Brexpiprazole oral soluble film composition and preparation method thereof

Abstract

The invention relates to a brexpiprazole oral soluble film and a preparation method thereof, the film agent does not use a thickening agent, and comprises 2%-10% of brexpiprazole, 60%-90% of a polymer film-forming material and 5%-30% of a plasticizer; the polymer film-forming material is a composition of hydroxypropyl methylcellulose and hydroxy propyl cellulose. The prepared brexpiprazole oral soluble film is flat in appearance, free of curl, uniform and smooth, free of visible particles, capable of being disintegrated rapidly and good in tensile strength and stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an orally disintegrating film of birepiperazole and its preparation method. Background Technology

[0002] Brepiprazole, jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharmaceuticals Ltd. of Denmark, is used to treat schizophrenia and major depressive disorder. The tablet form was approved by the FDA in July 2015. Its structural formula is as follows:

[0003]

[0004] As a treatment for mental illnesses, tablets are often poorly tolerated by patients, leading to issues such as refusal of treatment, hiding the medication, and vomiting, which hinders effective treatment. In contrast, oral dissolving films (ODFs) are a novel oral drug delivery system that has the advantages of adhering to the patient's mouth after administration, being difficult to spit out, requiring no swallowing, and rapidly disintegrating in the oral cavity.

[0005] Several patent documents in the prior art report the formulations and preparation methods of birepiperazole oral dissolving films. Among them, CN114767663A discloses a birepiperazole oral dissolving film with different combinations of polymeric film-forming materials as film-forming agents and the addition of 1% to 40% thickener. The main technical problem it addresses is: by adding a thickener to change the surface tension and viscosity of purified water, it solves the problem that hydrophobic birepiperazole disperses in purified water, agglomerates after standing, and the finished product has unqualified content and uniformity.

[0006] The researchers of this invention conducted an in-depth study on the above-mentioned technical solution of adding thickeners to avoid the aggregation of active pharmaceutical ingredients, and found that the formulation using thickeners has the following drawbacks:

[0007] ① The addition of thickeners will result in a longer defoaming time when the medicine solution is left to stand, which may easily lead to the separation of raw materials and excipients;

[0008] ② Choosing the wrong type of thickener can increase the risk of incompatibility with the active pharmaceutical ingredient.

[0009] Based on the above problems, the researchers of this invention did not use a thickener in the above formulation and successfully solved the problem of the active pharmaceutical ingredient easily agglomerating by micronizing birepiperazole. However, it was also found that the birepiperazole oral dissolution film without a thickener was prone to curling after film formation and drying, making it difficult to adhere to the lining material. There are few studies and reports on this technical problem in the prior art.

[0010] Oral dissolving film curling can cause a variety of adverse effects, such as: 1) If it curls after being taken out of the inner packaging bag, it is easy to clump in the mouth, prolonging the dissolving time; 2) If it curls during drying, it is easy to detach from the substrate and cannot be rolled up; 3) If it curls during inner packaging, it is easy to cause the oral dissolving film to fold and break in the inner packaging bag.

[0011] Therefore, optimizing the formulation of bripiprazole orally dissolving films without using thickeners to fundamentally overcome the problem of film curling after formation remains an unsolved technical problem in this field. The inventors of this application, while optimizing the types and amounts of film-forming materials in a formulation without thickeners, unexpectedly discovered that specific combinations of film-forming materials can effectively solve the problem of film curling during preparation, and the related formulation can shorten the disintegration time. The prepared bripiprazole orally dissolving films exhibit good safety and efficacy. Summary of the Invention

[0012] The technical problem to be solved by the present invention is: to fundamentally solve the problem of curling after drying of bripiprazole oral dissolving film by selecting appropriate film-forming materials and further optimizing their dosage without using thickeners, while ensuring that its disintegration time meets the requirements.

[0013] The technical problem of this invention is solved by the following technical solution:

[0014] On one hand, the present invention provides a bripiprazole oral dissolving film, which does not contain a thickener and comprises the following components in weight percentages of the film: bripiprazole 2% to 10%, polymeric film-forming material 60% to 90%, and plasticizer 5% to 30%; wherein the polymeric film-forming material is a combination of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0015] In some embodiments, the weight ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose in the polymeric film-forming material is 1:1 to 8:1.

[0016] In a further embodiment, the ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose in the polymeric film-forming material is 1:1 to 6.6:1.

[0017] In a further embodiment, the present invention provides a bripiprazole oral dissolving film, which is free of thickener and contains the following components in weight percentages of the film: bripiprazole 4% to 8%, hydroxypropyl cellulose 10% to 40%, hydroxypropyl methylcellulose 30% to 68%, and plasticizer 10% to 30%.

[0018] In a further embodiment, the present invention provides a bripiprazole oral dissolving film, which is free of thickener and contains the following components in weight percentages of the film: bripiprazole 4% to 8%, hydroxypropyl cellulose 10% to 25%, hydroxypropyl methylcellulose 50% to 65%, and plasticizer 10% to 30%.

[0019] In some embodiments, the plasticizer is selected from one or more combinations of polyethylene glycol 400, glycerol, propylene glycol, ethyl citrate, glyceryl triacetate, and castor oil.

[0020] In a further embodiment, the plasticizer is selected from one or more combinations of polyethylene glycol 400 and glycerin.

[0021] The thickeners described in this invention refer to substances that can alter the surface tension and viscosity of a film liquid, including but not limited to one or more of xanthan gum, carob gum, carrageenan, gum arabic, tragacanth gum, guar gum, sodium polyacrylate, sodium alginate, sodium carboxymethyl cellulose, sodium caseinate, trehalose, polyoxyethylene, polyvinylpyrrolidone, poloxamer, carbomer, maltodextrin, methylcellulose, hydroxyethyl cellulose, and propylene glycol alginate.

[0022] In some embodiments, the buripiperazole orally disintegrating film may further include one or more of the following: saliva stimulants, flavoring agents, fragrances, disintegrants, and colorants.

[0023] In a further embodiment, the saliva stimulant may be selected from one or more combinations of citric acid, malic acid, lactic acid, ascorbic acid, and tartaric acid, including but not limited to citric acid, malic acid, lactic acid, ascorbic acid, and tartaric acid.

[0024] In a further embodiment, the flavoring agent may be selected from one or more combinations of acesulfame potassium, sucralose, steviol glycosides, sodium saccharin, aspartame, cyclamate, glucose, fructose, sucrose, maltose, starch sugar, and lactose, including but not limited to acesulfame potassium, sucralose, steviol glycosides, sodium saccharin, aspartame, cyclamate, glucose, fructose, sucrose, maltose, starch sugar, and lactose.

[0025] In a further embodiment, the flavoring may be selected from one or more combinations of, but not limited to, peppermint flavoring, cocoa flavoring, strawberry flavoring, and orange flavoring.

[0026] In a further embodiment, the disintegrant is selected from one or more combinations of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone carboxymethyl cellulose sodium, crospovidone carboxymethyl starch sodium, starch, microcrystalline cellulose, and pregelatinized starch.

[0027] In a further embodiment, the colorant is selected from one or more combinations of titanium dioxide, pigments, and lakes, including but not limited to.

[0028] In some embodiments, the buripiperazole oral dissolving film of the present invention is composed of the following components in weight percentage: buripiperazole 4%–8%, glycerin 10%–30%, hydroxypropyl methylcellulose 30%–70%, and hydroxypropyl cellulose 10%–40%.

[0029] In a further embodiment, the birepiperazole orally disintegrating film of the present invention has any formulation consisting of the following components in weight percentages:

[0030] Prescription 1) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 52%, hydroxypropyl cellulose 24%;

[0031] Prescription 2) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 66%, hydroxypropyl cellulose 10%;

[0032] Prescription 3) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 64%, hydroxypropyl cellulose 12%;

[0033] Prescription 4) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 60%, hydroxypropyl cellulose 16%;

[0034] Prescription 5) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 38%, hydroxypropyl cellulose 38%;

[0035] Prescription 6) Biriperazole 5.8%, glycerin 20%, hydroxypropyl methylcellulose 62.8%, hydroxypropyl cellulose 11.4%;

[0036] Prescription 7) Buripiperazole 7%, glycerin 20%, hydroxypropyl methylcellulose 50%, hydroxypropyl cellulose 23%.

[0037] On the other hand, the present invention also provides a method for preparing a bripiprazole oral dissolving film, comprising the following steps:

[0038] a) Dissolve the prescribed amount of film-forming material in a suitable solvent to prepare a film-forming material solution, wherein the solvent may be selected from one or more of purified water and ethanol;

[0039] b) Prepare an API dispersion by sequentially adding the prescribed amount of plasticizer, birepiperazole and other excipients to a solvent;

[0040] c) Add the API dispersion to the film-forming material solution and stir until homogeneous. Let it stand to remove air bubbles before use.

[0041] d) Coat and dry, then store.

[0042] Compared with the prior art, the beneficial effects of the birepiperazole oral dissolving film of the present invention are as follows:

[0043] 1) Without using thickeners or other additional excipients that can make the drug film smooth, the problem of easy curling of biriperazole oral dissolution film after drying is fundamentally solved by selecting specific types of film-forming materials and optimizing their proportions, while also ensuring that its disintegration time meets the requirements (<60s).

[0044] 2) By controlling the amount of film-forming material, the disintegration time of the buripiperazole orally soluble film was further shortened (<30s).

[0045] 3) The birepiperazole orally disintegrating film prepared by this invention has a uniform and smooth surface, with no agglomeration of raw materials, and has good content uniformity and mechanical properties, which meet the requirements for clinical use. Detailed Implementation

[0046] The technical solution of the present invention will be further described below with reference to the embodiments. However, the scope of protection of the present invention includes, but is not limited to, these embodiments. Any changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0047] Unless otherwise specified, the average particle size (D) of biriperazole in the various embodiments and comparative examples described herein is as follows. 90 (Not exceeding 10μm)

[0048] The sources of some raw and auxiliary materials are shown below:

[0049] raw materials Function model factory biriperazole Active ingredients / Zhejiang Saimo Pharmaceutical Co., Ltd. Hydroxypropyl cellulose Film-forming materials EF PHARM Ashland (China) Investment Co., Ltd. Hydroxypropyl methylcellulose Film-forming materials SH-E15 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. glycerin plasticizer / Hunan Ercon Pharmaceutical Co., Ltd.

[0050] Example 1: Investigation of Film-Forming Material Types

[0051] Using polyethylene glycol 400 or glycerin as plasticizers, the effect of different types of polymeric film-forming materials on the film-forming phenomenon of birepiperazole oral dissolution film was investigated, with the smoothness of the film formed after coating as the indicator. Formulations 1-5 are shown in Table 1.

[0052] Table 1: Preliminary Test Prescriptions

[0053]

[0054]

[0055] Preparation process:

[0056] Preparation of film-forming material solution: Add the film-forming material slowly to water (water temperature ≥ 80℃) while stirring according to the prescription dosage, stir until evenly dispersed, add water to the prescription volume, then stir and cool to below 30℃ for later use;

[0057] API dispersion preparation: Add the prescribed amount of plasticizer and biriperazole to purified water in sequence, stir until evenly dispersed, and visually confirm that the material is evenly dispersed.

[0058] Mixing: Pour the prepared API dispersion into the film-forming material solution, rinse with purified water and transfer to the film-forming material, stir until completely mixed, and let stand to remove air bubbles before use;

[0059] Coating and drying: Set the coating speed to 0.07 m / min, the drying temperature to 60℃, and the drying time to 20 min-30 min. Adjust the coating thickness to keep the sheet weight within ±10% of the target sheet weight.

[0060] The results show that:

[0061] 1) Oral films made with a single film-forming material (Formulas 1-3) all exhibit varying degrees of curling after coating and drying, making them difficult to package.

[0062] 2) The combination of film-forming materials used, such as hydroxypropyl methylcellulose SH-E5 and hydroxypropyl methylcellulose SH-E15, resulted in an oral film (Formula 4) that also curled.

[0063] 3) The oral film (Formula 5) prepared by combining hydroxypropyl methylcellulose and hydroxypropyl cellulose was smooth after coating and drying. Therefore, hydroxypropyl methylcellulose and hydroxypropyl cellulose were initially selected as film-forming materials for the development of formulations.

[0064] Example 2:

[0065] Based on the screening results of Example 1, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) were selected as film-forming materials, and glycerol was selected as a plasticizer to prepare a bripiprazole oral dissolving film, with the following formulation.

[0066] Table 2: Prescription for Birepiperazole Oral Disintegrating Film in Example 2

[0067]

[0068]

[0069] Preparation process:

[0070] Preparation of film-forming material solution: While stirring, slowly add hydroxypropyl cellulose and hydroxypropyl methylcellulose to water (water temperature ≥ 80℃) and stir until evenly dispersed. Add water to the prescribed amount, then stir and cool to below 30℃ for later use.

[0071] API dispersion preparation: Add the prescribed amounts of glycerol and biriperazole to purified water in sequence, stir until evenly dispersed, and visually confirm that the material is evenly dispersed.

[0072] Mixing: Pour the prepared API dispersion into the film-forming material solution, rinse with purified water and transfer to the film-forming material, stir until completely mixed, and let stand to remove air bubbles before use;

[0073] Coating and drying: Set the coating speed to 0.07 m / min, the drying temperature to 60℃, and the drying time to 20 min-30 min. Adjust the coating thickness to keep the sheet weight within ±10% of the target sheet weight.

[0074] Storage: Place the dried sample in a polyethylene bag and store at room temperature.

[0075] The buripiperazole orally dissolving film prepared in Example 2 was a white, flat film that was not curled, had a uniform and smooth surface, and showed no aggregation of raw materials.

[0076] Examples 3-8: Investigation on the ratio and dosage of film-forming materials hydroxypropyl cellulose and hydroxypropyl methylcellulose

[0077] The formulation is shown in Table 3. The preparation process is the same as in Example 2. The effects of the weight ratio and amount of the film-forming materials hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) on the smoothness of the orally dissolving film were investigated. The formulation is as follows:

[0078] Table 3: Prescriptions for Biriperazole Oral Disintegrating Films in Examples 3-8

[0079]

[0080]

[0081] Comparative Examples 1-3

[0082] Comparative Example 1: Based on the formulation process of Example 2, the weight ratio of film-forming material hydroxypropyl methylcellulose to hydroxypropyl cellulose in the formulation was adjusted to 18:1.

[0083] Comparative Example 2: A sample was prepared according to the formulation of patent CN114767663A, with a weight ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose of film-forming material of 10:1, without the use of thickener polyvinylpyrrolidone.

[0084] Comparative Example 3: Based on the formulation process of Example 2, the weight ratio of film-forming material hydroxypropyl methylcellulose to hydroxypropyl cellulose in the formulation was adjusted to 0.5:1.

[0085] The formulations for Comparative Examples 1-3 are shown in Table 4, and the preparation process is the same as in Example 2.

[0086] Table 4: Prescriptions for Comparative Examples 1-3

[0087]

[0088] The results showed that different weight ratios of hydroxypropyl methylcellulose and hydroxypropyl cellulose affected the smoothness of the oral dissolution film after film formation.

[0089] When the weight ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose is greater than 10:1, the bripiprazole oral dissolution film prepared will curl and does not meet the requirements; when the weight ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose is 0.5:1, the bripiprazole oral dissolution film prepared will be flat, but the film will be too soft, difficult to peel off, and lack toughness, which does not meet the requirements.

[0090] When the weight ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose is 1:1 to 8:1, and more preferably 1:1 to 6.6:1, the resulting bripiprazole oral soluble film is a white, flat film that does not curl and meets the requirements.

[0091] Test Example 1

[0092] Further testing of disintegration time: determined according to the disintegration time test method (General Chapter 0921 of Chinese Pharmacopoeia 2020).

[0093] Table 5: Test Results

[0094]

[0095] Conclusion: When the ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose in the polymeric film-forming material is similar or the same, further reducing the ratio of the polymeric film-forming material to the active pharmaceutical ingredient birepiperazole results in shorter disintegration times and faster onset of action in Examples 7-8 compared to Examples 2 and 4.

[0096] Test Example 2

[0097] The chemical stability of Example 2 was tested after being placed at 60°C for 10 and 30 days, and the results are as follows.

[0098] Table 6: Chemical stability test results of Example 2

[0099]

[0100] The results above show that the buripiperazole oral dissolution film prepared by the present invention has excellent stability under high temperature conditions, and the impurity content increases slowly, far below the limit value. The oral dissolution film prepared by the present invention has a smooth and uniform appearance without curling, no visible particles, can disintegrate rapidly, and its tensile strength meets the relevant standards.

Claims

1. A birepiperazole orally dissolving film, characterized in that, It does not contain thickeners and contains the following components by weight percentage: buriperazole, a polymeric film-forming material and a plasticizer, wherein the polymeric film-forming material is a combination of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the weight ratio of the polymeric film-forming material hydroxypropyl methylcellulose to hydroxypropyl cellulose is 1:1 to 8:

1.

2. The birepiperazole orally dissolving film according to claim 1, characterized in that, It contains no thickeners and comprises the following components by weight percentage: 4%–8% bripiprazole, 10%–40% hydroxypropyl cellulose, 30%–68% hydroxypropyl methylcellulose, and 10%–30% plasticizer.

3. The birepiperazole orally dissolving film according to claim 1, characterized in that, The weight ratio of the polymeric film-forming material hydroxypropyl methylcellulose to hydroxypropyl cellulose is 1:1 to 6.6:

1.

4. The birepiperazole orally dissolving film according to claim 1, characterized in that, The plasticizer is selected from one or more of polyethylene glycol 400, glycerin, propylene glycol, ethyl citrate, glyceryl triacetate, and castor oil.

5. The birepiperazole orally dissolving film according to claim 1, characterized in that, It may further include one or more of the following: saliva stimulants, flavoring agents, disintegrants, flavorings, and colorings.

6. The birepiperazole orally dissolving film according to claim 5, characterized in that, The salivary stimulant is one or more of citric acid, malic acid, lactic acid, ascorbic acid, and tartaric acid; the flavoring agent is one or more of acesulfame potassium, sucralose, steviol glycosides, sodium saccharin, aspartame, cyclamate, glucose, fructose, sucrose, maltose, starch sugar, and lactose; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone carboxymethyl cellulose sodium, crospovidone carboxymethyl starch sodium, starch, microcrystalline cellulose, and pregelatinized starch; the flavoring is one or more of peppermint flavoring, cocoa flavoring, strawberry flavoring, and orange flavoring; and the coloring agent is one or more of titanium dioxide, pigments, and lakes.

7. The birepiperazole orally dissolving film according to claim 1, characterized in that, It consists of the following components by weight percentage: 4%–8% biriperazole, 10%–30% glycerin, 30%–70% hydroxypropyl methylcellulose, and 10%–40% hydroxypropyl cellulose.

8. The birepiperazole orally dissolving film according to claim 7, characterized in that, The birepiperazole orally disintegrating film has any formulation consisting of the following components in weight percentages: Prescription 1) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 52%, hydroxypropyl cellulose 24%; Prescription 2) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 66%, hydroxypropyl cellulose 10%; Prescription 3) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 64%, hydroxypropyl cellulose 12%; Prescription 4) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 60%, hydroxypropyl cellulose 16%; Prescription 5) Biriperazole 4%, glycerin 20%, hydroxypropyl methylcellulose 38%, hydroxypropyl cellulose 38%; Prescription 6) Biriperazole 5.8%, glycerin 20%, hydroxypropyl methylcellulose 62.8%, hydroxypropyl cellulose 11.4%; Prescription 7) Buripiperazole 7%, glycerin 20%, hydroxypropyl methylcellulose 50%, hydroxypropyl cellulose 23%.

9. The method for preparing bripiprazole orally dissolving film according to any one of claims 1 to 8, characterized in that, Includes the following steps: a) Dissolve the film-forming material in a suitable solvent to prepare a film-forming material solution; b) Prepare an API dispersion by sequentially adding the prescribed amount of plasticizer, birepiperazole and other excipients to a solvent; c) Add the API dispersion to the film-forming material solution and stir until homogeneous; d) Coat and dry, then store.

10. The use of birepiperazole orally disintegrating film as described in any one of claims 1 to 8 in the preparation of medicaments for treating major depressive disorder and schizophrenia.

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