Injection type long-acting cariprazine composition and preparation method thereof

Abstract

The invention relates to an injection type long-acting cariprazine composition which comprises the following components: cariprazine and at least one of the following components: one or more suspending agents, one or more buffering agents and one or more freeze-drying protective agents, the suspending aid is one of sodium carboxymethyl cellulose, gelatin, polyvinylpyrrolidone, methyl cellulose or Arabic gum; the buffering agent is one of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid or malic acid; the freeze-drying protective agent is one of lactose, mannitol, glycine or cane sugar. The cariprazine and other auxiliary materials are co-suspended and ground to prepare the long-acting parenteral injection which is continuously and uniformly released in a living body for a long time, so that the beneficial effects of reducing the administration frequency, relieving the pain of a patient and improving the medication compliance are achieved. The preparation method has the characteristics of simple formula process and excellent effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and specifically discloses an injection type long-acting cariprazine composition and a preparation method thereof. BACKGROUND

[0002] Cariprazine is an atypical antipsychotic drug, which exerts its effects through the partial agonist activity on central dopamine D2 and serotonin 5-HT1A receptors combined with the antagonist activity on serotonin 5-HT2A receptors. Cariprazine is a partial agonist with high binding affinity to dopamine D3 and D2 receptors, and is a partial agonist to serotonin 5-HT1A receptors. Cariprazine is an antagonist with high and moderate affinity to 5-HT2B and 5-HT2A receptors, respectively, and it also binds to histamine H1 receptors. Cariprazine has low binding affinity to serotonin 5-HT2C and alpha1A-adrenergic receptors, and has no significant affinity to cholinergic muscarinic receptors.

[0003] In the United States, cariprazine has been approved as an immediate-release oral capsule under the trade name Vraylar. Cariprazine was first disclosed in WO2005012266, which can be used for the following diseases: psychosis (such as schizophrenia, schizoaffective disorder, etc.), drug (such as alcohol, cocaine and nicotine, opioid drugs, etc.) abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive impairment, dementia, psychotic states associated with dementia, eating disorders (such as bulimia nervosa, etc.), attention deficit disorder, hyperactivity disorder in children, psychotic depression, mania, paranoid and delusional disorders, movement disorders (such as Parkinson's disease, neuroleptic-induced Parkinson's disease, tardive dyskinesia), anxiety disorders, sexual dysfunction, sleep disorders, vomiting, aggression, and autism.

[0004] WO20010009309 discloses an immediate-release solid oral composition of cariprazine. WO2009104739 discloses an immediate-release solid oral cariprazine composition containing lactose. WO2017178999 discloses another immediate-release granular composition containing cariprazine. All the compositions described in these references must be taken once a day.

[0005] Patients have the need to reduce the number of drug administrations, especially in the case of long-term treatment. In addition, a large part of the target population may be elderly and forgetful patients. Such patients often require time-consuming and expensive monitoring management. Reducing the number of drug administrations can reduce the indirect labor costs of drug treatment, improve patient compliance, and reduce the time required for doctor supervision of drug administration, thus having significant advantages.

[0006] WO 2018226941 discloses oral pharmaceutical compositions and methods for the sustained release delivery of cariprazine. However, after oral administration of cariprazine, symptoms such as abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain, etc. have been observed. The EMEA assessment report on immediate-release cariprazine capsules shows that the absolute bioavailability in rats is 52-63% and in dogs is about 64-80%, indicating incomplete absorption and a certain first-pass effect. It has been proven that the administration by parenteral route can accurately control the blood drug concentration and also reduce the adverse reactions after oral administration of drugs.

[0007] Therefore, there is a need in the art to develop a long-acting injectable cariprazine to solve the adverse reactions of oral administration.

[0008] In addition, the preparation method of injectable cariprazine also needs to be studied in the art. Some preparation methods of injectable cariprazine have been proposed in the prior art, but all have technical problems. For example, the patent application for invention with publication number CN108261394A discloses a cariprazine suspension injection capable of sustained release for one week and a preparation method thereof, which includes cariprazine, polysorbate 80, sodium carboxymethyl cellulose, sodium dihydrogen phosphate monohydrate and a lyophilization protective agent (such as mannitol). However, the stabilizer (such as polysorbate 80) used in the formula has adverse effects on the human body, and its use in treatment may have certain risks. The patent application for invention with publication number CN115554253A discloses a stable drug release and narrow particle size distribution injection of aripiprazole lyophilized preparation and a preparation method thereof, which includes aripiprazole monohydrate, sodium carboxymethyl cellulose, mannitol and buffer salt (such as sodium dihydrogen phosphate). However, the method needs to be repeated multiple times for grinding and mixing and dispersion, and the process is relatively complicated. The patent application for invention with publication number CN108379231A discloses an aripiprazole lyophilized preparation formed by a spray drying process and a corresponding preparation method, which includes aripiprazole, carboxymethyl cellulose (sodium), mannitol, sodium phosphate and sodium hydroxide. However, the method needs to use a spray drying device, which has a high production cost.

[0009] Based on this, the present application is proposed. SUMMARY

[0010] In view of the above technical problems of the prior art, the purpose of the present application is to provide an injection type long-acting cariprazine composition and a preparation method thereof, which includes a long-acting injection composition of cariprazine or its pharmaceutically acceptable salt, can reduce the frequency of administration and reduce adverse reactions. And the preparation method has the characteristics of simple formula process and excellent effect.

[0011] To achieve the above-mentioned purpose, the present application is realized by the following technical solutions:

[0012] An injection type long-acting cariprazine composition, comprising the following components: cariprazine, and at least one of the following ingredients: one or more suspending agents, one or more buffering agents, one or more lyophilization protectants; the suspending agent is at least one of sodium carboxymethylcellulose, gelatin, polyvinylpyrrolidone, methylcellulose or gum arabic; the buffering agent is at least one of monobasic sodium phosphate monohydrate, dibasic sodium phosphate, acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid or malic acid; the lyophilization protectant is at least one of lactose, mannitol, glycine or sucrose.

[0013] The suspending agent is sodium carboxymethylcellulose, the buffering agent is monobasic sodium phosphate monohydrate, and the lyophilization protectant is mannitol.

[0014] A preparation method of an injection type long-acting cariprazine composition, comprising the following steps: (1) suspending cariprazine, a suspending agent, a buffering agent and a lyophilization protectant in water; (2) stirring the liquid at low temperature to disperse it to a uniformly suspended state; (3) continuing to stir to promote dissolution at a lower speed; (4) grinding the obtained suspension and diluting; (5) filling into a Westlin bottle and freeze-drying.

[0015] In step (1), the final concentration of cariprazine before lyophilization is 10 mg / mL-100 mg / mL, preferably 33 mg / mL; the final concentration of the suspending agent before lyophilization is 1.0 mg / mL-10 mg / mL, preferably 1.4 mg / mL; the final concentration of the buffering agent before lyophilization is 0.1 mg / mL-1.0 mg / mL, preferably 0.13 mg / mL; and the final concentration of the lyophilization protectant before lyophilization is 1.0 mg / mL-10 mg / mL, preferably 6.9 mg / mL.

[0016] In step (2), the stirring speed is 100 rpm-1000 rpm, preferably 750 rpm; the temperature is 5°C-15°C, preferably 14°C; and the dispersion time is 10 min-100 min, preferably 30 min.

[0017] In step (3), the stirring speed is 100 rpm-1000 rpm, preferably 400 rpm; and the dispersion time is 10 min-100 min, preferably 60 min.

[0018] In step (4), the grinding method is ball milling, sand milling, jet milling or cutting milling, preferably ball milling; and the grinding time is 8 h-24 h, preferably 8 h.

[0019] In step (5), the sublimation temperature is 0°C-20°C, and the sublimation time is 10 h-24 h.

[0020] The sublimation temperature in the step (5) is 5-10℃, and the sublimation time is 12-23h.

[0021] The beneficial effects of the present application are as follows:

[0022] The injection type long-acting cariprazine composition of the present application is a suspension aqueous solution for injection, wherein the concentration of cariprazine hydrochloride is high, the stability is good, a high dosage can be obtained in a limited injection volume, the dosage can be flexibly adjusted according to the long-acting administration time, and the long-acting effect is achieved by controlling the particle size distribution and the injection dosage. The preparation method of the injection type cariprazine composition of the present application, the prepared injection preparation has good stability, high safety, and the method is simple and easy to operate, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Average plasma concentration-time curve of rats DETAILED DESCRIPTION

[0024] The present application will be further described below in conjunction with specific examples, but the scope of protection of the present application is not limited thereto.

[0025] In the prior art, after oral administration of cariprazine, abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain and the like have been observed. The EMEA evaluation report on immediate-release cariprazine capsules shows that the absolute bioavailability of rats after oral administration is 52-63%, and that of dogs is about 64-80%, indicating incomplete absorption and certain first-pass effect. It has been proved that parenteral administration can accurately control the blood drug concentration and also reduce the adverse reactions after oral administration of drugs.

[0026] There is a need in the art for an injectable dosage form of cariprazine to solve the adverse reactions of oral administration. The present application provides a long-acting injection composition containing cariprazine or a pharmaceutically acceptable salt thereof, which can reduce the administration frequency and reduce adverse reactions. The preparation of the injection solution requires sterile raw materials, which is high in cost, low in sterile guarantee level and difficult to be industrialized. The preparation of the injection solution requires long-time grinding, and the grinding beads may fall off into the sample to contaminate the sample, and the sterile conditions during the preparation process are easily destroyed.

[0027] Therefore, the embodiments of the present application are as follows:

[0028] Example 1

[0029] I. Container equipment, materials

[0030] 1. Container equipment

[0031]

[0032]

[0033] 2、Materials

[0034] Name Batch No. Manufacturer Dosage Cariprazine-base XJJ-2126-41-02 Huahai 1.0g Low endotoxin mannitol MP21019896 Shanghai Fenghong 0.208g Sodium phosphate dibasic dihydrate K95708718 Shanghai Fenghong 0.004g Sodium carboxymethylcellulose 7L2P 05523365901 Youpu Huisheng 0.042g Sodium hydroxide 100920230502 Hunan E'kang Pharmaceutical 0.1g

[0035] The preparation method comprises the following steps:

[0036] (1) Take cariprazine, low endotoxin mannitol, sodium carboxymethyl cellulose 7L2P in an empty jacketed beaker, add 50 ml purified water, and stir to a suspension.

[0037] (2) Prepare a 1% NaOH solution, control the temperature of the energy-saving intelligent constant temperature tank at 14°C, and stir at 750 rpm for 30 min.

[0038] (3) Reduce the stirring speed to 400 rpm, continue to stir for 60 min, and adjust the PH to 7.

[0039] (4) Put the suspension into a ball mill and mill at 600 rpm for 8 h, and measure the PH after ball milling.

[0040] (5) Put the ball-milled product into a culture dish for freeze-drying.

[0041] The freeze-drying parameters in this example are as follows:

[0042] Section Set temperature / ℃ Set time / h 01 -40 5 02 -30 4 03 -20 4 04 -10 4 05 -5 4 06 0 4 07 5 10 08 10 13

[0043] Example 2

[0044] The preparation method in this example 2 comprises the following steps:

[0045] (1) Take cariprazine, sodium dihydrogen phosphate dihydrate, low endotoxin mannitol, sodium carboxymethyl cellulose 7L2P in an empty jacketed beaker, add 50 ml purified water, and stir to a suspension;

[0046] (2) Prepare a 5% NaOH solution, control the temperature of the energy-saving intelligent constant temperature tank at 14°C, and stir at 750 rpm for 30 min.

[0047] (3) Reduce the stirring speed to 400 rpm, continue to stir for 60 min, and adjust the PH to 7.

[0048] (4) Put the suspension into a ball mill and mill at 600 rpm for 8 h, and measure the PH after ball milling.

[0049] (5) Put the ball-milled product into a culture dish for freeze-drying.

[0050] Example 3:

[0051] The preparation method of this Example 3 comprises the following steps:

[0052] (1) Dissolve 2.0 g of cariprazine, 0.416 g of mannitol, 0.008 g of sodium dihydrogen phosphate dihydrate and 0.084 g of sodium carboxymethyl cellulose in 40 mL of water and stir to disperse for a few minutes.

[0053] (2) Stir at 750 rpm for 30 min at 14°C.

[0054] (3) Stir at 400 rpm for 60 min at 14°C.

[0055] (4) Grind in a ball mill at 600 rpm for 8 h.

[0056] (5) Dilute the dispersion to 60 mL.

[0057] (6) Dispense and freeze-dry (-40°C to 5°C for about 25 h, 5°C for about 10 h, 10°C for about 13 h).

[0058] Example 4

[0059] The preparation method of this Example 4 comprises the following steps:

[0060] (1) Dissolve 2.0 g of cariprazine, 0.416 g of mannitol, 0.008 g of sodium dihydrogen phosphate dihydrate and 0.084 g of sodium carboxymethyl cellulose in 40 mL of water and stir to disperse for a few minutes.

[0061] (2) Stir at 100 rpm for 10 min at 5°C.

[0062] (3) Stir at 400 rpm for 60 min at 14°C.

[0063] (4) Grind in a ball mill at 100 rpm for 8 h.

[0064] (5) Dilute the dispersion to 60 mL.

[0065] (6) Dispense and freeze-dry (-40°C to 5°C for about 25 h, 5°C for about 10 h, 10°C for about 13 h).

[0066] Example 5

[0067] The preparation method of this Example 5 comprises the following steps:

[0068] (1) Dissolve 2.0 g of cariprazine, 0.416 g of mannitol, 0.008 g of sodium dihydrogen phosphate dihydrate and 0.084 g of sodium carboxymethyl cellulose in 40 mL of water and stir to disperse for a few minutes.

[0069] (2) Stir at 1000 rpm for 50 min at 10°C.

[0070] (3) 1000 rpm stirring at 10°C for 100 min.

[0071] (4) Ball mill at 100 rpm for 24 h.

[0072] (5) Dilute the dispersion to 60 mL.

[0073] (6) Dispense and freeze-dry (-40°C to 5°C for about 25 h, 5°C for about 10 h, and 10°C for about 13 h).

[0074] Performance test

[0075] The product obtained in Example 1 was suspended in 2 mL of water for injection, and was administered to SD rats at 0.6 mg / kg by intramuscular injection. After blood sampling of 0.25 mL at the predetermined sampling time points, the blood was centrifuged at 6800 g for 6 minutes at 2-8°C (within 0.5 hour) to determine the concentration of cariprazine by LC-MS / MS. The obtained cariprazine pharmacokinetic curve is shown in Figure 1 .

[0076] The present application prepares a long-acting parenteral injection for sustained and uniform long-term release in vivo by co-suspending and grinding cariprazine and other excipients, thereby producing the beneficial effects of reducing the frequency of administration, alleviating the pain of patients, and improving the compliance of medication. The preparation method has the characteristics of simple prescription process and excellent effect.

[0077] The above examples are only used to explain the inventive concept of the present application, and are not a limitation on the protection of the present application. Any non-substantial modification of the present application using this concept shall fall within the protection scope of the present application.

Claims

1. An injectable long-acting cariprazine composition, characterized in that... It includes the following components: cariprazine, and at least one of the following components: one or more suspending agents, one or more buffers, and one or more lyophilization protectants; The suspending agent is at least one of sodium carboxymethyl cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, or gum arabic; The buffer is at least one of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, or malic acid. The freeze-drying protectant is at least one of lactose, mannitol, glycine, or sucrose.

2. The injectable long-acting cariprazine composition according to claim 1, characterized in that: The suspending agent is sodium carboxymethyl cellulose, the buffer is sodium dihydrogen phosphate monohydrate, and the freeze-drying protectant is mannitol.

3. A method for preparing an injectable long-acting cariprazine composition, characterized in that... Includes the following steps: (1) Suspend cariprazine, suspending agent, buffer, and lyophilization protectant in water; (2) Stir the liquid at low temperature to disperse it into a uniform suspension; (3) Continue stirring at a lower speed to promote dissolution; (4) Grind the resulting suspension and dilute it; (5) Fill into vials and freeze dry.

4. The method for preparing the injectable long-acting cariprazine composition as described in claim 3, characterized in that: In step (1), the final concentration of cariprazine before lyophilization is 10 mg / mL-100 mg / mL, the final concentration of the suspending agent before lyophilization is 1.0 mg / mL-10 mg / mL, the final concentration of the buffer before lyophilization is 0.1 mg / mL-1.0 mg / mL, and the final concentration of the lyophilization protectant before lyophilization is 1.0 mg / mL-10 mg / mL.

5. The method for preparing the injectable long-acting cariprazine composition as described in claim 3, characterized in that: The stirring rate in step (2) is 100rpm-1000rpm, the temperature is 5℃-15℃, and the dispersion time is 10min-100min.

6. The method for preparing the injectable long-acting cariprazine composition according to claim 3, characterized in that: The stirring rate in step (3) is 100 rpm to 1000 rpm, and the dispersion time is 10 min to 100 min.

7. The method for preparing the injectable long-acting cariprazine composition according to claim 3, characterized in that: The grinding method in step (4) is ball milling, sand milling, air jet milling or cutting milling, and the grinding time is 8h-24h.

8. The method for preparing the injectable long-acting cariprazine composition as described in claim 3, characterized in that: The sublimation temperature in step (5) is 0℃-20℃, and the sublimation time is 10h-24h.

9. The method for preparing the injectable long-acting cariprazine composition as described in claim 8, characterized in that: The sublimation temperature in step (5) is 5℃-10℃, and the sublimation time is 12h-23h.

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