Betahistine oral solid preparation with improved stability and preparation method thereof

Abstract

The invention provides a betahistine oral solid preparation with improved stability and a preparation method thereof. The oral solid preparation comprises betahistine or a salt thereof and a non-inorganic salt antioxidant. In addition, the invention also discloses a preparation method of the medicinal composition. According to the technical scheme provided by the invention, the problems of control and growth of N-nitroso betahistine in a betahistine solid preparation are effectively solved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a betahistine solid preparation which can effectively solve the problem of controlling and increasing the genotoxic impurity N-nitroso-betahistine in a betahistine oral solid preparation. Background Art

[0002] Betahistine is a histamine H1 receptor agonist. It is a first-line drug for the clinical treatment of otopathic vertigo by increasing the blood flow to the inner ear and vestibule, alleviating symptoms such as inner ear vertigo, ear closure and tinnitus. In addition, betahistine can also dilate the cardiovascular and cerebrovascular systems, especially the conobasal artery system, increase the blood flow to the cardiovascular and cerebrovascular systems and peripheral circulatory systems, improve systemic blood circulation, have a hypotensive effect, inhibit platelet aggregation, prevent thrombosis, and have a slight diuretic effect. Betahistine is mainly used in clinical practice to improve the dizziness and vertigo associated with diseases such as Meniere's disease, Meniere's syndrome, and vertigo.

[0003] Currently, the drugs containing betahistine as the active ingredient on the market include betahistine hydrochloride and betahistine mesylate. The former is available in multiple dosage forms such as tablets, oral solution, injection and lyophilized solution, while the latter is only available in tablets.

[0004] Chinese patent CN111249237A discloses a preparation process, wherein betahistine hydrochloride, citric acid and 16-20 parts by weight of water are mixed to obtain a wetting agent. Microcrystalline cellulose and mannitol are mixed and granulated to obtain a first masterbatch. The first masterbatch is mixed and granulated with a wetting agent to obtain a second masterbatch. The second masterbatch, silicon dioxide and stearic acid are mixed and tableted. Although this method can make the components mix evenly, and the disintegration and dissolution meet the requirements. However, this preparation process does not involve the genotoxic impurity "N-nitroso-betahistine" in betahistine hydrochloride tablets, nor does it involve solving the problem of its over-limit and increasing growth during storage.

[0005] Patent WO2015 / 053620A1 discloses Betahistine Hydrochloride Tablets of Mylan Company The wet granulation method is used to prepare the betahistine hydrochloride immediate-release tablets, and a pH regulator needs to be added to improve the stability of the tablets. At the same time, considering the physical and chemical properties of betahistine hydrochloride, which is easy to deliquesce, and the public reports of the review reports of the generic betahistine hydrochloride tablets (Sandoz, Accord) that have been launched in the Netherlands, the wet granulation process is adopted, and the betahistine hydrochloride raw material is first dissolved in water and then granulated, and the wet granulation process is adopted.

[0006] Betahistine mesylate tablets from Eisai The end point control range of the air outlet temperature during fluidized bed drying was changed, indicating that the original research of Betahistine Mesylate Tablets The process is a non-dry process.

[0007] Patent CN101797237A discloses a method for preparing an orally disintegrating tablet of betahistine mesylate, providing a novel method for preparing tablets that can rapidly disintegrate or dissolve in the oral cavity without the need for water. However, the prescription and process do not involve N-nitroso-betahistine, let alone solving the problem of the generation and growth of N-nitroso-betahistine. Summary of the invention

[0008] EMA (European Medicines Agency) announced the acceptable daily intake of N-nitroso-betahistine (18 ng / day) on July 1, 2023. The maximum daily doses of betahistine hydrochloride tablets and betahistine mesylate tablets are 48 mg / day and 36 mg / day, respectively, so the limit of N-nitroso-betahistine in the former should be 0.375 ppm, and the limit of the latter should be 0.500 ppm.

[0009] After research, the currently marketed betahistine hydrochloride tablets in China and the reference preparation marketed in the EU The N-nitroso-betahistine in the samples exceeded the acceptable limit (0.375 ppm); the original research and localization of betahistine mesylate tablets Close to the upper limit (0.500ppm), the results are shown in Table 1.

[0010] Table 1 N-nitroso-betahistine content in betahistine tablets from different sources

[0011]

[0012]

[0013] When the tablets in the above table are placed under the accelerated research conditions (40°C / 75%RH) and long-term research conditions (30°C / RH65%) of drug stability research, the N-nitroso-betahistine content in the tablets will further increase with the extension of time.

[0014] Table 2 Growth of N-nitroso-betahistine in the reference preparation of betahistine tablets in the stability study

[0015]

[0016] When betahistine hydrochloride and mesylate exist in solution in water, N-nitroso-betahistine will gradually be generated, and as the storage time increases, N-nitroso-betahistine will gradually increase. The research results of its increase rate are shown in Table 3.

[0017] Table 3 API test solution (concentration: 0.2 mg / ml, solvent: water-acetonitrile (10:90)) room temperature stability

[0018]

[0019] The present invention provides a stable formulation composition that can effectively inhibit the generation of N-nitroso-betahistine, and adopts a dry process to inhibit the growth of N-nitroso-betahistine, thereby solving the stability problem of oral solid preparations. The technical solution adopted by the present invention is: an antioxidant is added to the preparation formula, and a non-wet granulation process is adopted to avoid the material from contacting with water, so as to prepare a solid preparation, and achieve an oral solid preparation that maintains stability in stability research with a low content level of N-nitroso-betahistine that meets the limit requirements.

[0020] The invention provides a betahistine oral solid preparation with improved stability. The betahistine oral solid preparation comprises betahistine or a salt thereof and a non-inorganic salt antioxidant.

[0021] In an embodiment, the oral solid preparation of betahistine is prepared by a dry process.

[0022] In some embodiments, the non-inorganic salt antioxidant accounts for no less than 0.1% of the prescription weight (i.e., the weight of the betahistine oral solid preparation), or is 0.1% to 10%, 0.5% to 10%, or 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%.

[0023] In some embodiments, the composition of the betahistine oral solid preparation includes 0.1 wt% to 10 wt% of a non-inorganic salt antioxidant, 2 wt% to 10 wt% of betahistine or its salt, 70 wt% to 90 wt% of a filler, 1 wt% to 3 wt% of a pH adjuster, 1 wt% to 3 wt% of a glidant, and 2 wt% to 8 wt% of a lubricant.

[0024] In some embodiments, the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose (anhydrate or hydrate), mannitol, calcium hydrogen phosphate, starch, pregelatinized starch and microcrystalline cellulose; preferably, microcrystalline cellulose and mannitol.

[0025] In some embodiments, the pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; preferably, citric acid.

[0026] In some embodiments, the glidant is selected from one or more of silicon dioxide, talc, and hydrogenated vegetable oil; preferably, silicon dioxide and talc.

[0027] In some embodiments, the non-inorganic salt antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride, and cysteine; preferably, it is ascorbyl palmitate.

[0028] In some embodiments, the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and docusate sodium; preferably, talc.

[0029] On the other hand, the present invention provides a preparation process of the above-mentioned betahistine oral solid preparation, wherein the preparation process is to directly mix the powders or dry granulate them, then add auxiliary materials and mix them, directly package them into powders / granules, or directly fill them into capsules, or compress them into tablets, etc., and comprises the following steps:

[0030] a) betahistine or its salt, non-inorganic salt antioxidant and other auxiliary materials are sieved separately;

[0031] b) pouring the API and the excipients into a mixer for mixing, or performing dry granulation after mixing;

[0032] c) adding auxiliary materials to the mixed powder or granules obtained in step b) to obtain a total mixed powder or total granules;

[0033] d) directly packing the total mixed powder or total granules into powders / granules, or directly filling capsules, or pressing into tablets;

[0034] In some embodiments, the preparation process comprises the following steps:

[0035] a) Processing of raw materials and auxiliary materials: the flow aid is passed through an 80-mesh sieve, and the pH adjuster is ground and passed through an 80-mesh sieve, and the fine powder under the sieve is taken for later use;

[0036] b) Premixing: Mix the pH adjuster and the filler in an equal amount in an equal and increasing manner in a stirring mixer to obtain a mixed powder ①; first mix the non-inorganic salt antioxidant and the glidant, then add betahistine or its salt and mix, then add the filler and mix in a stirring mixer to obtain a mixed powder ②; add the mixed powder ① to the mixed powder ②, mix in a stirring mixer to obtain a mixed powder ③, then add the glidant and the lubricant and mix to obtain a mixed powder ③;

[0037] c) Total mixing: putting the mixed powder ③ into a mixer, adding a flow aid and a lubricant to obtain a total mixed powder;

[0038] d) Preparation of finished products: The total mixed powder preparation is packaged into powders, or filled into capsules, or directly compressed into tablets.

[0039] In some embodiments, the preparation process comprises the following steps:

[0040] a) Processing of raw materials and auxiliary materials: the flow aid is passed through an 80-mesh sieve, and the pH adjuster is ground and passed through an 80-mesh sieve, and the fine powder under the sieve is taken for later use;

[0041] b) Premixing: Mix the pH adjuster and the filler in an equal amount in an equal and increasing manner in a stirring mixer to obtain a mixed powder ①; first mix the non-inorganic salt antioxidant and the glidant, then add betahistine or its salt and mix, then add the filler and mix in a stirring mixer to obtain a mixed powder ②; add the mixed powder ① to the mixed powder ②, mix in a stirring mixer to obtain a mixed powder ③, then add the glidant and the lubricant and mix to obtain a mixed powder ③;

[0042] c) Granulation: putting the mixed powder ③ into a dry granulator for granulation to obtain drug-containing granules;

[0043] d) Total mixing: adding silicon dioxide and talcum powder to the drug-containing granules and then tableting to obtain betahistine tablets.

[0044] In another aspect, the present invention provides a betahistine oral solid preparation obtained by the above preparation process.

[0045] The technology of the present invention is characterized in that an antioxidant is added to the prescription to inhibit the growth of N-nitroso-betahistine, and a dry process is used to prevent the prescription from being affected by wet and hot conditions, thereby improving the stability of the preparation during the preparation process and during the influencing factors and stability tests, and inhibiting the generation of the genotoxic impurity N-nitroso-betahistine.

[0046] Detection instrument for genotoxic impurity N-nitroso-betahistine: Agilent 6470QQQ LC / MS

[0047] Determined by high performance liquid chromatography and mass spectrometry (General Rules 0512 and 0431 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0048] Solvent water-acetonitrile (10:90)

[0049] The test solution is freshly prepared before use. Take an appropriate amount of the product, weigh it accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing about 0.2 mg per 1 ml.

[0050] Reference solution: Take an appropriate amount of N-nitroso-betahistine reference substance, weigh it accurately, dissolve it in a solvent and quantitatively dilute it to make a solution containing about 0.075 ng of N-nitroso-betahistine per 1 ml.

[0051] The chromatographic conditions were as follows: HlLICC was used as the filler (e.g. ACQUITY UPLC BEH HlLlC 1.7 μm, 2.1×50 mm or a chromatographic column of equivalent performance), and water-acetonitrile-formic acid (10:90:0.1) (containing 5 mmol / L ammonium formate) was used as the mobile phase; the flow rate was 0.2 ml per minute; the column temperature was 35°C; the injection volume was 5 μl; and the sample tray temperature was 4°C.

[0052] Mass spectrometry conditions (reference instrument model: Agilent 6470QQQ LC-MS / MS, parameters can be adjusted according to the specific instrument to meet the detection requirements): ESI+, MRM mode, ion pair 166→93, Dwell200, Fragmentor 60 (V), CCollision Energy 10 (V), CellAccelerator Voltage 5 (V), carrier gas temperature 300 °C, carrier gas flow rate 10 L per minute, nebulizer pressure 45 psi, sheath gas temperature 250 °C, sheath gas flow rate 11 L per minute, capillary voltage 3500 V, nozzle voltage 500 V.

[0053] Switching valve:

[0054]

[0055] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the mass spectrum.

[0056] If there are impurity peaks in the mass spectrum of the limit test solution, the N-nitroso-betahistine in betahistine hydrochloride preparations shall not exceed 0.0000375%, and the N-nitroso-betahistine in betahistine mesylate preparations shall not exceed 0.00005%. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 is the structural formula of N-nitroso-betahistine;

[0058] Figure 2 The stability comparison between the examples of the present invention and the betahistine reference preparation is shown;

[0059] Figure 3 The growth trend of N-nitroso-betahistine in betahistine hydrochloride preparations

[0060] Figure 4 The growth trend of N-nitroso-betahistine in betahistine mesylate preparations DETAILED DESCRIPTION

[0061] The present invention is further described below by way of examples. For those skilled in the art, according to the teachings of the present invention, using the prior art to make equivalent replacement improvements to the following examples still falls within the protection scope of the present invention.

[0062] Comparative Example 1

[0063] Betahistine hydrochloride tablets were prepared as Comparative Example 1 according to Example 1 of Patent CN111249237A, and the preparation process was as follows:

[0064] (1) Dissolution of API: Dissolve betahistine hydrochloride and citric acid in water as a wetting agent for granulation;

[0065] (2) placing microcrystalline cellulose and mannitol in a wet granulator and mixing them evenly, and adding a wetting agent for wet granulation;

[0066] (3) drying the wet granules obtained in step (2) in a fluidized bed at an air inlet temperature of 55° C. until the moisture content does not exceed 3.0%, and then performing granulation;

[0067] (4) adding silicon dioxide and talc to the dry particles obtained in step (3) and mixing;

[0068] (4) tabletting to prepare betahistine hydrochloride tablets.

[0069] The weights of the raw materials and auxiliary materials used to prepare the above 1000 Betahistine tablets are shown in the following table:

[0070]

[0071] Comparative Example 2

[0072] Betahistine mesylate orally disintegrating tablets were prepared according to Example 1 of patent CN101797237A as Comparative Example 2, and the preparation process was as follows:

[0073] (1) Grinding betahistine mesylate and all other excipients into fine powder with a fineness of more than 80 mesh;

[0074] (2) All the crushed components are mixed evenly and compressed into tablets to prepare betahistine mesylate orally disintegrating tablets.

[0075] The weights of the raw materials and auxiliary materials used to prepare the above 1000 Betahistine tablets are shown in the following table:

[0076]

[0077] Example 1

[0078] Prepare a batch size of 1000 tablets according to the prescription in the table below.

[0079]

[0080]

[0081] Example 1 Preparation process:

[0082] (1) Dissolution of API: Dissolve betahistine hydrochloride and citric acid in water as a wetting agent for granulation;

[0083] (2) placing microcrystalline cellulose, mannitol, and ascorbyl palmitate in a wet granulator and mixing them evenly, and adding a wetting agent for wet granulation;

[0084] (3) drying the wet granules obtained in step (2) in a fluidized bed at an air inlet temperature of 60° C. until the moisture content does not exceed 1.5%, and then granulating;

[0085] (4) adding silicon dioxide and talc to the dry particles obtained in step (3) and mixing;

[0086] (5) tabletting to prepare betahistine hydrochloride tablets.

[0087] Embodiment 2-4

[0088]

[0089] Example 2-4 Preparation process:

[0090] (1) Grind citric acid and pass through an 80-mesh sieve, grind silicon dioxide and pass through an 80-mesh sieve, and grind betahistine hydrochloride and other auxiliary materials through a 60-mesh sieve for later use;

[0091] (2) All the sieved components are mixed evenly and compressed into tablets to prepare betahistine hydrochloride tablets.

[0092] Embodiment 5-6

[0093]

[0094] Example 5-6 Preparation process:

[0095] (1) Grind citric acid and pass through an 80-mesh sieve, grind silicon dioxide and pass through an 80-mesh sieve, and grind betahistine hydrochloride and other auxiliary materials through a 60-mesh sieve for later use;

[0096] (2) all the sieved components for dry granulation are mixed evenly and put into a dry granulator to obtain granules;

[0097] (3) Add silicon dioxide and talcum powder to the obtained granules according to the prescribed ratio, mix well and then compress into tablets.

[0098] Embodiment 7-8

[0099] Prepare tablets in batches of 1000 tablets according to the formulation in the table below.

[0100]

[0101] Example 7 Preparation process:

[0102] (1) placing betahistine mesylate, microcrystalline cellulose, mannitol, and cross-linked polyvinylpyrrolidone in a wet granulator and mixing them evenly, and adding a wetting agent for wet granulation;

[0103] (2) Drying the wet granules obtained in step (2) in a fluidized bed at an air inlet temperature of 60° C. until the moisture content does not exceed 1.5%, and then performing granulation;

[0104] (3) adding silicon dioxide, talcum powder and lemon essence to the dry particles obtained in step (3), and mixing;

[0105] (4) tabletting to prepare betahistine mesylate tablets.

[0106] Example 8 Preparation process:

[0107] (1) placing betahistine mesylate, microcrystalline cellulose, mannitol, crospovidone and ascorbyl palmitate in a wet granulator and mixing them evenly, and adding a wetting agent to perform wet granulation;

[0108] (2) Drying the wet granules obtained in step (2) in a fluidized bed at an air inlet temperature of 60° C. until the moisture content does not exceed 1.5%, and then performing granulation;

[0109] (3) adding silicon dioxide, talcum powder and lemon essence to the dry particles obtained in step (3), and mixing;

[0110] (4) tabletting to prepare betahistine mesylate tablets.

[0111] Examples 9-10

[0112] Prepare tablets in batches of 1000 tablets according to the formulation in the table below.

[0113]

[0114] Example 9-10 Preparation process:

[0115] (1) sieve the silicon dioxide through an 80-mesh sieve, and sieve the betahistine mesylate and other auxiliary materials through a 60-mesh sieve for later use;

[0116] (2) All the sieved components are mixed evenly and compressed into tablets to prepare betahistine mesylate tablets.

[0117] Stability studies

[0118] (1) Accelerated stability study and influencing factor condition study

[0119] The betahistine hydrochloride tablets and betahistine mesylate tablets obtained in the above-mentioned comparative examples 1-2 and examples 1-10 were placed under the conditions of 40°C and 60°C for studying the influencing factors. The changes in N-nitroso-betahistine are shown in Tables 4 and 5, and the changes in N-nitroso-betahistine in Example 5, Example 9 and the betahistine tablet reference preparation under accelerated conditions of 40°C / 75%RH are shown in Table 6.

[0120] Table 4 Comparative Example of Betahistine Tablets Changes in N-nitroso-Betahistine under High Temperature Conditions

[0121]

[0122] Table 5 Changes of N-nitroso-betahistine in betahistine hydrochloride tablets and betahistine mesylate tablets under high temperature conditions in the examples

[0123]

[0124]

[0125] Table 6 Changes of N-nitroso-betahistine in Examples and Reference Preparations under Accelerated Conditions

[0126]

[0127] From the above table N-nitroso-betahistine test results, we can know that:

[0128] 1) After adding non-inorganic salt antioxidants to the formulation of betahistine tablets, the tablets were placed at high temperatures of 40°C and 60°C for 30 days, which significantly inhibited the growth of N-nitroso-betahistine, and even had no growth trend;

[0129] 2) Compared with the wet granulation process, the use of powder direct compression or dry granulation process can prevent the betahistine prescription components from contacting with water and high temperature, and avoid the formation of N-nitroso-betahistine. However, the wet granulation process still cannot effectively solve the risk of excessive growth of N-nitroso-betahistine during tablet storage;

[0130] 3) The growth of N-nitroso-betahistine can be more effectively addressed by adding non-inorganic salt antioxidants to the solid preparation formula and combining it with a dry process to prepare the finished preparation.

Claims

1. A betahistine oral solid preparation, characterized in that: The invention comprises betahistine or its salt and a non-inorganic salt antioxidant.

2. The betahistine oral solid preparation according to claim 1, characterized in that The betahistine oral solid preparation is prepared by a dry process.

3. The betahistine oral solid preparation according to claim 1 or 2, characterized in that: The betahistine salt is betahistine hydrochloride or mesylate.

4. The betahistine oral solid preparation according to any one of claims 1 to 3, characterized in that The antioxidant accounts for no less than 0.1% of the weight of the prescription.

5. The betahistine oral solid preparation according to any one of claims 1 to 4, characterized in that The non-inorganic salt antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride and cysteine; preferably, it is ascorbyl palmitate.

6. The betahistine oral solid preparation according to any one of claims 1 to 5, characterized in that The betahistine oral solid preparation comprises 0.1 wt% to 1 wt% of a non-inorganic salt antioxidant, 2 wt% to 10 wt% of betahistine or its salt, 70 wt% to 90 wt% of a filler, 1 wt% to 3 wt% of a pH regulator, 1 wt% to 3 wt% of a glidant and 2 wt% to 8 wt% of a lubricant; Optionally, the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose (anhydrate or hydrate), mannitol, calcium hydrogen phosphate, starch, pregelatinized starch and microcrystalline cellulose; preferably, microcrystalline cellulose and mannitol; and / or The pH regulator is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; preferably, citric acid; and / or The glidant is selected from one or more of silicon dioxide, talc, and hydrogenated vegetable oil; preferably, silicon dioxide and talc; and / or The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and docusate sodium; preferably, talc.

7. The betahistine oral solid preparation according to claim 6, characterized in that: The betahistine oral solid preparation is a granule, a tablet or a capsule, preferably a tablet.

8. The method for preparing the betahistine oral solid preparation according to any one of claims 1 to 7, characterized in that: The preparation method comprises the steps of directly mixing the powders or granulating them by dry method, adding auxiliary materials, mixing and directly packaging, or directly filling or tableting.

9. The preparation method according to claim 8, characterized in that: The steps include: a) betahistine or its salt, non-inorganic salt antioxidant and other auxiliary materials are sieved separately; b) pouring the API and the excipients into a mixer for mixing, or performing dry granulation after mixing; c) adding auxiliary materials to the mixed powder or granules obtained in step b) to obtain a total mixed powder or total granules; d) directly packing, filling or tableting the total mixed powder or total granules.

10. The betahistine oral solid preparation prepared according to the preparation method of claim 8 or 9.

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