Brexpiprazole oral soluble film and preparation method thereof

Abstract

The invention provides a brexpiprazole oral soluble film and a preparation method thereof, the brexpiprazole oral soluble film comprises brexpiprazole, a film forming material and a plasticizer, the film forming material is a combination of polyvinyl alcohol and polyethylene glycol, and the plasticizer is glycerol. The brexpiprazole oral soluble film is not easy to curl in the preparation process, and the finished product is also not easy to curl; and after being placed under a high-temperature condition, oxidation impurities and total impurity growth are effectively inhibited, and the stability is excellent.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically 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] Because birepiperazole contains a relatively unique six-membered piperazine active ingredient, it is prone to aggregation and sedimentation during the preparation of birepiperazole orally dissolving films, affecting film formation. Oxidation of birepiperazole can also lead to excessive levels of related substances. Existing technologies disclose various formulations for birepiperazole orally dissolving films:

[0006] To overcome the problem of drug aggregation, patents CN115192548A and CN115192549A disclose an biriperazole oral film formulation, which uses polyvinyl alcohol and hydroxypropyl methylcellulose as film-forming materials and glycerin as a plasticizer. The formulation is developed by controlling the pH of the medicated solution (2.5–4.5) and the particle size (D) of biriperazole. 90 Techniques such as ≤30μm are used to avoid drug aggregation and prepare films with uniform quality. Patent CN114767663A discloses an orally disintegrating film of birepiperazole, which uses hydroxypropyl methylcellulose and hydroxypropyl cellulose as film-forming materials and glycerin as a plasticizer. By adding additional thickeners and controlling the amount, an orally disintegrating film with uniform dispersion of active pharmaceutical ingredients is prepared.

[0007] To overcome the problems of easy oxidation and excessive levels of related substances in birepiperazole, patent CN117838664A discloses a method to ensure the stability of birepiperazole orally dissolved films and inhibit the growth of oxidative impurities. This method uses hydroxypropyl methylcellulose E5 and E15 as film-forming agents and strictly controls the pH of the film-forming system between 6.5 and 7.0, effectively inhibiting the growth of oxidative impurities. However, the suitable pH range is relatively narrow, and improper control can still lead to the growth of oxidative impurities and decreased stability.

[0008] In reproducing the formulation and preparation process of the prior art birepiperazole orally dissolving film, the inventors discovered that the existing formulations all suffer from varying degrees of film curling during the preparation process. Orally dissolving film curling can cause several adverse effects, such as: 1) curling after removal from the inner packaging bag, which easily leads to clumping in the mouth and prolongs dissolving time; 2) curling during drying, which easily detaches from the substrate and cannot be rolled up; 3) curling during inner packaging, which easily causes the orally dissolving film to fold and break within the inner packaging bag.

[0009] When optimizing the types and amounts of film-forming materials and plasticizers, the inventors of this application unexpectedly discovered that a specific combination of film-forming materials and plasticizers could solve the problem of easy curling during the preparation process, and the relevant formulation could effectively inhibit the growth of oxidative impurities, resulting in a bripiprazole orally soluble film with good stability. Summary of the Invention

[0010] This invention optimizes the types and amounts of film-forming materials and plasticizers to prepare a bripiprazole orally soluble film that is not prone to curling, effectively inhibits the growth of oxidative impurities, and exhibits excellent stability.

[0011] On one hand, the present invention provides a buripiperazole orally dissolving film, comprising the active ingredient buripiperazole, a film-forming material and a plasticizer, wherein the film-forming material is polyvinyl alcohol and polyethylene glycol, and the plasticizer is glycerin.

[0012] In a further embodiment, the polyvinyl alcohol in the film-forming material is any one of polyvinyl alcohol 03-88, 05-88, 17-88, and 24-88; preferably polyvinyl alcohol 05-88.

[0013] In a further embodiment, the film-forming material polyethylene glycol is any one of polyethylene glycol 4000, polyethylene glycol 6000, or other polyethylene glycols that can be used as film-forming materials; preferably polyethylene glycol 4000.

[0014] In a further embodiment, the film-forming material is a combination of polyvinyl alcohol 05-88 and polyethylene glycol 4000.

[0015] In some embodiments, the weight ratio of the film-forming material to the plasticizer is 2.0:1 to 20.0:1; in further embodiments, the weight ratio of the film-forming material to the plasticizer is 2.8:1 to 11.7:1.

[0016] In some embodiments, the buripiperazole is present in the formulation at a weight percentage of 1 to 10%;

[0017] In a further embodiment, the buripiperazole is present in the formulation at a weight percentage of 2-8%; in an even further embodiment, the buripiperazole is present in the formulation at a weight percentage of 5%.

[0018] In some embodiments, the film-forming material constitutes 65% to 90% of the weight percentage in the formulation; in further embodiments, the film-forming material constitutes 70% to 87.5% of the weight percentage in the formulation.

[0019] In some embodiments, the polyvinyl alcohol in the film-forming material comprises 55% to 80% by weight in the formulation; in further embodiments, the polyvinyl alcohol in the film-forming material comprises 60% to 77.5% by weight in the formulation.

[0020] In some embodiments, the polyethylene glycol in the film-forming material comprises 10% to 20% by weight in the formulation; in further embodiments, the polyethylene glycol in the film-forming material comprises 10% by weight in the formulation.

[0021] In some embodiments, the plasticizer glycerin accounts for 5% to 30% by weight in the formulation; in further embodiments, the plasticizer accounts for 7.5% to 25% by weight in the formulation.

[0022] In some embodiments, the birepiperazole orally dissolving film provided by the present invention comprises the following components in weight percentage:

[0023]

[0024] In some embodiments, the birepiperazole orally dissolving film provided by the present invention comprises the following components in weight percentage:

[0025]

[0026] In some embodiments, the buripiperazole oral dissolving film provided by the present invention comprises the following components in weight percentage: buripiperazole 5%, polyvinyl alcohol 05-88 60%, polyethylene glycol 4000 10%, and glycerin 25%.

[0027] In some embodiments, the buripiperazole oral dissolving film provided by the present invention comprises the following components in weight percentages: buripiperazole 5%, polyvinyl alcohol 05-88 67.5%, polyethylene glycol 4000 10%, and glycerin 17.5%.

[0028] In some embodiments, the buripiperazole oral dissolving film provided by the present invention comprises the following components in weight percentages: buripiperazole 5%, polyvinyl alcohol 05-88 77.5%, polyethylene glycol 4000 10%, and glycerin 7.5%.

[0029] In some embodiments, the birepiperazole orally disintegrating film may optionally include one or more of a colorant, flavoring agent, disintegrant, filler, and saliva stimulant.

[0030] In a further embodiment, the colorant is selected from one or more of titanium dioxide and pigments, including but not limited to.

[0031] In a further embodiment, the flavoring agent is selected from one or more of the following: acesulfame potassium, sucralose, steviol glycosides, sodium saccharin, aspartame, cyclamate, glucose, fructose, sucrose, maltose, starch sugar, and lactose.

[0032] In a further embodiment, the disintegrant is selected from one or more of the following: low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, crospovidone sodium carboxymethyl starch, starch, microcrystalline cellulose, and pregelatinized starch.

[0033] In a further embodiment, the filler is selected from one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

[0034] In a further embodiment, the saliva stimulant is selected from one or more of, including but not limited to, citric acid, tartaric acid, malic acid, and mannitol.

[0035] On the other hand, the present invention also provides a method for preparing the birepiperazole oral dissolving film, which includes the following steps:

[0036] 1) Preparation of polyvinyl alcohol solution;

[0037] 2) Preparation of polyethylene glycol solution;

[0038] 3) Preparation of API dispersion;

[0039] 4) Mix the solutions from steps 1) to 3), add the plasticizer, mix, and let stand to remove air bubbles;

[0040] 5) Coating and drying.

[0041] In some embodiments, the preparation method includes the following steps:

[0042] 1) Preparation of polyvinyl alcohol 05-88 solution: Weigh the prescribed amount of polyvinyl alcohol and add it to purified water. Heat and stir until the material is completely dissolved. Cool to room temperature and replenish the water evaporated at high temperature. Set aside for later use.

[0043] 2) Preparation of polyethylene glycol 4000 solution: Weigh the prescribed amount of polyethylene glycol 4000 and add it to purified water. Heat and stir until the material is completely dissolved. Cool to room temperature and add the water evaporated at high temperature. Set aside for later use.

[0044] 3) Preparation of API dispersion: Measure purified water into a beaker, add the prescribed amount of glycerin, and add the prescribed amount of ibuprofen while stirring;

[0045] 4) Mixing: Cool the polyvinyl alcohol solution, add polyethylene glycol 4000 solution and bripiprazole dispersion in sequence, stir and mix, and let stand to remove air bubbles;

[0046] 5) Coating and drying.

[0047] Furthermore, the present invention also provides the application of the above-mentioned birepiperazole oral dissolving film in the preparation of drugs for treating depression or psychosis.

[0048] Compared with the prior art, the present invention uses polyvinyl alcohol 05-88 and polyethylene glycol 4000 as film-forming materials and glycerin as plasticizer. By further optimizing the ratio of film-forming materials and plasticizer, the prepared bripiprazole oral soluble film has good film-forming properties, is not easy to curl during the preparation process, and is also not easy to curl in the finished product. Under high temperature conditions, the growth of oxidative impurities and total impurities is effectively suppressed, and the stability is excellent. Attached Figure Description

[0049] Figure 1 The oral dissolving film prepared in Example 1 of this invention;

[0050] Figure 2 This is the oral dissolving film prepared in Example 5 of this invention. Detailed Implementation

[0051] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0052] Unless otherwise stated, the raw materials and reagents used in the following examples are all commercially available products, and the sources of some materials are shown in Table 1:

[0053] Table 1

[0054] Material Name Material source biriperazole Zhejiang Saimo Pharmaceutical Co., Ltd. Polyvinyl alcohol 05-88 Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd. Polyethylene glycol 4000 Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd. glycerin Hunan Ercon Pharmaceutical Co., Ltd.

[0055] Example 1

[0056] A birepiperazole orally dissolving film, the formulation and process of which are shown in Table 2.

[0057] Table 2

[0058] raw materials Dosage / mg weight percentage / % effect biriperazole 2 5％ Active ingredients Polyvinyl alcohol 05-88 24 60％ Film-forming materials Polyethylene glycol 4000 4 10％ Film-forming materials glycerin 10 25％ plasticizer total 40 100％ /

[0059] Process:

[0060] 1) Preparation of polyvinyl alcohol solution: Weigh the prescribed amount of polyvinyl alcohol and add it to purified water. Heat and stir until the material is completely dissolved. Cool to room temperature and add the water evaporated at high temperature. Set aside for later use.

[0061] 2) Preparation of polyethylene glycol 4000 solution: Weigh the prescribed amount of polyethylene glycol 4000 and add it to purified water. Heat and stir until the material is completely dissolved. Cool to room temperature and add the water evaporated at high temperature. Set aside for later use.

[0062] 3) Preparation of API dispersion: Measure purified water into a beaker, add the prescribed amount of glycerin, and add the prescribed amount of biriperazole while stirring to make the material disperse evenly without any dispersed agglomerates;

[0063] 4) Mixing: After the polyvinyl alcohol solution is cooled to below 30°C, polyethylene glycol 4000 solution and buriperazole dispersion are added in sequence, stirred and mixed, and allowed to stand to remove air bubbles, so that the material is evenly dispersed and free of any air bubbles.

[0064] 5) Coating and drying: Cover the coating machine with an anti-stick film, adjust the coating thickness and coating speed, set the coating speed to 0.1m / min, the drying time to 20min, the fan frequency to 10-50HZ, the exhaust frequency to 10-20HZ, and the drying temperature to 60-80℃. Adjust the coating thickness to keep the sheet weight within ±10% of the target sheet weight.

[0065] The birepiperazole oral film prepared according to the above formula and method did not curl upon drying, exhibited good film-forming properties, and met the requirements. (See below) Figure 1 .

[0066] Examples 2-5: Screening of Film-Forming Material Types

[0067] Referring to the formulation and process of Example 1, the effect of the type of film-forming material on the film-forming phenomenon of birepiperazole oral dissolution film was investigated using a single-factor method. The plasticizer was glycerin, with a weight percentage of 25%; birepiperazole, with a weight percentage of 5%. The relevant formulation and results are shown in Table 3.

[0068] Table 3

[0069]

[0070] " / " indicates that the film-forming material was not selected in the formulation.

[0071] The results show that:

[0072] ① Using a single film-forming material cannot meet the film-forming requirements of oral dissolving film: When hydroxypropyl cellulose is used alone as the film-forming material, the film is flat but not easy to form, and it is easy to break and has high brittleness; when polyvinyl alcohol or hydroxypropyl methylcellulose is used alone as the film-forming material, the film will curl and it will be difficult to adhere to the liner during subsequent packaging. Since polyvinyl alcohol has a lower degree of curling, it can be considered to further compound it with other film-forming materials to improve the properties of oral dissolving film.

[0073] ② In Example 5, the film prepared by compounding polyvinyl alcohol and hydroxypropyl cellulose curled up and did not meet the requirements. See Figure 2 ;

[0074] ③ In Example 1, polyvinyl alcohol 05-88 and polyethylene glycol 4000 were used in combination to prepare a film with a smooth surface and good film-forming properties, which met the film-forming requirements of oral dissolving film agents.

[0075] Therefore, based on the above investigation results, polyvinyl alcohol 05-88 and polyethylene glycol 4000 were selected as film-forming materials.

[0076] Example 6

[0077] Based on the selection of suitable film-forming material combinations, the effect of the weight ratio of film-forming material to plasticizer on the film-forming phenomenon of birepiperazole oral dissolution film was investigated.

[0078] (1) Polyvinyl alcohol 05-88 and polyethylene glycol 4000 were selected as film-forming materials, and glycerin was used as a plasticizer. The effect of the weight ratio of film-forming materials to plasticizer on film-forming properties was investigated. The formulation and investigation results are shown in Table 4.

[0079] Table 4

[0080]

[0081] (2) Based on the selection of a suitable weight ratio of film-forming material and plasticizer, the plasticizer was replaced with polyethylene glycol 400. The effect of the weight ratio of film-forming material to polyethylene glycol 400 on the film-forming phenomenon of bripiprazole oral dissolution film was investigated. The formulation and investigation results are shown in Table 5.

[0082] Table 5

[0083]

[0084] The preparation process is the same as in Example 1.

[0085] The results showed that both the type of plasticizer and its weight ratio to the film-forming material affected the film-forming properties of the oral solution film.

[0086] When the film-forming materials are polyvinyl alcohol 05-88 and polyethylene glycol 4000, and the plasticizer is glycerin, the weight ratio of the film-forming material to the plasticizer is 2.0:1 to 20:1, preferably 2.8:1 to 11.7:1, so that the film is flat, has good film-forming properties, and is convenient for subsequent packaging and use.

[0087] However, when the plasticizer glycerin was replaced with polyethylene glycol 400, the film curled up when the weight ratio of the film-forming material to polyethylene glycol 400 was 11.7:1.

[0088] Stability assessment:

[0089] According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" in General Chapter 9001 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, influencing factor tests were conducted to examine the stability of the preparation: the self-made product was simulated with the market packaging (polyester / aluminum / cast polyethylene pharmaceutical composite bag), placed in a 60℃ constant temperature incubator for 5 days, and samples were taken for testing.

[0090] The detection conditions for liquid chromatography are shown in Table 6:

[0091] Table 6

[0092]

[0093] The test results are shown in Table 7 below:

[0094] Table 7

[0095]

[0096]

[0097] Note: "ND" means Not Detected.

[0098] Results analysis:

[0099] The birepiperazole oral dissolving films of Examples 1 and 6-Formula 6 are all non-curled white opaque films with good film-forming properties;

[0100] However, the bripiprazole oral dissolving film of Example 6-Formulation 6 (replacing glycerin in Example 1 with polyethylene glycol 400) had oxidized impurities exceeding the limit after 5 days at high temperature, failing to meet the standard; the total impurity content was also significantly higher than that of Example 1, and continued storage resulted in impurity content exceeding the limit.

[0101] In summary, the bripiprazole oral soluble film (Example 1) with polyvinyl alcohol 05-88 and polyethylene glycol 4000 as film-forming materials and glycerin as plasticizer showed no significant increase in oxidative impurities and total impurities after high-temperature storage, which was far below the limit requirements, and exhibited excellent stability.

Claims

1. A buripiperazole orally dissolving film, comprising the active ingredient buripiperazole, a film-forming material, and a plasticizer, characterized in that: The film-forming materials are polyvinyl alcohol and polyethylene glycol, and the plasticizer is glycerin.

2. The birepiperazole orally dissolving film according to claim 1, characterized in that: The polyvinyl alcohol is any one of polyvinyl alcohol 03-88, 05-88, 17-88, and 24-88, preferably polyvinyl alcohol 05-88; the polyethylene glycol is one of polyethylene glycol 4000 and polyethylene glycol 6000, preferably polyethylene glycol 4000.

3. The birepiperazole orally dissolving film according to claim 1 or 2, characterized in that: The film-forming material accounts for 65% to 90% of the weight percentage in the formulation, and the plasticizer accounts for 5% to 30% of the weight percentage in the formulation. The weight ratio of the film-forming material to the plasticizer is 2.0:1 to 20.0:1, preferably 2.8:1 to 11.7:

1.

4. The birepiperazole orally dissolving film according to claim 3, characterized in that: The film-forming material comprises 70% to 87.5% by weight in the formulation, and the plasticizer comprises 7.5% to 25% by weight in the formulation.

5. The birepiperazole orally dissolving film according to claim 3, characterized in that: The buripiperazole orally disintegrating film comprises the following components by weight percentage:

6. The birepiperazole orally dissolving film according to claim 3, characterized in that: The buripiperazole orally disintegrating film comprises the following components by weight percentage:

7. The birepiperazole orally dissolving film according to claim 3, characterized in that: The birepiperazole orally disintegrating film is selected from any of the following formulations 1)-3): 1) 5% biriperazole, 60% polyvinyl alcohol 05-88, 10% polyethylene glycol 4000, and 25% glycerin, with a weight ratio of 2.8:1 for film-forming materials and plasticizers. 2) 5% biriperazole, 67.5% polyvinyl alcohol 05-88, 10% polyethylene glycol 4000, and 17.5% glycerin. The weight ratio of film-forming material to plasticizer is 4.4:

1. 3) 5% biriperazole, 77.5% polyvinyl alcohol 05-88, 10% polyethylene glycol 4000, and 7.5% glycerin. The weight ratio of the film-forming material to the plasticizer is 11.7:

1.

8. The birepiperazole orally dissolving film according to claim 3, characterized in that: The buripiperazole orally disintegrating film may also include one or more of the following: coloring agents, flavoring agents, disintegrants, fillers, and saliva stimulants.

9. A method for preparing a bripiprazole orally dissolving film as described in any one of claims 1-8, characterized in that: Includes the following steps: 1) Preparation of polyvinyl alcohol solution; 2) Preparation of polyethylene glycol solution; 3) Preparation of API dispersion; 4) Mix the solutions from steps 1) to 3), add the plasticizer, mix, and let stand to remove air bubbles; 5) Coating and drying.

10. The use of a birepiperazole orally disintegrating film as described in any one of claims 1-8 in the preparation of a medicament for treating depression or psychosis.

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