Cariprazine hydrochloride pharmaceutical composition

Abstract

The present invention relates to a cariprazine hydrochloride pharmaceutical composition, which comprises cariprazine hydrochloride, a filler and a lubricant, and the water content of the filler is 0.5-8%. The cariprazine hydrochloride capsule provided by the invention has the advantages of good dissolution rate, small batch-to-batch release degree difference, good mixing uniformity and good content uniformity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a cariprazine hydrochloride pharmaceutical composition. Background Art

[0002] Cariprazine (CARIPRAZINE), CAS number: 839712-12-8, chemical name N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea, is a new atypical antipsychotic drug used to treat bipolar I disorder and schizophrenia in adults with manic episodes or mixed episodes of mania and depression. Its mechanism of action is a partial agonist of dopamine D2 and D3 receptors and 5-HT1A receptors, and it has higher selectivity for D3 receptors. Clinical study results show that compared with many other atypical antipsychotics, cariprazine causes less weight gain, has no clinically relevant side effects such as metabolic changes, increased prolactin and prolonged QT interval, and has potential positive effects on cognition. Forest Laboratory's cariprazine hydrochloride capsules were approved for marketing by the FDA in 2015, with the trade name Oral once daily for the treatment of schizophrenia and bipolar disorder.

[0003] In vitro dissolution or release testing is a crucial component of pharmaceutical production and quality control, playing a crucial role in ensuring consistent quality across approved products. Large batch-to-batch variability in drug release can make it difficult for physicians to accurately predict medication use and, more seriously, may prevent the desired therapeutic effect and minimize side effects.

[0004] The vast majority of pharmaceutical preparations involve a process for uniformly mixing various raw and excipient ingredients. Instability or imperfections in this process can lead to significant variations in the content of each product within a batch. This is particularly true when the absolute amount of the principal ingredient in a single dose is small, or when the principal ingredient accounts for a small proportion of the entire formulation, it can be difficult to evenly mix the principal ingredient with the other ingredients and excipients, resulting in batch inhomogeneity and, in turn, affecting the drug's efficacy.

[0005] The cariprazine hydrochloride capsules that have been marketed by Forest Laboratory are drugs with a small absolute amount of the main ingredient. The inventors of this application studied the cariprazine hydrochloride capsules of Forest Laboratory and found that they had defects such as large differences in release between batches, poor mixing uniformity, and poor content uniformity. Summary of the Invention

[0006] The invention provides a cariprazine hydrochloride capsule with good dissolution, small difference in release between batches, good mixing uniformity and good content uniformity.

[0007] The present invention solves the above technical problems through the following technical solutions:

[0008] The present invention provides a cariprazine hydrochloride pharmaceutical composition, comprising cariprazine hydrochloride, a filler and a lubricant, characterized in that the water content of the filler is 0.5-8%, preferably 1.7-7.82%, and more preferably 2-5%.

[0009] Furthermore, the water content of the filler of the present invention is 3.7%.

[0010] The filler of the present invention is selected from one or more of microcrystalline cellulose, starch, lactose, pregelatinized starch, mannitol, and sorbitol, preferably pregelatinized starch.

[0011] The amount of the pregelatinized starch used in the present invention is 92-98% wt, preferably 92.49-97.37% wt.

[0012] The lubricant of the present invention is selected from one or more of magnesium stearate, talc, and micro-powdered silica gel, preferably magnesium stearate.

[0013] The amount of magnesium stearate used in the present invention is 0.1-5%wt, preferably 1%wt.

[0014] The dosage of the cariprazine hydrochloride of the present invention is 1-8%wt, preferably 1.63-6.51%wt.

[0015] The pharmaceutical composition of the present invention contains the following components and contents:

[0016] Cariprazine hydrochloride 1-8%wt Pregelatinized starch 92-98% wt magnesium stearate 0.1-5%wt

[0017] The water content of the pregelatinized starch is 0.5-8%.

[0018] Furthermore, the pharmaceutical composition of the present invention contains the following components and contents:

[0019] Cariprazine hydrochloride 1.63-6.51%wt Pregelatinized starch 92.49-97.37% wt magnesium stearate 1%wt

[0020] The water content of the pregelatinized starch is 1.7-7.82%, preferably 2-5%, and more preferably 3.7%.

[0021] The present invention provides a preparation method of a cariprazine hydrochloride composition, comprising the steps of mixing cariprazine hydrochloride with a portion of pregelatinized starch, mixing the mixed powder with a portion of the pregelatinized starch, mixing the mixed powder with the remaining pregelatinized starch, and mixing the mixed powder with magnesium stearate before filling a capsule.

[0022] The present invention tests different types of commercially available pregelatinized starch, for example, starch500 with a water content of 0-8.77%, starcap1500 with a water content of 0-8.72%, and SH-YJ-L with a water content of 0-10%. When the water content is reduced to below 8%, the cumulative dissolution rate of cariprazine hydrochloride capsules in 10 minutes can reach 90% or more, and the RSD value is controlled within 15%; when the water content is reduced to 2-5%, the cumulative dissolution rate of cariprazine hydrochloride capsules in 10 minutes can reach 90% or more, and the RSD value is controlled within 6%. Specific embodiments

[0023] Dissolution test method: The dissolution test method for cariprazine hydrochloride capsules recommended by the FDA dissolution database was used to test the dissolution rate. The specific conditions are as follows:

[0024]

[0025] Moisture detection method: Take about 1.0g of pregelatinized starch / powder and dry it at 105℃ (halogen moisture meter).

[0026] Example 1

[0027] According to the prescription ratio in Table 1, cariprazine hydrochloride capsules were prepared using the following preparation method.

[0028] Table 1

[0029]

[0030] Preparation method: The prescribed amount of cariprazine hydrochloride and twice the amount of pregelatinized starch are sieved through a 65-mesh sieve and mixed to obtain mixture A; mixture A is mixed with twice the amount of pregelatinized starch to obtain mixture B; mixture B is mixed with the remaining amount of pregelatinized starch to obtain premixed powder; the premixed powder is mixed with the prescribed amount of magnesium stearate to obtain a total mixed powder; the final mixture is filled into capsules.

[0031] 1. Investigate the water content of the above-mentioned finished preparations

[0032] The capsules of prescriptions 1-5 prepared in Example 1 were tested for water content. The water content results of the preparations are shown in Table 2:

[0033] Table 2

[0034]

[0035] 2. Investigate the dissolution of the capsules prepared by the above prescription

[0036] The capsules of prescriptions 1-5 prepared in Example 1 were examined for dissolution. The dissolution results are shown in Table 3:

[0037] Table 3

[0038]

[0039] Only formulations 3-5 could achieve a cumulative dissolution rate of more than 90% within 10 min and an RSD value within 15%.

[0040] Example 2

[0041] According to the prescription ratio in Table 4, cariprazine hydrochloride capsules were prepared using the following preparation method.

[0042] Table 4

[0043]

[0044]

[0045] The preparation method is the same as that of Example 1.

[0046] 1. Investigate the water content of the above-mentioned finished preparations

[0047] The capsules of prescriptions 6 and 7 prepared in Example 2 were taken and the water content of the preparations was tested. The water content results of the preparations are shown in Table 5:

[0048] Table 5

[0049]

[0050] 2. Investigate the dissolution of the capsules prepared by the above prescription

[0051] The capsules of prescriptions 6 and 7 prepared in Example 2 were taken and their dissolution was investigated. The dissolution results are shown in Table 6:

[0052] Table 6

[0053]

[0054] Example 3

[0055] According to the prescription ratio in Table 7, cariprazine hydrochloride capsules were prepared using the following preparation method.

[0056] Table 7

[0057]

[0058] Preparation method: The prescribed amount of cariprazine hydrochloride and twice the amount of pregelatinized starch are sieved through a 65-mesh sieve and mixed to obtain mixture A; mixture A is mixed with twice the amount of pregelatinized starch to obtain mixture B; mixture B is mixed with the remaining amount of pregelatinized starch to obtain premixed powder; the premixed powder is mixed with the prescribed amount of magnesium stearate to obtain a total mixed powder; the final mixture is filled into capsules.

[0059] Investigation Result 1:

[0060] The total mixed powder prepared in Example 3 was tested for powder mixing uniformity, and the test results are shown in Table 8. The results show that the powder mixing uniformity is very good.

[0061] Table 8

[0062]

[0063] Investigation Result 2:

[0064] The capsules prepared in Example 3 were tested for content uniformity, and the test results are shown in Table 9. The results showed that the content uniformity of the capsules was very good.

[0065] Table 9

[0066]

Claims

1. A cariprazine hydrochloride pharmaceutical composition comprising cariprazine hydrochloride, a filler and a lubricant, characterized in that: The water content of the filler is 0.5-8%, preferably 1.7-7.82%, more preferably 2-5%.

2. The pharmaceutical composition according to claim 1, characterized in that The water content of the filler is 3.7%.

3. The pharmaceutical composition according to claim 1, characterized in that The filler is selected from one or more of microcrystalline cellulose, starch, lactose, pregelatinized starch, mannitol, and sorbitol, preferably pregelatinized starch.

4. The pharmaceutical composition according to claim 3, characterized in that The amount of the pregelatinized starch is 92-98% wt, preferably 92.49-97.37% wt.

5. The pharmaceutical composition according to claim 1, characterized in that The lubricant is selected from one or more of magnesium stearate, talc, and micro-powdered silica gel, preferably magnesium stearate.

6. The pharmaceutical composition according to claim 1, characterized in that The amount of magnesium stearate used is 0.1-5%wt, preferably 1%wt.

7. The pharmaceutical composition according to claim 1, characterized in that The amount of cariprazine hydrochloride used is 1-8% wt, preferably 1.63-6.51% wt.

8. The pharmaceutical composition according to claim 1, characterized in that Contains the following components and contents: The water content of the pregelatinized starch is 1-8%. It preferably contains the following components and contents: The water content of the pregelatinized starch is 1.7-7.82%, preferably 2-5%, and more preferably 3.7%.

9. The pharmaceutical composition according to claims 1-8, characterized in that The preparation method comprises mixing cariprazine hydrochloride with a portion of pregelatinized starch, mixing the mixed powder with a portion of the pregelatinized starch, mixing the mixed powder with the remaining pregelatinized starch, mixing the mixed powder with magnesium stearate, and then filling capsules.

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