Bilastine oral liquid preparation and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically provides a bilastine oral liquid preparation and a preparation method thereof. The bilastine oral liquid preparation comprises bilastine and pharmaceutically acceptable excipients; wherein the concentration of the bilastine is 0.25% w / v; the pharmaceutically acceptable excipients include one or more of a solubilizer, a preservative, a thickener, a sweetener, a fragrance, and a pH regulator; wherein the solubilizer is β-cyclodextrin, and the pH value of the solution required for its solubilization to take effect is in the range of 1 to 3. The present invention provides a bilastine oral liquid preparation, wherein bilastine is slightly soluble in water, and the present invention uses β-cyclodextrin as a solubilizer. Bilastine has good solubility in a strongly acidic β-cyclodextrin solution, and the lower the pH, the higher the solubility of bilastine. The present invention uses bilastine as a raw material drug and β-cyclodextrin as a solubilizer, and a uniform and clear bilastine oral solution is obtained through a new preparation method.

Description

Technical Field

[0001] The present invention relates to the technical field of medicines, and in particular to a bilastine oral liquid preparation and a preparation method thereof. Background Art

[0002] Bilastine is a non-sedating, long-acting antihistamine that selectively antagonizes peripheral H1 receptors, has no affinity for muscarinic receptors, and has low affinity for other receptors. It is indicated for the treatment of allergic rhinitis and urticaria in adults and adolescents aged 12 years and older. Compared with cetirizine, bilastine has greater selectivity for H1 receptors, less impact on the central nervous system, and is superior in improving patient symptoms and quality of life, providing a new medication option for urticaria and other allergic diseases.

[0003] Bilastine was developed by the Spanish company FAES FARMA for the treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. It was first approved for marketing by the EU in August 2010 and is now available in 10 European countries, including the UK, Spain, Germany, Denmark, Bulgaria, and Sweden. Currently, the EU-approved dosage forms include tablets, orally disintegrating tablets, and oral solutions. However, no bilastine-related drugs have been approved for marketing in China.

[0004] Bilastine is slightly soluble in water and belongs to the BCS Class II drug class, with low solubility and high permeability. While preparing a liquid solution is difficult, oral liquid formulations offer significant convenience for children and patients with dysphagia. Therefore, providing a stable, safe, and effective oral solution of bilastine is crucial.

[0005] Cyclodextrins, cyclic oligosaccharides composed of six or more glucopyranose molecules, can form complexes with poorly soluble compounds, increasing drug solubility and enhancing bioavailability. Cyclodextrins are very stable in alkaline media, but can be broken down by strong acids. They crystallize well in aqueous and alcohol-water solutions. They have no fixed melting point and begin to decompose when heated to approximately 200°C, demonstrating good thermal stability. They are non-hygroscopic but readily form various stable hydrates.

[0006] Existing literature discloses compositions containing bilastine for various administration routes, but does not disclose the composition and preparation method of bilastine oral solution. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a stable and effective bilastine oral liquid preparation suitable for children and a preparation method thereof.

[0008] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] The present invention provides a bilastine oral liquid preparation comprising bilastine and pharmaceutically acceptable excipients; wherein the concentration of the bilastine is 0.25% w / v; the pharmaceutically acceptable excipients include one or more of a solubilizer, a preservative, a thickener, a sweetener, a flavoring agent, and a pH adjuster; wherein the solubilizer is β-cyclodextrin, and the pH value of the solution required for its solubilization effect is in the range of 1 to 3. W / v means mass volume percentage.

[0010] Furthermore, the β-cyclodextrin is one or more of alkyl-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, sulfoalkyl-β-cyclodextrin and mixtures thereof.

[0011] Furthermore, the molar ratio of bilastine to β-cyclodextrin is 0.6 to 1.3. Still further, the molar ratio of bilastine to β-cyclodextrin is 0.8 to 1.0.

[0012] Furthermore, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, butylparaben or pharmaceutically acceptable salts thereof.

[0013] Furthermore, the thickener is selected from one or more combinations of glycerin, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and carbomer.

[0014] Furthermore, the sweetener is selected from one or more combinations of sorbitol, sucrose, triple-filtered sucrose, stevioside, and aspartame.

[0015] Furthermore, the pH range of the bilastine oral liquid preparation is 2.0 to 5.0. Furthermore, the pH range of the bilastine oral liquid preparation is 3.0 to 4.0.

[0016] The present invention also provides a method for preparing a bilastine oral liquid preparation, comprising the following steps: 1) weighing a prescribed amount of bilastine, β-cyclodextrin, a preservative, a thickener, a sweetener, and a fragrance; 2) dissolving the β-cyclodextrin in hot water at 50° C. to 70° C., and adjusting the pH to 1 to 3 with a dilute hydrochloric acid solution to obtain a β-cyclodextrin solution; 3) dissolving the bilastine in the β-cyclodextrin solution; 4) dissolving the preservative in purified water, stirring to dissolve, and adding the solution to the solution obtained in step 3) and mixing uniformly; 5) adding the thickener, sweetener, and fragrance to the solution obtained in step 4), adjusting the pH with a dilute hydrochloric acid solution or a dilute sodium hydroxide solution, adding purified water to the prescribed amount, and filling to obtain the bilastine oral liquid preparation.

[0017] Compared with the existing technology, the technical solution provided by the present invention has at least the following advantages:

[0018] The present invention provides a bilastine oral liquid preparation. Bilastine is slightly soluble in water. Beta-cyclodextrin is used as a solubilizing agent. Bilastine has good solubility in strongly acidic beta-cyclodextrin solutions, and the lower the pH, the higher the solubility of bilastine. The present invention uses bilastine as the API and beta-cyclodextrin as the solubilizing agent, and a novel preparation method is used to obtain a uniform and clear bilastine oral solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the solubility of bilastine in β-cyclodextrin solutions at different pH values. DETAILED DESCRIPTION

[0020] As can be seen from the background art, existing literature discloses compositions containing bilastine for various administration routes, but does not disclose the composition and preparation method of bilastine oral solution. The inventors have found that bilastine has good solubility in strongly acidic β-cyclodextrin solutions, and the lower the pH, the higher the solubility of bilastine.

[0021] Therefore, the present invention provides a bilastine oral liquid preparation comprising bilastine and pharmaceutically acceptable excipients; wherein the concentration of the bilastine is 0.25% w / v; the pharmaceutically acceptable excipients comprise one or more of a solubilizer, a preservative, a thickener, a sweetener, a fragrance, and a pH adjuster; wherein the solubilizer is β-cyclodextrin, and the pH value of the solution required for its solubilization effect is in the range of 1 to 3.

[0022] The present invention also provides a method for preparing a bilastine oral liquid preparation, comprising the following steps: 1) weighing a prescribed amount of bilastine, β-cyclodextrin, a preservative, a thickener, a sweetener, and a fragrance; 2) dissolving the β-cyclodextrin in hot water at 60° C., and adjusting the pH to 1-3 with a dilute hydrochloric acid solution to obtain a β-cyclodextrin solution; 3) dissolving the bilastine in the β-cyclodextrin solution; 4) dissolving the preservative in purified water, stirring to dissolve, and adding the solution to the solution obtained in step 3) and mixing uniformly; 5) adding the thickener, sweetener, and fragrance to the solution obtained in step 4), adjusting the pH with a dilute hydrochloric acid solution or a dilute sodium hydroxide solution, adding purified water to the prescribed amount, and filling to obtain the bilastine oral liquid preparation.

[0023] The present invention is described in detail below with reference to specific embodiments.

[0024] Example 1:

[0025] Element Prescription dosage Bilastin 2.5g Beta-cyclodextrin 5.5g Methylparaben 1.0g Propylparaben 0.2g Hydroxyethylcellulose 4.0g Sucralose 0.5g Raspberry flavor 2.0g hydrochloric acid appropriate amount Sodium hydroxide appropriate amount purified water Add to 1000mL

[0026] Preparation method: Weigh the prescribed amount of bilastine, β-cyclodextrin, preservative, thickener, sweetener, and fragrance; dissolve β-cyclodextrin in 60°C hot water and adjust the pH to 1.5±0.5 with dilute hydrochloric acid solution; add bilastine to dissolve, then add the preservative solution and mix well, and finally add the thickener, sweetener, and fragrance in sequence, and adjust the pH to 3.5±0.2 to obtain the bilastine oral liquid preparation.

[0027] Example 2: (Saturation Solubility Experiment)

[0028] Excess bilastine was added to a 0.5% w / v β-cyclodextrin solution at pH 1 to 10, and the mixture was shaken at 25°C for 48 h. After high-speed centrifugation, the supernatant was analyzed by HPLC. The results showed that the solubility of bilastine gradually decreased with increasing pH. Figure 1 shown.

[0029] Comparative Example 1: The commercially available bilastine oral solution produced by Spain's Faith Pharmaceutical Company was used as a comparative example.

[0030] The stability factors of the bilastine oral liquid preparation prepared in Example 1 and the original preparation under light and high temperature conditions were investigated. The results are shown in Table 1.

[0031] Table 1: Comparison of stability factors of the liquid preparation prepared in Example 1 of the present invention and the original preparation under light irradiation and high temperature conditions

[0032]

[0033]

[0034] As can be seen from Table 1, the bilastine oral solution prepared in the present invention has good stability and is of better quality than the original preparation.

[0035] Those skilled in the art will appreciate that the above-described embodiments are specific examples for implementing the present application, and that in actual applications, various changes in form and detail may be made thereto without departing from the spirit and scope of the present application. Any person skilled in the art may make changes and modifications without departing from the spirit and scope of the present application. Therefore, the scope of protection of the present application shall be subject to the scope defined in the claims.

Claims

1. A bilastine oral liquid preparation, characterized in that Comprising bilastine and pharmaceutically acceptable excipients; wherein the concentration of bilastine is 0.25% w / v; The pharmaceutically acceptable excipients include one or more of a solubilizer, a preservative, a thickener, a sweetener, a flavoring agent, and a pH adjuster; The solubilizing agent is β-cyclodextrin, the concentration of which is 0.5% w / v, and the pH range of the solution required for the solubilization effect is 1.5±0.5; the pH range of the bilastine oral liquid preparation is: 3.0-4.0; The bilastine oral liquid preparation is prepared by adjusting the pH twice; The preparation method of the bilastine oral liquid preparation comprises the following steps: 1) Weigh the prescribed amount of bilastine, β-cyclodextrin, preservatives, thickeners, sweeteners, and flavoring agents; 2) dissolving the β-cyclodextrin in hot water at 50° C. to 70° C., and adjusting the pH to 1.5±0.5 with a dilute hydrochloric acid solution to obtain a β-cyclodextrin solution; 3) dissolving the bilastine in the β-cyclodextrin solution; 4) dissolving the preservative in purified water, stirring to dissolve, and adding to the solution obtained in step 3) and mixing evenly; 5) adding the thickener, sweetener, and flavoring agent to the solution obtained in step 4), adjusting the pH with dilute hydrochloric acid solution or dilute sodium hydroxide solution, adding purified water to the prescribed amount, and filling to obtain the bilastine oral liquid preparation.

2. The bilastine oral liquid preparation according to claim 1, wherein The preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, butylparaben or pharmaceutically acceptable salts thereof.

3. The bilastine oral liquid preparation according to claim 1, characterized in that The thickener is selected from one or more combinations of glycerin, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and carbomer.

4. The bilastine oral liquid preparation according to claim 1, characterized in that The sweetener is selected from one or more combinations of sorbitol, sucrose, sucralose, stevioside, and aspartame.

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