Cariprazine long-acting injectable (LAI) composition

Abstract

A sustained release pharmaceutical composition in the form of a solution or suspension, comprising cariprazine, a biocompatible organic solvent, and optionally additional excipients, for use in the treatment of psychotic disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 483,031, filed February 3, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to a pharmaceutical composition for the sustained release of cariprazine over a period of at least one week. The present invention also relates to making and using said composition. [Background technology]

[0003] Cariprazine is an atypical antipsychotic. Its chemical name is trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea. Its empirical formula is C 21 H 32 ClNO and its molecular weight is 427.41 g / mol. The chemical structure is shown in Scheme I below:

[0004] [ka]

[0005] Cariprazine HCl, sold under the trade names Vraylar® and Reagila®, was created by Gedeon Richter [Laszlovszky, Istvan; Barabassy, ​​Agota; Nemeth, Gyorgy (2021) "Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety" Advances in Therapy. 38(7):3652-3673]. Vraylar® was approved for medical use in the United States on September 17, 2015. Vraylar® capsules are intended for oral administration only. Each hard gelatin capsule contains a white to off-white powder of cariprazine HCl, equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of cariprazine base. It is used for the treatment of schizophrenia in adults, the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults, and as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults [HIGHLIGHTS OF PRESCRIBING INFORMATION dated December 12, 2022, https: / / www.rxabbvie.com / pdf / vraylar_pi.pdf, retrieved January 23, 2023]. Cariprazine acts primarily as a partial agonist at D3 and D2 receptors, but prefers D3 receptors.Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and an antagonist at the 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor [Kiss B; Horvath A; Nemethy Z; Schmidt E; Laszlovszky I; Bugovics G; Fazekas K; Hornok K; Orosz S; Gyertyan I; Agai-Csongor E; Domany G; Tihanyi K; Adham N; Szombathelyi Z (2010). "Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3) / D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile". The Journal of Pharmacology and Experimental Therapeutics. 333(1):328-340].

[0006] Cariprazine has also been approved as a generic drug by the FDA for the treatment of schizophrenia in adults, for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults ["First Generic Drug Approvals 2022". US Food and Drug Administration. 17 October 2022, retrieved January 23, 2023].

[0007] Vraylar® is formulated as a capsule that releases cariprazine directly into the gastrointestinal tract when mixed with gastric or intestinal fluids. Vraylar® capsules are intended to be taken daily during treatment, which can be challenging for this special patient population and can lead to poor patient compliance. Furthermore, oral Vraylar® capsules also cause several side effects, such as abdominal pain, vomiting, diarrhea, nausea, and constipation. Therefore, there is an unmet medical need for a sustained-release dosage form that allows patients to take the drug less frequently, for example, once weekly, once monthly, once every three months, or once every six months. Several long-acting injectable compositions containing cariprazine have recently been disclosed in WO2023281404, US20230293514, WO2022195615, CN108261394, CN108261394, WO2022042642, US11344503, and WO2021119166. All of the disclosed long-acting injectable compositions containing cariprazine exist as non-aqueous and aqueous suspensions, microparticles, and in situ-forming polymer formulations. Solution-based compositions are the simplest form of long-acting injectable products and are easy to manufacture. Surprisingly, no solution-based long-acting injectable compositions containing cariprazine have been disclosed. Although all of the formulations described in these prior art purport to provide sustained release of cariprazine, there remains a need to develop better sustained release formulations of cariprazine that are easy to prepare and use, have better release profiles or pharmacokinetics, and can last for at least one week, one month, or more.

[0008] Therefore, the primary object of the present invention is to address the above-mentioned unmet medical needs by providing a long-acting injectable (LAI) formulation of cariprazine to significantly improve patient compliance and reduce side effects. Summary of the Invention

[0009] The present invention relates to a sustained release injectable (LAI) composition of cariprazine or its salts for sustained delivery of cariprazine over a period of at least one week, a process for preparing the LAI composition, and its use in the treatment of psychotic disorders.

[0010] The LAI composition comprises cariprazine free base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable organic solvent.

[0011] In one embodiment of the present invention, the LAI composition is a solution of cariprazine completely dissolved in a pharmaceutically acceptable solvent selected from the group consisting of glycerin, ethanol, ethyl alcohol, isopropyl alcohol, propylene glycol (PG), benzyl alcohol (BA), benzyl benzoate (BB), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), dimethylacetamide (DMAc or DMA), glycofurol, glycofurol 75, solketal, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, polyethylene glycol (PEG), polyethylene glycol 300 (PEG300), polyethylene glycol 400 (PEG400), medium chain triglycerides (MCT), vegetable oil, bean oil, sesame oil, castor oil, olive oil, peanut oil, mixtures or combinations thereof.

[0012] In another embodiment of the present invention, the LAI composition is a solution having a concentration of cariprazine free base or a pharmaceutically acceptable salt thereof of about 0.1% to about 50% by weight and a pharmaceutically acceptable solvent of about 50% to about 99.9% by weight.

[0013] In another embodiment of the invention, the LAI composition does not include biodegradable lactic acid or lactide-containing polymers or copolymers, including poly(D,L-lactide) or poly(D,L-lactide-co-glycolide).

[0014] The LAI compositions of the present invention provide a dosage form for administering cariprazine via subcutaneous or intramuscular routes to potentially avoid side effects associated with the gastrointestinal (GI) track or first pass.

[0015] The present invention provides a method for preparing an LAI composition of cariprazine that is convenient and suitable for commercial production.

[0016] The present invention provides a method for treating a patient suffering from a condition responsive to cariprazine or a pharmaceutically acceptable salt thereof. The method comprises intramuscularly or subcutaneously administering to a patient in need thereof a therapeutically effective level of a cariprazine LAI composition. The patient to be treated generally suffers from an indication such as schizophrenia, mania, bipolar disorder, and other related disorders.

[0017] The details of one or more embodiments of the invention are set forth in the following description. These and other embodiments, features, and advantages will become apparent to those skilled in the art upon review of the following description of various exemplary embodiments of the invention in conjunction with the accompanying drawings. The foregoing summary, as well as the following detailed description of the present invention, will be better understood when read in conjunction with the accompanying drawings. It is understood that the invention is not limited to the precise embodiments shown in the drawings. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows the in vitro release of cariprazine formulations. [Figure 2] FIG. 1 shows the PK profile of cariprazine formulations in Sprague-Dawley rats at a dose level of approximately 100 mg / kg. [Figure 3] FIG. 1 shows the PK profiles of cariprazine formulations in Sprague-Dawley and Wistar rats at a dose level of approximately 40 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0019] Various publications, articles, and patents are cited or described in the Background and throughout the Specification. Each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, and the like included in the present specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items form part of the prior art with respect to any invention disclosed or claimed.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Otherwise, specific terms used herein have the meanings described herein. All patents, published patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0021] (definition) It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" and similar referents are to be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context.

[0022] As used herein, the term "about" preceding a number or series of numbers means ±10% of the number unless otherwise indicated. For example, "about 100 mg" means 90 to 110 mg.

[0023] As used herein, the term "approximately" preceding a number or series of numbers means ±10% of the number unless otherwise indicated. For example, "about 100 mg" means 90 to 110 mg.

[0024] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0025] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to mean the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be replaced with the terms "containing" or "including," or, when used herein, can also be replaced with the term "having."

[0026] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Whenever used herein in the context of aspects or embodiments of the invention, any of the foregoing terms "comprising," "containing," "including," and "having" can be replaced with the terms "consisting of" or "consisting essentially of" to modify the scope of the disclosure.

[0027] As used herein, the connective term "and / or" between multiple listed elements is understood to encompass both individual and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the first element being applicable without the second element. The second alternative refers to the second element being applicable without the first element. The third alternative refers to the first and second elements being applicable together. Any one of these alternatives is understood to be within the meaning and therefore meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the alternatives is also understood to be within the meaning and therefore meets the requirements of the term "and / or."

[0028] The cariprazine may be in amorphous or crystalline form.

[0029] As used herein, the term "CAR" or "CRI" is intended to mean an abbreviation for cariprazine.

[0030] As used herein, the term "mixture" is a physical combination of two or more substances whose identity is maintained and mixed in the form of solutions, suspensions, and colloids.

[0031] As used herein, unless otherwise specified, "psychotic disease or disorder" refers to those provided in the Diagnostic and Statistical Manual (DSM IV), American Psychological Association (APA). Psychotic disorders are a group of serious illnesses that affect the mind. They make it difficult to think clearly, make sound judgments, react emotionally, communicate effectively, understand reality, and act appropriately. When symptoms are severe, people with psychotic disorders often have difficulty dealing with reality and are unable to cope with everyday life. Some examples are provided below.

[0032] Schizophrenia: People with this disease have behavioral changes and other symptoms (such as delusions and hallucinations) that last for more than six months. It usually affects them at work or school, as well as their relationships.

[0033] Schizoaffective disorder: People have symptoms of both schizophrenia and a mood disorder, such as depression or bipolar disorder.

[0034] Schizophreniform disorder: This includes symptoms of schizophrenia, but the symptoms last for a shorter period of time, such as 1 to 6 months.

[0035] Brief psychotic disorder: People with this disorder have sudden, short-term psychotic behavior, often in response to a highly stressful event such as a death in the family. Recovery is often rapid, usually less than a month.

[0036] As used herein, the term "substantially no burst" is intended to mean that upon subcutaneous or intramuscular administration of a cariprazine dosage form, which may be a prodrug or an active cariprazine compound, the ratio of the peak concentration of the detectable cariprazine compound in plasma during the first 48 hours after administration to the minimum concentration of the detectable cariprazine compound in plasma after the peak concentration during the first 48 hours after administration is less than 10, e.g., less than 5, less than 4 (substantially no detectable burst), preferably less than 3 (no detectable burst), and more preferably less than 2.

[0037] As used herein, the term "peak-to-trough ratio" or "peak-to-trough ratio," or P / T ratio, is intended to mean the ratio of the maximum plasma concentration to the minimum plasma concentration of cariprazine released from a cariprazine dosage form within a given period between doses.

[0038] As used herein, the term "steady state" is intended to refer to the pharmacokinetic profile after the third consecutive injection.

[0039] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to any acid addition salt between cariprazine and an acid. The acid may be known in the art and may be selected by one skilled in the art. The acid may include, but is not limited to, carboxylic acid, benzoic acid, sorbic acid, fumaric acid, adipic acid, citric acid, succinic acid, glutaric acid, malic acid, malonic acid, tartaric acid, acetic acid, glycolic acid, lactic acid, propionic acid, lauric acid, caprylic acid, capric acid, myristic acid, oleic acid, palmitic acid, pamoic acid, HBr, HCl, methanesulfonic acid, sulfuric acid, and p-toluenesulfonic acid.

[0040] As used herein, the term "prodrug" is intended to mean a cariprazine compound that undergoes biotransformation before exhibiting its pharmacological effects. Such prodrugs may be carrier-linked prodrugs that contain a temporary bond of cariprazine to a carrier group that provides improved physicochemical or pharmacokinetic properties and is easily removed in vivo, usually by hydrolytic cleavage. Such prodrugs may also be cascade-type prodrugs in which cleavage of the carrier group is only effective after unmasking of the activating group.

[0041] Biotransformation refers to the enzyme-mediated hydrolysis or autohydrolysis or autocleavage of the chemical bond linking cariprazine and the promoiety, resulting in the release of free cariprazine under physiological conditions in vitro or in vivo.

[0042] The linkers used in such carrier-bound prodrugs may be transient, meaning that they are non-enzymatically hydrolytically degradable (cleavable) under physiological conditions, e.g., with half-lives ranging from 1 hour to 3 months.

[0043] On the other hand, stable bonds, such as those used to link the backbone moiety and the spacer, are typically non-cleavable permanent bonds, meaning that the respective spacer or linking moiety has a half-life of at least 6 months under physiological conditions.

[0044] As used herein, the term "long-acting injectable (LAI) composition" refers to a cariprazine dosage form drug delivery system administered as a subcutaneous or intramuscular injection, capable of consistently releasing cariprazine over an extended period of time. LAI formulations release the drug over an extended period of time, from days to months, making them the counterparts of immediate-release dosage forms (e.g., uncoated tablets, hard capsules, inhalation preparations, and most intravenous parenteral medications). Typical uses include chronic diseases and long-term medications (e.g., hormone replacement, chemotherapy, rheumatoid arthritis, contraception) (see J.C. Wright and D.J.Burgess (2012) Long-acting injections and implants: Springer). Once applied, depot drugs are virtually impossible to remove from the body. Therefore, they are also suitable for neuroleptic therapy. This prevents non-adherent patients, often found in schizophrenia, from neglecting or stopping their medication (see C.E.A. Dams, M.K.P. Penton, S.Quraishi, A.S.David (2001) Systematic meta-review of depot antipsychotic drugs for people with schizophrenia, The British Journal of Psychiatry 179(4), 290-299).

[0045] As used herein, the term "peak concentration" is intended to mean the highest concentration obtained after administration of a cariprazine dosage form.

[0046] As used herein, the term "pharmaceutically acceptable" means approved by a regulatory authority, such as the EMEA (Europe) and / or the FDA (USA) and / or any other country's regulatory authority, for use in animals, preferably humans.

[0047] As used herein, the terms "pharmaceutical composition" or "composition" or "formulation" refer to one or more active ingredients and one or more inactive ingredients, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reaction or interaction of one or more ingredients. Thus, pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable excipient (a pharmaceutically acceptable carrier).

[0048] As used herein, the term "excipient" refers to a compound administered with a therapeutic agent, such as a solvent, buffer, tonicity adjuster, preservative, stabilizer, anti-adsorption agent, oxidation protectant, or other auxiliary agent. In some cases, however, a single excipient may have dual or triple functions.

[0049] As used herein, the term "stabilizer" refers to a compound used to stabilize a pharmaceutical composition.

[0050] As used herein, the term "weak acid" refers to compounds such as acetic acid, oxalic acid, phosphoric acid, and formic acid that do not completely dissociate in an aqueous environment or donate all of their hydrogen ions. pKa is a logarithmic scale of the acid dissociation constant, Ka. As used herein, strong acids have pKa values ​​in the range of -15 to 2, while weak acids have pKa values ​​in the range of 2 to 50.

[0051] "Oxidant protectant" refers to antioxidants such as ascorbic acid, ectoine, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, glutathione, lipoic acid, uric acid, carotene, retinol (vitamin A), α-tocopherol (vitamin E), ubiquinol (coenzyme Q), cysteine, methionine, L-methionine, chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid.

[0052] "Antimicrobial agent" refers to a chemical that kills or inhibits the growth of microorganisms such as bacteria, fungi, yeast, protozoa, and / or destroys viruses.

[0053] The terms "drug," "bioactive molecule," "bioactive moiety," "bioactive agent," "active drug," "active pharmaceutical ingredient, API," and the like refer to any substance that can affect any physical or biochemical property of a biological organism, including, but not limited to, viruses, bacteria, fungi, plants, animals, and humans. In particular, as used herein, a bioactive molecule includes any substance intended to diagnose, cure, mitigate, treat, or prevent disease in humans or other animals, or to otherwise enhance the physical or mental well-being of humans or animals.

[0054] As used herein, a "therapeutically effective amount" of cariprazine refers to an amount sufficient to cure, alleviate, or partially arrest the clinical symptoms of a given disease and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general condition of the subject. It should be understood that determining the appropriate dosage can be accomplished using routine experimentation by constructing a matrix of values ​​and testing different points within the matrix, all of which is within the ordinary skill of a trained physician or veterinarian.

[0055] As used herein, the term "rapid onset of action" is intended to mean that a therapeutically effective amount of cariprazine is reached in vivo, e.g., in human plasma, within a relatively short period of time, e.g., within 30 hours of administration, and typically within 24 hours of administration. In certain embodiments, therapeutic plasma concentrations of cariprazine are reached within the first 24 hours after administration.

[0056] As used herein, the term "continuously for at least one week" is intended to mean that cariprazine is released from the cariprazine depot to a subject, such as an animal or human, without interruption and such that a therapeutically effective amount of cariprazine is substantially maintained for one week or more.

[0057] As used herein, pharmaceutically acceptable solvents include polyethylene glycol (PEG), ethanol, propylene glycol (PG), benzyl alcohol (BA), benzyl benzoate (BB), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), dimethylacetamide (DMAc or DMA), vegetable oils, MCT, peanut oil, sesame oil, castor oil, olive oil, peanut oil, mixtures or combinations thereof, and the like.

[0058] As defined herein, an alcohol includes any organic compound whose molecule contains one or more hydroxyl groups attached to a carbon atom. As used herein, an alcohol is a liquid at 25°C.

[0059] As used herein, phospholipids include soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), egg sphingomyelin (ESM), egg phosphatidylcholine (EPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol ( DPPG), dioleoylphosphatidylglycerol (DOPG), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), dioleoylphosphatidylserine (DOPS), mixtures or combinations thereof, and the like.

[0060] The term "poly(ethylene glycol)" or "PEG" refers to a biocompatible, synthetic, hydrophilic polyether compound that has many applications, primarily in the medical industry, but also in chemical and industrial fields. The compound's structure is commonly represented as H-(O-CH-CH)-OH. PEG is synthesized by polymerizing ethylene oxide using a ring-opening technique, which allows for the construction of PEGs with a range of molecular weights and molecular weight distributions. This weight range makes PEG suitable for several applications.

[0061] As used herein, PEG has an average MW of 100 to 10,000 daltons, preferably PEG has an average MW of 200 daltons (PEG200), 300 daltons (PEG300), and 400 daltons (PEG400), or mixtures thereof. As used herein, PEG is methoxypolyethylene glycol 350, having an average MW of about 400 daltons (mPEG350).

[0062] As used herein, PEG is tetrahydrofurfuryl alcohol polyethylene glycol ether or tetraethylene glycol or glycofurol.

[0063] As used herein, PEG includes polyethoxylated castor oil or derivatives thereof, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, block copolymers of polyethylene oxide-polypropylene oxide-polyethylene oxide, block copolymers of polypropylene oxide-polyethylene oxide-polypropylene oxide, tetrafunctional block copolymers of polyethylene oxide-polypropylene oxide, or tetrafunctional block copolymers of polypropylene oxide-polyethylene oxide.

[0064] (Long-Acting Injectable (LAI) Composition) The present invention relates to an LAI composition of cariprazine or its salt. The LAI composition can be a suspension or solution of cariprazine in a pharmaceutically acceptable organic solvent, or a mixture or combination of two or more solvents. The LAI composition can be a slurry, semi-solid, or non-flowable gel, or a cream. The LAI composition can be prepared as exemplified by the following description and examples, but is not limited to these. The components of the LAI composition can be sterilized by techniques known in the art, such as autoclaving, ionizing radiation (e.g., electron beam, X-ray, or gamma irradiation), dry heat, and ethylene oxide, and the composition can be manufactured by an aseptic process. Alternatively, the LAI composition of the present invention can be prepared using non-sterile components, and the final product can then be sterilized using terminal sterilization processes known in the art, such as autoclaving, ionizing radiation, dry heat, and ethylene oxide.

[0065] In one embodiment of the present invention, the LAI composition in the form of a solution comprises: (i) at least 1% (by weight) of cariprazine in the form of the free base or a pharmaceutically acceptable salt thereof; and (ii) a biocompatible organic solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate (BB), ethyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), glycofurol, solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, acetic acid, oleic acid, caprylic acid, capric acid, myristic acid, and combinations of two or more thereof.

[0066] In another embodiment of the present invention, the LAI composition in the form of a solution comprises: (i) at least 1% (by weight) of cariprazine in the form of the free base or a pharmaceutically acceptable salt thereof; (ii) at least 10% (by weight) of benzyl alcohol; and (iii) 0-90% (by weight) of a biocompatible organic solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate (BB), ethyl alcohol or ethanol, polyethylene glycol (PEG), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), glycofurol, solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, acetic acid, oleic acid, caprylic acid, capric acid, myristic acid, and combinations of two or more thereof. The solubility of cariprazine or a salt thereof in a combined solution of benzyl alcohol and other biocompatible organic solvents is at least 5% by weight.

[0067] In another embodiment of the invention, the LAI composition comprises cariprazine free base or a salt thereof and polyethylene glycol (PEG), ethanol, glycerin, isopropyl alcohol, propylene glycol (PG), benzyl alcohol (BA), benzyl benzoate (BB), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), dimethylacetamide (DMAc or DMA), glycofurol, solketal, glycerol formal, acetone, tetrahydrofurfuryl aliphatic acid (TFA), tetrahydrofuran, ... and a biocompatible organic solvent selected from the group consisting of alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, medium-chain triglycerides (MCT), vegetable oil, soybean oil, sesame oil, castor oil, olive oil, peanut oil, and mixtures or combinations thereof, wherein the cariprazine is in a particulate form having a particle size, as defined by D50, ranging from 0.01 μm to about 250 μm, preferably from 0.1 μm to about 100 μm, more preferably from 1.0 μm to about 50 μm, and most preferably from 5 μm to about 25 μm.

[0068] In a further aspect of the invention, the LAI composition comprises cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in a particulate form having a particle size, as defined by D50, ranging from 0.01 μm to about 250 μm, preferably from 0.1 μm to about 100 μm, more preferably from 1.0 μm to about 50 μm, and most preferably from 5 μm to about 25 μm.

[0069] In one embodiment, the synthetic process for producing cariprazine is described in U.S. Patent No. 7,737,142. The particle size of cariprazine, as defined by D50, ranges from about 0.1 μm to about 250 μm. The D50 of cariprazine is preferably less than about 50 μm, less than about 40 μm, less than about 30 μm, less than about 20 μm, less than about 10 μm, less than about 5 μm, less than about 2 μm, less than about 1 μm, or less than about 0.1 μm.

[0070] In certain embodiments, cariprazine is micronized to a desired size. Particle size and size distribution affect the dissolution and release rate of cariprazine. The larger the particle size, the slower cariprazine dissolves and therefore the slower it is released. Cariprazine can be micronized by methods known in the art, including milling, wet milling, and jet milling, as well as the method disclosed in U.S. Patent No. 9,439,906. Cariprazine particles with different particle sizes and distributions can also be prepared by the method described in U.S. Patent Application Publication No. 20210015752A1. Furthermore, cariprazine particles can be prepared by solvent evaporation, lyophilization, spray drying, freeze drying, spray freeze drying, or a combination thereof.

[0071] In certain embodiments, the particle size of cariprazine is characterized by its size distribution within a sample. The particle sizes at 10%, 50%, and 90% undersize (referred to as D10, D50, and D90, respectively) are used. D50 is also known as the median particle size. In certain embodiments, D50 is a diameter less than 250 μm (e.g., 50% of the particles are less than 250 μm). In certain embodiments, D50 is in the range of 100 nm to 20 μm. In further embodiments, D50 is in the range of 500 nm to 50 μm. In further embodiments, D50 is about 900 nm to 50 μm.

[0072] In some embodiments, the particle size of cariprazine is characterized by specific surface area (SSA). As used herein, the surface area of ​​cariprazine is defined as 0.1 to 25 m 2 In certain embodiments, the surface area may range from 0.5 to 15 m 2 In other embodiments, the surface area is in the range of 1 to 10 m 2 / g range, or 2-10m 2 / g range, or 4-12m 2 / g range, or 5-15m 2 / g range.

[0073] In some embodiments, cariprazine is present as a free base (unprotonated) form. In some other embodiments, cariprazine is present as a pharmaceutically acceptable salt form.

[0074] In some embodiments, the PEG has an average molecular weight (MW) ranging from about 100 to about 10,000 daltons.

[0075] In certain embodiments, PEG refers to polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol, and copolymers thereof). In some other embodiments, the PEG or polyethylene glycol is selected from the group consisting of PEG200, PEG300, PEG400, PEG600, PEG1000, PEG1100, PEG1900, PEG2000, PEG2800, PEG2900, PEG3350, PEG4000, PEG6000, PEG8000, PEG8400, PEG10,000, etc.

[0076] In one preferred embodiment, the PEG has an average MW of 200 daltons (PEG200).

[0077] In a preferred embodiment, the PEG has an average MW of about 300 daltons (PEG300).

[0078] In another preferred embodiment, the PEG has an average MW of about 400 daltons (PEG400).

[0079] In another preferred embodiment, the PEG is methoxypolyethylene glycol 350, having an average MW of about 400 daltons (mPEG350).

[0080] In another preferred embodiment, the PEG is tetrahydrofurfuryl alcohol polyethylene glycol ether or tetraethylene glycol or glycofurol. In certain embodiments, the PEG comprises polyethoxylated castor oil or a derivative thereof, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, a block copolymer of polyethylene oxide-polypropylene oxide-polyethylene oxide, a block copolymer of polypropylene oxide-polypropylene oxide-polypropylene oxide, a tetrafunctional block copolymer of polyethylene oxide-polypropylene oxide, or a tetrafunctional block copolymer of polypropylene oxide-polyethylene oxide. In further embodiments, the PEG comprises a triblock polymer of polypropylene glycol adjacent to polyethylene glycol (e.g., poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poloxamer 407, etc.).

[0081] In certain embodiments, the PEG is liquid or flowable at 25°C.

[0082] In certain embodiments, cariprazine can be formulated as a suspension in PEG. The suspension may further comprise one or more additives such as a buffering agent, an isotonicity agent, a preservative, a surfactant, a wetting agent, a suspending agent, etc.

[0083] In certain embodiments, the suspension comprises a suspending agent selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene, and polyoxypropylene ether. Preferably, sodium carboxymethylcellulose is used at a concentration of 0.5-2%, most preferably 1% (w / v).

[0084] In certain embodiments, the suspension comprises a wetting agent selected from the group consisting of polyoxyethylene derivatives of sorbitan esters, such as polysorbate 20 and polysorbate 80, Tween 20 and Tween 80, lecithin, polyoxyethylene and polyoxypropylene ethers, and sodium deoxycholate. Preferably, polysorbate 20 is used at a concentration of 0.5-3%, more preferably 0.5-2%, and most preferably 1.1% (w / v).

[0085] In certain embodiments, the suspension contains a buffering agent that is a salt of a weak acid, which should be used in an amount sufficient to provide a dispersion with a pH in the range of 4.0 to 10, preferably neutral to very slightly basic (pH 7.0 to 8.5), more preferably in the pH range of 7 to 7.5. The use of a mixture of disodium hydrogen phosphate (anhydrous) (typically about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w / v)) is particularly preferred. This buffering agent also renders the dispersion isotonic.

[0086] In certain embodiments, the suspension comprises a preservative, e.g., an antimicrobial agent and an antioxidant selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallic acid, hydroxybenzoic acid, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-gamma-picolinium chloride, phenylmercuric acetate, thimerosal, ascorbic acid, ectoine, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, glutathione, lipoic acid, uric acid, carotene, retinol (vitamin A), α-tocopherol (vitamin E), ubiquinol (coenzyme Q), cysteine, methionine, L-methionine, and combinations thereof; a chelating agent, e.g., citric acid, EDTA, hexaphosphate, thioglycolic acid, and combinations thereof.

[0087] In certain embodiments, the suspension contains a tonicity agent selected from the group consisting of sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate, and combinations thereof. The suspension advantageously contains 0 to 10% (w / v) of the tonicity agent. Mannitol may be used at a concentration of 0 to 7%. However, more preferably, about 1 to about 3% (w / v), particularly about 1.5 to about 2% (w / v), of one or more electrolytes are used to make the suspension isotonic, as the ions help prevent the suspended ester from coagulating. In particular, the electrolytes of the buffer act as the tonicity agent.

[0088] In some embodiments, the composition comprises at least 1% (w / w) cariprazine in the form of the free base or a pharmaceutically acceptable salt, the concentration of which ranges from approximately 10 mg / ml or more to approximately 800 mg / ml.

[0089] In some embodiments, the composition comprises from about 1% (w / w) to about 80% (w / w) cariprazine by weight, based on the total weight of the composition, In such embodiments, the cariprazine is present in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% by weight, or any percentage therebetween.

[0090] In some embodiments, the composition is in the form of a suspension, solution, slurry, semisolid, cream, paste, or gel. In such embodiments, the solubility of cariprazine in the selected solvent is less than 10 mg / mL at 25° C.

[0091] In some embodiments, the LAI composition comprises propyl glycol, glycol, tetraglycol, triglycol, pentaethylene glycol, propyl alcohol, ethanol, or the like.

[0092] In some embodiments, the composition further comprises a non-ionic surfactant selected from the group consisting of Tween 20, Tween 80, poloxamer, and phospholipid.

[0093] In some embodiments, the composition further comprises a pharmaceutically acceptable salt or sugar to adjust the tonicity of the composition, and / or a preservative.

[0094] In some embodiments, the composition further comprises a pharmaceutically acceptable salt or sugar to adjust the tonicity of the composition, and / or a preservative selected from the group consisting of methylparaben, propylparaben, and benzyl alcohol.

[0095] In some embodiments, there is provided a method of making the composition comprising mixing PEG or other selected solvent with any further optional ingredients, adding cariprazine along with milling media, and milling the suspension until the required particle size is achieved.

[0096] In some embodiments, the present invention provides an LAI composition in the form of a solution comprising: (i) at least 1% (by weight) of cariprazine in the form of the free base or a pharmaceutically acceptable salt thereof; and (ii) a biocompatible organic solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate (BB), ethyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), glycofurol, solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, acetic acid, oleic acid, caprylic acid, capric acid, myristic acid, and combinations of two or more thereof.

[0097] In some embodiments, the LAI composition in the form of a solution or suspension does not contain any polymer selected from the group consisting of polyesters of hydroxy fatty acids and derivatives thereof, polymers of alkyl α-cyanoacrylates, polyalkylene oxalates, poly(ortho)esters, polycarbonates, polyorthocarbonates, polyamino acids, hyaluronic acid esters, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxonones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and mixtures thereof.

[0098] Long-release injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been commercialized for many years. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintaining the drug's therapeutic window. Despite extensive research, the inherent complexity of PLGA copolymers still presents significant challenges associated with developing generic or novel formulations. Furthermore, small changes to PLGA's physiochemical properties or the formulation manufacturing process can significantly impact the drug release profile of these long-release formulations [Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants, Mark A. Costello, et al., Mol Pharmaceutics 2023, 20, 12, 6330-6344]. Developing better sustained-release products without using PLGA or other complex polymers would be a significant advance.

[0099] In some embodiments, the LAI composition is in the form of a solution or suspension that does not contain any polymer selected from the group consisting of polylactide, poly(D,L-lactide), poly(D,L-lactic acid), poly(D,L-lactide-co-glycolide), poly(D,L-lactic acid-co-glycolic acid), polyglycolide, poly(glycolic acid), poly-L-lactic acid, and mixtures thereof.

[0100] In some embodiments, the LAI composition is in the form of a solution and cariprazine is present in an amount of 1% to 55% by weight, hi such embodiments, cariprazine is present in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% by weight, or any percentage therebetween.

[0101] In some embodiments, the LAI composition is in the form of a solution and the biocompatible organic solvent is benzyl alcohol (BA).

[0102] In some embodiments, the LAI composition is in the form of a solution, and the biocompatible organic solvent is benzyl alcohol in combination with one or more solvents selected from the group consisting of benzyl benzoate (BB), ethyl alcohol (BA), polyethylene glycol (PEG), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), glycofurol, solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, acetic acid, oleic acid, caprylic acid, capric acid, and myristic acid.

[0103] In some embodiments, the LAI composition is in the form of a solution, with the benzyl alcohol (BA) in the combined solvent being from about 1% to about 99% by weight.

[0104] In some embodiments, the LAI composition is in the form of a solution further comprising ascorbic acid, vitamin E, monothioglycerol, butylated hydroxytoluene, butylated hydroxyanisole, or a combination of two or more thereof in an amount of 0.01% to 10% by weight.

[0105] In some embodiments, the LAI composition in the form of a solution is sterile and is administered to a patient subcutaneously or intramuscularly.

[0106] In some embodiments, the LAI composition is in the form of a solution that is sterilized by sterile filtration.

[0107] In some embodiments, the present invention provides an LAI composition comprising cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in a particulate form having a particle size, as defined by D50, ranging from 0.01 μm to about 250 μm, preferably from 0.1 μm to about 100 μm, more preferably from 1.0 μm to about 50 μm, and most preferably from 5 μm to about 25 μm. In such embodiments, the D50 particle size is about 1 μm, 2 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 100 μm, 120 μm, 150 μm, 200 μm, 250 μm, or any size in between.

[0108] In some embodiments, the phospholipid in the LAI composition is soybean phosphatidylcholine (SPC), the alcohol is ethanol, and the solubility of cariprazine in aqueous solution is less than 1% by weight.

[0109] In some embodiments, the LAI composition comprises from about 1% to about 80% by weight of cariprazine in free base or pharmaceutically acceptable salt form, based on the total weight of the composition. In some embodiments, the LAI composition is in the form of a suspension, a slurry, a semi-solid, a cream, a paste, or a gel.

[0110] In some embodiments, the LAI composition further comprises a pharmaceutically acceptable salt or sugar to adjust the tonicity of the composition, and / or a preservative selected from the group consisting of methylparaben, propylparaben, and benzyl alcohol.

[0111] In some embodiments, the present invention provides methods of treating a patient, delivering a therapeutically effective dose of cariprazine of about 1 to about 8 milligrams (mg) per day.

[0112] In some embodiments, the composition releases cariprazine continuously for at least one week with an immediate onset of action, and the composition has an in vivo pharmacokinetic profile with substantially no burst release of cariprazine.

[0113] In some embodiments, the composition is characterized by releasing cariprazine such that therapeutic plasma levels of cariprazine are achieved within 24 hours of administration, for example, within 18 or 12 hours of administration.

[0114] In some embodiments, the pharmacokinetic profile is measured in mammalian plasma, such as human plasma. Plasma cariprazine concentrations can be measured using mass spectrometry methods known in the art by relating the results to a calibration curve obtained from cariprazine standards. For statistical significance, experiments are performed with an appropriate number of biological and technical replicates, and mean and median values ​​are calculated to adjust for biological and technical variations.

[0115] In some embodiments, a method of terminally sterilizing a prepared composition is provided, comprising filling the composition into a pharmaceutically acceptable syringe, cartridge, vial, or ampoule, appropriately sealing the syringe, cartridge, vial, or ampoule, and terminally sterilizing the syringe, cartridge, vial, or ampoule by autoclaving or irradiation (gamma, or x-ray, or electron beam).

[0116] In some embodiments, methods of treating a patient are provided that deliver a therapeutically effective dose of cariprazine of about 1 to about 8 milligrams (mg) per day.

[0117] In some embodiments, cariprazine can be continuously released from the composition for a period of one week or more, with therapeutically effective plasma concentrations achieved within the first 24 hours after subcutaneous or intramuscular injection without a substantial burst release. Furthermore, avoiding a burst of cariprazine reduces the risk of adverse side effects in patients.

[0118] The present invention provides a pharmaceutical composition having a once-weekly, once-monthly, or even less frequent administration profile without the need for additional oral or injectable medications. In one embodiment, the release of cariprazine in vivo after subcutaneous or intramuscular administration to a subject is sustained for at least one week.

[0119] The present invention provides a cariprazine depot, a long-acting injectable formulation having a low peak-to-trough ratio (P / T) in plasma concentration. The P / T ratio is less than 10, preferably less than 8, and more preferably less than 5, during a given treatment period, such as 1, 2, or 3 months. In one embodiment, the in vivo plasma concentration of cariprazine after subcutaneous or intramuscular administration to a subject has a peak-to-trough ratio of less than about 10 over a 28-day period after administration. Further advantages will become apparent upon reading this specification and the examples that follow. [Example]

[0120] Example 1. Long-Acting Injectable (LAI) Formulation of CAR

[0121] LAI CAR formulations are 1) solution-based formulations containing a pharmaceutically acceptable solvent, or 2) suspension-based formulations in a non-aqueous or aqueous solution. Solution-based formulations include i) different salt forms of CAR, such as pamoate (PAM), mesylate (MS), tosylate (Tos), hydrochloride (HCl), or free base form of CAR, and ii) a pharmaceutically acceptable organic solvent, alone or in combination with other pharmaceutically acceptable solvents, such as oil, propylene glycol (PG), poly(ethylene) oxide (PEO), poly(ethylene) glycol (PEG), benzyl benzoate (BB), N-methylpyrrolidone (NMP), ethanol (EtOH), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), dimethylacetamide (DMAc), and triacetin. The suspension formulation includes i) different salt forms of CAR, such as pamoate (PAM), mesylate (MS), tosylate (Tos), hydrochloride (HCl), or free base form of CAR; ii) a non-aqueous and water-miscible solvent, such as EtOH; and iii) a surfactant, such as a non-ionic surfactant, an ionic surfactant, and a phospholipid.

[0122] Example 2. Synthesis of the pamoate salt of CAR

[0123] CAR (414 mg) was dissolved in 27.6 mL of phosphoric acid solution (5.4 mg / mL) to obtain solution A, and pamoic acid (188 mg) was dissolved in 5.23 mL of 0.2 N NaOH to obtain solution B. Solution B was then slowly added dropwise (0.5 mL / min) to solution A while stirring at 500-700 rpm using a magnetic stirrer at room temperature. After the addition of solution B was complete, the suspension was stirred for an additional 10 min. The resulting CAR-PAM salt was collected by filtration, and the salt was further washed with deionized water. After drying in an oven at 40 °C for 2 days, CAR-PAM salt (548 mg, yield: 91.0%) was obtained as a pale yellow powder. The melting point of CAR-PAM was 164-175 °C. NMR (400 MHz, d6-DMSO): 0.98-1.01 (m, 2H), 1.19-1.25 (m, 3H), 1.57-1.59 (m, 2H), 1.76 (t, 4H), 2.75 (s, 6H), 3.10-3.25 (m, 4H), 3.34-3.40 (m, 6H), 4.72 (s, 1H), 5.84 (d, 2H), 7.07-1.10 (m, 1H), 7.18-7.22 (m, 2H), 7.33-7.36 (m, 2H), 7.32 (d, 1H), 8.17 (d, 1H), 8.29 (s, 1H). Based on NMR analysis, the CAR-PAM salt was (CAR)2-PAM (ratio of CAR to PAM was 2 / 1). The CAR / PAM ratio can be adjusted by adding different amounts of CAR and PAM starting materials.

[0124] Example 3. Synthesis of CAR tosylate salt

[0125] CAR (500 mg) and p-toluenesulfonic acid monohydrate (PTSA) were dissolved separately in 33.4 mL of phosphoric acid (5.4 mg / mL) and 1.25 mL of DI water, respectively. The PTSA solution was then slowly added (0.5 mL / min) to the CAR solution while stirring at 500-700 rpm using a magnetic stirrer at room temperature. The suspension was stirred at 500-700 rpm for an additional 15 minutes. The resulting salt was collected by filtration and washed with deionized water. After drying overnight in an oven at 40 °C, the final CAR-Tos salt (442 mg, 63.1%) was obtained as a white powder. The melting point of CAR-Tos was 228-230 °C. The CAR / Tos ratio could be adjusted by adding different amounts of CAR and Tos starting materials.

[0126] Example 4. Synthesis of CAR mesylate

[0127] CAR (500 mg) was dissolved in 33.4 mL of phosphoric acid (5.4 mg / mL). Then, 79.7 μL of methanesulfonic acid (MSOH) was added all at once to the CAR solution while stirring at 500-700 rpm using a magnetic stirrer at room temperature. The solution was stirred at 500-700 rpm for an additional 15 minutes at room temperature. The solution was frozen, placed in a freeze dryer, and lyophilized for two days. The lyophilized cake was rehydrated with deionized water, and the pH of the solution (approximately 1.5-2.5) was measured. The rehydrated solution was then frozen, placed in a freeze dryer, and lyophilized for another two days. After two drying cycles, CAR-MS was obtained as a white powder, and a small aliquot was removed for pH determination. The melting point of CAR-MS was 190-193 °C. The CAR / MS ratio could be adjusted by adding different amounts of CAR and MS starting materials.

[0128] Example 5. Solubility of CAR in organic solvents and pharmaceutical oils.

[0129] The solubility of CAR in different organic solvents and pharmaceutically acceptable oils, alone or in combination, was determined. As shown in Table 1, an excess amount of CAR was dispersed in the corresponding pharmaceutically acceptable solvent (1 mL) and stirred at 25 °C. After overnight centrifugation (14,000 rpm for 5 min), the supernatant was carefully removed, and the solubility of CAR in these solvents was then determined by UPLC. Among the pharmaceutically acceptable organic solvents, benzyl alcohol (BA) surprisingly showed much higher solubility than the other organic solvents. The combinations of these solvents tested here did not result in any synergistic effect on solubility. On the other hand, as shown in Table 1, the solubility of CAR in pharmaceutical oils was low, even when supplemented with organic solvents.

[0130] [Table 1]

[0131] Example 6. Solubility of CAR in combinations of benzyl alcohol (BA) and fatty acids.

[0132] The solubility of CAR in combinations of BA and saturated or unsaturated fatty acids, such as oleic acid (OA) or capric acid (CPA), was determined. Generally, an excess amount of CAR was dispersed in these solutions (1 mL) at 25°C in a 2R vial and stirred. After overnight stirring, the supernatant of each solution was carefully removed after centrifugation at 14,000 rpm for 5 minutes. The equilibrium solubility of CAR in these solutions was determined by UPLC. As shown in Table 2, a synergistic effect on solubility was observed in the BA / OA combination solution. The BA / OA combination solvent exhibited higher CAR solubility than either BA or OA alone. Even higher CAR solubility can be achieved with CPA. The increased solubility may be due to the formation of an ion pair between the tertiary amine of CAR and the carboxylate of the fatty acid.

[0133] [Table 2]

[0134] Example 7. Solubility of CAR in combinations of EtOH and phospholipids.

[0135] Amphiphilic phospholipids, such as soybean phosphocholine (SPC), were investigated for their synergistic effect on the solubility of CAR. Excess CAR was dispersed in these solutions containing SPC in 2R vials at 25°C and stirred. After overnight stirring, the mixtures were centrifuged at 14,000 rpm for 5 minutes, and the supernatants of each solution were carefully removed. The equilibrium solubility of CAR in these solutions was determined by UPLC. All solutions containing SPC but not CAR, as shown in Table 3, were clear solutions. No clear solubility synergistic effect on CAR was observed in any of these solutions. Rather, certain solvent combinations further reduced the solubility of CAR. Low solubility may be advantageous for creating CAR suspensions.

[0136] [Table 3]

[0137] Example 8. Resuspension of CAR suspension in EtOH / SPC solution.

[0138] Cariprazine, with a particle size distribution (PSD) of 4.6 μm / 14.6 μm / 43.2 μm (D10 / D50 / D90), was prepared as a suspension in a solution containing SPC. Interestingly, the resuspension of CAR in these solutions was significantly affected by the presence of SPC. In the absence of SPC, CAR particles rapidly adhered to the bottom of the 2R vial and were unable to re-form a uniform suspension. On the other hand, resuspension of CAR in a solution containing SPC could be achieved by gentle hand shaking for less than 10 seconds. To further reduce the solubility of CAR in these solutions, water was added to the SPC / EtOH solution. In solutions containing less than 20% water, CAR solubility remained similar. Adding water to 45% significantly reduced CAR solubility by 10-fold. This lower solubility is advantageous for generating suspensions. Advantages include better particle size physical stability by avoiding dissolution or erosion of solid particles, and better chemical stability in the solid phase. The ease of resuspension makes it user-friendly. Resuspension can be achieved in less than one minute. In some cases, resuspension can be achieved in less than 30 seconds, or even less than 10 seconds.

[0139] Example 9. Solubility of CAR salts in pharmaceutically acceptable organic solvents.

[0140] The solubilities of CAR salts, such as pamoate (PAM), tosylate (Tos), HCl, and mesylate (Ms), alone or in combination with pharmaceutically acceptable solvents or oils, were determined in different pharmaceutically acceptable organic solvents. As shown in Table 4, excess amounts of CAR salts were dispersed in the corresponding pharmaceutically acceptable organic solvents (1 mL) and stirred at 25 °C. After overnight stirring, the mixture was centrifuged at 14,000 rpm for approximately 5 minutes, and the supernatant was carefully removed. The saturated solubilities of these CAR salts in these organic solvents were determined by UPLC. Interestingly, the CAR salts exhibited different solubility preferences in these organic solvents. The PAM salt of CAR showed a different tendency from the other CAR salts in NMP, being much more soluble in NMP than the other CAR salts. Compared to hydroxyl-containing organic solvents, benzyl alcohol (BA) showed much higher solubility of these salts than EtOH.

[0141] [Table 4]

[0142] Example 10. Solubility of CAR and its salts in PBS buffer at pH 7.

[0143] The aqueous solubilities of CAR and its salts, such as pamoate (PAM), tosylate (Tos), and HCl, were determined in PBS at pH 7. As shown in Table 5, an excess amount of CAR or its salts was dispersed in PBS at pH 7 (1 mL) and stirred at 37°C. After stirring overnight, the mixture was centrifuged at 14,000 rpm for approximately 5 minutes, and the supernatant was carefully removed. The saturated solubilities of CAR and its salts in PBS at pH 7 were determined by UPLC.

[0144] [Table 5]

[0145] Example 11. Solubility of CAR and pamoate salts in different solvents.

[0146] Excess CAR or CAR-PAM was added to the solvent. The mixture was then stirred at room temperature for 24 hours to reach equilibrium between a saturated solution and undissolved solids. Undissolved CAR or CAR-PAM was still visible at the end of the stirring period. After centrifugation at 14,000 rpm for approximately 5 minutes, the supernatant of the solution was carefully removed. The saturated or equilibrium solubility of CAR or CAR-PAM was determined by UPLC. All samples were diluted 5-fold with THF (100 μL of filtered solution in medium + 400 μL of THF), and some samples were further diluted with THF or acetonitrile to measurable concentrations. The solubility of CAR and CAR-PAM in different solvents at room temperature is shown in Table 6.

[0147] [Table 6]

[0148] Example 1: Solubility of CAR HCl in Benzyl Alcohol (BA)-Containing Solutions at 2.4°C

[0149] As shown in Table 7, an excess amount of CAR HCl was dispersed in each corresponding pharmaceutically acceptable solution (1 mL) and stirred at 4 °C. After overnight stirring, the solution was centrifuged at 14,000 rpm for approximately 5 minutes, and the supernatant was carefully removed. The saturated solubility of CAR HCl in these solutions was determined by UPLC. The solubility of CAR HCl in BA at 4 °C to 25 °C was comparable, as shown in Tables 4 and 7. Supplementing with other pharmaceutically acceptable solvents, such as BB, MCT, and PG, reduced the solubility of CAR HCl by up to 35%. Although the solubility of CAR HCl decreased in the combined solutions, the percentage of BA in these combined solutions can also be reduced. Using a lower percentage of BA in the combined solvent solution can mitigate any potential side effects caused by BA.

[0150] [Table 7]

[0151] Example 13. Stability of CAR or CAR HCl in BA, NMP, or BB Solutions

[0152] CAR or CAR HCl in BA, NMP, or BB solutions were prepared as follows: CAR or CAR HCl in BA solution was prepared by dissolving 100 mg of either CAR or CAR HCl with 900 mg of BA in a 2R vial after planetary mixing to obtain a clear solution. Other CAR or CAR HCl solutions containing either NMP or BB were prepared by first adding 100 mg of either CAR or CAR HCl and 900 mg of either NMP or BB to a 2R vial. Then, after planetary mixing, the supernatants of these suspensions were carefully removed into another 2R vial. According to the solubility results in Table 1, the concentration of CAR or CAR HCl in BA solution was much higher (10 wt%) than in other solvents (less than 1 wt%). Unexpectedly, after 1 day at 60°C, the purity loss (or impurity formation) of CAR or CAR HCl in BA solution was much less than that in NMP or BB solution, as shown in Table 8. Therefore, selecting a suitable solvent is not an easy task and is crucial for developing a beneficial sustained-release injectable composition.

[0153] [Table 8]

[0154] Example 14. Preparation and stability of CAR or CAR HCl formulations with BA alone or in combination with fatty acids.

[0155] CAR or CAR HCl formulations using BA alone or a combination of BA and fatty acids were prepared as follows. These CAR and CAR HCl formulations were prepared by dissolving 100 mg of either CAR or CAR HCl in 900 mg of BA, BA / OA (3 / 1 by weight), or BA / CPA (3 / 1 by weight) to obtain a clear solution after planetary mixing. These formulations were further dispensed into 2R vials, purged with nitrogen, stopped, crimped closed, and then incubated at 60°C. At predetermined time intervals, color change was recorded, and chemical purity was determined by UPLC. The stability of the CAR and CAR HCl formulations is shown in Tables 9 and 10, respectively. As shown in Table 9, CAR solubility was higher in both BA / OA and BA / CPA, but the color change and chemical stability of these formulations (F2 and F3) were poor. Formulation F1 (CAR in BA) demonstrated good physical and chemical stability at 60°C over various time intervals. On the other hand, as shown in Table 10, the chemical purity of both F4 and F5 formulations decreased significantly after incubation at 60°C for different times.

[0156] [Table 9]

[0157] [Table 10]

[0158] Example 15. Preparation and stability of CAR HCl formulations at 40° C. using BA alone or in combination with other pharmaceutically acceptable solvents.

[0159] CAR HCl was formulated with BA alone or in combination with other pharmaceutically acceptable solvents, including medium-chain triglycerides (MCT), benzyl benzoate (BB), and propylene glycol (PG). The composition of the BA co-solvents is shown in Table 11. For the preparation of these CAR HCl formulations, 200 mg of CAR HCl was dissolved in 800 mg of either BA alone or the BA co-solvent vehicle in a 2R vial after planetary mixing to obtain a clear formulation. The corresponding formulations (F4, F11–F16) were further dispensed into 2R vials, purged with nitrogen, stoppered, crimped shut, and then incubated at 40°C. Results showed that the purity of CAR HCl in all BA-containing formulations could still exceed 98% after 28 days of incubation at 40°C.

[0160] [Table 11]

[0161] Example 16. In vitro release of CAR in BA and CAR aqueous suspension formulations.

[0162] The in vitro release of these CAR formulations was evaluated at 37°C in PBS containing 0.2% Tween 80. These formulations included a solution-based formulation (F1, CAR in BA) and suspension formulations (F17 and F18). The preparation of F1 is disclosed in Example 14. The suspension formulations shown in Table 12 were prepared as follows: 100 mg of CAR was weighed and suspended in 900 mg of either an aqueous vehicle (F17) or an SPC-containing vehicle (F18) in a 20 mL scintillation vial after planetary mixing. As shown in Figure 1, F1 exhibited a much slower release rate than the two suspension-based formulations.

[0163] [Table 12]

[0164] Example 17. Pharmacokinetic (PK) study of cariprazine formulations following single subcutaneous administration of doses to Sprague-Dawley rats

[0165] PK studies of test formulations containing cariprazine were conducted in male Sprague-Dawley rats weighing approximately 330 grams. Solution-based test formulations were prepared by dissolving the appropriate amount of CAR, CAR HCl, or CAR / PAM (ratio: 1.6) in the corresponding solvent or solvent combination in a 6R vial. The suspension formulation FP-018-005 was prepared by dispersing 600 mg of CAR in 2400 mg of SPC / EtOH / water (15 / 45 / 45) in a 6R vial. The composition and drug load (DL) of these test formulations are shown in Table 13. Each test formulation was administered subcutaneously at a level of 100 mg / kg (CAR free base equivalent) via the dorsal thoracic site in three rats following standard animal care and acclimation.

[0166] [Table 13]

[0167] Blood samples were collected at designated time points (pre-dose, 4 hours post-dose, days 1, 4, 7, 14, 21, 28, and 35) by lateral vein bleeding using disodium EDTA as an anticoagulant. Collected blood samples were centrifuged at 1000 × g for 15 minutes within 60 minutes of collection. Plasma samples were stored in a freezer at a temperature below -60°C. CAR plasma levels in the samples were measured using LC-MS / MS.

[0168] As shown in Figure 2, all formulations tested in this study demonstrated sustained release of cariprazine. FP-018-001 and FP-018-005 and FP-018-006 also had peak-to-trough ratios (P / T) of less than 3 over 28 days. There were two sets of formulations: solution-based (FP-018-001-003 and FP-018-006) and suspension-based (FP-018-005). All solution-based formulations exhibited a relatively higher burst release than the suspension-based formulation, likely due to the higher solubility of CAR in the vehicle used in the solution-based formulations (Table 14). Both sets of formulations experienced a concentration decline around day 1 after administration and had relatively higher concentrations of CAR at later time points.

[0169] [Table 14]

[0170] In addition to the P / T ratio, bioavailability is another important PK parameter. The higher the bioavailability, the smaller the injection volume of the formulation required to achieve pharmacological efficacy. In Table 14, the amount of cariprazine recovered from the implants varied between groups, ranging from approximately 2% to 60%. For FP-018-005, approximately 58.4% remained in the implant 35 days after administration, indicating that delivery of cariprazine in FP-018-005 can be sustained for at least 4 weeks and very likely for more than 2 months.

[0171] The release of CAR in FP-018-003 was rapid but could be sustained for at least 3 weeks. The release of CAR in FP-018-001 showed a low P / T ratio, high bioavailability, and could be sustained for at least 35 days. However, one of the three rats in FP-018-001 died one day after injection. This was quite surprising, as benzyl alcohol is a well-understood parenteral solvent and is approved for human intravenous use at 1620 mg. This result indicates that the dose levels of 100 mg / kg of 10% cariprazine (cariprazine free base equivalent) in benzyl alcohol, or 900 mg / kg of benzyl alcohol via subcutaneous administration, are safety concerns and require further formulation optimization.

[0172] In other formulations containing benzyl alcohol (FP-018-002 and FP-018-006), no deaths were observed, but tissue necrosis was observed in rats. Rats treated with FP-018-002 and FP-018-006 experienced a 3% decrease in body weight (BW) on day 1 after administration, but recovered to baseline weight by 3–4 days. Surviving rats treated with FP-018-001 took longer to recover to baseline weight. The dose levels of cariprazine in FP-018-002 and FP-018-006 were the same as those in FP-018-001, but the dose level of benzyl alcohol in FP-018-002 and FP-018-006 (approximately 400 mg / kg) was approximately 50% lower than that used in FP-018-001 (900 mg / kg).

[0173] Injection site evaluation showed that tissue irritation or necrosis was observed with some solution-based formulations (FP-018-001-002 and 006). No tissue necrosis was observed in rats treated with the suspension-based formulation, FP-018-005. This difference may be caused by the solvents used in these two formulations. Optimizing the solution-based formulation to minimize local injection site reactions will be crucial.

[0174] Example 18: Size reduction of cariprazine particles by jet milling

[0175] The crystallized cariprazine powder was weighed to 5 grams and fed into a jet mill (Micromacinazione, Switzerland) at a rate of approximately 1 gram per 60 seconds. The feed pressure and grinding pressure were adjustable depending on the desired particle size to be recovered. After grinding, the cariprazine particles were collected, sealed, and stored under the desired storage conditions. To obtain large API particles with a narrow size distribution (i.e., particles with a D50 greater than 100 μm), the jet-milled API powder can also be further filtered through a 25 μm filter using 0.5% w / w Tween 80 aqueous solution as a dispersant, followed by oven drying. The particle size was then measured using a Malvern Mastersizer 3000 (Malvern Panalytical Ltd., UK).

[0176] Example 19: Preparation of cariprazine particles by ball milling

[0177] Approximately 15 mL of PEG300 was transferred to a 60 ml glass jar, and then cariprazine free base (5 g) was weighed into the jar. The jar was further placed inside approximately 20 half-inch Burundum grinding beads. The jar was closed with a lid and then placed on a jar mill and rotated at 60 rpm at room temperature for 24 hours. The cariprazine suspension was then filled into 1 ml glass ampoules. The filled ampoules were sealed and autoclaved at 121°C for 15 minutes. The mean particle size [D50] of cariprazine free base was measured to be 8.3 μm using a Malvern Mastersizer 3000.

[0178] Example 20: Preparation of cariprazine suspension

[0179] A suspension of cariprazine particles was prepared by mixing the cariprazine particles with the selected solvent. For example, using an overhead mixer, the desired amount of cariprazine particles was mixed with PEG300. Mixing was performed at room temperature. The cariprazine particles and PEG300 were weighed and transferred to a 25 mL glass vial. The particle loading was approximately 1% to approximately 80% by weight based on the total weight of the composition. Alternatively, the cariprazine concentration in the final formulation ranged from approximately 10 mg / mL to approximately 800 mg / mL. The particles were mixed into the suspension using an electric overhead stirrer (IKA C-Mag HS Digital Stirring Hot Plate) at 1000 rpm for approximately 5 minutes, and then homogenized for 10 minutes using a planetary mixer (Kurabo Mazerustar KK-50S, Kurabo Industries, Ltd., Japan) under the CH-2 program for viscous formulations. The formulation was filled into a glass syringe to obtain a ready-to-inject dosage form. The suspension was stored at refrigerated temperature (approximately 2-8°C or room temperature) prior to injection.

[0180] Example 21: Preparation of 20% and 40% cariprazine in PEG300

[0181] 1.260 g and 1.680 g of cariprazine free base were weighed into two separate 1-dram vials. 5.040 g and 2.520 g of PEG300 were then added to each vial accordingly. The vials were shaken and vortexed until the drug was completely wetted and suspended. Each suspension was then allocated and filled into a 3 mL syringe.

[0182] Example 22: Preparation of 20% and 40% cariprazine in PEG400

[0183] 1.260 g and 1.680 g of cariprazine free base were weighed into two separate 1-dram vials. 5.040 g and 2.520 g of PEG400 were then added to each vial accordingly. The vials were shaken and vortexed until the drug was completely wetted and suspended. Each suspension was then allocated and filled into a 3 mL syringe.

[0184] Example 23: Preparation of 50% cariprazine in PEG400

[0185] Ten grams of cariprazine free base and 10 grams of PEG 400 were weighed into a 25 mL vial and mixed using a magnetic stirrer at 1000 rpm at room temperature for approximately 5 minutes, followed by homogenization using a planetary mixer for 10 minutes. The formulation was stored at approximately 2-8°C or at room temperature prior to injection.

[0186] Example 24: Preparation of cariprazine suspensions in propylene glycol (PG), or N-methyl-2-pyrrolidone (NMP) and other solvents.

[0187] Cariprazine was jet-milled to obtain suitable particles. Suspensions of cariprazine particles in various solvents were prepared using procedures similar to those described in Examples 4 and 7. Particle size and distribution (PSD) were analyzed using a Malvern Mastersizer 3000.

[0188] Typically, for particle size analysis, approximately 50 mg of API or one drop of cariprazine suspension was transferred to a 20 mL glass vial, 10 mL of dispersant / suspending medium (0.5-1% Tween 20 in Mill-Q water) was added to the vial, vortexed to mix, and then sonicated and degassed for 2-5 minutes at room temperature (sonicator: BRANSON 2800) to obtain a well-dispersed suspension. Before analyzing the sample, the vial should be re-vortexed for 0.5-1 minute. Particle size and distribution results are shown in Table 15.

[0189] [Table 15]

[0190] Example 25. Pharmacokinetic (PK) study of cariprazine formulations following single subcutaneous administration of doses to Sprague-Dawley or Wistar rats

[0191] PK studies of test formulations containing cariprazine were conducted in male Sprague-Dawley or Wistar rats weighing approximately 330 grams. FP-018-006 was administered to both Sprague-Dawley and Wistar rats. The remaining test formulations were administered only to Wistar rats. All of these solution-based formulations were prepared in 6R vials by dissolving the appropriate amount of CAR HCl salt in the corresponding solvent or solvent combination. The composition and drug load (DL) of these test formulations are shown in Table 16.

[0192] For each test formulation, four rats were administered subcutaneously via the dorsal thoracic site at a level of approximately 40 mg / kg (equivalent to CAR) after standard animal care and acclimation.

[0193] [Table 16]

[0194] Blood samples were collected at designated time points (pre-dose, 4 hours post-dose, days 1, 4, 7, 14, 21, 28, and 35) by lateral vein bleeding using disodium EDTA as an anticoagulant. Collected blood samples were centrifuged at 1000 × g for 15 minutes within 60 minutes of collection. Plasma samples were stored in a freezer at a temperature below -60°C. CAR plasma levels in the samples were measured using LC-MS / MS.

[0195] The PK profiles and parameters of these test formulations are shown in Figure 3 and Table 17.

[0196] All solution-based formulations exhibited good sustained-release properties over a 28-day period after administration, as indicated by low P / T ratios (less than approximately 10). As shown in Table 16, the percentage of BA in FP-018-008–012 was reduced by using mixtures or combinations of benzyl alcohol and other biocompatible organic solvents, maintaining a similar concentration of cariprazine at approximately 20%. Interestingly, the PK profiles and parameters shown in Table 17 and Figure 3 were all comparable among all solution-based test formulations in WS rats. The addition of hydrophilic cosolvents, such as PG, or hydrophobic cosolvents, such as BB and MCT, in FP-018-008–012 did not affect the PK profile or cause tissue necrosis or death in the animals. Although the PK profiles and parameters of FP-018-008–012 were similar, FP-018-012 had relatively higher bioavailability than the others. Higher bioavailability means fewer injection volumes of the formulation are required to achieve pharmacological efficacy. In addition to higher bioavailability, the % of benzyl alcohol in FP-018-012 was the lowest. Therefore, the combination of benzyl alcohol with PG or other solvents may further alleviate the side effects associated with BA or other solvents.

[0197] [Table 17]

[0198] Those skilled in the art will appreciate that changes could be made to the above-described embodiments without departing from the broad inventive concept thereof. It is therefore to be understood that the invention is not limited to the particular embodiments disclosed, but that it is intended to cover modifications within the spirit and scope of the invention as defined by the specific descriptions.

Claims

1. 1. A sustained release injectable (LAI) composition in the form of a solution, comprising: (i) at least 1% (by weight) of cariprazine in the form of the free base or a pharmaceutically acceptable salt thereof; (ii) at least 10% (by weight) of benzyl alcohol; and (iii) 0 to 90% (by weight) of a biocompatible organic solvent selected from the group consisting of benzyl benzoate, polyethylene glycol (PEG), PEG 300, PEG 400, propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), glycofurol, solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, glycofurol 75, and combinations thereof.

2. 2. The composition of claim 1, wherein the solubility of cariprazine or a salt thereof in the solution is at least 5% by weight.

3. 10. The composition of claim 1, wherein the solution does not comprise poly(D,L-lactide), or poly(D,L-lactic acid), or poly(D,L-lactide-co-glycolide), or poly(D,L-lactic-co-glycolic acid), or any combination thereof.

4. 2. The composition of claim 1, wherein the release of cariprazine in vivo after subcutaneous administration to a subject is sustained for at least one week.

5. 2. The composition of claim 1, wherein the in vivo plasma concentration of cariprazine after subcutaneous administration to a subject has a peak-to-trough ratio of less than about 10 over a period of 28 days after administration.

6. 10. The composition of claim 1, further comprising ascorbic acid, vitamin E, monothioglycerol, butylated hydroxytoluene, butylated hydroxyanisole, or a combination of two or more thereof, in an amount of 0.01 wt. % to 10 wt. %, based on the total weight of the composition.

7. 1. A sustained release injectable (LAI) composition comprising cariprazine free base or a salt thereof and a biocompatible organic solvent selected from the group consisting of polyethylene glycol (PEG), ethanol, glycerin, isopropyl alcohol, propylene glycol, benzyl benzoate, glycofurol, solketal, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, medium chain triglycerides (MCT), vegetable oil, bean oil, sesame oil, castor oil, olive oil, cottonseed oil, peanut oil, and combinations thereof, wherein the cariprazine is in the form of microparticles having a particle size defined by D50 in the range of 0.01 μm to about 250 μm, and the solubility of cariprazine in the biocompatible organic solvent is less than 10 mg / mL.

8. 8. The composition of claim 7, wherein the PEG has an average MW of 300 Da (PEG300) or 400 Da (PEG400).

9. 8. The composition of claim 7, wherein the composition comprises approximately 1% to approximately 80% by weight of cariprazine in the form of the free base or the pharmaceutically acceptable salt, based on the total weight of the composition.

10. 8. The composition of claim 7, wherein the composition is in the form of a suspension, a slurry, a semi-solid, a cream, a paste, or a gel.

11. 8. The composition of claim 7, further comprising a pharmaceutically acceptable salt or sugar to adjust the tonicity of the composition, and / or a preservative.

12. 1. A sustained release injectable (LAI) composition comprising cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in a particulate form having a particle size defined by D50 in the range of 0.01 μm to about 250 μm, and wherein release of cariprazine in vivo following subcutaneous administration to a subject is sustained for at least 4 weeks.

13. 13. The composition of claim 12, wherein the phospholipid is soybean phosphatidylcholine (SPC), the alcohol is ethanol, and the solubility of cariprazine or its salt in the aqueous solution is less than 1% by weight.

14. 13. The composition of claim 12, wherein the composition comprises approximately 1% to approximately 80% by weight of cariprazine in the form of the free base or the pharmaceutically acceptable salt, based on the total weight of the composition.

15. 13. The composition of claim 12, wherein the composition is in the form of a suspension, a slurry, a semi-solid, a cream, a paste, or a gel.

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