Cyclodextrin composition for improving drug solubility and preparation method thereof

Abstract

The invention relates to a cyclodextrin composition capable of improving the dissolving property of a medicine and a preparation method of the cyclodextrin composition. The cyclodextrin composition capable of improving the dissolving property of the medicine comprises the following components in parts by mass: 15-30 parts of cyclodextrin, 5-15 parts of microcrystalline cellulose, 5-20 parts of modified calcium carbonate, 1-3 parts of silicon dioxide, 1-2 parts of salt and 1-5 parts of an auxiliary agent, wherein the modified calcium carbonate is obtained by reacting cyclodextrin, organic acid, a hydrophilic high-molecular polymer and calcium carbonate. According to the invention, cyclodextrin and microcrystalline cellulose are adopted as main bodies and are compounded with modified calcium carbonate and other components, so that the cyclodextrin composition capable of improving the drug solubility is obtained, the dissolvability of the product is remarkably improved, a better release effect is achieved, the defects in the prior art are overcome, and the cyclodextrin composition has important significance on development and popularization of the cyclodextrin composition product and has wide application prospects. The application prospect is good.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a cyclodextrin composition for improving drug solubility and a preparation method thereof. Background Art

[0002] Cyclodextrins (CDs), cyclic oligosaccharides composed of glucose units, play a crucial role in the field of pharmaceutical excipients due to their unique hydrophobic interior and hydrophilic exterior structure. Their core value lies in forming inclusion complexes with drug molecules, significantly improving the water solubility and dissolution rate of poorly soluble drugs, thereby enhancing the biopharmaceutical availability of oral, parenteral, and ophthalmic dosage forms. Furthermore, cyclodextrin compositions can effectively enhance drug stability, protecting them from degradation pathways such as oxidation, hydrolysis, volatilization, sublimation, or photolysis. They can also reduce local irritation and mask unpleasant odors by minimizing direct contact between the drug and biological tissue, thereby improving patient compliance. Under specific conditions, they can also participate in regulating drug release behavior.

[0003] The compounding of cyclodextrin with microcrystalline cellulose, calcium carbonate, silicon dioxide and other substances can further improve the performance of drug preparations and has been widely used. The addition of cellulose excipients effectively improves the processing properties of the powder, such as fluidity, compressibility, and formability, making it easier to prepare stable solid preparations. The cellulose matrix can also provide physical support for the cyclodextrin-drug inclusion complex, reducing dissociation or drug precipitation during storage and maintaining a high solubility state. Calcium carbonate and silicon dioxide are mainly used as diluents, pH regulators and taste modifiers in preparations. They have the effect of quickly neutralizing the local acidic environment and providing external buffering protection for acid-sensitive drugs. They can also improve the taste and mask the bitter taste, complementing the taste-masking effect of cyclodextrin and significantly improving patient compliance.

[0004] However, the current cyclodextrin composite products with various composition combinations still generally have certain defects. For example, substances such as calcium carbonate may adsorb drug ingredients on the surface or in the pore structure, but due to their insolubility in water, the active ingredients cannot be released in a dissolved state, reducing the effective solubility and dissolution rate of the drug; moreover, poorly soluble ingredients such as calcium carbonate may also form a physical barrier on the outside of the cyclodextrin inclusion complex, hindering water penetration and dissolution of the inclusion complex, further affecting the release of the drug and failing to meet the application needs within the industry.

[0005] In summary, it is necessary to develop a new technical solution to solve the deficiencies in the existing technology. Summary of the Invention

[0006] Based on this, the present invention provides a cyclodextrin composition for improving drug solubility, as well as its preparation method and application. The present invention utilizes cyclodextrin and microcrystalline cellulose as the main components, compounded with modified calcium carbonate and other ingredients, to produce a cyclodextrin composition for improving drug solubility. This significantly improves the product's solubility and provides a superior release effect, overcoming the shortcomings of the prior art.

[0007] One object of the present invention is to provide a cyclodextrin composition for improving drug solubility, wherein the cyclodextrin composition for improving drug solubility comprises the following components in parts by weight: 15-30 parts of cyclodextrin 5-15 parts of microcrystalline cellulose 5-20 parts modified calcium carbonate 1-3 parts of silicon dioxide 1-2 parts salt 1-5 parts of additives; The modified calcium carbonate is obtained by reacting cyclodextrin, organic acid, hydrophilic high molecular polymer and calcium carbonate.

[0008] Furthermore, the organic acid is tartaric acid, and the hydrophilic high molecular polymer is polyethylene glycol.

[0009] Furthermore, the cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin and γ-cyclodextrin.

[0010] Furthermore, it also includes pharmaceutical ingredients.

[0011] Furthermore, the salt is stearate.

[0012] Furthermore, the auxiliary agent is selected from one or more of preservatives, disintegrants, pigments, sweeteners and flavors.

[0013] Another object of the present invention is to provide a method for preparing the cyclodextrin composition for improving drug solubility, wherein the method comprises the following steps: S1. Mixing calcium carbonate and tartaric acid, heating and reacting under alkaline conditions to obtain an intermediate product; S2, mixing the intermediate product with a catalyst, a hydrophilic polymer, and cyclodextrin, and stirring the mixture to react to obtain modified calcium carbonate; S3. Mixing the modified calcium carbonate and other ingredients, stirring evenly, and grinding to obtain the cyclodextrin composition for improving drug solubility.

[0014] Furthermore, the mass ratio of the calcium carbonate to tartaric acid is (3-8):1.

[0015] Furthermore, the mass ratio of the intermediate product, the hydrophilic high molecular polymer and the cyclodextrin is 5:(1-10):(1-5).

[0016] Furthermore, in step S1, the pH of the alkaline condition is 7.5-9, and the temperature of the heating reaction is 40-50°C.

[0017] Furthermore, the method further comprises: adding cyclodextrin into 50-80° C. distilled water, then adding the drug component, stirring for 0.5-2 h, filtering, and freeze-drying to obtain a cyclodextrin inclusion compound.

[0018] Another object of the present invention is to provide use of the cyclodextrin composition for improving drug solubility in a pharmaceutical composition.

[0019] The present invention has the following beneficial effects: The cyclodextrin composition for improving drug solubility provided by the present invention is prepared by compounding components such as cyclodextrin, microcrystalline cellulose and modified calcium carbonate. The modified calcium carbonate first reacts calcium carbonate with tartaric acid having multiple hydroxyl and carboxyl functional groups, so that calcium ions on the surface of the calcium carbonate form a chelate reaction with the carboxyl groups, thereby obtaining a tartaric acid-modified intermediate product. The introduced carboxyl groups then react with polyethylene glycol to introduce hydrophilic polymer chain segments, thereby greatly improving the hydrophilicity of the calcium carbonate. Finally, the modified calcium carbonate is mixed with cyclodextrin and adsorbed to obtain a product, thereby enhancing the dissolution rate of the composition. The modified calcium carbonate has a large number of active hydroxyl groups, ester groups and other functional groups, which can form hydrogen bonds with components such as cyclodextrin and microcrystalline cellulose to exert an adhesive effect. It is also beneficial to combine with drug inclusion compound components, thereby improving the stability of tablet products, enabling longer-term storage and ensuring the effectiveness of the product. In addition, the modified calcium carbonate can also form a synergistic effect with cyclodextrin and cellulose, promoting rapid water penetration and effective dissolution of the inclusion compound, and exerting the function of jointly regulating drug release, thereby solving the shortcomings of the existing technology and having important significance for the development and promotion of cyclodextrin composition products. DETAILED DESCRIPTION

[0020] In order to more clearly illustrate the technical solutions of the present invention, the following examples are given. Unless otherwise stated, the raw materials, reactions and post-processing methods mentioned in the examples are common raw materials on the market and technical methods well known to those skilled in the art.

[0021] The terms "preferred," "preferably," "more preferred," and the like, used herein, refer to embodiments of the invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

[0022] It should be understood that, except in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties to be obtained by the present invention.

[0023] The medicinal ingredient in the embodiment of the present invention is vitamin D2.

[0024] The hydroxypropyl-β-cyclodextrin in the examples of the present invention was purchased from Xi'an Deli Biochemical Co., Ltd.

[0025] The salt in the embodiment of the present invention is magnesium stearate.

[0026] The auxiliary agents in the embodiment of the present invention are the disintegrant K30 and the sweetener aspartame in a mass ratio of 4:1.

[0027] The polyethylene glycol in the embodiment of the present invention is PEG-400.

[0028] The “parts” in the embodiments of the present invention refer to parts by mass. Example 1

[0029] A cyclodextrin composition for improving drug solubility, comprising the following components in parts by weight: 2 parts of drug ingredients 15 parts of hydroxypropyl-β-cyclodextrin 10 parts of microcrystalline cellulose 12 parts modified calcium carbonate 1 part silicon dioxide 1 part salt 1 part of auxiliary agent; The method for preparing the cyclodextrin composition for improving drug solubility comprises the following steps: S1. Calcium carbonate was added to anhydrous ethanol at a concentration of 0.03 g / mL and ultrasonically dispersed for 1 h to obtain a suspension. Tartaric acid was added to anhydrous ethanol at a concentration of 0.01 g / mL and then adjusted to pH 7 with 1 M sodium hydroxide solution to obtain a tartaric acid solution. The tartaric acid solution was added to the suspension (the mass ratio of tartaric acid to calcium carbonate was 1:5), stirred at 40° C. for 5 h, and filtered, washed, and dried to obtain an intermediate product; S2. Using cyclohexane as a solvent, the intermediate product, polyethylene glycol, and concentrated sulfuric acid were mixed, and the mixture was refluxed at 80° C. for 4 h. Hydroxypropyl-β-cyclodextrin was then added, and the mixture was ultrasonically reacted at 70° C. for 4 h. After cooling to room temperature, sodium bicarbonate was added until no bubbles were generated. After removing the solvent, modified calcium carbonate was obtained. The mass ratio of the intermediate product, polyethylene glycol, concentrated sulfuric acid and hydroxypropyl-β-cyclodextrin is 5:5:0.1:1; S3. According to the above mass fractions, add 15 parts of hydroxypropyl-β-cyclodextrin to 45 parts of 80°C hot water, stir to dissolve, add 2 parts of the drug component, stir for 1 hour, filter through a 0.22 μm microporous membrane, and freeze-dry to obtain a cyclodextrin inclusion compound; The cyclodextrin inclusion compound, modified calcium carbonate and other ingredients were mixed according to the above mass parts, stirred evenly, ground through a 100-mesh sieve, and tableted to obtain a product. Example 2

[0030] A cyclodextrin composition for improving drug solubility, comprising the following components in parts by weight: 2.6 parts of drug ingredients 20 parts of hydroxypropyl-β-cyclodextrin 12 parts microcrystalline cellulose 15 parts modified calcium carbonate 1.5 parts of silicon dioxide 1.2 parts salt 1 part of auxiliary agent; The method for preparing the cyclodextrin composition for improving drug solubility comprises the following steps: S1. Calcium carbonate was added to anhydrous ethanol at a concentration of 0.03 g / mL and ultrasonically dispersed for 1 h to obtain a suspension. Tartaric acid was added to anhydrous ethanol at a concentration of 0.01 g / mL and then adjusted to pH 7 with 1 M sodium hydroxide solution to obtain a tartaric acid solution. The tartaric acid solution was added to the suspension (the mass ratio of tartaric acid to calcium carbonate was 1:5), stirred at 40° C. for 5 h, and filtered, washed, and dried to obtain an intermediate product; S2. Using cyclohexane as a solvent, the intermediate product, polyethylene glycol, and concentrated sulfuric acid were mixed, and the mixture was refluxed at 80° C. for 4 h. Hydroxypropyl-β-cyclodextrin was then added, and the mixture was ultrasonically reacted at 70° C. for 4 h. After cooling to room temperature, sodium bicarbonate was added until no bubbles were generated. After removing the solvent, modified calcium carbonate was obtained. The mass ratio of the intermediate product, polyethylene glycol, concentrated sulfuric acid and hydroxypropyl-β-cyclodextrin is 5:5:0.1:1; S3. According to the above mass fractions, add 20 parts of hydroxypropyl-β-cyclodextrin to 60 parts of 80°C hot water, stir to dissolve, add 2.6 parts of the drug component, stir for 1 hour, filter through a 0.22 μm microporous membrane, and freeze-dry to obtain a cyclodextrin inclusion compound; The cyclodextrin inclusion compound, the modified calcium carbonate and other ingredients were mixed according to the above mass parts, stirred evenly, ground through a 100-mesh sieve, and tableted to obtain a product. Example 3

[0031] A cyclodextrin composition for improving drug solubility, comprising the following components in parts by weight: 3.2 parts of drug ingredients 25 parts of hydroxypropyl-β-cyclodextrin 15 parts of microcrystalline cellulose 20 parts of modified calcium carbonate 1.8 parts of silicon dioxide 1.6 parts salt 1.8 parts of additives; The method for preparing the cyclodextrin composition for improving drug solubility comprises the following steps: S1. Calcium carbonate was added to anhydrous ethanol at a concentration of 0.03 g / mL and ultrasonically dispersed for 1 h to obtain a suspension. Tartaric acid was added to anhydrous ethanol at a concentration of 0.01 g / mL and then adjusted to pH 7 with 1 M sodium hydroxide solution to obtain a tartaric acid solution. The tartaric acid solution was added to the suspension (the mass ratio of tartaric acid to calcium carbonate was 1:5), stirred at 40° C. for 5 h, and filtered, washed, and dried to obtain an intermediate product; S2. Using cyclohexane as a solvent, the intermediate product, polyethylene glycol, and concentrated sulfuric acid were mixed, and the mixture was refluxed at 80° C. for 4 h. Hydroxypropyl-β-cyclodextrin was then added, and the mixture was ultrasonically reacted at 70° C. for 4 h. After cooling to room temperature, sodium bicarbonate was added until no bubbles were generated. After removing the solvent, modified calcium carbonate was obtained. The mass ratio of the intermediate product, polyethylene glycol, concentrated sulfuric acid and hydroxypropyl-β-cyclodextrin is 5:5:0.1:1; S3. According to the above mass fractions, add 25 parts of hydroxypropyl-β-cyclodextrin to 75 parts of 80°C hot water, stir to dissolve, add 3.2 parts of the drug component, stir for 1 hour, filter through a 0.22 μm microporous membrane, and freeze-dry to obtain a cyclodextrin inclusion compound; The cyclodextrin inclusion compound, the modified calcium carbonate and other ingredients were mixed according to the above mass parts, stirred evenly, ground through a 100-mesh sieve, and tableted to obtain a product. Comparative Example 1

[0032] A cyclodextrin composition for improving drug solubility. The difference between this comparative example and Example 1 is that step S2 is deleted and modified calcium carbonate is replaced by an intermediate product. Other ingredients and preparation methods are the same as those in Example 1. Comparative Example 2

[0033] A cyclodextrin composition for improving drug solubility. This comparative example differs from Example 1 in that steps S1 and S2 are replaced by mixing calcium carbonate, polyethylene glycol, and hydroxypropyl-β-cyclodextrin in a mass ratio of 5:5:1, ultrasonically reacting at 70°C for 4 hours, filtering, washing, and drying to obtain modified calcium carbonate. The other ingredients and preparation method are the same as those in Example 1. Test Case

[0034] The cyclodextrin compositions for improving drug solubility prepared in Examples 1-3 and Comparative Examples 1-2 were subjected to performance tests.

[0035] Performance testing is carried out in accordance with the provisions of the Chinese Pharmacopoeia (2020 edition).

[0036] The test results are shown in Table 1:

[0037]

[0038] As can be seen from Table 1, the cyclodextrin compositions for improving drug solubility prepared in Examples 1-3 of the present invention have good appearance, excellent solubility, and a solubility of up to 88.9%, with significant improvement in solubility. Comparative Example 1 replaces the modified calcium carbonate with an intermediate product, and does not introduce a hydrophilic polymer or a cyclodextrin group. The hydrophilicity of the substance is reduced, and it is difficult for the various components to form a synergistic effect that promotes dissolution, so the solubility is significantly reduced. Comparative Example 2 directly uses calcium carbonate, polyethylene glycol, and cyclodextrin for mixing and heating. Only a small amount of hydrophilic substances are adsorbed on the surface of calcium carbonate, and the hydrophilicity of the product and the synergistic effect between the various components are further reduced. At the same time, it is difficult for the modified calcium carbonate to achieve sufficient adhesion, resulting in defects in appearance and a significantly reduced solubility.

[0039] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

[0040] 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 cyclodextrin composition for improving drug solubility, characterized in that: The cyclodextrin composition for improving drug solubility comprises the following components in parts by weight: 15-30 parts of cyclodextrin 5-15 parts of microcrystalline cellulose 5-20 parts modified calcium carbonate 1-3 parts of silicon dioxide 1-2 parts salt 1-5 parts of additives; The modified calcium carbonate is obtained by reacting cyclodextrin, organic acid, hydrophilic high molecular polymer and calcium carbonate.

2. The cyclodextrin composition for improving drug solubility according to claim 1, wherein: The organic acid is tartaric acid, and the hydrophilic high molecular polymer is polyethylene glycol.

3. The cyclodextrin composition for improving drug solubility according to claim 1, characterized in that: The cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin and γ-cyclodextrin.

4. The cyclodextrin composition for improving drug solubility according to claim 1, characterized in that: Also includes pharmaceutical ingredients.

5. The cyclodextrin composition for improving drug solubility according to claim 1, characterized in that: The auxiliary agent is selected from one or more of preservatives, disintegrants, pigments, sweeteners and flavors.

6. The method for preparing the cyclodextrin composition for improving drug solubility according to any one of claims 1 to 5, characterized in that: The method for preparing the cyclodextrin composition for improving drug solubility comprises the following steps: S1. Mixing calcium carbonate and tartaric acid, heating and reacting under alkaline conditions to obtain an intermediate product; S2, mixing the intermediate product with a catalyst, a hydrophilic polymer, and cyclodextrin, and stirring the mixture to react to obtain modified calcium carbonate; S3. Mixing the modified calcium carbonate and other ingredients, stirring evenly, and grinding to obtain the cyclodextrin composition for improving drug solubility.

7. The method for preparing a cyclodextrin composition for improving drug solubility according to claim 6, characterized in that: The mass ratio of the calcium carbonate to tartaric acid is (3-8):

1.

8. The method for preparing the cyclodextrin composition for improving drug solubility according to claim 6, characterized in that: The mass ratio of the intermediate product, the hydrophilic high molecular polymer and the cyclodextrin is 5:(1-10):(1-5).

9. The method for preparing a cyclodextrin composition for improving drug solubility according to claim 6, wherein: In step S1, the pH of the alkaline condition is 7.5-9, and the temperature of the heating reaction is 40-50°C.

10. The method for preparing the cyclodextrin composition for improving drug solubility according to claim 6, characterized in that: Also includes: Add cyclodextrin to 50-80° C. distilled water, then add the drug component, stir for 0.5-2 h, filter, and freeze-dry to obtain a cyclodextrin inclusion compound.

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