Cariprazine pharmaceutical composition, preparation method and application

Abstract

The present invention provides a pharmaceutical composition containing cariprazine, a preparation method and an application. The present invention discloses a cariprazine pharmaceutical composition, which comprises: solid particles of cariprazine dodecyl sulfate, wherein the particle size of the cariprazine solid particles is such that Dv(10) is less than or equal to 30 microns, Dv(50) is less than or equal to 50 microns and Dv(90) is less than or equal to 100 microns. The composition containing cariprazine drug of the present invention is a suspension aqueous solution during use, wherein the concentration of cariprazine free base is moderate, and a long-acting effect can be achieved by injection within a certain administration volume, reducing the number of drug administrations, improving the medication compliance of patients, having high bioavailability, and having good market prospects.

Description

[0001] This application is a divisional application of the invention patent application with the application date of August 26, 2021, application number 202110991010.6, and invention title "Cariprazine Pharmaceutical Composition, Preparation Method and Application".

[0002] This application claims the priority rights of the following prior applications: the Chinese invention patent application with the application number 202010870701.6 filed with the State Intellectual Property Office of China on August 26, 2020; the Chinese invention patent application with the application number 202010869671.7 filed with the State Intellectual Property Office of China on August 26, 2020; the Chinese invention patent application with the application number 202110324874.2 filed with the State Intellectual Property Office of China on March 26, 2021; and the Chinese invention patent application with the application number 202110330670.X filed with the State Intellectual Property Office of China on March 26, 2021. The full texts of the above prior applications are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of chemical medicine, in particular to a pharmaceutical composition containing cariprazine, a preparation method and an application. Background Art

[0004] Cariprazine hydrochloride (the chemical structure is shown in Formula I) is a novel atypical antipsychotic drug, which has antagonistic effects on dopamine D3, dopamine D2 and serotonin 2B receptors. It can be used for the treatment of schizophrenia and type 1 bipolar disorder. Currently, the marketed product is cariprazine hydrochloride capsules, which are oral preparations and need to be administered daily to maintain its blood drug concentration. However, due to the need for frequent administration, the medication compliance of patients is poor.

[0005]

[0006] Patent document CN108261394A discloses a cariprazine hydrochloride injection preparation, including the forms of suspension aqueous solution and freeze-dried agent, and can obtain sustained release for at least 1 week or longer. However, the inventors found during the research process that: the stability of the cariprazine hydrochloride aqueous solution is not ideal enough, and it will dissociate under weak acidic to alkaline conditions. Therefore, there is a risk of dissociation in the suspension aqueous solution, which is likely to cause changes in the properties and quality of the product, resulting in changes in drug dissolution and absorption, affecting the efficacy of the drug and the medication safety of patients. Moreover, the cariprazine concentration in the cariprazine hydrochloride injection preparation disclosed in patent document CN108261394A and the blood drug concentration in the animal pK experiment are too high. Considering the large inter-species differences in the elimination of cariprazine in the original research data (about 2 - 4 hours in rats and 3 - 9 days in humans), the too high blood drug concentration may lead to greater toxic and side effects and excessive accumulation of drugs in the human body.

[0007] There is no reported injectable preparation of the poorly soluble salts of cariprazine with improved performance currently. SUMMARY OF THE INVENTION

[0008] To address the problems existing in the prior art, the present invention provides a cariprazine pharmaceutical composition, which comprises solid particles of cariprazine, and the particle size Dv(10) of the solid particles of cariprazine is ≤ 30 μm, Dv(50) is ≤ 50 μm, and Dv(90) is ≤ 100 μm, preferably ≤ 10 μm.

[0009] According to an embodiment of the present invention, the solid particles of cariprazine may be selected from the solid particles of cariprazine, pharmaceutically acceptable salts of cariprazine and their solvates.

[0010] According to an embodiment of the present invention, the solvate may be selected from hydrates.

[0011] According to an embodiment of the present invention, the pharmaceutically acceptable salts of cariprazine include but are not limited to cariprazine pamoate.

[0012] According to an embodiment of the present invention, the said pamoic acid is also known as Pamoic acid, CAS No. 130 - 85 - 8.

[0013] According to an embodiment of the present invention, the solid particles of cariprazine may be in crystalline or amorphous form.

[0014] According to an embodiment of the present invention, the cariprazine pamoate is crystalline form A of cariprazine pamoate.

[0015] According to an embodiment of the present invention, the X - ray powder diffraction pattern of the crystalline form A of cariprazine pamoate has characteristic peaks at 2θ values of 13.1° ± 0.2°, 18.7° ± 0.2°, 21.0° ± 0.2°, etc.

[0016] Furthermore, the X - ray powder diffraction pattern of the crystalline form A of cariprazine pamoate has characteristic peaks at 2θ values of 4.8° ± 0.2°, 13.1° ± 0.2°, 18.7° ± 0.2°, 20.1° ± 0.2°, 21.0° ± 0.2°, 26.1° ± 0.2°, etc.

[0017] Furthermore, the X - ray powder diffraction pattern of the crystalline form A of cariprazine pamoate has characteristic peaks at 2θ values of 4.8° ± 0.2°, 9.7 ± 0.2°, 12.3° ± 0.2°, 13.1° ± 0.2°, 18.7° ± 0.2°, 20.1° ± 0.2°, 21.0° ± 0.2°, 26.1° ± 0.2°, etc.

[0018] Furthermore, the X-ray powder diffraction pattern of the caliperazine ditosylate polymorph A has absorption peaks at 2θ values of 4.8°±0.2°, 8.2°±0.2°, 9.7±0.2°, 11.6°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 16.6°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 26.1°±0.2°, etc.

[0019] Furthermore, the X-ray powder diffraction pattern of the caliperazine ditosylate polymorph A is substantially as Figure 2 shown.

[0020] The differential scanning calorimetry pattern of the caliperazine ditosylate polymorph A is substantially as Figure 3 shown, showing a melting point of about 166.5 °C.

[0021] The thermogravimetric analysis pattern of the caliperazine ditosylate polymorph A is substantially as Figure 4 shown, showing two weight losses before 115 °C, attributed to the loss of surface solvent and channel water, and a weight loss of about 1.1% at 115-165 °C, attributed to the loss of crystal water.

[0022] The NMR spectrum of the caliperazine ditosylate polymorph A is substantially as Figure 5 shown, showing that caliperazine and ditosylate form a salt in a molar ratio of 1:1.

[0023] According to an embodiment of the present invention, the method for preparing the caliperazine ditosylate polymorph A is as follows:

[0024] (1) Adding caliperazine ditosylate to a solvent, stirring for crystallization, to obtain the caliperazine ditosylate polymorph A;

[0025] The solvent is methanol;

[0026] (2) Dissolving caliperazine ditosylate in a good solvent, gradually adding an anti-solvent, stirring for crystallization, to obtain the caliperazine ditosylate polymorph A.

[0027] The good solvent is dibutyl ketone;

[0028] The anti-solvent is n-heptane.

[0029] According to an embodiment of the present invention, the caliperazine ditosylate is the caliperazine ditosylate polymorph F.

[0030] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine bisnaphthoate polymorph F has characteristic peaks at 2θ values of 4.9° ± 0.2°, 19.2° ± 0.2°, 21.0° ± 0.2°, etc.

[0031] Further, the X-ray powder diffraction pattern of cariprazine bisnaphthoate polymorph F has characteristic peaks at 2θ values of 4.9° ± 0.2°, 13.6° ± 0.2°, 19.2° ± 0.2°, 21.0° ± 0.2°, 24.0° ± 0.2°, 26.3° ± 0.2°, etc.

[0032] Further, the X-ray powder diffraction pattern of cariprazine bisnaphthoate polymorph F has characteristic peaks at 2θ values of 4.9° ± 0.2°, 12.8° ± 0.2°, 13.6° ± 0.2°, 19.2° ± 0.2°, 20.3° ± 0.2°, 21.0° ± 0.2°, 24.0° ± 0.2°, 26.3° ± 0.2°, etc.

[0033] Still further, according to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine bisnaphthoate polymorph F has characteristic peaks at 2θ values of 4.9° ± 0.2°, 8.4° ± 0.2°, 9.7 ± 0.2°, 10.4° ± 0.2°, 11.6° ± 0.2°, 12.8° ± 0.2°, 13.3° ± 0.2°, 13.6° ± 0.2°, 15.0° ± 0.2°, 15.4° ± 0.2°, 16.8° ± 0.2°, 17.0° ± 0.2°, 18.5° ± 0.2°, 18.8° ± 0.2°, 19.2° ± 0.2°, 19.5° ± 0.2°, 20.3° ± 0.2°, 21.0° ± 0.2°, 21.9° ± 0.2°, 22.2° ± 0.2°, 22.5° ± 0.2°, 24.0° ± 0.2°, 25.1° ± 0.2°, 25.7° ± 0.2°, 26.3° ± 0.2°, 26.8° ± 0.2°, 28.8° ± 0.2°, 29.6° ± 0.2°, etc.

[0034] Still further, the X-ray powder diffraction pattern of cariprazine bisnaphthoate polymorph F is substantially as Figure 6 shown.

[0035] The differential scanning calorimetry diagram of cariprazine bisnaphthoate polymorph F is substantially as Figure 7 shown, showing a melting point of about 166.6°C.

[0036] The thermogravimetric analysis diagram of cariprazine bisnaphthoic acid polymorph F is substantially as Figure 8As shown, there is about 1.3% weight loss before 115°C, attributed to the loss of channel water; and about 1.3% weight loss between 115°C and 175°C, attributed to the loss of crystal water.

[0037] The NMR spectrum of the described cariprazine pamoate polymorph F is substantially as Figure 9 shown, indicating that cariprazine and pamoic acid form a salt in a molar ratio of 1:1.

[0038] According to an embodiment of the present invention, the method for preparing the cariprazine pamoate polymorph F is as follows:

[0039] Form a slurry of cariprazine pamoate polymorph A in a solvent, stir and crystallize to obtain the cariprazine pamoate polymorph F;

[0040] The solvent is ethyl acetate, isopropyl acetate, methyl tert-butyl ether or n-heptane.

[0041] According to an embodiment of the present invention, the cariprazine pamoate is cariprazine pamoate polymorph D.

[0042] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the cariprazine pamoate polymorph D has characteristic peaks at 2θ values of 9.6° ± 0.2°, 11.9° ± 0.2°, 20.4° ± 0.2°, etc.

[0043] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate polymorph D has characteristic peaks at 2θ values of 9.6° ± 0.2°, 11.9° ± 0.2°, 16.6° ± 0.2°, 20.4° ± 0.2°, 24.5° ± 0.2°, 25.3° ± 0.2°, etc.

[0044] Furthermore, the X-ray powder diffraction pattern of the cariprazine pamoate polymorph D has characteristic peaks at 2θ values of 9.6° ± 0.2°, 11.9° ± 0.2°, 15.2° ± 0.2°, 16.6° ± 0.2°, 20.4° ± 0.2°, 20.7° ± 0.2°, 24.5° ± 0.2°, 25.3° ± 0.2°, etc.

[0045] Further, according to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine ditosylate polymorph D has characteristic peaks at 2θ values of 9.6°±0.2°, 10.1°±0.2°, 10.5±0.2°, 11.9°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.

[0046] Further, the X-ray powder diffraction pattern of cariprazine ditosylate polymorph D is substantially as Figure 10 shown.

[0047] The differential scanning calorimetry pattern of cariprazine ditosylate polymorph D is substantially as Figure 11 shown, showing a melting point of about 164.6 °C.

[0048] The thermogravimetric analysis pattern of cariprazine ditosylate polymorph D is substantially as Figure 12 shown, showing a weight loss of about 4% before 190 °C, attributed to the loss of water and ethanol.

[0049] The NMR spectrum of cariprazine ditosylate polymorph D is substantially as Figure 13 shown, showing that cariprazine forms a salt with ditosylic acid in a molar ratio of 1:1.

[0050] According to an embodiment of the present invention, the preparation method of cariprazine ditosylate polymorph D is as follows:

[0051] Cariprazine ditosylate is stirred and crystallized in ethanol to obtain cariprazine ditosylate polymorph D.

[0052] According to an embodiment of the present invention, the cariprazine ditosylate is cariprazine ditosylate polymorph B.

[0053] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine ditosylate polymorph B has characteristic peaks at 2θ values of 5.2°±0.2°, 10.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 17.5°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.9°±0.2°, 26.2°±0.2°, etc.

[0054] Further, the X-ray powder diffraction pattern of cariprazine ditosylate polymorph B is substantially as Figure 14 shown.

[0055] According to an embodiment of the present invention, the cariprazine dodecyl sulfate is cariprazine dodecyl sulfate crystal form C.

[0056] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form C has characteristic peaks at 2θ values of 8.6°±0.2°, 13.0°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.8°±0.2°, 22.1°±0.2°, 23.5°±0.2°, etc.

[0057] Further, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form C is substantially as Figure 15 shown.

[0058] According to an embodiment of the present invention, the cariprazine dodecyl sulfate is cariprazine dodecyl sulfate crystal form E.

[0059] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form E has characteristic peaks at 2θ values of 11.0°±0.2°, 12.8°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 18.4°±0.2°, 20.7°±0.2°, 23.4°±0.2°, etc.

[0060] Further, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form E is substantially as Figure 16 shown.

[0061] According to an embodiment of the present invention, the cariprazine dodecyl sulfate is cariprazine dodecyl sulfate crystal form G.

[0062] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form G has characteristic peaks at 2θ values of 8.7°±0.2°, 10.0°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 20.3°±0.2°, 23.2°±0.2°, 25.1°±0.2°, etc.

[0063] Further, the X-ray powder diffraction pattern of cariprazine dodecyl sulfate crystal form G is substantially as Figure 17 shown.

[0064] According to an embodiment of the present invention, the cariprazine dodecyl sulfate is cariprazine dodecyl sulfate crystal form I.

[0065] According to an embodiment of the present invention, the X-ray powder diffraction pattern of cariprazine ditartrate polymorph I has characteristic peaks at 2θ values of 10.0° ± 0.2°, 14.9° ± 0.2°, 16.3° ± 0.2°, 17.7° ± 0.2°, 18.5° ± 0.2°, 19.0° ± 0.2°, 21.1° ± 0.2°, 22.1° ± 0.2°, 24.5° ± 0.2°, etc.

[0066] Further, the X-ray powder diffraction pattern of cariprazine ditartrate polymorph I is substantially as Figure 18 shown.

[0067] According to an embodiment of the present invention, the cariprazine pharmaceutical composition may further include excipients, and the excipients may be selected from one or more of a suspending agent, a wetting agent, an osmotic pressure regulator, a solvent, a stabilizer, a buffer, and a surfactant.

[0068] According to an embodiment of the present invention, the concentration range of the suspending agent is 0 to 10 mg / mL, preferably 3.5 mg / mL to 5 mg / mL, such as 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, or 5.0 mg / mL.

[0069] According to an embodiment of the present invention, the suspending agent is selected from one or more of sodium carboxymethyl cellulose, methylcellulose, and polyvinylpyrrolidone, and preferably sodium carboxymethyl cellulose.

[0070] According to an embodiment of the present invention, the concentration range of the wetting agent is 1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 5 mg / mL, such as 1 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, or 5.0 mg / mL.

[0071] According to an embodiment of the present invention, the wetting agent is selected from one or more of Tween 20, Tween 80, and poloxamer 188, and preferably Tween 20.

[0072] According to an embodiment of the present invention, the concentration range of the osmotic pressure regulator is 20 to 30 mg / mL, preferably 23 mg / mL to 26 mg / mL, such as 23 mg / mL, 24.7 mg / mL, or 26 mg / mL.

[0073] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, and sucrose.

[0074] According to an embodiment of the present invention, the concentration range of the stabilizer is 0 to 30 mg / mL, preferably 1 mg / mL to 10 mg / mL, such as 1 mg / mL, 3 mg / mL, 5 mg / mL or 7.0 mg / mL.

[0075] According to an embodiment of the present invention, the stabilizer is PVP K12.

[0076] According to an embodiment of the present invention, the buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.

[0077] According to an embodiment of the present invention, the surfactant is sodium deoxycholate.

[0078] According to an embodiment of the present invention, the solvent is water, such as water for injection.

[0079] As an example, the cariprazine composition may include:

[0080] (a) cariprazine bitartrate;

[0081] (b) sodium carboxymethylcellulose;

[0082] (c) Tween 20;

[0083] (d) disodium hydrogen phosphate;

[0084] (e) sodium dihydrogen phosphate; and

[0085] (f) mannitol;

[0086] And, optionally, the cariprazine composition may contain sodium hydroxide or hydrochloric acid.

[0087] According to an embodiment of the present invention, the cariprazine composition is a cariprazine injection, such as a long-acting cariprazine injection.

[0088] According to an embodiment of the present invention, in the cariprazine composition or the long-acting cariprazine injection, the concentration of the cariprazine solid particles is not less than 15 mg / mL.

[0089] According to an embodiment of the present invention, the method for preparing the cariprazine composition comprises the following steps:

[0090] (1) Dissolve the wetting agent, buffer and osmotic pressure regulator in the solvent;

[0091] (2) Add cariprazine solid particles to obtain a suspension aqueous solution of coarse particles;

[0092] (3) Grind the above suspension aqueous solution of coarse particles using a ball mill to obtain a suspension;

[0093] (4) Add the suspending agent to the above suspension, mix well, and optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, then make up the volume to obtain the aqueous suspension solution.

[0094] According to an embodiment of the preparation method of the present invention, in step (1), the wetting agent, buffer, and osmotic pressure regulator can be dissolved in the solvent in sequence, for example, dissolved in water for injection.

[0095] According to an embodiment of the preparation method of the present invention, in step (4), the adjusted pH can be 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0.

[0096] The present invention provides the use of the cariprazine pharmaceutical composition in the preparation of a medicament for treating and / or preventing psychosis, bipolar disorder, and acute mania.

[0097] The present invention also provides a method for treating and / or preventing psychosis, bipolar disorder, or acute mania, which includes administering the cariprazine pharmaceutical composition to a patient in need.

[0098] According to an embodiment of the present invention, the "Dv(10)", "Dv(50)", and "Dv(90)" refer to volume-weighted particle diameters, where at the time of measurement, 10 v / v%, 50 v / v%, or 90 v / v% of the particles have equal or smaller diameters respectively. For example, if the Dv(50) of a particle population is about 25 microns, then 50% of the volume of the particles has a diameter less than or equal to about 25 microns.

[0099] On the basis of not violating the spirit of the present invention, those skilled in the art can combine the above preferred conditions to obtain various preferred examples of the present invention.

[0100] The reagents and raw materials used in the present invention are all commercially available.

[0101] According to an embodiment of the present invention, the room temperature refers to an ambient temperature of 10°C - 35°C.

[0102] Beneficial effects

[0103] Through continuous research, screening, and experimentation, the inventor of the present invention finally found that cariprazine ditanate in the poorly soluble salts of cariprazine conforms to the advantages of a long-acting sustained-release preparation and can be developed into a suspension injection. At the same time, it can overcome the risk of dissociation of cariprazine hydrochloride and achieve the effect of long-acting drug administration, as well as the relatively low blood drug concentration in rats, greatly improving the compliance of patients, the bioavailability of the drug, and the safety of drug use.

[0104] The cariprazine pharmaceutical composition of the present invention has the characteristics of sustained release, high bioavailability, good solution stability, and small administration volume. Administering once can sustain the release of cariprazine for at least one week or longer, and it has good market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 XRPD pattern of amorphous cariprazine dodecyl sulfate;

[0106] Figure 2 XRPD pattern of crystalline form A of cariprazine dodecyl sulfate;

[0107] Figure 3 DSC pattern of crystalline form A of cariprazine dodecyl sulfate;

[0108] Figure 4 TGA pattern of crystalline form A of cariprazine dodecyl sulfate;

[0109] Figure 5 For crystalline form A of cariprazine dodecyl sulfate 1 1H-NMR pattern;

[0110] Figure 6 XRPD pattern of crystalline form F of cariprazine dodecyl sulfate;

[0111] Figure 7 DSC pattern of crystalline form F of cariprazine dodecyl sulfate;

[0112] Figure 8 TGA pattern of crystalline form F of cariprazine dodecyl sulfate;

[0113] Figure 9 For crystalline form F of cariprazine dodecyl sulfate 1 1H-NMR pattern;

[0114] Figure 10 XRPD pattern of crystalline form D of cariprazine dodecyl sulfate;

[0115] Figure 11 DSC pattern of crystalline form D of cariprazine dodecyl sulfate;

[0116] Figure 12 TGA pattern of crystalline form D of cariprazine dodecyl sulfate;

[0117] Figure 13 For crystalline form D of cariprazine dodecyl sulfate 1 1H-NMR pattern;

[0118] Figure 14 XRPD pattern of crystalline form B of cariprazine dodecyl sulfate;

[0119] Figure 15 XRPD pattern of caliperazine ditartrate polymorph C;

[0120] Figure 16 XRPD pattern of caliperazine ditartrate polymorph E;

[0121] Figure 17 XRPD pattern of caliperazine ditartrate polymorph G;

[0122] Figure 18 XRPD pattern of caliperazine ditartrate polymorph I;

[0123] Figure 19 XRPD pattern of caliperazine hydrochloride polymorph I;

[0124] Figure 20 Results of in vitro dissolution simulation experiment (■ amorphous caliperazine ditartrate; ◆ caliperazine ditartrate polymorph A; ● caliperazine ditartrate polymorph B; ▲ caliperazine ditartrate polymorph G);

[0125] Figure 21 Overlay XRPD patterns of caliperazine ditartrate and caliperazine hydrochloride under pH 7.4 conditions in Comparative Example 4 (A is caliperazine free base; B is caliperazine hydrochloride polymorph I; C is caliperazine hydrochloride polymorph I after oscillation in pH 7.4 medium; D is caliperazine ditartrate polymorph A; E is caliperazine ditartrate polymorph A after oscillation in pH 7.4 medium).

[0126] Figure 22 : Graph depicting the relationship between the average plasma concentration of caliperazine and time for the oral sample of the formulation of Example 44 of the present invention in rats;

[0127] Figure 23 : Graph depicting the relationship between the average plasma concentration of caliperazine and time for the injection samples of the formulations of Examples 40 - 43 of the present invention in rats (■ amorphous caliperazine ditartrate; ◆ caliperazine ditartrate polymorph A; ● caliperazine ditartrate polymorph B; ▲ caliperazine ditartrate polymorph E);

[0128] Figure 24 : Figure 23 Partial enlarged view (graph of the relationship between the average plasma concentration of caliperazine and time from 0 to 24 hours) (■ amorphous caliperazine ditartrate; ◆ caliperazine ditartrate polymorph A; ● caliperazine ditartrate polymorph B; ▲ caliperazine ditartrate polymorph E). Detailed implementation mode

[0129] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0130] Unless otherwise specified, the raw materials and reagents in the following examples can be obtained commercially, or prepared by those skilled in the art according to methods known in the art.

[0131] Nuclear magnetic resonance ( 1 1H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage polarized light microscope (PLM), and high performance liquid chromatography (HPLC) were used to test the salt form compounds of the examples, and the test parameters are as follows:

[0132] (1) 1 The 1H-NMR test was carried out on a Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400 MHz, and the solvent used was deuterated DMSO.

[0133] (2) The DSC measurement was carried out in a sealed pan device of a TA Instruments Q2000. The sample (about 1 - 2 mg) was weighed in an aluminum pan and transferred to the instrument for measurement. The test parameters are as follows: The instrument was equilibrated at 30 °C and heated at a rate of 10 °C / min to 300 °C, and data was collected. The experimental atmosphere was nitrogen.

[0134] (3) The TGA measurement was carried out on a TA Instruments Q500 device. The sample (about 2 - 5 mg) was weighed in an aluminum pan and transferred to the instrument for measurement. The test parameters are as follows: The instrument was heated at a rate of 10 °C / min to 350 °C, and data was collected. The experimental atmosphere was nitrogen.

[0135] (4) The XRPD measurement was carried out on a Bruker D8 Advance X-ray powder diffractometer and a circular zero-background single-crystalline silicon sample stage was used. The scanning parameters are as follows: voltage 40 kv, current 40 mA, scanning range 3° - 45°, scanning step 0.02°, and the scanning mode was continuous scanning.

[0136] (5) The PLM measurement was carried out on a hot stage polarized light microscope of Shanghai Dianying Optical Instrument Model DYP990 / TPH350. A small amount of the sample was dispersed on a glass slide and photographed with a 10-fold eyepiece and a 5 - 40-fold objective lens.

[0137] (6) HPLC content and related substances detection method:

[0138] Content method:

[0139]

[0140] Content gradient elution program table:

[0141] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 60 40 2 40 60 5 15 85 5.1 60 40 10 60 40

[0142] Related substances method:

[0143]

[0144] Related gradient elution program table:

[0145]

[0146]

[0147] Unless otherwise specified, the detection conditions of the particle size detection instrument for the suspension aqueous solution of the cariprazine pharmaceutical composition in the context of the present invention are as follows:

[0148]

[0149] Example 1: Preparation of cariprazine docusate

[0150] Dissolve 4000 mg (9.36 mmol) of cariprazine in 200 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A; dissolve 3634 mg (9.36 mmol) of docusate in 100 mL (7.5 mg / mL) of sodium hydroxide solution to obtain solution B. Add 100 mL of solution B to 200 mL of solution A within 30 minutes under stirring, filter and separate the product, wash it with water, and dry it under vacuum at 40 °C for 12 hours to obtain 5840 mg of a light yellow solid, with a yield of 76% (calculated based on the free base).

[0151] The structure and molar ratio of the cariprazine docusate described in the present invention were confirmed by 1H-NMR.

[0152] 1 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 2H), 8.16 (d, 2H), 8.80 (d, 2H), 7.39 - 7.13 (m, 7H), 5.86 (d, 1H), 4.76 (s, 2H), 3.40 - 3.32 (m, 3H), 3.22 - 3.18 (m, 4H), 2.75 (s, 6H), 1.76 (t, 4H), 1.63 - 1.57 (m, 2H), 1.25 - 1.16 (m, 3H), 1.04 - 0.96 (m, 2H).

[0153] The nuclear magnetic resonance results showed that cariprazine and dithranol formed a salt in a molar ratio of 1:1.

[0154] The above sample was subjected to solid-phase characterization detection, and the XRPD pattern is shown in Figure 1 , and the detection results showed that it was amorphous.

[0155] Example 2: Preparation of amorphous cariprazine dithranolate

[0156] At 60 °C, 20 g (46.8 mmol) of cariprazine and 18.17 g (46.8 mmol) of dithranol were dissolved in 170 mL of a mixed solvent of THF:MeOH (2:1), filtered, and the solvent was removed by concentration under reduced pressure. Then, 300 mL of methanol was added, dissolved at 60 °C, the solvent was removed by concentration under reduced pressure, and vacuum dried at 40 °C for 12 hours to obtain 36.6 g of amorphous cariprazine dithranolate.

[0157] Example 3: Preparation of cariprazine semi-dithranolate

[0158] 200 mg (0.468 mmol) of cariprazine was dissolved in 10 mL (5.4 mg / mL) of phosphoric acid solution to obtain solution A; 90.85 mg (0.234 mmol) of dithranol was dissolved in 2.5 mL (7.5 mg / mL) of sodium hydroxide solution to obtain solution B. 2.5 mL of solution B was added to 10 mL of solution A within 30 minutes under stirring, the product was separated by filtration and washed with water, and vacuum dried at 40 °C for 12 hours to obtain 204 mg of a light yellow solid with a yield of 70%.

[0159] The structure and molar ratio of cariprazine dithranolate described in the present invention were confirmed by nuclear magnetic resonance hydrogen spectrum.

[0160] 1 H-NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 8.18 (d, 1H), 7.69 (d, 1H), 7.38 - 7.31 (m, 2H), 7.22 - 7.14 (m, 2H), 7.05 (t, 1H), 5.86 (d, 1H), 4.71 (s, 1H), 3.39 - 3.22 (m, 5H), 2.75 (s, 6H), 1.75 (t, 4H), 1.59 - 1.54 (m, 2H), 1.25 - 1.15 (m, 3H), 1.04 - 0.95 (m, 2H).

[0161] The nuclear magnetic resonance results showed that cariprazine and dithranol formed a salt in a molar ratio of 2:1.

[0162] The above sample was subjected to PLM detection, and it was shown that the sample was a non-polarized solid and was amorphous.

[0163] Example 4: Preparation of cariprazine 1-hydroxy-2-naphthoate

[0164] 100 mg (0.234 mmol) of cariprazine and 45 mg (0.234 mmol) of 1-hydroxy-2-naphthoic acid were added to 8 mL of methanol, stirred until dissolved and clarified, filtered, 3 volumes of n-heptane were added, and the mixture was evaporated to dryness at room temperature to obtain an oily substance, which was dried in vacuo at 40 °C for 4 hours to obtain a solid.

[0165] PLM detection found that the solid had polarization and began to melt at about 200 °C.

[0166] 1 1H-NMR (400 MHz, DMSO-d6): δ 8.23 (d, 1H), 7.80 - 7.74 (m, 2H), 7.57 - 7.53 (m, 1H), 7.48 - 7.44 (m, 1H), 7.38 - 7.31 (m, 2H), 7.20 - 7.16 (m, 2H), 5.86 (d, 1H), 3.36 - 3.09 (m, 10H), 2.75 (s, 6H), 1.74 (t, 4H), 1.61 - 1.56 (m, 2H), 1.33 - 1.15 (m, 5H), 1.02 - 0.83 (m, 3H).

[0167] The NMR results showed that cariprazine and 1-hydroxy-2-naphthoic acid formed a salt in a molar ratio of 1:1.

[0168] Example 5: Preparation of cariprazine laurate

[0169] 50 mg (0.117 mmol) of cariprazine and 23.7 mg (0.118 mmol) of lauric acid were added to 5 mL of methanol, dissolved at 50 °C, stirred at room temperature for 12 hours, 2 volumes of water were added, filtered, and the solid was dried in vacuo at 40 °C for 12 hours to obtain cariprazine laurate.

[0170] Example 6: Preparation of cariprazine palmitate

[0171] 50 mg (0.117 mmol) of cariprazine and 30.3 mg (0.118 mmol) of palmitic acid were added to 5 mL of methanol, dissolved at 50 °C, stirred at room temperature for 12 hours, 1 volume of water was added, filtered, and the solid was dried in vacuo at 40 °C for 12 hours to obtain cariprazine palmitate.

[0172] Example 7: Preparation of cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, cariprazine heptanoate

[0173] Weigh cariprazine and acid according to a molar ratio of 1:1.1. Dissolve each acid in methanol solvent respectively, and add the obtained acidic reagent to the cariprazine methanol solution at room temperature for salt formation reaction. Stir at room temperature for 12 hours, then let it volatilize and dry at room temperature to obtain the corresponding cariprazine salt.

[0174] Example 8: Preparation of cariprazine pamoate crystal form A

[0175] Take 2000 mg of cariprazine pamoate prepared in Example 1, add it to 20 mL of methanol, stir at room temperature for crystal precipitation for 24 hours, filter, and dry in vacuum at 55 °C to obtain 1900 mg of cariprazine pamoate crystal form A, with a yield of 95%.

[0176] Its X-ray powder diffraction pattern is as Figure 2 shown.

[0177] Its differential scanning calorimetry pattern is as Figure 3 shown, showing a melting point of 166.5 °C.

[0178] Its thermogravimetric analysis pattern is as Figure 4 shown, showing two weight losses before 115 °C, attributed to the loss of surface solvent and channel water, and at 115 - 165 °C, there is a weight loss of about 1.1%, attributed to the loss of crystal water.

[0179] Its NMR spectrum is as Figure 5 shown, showing that cariprazine and pamoic acid form a salt in a molar ratio of 1:1.

[0180] Example 9: Preparation of cariprazine pamoate crystal form A

[0181] Take 30 g of the amorphous solid sample of cariprazine pamoate prepared in Example 2, add it to 300 mL of methanol, stir at 10 °C for crystal precipitation for 24 hours, filter, and dry in vacuum at 55 °C to obtain 28.5 g of cariprazine pamoate crystal form A.

[0182] Example 10: Preparation of cariprazine pamoate crystal form B

[0183] Take 200 mg of cariprazine pamoate crystal form A obtained in Example 9 to form a slurry in methanol solvent. The weight-to-volume ratio of cariprazine pamoate crystal form A to the solvent is 40 mg / mL. Stir for 3 days for crystal precipitation to obtain 180 mg of cariprazine pamoate crystal form B.

[0184] Its X-ray powder diffraction pattern is as Figure 14 shown.

[0185] The NMR results show that it is a methanol solvate.

[0186] Example 11: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form B

[0187] Take 2 g of Cariprazine Dihydroxynaphthoate Crystal Form A prepared in Example 9, add it to 50 mL of methanol, stir and crystallize at room temperature for 72 hours, filter, and dry in vacuo at 55 °C to obtain 1.9 mg of Cariprazine Dihydroxynaphthoate Crystal Form B.

[0188] Example 12: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form C

[0189] Take the Cariprazine Dihydroxynaphthoate Crystal Form A obtained in Example 8 to form a slurry in acetone solvent. The weight - volume ratio of Cariprazine Dihydroxynaphthoate Crystal Form A to the solvent is 40 mg / mL. Stir for 3 days to crystallize to obtain Cariprazine Dihydroxynaphthoate Crystal Form C.

[0190] Its X - ray powder diffraction pattern is as Figure 15 shown.

[0191] The NMR results show that it is an acetone solvate.

[0192] Example 13: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form D

[0193] Take 200 mg of Cariprazine Dihydroxynaphthoate Crystal Form A prepared in Example 8, add it to 2 mL of ethanol, stir and crystallize at room temperature for 48 hours, filter, and dry in vacuo at 55 °C to obtain 190 mg of Cariprazine Dihydroxynaphthoate Crystal Form D, with a yield of 95%.

[0194] Its X - ray powder diffraction pattern is as Figure 10 shown.

[0195] Its differential scanning calorimetry pattern is as Figure 11 shown, showing a melting point of 164.6 °C.

[0196] Its thermogravimetric analysis pattern is as Figure 12 shown, showing a weight loss of about 4% before 190 °C, attributed to the loss of water and ethanol.

[0197] Its NMR spectrum is as Figure 13 shown, showing that Cariprazine and Dihydroxynaphthoic acid form a salt in a molar ratio of 1:1 and contain about 0.67 ethanol molecules.

[0198] Example 14: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form E

[0199] Take the Cariprazine Dihydroxynaphthoate Crystal Form A obtained in Example 8 to form a slurry in acetonitrile solvent. The weight - volume ratio of Cariprazine Dihydroxynaphthoate Crystal Form A to the solvent is 40 mg / mL. Stir for 3 days to crystallize to obtain Cariprazine Dihydroxynaphthoate Crystal Form E.

[0200] Its X - ray powder diffraction pattern is asFigure 16 as shown

[0201] Example 15: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form E

[0202] Take 2 g of Cariprazine Dihydroxynaphthoate Crystal Form A prepared in Example 9, add it to 50 mL of acetonitrile, stir and crystallize at room temperature for 72 hours, filter, and dry in vacuo at 55 °C to obtain 1.8 g of Cariprazine Dihydroxynaphthoate Crystal Form E.

[0203] Example 16: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form F

[0204] Take 200 mg of Cariprazine Dihydroxynaphthoate Crystal Form A prepared in Example 8, add it to 20 mL of isopropyl acetate, stir and crystallize at room temperature for 12 hours, filter, and dry in vacuo at 55 °C to obtain 180 mg of Cariprazine Dihydroxynaphthoate Crystal Form F, with a yield of 90%.

[0205] Its X-ray powder diffraction pattern is as Figure 6 shown

[0206] Its differential scanning calorimetry pattern is as Figure 7 shown, showing a melting point of about 166.6 °C.

[0207] Its thermogravimetric analysis pattern is as Figure 8 shown, showing a weight loss of about 1.3% before 115 °C, attributed to the loss of channel water; and a weight loss of about 1.3% between 115 and 175 °C, attributed to the loss of crystal water.

[0208] Its NMR pattern is as Figure 9 shown, showing that Cariprazine and Dihydroxynaphthoic acid form a salt in a molar ratio of 1:1.

[0209] Example 17: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form G

[0210] Take 200 mg of Cariprazine Dihydroxynaphthoate Crystal Form A obtained in Example 8, add 5 mL of acetonitrile to form a slurry, stir and crystallize for 5 days to obtain Cariprazine Dihydroxynaphthoate Crystal Form G.

[0211] Its X-ray powder diffraction pattern is as Figure 17 shown

[0212] NMR results show that it is an acetonitrile solvate.

[0213] Example 18: Preparation of Cariprazine Dihydroxynaphthoate Crystal Form I

[0214] Take 15 mg of the amorphous solid sample of Cariprazine Dihydroxynaphthoate obtained in Example 1 and expose it to light for 10 days to obtain Cariprazine Dihydroxynaphthoate Crystal Form I.

[0215] Its X-ray powder diffraction pattern is as follows Figure 18 as shown.

[0216] Example 19: Preparation of cariprazine hydrochloride polymorph I

[0217] Prepare a sample of cariprazine hydrochloride polymorph I according to the original research patent of cariprazine hydrochloride:

[0218] Add 1 g of commercially available cariprazine free base to a 25 mL round-bottom flask, add 2 mL of methanol and 8 mL of water, stir in an oil bath at 70 °C for 0.5 h, add a mixed solution of 0.226 mL of concentrated hydrochloric acid and 0.35 mL of water, filter while hot after dissolving clearly, turn off the heating and let it cool naturally overnight, and obtain 0.8 g of off-white solid.

[0219] Its X-ray powder diffraction pattern is as follows Figure 19 as shown, showing it is cariprazine hydrochloride polymorph I.

[0220] Comparative Example 1: Comparison of related substances and crystal form stability

[0221] Respectively take the amorphous cariprazine docusate prepared in Example 1, cariprazine docusate polymorph A prepared in Example 8, cariprazine docusate polymorph B prepared in Example 10, cariprazine docusate polymorph F prepared in Example 16, cariprazine docusate polymorph G prepared in Example 17, and cariprazine hydrochloride polymorph I prepared in Example 19 and place them under high temperature (60 °C), high humidity (25 °C / 90% RH), accelerated (40 °C / 75% RH), and light (1.2×10 6 Lux·hr) conditions, and sample for HPLC or XRPD detection at 0 day, 5 days, 7 days, and 10 days.

[0222] The results of related substances are shown in Table 1, showing that cariprazine docusate polymorph A, cariprazine docusate polymorph B, and cariprazine docusate polymorph G of the present invention, and cariprazine docusate polymorph A is relatively stable. After being placed for 10 days under various conditions, the total sum of related substances remains basically unchanged, while the amorphous cariprazine docusate is unstable under high temperature conditions and the impurities increase more.

[0223] The results of crystal form stability are shown in Table 2, which shows that compared with the known cariprazine hydrochloride polymorph I, cariprazine docusate polymorph A of the present invention has more excellent crystal form stability. After being placed for 10 days under various conditions, the crystal form has not changed and the crystallinity has not changed significantly either; cariprazine docusate polymorph F of the present invention is relatively stable under high temperature and light conditions, the crystal form has not changed, and it will transform into cariprazine docusate polymorph A under high humidity and accelerated conditions.

[0224] Table 1 Results of related substances

[0225]

[0226] Table 2 Crystal form stability results

[0227]

[0228] Comparative Example 2: Solubility comparison

[0229] Separate amorphous cariprazine dithionate prepared in Example 1, amorphous cariprazine hemidithionate prepared in Example 3, cariprazine laurate prepared in Example 5, cariprazine palmitate prepared in Example 6, cariprazine sebacate prepared in Example 7, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate, cariprazine heptanoate, crystalline form A of cariprazine dithionate prepared in Example 8, crystalline form B of cariprazine dithionate prepared in Example 10, crystalline form F of cariprazine dithionate prepared in Example 16, crystalline form G of cariprazine dithionate prepared in Example 17, crystalline form I of cariprazine hydrochloride prepared in Example 19, and cariprazine were separately added to the corresponding media, oscillated at 37°C for 24 hours, filtered through a 0.45 μm aqueous phase filter membrane, the filtrate was collected, and high performance liquid chromatography was used for solubility determination. Among them, pH 3, pH 4, pH 5, and pH 6 were acetic acid buffer solutions, and pH 7, pH 7.4, pH 8, and pH 9 were phosphate buffer solutions.

[0230] The results are shown in Table 3, indicating that the solubilities of cariprazine dithionate and its crystal forms and hemidithionate prepared in the present invention are all significantly lower. The solubility of cariprazine dithionate in water is 3 - 10 μg / mL, which is equivalent to one-eighteenth to one-sixtieth of cariprazine (about 180 μg / mL), one-thousandth to one-three thousand six hundredth of cariprazine hydrochloride (about 11 mg / mL), and is also lower in each pH medium. It has a sustained release effect by itself, and the solubility in each pH medium is quite similar. The release rate can minimally depend on pH, thereby avoiding the influence on its drug release rate in the pH environments of different regions in the body, avoiding the phenomenon of sudden release or excessive blood drug concentration in local regions of the body, and reducing the inter-individual drug release difference. Moreover, the crystal form of cariprazine dithionate has good stability, is suitable for use in long-acting preparations, can reduce the number of drug administrations, improve the medication compliance of patients, and has good market prospects.

[0231] Table 3 Solubility results

[0232]

[0233] Comparative Example 3: In vitro dissolution simulation experiment

[0234] Separate amorphous cariprazine dodecyl sulfate prepared in Example 1, crystalline form A of cariprazine dodecyl sulfate prepared in Example 8, crystalline form B of cariprazine dodecyl sulfate prepared in Example 10, and crystalline form G of cariprazine dodecyl sulfate prepared in Example 17 were added to a pH 7.4 phosphate buffer solution medium, shaken at 37 °C, and sampled for solubility detection at 1, 3, 5, 7, and 24 hours.

[0235] The results are shown in Table 4 and Figure 20 , which shows that the dissolution of the two crystalline form compounds of cariprazine dodecyl sulfate prepared in the present invention, crystalline form A and crystalline form B of cariprazine dodecyl sulfate, is smoother and the solubility at 24 hours is lower than that of the amorphous sample of cariprazine dodecyl sulfate under pH 7.4 conditions, indicating that the crystalline form compound is more suitable as a medicinal salt to avoid too high blood drug concentration.

[0236] Table 4 Results of in vitro dissolution simulation experiment

[0237]

[0238] Comparative Example 4: Comparison of solution stability

[0239] Separate crystalline form A of cariprazine dodecyl sulfate prepared in Example 8 and crystalline form I of cariprazine hydrochloride prepared in Example 19 were added to the corresponding media of pH 6, pH 7, pH 7.4, pH 8, pH 9, etc., shaken at 37 °C for 4 hours, centrifuged, and the residue was detected by XRPD. The results showed that crystalline form A of cariprazine dodecyl sulfate did not change, while crystalline form I of cariprazine hydrochloride dissociated into cariprazine free base. The comparison results at pH 7.4 are shown in Figure 21 (the rest are not shown). Thus, it can be seen that crystalline form A of cariprazine dodecyl sulfate is more stable in solution than crystalline form I of cariprazine hydrochloride, which can effectively avoid the change of drug efficacy caused by the change of crystalline form after administration and improve the safety of drug use.

[0240] Examples 20 - 25: Cariprazine dodecyl sulfate suspension aqueous solution with different suspending agent dosages

[0241]

[0242] Preparation process:

[0243] (1) Weigh the prescription amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and dissolve and disperse them in about 60% of the total amount of injection water.

[0244] (2) Add the prescription amount of crystalline form A of cariprazine dodecyl sulfate to obtain a suspension aqueous solution of coarse particles.

[0245] (3) Grind the above-mentioned suspension aqueous solution of coarse particles using a ball mill to obtain a suspension with Dv(90) less than or equal to 10 μm;

[0246] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above-mentioned suspension respectively, stir until completely dispersed, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, and make up the volume to obtain the suspensions of Examples 20 - 25.

[0247] Take the prescription samples prepared in Examples 20 - 25 respectively, and conduct investigations on needle penetration, suspension property, sedimentation ratio and redispersibility. It is found that the above-mentioned suspension samples can all pass through a 0.45 * 15 mm syringe needle, have good suspension property, and the 24-hour sedimentation ratio and redispersibility of the samples of Examples 22 - 25 are good.

[0248] Examples 26 - 30: Suspension aqueous solutions of cariprazine dodecyl sulfate with different amounts of wetting agent

[0249]

[0250] Preparation process:

[0251] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and dissolve and disperse them in about 60% of the total amount of injection water for preparation, and stir;

[0252] (2) Add the prescribed amount of crystalline form A of cariprazine dodecyl sulfate to obtain a suspension aqueous solution of coarse particles;

[0253] (3) Grind the above-mentioned suspension aqueous solution of coarse particles using a ball mill respectively to obtain a suspension with Dv(90) less than or equal to 10 μm;

[0254] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above-mentioned suspension respectively, stir until completely dispersed, optionally adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, and make up the volume to obtain the suspensions of Examples 26 - 30.

[0255] Take the prescription samples prepared in Examples 26 - 30 respectively, and conduct investigations on needle penetration, suspension property, sedimentation ratio and wettability. It is found that the above-mentioned suspension samples can all pass through a 0.45 * 15 mm syringe needle, and have good suspension property, sedimentation ratio and wettability.

[0256] Examples 31 - 34: Suspension aqueous solutions of cariprazine dodecyl sulfate with different particle sizes

[0257]

[0258] Preparation process:

[0259] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and about 60% of the total amount of injection water for preparation, and stir to dissolve and disperse;

[0260] (2) Add the prescribed amount of cariprazine dodecyl sulfate polymorph A to obtain a suspension aqueous solution of coarse particles;

[0261] (3) Grind and disperse the suspension aqueous solutions of coarse particles obtained in Examples 31 - 34 above using a ball mill respectively;

[0262] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above-mentioned suspension respectively, stir until completely dispersed, and make up to a constant volume to obtain the suspensions of Examples 32 - 35 with a pH of 7.4 ± 0.2;

[0263] (5) Use an OMEC LS-909 particle size analyzer to measure the particle size distribution of the samples in the examples after grinding. The results are shown in the following table:

[0264]

[0265]

[0266] It can be seen from the results in the above table that in the suspension aqueous solutions with the same prescription, by controlling the grinding parameters, suspension aqueous solutions with particles of different particle sizes (Dv90) can be prepared.

[0267] Examples 35 - 37: Suspension aqueous solutions of different polymorphs of cariprazine dodecyl sulfate

[0268]

[0269] Preparation process:

[0270] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and about 60% of the total amount of injection water for preparation, and stir to dissolve and disperse;

[0271] (2) Add the corresponding samples of cariprazine dodecyl sulfate in the prescribed amounts respectively to obtain a suspension aqueous solution of coarse particles;

[0272] (3) Grind and disperse the suspension aqueous solutions of coarse particles obtained in Examples 35 - 37 above using a ball mill respectively;

[0273] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above-mentioned suspension respectively, stir until completely dispersed, and make up to a constant volume to obtain the suspensions of Examples 35 - 37 with a pH of 7.4 ± 0.2;

[0274] (5) Use an OMEC LS-909 particle size analyzer to measure the particle size distribution of the samples in the examples after grinding. The results are shown in the following table:

[0275]

[0276] Respectively take the prescription samples prepared in Examples 35 - 37, and conduct investigations on needle penetration, suspension property, sedimentation ratio, and wettability. It is found that the above suspension samples can all pass through a 0.45 * 15 mm syringe needle, and the suspension property, sedimentation ratio, and wettability are all good.

[0277] Based on the results in the above table and the investigations on needle penetration, suspension property, sedimentation ratio, and wettability, for different crystal forms of cariprazine ditartrate in the mixed aqueous solution with the same prescription and under the same grinding parameters, they are all applicable.

[0278] Example 38: Aqueous suspension of cariprazine hydrochloride

[0279]

[0280] Preparation process:

[0281] (1) Weigh the prescribed amounts of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol and add them to about 60% of the total amount of injection water, stir to dissolve and disperse;

[0282] (2) Add the prescribed amount of cariprazine hydrochloride to obtain a coarse - grained aqueous suspension;

[0283] (3) Grind and disperse the above - obtained coarse - grained aqueous suspension using a ball mill;

[0284] (4) Add the prescribed amount of sodium carboxymethylcellulose to the above suspension, stir until completely dispersed, make up the volume to obtain the suspension of Example 38 with a pH of 7.4 ± 0.2;

[0285] (5) Use an OMEC LS - 909 particle size analyzer to measure the particle size distribution of the sample in Example after grinding. The results are shown in the following table:

[0286]

[0287] Example 39: Investigation on the stability of the aqueous suspension of cariprazine ditartrate and cariprazine hydrochloride at 60 °C

[0288] Take the aqueous suspension of cariprazine ditartrate prepared in Example 33 and the aqueous suspension of cariprazine hydrochloride prepared in Example 38, and detect the particle size and related substances at 0, 5, and 10 days under the condition of 60 °C. The results are shown in the following table:

[0289]

[0290]

[0291] According to the results in the above table, in the suspension aqueous solutions with the same prescription, the suspension aqueous solution of cariprazine dodecyl sulfate is significantly superior to the suspension aqueous solution of cariprazine hydrochloride in terms of the stability of impurities and particle size.

[0292] Examples 40 - 44: Pharmacokinetic study of the prescription of cariprazine dodecyl sulfate suspension in rats

[0293]

[0294] 1. Preparation process of the suspension injection in Examples 40 - 43:

[0295] (1) Weigh the prescribed amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethylcellulose and add them to about 60% of the total injection water volume, stir to dissolve and disperse.

[0296] (2) Add the corresponding samples of the prescribed amount of cariprazine dodecyl sulfate respectively, stir until completely dispersed, and make up the volume to obtain the suspension injections of Examples 40 - 43 with pH 7.4 ± 0.2.

[0297] (3) Use an OMEC LS - 909 particle size analyzer to measure the particle size distribution of the samples in Examples 41 - 43. The results are shown in the following table:

[0298]

[0299] 2. Preparation process of the oral suspension in Example 44:

[0300] (1) Weigh the prescribed amount of Tween 20, sodium carboxymethylcellulose and add them to about 60% of the total injection water volume, stir to dissolve and disperse.

[0301] (2) Add the prescribed amount of cariprazine dodecyl sulfate to obtain a suspension aqueous solution with coarse particles, adjust the pH to 5.0 - 5.5 with hydrochloric acid, and make up the volume to obtain the final oral suspension of Example 44.

[0302] Example 45: Pharmacokinetic experiment

[0303] Select the prescription samples of cariprazine dodecyl sulfate with different concentrations prepared in Examples 40 - 44 for in - vivo experiments in rats. The experiments are as follows:

[0304] Fifteen male SD rats were divided into five groups. Four of the groups were intramuscularly injected with different crystalline forms of cariprazine embonate prescription samples at a single dose of 9 mg / kg, and plasma was collected at 0, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 11 d, 15 d, 20 d, 25 d, and 30 d after administration. The remaining group was orally gavaged with the crystalline form A prescription sample of cariprazine embonate at a single dose of 0.3 mg / kg, and plasma was collected at 5 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. Throughout the experiment, animals in the intramuscular injection group had free access to food and water, while animals in the oral gavage group were fasted overnight before dosing and resumed eating 4 hours after dosing.

[0305] Plasma sample collection: Approximately 150 μL of jugular vein blood (the whole blood was centrifuged to separate plasma within 30 minutes) was placed in a test tube containing the anticoagulant EDTA-K2, and the plasma was stored in a -70 °C refrigerator for later use after treatment.

[0306] Plasma sample pretreatment: 200 μL of internal standard solution (40 ng / mL Glipizide acetonitrile solution) was added to 30 μL of plasma sample, vortex-mixed for 1 min, centrifuged at 5800 rpm for 10 min at 4 °C, 100 μL of the supernatant was transferred to a new plate, and 1 μL of the solution was subjected to LC-MS / MS analysis.

[0307] Chromatographic conditions:

[0308] Mobile phase composition: Mobile phase A: 0.025% formic acid in water - 1 mM ammonium acetate

[0309] Mobile phase B: 0.025% formic acid in methanol - 1 mM ammonium acetate

[0310] Gradient elution:

[0311] Time (minutes) Pump B (%) Initial 10 0.20 10 0.70 95 1.30 95 1.31 10 1.80 10

[0312] Chromatographic column: Waters ACQUITY UPLC BEH C18 (2.1×50 mm, 1.7 μm);

[0313] Flow rate: 0.60 mL / min;

[0314] Injection volume: 1 μL;

[0315] Column oven: 60 °C;

[0316] Retention time: Cariprazine: 1.16 min; Glipizide: 1.22 min.

[0317] Mass spectrometry conditions:

[0318] Using an electrospray ionization source (Turbo spray), in the positive ion detection mode, the multiple reaction monitoring (MRM) mode was selected for tandem mass spectrometry analysis. The mass spectrometry detection working parameters and ion source parameters are shown in the following table.

[0319]

[0320] It can be seen from Figure 22 - 24 that the orally administered group of cariprazine dodecyl sulfate was rapidly absorbed within 24 hours after administration, while the injection group of cariprazine dodecyl sulfate achieved sustained release for at least 11 days after administration compared with the oral group. Considering the interspecies differences, it is expected to achieve at least 30 days of release in humans. At the same time, among the various crystal forms of cariprazine dodecyl sulfate, the release duration of cariprazine dodecyl sulfate crystal form A was the best.

[0321] According to the experimental results of the present invention, it can be known that the cariprazine dodecyl sulfate injection preparation provided by the present invention, after being prepared into a suspension aqueous solution, has a small particle size and uniform distribution of cariprazine dodecyl sulfate, has good injectability, and at the same time has the characteristic of long-term sustained drug release (at least one week in SD rats).

Claims

1. A cariprazine pharmaceutical composition, characterized in that, The cariprazine pharmaceutical composition comprises cariprazine solid particles, wherein the particle size Dv(10) of the cariprazine solid particles is ≤ 30 μm, Dv(50) is ≤ 50 μm, and Dv(90) is ≤ 100 μm; The cariprazine solid particles are solid particles of cariprazine docusate polymorph A; The X-ray powder diffraction pattern of the cariprazine docusate polymorph A has characteristic peaks at 2θ values of 4.8° ± 0.2°, 9.7 ± 0.2°, 12.3° ± 0.2°, 13.1° ± 0.2°, 18.7° ± 0.2°, 20.1° ± 0.2°, 21.0° ± 0.2°, 26.1° ± 0.2°.

2. The cariprazine pharmaceutical composition according to claim 1, wherein, 10 μm ≤ Dv(90) ≤ 100 μm.

3. The cariprazine pharmaceutical composition according to claim 1, characterized in that, The X-ray powder diffraction pattern of the cariprazine docusate polymorph A is substantially as shown in Figure 2.

4. The cariprazine pharmaceutical composition according to claim 1 or 2, characterized in that, The composition is an injection preparation; the composition further comprises excipients, and the excipients are selected from one or more of a suspending agent, a wetting agent, an osmotic pressure regulator, a solvent, a stabilizer, a buffer, and a surfactant.

5. The cariprazine pharmaceutical composition according to claim 4, characterized in that, The concentration range of the suspending agent is 0 to 10 mg / mL; and / or, the suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone.

6. The cariprazine pharmaceutical composition according to claim 5, wherein, The concentration range of the suspending agent is 3.5 mg / mL to 5 mg / mL; and / or, the suspending agent is sodium carboxymethylcellulose.

7. The cariprazine pharmaceutical composition according to claim 4, wherein The concentration range of the wetting agent is 1 mg / mL to 10 mg / mL; and / or, the wetting agent is selected from one or more of Tween 20, Tween 80, and poloxamer 188.

8. The cariprazine pharmaceutical composition according to claim 7, wherein, The concentration range of the wetting agent is 1 mg / mL to 5 mg / mL; and / or, the wetting agent is Tween 20.

9. The cariprazine pharmaceutical composition according to claim 4, characterized in that, The concentration range of the osmotic pressure regulator is 20 to 30 mg / mL; and / or, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, and sucrose; and / or, the concentration range of the stabilizer is 0 to 30 mg / mL; and / or, the stabilizer is PVP K12; and / or, the buffer is selected from one or more of phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide; and / or, the surfactant is sodium deoxycholate; and / or, the solvent is water for injection.

10. The cariprazine pharmaceutical composition according to claim 9, wherein The concentration range of the osmotic pressure regulator is 23 mg / mL to 26 mg / mL; and / or, the concentration range of the stabilizer is 1 mg / mL to 10 mg / mL.

11. The cariprazine pharmaceutical composition according to claim 4, wherein, The composition comprises: (a) cariprazine docusate; (b) sodium carboxymethylcellulose; (c) Tween 20; (d) disodium hydrogen phosphate; (e) sodium dihydrogen phosphate; and (f) mannitol; And, the cariprazine composition comprises sodium hydroxide or hydrochloric acid.

12. The cariprazine pharmaceutical composition according to claim 11, wherein, The concentration of the cariprazine docusate solid particles is not less than 15 mg / mL.

13. The preparation method of the cariprazine pharmaceutical composition according to any one of claims 1-12, comprising the following steps: (1) Dissolve the wetting agent, buffer, and osmotic pressure regulator in water for injection in sequence; (2) Add cariprazine docusate solid particles to obtain a suspension aqueous solution of coarse particles; (3) Grind the above-mentioned coarse particle suspension aqueous solution using a ball mill to obtain a suspension; (4) Add a suspending agent with a certain concentration to the above-mentioned suspension, mix well, adjust the pH to 4.0 - 9.0 with sodium hydroxide or hydrochloric acid, and make up the volume to obtain a suspension aqueous solution.

14. Use of the cariprazine pharmaceutical composition according to any one of claims 1 - 12 in the preparation of a medicament for treating and / or preventing psychosis, bipolar disorder and / or acute mania.

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