Betahistine hydrochloride pharmaceutical preparation and preparation method thereof

Abstract

The invention provides a betahistine hydrochloride pharmaceutical preparation and a preparation method thereof. The betahistine hydrochloride pharmaceutical preparation comprises conjugated linoleic acid, betahistine hydrochloride and auxiliary materials. Conjugated linoleic acid and betahistine hydrochloride are combined together for the first time, and conjugated double bonds of conjugated linoleic acid can be specifically combined with nitrite to block the generation of nitrosamine, so that the content of N-nitrosobetahistine can be remarkably reduced. Based on the chemical characteristics of conjugated linoleic acid, conjugated linoleic acid is used as a functional additive, targeted removal of nitrosamine impurities is achieved, and meanwhile the situation that exogenous toxic substances are introduced to affect the drug effect of betahistine hydrochloride is avoided. In the experiment process, it is also accidentally found that after the conjugated linoleic acid is added, the positive effect on cerebrovascular diseases is also achieved.

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and preparations, and more particularly to a betahistine hydrochloride pharmaceutical preparation and a preparation method thereof. Background Art

[0002] Betahistine hydrochloride is a histamine analog widely used to treat Meniere's disease, vertigo, and cerebrovascular diseases. Its therapeutic effects work by dilating blood vessels in the inner ear and improving microcirculation. However, residual amines (such as unreacted methylamine) in the betahistine hydrochloride synthesis system or nitrite introduced during the process are susceptible to nitrosation, producing the carcinogenic N-nitroso-betahistine. The International Agency for Research on Cancer (IARC) has classified N-nitrosamine compounds as Class 1 carcinogens, and global pharmacopoeias (such as the USP and EP) are increasingly stringent in their control of nitrosamine impurities.

[0003] Current processes for removing this impurity face the following bottlenecks: 1. Difficulty in separation: The impurity's structural similarity to the main component makes it difficult to effectively separate using conventional purification methods (such as recrystallization and column chromatography), resulting in a high risk of impurity residue in the finished product. 2. Complex and costly processes: Existing methods require additional reagents or multiple processing steps, potentially introducing new impurities or increasing production energy consumption, making them incompatible with the requirements of green chemistry and industrialized production. Therefore, further improvement and development are needed. Summary of the Invention

[0004] In view of the various deficiencies of the existing technology and in order to solve the above problems, a betahistine hydrochloride pharmaceutical preparation and a preparation method thereof are proposed, and the following technical solutions are provided: A betahistine hydrochloride pharmaceutical preparation comprises conjugated linoleic acid, betahistine hydrochloride and excipients.

[0005] Furthermore, the mass ratio of betahistine hydrochloride to conjugated linoleic acid is 10:1-1.5.

[0006] Furthermore, the auxiliary materials include oily auxiliary materials.

[0007] Furthermore, the oily auxiliary material is glycerol.

[0008] Furthermore, the mass ratio of betahistine hydrochloride, conjugated linoleic acid and glycerol is 10:1-1.5:1-3.

[0009] Furthermore, the betahistine hydrochloride pharmaceutical preparation is a tablet, capsule or oral solution preparation.

[0010] Furthermore, the betahistine hydrochloride pharmaceutical preparation is an oral solution preparation, and the excipient further includes a mixed solvent of ethanol and water.

[0011] Furthermore, the mass ratio of the mixed solvent of betahistine hydrochloride, conjugated linoleic acid, glycerol and ethanol to water is 10:1-1.5:1-3:5-20.

[0012] In addition, the present invention also provides a method for preparing the above-mentioned betahistine hydrochloride pharmaceutical preparation, wherein conjugated linoleic acid, betahistine hydrochloride and excipients are mixed to prepare the betahistine hydrochloride pharmaceutical preparation.

[0013] Due to the adoption of the above technical solution, the beneficial technical effects of the present invention are: 1. This invention combines conjugated linoleic acid and betahistine hydrochloride for the first time. The conjugated double bonds of conjugated linoleic acid can specifically bind to nitrite to block the formation of nitrosamines, significantly reducing the content of N-nitroso-betahistine. This provides an innovative solution for the industrial production of high-purity betahistine hydrochloride. 2. Conjugated linoleic acid can also enhance the body's immune ability and improve the efficacy of betahistine hydrochloride. DETAILED DESCRIPTION

[0014] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention is clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by ordinary technicians in this field without making any creative work should fall within the scope of protection of this application.

[0015] The present application provides a novel betahistine hydrochloride pharmaceutical preparation, comprising conjugated linoleic acid, betahistine hydrochloride and excipients. For the first time, conjugated linoleic acid and betahistine hydrochloride are combined together, and the conjugated double bonds of conjugated linoleic acid are utilized to specifically bind to nitrites to block the generation of nitrosamines, which can significantly reduce the content of N-nitroso-betahistine. The present invention is based on the chemical properties of conjugated linoleic acid, using it as a functional additive to achieve targeted removal of nitrosamine impurities, while avoiding the introduction of exogenous toxic substances to affect the efficacy of betahistine hydrochloride itself. During the experiment, it was also unexpectedly found that after adding conjugated linoleic acid, it also has a positive effect on cerebrovascular diseases.

[0016] Example 1 According to the calculation of the mass in grams, 10 grams of betahistine hydrochloride, 1.2 grams of conjugated linoleic acid, 2 grams of glycerol, and 10 grams of a mixed solvent of ethanol and water, wherein the mass ratio of ethanol to water is 1:9, are uniformly mixed to prepare a betahistine hydrochloride oral solution.

[0017] Example 2 Betahistine hydrochloride was ground and passed through a 60-mesh sieve. 10 g of betahistine hydrochloride, 1 g of conjugated linoleic acid, and 1 g of glycerol were mixed uniformly according to the weight in grams, dried, and tableted to prepare betahistine hydrochloride tablets.

[0018] Example 3 According to the weight in grams, 10 grams of betahistine hydrochloride, 1.5 grams of conjugated linoleic acid, and 3 grams of glycerol are mixed evenly and then filled into a capsule shell in the prior art to prepare a betahistine hydrochloride capsule preparation.

[0019] Example 4 Betahistine hydrochloride was ground and passed through a 60-mesh sieve. 10 g of betahistine hydrochloride, 1.2 g of conjugated linoleic acid, and 2 g of glycerol were mixed uniformly according to the weight in grams, dried, and tableted to prepare betahistine hydrochloride tablets.

[0020] Example 5 According to the calculation of the mass in grams, 10 grams of betahistine hydrochloride, 1.1 grams of conjugated linoleic acid, 2.5 grams of glycerol, and 20 grams of a mixed solvent of ethanol and water, wherein the mass ratio of ethanol to water is 1:9, are mixed uniformly to prepare a betahistine hydrochloride oral solution.

[0021] Example 6 According to the calculation of the mass in grams, 10 grams of betahistine hydrochloride, 1.5 grams of conjugated linoleic acid, 3 grams of glycerol, and 5 grams of a mixed solvent of ethanol and water, wherein the mass ratio of ethanol to water is 1:9, are uniformly mixed to prepare a betahistine hydrochloride oral solution.

[0022] Example 7 Betahistine hydrochloride was ground and passed through a 60-mesh sieve. 10 g of betahistine hydrochloride and 1.2 g of conjugated linoleic acid were mixed uniformly according to the weight in grams, dried, and tableted to prepare betahistine hydrochloride tablets.

[0023] Comparative Example 1 Betahistine hydrochloride was ground and passed through a 60-mesh sieve. 10 g of betahistine hydrochloride and 1 g of glycerol were mixed evenly according to the weight in grams, dried, and tableted to prepare betahistine hydrochloride tablets.

[0024] Comparative Example 2 Betahistine hydrochloride was ground and passed through a 60-mesh sieve. 10 g of betahistine hydrochloride, 0.5 g of conjugated linoleic acid, and 0.5 g of glycerol were mixed uniformly according to the weight in grams, dried, and tableted to prepare betahistine hydrochloride tablets.

[0025] (1) Drug stability study The betahistine hydrochloride preparations obtained in Examples 1-7 and Comparative Examples 1-2 were placed at 40° C. and 60° C., respectively, to examine the changes in N-nitroso-betahistine, as shown in Table 1.

[0026] The detection method of N-nitroso-betahistine is as follows: using an Agilent 6470QQQ liquid spectrometer for determination, take an appropriate amount of the test sample, accurately weigh it, add the solvent water-acetonitrile (10:90) to dissolve it, and quantitatively dilute it to make a solution containing approximately 0.2 mg per 1 ml.

[0027] Reference solution: Take an appropriate amount of N-nitroso-betahistine reference substance, accurately weigh it, dissolve it in solvent and quantitatively dilute it to make a solution containing approximately 0.075 ng of N-nitroso-betahistine per 1 ml.

[0028] Chromatographic conditions: Use HlLICC as the filler (e.g., ACQUITY UPLC BEH HlLlC 1.7 μm, 2.1×50 mm or a column of equivalent performance), water-acetonitrile-formic acid (10:90:0.1) (containing 5 mmol / L ammonium formate) as the mobile phase; flow rate, 0.2 ml / min; column temperature, 35°C; injection volume, 5 μl; sample tray temperature, 4°C.

[0029] Mass spectrometry conditions (reference instrument model: Agilent 6470QQQ liquid spectrometer, 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 / min, nebulizer pressure 45 psi, sheath gas temperature 250°C, sheath gas flow rate 11 L / min, capillary voltage 3500 V, nozzle voltage 500 V.

[0030] Switching valve: Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the mass spectrum.

[0031] If there are impurity peaks in the mass spectrum of the limit test solution, the N-nitroso-betahistine in the betahistine hydrochloride preparation shall not exceed 0.0000375% by calculating the peak area according to the external standard method.

[0032] Table 1 Changes of N-nitroso-betahistine in the betahistine hydrochloride preparations obtained in Examples 1-7 and Comparative Examples 1-2 at 40°C and 60°C The test results in the table above show that when conjugated linoleic acid is added to betahistine hydrochloride and placed at 40 and 60°C for 30 days, the growth of N-nitroso-betahistine can be significantly inhibited. Furthermore, the tablet or capsule dosage form is superior to the solution dosage form. Furthermore, the present application also incorporates a glycerol oil excipient, which further inhibits the growth of N-nitroso-betahistine.

[0033] (2) Efficacy experiments Male rats, weighing 190-215g each, were selected for modeling. Each rat was housed individually in a stimulation cage. Prior to stimulation, rats were housed normally for one week. Stimulation was then initiated, with stimulation administered twice daily for 2 hours in the morning and afternoon, for approximately 8 weeks. Following modeling, a glucose tolerance test was performed. An oral glucose tolerance test (OGTV) was performed: After fasting for 12 hours, rats were gavaged with 2.5g / kg of 50% glucose solution. Blood glucose levels were collected from the tail vein for 2 hours. Rats with blood glucose levels below 6.20mmol / L and those weighing less than 350g were eliminated. Thirty rats meeting the model were then divided equally into three groups: Group 1, Group 2, and Group 3. The details are shown in Table 2.

[0034] Table 2 Grouping and drug administration of rats in each group During the administration period, the mice were still fed with high-fat feed (formula of high-fat feed: casein 28%, maltodextrin 20%, L-cysteine 1%, sucrose 13%, cellulose 5%, soybean oil 3%, lard 35%) by gavage three times a day, at 6:00, 14:00, and 22:00 respectively, for 10 consecutive weeks.

[0035] After 10 weeks of administration, the serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) of mice in each group were measured. The results are shown in Table 3.

[0036] Table 3 Effects of lipid levels in the blood of rats in each group (mmol / L) As can be seen from Table 3, the present invention can be seen from the above-mentioned efficacy experiments that the combined treatment of conjugated linoleic acid and betahistine hydrochloride can also improve the levels of cholesterol and triglycerides in the blood.

[0037] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A betahistine hydrochloride pharmaceutical preparation, characterized in that: Contains conjugated linoleic acid, betahistine hydrochloride and excipients.

2. A betahistine hydrochloride pharmaceutical preparation according to claim 1, characterized in that: The mass ratio of betahistine hydrochloride to conjugated linoleic acid is 10:1-1.

5.

3. A betahistine hydrochloride pharmaceutical preparation according to claim 1, characterized in that: Auxiliary materials include oily auxiliary materials.

4. A betahistine hydrochloride pharmaceutical preparation according to claim 3, characterized in that: The oily auxiliary material is glycerin.

5. A betahistine hydrochloride pharmaceutical preparation according to claim 4, characterized in that: The mass ratio of betahistine hydrochloride, conjugated linoleic acid and glycerol is 10:1-1.5:1-3.

6. A betahistine hydrochloride pharmaceutical preparation according to claim 1, characterized in that: The betahistine hydrochloride pharmaceutical preparation is a tablet, capsule or oral solution preparation.

7. A betahistine hydrochloride pharmaceutical preparation according to claim 6, characterized in that: The betahistine hydrochloride pharmaceutical preparation is an oral solution preparation, and the excipient further comprises a mixed solvent of ethanol and water.

8. A betahistine hydrochloride pharmaceutical preparation according to claim 7, characterized in that: The mass ratio of the mixed solvent of betahistine hydrochloride, conjugated linoleic acid, glycerol, ethanol and water is 10:1-1.5:1-3:5-20.

9. The method for preparing a betahistine hydrochloride pharmaceutical preparation according to any one of claims 1 to 8, characterized in that: The betahistine hydrochloride pharmaceutical preparation is prepared by mixing conjugated linoleic acid, betahistine hydrochloride and auxiliary materials.

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