Method for preparing cariprazine microspheres, microspheres prepared thereby, and pharmaceutical composition comprising microspheres

Abstract

The present invention provides a method for preparing cariprazine microspheres, comprising the steps of: (a) preparing a dispersed phase by dissolving or dispersing cariprazine or a pharmaceutically acceptable salt thereof and at least one biocompatible polymer in a mixed solvent of methanol and dichloromethane, (b) adding the prepared dispersed phase to the continuous phase and stirring to form microspheres, and (c) removing the solvent; microspheres prepared by the method; and a pharmaceutical composition comprising the microspheres.

Description

Technical Field

[0001] This application claims the benefit of priority to Korean Patent Application No. 10-2023-0090238, filed on July 12, 2023, the entire contents of which are incorporated herein by reference.

[0002] This invention relates to a method for preparing cariprazine microspheres, the microspheres prepared therefrom, and a pharmaceutical composition comprising said microspheres. Background Technology

[0003] Cariprazine is a D3 / D2 receptor partial agonist of dopamine D3. Cariprazine is used to treat and / or prevent pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia, schizoaffective disorder, etc.), drug abuse (e.g., alcohol, cocaine, nicotine, opioids, etc.), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations; and negative symptoms such as lack of motivation and social withdrawal, as well as cognitive symptoms such as postural and memory problems), mild cognitive impairment, moderate cognitive impairment, dementia, dementia-related mental states, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, ADHD in children, psychotic depression, mania, paranoia, delusional disorder, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggression, autism, etc.

[0004] Cariprazine is typically delivered via immediate-release oral formulations. However, because cariprazine is a drug requiring long-term administration, immediate-release oral formulations need to improve dosing convenience. Therefore, sustained-release formulations, nanoparticle formulations, or delivery systems of cariprazine microspheres that can provide prolonged drug release, ease of administration, and high patient compliance are being investigated.

[0005] For example, Korean Patent Publication No. 10-2022-0127254 discloses a long-acting injectable formulation and delivery system for cariprazine. However, the disclosed technology only proposes a formulation capable of drug release for 10 days, limiting its ability to provide prolonged drug release, ease of administration, and high patient compliance.

[0006] [Existing technical documents]

[0007] [Patent Literature]

[0008] Korean Patent Publication No. 10-2022-0127254. Summary of the Invention

[0009] Technical issues

[0010] The inventors of this invention have conducted repeated research to solve the above-mentioned problems of the prior art and have developed a microsphere in which cariprazine is encapsulated at a high concentration and continuously released over a long period of time without initial burst release.

[0011] Therefore, the present invention aims to provide a microsphere, a method for preparing the same, and a pharmaceutical composition comprising the microsphere, wherein the microsphere exhibits stable drug release over a long period of time and can maintain an effective concentration of cariprazine in the blood for a certain period of time, thereby prolonging the dosing cycle, improving patient drug compliance, and reducing side effects caused by rapid initial drug release.

[0012] Technical solution

[0013] To address the above problems, the present invention provides a method for preparing microspheres, comprising the following steps: (a) A dispersed phase is prepared by dissolving or dispersing cariprazine or a pharmaceutically acceptable salt thereof and at least one biocompatible polymer in a mixed solvent of methanol and dichloromethane; (b) The prepared dispersed phase is added to the continuous phase and stirred to form microspheres; and (c) Remove the solvent.

[0014] In addition, the present invention provides microspheres prepared by the above method, the microspheres comprising cariprazine or a pharmaceutically acceptable salt thereof and a biocompatible polymer.

[0015] In addition, the present invention provides a pharmaceutical composition comprising the microspheres of the present invention.

[0016] Beneficial effects

[0017] The microspheres of this invention exhibit stable drug release over a prolonged period, enabling cariprazine to maintain an effective concentration in the blood for a duration, thereby extending the dosing cycle and improving patient medication adherence. Furthermore, initial burst release is minimized, thus reducing side effects caused by rapid initial drug release.

[0018] Furthermore, the method for preparing microspheres according to the present invention provides the effect of effectively preparing microspheres with excellent loading and encapsulation efficiency as well as minimized initial burst release and sustained release performance.

[0019] Furthermore, the pharmaceutical compositions of the present invention, by comprising the microspheres, provide excellent effects in the prevention or treatment of schizophrenia, mania, bipolar disorder, etc. Attached Figure Description

[0020] Figure 1 These are scanning electron microscope (SEM) images of the morphology of the microspheres prepared in Example 1 of this invention. Figure 2 This is a graph illustrating the results of measuring the size of the microspheres prepared in Example 1 of the present invention.

[0021] Figure 3 This is a graph illustrating the in vitro release test results of the microspheres prepared in Example 1 of this invention. Figure 4 This is a graph illustrating the in vitro release test results of the microspheres prepared in Comparative Example 1 of the present invention. Detailed Implementation

[0022] The invention will be described in more detail below.

[0023] Unless otherwise defined, all technical terms used in this invention are used with the same meaning as commonly understood by those skilled in the art related to this invention. Furthermore, methods or samples similar to or equivalent to those described in this specification are also included within the scope of this invention. The contents of all publications referenced in this specification are incorporated herein by reference in their entirety.

[0024] In this invention, cariprazine or its pharmaceutically acceptable salts may be collectively referred to as cariprazine.

[0025] This invention relates to a method for preparing microspheres, comprising the following steps: (a) A dispersed phase is prepared by dissolving or dispersing cariprazine or a pharmaceutically acceptable salt thereof and one or more biocompatible polymers in a mixed solvent of methanol and dichloromethane; (b) The prepared dispersed phase is added to the continuous phase and stirred to form microspheres; and (c) Remove the solvent.

[0026] Cariprazine is a compound with the chemical name trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethylurea.

[0027] Cariprazine is a D3 / D2 receptor partial agonist of dopamine D3 preferred. Cariprazine can be used to treat and / or prevent pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia, schizoaffective disorder, etc.), drug abuse (e.g., alcohol, cocaine, nicotine, opioids, etc.), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations; and negative symptoms such as lack of motivation and social withdrawal, as well as cognitive symptoms such as postural and memory problems), mild cognitive impairment, moderate cognitive impairment, dementia, dementia-related mental states, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, ADHD in children, psychotic depression, mania, paranoia, delusional disorder, movement disorders (e.g., Parkinson's disease, antipsychotic-induced Parkinson's syndrome, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggression, autism, etc.

[0028] In one embodiment of the invention, a pharmaceutically acceptable salt of cariprazine may be selected from, but is not limited to, cariprazine hydrochloride, sulfate, phosphate, methanesulfonate, camphorsulfonate, oxalate, maleate, succinate, citrate, formate, hydrobromide, benzoate, tartrate, fumarate, salicylate, mandelate, and carbonate.

[0029] Cariprazine salts can be prepared using conventional techniques, such as by adding an acid to free cariprazine to convert it into an acid addition salt, or by converting one acid addition salt into another.

[0030] In one embodiment of the invention, in step (a), the mixed solvent of methanol and dichloromethane can be used at a mixing weight ratio of 1:1 to 8.5, 1:1.1 to 7, 1:1.1 to 6, or 1:5 to 6. If the weight ratio of dichloromethane is less than 1, problems may arise in the microspheres, resulting in severe pore structures or improper microsphere formation; if it exceeds 8.5, problems may arise in the initial burst release, which is not preferred.

[0031] In one embodiment of the invention, the weight ratio of the combination of cariprazine or its pharmaceutically acceptable salt and biocompatible polymer to the mixed solvent in step (a) can be 1:1 to 10, 1:1 to 8, 1:1 to 5, or 1:1 to 3. If the weight ratio of the mixed solvent is less than 1, the drug may precipitate, and when microspheres are formed, the drug may be distributed outside the microspheres, leading to problems with high initial burst release. If it exceeds 10, the microspheres may not form well, or problems with initial burst release may occur, which is not preferred.

[0032] In one embodiment of the invention, in step (a), the biocompatible polymer may be included in an amount of 10% to 50% by weight or 15% to 45% by weight, based on the total weight of the dispersed phase. If the weight percentage of the biocompatible polymer is less than 10% by weight, problems such as the drug not being encapsulated in the microspheres or the microspheres not forming properly may occur; if it exceeds 50% by weight, the viscosity of the dispersed phase may be too high, which may lead to problems such as the microspheres not forming, and is not preferred.

[0033] In this invention, microspheres refer to microspheres prepared using a biocompatible polymer in which caliprazine or a pharmaceutically acceptable salt thereof is encapsulated, and are simply referred to as caliprazine-containing microspheres, caliprazine microspheres, or microspheres. Any microspheres prepared using a biocompatible polymer, regardless of the type of biocompatible polymer used, are included within the scope of this invention as long as caliprazine or a pharmaceutically acceptable salt thereof is encapsulated in them.

[0034] In this invention, "biocompatible polymer" refers to a polymer whose safety is guaranteed because the polymer and its degradation products do not cause cytotoxicity or inflammatory reactions in vivo, and are also referred to as polymer in this specification.

[0035] In this invention, the biocompatible polymer can be selected based on its intrinsic viscosity. A suitable intrinsic viscosity can be from 0.1 dL / g to 1.9 dL / g, preferably from 0.1 dL / g to 1.2 dL / g, and more preferably from 0.1 dL / g to 1.0 dL / g. When the intrinsic viscosity is less than 0.1 dL / g, the biocompatible polymer may decompose too quickly, making it difficult to maintain the release of cariprazine for the required time period. When the intrinsic viscosity exceeds 1.9 dL / g, the polymer may decompose too slowly, resulting in an insufficient release of cariprazine.

[0036] In one embodiment of the present invention, the biocompatible polymer may be at least one selected from polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolic acid copolymer (PLGA), polyphosphazene, polyimide carbonate, polyphosphate, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and copolymer of lactic acid and amino acids.

[0037] Polylactic acid is a particularly preferred choice.

[0038] In one embodiment of the invention, the weight of cariprazine or a pharmaceutically acceptable salt thereof encapsulated in the microspheres obtained according to the preparation method may be 70%, 80%, 85%, or 90% or more, relative to the weight of cariprazine or a pharmaceutically acceptable salt thereof dissolved in step (a). In this case, the upper limit may be less than 100%, less than 98%, less than 96%, or less than 94% by weight.

[0039] Step (b) is a step of solidifying microspheres by dispersing the dispersed phase prepared in step (a) in an external continuous phase to prepare an emulsion solution (O / W).

[0040] In step (b), a hydrophilic polymer may be included as a surfactant, and there is no particular limitation on its type. Any of these surfactants may be used that can help the dispersed phase containing cariprazine or its pharmaceutically acceptable salt and biocompatible polymer to form a stable droplet dispersion within an external continuous phase.

[0041] The hydrophilic polymer may preferably be selected from methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene dehydrated sorbitol fatty acid ester, polyoxyethylene castor oil derivative, and mixtures thereof, and polyvinyl alcohol may preferably be used.

[0042] In step (b), the external continuous phase may be an aqueous solution of a hydrophilic polymer of 0.1% to 5% (w / v), preferably 0.1% to 3% (w / v), wherein the weight-average molecular weight of the hydrophilic polymer may be 7,000 to 40,000 and the degree of hydrolysis may be 80% to 90%.

[0043] In step (b), the dispersed phase prepared in step (a) comprising cariprazine or a pharmaceutically acceptable salt thereof and a biocompatible polymer is added dropwise or by using an online mixer to an external continuous phase comprising a hydrophilic polymer, and the mixture is vigorously stirred to prepare an emulsion solution (O / W). In this process, cariprazine or a pharmaceutically acceptable salt thereof is encapsulated in biocompatible polymer microspheres.

[0044] Next, in step (c), the solvent is removed, and after routine filtration and washing, the desired microspheres can be obtained. That is, if desired, a further step of washing the obtained microspheres with an organic solvent such as ethanol can be included to enhance the initial release inhibition.

[0045] The present invention also provides microspheres prepared by the above method, which comprise cariprazine or a pharmaceutically acceptable salt thereof and a biocompatible polymer.

[0046] Regarding microspheres, all the content described in the above microsphere preparation method can be applied. Therefore, any repetition can be omitted below.

[0047] In one embodiment of the invention, the biocompatible polymer may be contained in amounts of 70% to 99% by weight, 72% to 90% by weight, or 73% to 80% by weight, based on the total weight of the microspheres. When the weight percentage of the biocompatible polymer is less than 72% by weight, the distribution of cariprazine or its pharmaceutically acceptable salts may be relatively increased, which may lead to problems such as initial over-release or inability to maintain efficacy for the desired period of time. When it exceeds 99% by weight, the solubility of cariprazine may not be effectively achieved, and the amount to be administered to the patient may become too large, making administration difficult or impossible.

[0048] In one embodiment of the invention, based on the total weight of the microspheres, cariprazine or a pharmaceutically acceptable salt thereof may be contained in amounts of 1% to 30% by weight, 5% to 30% by weight, or 20% to 30% by weight.

[0049] In one embodiment of the invention, the microspheres can maintain the release of cariprazine for more than 10 days, 14 days, 21 days, or 28 days. However, a drawback of conventional cariprazine microspheres is that they do not provide convenient administration for patients because the release of cariprazine cannot be sustained for more than 10 days. The microspheres of the present invention can extend the duration of efficacy to at least one month, thereby significantly improving the convenience of administration.

[0050] In one embodiment of the invention, the cariprazine contained in the microspheres can be released within one day in an amount of 10% by weight or less, preferably 7% by weight or less, more preferably 6% by weight or less. Furthermore, the release amount within 5 days can be 20% by weight or less, preferably 18% by weight or less, more preferably 15% by weight or less. Furthermore, the release amount within 10 days can be 30% by weight or less, preferably 28% by weight or less, more preferably 25% by weight or less.

[0051] In one embodiment of the invention, the microspheres may contain impurities (other than cariprazine or its pharmaceutically acceptable salts and biocompatible polymers) included during the preparation process, in a content of less than 5% by weight based on the total weight of the microspheres. Given these impurities, the content of the biocompatible polymer may be reduced due to the amount of impurities.

[0052] In one embodiment of the invention, the microspheres may be provided in a controlled or extended release form of encapsulated cariprazine or a pharmaceutically acceptable salt thereof. The terms "controlled or extended release" are to be understood to have the same meaning as "sustained release," "controlled release," or "delayed release."

[0053] The present invention also provides a pharmaceutical composition comprising the microspheres and a pharmaceutically acceptable carrier.

[0054] This pharmaceutical composition can be used to treat and / or prevent pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia, schizoaffective disorder, etc.), drug abuse (e.g., alcohol, cocaine, nicotine, opioids, etc.), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations; and negative symptoms such as lack of motivation and social withdrawal, as well as cognitive symptoms such as posture and memory problems), mild cognitive impairment, moderate cognitive impairment, dementia, mental states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, ADHD in children, psychotic depression, mania, paranoia, delusional disorder, movement disorders (e.g., Parkinson's disease, antipsychotic-induced Parkinson's syndrome, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggression, autism, etc.

[0055] In one embodiment of the invention, the pharmaceutical composition can be formulated for parenteral administration.

[0056] Pharmaceutical compositions for parenteral administration may comprise microspheres alone, or may further comprise pharmaceutically acceptable carriers for parenteral administration that can be routinely added to the pharmaceutical composition. Furthermore, they may further comprise excipients or diluents. Carriers include all types of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads, and microparticles.

[0057] Carriers for parenteral administration may contain water, suitable oils, saline solutions, aqueous glucose, and glycols, and may further contain stabilizers and preservatives.

[0058] Suitable stabilizers may include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives may include benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol.

[0059] In addition to the components described above, the pharmaceutical compositions of the present invention may further comprise lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, etc. Other pharmaceutically acceptable carriers and formulations can be found in the descriptions in the following literature (Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing, Easton, PA, 1995).

[0060] The parenteral administration method of the present invention can be administered to patients (e.g., people who need this drug) or other animals via intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intraenteral, intravaginal, intrapulmonary, suppository, local, sublingual, or rectal administration, but is not limited thereto.

[0061] In this invention, "treatment" refers to any act that improves or beneficially alters (acute or chronic) diseases, conditions, and resulting symptoms by administering a pharmaceutical composition. Furthermore, "treatment" broadly includes the meaning of "prevention," which refers to any act that inhibits or delays the onset of diseases and symptoms arising therefrom by administering a pharmaceutical preparation. This "treatment" includes, for example, preventing, alleviating, improving, stopping, inhibiting, delaying, and reversing the progression of (acute or chronic) diseases, conditions, and resulting symptoms.

[0062] The dosage of the microspheres or pharmaceutical compositions of the present invention will vary depending on factors such as the frequency and duration of administration, the nature and severity of the disease to be treated, the age and overall health of the subject (host), and the subject's (host's) tolerance to the active ingredient. Taking these factors into account, those skilled in the art will be able to determine the appropriate effective dosage of the compositions of the present invention. There are no particular limitations on the formulation, route of administration, or method of administration of the pharmaceutical compositions of the present invention, as long as they exhibit the effects of the present invention.

[0063] The invention will be described in detail below by way of embodiments. However, embodiments of the invention can be modified in various ways, and the scope of the invention should not be construed as limited to the embodiments described below. These embodiments of the invention are provided to explain the invention more fully to those skilled in the art.

[0064] Example 1: Preparation of cariprazine microspheres

[0065] Weigh 0.3g of cariprazine (manufacturer: Synaptics Labs) and 0.9g of biocompatible polymer (Resormer 203H, manufacturer: Evonik) and place them in a vial. Mix with 0.475g of methanol (manufacturer: Deoksan) and 2.394g of dichloromethane (manufacturer: Deoksan) to complete the dispersion phase.

[0066] The continuous phase used was a 0.5% aqueous solution of polyvinyl alcohol (manufacturer: Sigma-Aldrich, molecular weight: 9,000-10,000). 1,000 ml of the continuous phase was placed in a production tank, and the dispersed phase prepared above was injected at 25°C. Microspheres were then prepared using a homogenizer (Kinematica, Switzerland).

[0067] The organic solvent was then removed by heating the mixture at 25°C for 5 hours, followed by raising the temperature to 35°C and holding for 19 hours. The prepared microspheres were washed several times with water for injection to remove residual polyvinyl alcohol, and then freeze-dried.

[0068] Comparative Example 1: Preparation of Caliprazine Microspheres

[0069] Weigh 0.3 g of cariprazine (manufacturer: Synaptics Labs) and 0.9 g of biocompatible polymer (Resormer 203H, manufacturer: Evonik) and place them in a vial, then mix with 26.6 g of dichloromethane (manufacturer: Deoksan) to form a dispersed phase.

[0070] The continuous phase used was a 0.5% aqueous solution of polyvinyl alcohol (manufacturer: Sigma-Aldrich, molecular weight: 9,000-10,000). 1,000 ml of the continuous phase was placed in a production tank, and the dispersed phase prepared above was injected at 25°C. Microspheres were prepared using a homogenizer (Kinematica, Switzerland).

[0071] The organic solvent was then removed by heating the mixture at 25°C for 5 hours, followed by raising the temperature to 35°C and holding for 19 hours. The prepared microspheres were washed several times with water for injection to remove residual polyvinyl alcohol, and then freeze-dried.

[0072] Experimental Example 1: Morphological Confirmation of Cariprazine Microspheres

[0073] To confirm the morphology of the microspheres prepared in Example 1 and Comparative Example 1, they were analyzed using a scanning electron microscope (SEM). Approximately 20 mg of microspheres were fixed onto an aluminum sample stage and mounted in an SEM (equipment name: Hitachi TM4000Plus) to observe the surface of the microspheres. All images were observed using a 5 keV electron beam at a magnification of approximately 500X.

[0074] The above observations are as follows Figure 1 As shown. Figure 1 As shown, in Example 1, due to the use of a small amount of solvent, it can be seen that no drug crystals precipitate on the outside of the spherical microspheres. On the other hand, in Comparative Example 1, it can be seen that a large amount of crystalline drug precipitates on the outside of the microspheres.

[0075] Experimental Example 2: Size Measurement of Caliprazine Microspheres

[0076] The size of the microspheres prepared in Example 1 and Comparative Example 1 was measured using a particle size analyzer (PSA). Approximately 100 mg of each type of microsphere was placed in a 1.5 mL EP tube, 1 mL of deionized water was added, and the mixture was vortexed for 1 minute. The microspheres were then placed in a PSA (Horiba LA-960S2) cuvette, and the size of the microspheres was measured. The measurement results are shown in Table 1 below. Figure 2 middle.

[0077] [Table 1]

[0078] From Table 1 and Figure 2 The results confirm that, compared to using dichloromethane alone, by using a co-solvent to reduce the total amount of solvent, the microspheres of Example 1 were easier to prepare into microspheres of the target size, and no drug precipitation occurred, making release easier to control. Therefore, Example 1 of the present invention is superior to the microspheres of Comparative Example 1 in this respect.

[0079] Experimental Example 3: Confirmation of loading rate and encapsulation efficiency of caliprazine microspheres

[0080] Approximately 12 mg of each microsphere prepared in Example 1 and Comparative Example 1 was placed in a 20 mL flask and completely dissolved in 10 mL of acetonitrile. The solution was then filtered through a 0.22 μm RC syringe filter until the volume was adjusted to the label with distilled water. The solution was analyzed using an HPLC (Agilent 1260) UV-Vis spectrophotometer. Columns were packed with L1, 4.6 mm × 250 mm inner diameter, and 3.5 μm thickness.

[0081] The test results are shown in Table 2 below.

[0082] [Table 2]

[0083] Example 4: In vitro release test and evaluation of initial release rate

[0084] Approximately 1 mg of each microsphere prepared in Example 1 and Comparative Example 1 was placed in a vial, and 8 mL of PBS solution at pH 6.0 was added. The vial was stirred at 100 rpm and maintained at 37°C. To measure the release over a specific time period, 8 mL of the supernatant was filtered through a 0.22 μm RC filter and used as the test solution, and 8 mL of fresh release solution was placed in a vial. The test solution was analyzed using an HPLC (Agilent 1260) UV-Vis spectrophotometer. A column was packed with an L1 column, an inner diameter of 4.6 mm × 250 mm, and a thickness of 5 μm.

[0085] The test results are shown in Table 3 below and Figure 3 and Figure 4 middle.

[0086] [Table 3]

[0087] from Figure 3 It can be seen that the microspheres prepared in Example 1 steadily released 28% of cariprazine within 14 days, without any initial burst release. Conversely, from... Figure 4 It can be seen that the microspheres prepared in Comparative Example 1 rapidly released 56% of cariprazine within the first 6 hours of the experiment.

[0088] Therefore, these results confirm that the cariprazine microspheres of Example 1 of the present invention can utilize a small amount of solvent by using methanol and dichloromethane as a co-solvent, thereby preventing drug precipitation and significantly reducing initial burst release. Furthermore, it can be seen that they exhibit excellent sustained-release performance by continuously releasing the drug for 14 days.

Claims

1. A method for preparing microspheres, comprising the following steps: (a) A dispersed phase is prepared by dissolving or dispersing cariprazine or a pharmaceutically acceptable salt thereof and one or more biocompatible polymers in a mixed solvent of methanol and dichloromethane; (b) The prepared dispersed phase is added to the continuous phase and stirred to form microspheres; and (c) Remove the solvent.

2. The method for preparing microspheres according to claim 1, wherein, In step (a), the mixing weight ratio of methanol and dichloromethane in the mixed solvent is 1:1 to 8.

5.

3. The method for preparing microspheres according to claim 1, wherein, In step (a), the weight ratio of the combination of cariprazine or its pharmaceutically acceptable salt and biocompatible polymer to the weight of the mixed solvent is 1:1 to 10.

4. The method for preparing microspheres according to claim 1, wherein, In step (a), the biocompatible polymer is included in an amount of 10% to 50% by weight, based on the total weight of the dispersed phase.

5. The method for preparing microspheres according to claim 1, wherein, The biocompatible polymer is selected from at least one of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolic acid copolymer (PLGA), polyphosphazene, polyimide carbonate, polyphosphate, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and copolymer of lactic acid and amino acids.

6. The method for preparing microspheres according to claim 2, wherein, The biocompatible polymer is polylactic acid.

7. The method for preparing microspheres according to claim 1, wherein, Based on the free base of cariprazine, the weight of cariprazine or its pharmaceutically acceptable salt encapsulated in the microspheres obtained according to the preparation method is more than 70% by weight of the weight of cariprazine or its pharmaceutically acceptable salt dissolved in step (a).

8. A microsphere prepared by the method of claim 1, comprising cariprazine or a pharmaceutically acceptable salt thereof and a biocompatible polymer.

9. The microspheres according to claim 8, wherein, Based on the total weight of the microspheres, the biocompatible polymer is contained in an amount of 70% to 99% by weight.

10. The microspheres according to claim 8, wherein, The biocompatible polymer is selected from at least one of polylactic acid, polylactide, polylactic acid-glycolic acid copolymer, polylactide-glycolic acid copolymer (PLGA), polyphosphazene, polyimide carbonate, polyphosphate, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and copolymer of lactic acid and amino acids.

11. The microspheres according to claim 8, wherein, The biocompatible polymer is polylactic acid.

12. The microspheres according to claim 8, wherein, The microspheres are those that release carilarazine for more than 10 days.

13. The microspheres according to claim 8, wherein, The release of carilarazine contained in the microspheres is less than 10% by weight within 1 day.

14. A pharmaceutical composition comprising the microspheres of claim 8 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, wherein, The pharmaceutical composition is used for the prevention or treatment of schizophrenia, mania, and bipolar disorder.

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