Pimavanserin tartrate pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to a tartaric acid pimavanserin pharmaceutical composition, which is prepared from the following components in percentage by weight: 20 to 60 percent of tartaric acid pimavanserin, 15 to 50 percent of filling agent, 5 to 30 percent of disintegrating agent, 1 to 25 percent of flavoring agent, 0.1 to 5 percent of flow aid and 0.1 to 10 percent of lubricating agent. The tartaric acid pimavanserin composition has the advantages of being high in stability, good in quality uniformity, low in friability, stable in blood concentration, small in in-vivo variation, capable of improving irritation and patient medication compliance, better in cost and the like, and the safety effectiveness of the medicine is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a pimavanserin tartrate pharmaceutical composition, a preparation method thereof and an application thereof. Background Art

[0002] There are more than 10 million Parkinson's disease patients worldwide, and the number of new patients is increasing by more than 100,000 each year. More than 50% of Parkinson's disease patients have psychiatric symptoms (PDP) such as hallucinations and delusions, which poses challenges to their treatment and care. Dopamine is a drug used clinically to treat Parkinson's disease, but most antipsychotic drugs block dopamine receptors in the brain and worsen the motor dysfunction of Parkinson's patients.

[0003] Pimavanserin is a new type of non-dopamine neurotransmitter antipsychotic drug that selectively blocks 5-HT2A receptors and does not block dopamine receptors. It is clinically used to treat Parkinson's psychosis and hallucinations and delusions associated with Parkinson's disease psychosis (recommended dose 34 mg, once a day, 1 tablet orally each time). It is effective and well tolerated in treating Parkinson's disease psychosis, and does not cause worsening of Parkinson's disease symptoms or aggravation of motor symptoms. The results of a six-week randomized, double-blind, placebo-controlled trial (199 patients) showed that the average score of patients in the pimavanserin group on the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) decreased by 5.79 points, and significantly improved the clinical global impression scale and caregiver burden scale, which was statistically significant compared with the placebo group (average score decreased by 2.73 points) (P≤0.001). However, there is still a need to improve the dissolution, tablet weight, irritation, blood drug concentration and other aspects of pimavanserin. In addition, the orally disintegrating tablets of pimavanserin reported in the literature have defects such as heavy tablet weight, high irritation, and substandard friability. Therefore, it is necessary to develop a more efficient and safe pimavanserin pharmaceutical composition to meet clinical drug needs. Summary of the invention

[0004] The present invention aims to provide a pimavanserin tartrate pharmaceutical composition, which contains, by weight percentage, 20-60% of pimavanserin tartrate, 15-50% of a filler, 5-30% of a disintegrant, 1-25% of a flavoring agent, 0.1-5% of a glidant and 0.1-10% of a lubricant.

[0005] According to a preferred technical solution of the present invention, the composition contains 22-57% (w / w) pimavanserin tartrate, preferably 30-50% (w / w), by weight percentage.

[0006] In a preferred technical solution of the present invention, the filler is selected from any one of mannitol, microcrystalline cellulose, sorbitol, lactose, starch or a combination thereof.

[0007] In a preferred technical solution of the present invention, the filler is composed of microcrystalline cellulose and mannitol in a mass ratio of 1-6:1, preferably 1-4:1.

[0008] According to a preferred technical solution of the present invention, the composition contains 20-45% (w / w), preferably 25-40% (w / w) of filler in terms of weight percentage.

[0009] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or a combination thereof.

[0010] In a preferred technical solution of the present invention, the composition contains 10-28% (w / w) of disintegrant, preferably 12-20% (w / w), by weight.

[0011] According to a preferred technical solution of the present invention, the flavoring agent is selected from any one of neotame, sucralose, aspartame, acesulfame potassium, sucrose, sodium cyclamate, saccharin sodium, fumaric acid, ascorbic acid, sorbic acid, citric acid, malic acid, maleic acid, tartaric acid, disodium edetate, calcium gluconate, and sodium acetate trihydrate, or a combination thereof.

[0012] In a preferred technical solution of the present invention, the composition contains 2-21% (w / w), preferably 5-17% (w / w), of flavoring agent in terms of weight percentage.

[0013] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

[0014] In the preferred technical solution of the present invention, the composition contains 0.8-8% lubricant by weight, preferably 0.9-6%.

[0015] In a preferred technical solution of the present invention, the glidant is selected from any one of talc, micro-powder silica, colloidal silicon dioxide or a combination thereof.

[0016] In a preferred technical solution of the present invention, the composition contains 0.4-2% (w / w), preferably 0.45-1.5% (w / w), of the glidant by weight.

[0017] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 20-60% of pimavanserin tartrate, 5-30% of silicified microcrystalline cellulose, 1-25% of mannitol, 5-30% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.1-5% of neotame, 1-20% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.1-10% of sodium stearyl fumarate, and 0.1-5% of colloidal silicon dioxide.

[0018] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 22-57% of pimavanserin tartrate, 10-25% of silicified microcrystalline cellulose, 4-20% of mannitol, 10-28% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.2-3% of neotame, 5-19% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.8-8% of sodium stearyl fumarate, and 0.4-2% of colloidal silicon dioxide.

[0019] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 30-50% of pimavanserin tartrate, 15-21% of silicified microcrystalline cellulose, 10-17% of mannitol, 12-20% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.5-2% of neotame, 6-10% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.9-6% of sodium stearyl fumarate, and 0.45-1.5% of colloidal silicon dioxide.

[0020] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 38.1% pimavanserin tartrate, 16.67% silicified microcrystalline cellulose, 16.67% mannitol, 18.1% cross-linked polyvinylpyrrolidone, 1.43% neotame, 7.62% fumaric acid, 0.95% sodium stearyl fumarate and 0.48% colloidal silicon dioxide.

[0021] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 25% pimavanserin tartrate, 23% silicified microcrystalline cellulose, 20% mannitol, 23% cross-linked polyvinylpyrrolidone, 2% neotame, 2% fumaric acid, 3% sodium stearyl fumarate and 2% colloidal silicon dioxide.

[0022] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 57.14% of pimavanserin tartrate, 10.14% of silicified microcrystalline cellulose, 10.14% of mannitol, 11.71% of cross-linked polyvinylpyrrolidone, 0.71% of neotame, 8.57% of fumaric acid, 1% of sodium stearyl fumarate and 0.57% of colloidal silicon dioxide.

[0023] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 38.1% pimavanserin tartrate, 16.67% silicified microcrystalline cellulose, 4.76% mannitol, 18.1% cross-linked polyvinylpyrrolidone, 1.9% neotame, 19.05% fumaric acid, 0.95% sodium stearyl fumarate and 0.48% colloidal silicon dioxide.

[0024] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 40% pimavanserin tartrate, 20.5% silicified microcrystalline cellulose, 12.5% ​​mannitol, 12% cross-linked polyvinylpyrrolidone, 0.5% neotame, 6% fumaric acid, 8% sodium stearyl fumarate and 0.5% colloidal silicon dioxide.

[0025] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 40% pimavanserin tartrate, 20.5% silicified microcrystalline cellulose, 14.5% mannitol, 12% cross-linked polyvinylpyrrolidone, 0.5% neotame, 6% fumaric acid, 6% sodium stearyl fumarate and 0.5% colloidal silicon dioxide.

[0026] In the preferred technical solution of the present invention, the composition contains, by weight percentage, 43.48% of pimavanserin tartrate, 10.33% of silicified microcrystalline cellulose, 10.33% of mannitol, 20.65% of cross-linked polyvinylpyrrolidone, 1.63% of neotame, 8.7% of fumaric acid, 4.35% of sodium stearyl fumarate and 0.54% of colloidal silicon dioxide.

[0027] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 43.48% of pimavanserin tartrate, 10.33% of silicified microcrystalline cellulose, 10.33% of mannitol, 20.65% of cross-linked polyvinylpyrrolidone, 1.63% of neotame, 8.7% of citric acid, 4.35% of sodium stearyl fumarate and 0.54% of colloidal silicon dioxide.

[0028] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 44.44% of pimavanserin tartrate, 10.56% of silicified microcrystalline cellulose, 10.56% of mannitol, 21.11% of cross-linked polyvinylpyrrolidone, 1.67% of neotame, 8.89% of any one or a combination of calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, and sodium acetate trihydrate, 2.22% of sodium stearyl fumarate, and 0.56% of colloidal silicon dioxide.

[0029] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 23.53% of pimavanserin tartrate, 17.65% of microcrystalline cellulose, 16.47% of mannitol, 13.53% of cross-linked polyvinylpyrrolidone, 13.53% of sodium carboxymethyl starch, 1.18% of neotame, 5.88% of DL-tartaric acid, 2.35% of sodium stearyl fumarate, 1.18% of colloidal silicon dioxide and 4.71% of flavor.

[0030] In a preferred technical solution of the present invention, the composition is an oral preparation.

[0031] In a preferred technical solution of the present invention, the composition is selected from any one of chewable tablets, orally disintegrating tablets, dispersible tablets, granules, anhydrous swallowable granules, and suspensions.

[0032] In a preferred technical solution of the present invention, the disintegration time of the composition is no more than 60 s, preferably no more than 20 s.

[0033] In a preferred technical solution of the present invention, the friability of the composition is not higher than 1%, preferably not higher than 0.9%.

[0034] In a preferred technical solution of the present invention, the solubility of the composition placed in a hydrochloric acid solution (pH 1.2) for 5 minutes is ≥90%, preferably ≥95%.

[0035] In a preferred technical solution of the present invention, the solubility of the composition placed in a hydrochloric acid solution (pH 1.2) for 10 minutes is ≥95%, preferably ≥98%.

[0036] In a preferred technical solution of the present invention, the irritation score of the composition is less than 5 points, preferably less than 4.5 points.

[0037] Another object of the present invention is to provide a method for preparing a pimavanserin tartrate pharmaceutical composition. The composition contains, by weight percentage, 20-60% of pimavanserin tartrate, 15-50% of a filler, 5-30% of a disintegrant, 1-25% of a flavoring agent, 0.1-5% of a glidant and 0.1-10% of a lubricant. The method comprises the following steps: uniformly mixing the required amounts of the components and tableting to obtain the pharmaceutical composition.

[0038] According to a preferred technical solution of the present invention, the composition contains 22-57% (w / w) pimavanserin tartrate, preferably 30-50% (w / w), by weight percentage.

[0039] In a preferred technical solution of the present invention, the filler is selected from any one of mannitol, microcrystalline cellulose, sorbitol, lactose, starch or a combination thereof.

[0040] In a preferred technical solution of the present invention, the filler is composed of microcrystalline cellulose and mannitol in a mass ratio of 1-6:1, preferably 1-4:1.

[0041] According to a preferred technical solution of the present invention, the composition contains 20-45% (w / w), preferably 25-40% (w / w) of filler in terms of weight percentage.

[0042] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or a combination thereof.

[0043] In a preferred technical solution of the present invention, the composition contains 10-28% (w / w) of disintegrant, preferably 12-20% (w / w), by weight.

[0044] According to a preferred technical solution of the present invention, the flavoring agent is selected from any one of neotame, sucralose, aspartame, acesulfame potassium, sucrose, sodium cyclamate, saccharin sodium, fumaric acid, ascorbic acid, sorbic acid, citric acid, malic acid, maleic acid, tartaric acid, disodium edetate, calcium gluconate, and sodium acetate trihydrate, or a combination thereof.

[0045] In a preferred technical solution of the present invention, the composition contains 2-21% (w / w), preferably 5-17% (w / w), of flavoring agent in terms of weight percentage.

[0046] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

[0047] In the preferred technical solution of the present invention, the composition contains 0.8-8% lubricant by weight, preferably 0.9-6%.

[0048] In a preferred technical solution of the present invention, the glidant is selected from any one of talc, micro-powder silica, colloidal silicon dioxide or a combination thereof.

[0049] In a preferred technical solution of the present invention, the composition contains 0.4-2% (w / w), preferably 0.45-1.5% (w / w), of the glidant by weight.

[0050] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 20-60% of pimavanserin tartrate, 5-30% of silicified microcrystalline cellulose, 1-25% of mannitol, 5-30% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.1-5% of neotame, 1-20% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.1-10% of sodium stearyl fumarate, and 0.1-5% of colloidal silicon dioxide.

[0051] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 22-57% of pimavanserin tartrate, 10-25% of silicified microcrystalline cellulose, 4-20% of mannitol, 10-28% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.2-3% of neotame, 5-19% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.8-8% of sodium stearyl fumarate, and 0.4-2% of colloidal silicon dioxide.

[0052] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 30-50% of pimavanserin tartrate, 15-21% of silicified microcrystalline cellulose, 10-17% of mannitol, 12-20% of any one or a combination of cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch, 0.5-2% of neotame, 6-10% of any one or a combination of fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, and sodium acetate trihydrate, 0.9-6% of sodium stearyl fumarate, and 0.45-1.5% of colloidal silicon dioxide.

[0053] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 38.1% pimavanserin tartrate, 16.67% silicified microcrystalline cellulose, 16.67% mannitol, 18.1% cross-linked polyvinylpyrrolidone, 1.43% neotame, 7.62% fumaric acid, 0.95% sodium stearyl fumarate and 0.48% colloidal silicon dioxide.

[0054] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 25% pimavanserin tartrate, 23% silicified microcrystalline cellulose, 20% mannitol, 23% cross-linked polyvinylpyrrolidone, 2% neotame, 2% fumaric acid, 3% sodium stearyl fumarate and 2% colloidal silicon dioxide.

[0055] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 57.14% of pimavanserin tartrate, 10.14% of silicified microcrystalline cellulose, 10.14% of mannitol, 11.71% of cross-linked polyvinylpyrrolidone, 0.71% of neotame, 8.57% of fumaric acid, 1% of sodium stearyl fumarate and 0.57% of colloidal silicon dioxide.

[0056] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 38.1% pimavanserin tartrate, 16.67% silicified microcrystalline cellulose, 4.76% mannitol, 18.1% cross-linked polyvinylpyrrolidone, 1.9% neotame, 19.05% fumaric acid, 0.95% sodium stearyl fumarate and 0.48% colloidal silicon dioxide.

[0057] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 40% pimavanserin tartrate, 20.5% silicified microcrystalline cellulose, 12.5% ​​mannitol, 12% cross-linked polyvinylpyrrolidone, 0.5% neotame, 6% fumaric acid, 8% sodium stearyl fumarate and 0.5% colloidal silicon dioxide.

[0058] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 40% pimavanserin tartrate, 20.5% silicified microcrystalline cellulose, 14.5% mannitol, 12% cross-linked polyvinylpyrrolidone, 0.5% neotame, 6% fumaric acid, 6% sodium stearyl fumarate and 0.5% colloidal silicon dioxide.

[0059] In the preferred technical solution of the present invention, the composition contains, by weight percentage, 43.48% of pimavanserin tartrate, 10.33% of silicified microcrystalline cellulose, 10.33% of mannitol, 20.65% of cross-linked polyvinylpyrrolidone, 1.63% of neotame, 8.7% of fumaric acid, 4.35% of sodium stearyl fumarate and 0.54% of colloidal silicon dioxide.

[0060] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 43.48% of pimavanserin tartrate, 10.33% of silicified microcrystalline cellulose, 10.33% of mannitol, 20.65% of cross-linked polyvinylpyrrolidone, 1.63% of neotame, 8.7% of citric acid, 4.35% of sodium stearyl fumarate and 0.54% of colloidal silicon dioxide.

[0061] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 44.44% of pimavanserin tartrate, 10.56% of silicified microcrystalline cellulose, 10.56% of mannitol, 21.11% of cross-linked polyvinylpyrrolidone, 1.67% of neotame, 8.89% of any one or a combination of calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, and sodium acetate trihydrate, 2.22% of sodium stearyl fumarate, and 0.56% of colloidal silicon dioxide.

[0062] In the preferred technical scheme of the present invention, the composition contains, by weight percentage, 23.53% of pimavanserin tartrate, 17.65% of microcrystalline cellulose, 16.47% of mannitol, 13.53% of cross-linked polyvinylpyrrolidone, 13.53% of sodium carboxymethyl starch, 1.18% of neotame, 5.88% of DL-tartaric acid, 2.35% of sodium stearyl fumarate, 1.18% of colloidal silicon dioxide and 4.71% of flavor.

[0063] In a preferred technical solution of the present invention, the composition is an oral preparation.

[0064] In a preferred technical solution of the present invention, the composition is selected from any one of chewable tablets, orally disintegrating tablets, dispersible tablets, granules, anhydrous swallowable granules, and suspensions.

[0065] In a preferred technical solution of the present invention, the disintegration time of the composition is no more than 60 s, preferably no more than 20 s.

[0066] In a preferred technical solution of the present invention, the friability of the composition is not higher than 1%, preferably not higher than 0.9%.

[0067] In a preferred technical solution of the present invention, the solubility of the composition placed in a hydrochloric acid solution (pH 1.2) for 5 minutes is ≥90%, preferably ≥95%.

[0068] In a preferred technical solution of the present invention, the solubility of the composition placed in a hydrochloric acid solution (pH 1.2) for 10 minutes is ≥95%, preferably ≥98%.

[0069] In a preferred technical solution of the present invention, the irritation score of the composition is less than 5 points, preferably less than 4.5 points.

[0070] Another object of the present invention is to provide the use of the pimavanserin tartrate pharmaceutical composition in preparing a drug for preventing and treating mental illness (hallucination and delusion) complicated by Parkinson's disease.

[0071] Unless otherwise stated, the present invention uses the following detection methods:

[0072] 1. Disintegration time: Using the USP basket assembly method, observe the dissolution time of the tablets in purified water at approximately 37°C.

[0073] 2. Friability: According to the tablet friability test method in accordance with the general rules 0923 of the third volume of the Chinese Pharmacopoeia 2020 edition.

[0074] 3. Hardness: Use a hardness tester to test the hardness of tablets.

[0075] 4. Dissolution: According to the General Rules 0931 Dissolution and Release Determination Method (Method 1) of Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0076] 5. The impurity content was detected by high performance liquid chromatography. The chromatographic conditions were as follows: octadecyl bonded silica gel was used as the filler, mobile phase A was an ion pair solution (pH 3.0 was adjusted with phosphoric acid), mobile phase B was acetonitrile, flow rate was 1.0 ml / min, column temperature was 30°C, detection wavelength was 215 nm, injection volume was 10 μl, and gradient elution was used.

[0077] Time / min Mobile phase A% Mobile phase B% 0 70 30 30 15 85 35 5 95 45 5 95 55 70 30 65 70 30

[0078] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0079] Compared with the prior art, the present invention has the following beneficial technical effects:

[0080] 1. The composition and ratio of the pimavanserin tartrate pharmaceutical composition of the present invention are scientifically screened. The pimavanserin tartrate composition has the advantages of high stability, good quality uniformity, low friability, stable blood drug concentration, small in vivo variation, improved irritation and patient compliance, better cost, etc., which significantly improves the safety and effectiveness of the drug.

[0081] 2. The preparation method of the present invention has the advantages of simple operation, environmental protection, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 In vitro dissolution study of the pharmaceutical composition of the present invention.

[0083] Figure 2 In vivo absorption study of the pharmaceutical composition of the present invention. DETAILED DESCRIPTION

[0084] The present invention is described below with reference to Examples, but the present invention is not limited to the Examples.

[0085] Impurity numbers and chemical names of specific embodiments:

[0086]

[0087] Example 1 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0088] The composition of the pimavanserin tartrate pharmaceutical composition:

[0089] Components Dosage(g) Pimavanserin tartrate 16 Silicified Microcrystalline Cellulose 7 Mannitol 7 Crospovidone 7.6 Neotame 0.6 Fumaric Acid 3.2 Sodium stearyl fumarate 0.4 Colloidal Silica 0.2 total 42

[0090] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 105 mg, has a hardness of 22.3N, and a friability of 0.31%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 13.5 seconds.

[0091] Example 2 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0092] The composition of the pimavanserin tartrate pharmaceutical composition:

[0093] Components Dosage(g) Pimavanserin tartrate 4 Silicified Microcrystalline Cellulose 3.68 Mannitol 3.2 Crospovidone 3.68 Neotame 0.32 Fumaric Acid 0.32 Sodium stearyl fumarate 0.48 Colloidal Silica 0.32 total 16

[0094] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 160 mg, has a hardness of 22.6 N, and a friability of 0.28%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 15.3 s.

[0095] Example 3 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0096] The composition of the pimavanserin tartrate pharmaceutical composition:

[0097] Components Dosage(g) Pimavanserin tartrate 4 Silicified Microcrystalline Cellulose 0.71 Mannitol 0.71 Crospovidone 0.82 Neotame 0.05 Fumaric Acid 0.6 Sodium stearyl fumarate 0.07 Colloidal Silica 0.04 total 7

[0098] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 70 mg, has a hardness of 9.9N, and a friability of 0.82%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 50.5s.

[0099] Example 4 Preparation of Pimavanserin Tartrate Pharmaceutical Composition

[0100] The composition of the pimavanserin tartrate pharmaceutical composition:

[0101]

[0102]

[0103] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 105 mg, has a hardness of 16.6 N, and a friability of 0.38%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 10.7 s.

[0104] Example 5 Preparation of pimavanserin tartrate pharmaceutical composition

[0105] The composition of the pimavanserin tartrate pharmaceutical composition:

[0106] Components Dosage(g) Pimavanserin tartrate 4 Silicified Microcrystalline Cellulose 2.05 Mannitol 1.25 Crospovidone 1.2 Neotame 0.05 Fumaric Acid 0.6 Sodium stearyl fumarate 0.8 Colloidal Silica 0.05 total 10

[0107] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain (each tablet weighs 100 mg, has a hardness of 14.1 N, and a friability of 0.6%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 22.1 s.

[0108] Example 6 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0109] The composition of the pimavanserin tartrate pharmaceutical composition:

[0110] Components Dosage(g) Pimavanserin tartrate 40 Silicified Microcrystalline Cellulose 20.5 Mannitol 14.5 Crospovidone 12 Neotame 0.5 Fumaric Acid 6 Sodium stearyl fumarate 6 Colloidal Silica 0.5 total 100

[0111] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame and fumaric acid, mixing them evenly, then adding the required amount of sodium stearyl fumarate, mixing them evenly, and directly tableting them to obtain (each tablet weighs 100 mg, hardness is 15.8N, friability is 0.58%). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 12.3s.

[0112] Example 7 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0113] The composition of the pimavanserin tartrate pharmaceutical composition:

[0114] Components Dosage(g) Pimavanserin tartrate 20 Silicified Microcrystalline Cellulose 4.75 Mannitol 4.75 Crospovidone 9.5 Neotame 0.75 Fumaric Acid 4.0 Sodium stearyl fumarate 2.0 Colloidal Silica 0.25 total 46

[0115] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, silicified microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, neotame, and fumaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 92 mg, has a hardness of 13.8N, and a friability of 0.42%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 20 seconds.

[0116] Example 8 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0117] The composition of the pimavanserin tartrate pharmaceutical composition:

[0118]

[0119]

[0120] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and citric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain (each tablet weighs 92 mg, has a hardness of 12N, and a friability of 0.59%). According to the method described in the present invention, the tablets obtained are complete in shape, have no cracks or fragments, and have a disintegration time of 24 seconds.

[0121] Example 9 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0122] The composition of the pimavanserin tartrate pharmaceutical composition:

[0123] Components Dosage(g) Pimavanserin tartrate 8.0 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 Calcium Gluconate 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0124] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and calcium gluconate, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 14N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 21s.

[0125] Example 10 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0126] The composition of the pimavanserin tartrate pharmaceutical composition:

[0127] Components Dosage(g) Pimavanserin tartrate 8.0 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 Maleic acid 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0128] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and maleic acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 13.4 N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 18 seconds.

[0129] Example 11 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0130] The composition of the pimavanserin tartrate pharmaceutical composition:

[0131]

[0132]

[0133] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and sorbic acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 14N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 16s.

[0134] Example 12 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0135] The composition of the pimavanserin tartrate pharmaceutical composition:

[0136] Components Dosage(g) Pimavanserin tartrate 8 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 DL-Malic Acid 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0137] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and DL-malic acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 17.8N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 36s.

[0138] Example 13 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0139] The composition of the pimavanserin tartrate pharmaceutical composition:

[0140] Components Dosage(g) Pimavanserin tartrate 8 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 Edetate Disodium 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0141] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and disodium edetate, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 16.8N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 26s.

[0142] Example 14 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0143] The composition of the pimavanserin tartrate pharmaceutical composition:

[0144] Components Dosage(g) Pimavanserin tartrate 8 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 L-Malic Acid 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0145] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and L-malic acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 14.5N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 25s.

[0146] Example 15 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0147] The composition of the pimavanserin tartrate pharmaceutical composition:

[0148]

[0149]

[0150] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and ascorbic acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 90 mg and has a hardness of 12.3N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 26s.

[0151] Example 16 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0152] The composition of the pimavanserin tartrate pharmaceutical composition:

[0153] Components Dosage(g) Pimavanserin tartrate 8 Microcrystalline Cellulose 6 Mannitol 5.6 Crospovidone 4.6 Sodium starch glycolate 4.6 Neotame 0.4 DL-Tartaric acid 2 Mint powder flavor 1.6 Sodium stearyl fumarate 0.8 Colloidal Silica 0.4 total 34

[0154] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, neotame, mint powder flavor and DL-tartaric acid, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets to obtain the tablets (each tablet weighs 170 mg and has a hardness of 18.9 N). According to the method described in the present invention, the tablets obtained are complete in shape, without cracks and fragments, and the disintegration time is 33 seconds.

[0155] Example 17 Preparation of the pimavanserin tartrate pharmaceutical composition of the present invention

[0156] The composition of the pimavanserin tartrate pharmaceutical composition:

[0157] Components Dosage(g) Pimavanserin tartrate 8.0 Silicified Microcrystalline Cellulose 1.9 Mannitol 1.9 Crospovidone 3.8 Neotame 0.3 Sodium acetate trihydrate 1.6 Sodium stearyl fumarate 0.4 Colloidal Silica 0.1 total 18

[0158] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing required amounts of pimavanserin tartrate, colloidal silicon dioxide, mannitol, silicified microcrystalline cellulose, cross-linked polyvinylpyrrolidone, neotame and sodium acetate trihydrate, mixing them evenly, then adding sodium stearyl fumarate, mixing them evenly, and directly pressing the powder into tablets (each tablet weighs 90 mg and has a hardness of 13.5 N). According to the method described in the present invention, the tablets obtained are complete in shape without cracks and fragments.

[0159] Comparative Example 1 Preparation of Pimavanserin Tartrate Pharmaceutical Composition

[0160] The composition of the pimavanserin tartrate pharmaceutical composition:

[0161] Components Dosage(g) Pimavanserin tartrate 8 Mannitol 45 Crospovidone 4 Sucralose 0.4 Mint powder flavor 0.2 Magnesium Stearate 0.6 Colloidal Silica 0.6 total 58.8

[0162] The preparation of the pimavanserin tartrate pharmaceutical composition comprises the following steps: weighing the required amount of pimavanserin tartrate, colloidal silicon dioxide, mannitol, cross-linked polyvinylpyrrolidone, sucralose and mint powder essence, mixing them evenly, then adding magnesium stearate, mixing them evenly, and directly pressing the powder into tablets to obtain (each tablet weighs 294 mg, has a hardness of 12.8N and a friability of 1.22%). According to the method described in the present invention, the disintegration time of the preparation tablet is 21 seconds.

[0163] Test Example 1: Dissolution Study of the Pimavanserin Tartrate Pharmaceutical Composition of the Present Invention

[0164] According to the dissolution and release determination method of the second method of Part IV General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia, 900 ml of pH 1.2 hydrochloric acid buffer was used as the dissolution medium, the paddle method (100 rpm), and the pharmaceutical composition of Example 1 and the original capsule (trade name Nuplazid, Acadia Pharmaceuticals Inc.) were used as examples. The in vitro dissolution of the pharmaceutical composition of the present invention was tested at 0 min, 5 min, 10 min, 15 min, 30 min, and 60 min. The results are shown in Table 1. Figure 1 .

[0165] Test Example 2 Stability Study of the Pimavanserin Tartrate Pharmaceutical Composition of the Present Invention

[0166] Taking the pimavanserin tartrate pharmaceutical composition of Example 7 as an example, the composition was placed at 60° C. for 2 weeks. The stability of the composition of the present invention was investigated and the results are shown in Table 1.

[0167] Table 1

[0168]

[0169] Taking the pimavanserin tartrate pharmaceutical composition of Example 1 as an example, the composition was placed at 40° C. and 75% relative humidity (RH) for 6 months to investigate the stability of the composition of the present invention. The results are shown in Table 2.

[0170] Table 2

[0171]

[0172] Test Example 3 Study on the Improvement of Irritation of the Pimavanserin Tartrate Pharmaceutical Composition of the Present Invention

[0173] The following method was used to investigate the irritation improvement of the pimavanserin tartrate pharmaceutical composition of the present invention:

[0174] 1) Before tasting, rinse your mouth with water, place the pharmaceutical composition to be tested on the tongue, wait for it to completely disintegrate for about 5 seconds, then spit it out and rinse your mouth with water;

[0175] 2) About 1 minute after tasting, test the initial irritation;

[0176] 3) About 10 minutes after tasting, test the aftertaste.

[0177] Scoring criteria: The irritation of pimavanserin tartrate was scored as 10 points, the upper limit was 20 points, the lower limit was 0 points, and 5 points was the upper limit of the acceptable score. The results are shown in Table 3.

[0178] Table 3

[0179] serial number Initial irritation Aftertaste irritation Comparative Example 1 5 8 Example 1 4.5 3.5 Example 4 3 2.8 Example 5 2.5 2.5 Example 6 2.5 2.5 Example 7 4.5 3.5 Example 8 3.5 3.5 Example 10 4.3 4.3 Embodiment 14 3.5 3.5

[0180] Test Example 4 Investigation of blood concentration of the pimavanserin tartrate pharmaceutical composition of the present invention

[0181] Eight male cynomolgus monkeys weighing ≥2kg and aged ≥1.5 years were selected and randomly divided into two groups, 4 in each group. The experimental animals were fasted overnight and provided with 120g of food 4 hours after administration. The drug group (oral administration of the drug composition of Example 1, the dose is 34mg / monkey / time) and the control group (the capsule drug of the original research company, Nuplazid, Acadia Pharmaceuticals Inc.) were administered with a volume of 10mL / monkey. Blood samples were collected for testing at 0.5h, 1h, 2h, 4h, 8h, 12h and 24h after administration. The blood drug concentration curve and its individual differences are shown in Table 4. Figure 2 The pharmaceutical composition of the present invention has the advantages of good in vivo absorption and small variation, faster onset of effect and long-term effect.

[0182] Table 4

[0183]

[0184] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical composition of pimavanserin tartrate, which comprises, by weight percentage, 20-60% of pimavanserin tartrate, 15-50% of a filler, 5-30% of a disintegrant, 1-25% of a flavoring agent, 0.1-5% of a glidant and 0.1-10% of a lubricant.

2. The pharmaceutical composition according to claim 1, wherein the composition contains 20-45% (w / w) of a filler, by weight percentage, wherein the filler is selected from any one of mannitol, microcrystalline cellulose, sorbitol, lactose, starch, or a combination thereof, and preferably the composition contains 25-40% (w / w) of a filler.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the composition contains 10-28% (w / w) of a disintegrant, and the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch, or a combination thereof, and preferably the composition contains 12-20% (w / w) of a disintegrant.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition contains 2-21% (w / w) of flavoring agent by weight percentage, and the flavoring agent is selected from any one of neotame, sucralose, aspartame, acesulfame potassium, sucrose, sodium cyclamate, saccharin sodium, fumaric acid, ascorbic acid, sorbic acid, citric acid, malic acid, maleic acid, tartaric acid, disodium edetate, calcium gluconate, and sodium acetate trihydrate, or a combination thereof, and preferably the composition contains 5-17% (w / w) of flavoring agent.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition contains 0.8-8% lubricant by weight, wherein the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate or a combination thereof, and preferably the composition contains 0.9-6% lubricant.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition contains 0.4-2% (w / w) of a glidant, by weight percentage, wherein the glidant is selected from any one of talc, micropowdered silica, colloidal silicon dioxide, or a combination thereof, and preferably the composition contains 0.45-1.5% (w / w) of the glidant.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition contains, by weight percentage, 20-60% pimavanserin tartrate, 5-30% silicified microcrystalline cellulose, 1-25% mannitol, 5-30% crospovidone or sodium carboxymethyl starch, 0.1-5% neotame, 1-20% fumaric acid, citric acid, calcium gluconate, maleic acid, sorbic acid, DL-malic acid, disodium edetate, L-malic acid, ascorbic acid, DL-tartaric acid, sodium acetate trihydrate, 0.1-10% sodium stearyl fumarate and 0.1-5% colloidal silicon dioxide.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is an oral preparation, preferably selected from any one of chewable tablets, orally disintegrating tablets, dispersible tablets, granules, anhydrous swallowable granules, and suspensions.

9. A method for preparing the pimavanserin tartrate pharmaceutical composition according to any one of claims 1 to 8, wherein the composition contains, by weight percentage, 20-60% of pimavanserin tartrate, 15-50% of a filler, 5-30% of a disintegrant, 1-25% of a flavoring agent, 0.1-5% of a glidant and 0.1-10% of a lubricant, and the method comprises the following steps: uniformly mixing the required amounts of the components and tableting to obtain the pharmaceutical composition.

10. Use of the pimavanserin tartrate pharmaceutical composition according to any one of claims 1 to 8 or the pimavanserin tartrate pharmaceutical composition obtained by the preparation method according to claim 9 in preparing a drug for preventing and treating mental illness (hallucination and delusion) complicated by Parkinson's disease.

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