A cyclodextrin-based pharmaceutical excipient and a method for preparing the same

Abstract

The application relates to a cyclodextrin-based pharmaceutical excipient and a preparation method thereof, the cyclodextrin-based pharmaceutical excipient comprising the following components in mass fractions: 300-320 parts of gamma-cyclodextrin, 15-20 parts of a sugar, 15-20 parts of calcium carbonate, 20-30 parts of modified silicon dioxide, 3-4 parts of magnesium stearate and 2-4 parts of other auxiliaries; wherein the modified silicon dioxide is hydroxylated silicon dioxide, which is the product of grafting gluconic acid. The modified silicon dioxide introduces a large number of hydroxyl groups through gluconic acid, the hydroxyl groups can improve the compatibility of the components, promote the uniform distribution of the components, improve the fluidity, and make the stability better; in addition, the particle size of the modified silicon dioxide is extremely small, the modified silicon dioxide is uniformly dispersed in all particle gaps, a large number of very narrow pore channels are formed, the release curve is more gentle, the slow-release time is prolonged, and the modified silicon dioxide can be adsorbed on the surface of the gamma-cyclodextrin, thereby improving the slow-release capacity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a cyclodextrin-based pharmaceutical excipient and its preparation method. Background Technology

[0002] Cyclodextrin is a cyclic oligosaccharide produced by the enzymatic hydrolysis of starch by cyclodextrin glucosyltransferase. It has a hollow truncated cone structure and belongs to the mainstream supramolecular inclusion excipients in pharmaceuticals. It relies on hydrophobic interactions, van der Waals forces, and molecular hydrogen bonds to pack drug molecules into the cavity to form an inclusion complex. After oral administration, it dissociates and releases the drug in the gastrointestinal tract.

[0003] Specifically, the main reasons for using cyclodextrin as a drug inclusion complex include: addressing the pain points of poorly soluble drugs and significantly improving dissolution and bioavailability. Some chemical drugs and lipid-soluble active ingredients have extremely poor water solubility, resulting in slow dissolution, low absorption, and weak efficacy when directly compressed into tablets. Therefore, the drug penetrates the cyclodextrin cavity, and the numerous hydrophilic hydroxyl groups on the outer side directly improve the apparent solubility of the drug; improving the storage stability of drugs and formulations, as the cyclodextrin cavity acts as a molecular "protective shield," isolating external destructive factors. Therefore, it can isolate oxygen and ultraviolet light, preventing drug oxidation, discoloration, and the generation of toxic impurities, and isolate moisture, reducing drug decomposition upon contact with water; masking bitterness and odors, reducing gastrointestinal irritation, and improving medication adherence. Because bitter and irritating drugs are enclosed within the cyclodextrin cavity, the amount of drug contacting the taste buds in the mouth is significantly reduced, eliminating the need for large amounts of sweeteners to mask the taste. Furthermore, after oral administration, the drug does not instantly reach a high concentration on the gastric mucosa, reducing stomach pain, nausea, and acid reflux.

[0004] However, the use of cyclodextrin as a drug inclusion complex still has some problems, including: insufficient sustained-release effect, resulting in rapid and large-volume drug release from tablets upon contact with water, extremely high gastrointestinal drug concentrations in a short time, exceeding the peak blood drug level, aggravating toxic side effects, and significantly shortening the duration of drug efficacy, requiring frequent dosing, large fluctuations in blood drug concentration peaks and troughs, and unstable therapeutic effects; insufficient stability, resulting in a large number of tablets breaking and powdering during tableting, sieving, and packaging, significantly reducing the yield of finished products, increasing production costs, and the surface area of ​​the broken tablets increases dramatically, making cyclodextrin and drugs more susceptible to moisture absorption and oxidation, and rapidly increasing impurities.

[0005] In conclusion, it is necessary to develop a new technical solution to address the shortcomings of existing technologies. Summary of the Invention

[0006] This invention provides a cyclodextrin-based pharmaceutical excipient and its preparation method. The cyclodextrin-based pharmaceutical excipient includes γ-cyclodextrin, modified silica, and other components. The modified silica introduces a large number of hydroxyl groups through gluconic acid, improving the compatibility of the components, promoting uniform distribution of the components, improving flowability, and enhancing stability and sustained-release effect.

[0007] The purpose of this invention is to provide a cyclodextrin-based pharmaceutical excipient, which comprises the following components in parts by weight: 300-320 parts of γ-cyclodextrin 15-20 servings of carbohydrates 15-20 parts calcium carbonate 20-30 parts of modified silica 3-4 parts magnesium stearate Other auxiliary agents, 2-4 parts; The modified silica is a product of hydroxylated silica grafted with gluconic acid.

[0008] Furthermore, the other additives are selected from one or more of the following: adhesives, disintegrants, sweeteners, preservatives, pigments, flavorings, and multifunctional additives.

[0009] Furthermore, the sugar is selected from one or more of sucrose, glucose, and lactose.

[0010] Another object of the present invention is to provide a method for preparing the cyclodextrin-based pharmaceutical excipient, the method comprising the following steps: S1. Hydroxylated silicon dioxide is obtained by hydroxylating silicon dioxide; S2. The hydroxylated silica and gluconic acid are mixed and heated to react, thereby obtaining modified silica; S3. The modified silica is mixed with the remaining components, stirred evenly, and ground to obtain the cyclodextrin-based pharmaceutical excipient.

[0011] Furthermore, in step S1, the hydroxylation temperature is 60-80°C.

[0012] Furthermore, in step S1, the hydroxylation time is 0.5-2 hours.

[0013] Further, in step S2, the mass ratio of the hydroxylated silica to gluconic acid is (1-5):(1-8).

[0014] Furthermore, in step S2, the heating temperature is 50-70°C.

[0015] Another object of the present invention is to provide the use of the cyclodextrin-based pharmaceutical excipient in a pharmaceutical formulation comprising the following components in parts by weight: 8-10 parts of drug ingredients 300-320 parts of γ-cyclodextrin 15-20 servings of carbohydrates 15-20 parts calcium carbonate 20-30 parts of modified silica 3-4 parts magnesium stearate Other auxiliary agents, 2-4 parts; The modified silica is a product of hydroxylated silica grafted with gluconic acid.

[0016] Furthermore, the application of the cyclodextrin-based pharmaceutical excipient in pharmaceutical formulations includes the following steps: M1. Hydroxylated silicon dioxide is obtained by hydroxylating silicon dioxide. M2. The hydroxylated silica and gluconic acid are mixed and heated to react, thereby obtaining modified silica; M3. γ-Cyclodextrin and the drug component are mixed, stirred, filtered, and freeze-dried to obtain γ-cyclodextrin inclusion complex; M4. The γ-cyclodextrin inclusion complex, modified silica, and other components are mixed, stirred evenly, and ground to obtain the product.

[0017] The present invention has the following beneficial effects: This invention provides a cyclodextrin-based pharmaceutical excipient and its preparation method. The modified silica is obtained by first hydroxylating silica to obtain hydroxylated silica, and then reacting it with gluconic acid to graft gluconic acid onto the surface of hydroxylated silica, thereby introducing a large number of hydroxyl groups onto the surface of hydroxylated silica.

[0018] The modified silica of this invention introduces a large number of hydroxyl groups through gluconic acid. These hydroxyl groups improve the compatibility of the components, promote uniform distribution, and enhance flowability. This ensures uniform compression of all components during tableting, significantly reducing internal residual stress, increasing mechanical strength, and preventing breakage. Furthermore, the extremely small particle size of the modified silica fills the gaps between particles of varying sizes, resulting in a denser, more robust tablet core after compression. Hydrogen bonds further enhance particle bonding, improving stability. Additionally, the extremely small particle size of the modified silica, evenly dispersed in all particle gaps, forms numerous very narrow micropores. When water enters the tablet, it can only slowly pass through these micropores, preventing rapid, large-area wetting of the tablet. This significantly slows down the swelling and dissociation rate of the tablet, preventing... The initial release of the drug is rapid and substantial, resulting in a smoother release curve and a longer sustained-release duration. Furthermore, the hydroxyl groups on the surface of modified silica and γ-cyclodextrin can form hydrogen bonds, allowing modified silica to adsorb onto the surface of γ-cyclodextrin and construct a modified silica-γ-cyclodextrin framework structure. This increases resistance to drug release and enhances sustained-release capability. Moreover, because modified silica has significantly more hydroxyl groups than hydroxylated silica, the hydrogen bonding between modified silica and γ-cyclodextrin is more pronounced than that between hydroxylated silica and γ-cyclodextrin. Consequently, the framework structure constructed by modified silica and γ-cyclodextrin is more robust, stable, and exhibits better performance. The synergistic effect of all components further improves the overall performance of the product. Detailed Implementation

[0019] To more clearly illustrate the technical solution of the present invention, the following embodiments are provided. Unless otherwise stated, the raw materials, reactions, and post-processing methods appearing in the embodiments are all commercially available raw materials and technical methods well known to those skilled in the art.

[0020] The terms "preferred," "more preferably," and "more suitable" used in this invention refer to embodiments of the invention that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this invention.

[0021] It should be understood that, except in any operational instance or otherwise indicated, the amounts or all figures representing ingredients used, for example, in the specification and claims, should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise stated, the numerical parameters set forth in the following specification and appended claims are approximate values ​​varying according to the desired performance to be obtained according to the invention.

[0022] The embodiments and application examples of this invention use the following raw materials: Drug ingredient: Zolpidem tartrate.

[0023] γ-Cyclodextrin: Purchased from Hebei Kelongduo Biotechnology Co., Ltd.

[0024] Carbohydrates: Lactose, purchased from Shaanxi Panlong Yihai Pharmaceutical Co., Ltd.

[0025] Calcium carbonate: purchased from Xi'an Hongyao Pharmaceutical Excipients Co., Ltd.

[0026] Silica: Particle size 40-90nm.

[0027] Other excipients: binder (hydroxypropyl methylcellulose, purchased from Hebei Runbu Biotechnology Co., Ltd.), sweetener (pharmaceutical grade aspartame, purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.), and colorant (caramel, purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.) are mixed in a mass ratio of 3:1:1. Example

[0028] A cyclodextrin-based pharmaceutical excipient, comprising the following components in parts by weight: 320 parts of γ-cyclodextrin 20 servings of carbohydrates 20 parts of calcium carbonate 30 parts modified silica 4 parts magnesium stearate Four parts of other auxiliary agents; The method for preparing the cyclodextrin-based pharmaceutical excipient includes the following steps: S1. Immerse silica in a mixture of concentrated sulfuric acid and hydrogen peroxide (mass concentration of 30%) with a volume ratio of 7:3, heat at 70°C for 1 hour, filter, wash and dry to obtain hydroxylated silica. S2. Using water as a solvent, the hydroxylated silica and gluconic acid are mixed at a mass ratio of 2:3, heated to 60°C and ultrasonically reacted for 10 hours, filtered, washed and dried to obtain modified silica. S3. According to the above-mentioned mass proportions, the modified silica is mixed with the remaining components, stirred evenly, ground through a 100-mesh sieve, and compressed into tablets to obtain a cyclodextrin-based pharmaceutical excipient.

[0029] Application Examples 1-3 The components and mass fractions of the pharmaceutical preparations used in Examples 1-3 are shown in Table 1.

[0030] Table 1. Composition and mass fractions of pharmaceutical preparations used in Application Examples 1-3

[0031] The application of a cyclodextrin-based pharmaceutical excipient in a pharmaceutical formulation includes the following steps: M1. Immerse silica in a mixture of concentrated sulfuric acid and hydrogen peroxide (mass concentration of 30%) with a volume ratio of 7:3, heat at 70°C for 1 hour, filter, wash and dry to obtain hydroxylated silica. M2. Using water as a solvent, the hydroxylated silica and gluconic acid are mixed at a mass ratio of 2:3, heated to 60°C and ultrasonically reacted for 10 hours, filtered, washed and dried to obtain modified silica. M3. According to the above mass fractions, add γ-cyclodextrin to 900 parts of deionized water at 80°C, stir to dissolve, then add the drug component, stir for 1 hour, filter through a 0.25 μm microporous membrane, freeze dry to obtain γ-cyclodextrin inclusion complex. M4. According to the above-mentioned mass proportions, the γ-cyclodextrin inclusion complex, modified silica and the remaining components are mixed, stirred evenly, ground through a 100-mesh sieve, and compressed into tablets to obtain the pharmaceutical preparation.

[0032] Comparative Application Example 1 The difference between Application Example 1 and Application Example 2 is that step S2 is deleted and the modified silica is replaced with an equal mass of hydroxylated silica. The remaining components and preparation methods are the same as in Application Example 1.

[0033] Comparative Application Example 2 The difference between Application Example 2 and Application Example 1 is that steps S1 and S2 are deleted, and the modified silicon dioxide is replaced with an equal mass of silicon dioxide. The remaining components and preparation methods are the same as in Application Example 1.

[0034] Test case For example use 1, compare the performance of the products from example 1-2 with those from example 1-2.

[0035] Test method: Dissolution test: The test was conducted in accordance with the 2020 edition of the Chinese Pharmacopoeia.

[0036] Stability: Stability was tested according to the 2020 edition of the Chinese Pharmacopoeia, and friability was used to evaluate stability.

[0037] The test results are shown in Table 2.

[0038] Table 2 Test Results

[0039] As can be seen from Table 2, the effect of Application Example 1 is better than that of Comparative Application Examples 1-2. This is because the hydroxylated silica in Comparative Application Example 1 did not introduce gluconic acid, which reduced the compatibility of the components and weakened the hydrogen bonding, resulting in a decrease in the performance of the product. In contrast, Comparative Application Example 2 did not modify the silica, which further reduced the compatibility of the components and the hydrogen bonding, resulting in a decrease in the performance of the product.

[0040] 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 implemented 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 exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0041] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A pharmaceutical excipient based on cyclodextrin, characterized in that, The cyclodextrin-based pharmaceutical excipient comprises the following components in parts by weight: 300-320 parts of γ-cyclodextrin 15-20 servings of carbohydrates 15-20 parts calcium carbonate 20-30 parts of modified silica 3-4 parts magnesium stearate Other auxiliary agents, 2-4 parts; The modified silica is a product of hydroxylated silica grafted with gluconic acid.

2. The cyclodextrin-based pharmaceutical excipient according to claim 1, characterized in that, The other additives are selected from one or more of the following: adhesives, disintegrants, sweeteners, preservatives, pigments, flavorings, and multifunctional additives.

3. The cyclodextrin-based pharmaceutical excipient according to claim 1, characterized in that, The sugars are selected from one or more of sucrose, glucose, and lactose.

4. The method for preparing the cyclodextrin-based pharmaceutical excipient according to any one of claims 1-3, characterized in that, The method for preparing the cyclodextrin-based pharmaceutical excipient includes the following steps: S1. Hydroxylated silicon dioxide is obtained by hydroxylating silicon dioxide; S2. The hydroxylated silica and gluconic acid are mixed and heated to react, thereby obtaining modified silica; S3. The modified silica is mixed with the remaining components, stirred evenly, and ground to obtain the cyclodextrin-based pharmaceutical excipient.

5. The method for preparing cyclodextrin-based pharmaceutical excipients according to claim 4, characterized in that, In step S1, the hydroxylation temperature is 60-80°C.

6. The method for preparing cyclodextrin-based pharmaceutical excipients according to claim 4, characterized in that, In step S1, the hydroxylation time is 0.5-2 hours.

7. The method for preparing pharmaceutical excipients based on cyclodextrin according to claim 4, characterized in that, In step S2, the mass ratio of hydroxylated silica to gluconic acid is (1-5):(1-8).

8. The method for preparing pharmaceutical excipients based on cyclodextrin according to claim 4, characterized in that, In step S2, the heating temperature is 50-70℃.

9. The use of the cyclodextrin-based pharmaceutical excipient according to any one of claims 1-3 in pharmaceutical formulations, characterized in that, The pharmaceutical preparation comprises the following components in parts by weight: 8-10 parts of drug ingredients 300-320 parts of γ-cyclodextrin 15-20 servings of carbohydrates 15-20 parts calcium carbonate 20-30 parts of modified silica 3-4 parts magnesium stearate Other auxiliary agents, 2-4 parts; The modified silica is a product of hydroxylated silica grafted with gluconic acid.

10. The application of the cyclodextrin-based pharmaceutical excipient according to claim 9 in pharmaceutical formulations, characterized in that, The application of the cyclodextrin-based pharmaceutical excipients in pharmaceutical formulations includes the following steps: M1. Hydroxylated silicon dioxide is obtained by hydroxylating silicon dioxide. M2. The hydroxylated silica and gluconic acid are mixed and heated to react, thereby obtaining modified silica; M3. γ-Cyclodextrin and the drug component are mixed, stirred, filtered, and freeze-dried to obtain γ-cyclodextrin inclusion complex; M4. The γ-cyclodextrin inclusion complex, modified silica, and other components are mixed, stirred evenly, and ground to obtain the product.

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