Betahistine oral soluble film and preparation method thereof

Abstract

The invention provides a betahistine oral soluble film and a preparation method thereof. The betahistine oral soluble film comprises the following components: 4-20 parts of betahistine hydrochloride, 25-40 parts of hydroxypropyl methylcellulose, 10-16 parts of triethyl citrate, 5-10 parts of talcum powder and 5-8 parts of a stabilizer. According to the preparation method, a hot melt extrusion method is adopted, and the prepared betahistine oral soluble film is good in folding resistance, rapid in dissolution, high in tensile strength, capable of being placed for 6 months in an accelerated manner and stable in quality.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a betahistine orally disintegrating film and its preparation method. Background Technology

[0002] Betahistine hydrochloride, developed by Formenti Pharmaceuticals in Italy, is a histamine H1 receptor agonist with the following structural formula. Its main effects include capillary dilation, relaxation of the anterior capillary sphincter, increased microcirculation blood flow in the anterior capillary, and relaxation of the anterior capillary sphincter in the inner ear. By increasing blood flow to the inner ear and vestibular system, it alleviates symptoms such as inner ear vertigo, a feeling of ear blockage, and tinnitus, making it a first-line drug for treating otogenic vertigo. In addition, betahistine can dilate cardiovascular and cerebrovascular vessels, with a particularly significant effect on the pyloric arterial system, increasing blood flow to the heart, brain, and peripheral circulation, improving systemic blood circulation, lowering blood pressure, inhibiting platelet aggregation, preventing thrombosis, and having a mild diuretic effect. Clinically, betahistine is mainly used to improve vertigo and dizziness associated with Meniere's disease, Meniere's syndrome, and vertigo.

[0003] Currently available drug formulations include betahistine hydrochloride tablets, oral solutions, and injections.

[0004] Orally dissolving films are a novel drug formulation, typically made by dissolving or dispersing drugs in a film-forming material to create a thin film. About the size of a postage stamp, they dissolve rapidly in the mouth (on the tongue), releasing the drug quickly. Because the drug dissolves in the mouth, it avoids prolonged residence and irritation in the gastrointestinal tract, reducing gastrointestinal discomfort and side effects. Furthermore, no water or food is needed to aid swallowing, making it convenient for patients, especially children, the elderly, and those experiencing dizziness or difficulty swallowing.

[0005] There are no reports of oral dissolving film formulations of betahistine hydrochloride in the current technology. Therefore, it is necessary to study the technology of oral dissolving film formulations of betahistine hydrochloride to provide a drug with high dissolution, high tensile strength and stable quality, so as to improve the convenience of clinical application. Summary of the Invention

[0006] This invention provides a betahistine orally dissolving film, comprising the following components: Betahistine hydrochloride 4-20 parts 25-40 parts of hydroxypropyl methylcellulose 10-16 parts of triethyl citrate 5-10 parts talcum powder 5-8 parts stabilizer Furthermore, the aforementioned betahistine D hydrochloride 90 Less than or equal to 20 μm, D50 Less than or equal to 10 μm; the talc powder D 90 Less than or equal to 18μm, D 50 Less than or equal to 7 μm; the stabilizer D 90 Less than or equal to 25 μm, D 50 Less than or equal to 15μm.

[0007] Furthermore, the aforementioned betahistine D hydrochloride 90 Greater than or equal to 14 μm, D 50 Greater than or equal to 5 μm; the talc powder D 90 Greater than or equal to 10 μm, D 50 Greater than or equal to 3 μm; the stabilizer D 90 Greater than or equal to 16 μm, D 50 Greater than or equal to 6μm.

[0008] In some embodiments of the present invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E50.

[0009] In some embodiments of the present invention, the stabilizer plays a stabilizing role in the film-forming agent, preferably sodium chloride or citric acid.

[0010] In some embodiments of the present invention, the weight ratio of hydroxypropyl methylcellulose to triethyl citrate is 2.5:1.

[0011] The oral dissolution film has a thickness of 5-200 μm, preferably 50-150 μm; more preferably 70-90 μm.

[0012] In some embodiments of the present invention, the thickness is 85 μm.

[0013] The oral film is prepared by hot melt extrusion, and the die temperature of the hot melt extrusion is 130℃~150℃, preferably 140℃.

[0014] Furthermore, the method for preparing the oral dissolving film includes the following steps: (1) Mixing: Betahistine hydrochloride, hydroxypropyl methylcellulose, triethyl citrate, talc, and stabilizer are mixed; (2) Add the mixture from step (1) into a hot melt extrusion device, and stretch it into a film after extrusion, wherein the die temperature of the hot melt extrusion is 130℃~150℃; (3) Cut the prepared membrane into membrane agents of different sizes and shapes, package them, and obtain oral dissolving membrane.

[0015] This invention achieves a reasonable formulation by controlling the particle size of betahistine hydrochloride, talc, and stabilizer, resulting in a betahistine oral soluble film with good folding resistance, rapid dissolution, high tensile strength, and stable quality even after 6 months of accelerated storage. Detailed Implementation

[0016] This invention discloses a betahistine orally disintegrating film and its preparation method. Those skilled in the art can refer to the content of this invention and, in conjunction with the relevant principles of pharmaceutical formulation, appropriately modify the process parameters to achieve the same result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention. The application of this invention has been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0017] To better understand the invention and not to limit its scope, all figures indicating amounts, percentages, and other numerical values ​​used in this application should, in all cases, be understood to be modified by the word "approximately." Each numerical parameter should at least be considered as obtained based on reported significant figures and through conventional rounding methods.

[0018] The present invention will be further illustrated by the following examples, but the examples do not limit the present invention in any way.

[0019] The particle sizes of betahistine hydrochloride, talc, sodium chloride, and citric acid used in the embodiments of this invention are shown in the table below: Dissolution determination Dissolution medium: pH 1.2 hydrochloric acid solution; 900 ml; rotation speed: 50 rpm; dissolution rate: not less than 85% within 15 min.

[0020] Tensile strength test: Using a medical packaging performance tester, cut 5cm samples from each batch, set the clamp spacing to 20mm, and the testing speed to 5mm / min. Test 3 samples per batch and record the average tensile strength, which should not be less than 32MPa. Folding endurance: Folded twice without breaking. Content and related substances: The content was tested according to the method for betahistine hydrochloride tablets in the 2020 edition of the Chinese Pharmacopoeia. The content was not less than 98.5% and the total related substances were not more than 1.5%.

[0021] Examples 1-12: Betahistine Oral Dissolving Film I. Prescription Composition: The betahistine hydrochloride, talc, sodium chloride, and citric acid used are shown in the table below.

[0022] Table: Betahistine hydrochloride, talc, sodium chloride, and citric acid used in Examples 1-12 II. Preparation method: (1) Mixing: Betahistine hydrochloride, hydroxypropyl methylcellulose, triethyl citrate, talc, and stabilizer are mixed for 10 min; (2) The mixture from step (1) is added to a hot melt extrusion device, and after extrusion, it is stretched into a film, wherein the die temperature of the extrusion is 140°C and the film thickness is 85μm.

[0023] (3) Cut the prepared membrane into 10,000 pieces, each containing 10 mg, to obtain an oral dissolving membrane.

[0024] III. Test Results: The tensile strength, flexural endurance, dissolution rate, content, and total related substances of the prepared material were determined, and the results are shown in the table below.

[0025] Table: Results of betahistine oral dissolution films prepared in Examples 1-12 Examples 13-14: Betahistine Oral Dissolving Film I. Prescription Composition: II. Preparation method: Same as in Example 1.

[0026] III. Test Results: The tensile strength, flexural endurance, and dissolution rate of the prepared material were measured, and the results are shown in the table below.

[0027] Table: Results of betahistine oral dissolution films prepared in Examples 13-14 Analysis of the results from Examples 1-14 combined with Example 15 revealed that: (1) Betahistine hydrochloride oral films prepared from betahistine hydrochloride, talc, sodium chloride and citric acid within the characteristic particle size range (such as Examples 1-2 and Examples 13-14) not only have high dissolution, high tensile strength, good folding resistance and high content, but also have stable quality after 6 months of accelerated storage (no significant changes in dissolution, tensile strength, folding resistance, content and related substances).

[0028] (2) When only betahistine hydrochloride of other particle sizes is used, as shown in Examples 3-4, at the beginning of preparation, the dissolution rate is high, the tensile strength is high, the folding resistance is good, and the content is high, which is not significantly different from Example 1. However, after 6 months of accelerated storage, the dissolution rate drops significantly to less than 85%, which does not meet the requirements.

[0029] (3) When only talc powder of other particle sizes is used, as shown in Examples 5-6, the initial dissolution rate is high, the flexural strength is good, and the content is high, which is not significantly different from Example 1. However, the tensile strength is significantly lower than that of Example 1, which is lower than 32 MPa and does not meet the requirements.

[0030] (4) When only sodium chloride of other particle sizes is used, as shown in Examples 7-8, at the beginning of preparation, the dissolution rate is high, the tensile strength is high, the folding resistance is good, and the content is high, which is not significantly different from Example 1. However, after being placed for 6 months, the content decreases significantly and is lower than 98.5%; related substances increase significantly and are higher than 1.5%, the product is unstable and does not meet the requirements.

[0031] (5) When only citric acid of other particle sizes is used, as shown in Examples 9-10, at the beginning of preparation, the dissolution rate is high, the tensile strength is high, the folding resistance is good, and the content is high, which is not significantly different from Example 1. However, after being placed for 6 months, the content decreases significantly and is lower than 98.5%; related substances increase significantly and are higher than 1.5%, the product is unstable and does not meet the requirements.

[0032] (6) When betahistine hydrochloride, talc, sodium chloride and citric acid of other particle size ranges are used at the same time, as shown in Example 12, the dissolution rate and tensile strength are low at the beginning of preparation, which do not meet the requirements.

[0033] Comparative Examples 1-2: Effect of Hydroxypropyl Methylcellulose Type I. Formulation Composition: Hydroxypropyl methylcellulose is as follows, and other components are as in Example 1. II. Preparation method: Same as in Example 1.

[0034] III. Test Results: The tensile strength, flexural endurance, and dissolution rate of the prepared material were measured, and the results are shown in the table below.

[0035] Table: Results of betahistine oral dissolution films prepared in Comparative Examples 1-2 Comparative analysis of Example 1 and Comparative Examples 1-2 shows that the type (or viscosity) of hydroxypropyl methylcellulose affects the dissolution rate of the oral dissolving film. E50 is significantly better than E5 or E15, achieving unexpected technical results in terms of dissolution rate.

[0036] Comparative Examples 3-5: Effects of Components I. Prescription composition: Talc, sodium chloride, and citric acid are shown in the table below, and the rest are the same as in Example 1.

[0037] II. Preparation method: Same as in Example 1.

[0038] III. Test Results: The tensile strength, flexural endurance, and dissolution rate of the prepared material were measured, and the results are shown in the table below.

[0039] Table: Results of betahistine oral dissolution films prepared in Comparative Examples 3-5 Comparative analysis of Example 1 and Comparative Example 3 shows that the addition of talc significantly enhances the tensile strength and folding resistance of the oral dissolving film, achieving unexpected technical effects.

[0040] Comparative analysis of Example 1 and Comparative Examples 4-5, and in conjunction with the stability data of Example 15, showed that the addition of sodium chloride and citric acid significantly enhanced the content of the oral dissolving film and the stability of related substances, achieving unexpected technical effects.

[0041] Comparative Examples 6-7: Effect of the ratio of hydroxypropyl methylcellulose E50 and triethyl citrate I. Formulation composition: Hydroxypropyl methylcellulose E50 and triethyl citrate are shown in the table below by weight, and the rest are the same as in Example 1.

[0042] II. Preparation method: Same as in Example 1.

[0043] III. Test Results: The tensile strength, flexural endurance, and dissolution rate of the prepared material were measured, and the results are shown in the table below.

[0044] Table: Results of betahistine oral dissolution films prepared in Comparative Examples 6-7 Comparative analysis of Example 1 and Comparative Examples 6-7 showed that a weight ratio of 2.5:1 hydroxypropyl methylcellulose E50 and triethyl citrate significantly enhanced the dissolution and tensile strength of the oral dissolving film, achieving unexpected technical effects.

[0045] Example 15: Stability Test The betahistine orally dissolving films prepared in Examples 1-4, 7-11, 13-14 and Comparative Examples 4-5 were tested for dissolution rate, tensile strength, folding endurance, content and related substances after being placed under accelerated conditions for 6 months.

[0046] Table: Results of betahistine oral dissolving films prepared in Examples 1-4, 7-11, 13-14 and Comparative Examples 4-5 Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A betahistine orally disintegrating film, comprising the following components: Betahistine hydrochloride 4-20 parts 25-40 parts of hydroxypropyl methylcellulose 10-16 parts of triethyl citrate 5-10 parts talcum powder 5-8 parts stabilizer The hydroxypropyl methylcellulose mentioned is hydroxypropyl methylcellulose E50; The stabilizer is sodium chloride or citric acid.

2. The betahistine orally dissolving film as described in claim 1, characterized in that, The aforementioned betahistine D hydrochloride 90 Less than or equal to 20 μm, D 50 Less than or equal to 10 μm; the talc powder D 90 Less than or equal to 18μm, D 50 Less than or equal to 7 μm; the stabilizer D 90 Less than or equal to 25 μm, D 50 Less than or equal to 15μm.

3. The betahistine orally dissolving film as described in claim 2, characterized in that, Betahistine D Hydrochloride 90 Greater than or equal to 14 μm, D 50 Greater than or equal to 5 μm; the talc powder D 90 Greater than or equal to 10 μm, D 50 Greater than or equal to 3 μm; the stabilizer D 90 Greater than or equal to 16 μm, D 50 Greater than or equal to 6μm.

4. The betahistine oral dissolving film as described in claim 1, characterized in that, The weight ratio of hydroxypropyl methylcellulose to triethyl citrate is 2.5:

1.

5. The betahistine oral dissolving film as described in claim 1, characterized in that, The thickness is 50-150μm; more preferably 70-90μm.

6. A method for preparing a betahistine orally dissolving film according to any one of claims 1 to 5, characterized in that, It is a hot melt extrusion method, and the die temperature of hot melt extrusion is 130℃~150℃.

7. The preparation method according to claim 6, characterized in that, Includes the following steps: (1) Mixing: Betahistine hydrochloride, hydroxypropyl methylcellulose, triethyl citrate, talc, and stabilizer are mixed; (2) Add the mixture from step (1) into a hot melt extrusion device, and stretch it into a film after extrusion, wherein the die temperature of the hot melt extrusion is 130℃~150℃; (3) Cut the prepared membrane into membrane agents of different sizes and shapes, package them, and obtain oral dissolving membrane.

8. The preparation method according to claim 6, characterized in that, The die temperature for hot melt extrusion is 140℃.

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