Long-acting injectable (LAI) composition of cariprazine

Abstract

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

Description

[0001] Docket No.: 4840-0013PCT Long-Acting Injectable (LAI) Composition of Cariprazine CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Patent Application No.63 / 483,031 filed on February 3, 2023, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present invention relates to a pharmaceutical composition for sustained release of cariprazine over a time period of at least one week. The present invention also relates to the make and use of the composition. BACKGROUND Cariprazine is an atypical antipsychotic. The chemical name of cariprazine is trans-N-{4- [2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea; its empirical formula is C21H32Cl2N4O, and its molecular weight is 427.41 g / mol. The chemical structure is shown in Scheme I below: Scheme I Cariprazine HCl, sold under the brand names Vraylar® and Reagila® among others, was originated by Gedeon Richter [Laszlovszky, István; Barabássy, Ágota; Németh, György (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, which is equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of cariprazine base. It is used in the treatment of schizophrenia in adults, acute treatment of manic or mixed Docket No.: 4840-0013PCT episodes associated with bipolar I disorder in adults, treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults, and adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults [HIGHLIGHTS OF PRESCRIBING INFORMATION, https: / / www.rxabbvie.com / pdf / vraylar_pi.pdf, dated on 12 / 2022. Retrieved on January 23, 2023]. Cariprazine acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor [Kiss B; Horváth A; Némethy Z; Schmidt E; Laszlovszky I; Bugovics G; Fazekas K; Hornok K; Orosz S; Gyertyán I; Agai-Csongor E; Domány 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]. Cariprazine is also approved by the FDA as a generic medication ["First Generic Drug Approvals 2022". U.S. Food and Drug Administration.17 October 2022. Retrieved January 23, 2023] for the treatment of schizophrenia in adults; for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults; for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults. Vraylar® is formulated as capsules that discharge cariprazine into digestive tracts directly when mixed with gastric or intestine fluid. Vraylar® capsules are intended to be taken daily during the treatment period, which poses a challenge to this special population of patients and results in poor patient’s compliance. In addition, oral Varylar® capsules also cause some side effects, such as abdominal pain, vomiting, diarrhea, nausea, constipation, etc. Therefore, there is an unmet medical need for a long-acting sustained release dosage form that allows patients to take the medication less frequently, such as once every week, or once every month, or once every three months, or once every six months. Several long-acting injectable compositions comprising cariprazine have been disclosed recently in WO 2023281404, US 20230293514, WO 2022195615, CN 108261394, CN 108261394, WO 2022042642, US11344503, and WO 2021119166. All the long-acting injectable compositions comprising caripirazine disclosed present as non-aqueous and aqueous suspension, microparticle, and in-situ forming polymeric formulation. Solution-based compositions represent the simplest form of long-acting injectable products and easy to manufacture. Surprisingly, no solution-based long-acting injectable composition comprising caripirazine has not been disclosed. Although all the formulations Docket No.: 4840-0013PCT described in these prior arts allegedly provide sustained release of cariprazine, there is still a need to develop better sustained release formulations of cariprazine that are easy to prepare and easy to use, with better release profiles or pharmacokinetics, and that can last at least a week, a month, or longer. Accordingly, it is the primary object of the present invention to address the above- mentioned unmet medical need by providing a long-acting injectable (LAI) formulation of cariprazine to significantly improve patient’s compliance and reduce side effects. BRIEF SUMMARY OF THE INVENTINON The present invention is directed to a long-acting injectable (LAI) composition of cariprazine or its salts thereof for sustained release delivery of cariprazine over a time period of at least one week, the process to prepare the LAI composition thereof, and the use of the same in the treatment of psychotic disorders. The LAI composition comprises a cariprazine free base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable organic solvent. In one aspect of the present invention, the LAI composition is a solution wherein cariprazine is 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, soil bean oil, sesame oil, castor oil, olive oil, peanut oil, a mixture or combination thereof. In another aspect of the present invention, the LAI composition is a solution wherein the concentration of cariprazine free base or its pharmaceutically acceptable salt thereof is about 0.1% to about 50% by weight and the pharmaceutically acceptable solvent is about 50% to about 99.9% by weight. In another aspect of the present invention, the LAI composition does not comprise a biodegradable lactic acid or lactide containing polymers or copolymers including poly(D,L- lactide) or poly(D,L-lactide-co-glycolide). Docket No.: 4840-0013PCT The LAI composition of the present invention provides a dosage form for the administration of cariprazine through subcutaneous or intramuscular route to potentially avoid gastrointestinal (GI) track or first pass related side effects. The present invention provides a method for preparing the LAI composition of cariprazine that is simple and suitable for commercial production. The present invention provides a method for treating a patient having a condition that is responsive to cariprazine or its pharmaceutically acceptable salts thereof. The method comprises intramuscularly or subcutaneously administering a therapeutically effective level of the LAI composition of cariprazine to a patient in need. The patients to be treated generally involve the following indications, such as schizophrenia, mania, bipolar disorder, and other related diseases. The details of one or more embodiments of the present invention are set forth in the description below. These and other embodiments, features, and advantages will become apparent to those skilled in the art when taken with reference to the following description of various exemplary embodiments of the present invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings. FIG 1. In vitro release of cariprazine formulations. FIG 2. PK profiles of cariprazine formulations in Spraque-Dawley rats at the dose levels of about 100 mg / kg. FIG 3. PK profiles of cariprazine formulations in Spraque-Dawley and Wistar rats at the dose levels of about 40 mg / kg. DETAILED DESCRIPTION OF PREFRRED EMBODIMENTS Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its Docket No.: 4840-0013PCT entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein. Definitions It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” and similar referents are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. As used herein, the term “about” preceding a numerical value or a series of numerical values means ±10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg. As used herein, the term “approximately” preceding a numerical value or a series of numerical values means ±10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg. Unless otherwise indicated, the term “at least” preceding a series of elements is to 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 invention. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply 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 integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of” excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of” does not exclude materials or Docket No.: 4840-0013PCT steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising”, “containing”, “including”, and “having”, whenever used herein in the context of an aspect or embodiment of the invention can be replaced with the term “consisting of” or “consisting essentially of” to vary scopes of the disclosure. As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.” The cariprazine is in the amorphous form or in crystalline form. The term “CAR” or “CRI” as used herein is intended to mean the abbreviation of cariprazine. As used herein, the term “mixture” is the physical combination of two or more substances in which the identities are retained and are mixed in the form of solutions, suspensions, and colloids. As used herein, unless otherwise noted, “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 hard for someone to think clearly, make good judgments, respond emotionally, communicate effectively, understand reality, and behave appropriately. When symptoms are severe, people with psychotic disorders have trouble staying in touch with reality and often are unable to handle daily life. Some examples are shown below. Schizophrenia: People with this illness have changes in behavior and other symptoms -- such as delusions and hallucinations - that last longer than 6 months. It usually affects them at work or school, as well as their relationships. Schizoaffective disorder: People have symptoms of both schizophrenia and a mood disorder, such as depression or bipolar disorder. Schizophreniform disorder: This includes symptoms of schizophrenia, but the symptoms last for a shorter time: between 1 and 6 months. Docket No.: 4840-0013PCT Brief psychotic disorder: People with this illness have a sudden, short period of psychotic behavior, often in response to a very stressful event, such as a death in the family. Recovery is often quick - usually less than a month. 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 a detectable cariprazine compound in blood plasma during the first 48 hours after administration, to the lowest concentration of a detectable cariprazine compound in blood plasma after the peak concentration during the first 48 hours after administration is less than 10, such as less than 5, less than 4 (substantially no burst detectable), preferred less than 3 (no burst detectable), more preferably less than 2. As used herein, the term “peak to trough ratio” or “ratio of peak to trough”, or P / T ratio is intended to mean the ratio between the highest plasma concentration and the lowest plasma concentration of cariprazine released from a cariprazine dosage form, within a given period between administrations. As used herein, the term “steady state” is intended to refer to a pharmacokinetic profile after a third consecutive injection. As used herein, the term “salt” or “pharmaceutically acceptable salt” is intended to refer to any acid addition salts between cariprazine and an acid. The acid may be known in the art and can be selected by one skilled in the art. The acids include, without limitation, 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-toluene sulfonic acid. 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 containing a temporary linkage of cariprazine with a carrier group that produces improved physicochemical or pharmacokinetic properties and that is easily removed in vivo, usually by a hydrolytic cleavage; such prodrugs may also be cascade-type prodrugs for which the cleavage of the carrier group becomes effective only after unmasking an activating group. Docket No.: 4840-0013PCT Biotransformation refers to enzyme mediated hydrolysis or autohydrolysis or autocleavage of a chemical bond connecting cariprazine and a pro-moiety and resulting in the release of free cariprazine in vitro or in vivo under physiological conditions. The linkers employed in such carrier-linked prodrugs may be transient, meaning that they are non-enzymatically hydrolytically degradable (cleavable) under physiological conditions with half-lives ranging from, for example, one hour to three months. On the other hand, stable linkages, such as employed in connecting backbone moieties and spacer, are typically non-cleavable permanent bonds meaning that the respective spacer or connecting moiety have a half-life of at least six months under physiological conditions. As used herein, the term “long-acting injectable (LAI) composition” is intended to mean a drug delivery system, administered as a subcutaneous or intramuscular injection, of a cariprazine dosage form, capable of consistently releasing cariprazine over an extended period of time. LAI formulations are counterparts of immediate-release dosage forms (e.g., uncoated tablets, hard capsules, preparations for inhalation and most intravenous parenteral drugs) as they release the drug over prolonged periods of days to months. Typical applications include chronic diseases and long-term medications (e.g., hormone replacement, chemotherapy, rheumatoid arthritis, contraception) (See: J. C. Wright, D. J. Burgess (2012) Long acting injections and implants: Springer). Once applied it is hardly possible to remove a depot drug from the body. Hence, they are suitable for neuroleptic therapies as well. Thereby, non-compliant patients, who are often found with schizophrenia, cannot neglect or discontinue their medication (See: C. E. Adams, M. K. P. Fenton, 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). As used herein, the term “a peak concentration” is intended to mean the highest concentration obtained after administration of a cariprazine dosage form. As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency such as the EMEA (Europe) and / or the FDA (US) and / or any other national regulatory agency for use in animals, preferably in humans. As used herein, the term “pharmaceutical composition” or “composition” or “formulation” means one or more active ingredients, and one or more inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any Docket No.: 4840-0013PCT composition made by admixing a compound of the present invention and a pharmaceutically acceptable excipient (pharmaceutically acceptable carrier). As used herein, the term “excipients” refers to compounds administered together with the therapeutic agent, for example, solvents, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, or other auxiliary agents. However, in some cases, one excipient may have dual or triple functions. As used herein, the term “stabilizers” refers to compounds used to stabilize the pharmaceutical composition. As used herein, the term “weak acid” refers to compound that does not dissociate completely or provide all its hydrogen ions in aqueous environment, such as acetic acid, oxalic acid, phosphoric acid, and formic acid. pKa is the log scale of acid dissociation constant, Ka. As used herein, strong acids have a pKa ranging from -15 to 2 and weak acids have a pKa ranging from 2 to 50. “Oxidation protection agents” refers to antioxidants, such as ascorbic acid, ectoine, monothioglycerol, morin, polyethylenimine (PEI), propyl gallate, glutathione, lipoic acid, uric acid, carotenes, 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. “Antimicrobial” refers to a chemical substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, yeasts, protozoans and / or destroys viruses. The terms “drug”, “biologically active molecule”, “biologically active moiety”, “biologically active agent”, “active agent”, “active pharmaceutical ingredient, API”, and the like mean any substance which can affect any physical or biochemical properties of a biological organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. In particular, as used herein, biologically active molecules include any substance intended for diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals. A “therapeutically effective amount” of cariprazine as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It is understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of Docket No.: 4840-0013PCT values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. The term “immediate onset of action” as used herein is intended to mean that a therapeutically effective amount of the cariprazine is reached in vivo, such as in the human plasma, within a relatively short time period, such as within 30 hours of administration, typically within 24 hours of administration. In a particular embodiment, the therapeutic plasma concentration of cariprazine is reached within the first 24 hours after dosing. The term “continuously for at least one week” as used herein is intended to mean that cariprazine is released in a subject, such as an animal or a human, without interruptions from a cariprazine depot and in such a way that the therapeutically effective amount of cariprazine is substantially maintained over one week or longer. As used herein, the pharmaceutically acceptable solvent comprises 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 oil, MCT, soil bean oil, sesame oil, castor oil, olive oil, peanut oil, a mixture or combination thereof, and the like. As defined herein, an alcohol comprises any organic compound whose molecule contains one or more hydroxyl groups attached to a carbon atom. As used herein, the alcohol is a liquid at 25oC. As used herein, phospholipids comprise soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), egg sphingomyelin (ESM), egg phosphatidylcholine (EPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosph, datidylcholine (DPPC), dioleoyl phosphatidylcholine (DOPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), dioleoyl phosphatidylglycerol (DOPG), distearoyl phosphatidylglycerol (DSPG), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), dioleoyl phosphatidylethanolamine (DOPE), dimyristoyl phosphatidylserine (DMPS), dipalmitoyl phosphatidylserine (DPPS), dioleoyl phosphatidylserine (DOPS), a mixture or combination thereof, and the like.. The term “poly(ethylene glycol)” or “PEG” refers to a biocompatible, synthetic, hydrophilic polyether compound that has many applications, mostly in the medical industry, but also in the chemical and industrial sectors. The structure of the compound is commonly expressed as H−(O−CH2−CH2)n−OH. PEG is synthesized by polymerizing ethylene oxide using Docket No.: 4840-0013PCT a ring-opening technique, which allows for PEGs of a range of molecular weights and molecular weight distributions to be constructed. This range in weights is what makes it suitable for several uses. As used herein, the PEG has an average MW of from 100 to 10,000 dalton, preferably the PEG has an average MW of 200 dalton (PEG 200), 300 dalton (PEG 300) and 400 dalton (PEG 400), or a mixture thereof. As used herein, the PEG is methoxypolyethylene glycol 350 and has an average MW of about 400 dalton (mPEG 350). As used herein, the PEG is tetrahydrofurfuryl alcohol polyethylene glycol ether or tetraethylene glycol or glycofurol. As used herein, the PEG comprises a polyethoxylated castor oil or derivative thereof, a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, a block copolymer of polyethylene oxide-polypropylene oxide-polyethylene oxide, a block copolymer of polypropylene oxide-polyethylene oxide-polypropylene oxide, a tetra- functional block copolymer of polyethylene oxide-polypropylene oxide, or a tetra-functional block copolymer of polypropylene oxide-polyethylene oxide. Long-Acting Injectable (LAI) Compositions The present invention relates to LAI composition of cariprazine or its salts thereof. The LAI composition may be a suspension or a solution of cariprazine in a pharmaceutically acceptable organic solvent, or a mixture or a combination of two or more solvents. The LAI composition may be a slurry, a semi-solid, or a non-flowable gel, or a cream. The LAI composition may be prepared as exemplified by the descriptions and examples below, without limitation. The components of the LAI composition may be sterilized by techniques known in the art, such as autoclave, ionizing radiation (e.g., e-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 may be prepared using non-sterile components and the final product can then be sterilized using a terminal sterilization process known in the art such as autoclave, ionizing radiation, dry heat, and ethylene oxide. In one aspect of the present invention, the LAI composition in the form of a solution comprises: (i) at least 1% (wt) cariprazine in the form of a free base or a pharmaceutically acceptable salt thereof, and (ii) a biocompatible organic solvent selected from the group Docket No.: 4840-0013PCT consisting of benzyl alcohol (BA), benzyl benzoate (BB), ethyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dimethyl acetamide (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 a combination of two or more thereof. In another aspect of the present invention, the LAI composition in the form of a solution comprises: (i) at least 1% (wt) cariprazine in the form of a free base or a pharmaceutically acceptable salt thereof, (ii) at least 10% (wt) benzyl alcohol, and (iii) 0 to 90% (wt) 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), dimethyl acetamide (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 a combination of two or more thereof. The solubility of cariprazine or salt thereof in the combination solution of benzyl alcohol with other biocompatible organic solvents is at least 5% by weight. In another aspect of the present invention, the LAI composition comprises: a cariprazine free base or a salt thereof and a biocompatible organic solvent selected from a group consisting of 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 alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, medium-chain triglycerides (MCT), vegetable oil, soil bean oil, sesame oil, castor oil, olive oil, peanut oil, and a mixture or combination thereof, wherein the cariprazine is in particulate form with 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, most preferably from 5 µm to about 25 µm. In further aspect of the present invention, the LAI composition comprises: a cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in particulate form with a particle size as defined by D50 ranging from 0.01 µm to Docket No.: 4840-0013PCT about 250 µm, preferably from 0.1 µm to about 100 µm, more preferably from 1.0 µm to about 50 µm, most preferably from 5 µm to about 25 µm. In one embodiment, the synthetic process of cariprazine production 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, about 40 µm, about 30 µm, about 20 µm, about 10 µm, about 5 µm, about 2 µm, about 1μm or about 0.1 µm. In certain embodiments, cariprazine is micronized to desired sizes. The particle sizes and size distribution impact the dissolution and release rate of cariprazine. The larger the particle sizes, the slower for cariprazine to dissolve and therefore the slower to release. Micronization of cariprazine may be carried out by methods known in the art, including milling, wet milling, jet milling as well as those disclosed in U.S. Pat. No.9,439, 906. The particles of cariprazine with different particle size and distribution may also be prepared by the method described in U.S. Patent Application Publication No. U.S.20210015752A1. In addition, cariprazine particles may be prepared by solvent evaporation, lyophilization, spray-drying, freeze-drying, spray-freeze drying, or a combination thereof. In certain embodiments, the particle sizes of cariprazine are characterized by size distribution within a sample. The particle sizes at the undersize values of 10%, 50%, and 90% (denoted as D10, D50, and D90, respectively) are used. D50 is also known as the median particle size. In certain embodiments, D50 is less than 250 µm in diameters (e.g., 50% of 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. In some embodiments, particle sizes of cariprazine are characterized by specific surface area (SSA). As used herein, the surface area of cariprazine may be in the range of 0.1-25 m2 / g. In certain embodiments, the surface area is in the range of 0.5-15 m2 / g. In other embodiments, the surface area is in the range of 1-10 m2 / g, or in the range of 2-10 m2 / g, or in the range of 4-12 m2 / g, or in the range of 5-15 m2 / g. In some embodiments, the cariprazine is present as the free base (unprotonated) form. In some other embodiments, the cariprazine is present as a pharmaceutically acceptable salt form. In some embodiments, the PEG has an average molecular weight (MW) ranging from about 100 to about 10,000 dalton. Docket No.: 4840-0013PCT In certain embodiments, the PEG refers to polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol, and copolymers thereof); and in some other embodiments, the PEG or polyethylene glycol is selected from the group of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1100, PEG 1900, PEG 2000, PEG 2800, PEG 2900, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 8400, PEG 10,000, etc. In one preferred embodiment, the PEG has an average MW of 200 dalton (PEG 200). In a preferred embodiment, the PEG has an average MW of about 300 dalton (PEG 300). In another preferred embodiment, the PEG has an average MW of about 400 dalton (PEG 400). In another preferred embodiment, the PEG is methoxypolyethylene glycol 350 and has an average MW of about 400 dalton (mPEG 350). In another preferred embodiment, the PEG is tetrahydrofurfuryl alcohol polyethylene glycol ether or tetraethylene glycol or glycofurol. In certain embodiments, the PEG comprises a polyethoxylated castor oil or derivative thereof, a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, a block copolymer of polyethylene oxide-polypropylene oxide- polyethylene oxide, a block copolymer of polypropylene oxide-polyethylene oxide- polypropylene oxide, a tetra-functional block copolymer of polyethylene oxide-polypropylene oxide, or a tetra-functional block copolymer of polypropylene oxide-polyethylene oxide. In further embodiments, the PEG comprises triblock polymer of polypropylene glycol flanked by polyethylene glycol (e.g., poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poloxamer 407, etc.). In certain embodiments, the PEG is liquid or flowable at 25oC. In certain embodiments, cariprazine can be formulated as a suspension in PEG. The suspension may further include one or more additives, such as buffers, isotonizing agents, preservatives, surfactants, wetting agents, suspending agents, and the like. In certain embodiments, the suspension comprises a suspending agent selected from the group of methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, Docket No.: 4840-0013PCT polyoxyethylene and polyoxypropylene ethers. Preferably, sodium carboxymethyl cellulose is used in a concentration of 0.5 to 2%, most preferably 1% (w / v). In certain embodiments, the suspension comprises a wetting agent selected from the group of polyoxyethylene derivatives of sorbitan esters, e.g., polysorbate 20 and polysorbate 80, Tween 20 and Tween 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate. Preferably, polysorbate 20 is used in a concentration of 0.5 to 3%, more preferably 0.5 to 2%, most preferably 1.1% (w / v). In certain embodiments, the suspension comprises a buffering agent, which is a salt of a weak acid and should be used in an amount sufficient to render the dispersion to have a pH ranging from 4.0 to 10, preferably neutral to very slightly basic (pH is 7.0-8.5), more preferably in the pH range of 7 to 7.5. Particularly preferred is 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)). This buffering agent also renders the dispersion isotonic. In certain embodiments, the suspension comprises a preservative, such as antimicrobials and anti-oxidants selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-gamma-picolinium chloride, phenylmercuric acetate, thimerosal, ascorbic acid, ectoine, monothioglycerol, morin, polyethylenimine (PEI), propyl gallate, glutathione, lipoic acid, uric acid, carotenes, retinol (vitamin A), α-Tocopherol (vitamin E), ubiquinol (coenzyme Q), cysteine, methionine, L- methionine, and combinations thereof, chelating agents, such as citric acid, EDTA, hexaphosphate, thioglycolic acid, and combinations thereof. In certain embodiments, the suspension comprises an isotonizing agent selected from the group consisting of sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate, and combinations thereof. The suspensions conveniently comprise from 0 to 10% (w / v) isotonizing agent. Mannitol may be used in a concentration from 0 to 7%. More preferably, however, from about 1 to about 3% (w / v), especially from about 1.5 to about 2% (w / v) of one or more electrolytes are used to render the suspension isotonic, because ions help to prevent flocculation of the suspended ester. In particular, electrolytes of the buffer serve as isotonizing agents. Docket No.: 4840-0013PCT In some embodiments, the composition comprises at least 1% (w / w) of cariprazine in the form of the free base or a pharmaceutically acceptable salt. The concentration of cariprazine ranges from greater than or equal to approximately 10 mg / ml to approximately 800 mg / ml. In some embodiments, the composition comprises cariprazine from approximately 1% (w / w) to approximately 80% (w / w) by weight relative to 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 in between. In some embodiments, the composition is in the form of a suspension, a solution, a slurry, a semisolid, a cream, a paste, or gel. In such embodiments, the solubility of cariprazine in the selected solvent is less than 10 mg / mL at 25oC. In some embodiments, the LAI composition comprises propyl glycol, glycol, tetraglycol, triglycol, pentaethylene glycol, propyl alcohol, ethanol, and the like. In some embodiments, the composition further comprises a nonionic surfactant selected from the group consisting of Tween 20, Tween 80, poloxamers, and phospholipids. In some embodiments, the composition further comprises pharmaceutically acceptable salts or sugars to adjust the tonicity of the composition, and / or preservatives. In some embodiments, the composition further comprises pharmaceutically acceptable salts or sugars to adjust the tonicity of the composition, and / or preservatives selected from the group consisting of methylparaben, propylparaben and benzyl alcohol. In some embodiments, there is provided a method of making the composition comprising: mixing the PEG or other selected solvent with any further optional component; adding the cariprazine along with a grinding medium; and grinding the suspension until a required particle size is achieved. In some embodiments, the present invention provides a LAI composition in the form of a solution that comprises: (i) at least 1% (wt) cariprazine in the form of a 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), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), glycofurol, Solketal, Docket No.: 4840-0013PCT glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, glycofurol 75, acetic acid, oleic acid, caprylic acid, capric acid, myristic acid, and a combination of two or more thereof. In some embodiments, the LAI composition in the form of a solution or suspension does not comprise any polymer selected from the group consisting of: a polyester of a hydroxy fatty acid and derivatives thereof, a polymer of an alkyl alpha-cyanoacrylate, a polyalkylene oxalate, a poly(ortho) ester, a polycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, a poly(aliphatic carboxylic acids), a copolyoxalates, a polycaprolactone, a polydioxonone, a poly(ortho carbonates), a poly(acetals), a poly(lactic acid-caprolactone), a polyorthoesters, a poly(glycolic acid-caprolactone), a polyanhydrides, and mixtures thereof. Long-acting 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 maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic or novel formulations. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting 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]. It would be a significant advancement to develop a better sustained delivery product without using PLGA or other complex polymers. In some embodiments, the LAI composition is in the form of a solution or suspension does not comprise 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. In some embodiments, the LAI composition is in the form of a solution and the cariprazine is present in an amount of 1% to 55% by weight. In such embodiments, the cariprazine is present in an amount of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% by weight, or any percentage in between. In some embodiments, the LAI composition is in the form of a solution and the biocompatible organic solvent is benzyl alcohol (BA). Docket No.: 4840-0013PCT In some embodiments, the LAI composition is in the form of a solution and the biocompatible organic solvent is a combination of benzyl alcohol 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), dimethyl acetamide (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. In some embodiments, the LAI composition is in the form of a solution and the benzyl alcohol (BA) in the combination solvents is about 1% to about 99% by weight. In some embodiments, the LAI composition is in the form of a solution further comprises ascorbic acid, vitamin E, monothioglycerol, butylated hydoxytoluene, butylated hydroxyanisole, or a combination of two or more thereof, in an amount of 0.01% to 10% by weight. In some embodiments, the LAI composition in the form of a solution is sterile and is administered to patients subcutaneously or intramuscularly. In some embodiments, the LAI composition is in the form of a solution is sterilized by sterile filtration. In some embodiments, the present invention provides a LAI composition that comprises: a cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in particulate form with 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, most preferably from 5 µm to about 25 µm. In such embodiments, the particle size of D50 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 sizes in between. In some embodiments, the phospholipid in the LAI composition is soybean phosphatidylcholine (SPC), and the alcohol is ethanol, and the solubility of cariprazine in the aqueous solution is less than 1% by weight. In some embodiments, the LAI composition comprises cariprazine in the form of free base or a pharmaceutically acceptable salt from approximately 1% to approximately 80% by weight relative to the total weight of the composition. Docket No.: 4840-0013PCT In some embodiments, the LAI composition is in the form of a suspension, a slurry, a semisolid, a cream, a paste, or a gel. In some embodiments, the LAI composition further comprises pharmaceutically acceptable salts or sugars to adjust the tonicity of the composition, and / or preservatives selected from the group consisting of methylparaben, propylparaben and benzyl alcohol. In some embodiments, the present invention provides a method of treating a patient which delivers a therapeutically effective dosage of the cariprazine thereof from about 1 to about 8 milligrams (mg) per day. In some embodiments, the composition releases the cariprazine with an immediate onset of action and continuously for at least one week, and wherein the composition has a pharmacokinetic profile in vivo with substantially no burst release of cariprazine. In some embodiments, the composition is characterized by releasing the cariprazine in such a way that the therapeutic plasma levels of cariprazine are reached within 24 hours of administration, such as within 18 or 12 hours of administration. In some embodiments, the pharmacokinetic profile is measured in mammalian blood plasma, such as human blood plasma. Plasma cariprazine concentrations can be measured with mass spectrometry methods known in the art and by relating the results to a calibration curve obtained from a cariprazine standard. For statistical significance, the experiment is run with a suitable number of biological and technical replicates and the mean and median values are calculated to adjust for biological and technical variability. In some embodiments, there is provided a method of terminally sterilizing the composition prepared comprising: filling the composition in pharmaceutically acceptable syringes, cartridges, vials or ampoules and properly sealing the syringes, cartridges, vials or ampoules; and terminally sterilizing the syringes, cartridges, vials or ampoules by autoclaving or irradiation (gamma, or X-ray, or electron beam). In some embodiments, there is provided a method of treating a patient which delivers a therapeutically effective dosage of cariprazine thereof from about 1 to about 8 milligrams (mg) per day. In some embodiments, cariprazine can be continuously released for a period of one week or longer from a composition wherein the therapeutic effective plasma concentration is attained Docket No.: 4840-0013PCT within the first 24 hours or shorter, after subcutaneous or intramuscular injection without substantial burst release. Furthermore, by avoiding a burst of cariprazine the risk of harmful side- effects in a patient is reduced. The present invention provides a pharmaceutical composition with a profile of dosing once a week, or once a month or even less frequently, without the need for additional oral or injectable medication. In one embodiment, the release of cariprazine in vivo after administration to a subject subcutaneously or intramuscularly lasts for at least one week. The present invention provides a long acting injectable cariprazine depot having a low ratio of peak to trough (P / T) in plasma concentrations. The P / T ratio is less than 10 for predefined treatment duration such as 1, or 2, or 3 months, preferably less than 8, more preferably less than 5. In one embodiment, the plasma concentration of cariprazine in vivo after administration to a subject subcutaneously or intramuscularly has a peak to trough ratio less than about 10 over a period of 28 days post administration. Further advantages will be apparent when reading the present description and the examples described below. EXAMPLES Example 1. Long-acting injectable (LAI) formulation of CAR The LAI CAR formulations are 1) solution-based formulation with pharmaceutical acceptable solvent or 2) suspension-based formulation in non-aqueous solution or aqueous solution. The 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; ii) pharmaceutical acceptable organic solvent alone or in combination with other pharmaceutical acceptable solvents, such as oil, propylene glycol (PG), poly(ethylene) oxide (PEO), poly(ethylene) glycol (PEG), benzyl benzoate (BB), N-methyl pyrrolidone (NMP), ethanol (EtOH), dimethyl sulfoxide (DMSO), methylsulfonylmethane (MSM), dimethylacetamide (DMAc), and triacetin. The suspension formulations include i) different salt forms of CAR, such as pamoate (PAM), mesylate (MS), tosylate (Tos), hydrochloride (HCl), or free base form of CAR; ii) non-aqueous and water miscible solvent, such as EtOH; iii) surfactants, such as non- ionic surfactants, ionic surfactants and phospholipids. Docket No.: 4840-0013PCT Example 2. Synthesis of pamoate salt of CAR 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 0.2N NaOH to obtain solution B. Then, solution B was slowly dropped (0.5 mL per min) into solution A under stirring at a rate of 500-700 rpm by using a magnetic stir bar at room temperature. After addition of solution B was completed, the suspension was further stirred for an additional 10 min. The resulting CAR-PAM salt was collected by filtration and the salt was further washed using deionized water. The CAR-PAM salt (548 mg, Yield: 91.0%) was obtained as a lightly yellow powder after drying in an oven at 40℃ for two days. The melting point of CAR-PAM was 164- 175℃. 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 ratio of CAR / PAM can be adjusted by charging different amounts of starting materials of CAR and PAM. Example 3. Synthesis of tosylate salt of CAR CAR (500 mg) and p-toluene sulfonic acid monohydrate (PTSA) were separately dissolved in 33.4 mL of phosphoric acid (5.4 mg / mL) and 1.25 mL of DI-water, respectively. The PTSA solution was then added slowly (0.5 mL per min) to the CAR solution under stirring at a rate of 500-700 rpm by using a magnetic stir bar at room temperature. The suspension was further stirred at a rate of 500-700 rpm for an additional 15 min. The resulting salt was collected by filtration and washed with deionized water. The resulting CAR-Tos salt (442 mg, 63.1%) was obtained as white powder after drying in an oven at 40℃ overnight. The melting point of CAR- Tos was 228-230℃. The ratio of CAR / Tos may be adjusted by charging different amounts of starting materials of CAR and Tos. Example 4. Synthesis of mesylate salt of CAR CAR (500 mg) was dissolved in 33.4 mL of phosphoric acid (5.4 mg / mL).79.7 µL of methsulfonic acid (MsOH) was then added in one portion into the CAR solution under stirring at a rate of 500-700 rpm by using a magnetic stir bar at room temperature. The solution was further stirred at 500-700 rpm at room temperature for an additional 15 min. The solution was frozen, Docket No.: 4840-0013PCT placed on a lyophilizer, and lyophilized for 2 days. The lyophilized cake was rehydrated with deionized water and pH of solution (~1.5-2.5) was measured. The rehydrated solution was then frozen, placed on a lyophilizer, and lyophilized for another 2 days. After 2 cycles of drying, the CAR-MS was obtained as a white powder and then taken as a small aliquot to determine pH. The melting point of CAR-MS was 190-193℃. The ratio of CAR / MS can be adjusted by charging different amounts of starting materials of CAR and MS. Example 5. Solubility of CAR in organic solvents and pharmaceutical oils. The solubility of CAR was determined in different organic solvents and pharmaceutically acceptable oils, alone or in combination. As shown in Table 1, an excess amount of CAR was dispersed in corresponding pharmaceutically acceptable solvents (1 mL) and stirred at 25oC. After overnight, the supernatant was carefully withdrawn after centrifugation (14,000 rpm for 5 min), and then the solubility of CAR in these solvents was determined by UPLC. Among pharmaceutically acceptable organic solvents, benzyl alcohol (BA) surprisingly showed much higher solubility than other organic solvents. The combination of these solvents tested here didn’t provide any synergistic effect on the solubility. On the other hand, the solubility of CAR in pharmaceutical oils was low even when supplemented with organic solvents as shown in Table 1. Table 1. Solubility of CAR in organic solvents and pharmaceutical oilsSolvents Solubility (mg / mL) at 25℃Benzyl benzoate (BB) <5Methanol (MeOH) >10Ethanol (EtOH) <7Isopropyl alcohol (IPA) <5 Octanol <5Benzyl alcohol (BA) >160BB / BA (1 / 1) <50BB / BA / EtOH (1 / 1 / 1) <150Castor oil <10Cottonseed oil <10 MCT <10 Docket No.: 4840-0013PCT Sesame oil <10 BA / Sesame oil (1 / 9) <10 BA / EtOH / Castor oil (15 / 15 / 70) <10 BA / EtOH / BB / Castor oil <10 (15 / 15 / 15 / 55) Example 6. Solubility of CAR in a combination of benzyl alcohol (BA) with a fatty acid. The solubility of CAR in combinations of BA with a saturated or unsaturated fatty acid, such as oleic acid (OA) or capric acid (CPA), was determined. In general, an excess amount of CAR was dispersed in these solutions (1 mL) and stirred in a 2R vial at 25℃. After stirring overnight, the supernatant of each solution was carefully withdrawn after centrifugation at 14,000 rpm for 5 min. The equilibrium solubility of CAR in these solutions was determined by UPLC. As shown in Table 2, a synergistic effect on the solubility was observed in BA / OA combination solution. The BA / OA combination solvent presented higher CAR solubility than BA or OA alone. With CPA, an even higher solubility of CAR can be achieved. The solubility increase might be attributed to the formation of ion-pair between tertiary amine of CAR and carboxylate of fatty acid. Table 2. Solubility of CAR in combination solvent of BA with OA or CPA Solvent Solubility (by weight) at 25℃ BA 13.57% OA 15.79% OA / BA 10:90 17.19% OA / BA 25:75 21.14% OA / BA 50:50 19.32% CPA / BA 10:90 19.70% CPA / BA 25:75 >23% CPA / BA 50:50 >24% CPA >25% Docket No.: 4840-0013PCT Example 7. Solubility of CAR in combinations of EtOH with a phospholipid. Amphiphilic phospholipid, such as soybean phosphocholine (SPC), was investigated for its synergistic effect on the solubility of CAR. An excess amount of CAR was dispersed and stirred in a 2R vial at 25℃ in these solutions containing SPC. After stirring overnight, supernatant of each solution was carefully withdrawn after centrifugation of the mixture at 14,000 rpm for 5 min. The equilibrium solubility of CAR in these solutions was determined by UPLC. All solutions containing SPC without CAR shown in Table 3 were clear solutions. No clear solubility synergistic effect for CAR was observed in any of these solutions. Rather in certain combination solvents, the solubility of CAR is further reduced. The low solubility may be advantageous to make a suspension of CAR. Table 3. Solubility of CAR free base in solutions containing SPC Solvents (weight ratio) Solubility (by weight) at 25℃ EtOH 0.71% SPC / EtOH (39 / 61) 0.52% SPC / EtOH / BB (21 / 33 / 46) 1.43% SPC / EtOH / H2O (38 / 61 / 1) 0.68% SPC / EtOH / H2O (36 / 57 / 7) 0.81% SPC / EtOH / H2O (31 / 50 / 18) 0.39% SPC / EtOH / H2O (10 / 45 / 45) 0.08% Example 8. Re-suspendibility of CAR suspension in EtOH / SPC solutions. 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 the solutions containing SPC. Interestingly, the re-suspendibility of CAR in these solutions was significantly affected by the presence of SPC. Without SPC, the CAR particles were quickly stuck to the bottom of 2R vial and not be able to re-form a homogeneous suspension. On the other hand, the re-suspendibility of CAR in solutions containing SPC can be achieved by gentle hand shaking in less than 10 seconds. In order to further decrease the solubility of CAR in these solutions, water was added to SPC / EtOH solution. In solutions with less than 20% water, the solubility of CAR was comparable. While adding water to 45%, the solubility of CAR can be significantly reduced by 10 folds. This lower solubility is advantageous to generate suspensions. The advantages include better particle size Docket No.: 4840-0013PCT physical stability by avoiding dissolution or eroding of the solid particles and better chemical stability in a solid phase. The ease of re-suspension is user friendly. The re-suspension can be achieved in less than one minute. In some cases, the re-suspension can be achieved in less than 30 seconds, or even less than 10 seconds. Example 9. Solubility of CAR salts in pharmaceutically acceptable organic solvents. The solubility of CAR salts, such as pamoate (PAM), tosylate (Tos), HCl, and mesylate (Ms) was determined in different pharmaceutically acceptable organic solvents, alone or in combination with pharmaceutically acceptable solvents or oils. As shown in Table 4, excess amounts of CAR salts were dispersed in corresponding pharmaceutically acceptable organic solvents (1 mL) and stirred at 25℃. After stirring overnight, the supernatant was carefully withdrawn after centrifugation at 14,000 rpm for about 5 min and the saturated solubility of these CAR salts in these organic solvents was determined by UPLC. Interestingly, the CAR salts presented different solubility preferences in these organic solvents. PAM salt of CAR showed a different trend than other salts of CAR in NMP, having much higher solubility in NMP than other salts of CAR. Compared with hydroxyl-containing organic solvents, benzyl alcohol (BA) showed much higher solubility of these salts than EtOH. Table 4. Solubility of CAR salts in pharmaceutically acceptable organic solvents Solubility (% by weight) at 25℃ Salt of CAR NMP BA EtOH BA / 10%MCT BA / 10%CTOPAM 27.812.3ND ND NDHCl 0.924.5ND>20 >20Tos 1.917.3 0.95ND NDMs 4.010.4ND ND NDNote: ND – Not determined. Example 10. Solubility of CAR and its salts in pH 7 PBS buffer. The aqueous solubility of CAR and its salts, such as pamoate (PAM), tosylate (Tos) and HCl, was determined in PBS at pH 7. As shown in Table 5, excess amounts of CAR or its salts were dispersed in PBS at pH 7 (1 mL) and stirred at 37℃. After stirring overnight, the supernatant was carefully withdrawn after centrifugation at 14,000 rpm for about 5 min and the saturated solubility of CAR and its salts in PBS at pH 7 was determined by UPLC. Docket No.: 4840-0013PCT Table 5. Solubility of CAR and its salts in PBS at pH 7 Form of CAR Solubility (μg / mL) 37℃ Base PAM salt HCl salt Tos salt 0.01M PBS 0.52 9.5 1.7 23.6 Example 11. Solubility of CAR and pamoate salt in different solvents. An excess of CAR or CAR-PAM was added to a solvent. The mixture was then stirred for 24 hours at room temperature to reach an equilibrium between the saturated solution and undissolved solid. The undissolved CAR or CAR-PAM could still be visible at the end of the stirring period. The supernatant of the solution was carefully withdrawn after centrifugation at 14,000 rpm for about 5 min. The saturated or equilibrium solubility of CAR or CAR-PAM was determined by UPLC. All the samples were diluted 5-fold by THF (100 µL filtered solution in medium plus 400 µL THF), and some samples were further diluted to measurable concentration with THF or Acetonitrile. The solubility of CAR and CAR-PAM in different solvents at room temperature is shown in Table 6. Table 6. Solubility of CAR and CAR-PAM in different solvents at RT. Solvent CAR (mg / mL) CAR-PAM (mg / mL) EtOH 6.31 28.74 NMP 14.64 >250 Benzyl Benzoate (BB) 6.54 12.02 PEG 400 1.89 103.27 Sesame oil 0.50 0.42 Castor oil 1.52 ND Mig 812 (MCT) 0.66 ND Propylene Glycol (PG) 2.15 1.26 Isoocatne 0.048 ND Hexane 0.043 ND Heptane 0.045 ND Note: ND – Not determined. Docket No.: 4840-0013PCT Example 12. Solubility of CAR HCl in benzyl alcohol (BA) containing solutions at 4℃ 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℃. After stirring overnight, the supernatant was carefully withdrawn after centrifugation at 14,000 rpm for 5 min and the saturated solubility of CAR HCl in these solutions was determined by UPLC. The solubility of CAR HCl in BA between 4 and 25℃ was comparable as shown in Table 4 and Table 7. With supplementation of other pharmaceutically acceptable solvents, such as BB, MCT, and PG, the solubility of CAR HCl was decreased by up to 35%. Although the solubility of CAR HCl in combination solutions was reduced, the percentage of BA in these combination solutions can also be reduced. The lower percentage of BA in the combination solvent solutions can be used to mitigate any potential side effects due to BA. Table 7. Solubility of CAR HCl in BA and solutions containing BA at 4℃ Solubility (% by weight, calculated as liberated CAR) at 4℃BA 10% MCT / BA 30% PG / BA 40% PG / BA 50% PG / BA 20% BB / BA24.7 21.0 21.8 18.0 15.9 20.3Example 13. Stability of CAR or CAR HCl in BA, NMP or BB solution The preparation of CAR or CAR HCl in BA, NMP or BB solution was performed 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 clear solution. The other CAR or CAR HCl solutions with either NMP or BB were prepared firstly by adding 100 mg of either CAR or CAR HCl with 900 mg of either NMP or BB in a 2R vial. Then after planetary mixing, the supernatant of these suspension was carefully withdrawn in another 2R vial. According to solubility result in Table 1, the concentration of CAR or CAR HCl in BA solution was much higher (10% by weight) than other solvents (less than 1% by weight). Unexpectedly, after one day at 60℃, the decrease of purity of CAR or CAR HCl (or impurity generation) in BA solution was much smaller than that in NMP or BB solution as shown in Table 8. Therefore, the selection of a suitable solvent is not an easy task and critical to develop a beneficial long-acting injectable composition. Docket No.: 4840-0013PCT Table 8. Stability of CAR or CAR HCl in BA or NMP or BB solution at 60℃ Composition Impurity after 24 h at 60℃ (%)CAR in BA 0.06CAR in NMP 1.31CAR in BB 9.03 CAR HCl in BA 0.18 CAR HCl in NMP 1.08CAR HCl in BB >30Example 14. Preparation and stability of CAR or CAR HCl formulations with BA alone or a combination of BA with fatty acids. The preparation of CAR or CAR HCl formulations with BA alone or a combination of BA with fatty acid was performed as follows. These CAR and CAR HCl formulations were prepared by dissolving 100 mg of either CAR or CAR HCl with 900 mg of BA or BA / OA (3 / 1 by weight) or BA / CPA (3 / 1 by weight) after planetary mixing to obtain clear solutions. These formulations were further aliquoted in 2R vials, purged with nitrogen, stopped, and closed by crimping, and then incubated at 60℃. At pre-defined time intervals, color change was recorded, and chemical purity was determined by UPLC. The stability of CAR and CAR HCl formulations is shown in Table 9 and Table 10, respectively. As shown in Table 9, even though the solubility of CAR in both BA / OA or BA / CPA was higher, the discoloration and chemical stability of these formulations (F2 and F3) were not good. Formulation F1 (CAR in BA) showed good physical and chemical stability at 60℃ for various time intervals. On the other hand, as shown in Table 10, the chemical purity of both F4 and F5 formulations deteriorated significantly after incubation at 60oC for different times. Table 9. Stability of CAR in BA alone or in combination of OA or CPA Purity (%) Formulations Note d0 d7 d14 d28 F1 (in BA) 99.59 99.03 98.93 98.09 No discolorationF2 (in BA / OA) 99.59 95.88 ND ND Yellow at d2F3 (in BA / CPA) 99.65 95.17 ND ND Light yellow at d5Note: ND – Not determined. Docket No.: 4840-0013PCT Table 10. Stability of CAR HCl in BA alone or in combination with OA Purity (%) Formulations Note F4 (in BA) 99.27 97.64 96.85 No discolorationF5 (in BA / OA) 98.7 95.72 92.69 Pale yellow at d3Example 15. Preparation and Stability of CAR HCl formulations with BA alone or in combination with other pharmaceutically acceptable solvents at 40℃. The CAR HCl was formulated with BA alone or in combination with other pharmaceutically acceptable solvents, which include medium chain triglycerides (MCT), benzyl benzoate (BB), and propylene glycol (PG). The composition of BA co-solvent is shown in Table 11. For these CAR HCl formulations’ preparation, 200 mg of CAR HCl was dissolved with 800 mg of either BA only or BA co-solvent vehicles in a 2R vial after planetary mixing to obtain clear formulations. The corresponding formulations (F4, F11 to F16) were further aliquoted into 2R vials, purged with nitrogen, stoppered and closed by crimping, and then incubated at 40℃. The result showed the purity of CAR HCl in all BA-containing formulations can be still over 98% after incubation at 40℃ for 28 days. Table 11. Stability of CAR HCl in BA containing solutions Purity (%) after 40℃ Formulation d0 d7 d14 d28F4 (BA) 99.83 99.24 99.18 98.70F11 (10%MCTinBA) 99.87 99.42 99.13 98.64F12 (10% CTO in BA) 99.82 99.88 99.15 98.63 F13 (3% Chol in BA) 99.83 99.26 98.90 98.61 F14 (10% MCT / 3% Chol in BA) 99.85 99.12 98.73 98.68 F15 (20% BB in BA) 99.97 99.35 98.77 98.42 F16 (30% PG in BA) 99.82 99.31 99.03 97.96 Docket No.: 4840-0013PCT Example 16. In vitro release of CAR in BA and CAR aqueous suspension formulations. The in vitro release of these CAR formulations was evaluated in PBS with 0.2% Tween 80 at 37℃. These formulations included solution-based formulation (F1, CAR in BA) and suspension formulations (F17 and F18). The preparation of F1 was disclosed in Example 14. The suspension formulations as shown in Table 12 were prepared as the following procedure. The 100 mg of CAR was weighed and suspended with 900 mg of either aqueous vehicle (F17) and SPC containing vehicle (F18) in a 20 mL scintillation vial after planetary mixer. As shown in Figure 1, the F1 presented a much slower release rate than two suspension-based formulations. Table 12. Composition of CAR base suspension formulations Formulations Vehicle F1 Benzyl alcohol (BA) F17 0.2% T20 / 3% PEG4kin water (w / w) F18 30% H2O / 23.3% SPC / 46.6% EtOH Example 17. Pharmacokinetic (PK) studies of cariprazine formulations following single subcutaneous administration of doses to Sprague-Dawley rats A PK study of test formulations containing cariprazine was conducted in male Sprague- Dawley rats with a body weight of ~330 grams. The solution-based test formulations were prepared by dissolving an appropriate amount of either CAR or CAR HCl or CAR / PAM (ratio: 1.6) in the corresponding solvent or combination of solvents 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 loading (DL) of these test formulations are shown in Table 13. For each test formulation, three rats, after standard animal care and acclimation, were administered subcutaneously through the site of dorsal thoracic at the level of 100 mg / kg (CAR free base equivalent). Docket No.: 4840-0013PCT Table 13. Composition of test formulations of CAR Test DL (%, Particle Size (µm) Composition Formulation w / w) D10 D50 D90 FP-018-001 CAR in BA 10 FP-018-002 CAR in BA / OA (3 / 1) 18 CAR / PAM (1.6 / 1) in FP-018-003 12 NMP CAR in SPC / EtOH / water FP-018-005 20 4.63 14.6 43.2 (15 / 45 / 45) suspension FP-018-006 CAR HCl in BA 20 Blood samples were collected at pre-defined time points (pre-dose, 4h, day1, day4, day7, day14, day21, day28, and day35 post-dose) by bleeding the lateral veins with EDTA disodium as anti-coagulant. Collected blood samples were centrifuged for 15 min at 1000 × g within 60 minutes after blood collection. The plasma samples were stored in a freezer at a temperature below -60oC. CAR plasma levels in samples were measured using LC-MS / MS. As shown in Figure 2, all formulations tested in this study presented sustained release of cariprazine. FP-018-001 and FP-018-005 & 6 even have a peak to trough ratio (P / T) less than 3 over 28-days. There were two sets of formulations, solution-based (FP-018-001 to 003 and 006) and suspension-based (FP-018-005). The solution-based formulations all showed relatively higher burst release than suspension-based formulations probably due to higher solubility of CAR in vehicle (Table 14) used in the solution-based formulations. Both sets of formulations experienced a concentration drop around day 1 post-dose and had relatively higher concentration of CAR at later time points.

[0002] Docket No.: 4840-0013PCT Table 14. PK parameters of FP-018-001 to 006 (dose level 100 mg / kg) CAR (% Test Dose Cmax C28dTmax AUC28dAUCinf(μg · retrieved formulations (mg / kg) (μg / mL) (ug / mL) (d) (μg · d / mL) d / mL) 35dfrom implant) FP-018-001 100 70.8 24.9 14 1152.5 1468.4 2.8 4.4 22.1 ± 8 FP-018-002 100 118.7 12.1 1 1608.2 1714.4 9.8 15.9 4.1 ± 0.5 FP-018-003 50 130.7 4.2 0.17 884.4 912.0 30.9 61.3 1.7 ± 1.3 FP-018-005 100 28.8 17.3 14 527.6 1065.6 1.7 1.7 58.4 ± 22.3 FP-018-006 100 83.4 26.9 0.17 1273.7 1796.0 3.1 4.9 9.8 ± 10.9 Besides the P / T ratio, the bioavailability is another important PK parameter. With higher bioavailability, smaller injection volume of formulation would be required to achieve pharmacological efficacy. In Table 14, the amount of cariprazine in the retrieved implants among groups varied from ~2% to 60%. In FP-018-005, there was about 58.4% left in the implant at 35 days post dose, indicating that the delivery of cariprazine in FP-018-005 can last for at least four weeks and very likely for longer than two months. The release of CAR in FP-018-003 was fast but can last for at least 3 weeks. The release of CAR in FP-018-001 showed a low P / T ratio, a high bioavailability, and could last for at least 35 days. However, one of three rats in FP-018-001 died after one day post injection. This is quite surprising as benzyl alcohol is a well understood parenteral solvent and has been approved for human intravenous use at 1620 mg. This result indicates that the dose level of 10% cariprazine in benzyl alcohol at 100 mg / kg (cariprazine free base equivalent) or in term of benzyl alcohol at 900 mg / kg, by subcutaneously administration is a safety concern and further formulation optimization is needed. In other formulations containing benzyl alcohol (FP-018-002 and FP-018-006), no death was observed, but tissue necrosis in rats was observed. The body weight (BW) of rats in FP-018-002 and FP-018-006 experienced about 3% drop at day one post-dose, but weights were recovered back to the baseline after 3 to 4 days. The surviving rats in FP-018-001 took longer time for the weights to be recovered back to the baseline. The dose levels of cariprazine in FP-018-002 and FP-018-006 is the same as that in FP-018-001, but the dose levels of benzyl alcohol (about 400 Docket No.: 4840-0013PCT mg / kg) in FP-018-002 and FP-018-006 were about more than 50% less than that used in FP-018- 001 (900 mg / kg). The injection site evaluation showed that tissue irritation or necrosis was observed in some solution-based formulations (FP-018-001 to 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 types of formulations. It will be critical to optimize the solution-based formulation to minimize local injection site reactions. Example 18: Size reduction of cariprazine particles via jet milling Up to 5 grams of crystalized cariprazine powders were weighed and fed into the jet mill (Micromacinazione, Switzerland) at a rate of about 1 gram per 60 seconds. The feeding pressure and grinding pressure were tunable, depending on the desired particle size to be collected. After milling cariprazine particles were collected, sealed, and preserved under the desired storage condition. In order to acquire large API particles (i.e., particles with D50 above 100 µm) with narrow size distribution, jet milled API powders could also be further filtered through 25 µm filter using 0.5% w / w Tween 80 aqueous solution as a dispersant, followed by oven drying. Particle size was then measured by Malvern Mastersizer 3000 (Malvern Panalytical Ltd, United Kingdom). Example 19: Preparation of cariprazine particles via ball milling About 15 mL of PEG300 was transferred to a 60-ml glass jar, and cariprazine free base (5 g) was then weighed in the jar. The jar was further placed in about 20 half inch size Burundum grinding beads. The jar was closed with a lid and then placed on a jar mill to rotate at 60 rpm at room temperature for 24 hours. The cariprazine suspension was then filled in 1-ml glass ampoules. The filled ampoules were sealed and autoclaved at 121°C for 15 minutes. Mean cariprazine free base particle size [D50] was measured to be 8.3 μm by the Malvern Mastersizer 3000. Example 20: Preparation of cariprazine suspensions Suspensions of cariprazine particles were prepared by mixing cariprazine particles with a selected solvent. For example, the desired amount of cariprazine particles was mixed with Docket No.: 4840-0013PCT PEG300 using an overhead mixer. The mixing was performed at room temperature. The cariprazine particles and PEG300 were weighed and transferred into a 25 mL glass vial. The particle loading was from approximately 1% to approximately 80% by weight relative to the total weight of the composition. Alternatively, the concentration of cariprazine in the final formulation ranges from approximately 10 mg / mL to approximately 800 mg / mL. An electric overhead stirrer was used to blend the particles into the suspension at 1000 rpm (IKA C-Mag HS Digital Stirring Hot Plate) for approximately 5 minutes, and then homogenized by Planetary Mixer (Kurabo Mazerustar KK-50S, Kurabo Industries LTD, Japan) for 10 mins under CH-2 program for viscous formulations. The formulations were filled into glass syringes, resulting in an injection-ready dosage form. The suspensions were stored at a refrigerated temperature (approximately 2-8 °C or room temperature) prior to injection. Example 21: Preparation of 20% and 40% cariprazine in PEG300 1.260 g and 1.680 g cariprazine free base were weighed into two separate 1-drum vials. 5.040 g and 2.520 g PEG300 were then added to each vial accordingly. The vials were shaken and vortexed until the drug was fully wetted and suspended. Each suspension was then allocated and loaded into 3 mL syringes. Example 22: Preparation of 20% and 40% cariprazine in PEG400 1.260 g and 1.680 g cariprazine free base were weighed into two separate 1-drum vials. 5.040 g and 2.520 g PEG400 were then added to each vial accordingly. The vials were shaken and vortexed until the drug was fully wetted and suspended. Each suspension was then allocated and loaded into 3 mL syringes. Example 23: Preparation of 50% cariprazine in PEG400 10 g cariprazine free base and 10 g PEG400 were weighed into a 25 mL vial and mixed using a magnetic stirrer at 1000 rpm approximately for 5 minutes at room temperature, and then homogenized using Planetary Mixer for 10 mins. The formulation was stored at approximately 2-8 °C or room temperature prior to injection. Example 24: Preparation of cariprazine suspensions in propylene glycol (PG), or N-methyl-2- pyrrolidone (NMP) and other solvents. Docket No.: 4840-0013PCT Cariprazine was jet milled to obtain suitable particles. The suspensions of cariprazine particles in various solvents were prepared using the similar procedure as described in Example 4 & 7. Particle size and distribution (PSD) were analyzed using Malvern Mastersizer 3000. Typically, for particle size analysis, transfer ~50 mg of API or one drop of cariprazine suspension into a 20 mL glass vial, add 10 mL of dispersant / suspending medium (0.5-1% Tween 20 in mill-Q water) to the vial, vortex to mix, and then sonicate and degas (Sonicator: BRANSON 2800) at room temperature 2-5 minutes in order to obtain a well dispersed suspension. Prior to analyzing the sample, the vial should be re-vortexed for 0.5-1 minutes. The particle size and distribution results are shown in Table 15. Table 15. Typical formulation and corresponding PSD Composition D10 / D50 / D90 / D(4,3) / D(3,2) Span Surface area (µm) (m2 / kg) Cariprazine / PEG400 2.24 / 6.04 / 17.3 / 8.52 / 4.71 2.572 1213 (1:1, w / w) Cariprazine / PEG400 / Water 2.23 / 5.79.17.0 / 8.08 / 4.62 2.576 1083 (4:3:3, w / w / w) Cariprazine / PG (1:1, w / w) 2.32 / 6.14 / 17.6 / 8.27 / 4.80 2.490 1041 Cariprazine / PG 2.26 / 6.06 / 17.7 / 8.29 / 4.72 2.556 1060 (1.5:1, w / w) Cariprazine / NMP 2.98 / 7.53 / 19.3 / 9.65 / 5.91 2.175 966.4 (1.5:1, w / w) Criprazine / NMP 2.93 / 7.09 / 16.2 / 8.48 / 5.65 1.863 1011 (1.75:1, w / w) Cariprazine alone 2.19 / 5.89 / 18.0 / 8.35 / 4.59 2.678 1089 Note: PEG: polyethylene glycol, PG: propylene glycol, NMP: N-methylpyrrolidone. Example 25. Pharmacokinetic (PK) studies of cariprazine formulations following single subcutaneous administration of doses to Sprague-Dawley or Wistar rats A PK study of test formulations containing cariprazine was conducted in male Sprague- Dawley or Wistar rats with a body weight of ~330 grams. FP-018-006 was administered in both Sprague-Dawley and Wistar rats. The rest of the test formulations were administered in Wistar rats only. All these solution-based formulations were prepared by dissolving an appropriate amount of CAR HCl salt in the corresponding solvent or combination of solvents in a 6R vial. The composition and drug loading (DL) of these test formulations are shown in Table 16. For each test formulation, four rats, after standard animal care and acclimation, were administrated Docket No.: 4840-0013PCT subcutaneously through the site of dorsal thoracic at the level of about 40 mg / kg (equivalent to CAR). Table 16. Composition of test formulations of CAR Test Formulation Composition DL (%) FP-018-006 CAR HCl in BA 20 FP-018-008 CAR HCl in 10% MCT / BA 20 FP-018-009 CAR HCl in 3% Chol / BA 20 FP-018-010 CAR HCl in 10%MCT / 3% Chol / BA 20 FP-018-011 CAR HCl in 20% BB / BA 20 FP-018-012 CAR HCl in 30% PG / BA 20 Blood samples were collected at pre-defined time points (pre-dose, 4h, day1, day4, day7, day14, day21, day28, and day35 post-dose) by bleeding the lateral veins with EDTA disodium as anti-coagulant. Collected blood samples were centrifuged for 15 min at 1000 × g within 60 minutes after blood collection. The plasma samples were stored in a freezer at a temperature below -60oC. CAR plasma level in samples were measured using LC-MS / MS. The PK profiles and parameters of these test formulations are shown in Figure 3 and Table 17. All solution-based formulations show good sustained release characteristics as indicated by a low P / T ratio (less than about 10) over a period of 28 days post administration. As shown in Table 16, the % of BA in FP-018-008 to 012 was reduced by using a mixture or combination of benzyl alcohol with other biocompatible organic solvents to maintain similar concentration of cariprazine at about 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 hydrophilic co-solvent, such as PG, or hydrophobic co-solvent, such as BB and MCT, in FP-018-008 to 012 didn’t affect PK profiles and did not cause tissue necrosis or death of animals. Although the PK profiles and parameters of FP-018-008 to 012 were similar, the FP- 018-012 had relatively higher bioavailability than others. With higher bioavailability, smaller injection volume of formulation would be required to achieve pharmacological efficacy. Besides the 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 mitigate the side effects related to BA or other solvents. Docket No.: 4840-0013PCT Table 17. PK parameters of FP-018-006 and 008 to 012 (dose level 40 mg / kg) FP-018-006 SD 26.4 0.17 376.6 417.8 5.7 0.7 ± 1.1 FP-018-008 WS 23.0 0.17 230.2 263.0 6.7 1.1 ± 2.2 FP-018-009 WS 20.8 0.17 263.1 281.2 8.2 1.6 ± 2.2 FP-018-010 WS 31.6 0.17 283.0 305.9 10.3 1.3 ± 2.6 FP-018-011 WS 31.8 0.17 293.0 335.8 7.5 2.3 ± 4.7 FP-018-012 WS 22.5 0.17 328.3 367.0 5.5 0.7 ± 1.3 It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present inventions as defined by the specific description.

Claims

Docket No.: 4840-0013PCT CLAIMS What is claimed is:

1. A long-acting injectable (LAI) composition in the form of a solution comprising: (i) at least 1% (wt) cariprazine in the form of a free base or a pharmaceutically acceptable salt thereof, (ii) at least 10% (wt) benzyl alcohol, and (iii) 0 to 90% (wt) 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), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), glycofurol, Solketal, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, glycofurol 75, and combinations thereof.

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

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

4. The composition according to claim 1, wherein the release of cariprazine in vivo after administration to a subject subcutaneously lasts for at least one week.

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

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

7. A long-acting injectable (LAI) composition comprising: a 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, soil bean oil, sesame oil, castor oil, olive oil, cottonseed oil, peanut oil, and combinations thereof, wherein the cariprazine is in the form of particulates with aDocket No.: 4840-0013PCT particle size as defined by D50 ranging from 0.01 μm to about 250 μm and wherein the solubility of cariprazine in the biocompatible organic solvent is less than 10 mg / mL.

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

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

10. The composition according to claim 7, wherein the composition is in the form of a suspension, a slurry, a semisolid, a cream, a paste, or a gel.

11. The composition according to claim 7 further comprising pharmaceutically acceptable salts or sugars to adjust the tonicity of the composition, and / or a preservative.

12. A long-acting injectable (LAI) composition comprising: a cariprazine free base or a salt thereof and an aqueous solution of a phospholipid and an alcohol, wherein the cariprazine is in particulate form with a particle size as defined by D50 ranging from 0.01 μm to about 250 μm and wherein the release of cariprazine in vivo after administration to a subject subcutaneously lasts for at least four weeks.

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

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

15. The composition according to claim 12, wherein the composition is in the form of a suspension, a slurry, a semisolid, a cream, a paste, or a gel.

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