solution-mediated transformation. In addition, the K eu The values were reduced in the presence of drug solubilizers in FaSSIF and FeSSIF media, indicating a reduction in SA or an advantage of cocrystal solubility over the drug (S cc / S 薬物 ) advantages.

[0069] The effect of pH on the solubility of the drug crystal (PSZ) and cocrystal (PSZ-4ABA) was investigated using [PSZ] eu , [4ABA] eu , and K. eu The pH dependence of [PSZ] was determined by analyzing the eu corresponds to PSZ solubility, which decreases 700–800 fold with increasing pH from 1.9 to 5.1, while S cc decreases 20-fold over the same pH range, indicating that the PSZ-4ABA cocrystal has a much weaker pH dependence than the drug crystal.

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Claims

1. A co-crystal comprising posaconazole and a coformer.

2. 2. The co-crystal of claim 1, wherein the coformer comprises a functional group selected from the group consisting of carboxyl, hydroxyl, carbonyl, amine, amide, nitro, and any combination thereof.

3. 3. The co-crystal of claim 1 or 2, wherein the coformer comprises phenol, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 5-nitroisophthalic acid, adipic acid, arginine, aspartic acid, benzoic acid, caffeine, cholic acid, cinnamic acid, citric acid, fumaric acid, glutamic acid, glutaric acid, hippuric acid, m-nitrobenzoic acid, maleic acid, malic acid, malonic acid, mandelic acid, methionine, methylparaben, nicotinic acid, nicotinamide, oxalic acid, phthalic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, saccharin, suberic acid, succinic acid, d-tartaric acid, l-tartaric acid, DL-tartaric acid, theophylline, tryptophan, o-toluic acid, vanillin, or a mixture thereof.

4. 4. The co-crystal of claim 1, wherein the coformer comprises 4-aminobenzoic acid (4ABA).

5. 5. The co-crystal of claim 4, wherein the posaconazole and 4ABA are present in a molar ratio of posaconazole:4ABA of 1:4 to 4:

1.

6. 6. The co-crystal of claim 5, wherein the molar ratio of posaconazole:4ABA is 2:

3.

7. 7. The co-crystal of any one of claims 4 to 6, characterized by an X-ray powder diffraction (XRPD) pattern using Cu Kα radiation comprising peaks at 5.8, 10.3, 11.5, 18.9, 19.3, 21.7, 22.4±0.2 degrees 2θ.

8. 8. The co-crystal of claim 7, further characterized by XRPD pattern peaks at 12.9, 13.3, 20.1, 25.0, 25.3, 26.3±0.2 degrees 2θ using Cu Kα radiation.

9. 9. The co-crystal of any one of claims 4 to 8, having an XRPD pattern substantially as shown in Figure 3.

10. 10. The co-crystal of any one of claims 4 to 9, wherein the endothermic transition is 154.1±0.6°C as measured by differential scanning calorimetry (DSC).

11. 11. The co-crystal of any one of claims 4 to 10, having a Raman spectrum substantially as shown in Figure 6.

12. 4. The co-crystal of claim 1, wherein the coformer comprises 4-hydroxybenzoic acid.

13. 4. The co-crystal of claim 1, wherein the coformer comprises malic acid.

14. A method for making the co-crystal of any one of claims 1 to 13, comprising the steps of:

1. A method comprising combining posaconazole and a coformer in a solvent to form a co-crystal; and isolating the co-crystal.

15. 15. The method of claim 14, wherein the blending is carried out at 0°C to 40°C.

16. 16. The method of claim 15, wherein the blending is carried out at 20°C to 40°C.

17. 17. The method of claim 15 or 16, wherein the solvent comprises acetonitrile, methanol, acetone, ethyl acetate, ethanol, 1-propanol, 2-propanol, chloroform, or a mixture thereof.

18. 18. The method of claim 17, wherein the solvent comprises acetonitrile, methanol, or ethyl acetate.

19. 20. The method of claim 18, wherein the solvent comprises acetonitrile.

20. A pharmaceutical composition comprising the cocrystal of any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

21. 21. The composition of claim 20 as a tablet, capsule, or suspension.

22. 22. A method of preventing or treating a fungal, yeast, or dermatophyte infection in a subject in need thereof, comprising administering to the subject an effective amount of a cocrystal of any one of claims 1 to 13 or a composition of claim 20 or 21.

23. 23. The method of claim 22, wherein the subject is a mammal.

24. 24. The method of claim 23, wherein the mammal is a human.

25. 25. The method of any one of claims 22-24, wherein said administering is via oral administration of said cocrystal or composition.

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