Orally disintegrating tablet of pimavanserin or salt thereof and preparation method of orally disintegrating tablet

Abstract

The invention relates to a pharmaceutical preparation, and relates to an orally disintegrating tablet of pimavanserin or a salt thereof and a preparation method thereof. The orally disintegrating tablet of the pimavanserin or the salt thereof prepared by the technology provided by the invention is good in taste and convenient to take, can be rapidly disintegrated in the oral cavity and rapidly take effect, and solves the problems of Tibetan medicine, difficulty in swallowing and the like of Parkinson's psychosis patients.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to an orally disintegrating tablet of pimavanserin or a salt thereof and a preparation method thereof. Background Art

[0002] Parkinson's disease (PD) is the second largest neurodegenerative disease in the world, and patients are mainly elderly people over 60 years old. It is reported that the prevalence of Parkinson's disease in China in the world population in 2000 was 16-440.3 / 100,000, and the annual incidence was 1.5-8.7 / 100,000. Parkinson's disease psychosis (PDP) refers to a group of spectrum manifestations that appear in the course of Parkinson's disease. Patients have a series of positive clinical manifestations such as hallucinations, illusions, pseudohallucinations or delusions. It is one of the common non-motor symptoms of Parkinson's disease. PDP has a high incidence, is difficult to treat, and has more serious harm among Parkinson's non-motor symptoms. It has received widespread attention in recent years. The incidence of PDP is about 25% to 30%, and the results are slightly different due to different methods of epidemiological surveys.

[0003] Pimavanserin was developed by Acadia Pharmaceuticals in the United States and is the first drug approved by the U.S. FDA for the treatment of Parkinson's disease.

[0004]

[0005] Studies published in professional journals related to Parkinson's diseases show that about 80% of PD patients have difficulty swallowing, especially after ten years of PD course, a considerable number of Parkinson's psychosis patients have encountered difficulties in taking medicine. According to literature reports, 60% of patients choose to crush the tablets, and 68% of patients choose to open the capsule contents before taking them. Although the original preparation Nuplazid (patent US10449185B2) mentioned that the capsule can be taken as a whole, it can also be opened and then the entire contents can be sprinkled on a tablespoon (15mg) of applesauce, yogurt, pudding or liquid nutritional supplement. Patents WO2019025934A1, CN109498582A, CN106265605A, etc. all mention that pimavanserin or its salts have a strong bitter taste, so the instructions also mention that the drug / food mixture should be taken immediately without chewing. Don't chew and swallow the whole mouthful. This move undoubtedly increases the difficulty for patients with dysphagia to take the preparation. The strong bitter taste will trigger resistance from patients, which in turn leads to the problem of hiding medicine. Applesauce, pudding and other foods taken with meals are not common foods taken with meals by Chinese residents, and they will also increase the blood sugar burden of elderly diabetic patients. The inventor prepared comparative examples to reproduce that the existing invention technology cannot achieve an oral solid preparation that is easy to prepare, effectively masks the bitterness, and disintegrates quickly for easy patient consumption.

[0006] Patent CN109498582A discloses a method for preparing a pimavanserin orodisintegrating tablet, aiming to provide a rapidly disintegrating oral solid preparation. However, after using its optimal solution to prepare a comparative example, it was found that the taste test using an electronic tongue revealed that the tablet had a distinct bitter taste, and the addition of a flavoring agent did not completely cover the bitter taste.

[0007] Patent CN109908097A discloses a method for preparing a pimavanserin sustained-release orally disintegrating tablet, but the preparation method is a micropellet coated sustained-release tablet, which has special requirements for the process and equipment, and is difficult to achieve industrialization.

[0008] Patent CN106265605A aims to provide a pimavanserin orodispersible film with good taste, easy production and solving the problem of drug storage in patients. However, after using its embodiment to prepare comparative examples, it was found that the taste test using an electronic tongue showed that it had a significant bitter taste and did not solve the taste problem of pimavanserin.

[0009] Patent WO2019025934 A1 discloses a pimavanserin orodisintegrating tablet, which uses a combination of polymer materials and flavoring agents to prepare a finished product by direct mixing or wet granulation. However, the inventors found that because pimavanserin becomes sticky when exposed to water, it does not disintegrate quickly enough in the mouth. The Chinese Pharmacopoeia oral disintegration test method requires 124 seconds, and patients still need to take it with water, which does not actually solve the problem of convenient administration.

[0010] Therefore, it is very necessary to invent an oral solid preparation of pimavanserin or its salt which is easy to take, has a good taste, disintegrates quickly, and improves the patient's compliance with the preparation. Summary of the invention

[0011] The content of the present invention is to overcome the deficiencies of the prior art. The technical problem to be solved by the present invention is to provide an oral solid preparation of pimavanserin or its salt which is easy to take, has a good taste, disintegrates quickly and improves the compliance of patients.

[0012] In order to solve the above problems, the technical solution provided by the present invention is as follows:

[0013] An orally disintegrating tablet of pimavanserin or its salt, comprising the following components:

[0014] Pimavanserin or its salt, disintegrant, filler, flavoring agent, lubricant, glidant; the flavoring agent comprises a combination of sour agent, sweetener and flavoring agent.

[0015] Preferably, the acidulant is selected from one or more of citric acid, fumaric acid, malic acid, and tartaric acid; the sweetener is selected from one or more of neotame, sucralose, stevioside, aspartame, and saccharin sodium; and the flavoring agent is selected from one or more of strawberry flavor, mint flavor, cherry flavor, and orange flavor.

[0016] Preferably, the weight percentage of the acidulant in the orodisintegrating tablet is 2.00-8.00%; the weight percentage of the sweetener in the orodisintegrating tablet is 0.50-2.00%; the weight percentage of the flavoring agent in the orodisintegrating tablet is 0.50-2.00%. The types and proportions of API, disintegrant, filler, lubricant, and glidant can be selected by those skilled in the art from the existing technology without creative labor.

[0017] Preferably, an orally disintegrating tablet of pimavanserin or its salt comprises the following components:

[0018] 20% by weight of pimavanserin or its salt;

[0019] A disintegrant accounting for 0.00-12.00% by weight of the orally disintegrating tablet;

[0020] A filler accounting for 54.00-72.50% by weight of the orally disintegrating tablet;

[0021] A flavoring agent accounting for 3.00 to 12.00% by weight of the orally disintegrating tablet; the flavoring agent comprises a combination of a sour agent, a sweetener and a flavoring agent;

[0022] A flavoring agent accounting for 0.50 to 2.00% by weight of the orally disintegrating tablet;

[0023] A lubricant accounting for 1.50 to 3.00% by weight of the orally disintegrating tablet;

[0024] The glidant accounts for 1.75-2.00% of the weight percentage of the orally disintegrating tablet.

[0025] Preferably, the pimavanserin orodisintegrating tablets of the present invention are composed of a filler, a disintegrant, a glidant, an acidulant, a sweetener, a flavoring agent and a lubricant.

[0026] Preferably, the filler is selected from one of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol-microcrystalline cellulose co-processed product, microcrystalline cellulose cross-linked calcium co-processed product and the like.

[0027] Preferably, the disintegrant is selected from one of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl methylcellulose and the like.

[0028] Preferably, the glidant is selected from one or more of talc, stearic acid, colloidal silicon dioxide, fumed silicon dioxide and the like.

[0029] Preferably, the acidulant is selected from one or more of citric acid, fumaric acid, tartaric acid, malic acid and the like.

[0030] Preferably, the sweetener is selected from one or more of sucralose, neotame, aspartame, steviol glycosides, saccharin sodium and the like.

[0031] Preferably, the flavoring agent is selected from one or more of strawberry flavor, mint flavor, cherry flavor, orange flavor and the like.

[0032] Preferably, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, calcium stearate and the like.

[0033] Preferably, in one or more patent embodiments of the orodisintegrating tablets described above, the proportion of filler is 54.00-72.50%, the proportion of disintegrant is 0.00-12.00%, the proportion of glidant is 1.75-2.00%, the proportion of lubricant is 1.50-3.00%, the proportion of sour agent is 2.00-8.00%, the proportion of sweetener is 0.50-2.00%, and the proportion of flavoring agent is 0.50-2.00%.

[0034] Furthermore, the filler is preferably silicified microcrystalline cellulose, the disintegrant is preferably cross-linked polyvinylpyrrolidone, the glidant is preferably colloidal silicon dioxide and talc, the acidulant is preferably fumaric acid, the sweetener is preferably neotame, the flavoring agent is preferably mint essence, and the lubricant is preferably sodium stearyl fumarate.

[0035] Further, the most preferred invention prescription of the present invention is as follows:

[0036] Table 1: The most preferred prescription of the present invention

[0037]

[0038]

[0039] First, pimavanserin or its salt is mixed with a glidant, and the mixture is passed through a 40-mesh sieve. The remaining excipients are added to the pimavanserin or its salt silicon dioxide co-processed product, and mixed for 5 to 10 minutes using a multi-directional mixer. Tablets are pressed to obtain orally disintegrating tablets.

[0040] Patents WO2019025934 A1, CN109498582A, CN106265605A, etc. all mention that pimavanserin or its salts have a strong bitter taste. During the research process, it was found that conventional flavoring agents and their combinations cannot effectively cover up the discomfort of pimavanserin. Although patent WO2019025934 A1 mentions that its bitterness can be covered up by adding flavoring agents and flavoring agents. However, after many experiments, the inventors found that although conventional flavoring agent combinations can cover up part of the bitterness, they cannot cover up its bitter aftertaste (bitter aftertaste is the bitterness that remains in the mouth after taking the drug). In the process of optimizing the flavoring agent prescription, the inventors were surprised to find that the commonly used pH adjuster as an acidulant, combined with the sweetener neotame and the flavoring agent mint essence in a specific ratio, had an unexpected effect.

[0041] Bitterness and bitter aftertaste were evaluated by volunteers and electronic tongue.

[0042] Refer to the evaluation method for establishing bitterness scoring standards in the taste masking study of levocetirizine hydrochloride in Drug Evaluation Research (Volume 46, Issue 9, September 2023). Ten volunteers were trained to select different concentrations of pimavanserin tartrate solution as the reference solution for bitterness scoring. The results are shown in Table 2.

[0043] Table 2: Bitterness Rating Criteria

[0044] serial number Taste Description grade Bitterness Reference solution 1 Almost no bitterness Ⅰ 0.5～1.5 0.00mg / ml 2 Slightly bitter Ⅱ 1.5～2.5 0.25mg / ml 3 Acceptable bitterness Ⅲ 2.5～3.5 0.50mg / ml 4 Bitter, but still acceptable Ⅳ 3.5～4.5 0.75mg / ml 5 Unbearable bitterness Ⅴ 4.5～5.5 1mg / ml

[0045] The disintegration time was evaluated according to the Chinese Pharmacopoeia orally disintegrating tablet test method.

[0046] In addition, the researchers also found that due to the high viscosity of pimavanserin, the currently prepared orodisintegrating tablets, such as patents WO2019025934A1 and CN109498582A, cannot achieve the expected effect of rapid disintegration in the mouth. During the prescription screening process, the R&D personnel found that, inconsistent with conventional cognition, the amount of disintegrant did not significantly affect the disintegration performance of pimavanserin. However, the researchers were surprised to find that silicified microcrystalline cellulose, a filler conventionally used for dry granulation, played an unexpected role in this product and greatly improved the disintegration performance.

[0047] Compared with the prior art, the present invention has the following advantages: the pimavanserin solid preparation of the present invention has the technical characteristics of being able to dissolve quickly in the oral cavity, having a good taste, and avoiding the behavior of mental patients hiding medicine to resist. It is convenient to take, has a good taste, has a good effect of masking bitterness and bitter aftertaste, and disintegrates quickly within 60 seconds, thereby improving the patient's compliance with taking. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 These are graphs showing the bitter taste evaluation of the electronic tongue and volunteers in Examples 1 to 8;

[0049] Figure 2 The electronic tongue evaluation bitter aftertaste graphs of Examples 1 to 8;

[0050] Figure 3 These are bitter taste evaluation diagrams of the electronic tongue and volunteers in Examples 9 to 17;

[0051] Figure 4 These are graphs showing the bitter aftertaste evaluated by the electronic tongue in Examples 9 to 17. DETAILED DESCRIPTION

[0052] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0053] Comparative Example 1 (Reproduced from patent CN109498582A embodiment):

[0054] Table 3: Comparative Example 1 Prescription Table

[0055] Raw materials percentage Single tablet dosage (mg) Pimavanserin 8.50％ 34.00 Mannitol 42.00％ 168.00 Microcrystalline Cellulose 42.00 168.00 Crospovidone 6.00 24.00 Aspartame 1.00 4.00 Micro powder silica gel 1.20 4.80 Magnesium Stearate 1.00 4.00

[0056] Preparation process:

[0057] (1) Pass pimavanserin through a 100-mesh sieve and set aside.

[0058] (2) Take the prescribed amount of raw materials and auxiliary materials and mix them evenly in a small three-dimensional mixer.

[0059] (3) Determine the drug content of the mixture and calculate the tablet weight.

[0060] (4) Direct tableting.

[0061] Comparative Example 2 (Reproduced from patent US10449185B2 embodiment):

[0062] Table 4: Comparative Example 2 Prescription Table

[0063] Raw materials percentage Single tablet dosage (mg) Pimavanserin tartrate 40.00％ 40.00 Microcrystalline Cellulose 59.00％ 59.00 Magnesium Stearate 1.00％ 1.00 Hydroxypropyl methylcellulose capsules One One

[0064] Preparation process

[0065] (1) Pimavanserin is granulated with water to prepare a large-particle API with a Dv90 greater than 200 μm.

[0066] (2) Take the prescribed amount of raw materials and auxiliary materials and mix them evenly.

[0067] (3) Capsule filling.

[0068] Comparative Example 3 (Reproduced from patent CN106265605A embodiment):

[0069] Table 5: Comparative Example 3 Prescription Table

[0070] Raw materials Single tablet dosage (mg) Pimavanserin tartrate 20.00 Sucralose 2.00 Citric acid 1.50 Microcrystalline Cellulose 4.00 glycerin 2.00 Hydroxypropyl methylcellulose 18.00 Purified water qs

[0071] Preparation process:

[0072] Add pimavanserin tartrate, sucralose, anhydrous citric acid, microcrystalline cellulose, and hydroxypropyl methylcellulose to an appropriate amount of purified water, stir evenly, slowly swell for about 30 minutes, then add glycerol and stir evenly. Stand to degas, apply, dry at 60°C, remove the film, and cut according to specifications to obtain pimavanserin tartrate oral fast-dissolving film.

[0073] Comparative Example 4 ( Reproduced from patent WO2019025934A1 embodiment):

[0074] Table 6: Comparative Example 4 Prescription Table

[0075] Raw materials Single tablet dosage (mg) Pimavanserin tartrate 40.00 Mannitol 225.00 Crospovidone 20.00 Colloidal Silica 3.00 Sucralose 2.00 Cherry flavor 1.00 Magnesium Stearate 3.00 total 0.00

[0076] Preparation process:

[0077] 1) Add half of the mannitol (passed through a 25-mesh sieve), pimavanserin (passed through a 25-mesh sieve), and the remaining mannitol into a blender and mix for 5 minutes.

[0078] 2) Add other excipients except magnesium stearate and colloidal silicon dioxide and mix for 3 minutes.

[0079] 3) Add magnesium stearate and colloidal silicon dioxide and mix for 5 minutes.

[0080] 4) Tablet pressing.

[0081] Table 7: Comparison of disintegration time of comparative examples 1 and 4 with the preferred formulation of the present invention (including stability)

[0082]

[0083] Table 8: Comparative results of electronic tongue testing and volunteer trials in Examples 1, 2, 3, 4 and the preferred prescription of the present invention

[0084]

[0085] Flavor correctors significantly affect the taste masking performance, and thus affect the taste. Therefore, it is necessary to study their types and dosages. According to the flavor provided by different flavor correctors, they are divided into acidulants, sweeteners, and flavoring agents. Among them, the acidulants are fumaric acid and citric acid, the sweeteners are neotame and sucralose, and the flavoring agents are strawberry flavor and mint flavor. The following 8 examples of DOE experiments were designed, and the response evaluation of bitterness and bitter aftertaste was carried out by electronic tongue and volunteers. Its prescription and test results are shown in Table 9 and Table 10:

[0086] Specific embodiments 1 to 8:

[0087] Table 9: Prescription table of Examples 1 to 8

[0088]

[0089] First, pimavanserin tartrate and colloidal silicon dioxide are mixed together and passed through a 40-mesh sieve. The remaining excipients are added to the pimavanserin or its salt silicon dioxide co-processed product, mixed for 5 to 10 minutes using a multi-directional mixer, and tablets are pressed to obtain orally disintegrating tablets.

[0090] Table 10: Electronic tongues of Examples 1 to 8 and volunteer evaluation results

[0091]

[0092]

[0093] The researchers were surprised to find that Example 5 had an unexpected masking effect on both bitterness and bitter aftertaste. Therefore, a more detailed study was conducted on the dosage ratio of the three.

[0094] Specific embodiments 9 to 17:

[0095] Table 11: Prescription table of Examples 9 to 17

[0096]

[0097] First, pimavanserin tartrate and colloidal silicon dioxide are mixed together and passed through a 40-mesh sieve. The remaining excipients are added to the pimavanserin tartrate and silicon dioxide co-processed product, mixed for 5 to 10 minutes using a multi-directional mixer, and tablets are pressed to obtain orally disintegrating tablets.

[0098] Table 12: Electronic tongues of Examples 9 to 17 and volunteer evaluation results

[0099]

[0100] Specific embodiments 18 to 25:

[0101] Table 13: Prescription table of Examples 18 to 25

[0102]

[0103] First, pimavanserin tartrate and colloidal silicon dioxide are mixed together and passed through a 40-mesh sieve. The remaining excipients are added to the pimavanserin or its salt silicon dioxide co-processed product, mixed for 5 to 10 minutes using a multi-directional mixer, and tablets are pressed to obtain orally disintegrating tablets.

[0104] Table 14: Electronic tongues of Examples 18 to 25 and volunteer evaluation results

[0105]

[0106]

[0107] Therefore, in combination with Examples 1 to 25, when the amount of fumaric acid is 4.00 to 16.00 mg, the amount of neotame is 1.00 to 4.00 mg, and the amount of mint flavor is within the range of 1.00 to 4.00 mg, an unexpected bitterness and bitter aftertaste masking effect can be achieved. The study also found that a simple combination cannot achieve a taste masking effect, and the selected combination has an obvious interactive effect, which improves the taste masking performance of the combination.

[0108] Specific Examples 26-32: Screening of Doses of Fillers and Disintegrants

[0109] Table 15: Prescription table of Examples 26 to 32

[0110]

[0111] First, pimavanserin tartrate and colloidal silicon dioxide were mixed together and passed through a 40-mesh sieve. The remaining excipients were added to the pimavanserin tartrate and silicon dioxide co-processed product, mixed for 5 to 10 minutes using a multi-directional mixer, and tablets were pressed to obtain orally disintegrating tablets. Test results:

[0112] Table 16: Disintegration time of Examples 26 to 32

[0113]

[0114] The results show that in this invention, the disintegrant has little effect on improving the disintegration performance. The silicified microcrystalline cellulose plays a decisive role in the disintegration performance in the formulation.

[0115] The influencing factors and accelerated stability results of Example 14 are as follows, see Table 17:

[0116] Table 17: Results of investigation on influencing factors of Example 14

[0117]

[0118] Table 18: Accelerated investigation results of Example 14

[0119]

[0120] From the stability results, it can be seen that the prepared samples have better stability. The relevant disintegration of the preparation samples under the formulation influencing factors and accelerated conditions meets the requirements and there is no tendency to exceed the limit.

[0121] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. An orally disintegrating tablet of pimavanserin or a salt thereof, characterized in that: The composition includes the following components: Pimavanserin or its salt, disintegrant, filler, flavoring agent, lubricant, glidant; the flavoring agent comprises a combination of sour agent, sweetener and flavoring agent.

2. The orally disintegrating tablet according to claim 1, wherein The acidulant is selected from one or more of citric acid, fumaric acid, malic acid, and tartaric acid; the sweetener is selected from one or more of neotame, sucralose, steviol glycosides, aspartame, and saccharin sodium; and the flavoring agent is selected from one or more of strawberry flavor, mint flavor, cherry flavor, and orange flavor.

3. The orally disintegrating tablet according to claim 2, characterized in that The weight percentage of the acidulant in the orodisintegrating tablet is 2.00-8.00%; the weight percentage of the sweetener in the orodisintegrating tablet is 0.50-2.00%; and the weight percentage of the flavoring agent in the orodisintegrating tablet is 0.50-2.00%.

4. The orally disintegrating tablet according to claim 1, wherein The press includes the following components: 20% by weight of pimavanserin or its salt; A disintegrant accounting for 0.00-12.00% by weight of the orally disintegrating tablet; A filler accounting for 54.00-72.50% by weight of the orally disintegrating tablet; A flavoring agent accounting for 3.00 to 12.00% by weight of the orally disintegrating tablet; the flavoring agent comprises a combination of a sour agent, a sweetener and a flavoring agent; A flavoring agent accounting for 0.50 to 2.00% by weight of the orodisintegrating tablet; A lubricant accounting for 1.50 to 3.00% by weight of the orally disintegrating tablet; The glidant accounts for 1.75-2.00% of the weight percentage of the orally disintegrating tablet.

5. The orally disintegrating tablet according to claim 4, characterized in that The disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl methylcellulose; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and hydrogenated castor oil.

6. The orally disintegrating tablet according to claim 4, characterized in that The filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol-microcrystalline cellulose co-processed product, and microcrystalline cellulose cross-linked calcium co-processed product; the glidant is selected from one or more of talc, stearic acid, colloidal silicon dioxide, and fumed silicon dioxide.

7. The orally disintegrating tablet according to claim 4, wherein The acidulant is selected from one or more of citric acid, fumaric acid, malic acid and tartaric acid.

8. The orally disintegrating tablet according to claim 4, wherein The weight percentage of the sour agent in the orally disintegrating tablet is 2.00-8.00%.

9. The orally disintegrating tablet according to claim 4, characterized in that The sweetener is selected from one or more of neotame, sucralose, steviol glycosides, aspartame, and saccharin sodium.

10. The orally disintegrating tablet according to claim 4, characterized in that The weight percentage of the sweetener in the orally disintegrating tablet is 0.50-2.00%.

11. The orally disintegrating tablet according to claim 4, characterized in that The flavoring agent is selected from one or more of strawberry flavor, mint flavor, cherry flavor, and orange flavor.

12. The orally disintegrating tablet according to claim 4, characterized in that The flavoring agent accounts for 0.50-2.00% by weight of the orally disintegrating tablet.

13. An orally disintegrating tablet of pimavanserin or a salt thereof, characterized in that: By weight percentage, it includes the following components: Pimavanserin tartrate 20.00%; Silicified microcrystalline cellulose 61.50%; Colloidal silicon dioxide 0.50%; Crospovidone 9.00%; Neotame 1.00%; Fumaric acid 4.00%; Mint flavor 1.00%; Sodium stearyl fumarate 1.50%; Talc 1.50%.

14. A method for preparing an orally disintegrating tablet according to any one of claims 1 to 13, characterized in that: The specific steps are as follows: firstly, pimavanserin or its salt is mixed with colloidal silicon dioxide, and the mixture is passed through a 40-mesh sieve, and the remaining auxiliary materials are added to the pimavanserin or its salt silicon dioxide co-processed product, and the mixture is mixed for 5 to 10 minutes using a multi-directional mixer, and tablets are pressed to obtain orally disintegrating tablets.

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