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

Abstract

Disclosed are an orally disintegrating tablet of Pimavanserin or a salt thereof, and a preparation method therefor. The orally disintegrating tablet comprises Pimavanserin or a salt thereof, a disintegrant, a filler, a corrigent, a lubricant, and a glidant, wherein the corrigent comprises a combination of an acidulant, a sweetener, and a flavoring agent; 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 sodium saccharin; and the flavoring agent is selected from one or more of strawberry essence, mint essence, cherry essence, and orange essence.

Description

A method for preparing orally disintegrating tablets of pimozide or its salts. Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to an orally disintegrating tablet of pimovaserine or its salt and a method for preparing the same. Background Technology

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, primarily affecting people over 60 years of age. Reports indicate that in 2000, the prevalence of PD in China was 16–440.3 per 100,000, with an annual incidence rate of 1.5–8.7 per 100,000. Parkinson's disease psychosis (PDP) refers to a spectrum of manifestations that occur during the course of PD, characterized by hallucinations, illusions, pseudo-hallucinations, or delusions, and is one of the common non-motor symptoms of PD. PDP has a high incidence, is difficult to treat, and is considered one of the most serious non-motor symptoms of PD, thus receiving widespread attention in recent years. The incidence of PDP is approximately 25%–30%, with slight variations depending on the epidemiological survey methods.

[0003] Pimovanserine, developed by Acadia Pharmaceuticals, is the first drug approved by the FDA for the treatment of Parkinson's disease.

[0004] Studies published in relevant Parkinson's disease journals show that approximately 80% of PD patients experience difficulty swallowing, especially after ten years of PD progression, with a significant proportion encountering medication difficulties. According to literature reports, 60% of patients choose to crush the tablets, and 68% choose to open the capsule contents before taking the medication. While the original formulation Nuplazid (patent US10449185B2) mentions that the capsule can be taken whole or opened and then sprinkled with a tablespoon (15mg) of applesauce, yogurt, pudding, or liquid nutritional supplement, patents WO2019025934A1, CN109498582A, and CN106265605A all mention that pimovarselin or its salt has a strong bitter taste, therefore the instructions also state that the medication / food mixture should be taken immediately without chewing. Swallowing it whole without chewing undoubtedly increases the difficulty for patients with dysphagia to take the preparation. The strong bitterness can trigger resistance in patients, leading to issues related to medication reflux. Consuming applesauce, pudding, and similar foods with meals is not common among Chinese residents, and these can increase the glycemic burden in elderly diabetic patients. Through comparative examples prepared and reproduced by the inventors, it has been found that existing technologies cannot produce an oral solid dosage form that is easy to prepare, effectively masks bitterness, and disintegrates rapidly for convenient patient administration.

[0005] Patent CN109498582A discloses a method for preparing pimovacerin orally disintegrating tablets, aiming to provide a rapidly disintegrating oral solid dosage form. However, after preparing the comparative example using its optimal scheme, it was found that when the taste test was conducted using an electronic tongue, it was found that the bitterness was obvious, and the addition of the flavoring agent did not completely mask the bitterness.

[0006] Patent CN109908097A discloses a method for preparing pimovaserine sustained-release orally disintegrating tablets, but it prepares micro-particle-coated sustained-release tablets, which have special requirements for the process and equipment, making industrialization difficult.

[0007] Patent CN106265605A aims to provide an oral disintegrating film for pimovaserine that has a good taste, is easy to produce, and solves the problem of pimovaserine's taste in Tibetan medicine. However, after preparing comparative examples using its embodiments, it was found that taste tests conducted using an electronic tongue revealed a significant bitterness, and the taste problem of pimovaserine was not solved.

[0008] Patent WO2019025934 A1 discloses a pimovaserin orally disintegrating tablet, which is prepared by direct mixing or wet granulation using a combination of polymer materials and flavoring agents. However, the inventors found that because pimovaserin becomes sticky when it comes into contact with water, its disintegration in the oral cavity is not rapid enough. The oral disintegration test method in the Chinese Pharmacopoeia requires 124 seconds, and patients still need to take it with water, which does not actually solve the problem of convenient administration.

[0009] Therefore, it is essential to invent an oral solid dosage form of pimovaserine or its salts that is convenient to take, has a good taste, disintegrates rapidly, and improves patient compliance. Summary of the Invention

[0010] The present invention aims to overcome the shortcomings of the prior art. The technical problem to be solved by the present invention is to provide an oral solid dosage form of pimovaserine or its salt that is convenient to take, has a good taste, disintegrates rapidly, and improves patient compliance.

[0011] To address the above problems, the technical solution provided by this invention is as follows:

[0012] A pimozantrone orally disintegrating tablet or a salt thereof, comprising the following components:

[0013] Pimovanserine or its salts, disintegrants, fillers, flavoring agents, lubricants, and flow aids; the flavoring agents include combinations of acidulants, sweeteners, and flavoring agents.

[0014] 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, steviol glycosides, aspartame, and sodium saccharin; and the flavoring agent is selected from one or more of strawberry flavoring, peppermint flavoring, cherry flavoring, and orange flavoring.

[0015] Preferably, the acidulant accounts for 2.00-8.00% of the weight of the orally disintegrating tablet; the sweetener accounts for 0.50-2.00% of the weight of the orally disintegrating tablet; and the flavoring agent accounts for 0.50-2.00% of the weight of the orally disintegrating tablet. Those skilled in the art can select appropriate existing technical solutions for the types and proportions of APIs, disintegrants, fillers, lubricants, and gliding agents without requiring creative effort.

[0016] Preferably, an orally disintegrating tablet of pimozide or a salt thereof comprises the following components:

[0017] 20% by weight of pimozantrone or its salt in orally disintegrating tablets;

[0018] Disintegrant comprising 0.00-12.00% by weight of orally disintegrating tablets;

[0019] Filler comprising 54.00-72.50% by weight of orally disintegrating tablets;

[0020] A flavoring agent comprising 3.00–12.00% by weight of the orally disintegrating tablets; said flavoring agent comprising a combination of acidulants, sweeteners, and flavoring agents;

[0021] Flavoring agent comprising 0.50–2.00% by weight of orally disintegrating tablets;

[0022] A lubricant comprising 1.50–3.00% by weight of the disintegrating tablets;

[0023] A gliding agent comprising 1.75–2.00% of the weight of orally disintegrating tablets.

[0024] Preferably, the pimozantrone orally disintegrating tablets of the present invention are composed of fillers, disintegrants, gliding agents, acidulants, sweeteners, flavoring agents and lubricants.

[0025] Preferably, the filler is selected from one of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol microcrystalline cellulose co-treated product, microcrystalline cellulose cross-linked calcium co-treated product, etc.

[0026] Preferably, the disintegrant is selected from one of croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl methylcellulose, etc.

[0027] Preferably, the flow aid is selected from one or more of talc, stearic acid, colloidal silica, fumed silica, etc.

[0028] Preferably, the acidulant is selected from one or more of citric acid, fumaric acid, tartaric acid, and malic acid.

[0029] Preferably, the sweetener is selected from one or more of sucralose, neotame, aspartame, steviol glycosides, and sodium saccharin.

[0030] Preferably, the flavoring agent is selected from one or more of strawberry flavoring, mint flavoring, cherry flavoring, orange flavoring, etc.

[0031] Preferably, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, glyceryl behenate, hydrogenated castor oil, and calcium stearate.

[0032] Preferably, in one or more of the above-mentioned orally disintegrating tablets, 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 acidulant 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%.

[0033] Furthermore, the filler is preferably silicified microcrystalline cellulose, the disintegrant is preferably crospovidone, the flow aid is preferably colloidal silica and talc, the acidulant is preferably fumaric acid, the sweetener is preferably neotame, the flavoring agent is preferably peppermint flavoring, and the lubricant is preferably sodium stearate fumarate.

[0034] Furthermore, the most preferred formulation of this invention is as follows:

[0035] Table 1: Optimal Prescription of the Invention

[0036] First, mix pimova serine or its salt with a gliding agent and pass them through a 40-mesh sieve. Then, add the remaining excipients to the pimova serine or its salt silica co-treated material and mix for 5-10 minutes using a multi-directional mixer. Finally, compress the mixture into tablets to obtain orally disintegrating tablets.

[0037] Patents WO2019025934 A1, CN109498582A, and CN106265605A all mention pimovaserine or its strong bitter taste. During research, it was found that conventional flavoring agents and their combinations cannot effectively mask the unpleasant taste of pimovaserine. While patent WO2019025934 A1 mentions that bitterness can be masked by adding flavoring agents, the inventors discovered through numerous experiments that while conventional flavoring agent combinations can mask some bitterness, they cannot mask the bitter aftertaste (the lingering bitterness in the mouth after taking the medication). During the optimization of the flavoring agent formulation, the inventors surprisingly discovered that combining a commonly used pH adjuster as an acidulant with the sweetener neotame and the flavoring agent peppermint extract in a specific ratio produced unexpected results.

[0038] The bitterness and bitter aftertaste were evaluated using volunteers and electronic tongue assessments.

[0039] The evaluation method for establishing a bitterness scoring standard in the study of levocetirizine hydrochloride masking was referenced in *Drug Evaluation Research* (Vol. 46, No. 9, September 2023). Ten volunteers, after training, were selected and bitterness scores were calculated using different concentrations of pimovasselin tartrate solution as reference solutions. The results are shown in Table 2.

[0040] Table 2: Bitterness Scoring Criteria

[0041] The disintegration time was evaluated according to the method for determining orally disintegrating tablets in the Chinese Pharmacopoeia.

[0042] Furthermore, researchers found that due to the high viscosity of pimova serline, currently prepared orally disintegrating tablets, such as those with patents WO2019025934A1 and CN109498582A, cannot achieve the expected rapid disintegration in the oral cavity. During the formulation screening process, researchers discovered, contrary to conventional understanding, that the amount of disintegrant did not significantly affect the disintegration performance of pimova serline. However, researchers surprisingly found that silicified microcrystalline cellulose, a filler commonly used in dry granulation, had an unexpected effect in this product, greatly improving its disintegration performance.

[0043] Compared with the prior art, the present invention has the following advantages: The pimovaniline solid dosage form of the present invention is characterized by rapid dissolution in the oral cavity, excellent taste, and avoidance of drug resistance in psychiatric patients. It is convenient to take, has an excellent taste, good masking of bitterness and bitter aftertaste, and disintegrates rapidly within 60 seconds, improving patient compliance. Attached Figure Description

[0044] Figure 1 shows the electronic tongue and volunteers' bitterness evaluation in Examples 1-8;

[0045] Figure 2 shows the electronic tongue evaluation of bitter aftertaste in Examples 1-8;

[0046] Figure 3 shows the bitterness evaluation charts of electronic tongues and volunteers in Examples 9-17;

[0047] Figure 4 shows the bitter aftertaste evaluation diagrams of Examples 9-17 using the electronic tongue. Detailed Implementation

[0048] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0049] Comparative Example 1 (reproduced from Example CN109498582A):

[0050] Table 3: Prescription Table for Comparative Example 1

[0051] Preparation process:

[0052] (1) Take pimovanseline and pass it through a 100-mesh sieve for later use.

[0053] (2) Take the prescribed amount of raw materials and excipients and mix them evenly in a small three-dimensional mixer.

[0054] (3) Determine the drug content of the mixture and calculate the tablet weight.

[0055] (4) Direct compression.

[0056] Comparative Example 2 (reproduced from Example 2 of Patent US10449185B2):

[0057] Table 4: Prescription Table for Comparative Example 2

[0058] Preparation process

[0059] (1) Pimofanserine was granulated with water to prepare a large particle size active pharmaceutical ingredient with a Dv90 greater than 200 μm.

[0060] (2) Take the prescribed amount of raw materials and excipients and mix them evenly.

[0061] (3) Capsule filling.

[0062] Comparative Example 3 (reproduced from Example CN106265605A):

[0063] Table 5: Prescription Table for Comparative Example 3

[0064] Preparation process:

[0065] Add pimova serline tartrate, sucralose, anhydrous citric acid, microcrystalline cellulose, and hydroxypropyl methylcellulose to an appropriate amount of purified water, stir well, and allow to slowly swell for about 30 minutes. Then add glycerin and stir well. Allow to stand to degas, spread, dry at 60°C, remove from film, and cut to specifications to obtain pimova serline tartrate oral instant film.

[0066] Comparative Example 4 (reproduced from Example 4 of Patent WO2019025934A1):

[0067] Table 6: Prescription Table for Comparative Example 4

[0068] Preparation process:

[0069] 1) Add half of the mannitol (passed through a 25-mesh sieve), pimozantrone (passed through a 25-mesh sieve), and the remaining mannitol to a mixer and mix for 5 minutes.

[0070] 2) Add all auxiliary materials except magnesium stearate and colloidal silica, and mix for 3 minutes.

[0071] 3) Add magnesium stearate and colloidal silica, and mix for 5 minutes.

[0072] 4) Tableting.

[0073] Table 7: Comparison of disintegration time of Comparative Examples 1 and 4 with the preferred formulation of the present invention (including stability)

[0074] Table 8: Comparative Results of Electronic Tongue Detection and Volunteer Trial of Examples 1, 2, 3, and 4 with the Preferred Prescription of the Present Invention

[0075] Flavoring agents significantly affect taste-masking properties, thus influencing flavor. Therefore, their types and dosages need to be studied. Based on the flavors provided by different flavoring agents, they are categorized into acidulants, sweeteners, and flavoring agents. Fumaric acid and citric acid were selected as acidulants, neotame and sucralose as sweeteners, and strawberry and mint flavorings as flavoring agents. The DOE experimental design is illustrated in the following eight examples. Responses to bitterness and bitter aftertaste were evaluated using an electronic tongue and on volunteers. The formulations and test results are shown in Tables 9 and 10.

[0076] Specific embodiments 1-8:

[0077] Table 9: Prescription Tables for Examples 1-8

[0078] First, pimova serin tartrate is mixed with colloidal silica and passed through a 40-mesh sieve. The remaining excipients are added to the pimova serin or its salt silica co-treated product and mixed for 5-10 minutes using a multi-directional mixer. The mixture is then compressed into tablets to obtain orally disintegrating tablets.

[0079] Table 10: Electronic tongues and volunteer evaluation results in Examples 1-8

[0080] Researchers were surprised to find that Example 5 had an unexpected masking effect on both bitterness and bitter aftertaste. Therefore, further detailed studies were conducted on the proportions of the three ingredients.

[0081] Specific embodiments 9-17:

[0082] Table 11: Prescription Tables for Examples 9-17

[0083] First, pimova serin tartrate and colloidal silica are mixed together and passed through a 40-mesh sieve. The remaining excipients are added to the pimova serin tartrate and silica co-treated mixture and mixed for 5-10 minutes using a multi-directional mixer. The mixture is then compressed into tablets to obtain orally disintegrating tablets.

[0084] Table 12: Electronic tongue and volunteer evaluation results in Examples 9-17

[0085] Specific embodiments 18-25:

[0086] Table 13: Prescription Tables for Examples 18-25

[0087] First, pimova serin tartrate is mixed with colloidal silica and passed through a 40-mesh sieve. The remaining excipients are added to the pimova serin or its salt silica co-treated product and mixed for 5-10 minutes using a multi-directional mixer. The mixture is then compressed into tablets to obtain orally disintegrating tablets.

[0088] Table 14: Electronic tongue and volunteer evaluation results in Examples 18-25

[0089] Therefore, in conjunction with Examples 1-25, within the dosage ranges of 4.00-16.00 mg of fumaric acid, 1.00-4.00 mg of neotame, and 1.00-4.00 mg of peppermint flavoring, an unexpected masking effect on bitterness and bitter aftertaste can be achieved. The study also found that simple combinations do not achieve a masking effect; the selected combinations exhibit a significant interaction effect, enhancing the masking performance of the combination.

[0090] Specific Examples 26-32: Screening of Filler and Disintegrant Dosage

[0091] Table 15: Prescription Tables for Examples 26-32

[0092] First, pimova serin tartrate and colloidal silica are mixed and passed through a 40-mesh sieve. The remaining excipients are then added to the pimova serin tartrate and silica mixture, and the mixture is stirred for 5–10 minutes using a multi-directional mixer. The mixture is then compressed into tablets to obtain orally disintegrating tablets. Test results:

[0093] Table 16: Disintegration time of Examples 26-32

[0094] The results showed that, in this invention, the disintegrant had little effect on improving disintegration performance. Silicified microcrystalline cellulose played a decisive role in the disintegration efficiency of the formulation.

[0095] The influencing factors and accelerated stability results of Example 14 are as follows, as shown in Table 17:

[0096] Table 17: Results of the investigation of influencing factors in Example 14

[0097] Table 18: Results of accelerated testing in Example 14

[0098] The stability results show that the prepared sample has good stability. The disintegration of the sample under the influence of formulation factors and accelerated conditions meets the requirements and there is no tendency to exceed the limit.

[0099] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A mouth disintegrating tablet of pimavanserin or a salt thereof, characterized in that, Includes the following components: Pimovanserine or its salts, disintegrants, fillers, flavoring agents, lubricants, and flow aids; the flavoring agents include combinations of acidulants, sweeteners, and flavoring agents.

2. The orally disintegrating tablet as described in claim 1, characterized in that, 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 sodium saccharin; and the flavoring agent is selected from one or more of strawberry flavoring, peppermint flavoring, cherry flavoring, and orange flavoring.

3. The orally disintegrating tablet as described in claim 2, characterized in that, The acidulant accounts for 2.00–8.00% of the weight of the orally disintegrating tablets; the sweetener accounts for 0.50–2.00% of the weight of the orally disintegrating tablets; and the flavoring agent accounts for 0.50–2.00% of the weight of the orally disintegrating tablets.

4. The orally disintegrating tablet as described in claim 1, characterized in that, According to the following components: 20% by weight of pimozantrone or its salt in orally disintegrating tablets; Disintegrant comprising 0.00-12.00% by weight of orally disintegrating tablets; Filler comprising 54.00-72.50% by weight of orally disintegrating tablets; A flavoring agent comprising 3.00–12.00% by weight of the orally disintegrating tablets; said flavoring agent comprising a combination of acidulants, sweeteners, and flavoring agents; Flavoring agent comprising 0.50–2.00% by weight of orally disintegrating tablets; A lubricant comprising 1.50–3.00% by weight of the disintegrating tablets; A gliding agent comprising 1.75–2.00% of the weight of orally disintegrating tablets.

5. The orally disintegrating tablet as described in claim 4, characterized in that, The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl methylcellulose; the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, glyceryl behenate, calcium stearate, and hydrogenated castor oil.

6. The orally disintegrating tablet as described in claim 4, characterized in that, The filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol microcrystalline cellulose co-treated product, and microcrystalline cellulose cross-linked calcium co-treated product; the flow aid is selected from one or more of talc, stearic acid, colloidal silica, and fumed silica.

7. The orally disintegrating tablet as described in claim 4, characterized in that, The acidulant is selected from one or more of citric acid, fumaric acid, malic acid, and tartaric acid.

8. The orally disintegrating tablet as described in claim 4, characterized in that, The acidulant accounts for 2.00% to 8.00% of the weight of the orally disintegrating tablets.

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

10. The orally disintegrating tablet as described in claim 4, characterized in that, The sweetener accounts for 0.50–2.00% of the weight of the orally disintegrating tablets.

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

12. The orally disintegrating tablet as described in claim 4, characterized in that, The flavoring agent accounts for 0.50–2.00% of the weight of the orally disintegrating tablets.

13. An orally disintegrating tablet of pimozide or its salt, characterized in that, By weight percentage, it includes the following components: Pimovanserine tartrate 20.00%; 61.50% siliconized microcrystalline cellulose; Colloidal silica 0.50%; Cross-linked polyvinylpyrrolidone 9.00%; Neotame 1.00%; Fumaric acid 4.00%; Peppermint flavoring 1.00%; Sodium stearate 1.50%; Talc powder 1.50%.

14. A method for preparing orally disintegrating tablets as described in any one of claims 1 to 13, characterized in that, The specific steps are as follows: First, mix pimova serin or its salt with colloidal silica and pass them through a 40-mesh sieve. Then, add the remaining excipients to the pimova serin or its salt silica co-processed material and mix for 5-10 minutes using a multi-directional mixer. Finally, compress the mixture into tablets to obtain orally disintegrating tablets.

Images