Medical biological dressing suppository matrix and preparation method thereof

Abstract

The invention discloses a medical biological dressing suppository matrix and a preparation method thereof, and relates to the technical field of suppositories, the medical biological dressing suppository matrix is prepared by taking gelatin, glycerol, polyethylene glycol derivatives and chitosan quaternary ammonium salt as raw materials, the biocompatibility of the suppository matrix is good, and stimulation and anaphylactic reaction cannot be generated on a medication cavity; and after the suppository matrix is dissolved in the cavity, a film with good adhesion can be formed on the mucous membrane of the cavity, so that the released medicine is fully contacted with the focus for a long time, the curative effect and bioavailability of the medicine are improved, and the suppository is suitable for preparing suppositories for treating gynecological diseases, anorectal diseases and prostate diseases.

Description

Technical Field

[0001] This invention relates to the field of suppository technology, specifically to a medical biological dressing suppository matrix and its preparation method. Background Technology

[0002] Suppositories are preparations of a specific shape made from drugs and a suitable base, intended for intracavitary administration. Suppositories are solid at room temperature, but after insertion into a cavity, they rapidly soften, melt, or dissolve in secretions at body temperature, gradually releasing the drug to produce local or systemic effects. Suppositories have the following characteristics: ① The drug is not or minimally affected by the pH or enzymes of the gastrointestinal tract; ② They avoid irritation to the gastric mucosa; ③ They avoid the first-pass effect of the liver; ④ They are suitable for patients who cannot or do not wish to take oral medications; ⑤ They can provide local effects such as lubrication, antibacterial, insecticidal, astringent, analgesic, and antipruritic effects within the cavity; ⑥ They are suitable for drugs that are not suitable for oral administration.

[0003] Suppositories bases include oily bases and water-soluble (hydrophilic) bases. Oily bases are characterized by good lubricity and plasticity, and can rapidly melt and release drugs at body temperature; typical examples are cocoa butter and fatty acid glycerides. Water-soluble (hydrophilic) bases enable suppositories to dissolve and release drugs rapidly in body cavities; typical examples are gelatin, glycerin, and polyethylene glycol. The suppository base is the carrier for drug release, and its properties directly determine the rate and manner of drug release from the base, thus affecting the absorption efficiency of the drug on the mucous membrane of body cavities. The selection of suppository bases requires comprehensive consideration of drug characteristics, treatment needs, and individual patient differences. By rationally designing the base, the drug release rate can be controlled, thereby improving absorption efficiency and therapeutic efficacy. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing a medical biological dressing plug matrix. First, a polyethylene glycol derivative and a chitosan quaternary ammonium salt are cross-linked to prepare a polyethylene glycol derivative / chitosan quaternary ammonium salt complex. Then, gelatin, glycerin and the polyethylene glycol derivative / chitosan quaternary ammonium salt complex are mixed by heating to prepare a medical biological dressing plug matrix.

[0005] The technical problem to be solved by this invention is achieved by the following technical solution: The first objective of this invention is to provide a method for preparing a matrix for a medical biological dressing plug, comprising the following steps: S1. Crosslink polyethylene glycol derivative with chitosan quaternary ammonium salt to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex. S2. Gelatin, glycerin and polyethylene glycol derivative / chitosan quaternary ammonium salt complex are heated and mixed to obtain a medical biological dressing plug matrix.

[0006] Furthermore, the polyethylene glycol derivative is methoxy polyethylene glycol-glycidyl ether. The methoxy polyethylene glycol-glycidyl ether molecule contains epoxy groups, which can chemically crosslink with the hydroxyl groups contained in the chitosan quaternary ammonium salt. Simultaneously, the methoxy polyethylene glycol-glycidyl ether and the chitosan quaternary ammonium salt undergo physical crosslinking to form a unique three-dimensional network structure.

[0007] Furthermore, the molecular weight of the methoxy polyethylene glycol-glycidyl ether is 5000~10000.

[0008] Furthermore, the chitosan quaternary ammonium salt has a molecular weight of 100,000 to 300,000 and a degree of substitution ≥90%. The chitosan quaternary ammonium salt can impart certain antibacterial properties to the matrix, while its chitosan molecular structure undergoes a cross-linking reaction with polyethylene glycol derivatives.

[0009] Furthermore, the mass ratio of the polyethylene glycol derivative to the chitosan quaternary ammonium salt is (20~30): (10~20).

[0010] Furthermore, the mass ratio of the gelatin, glycerin and polyethylene glycol derivative / chitosan quaternary ammonium salt complex is 10: (30~40): (10~20).

[0011] Furthermore, the crosslinking reaction is carried out in the presence of a catalyst, which includes, but is not limited to, sodium hydroxide, potassium hydroxide, and p-toluenesulfonic acid. Even further, the amount of catalyst used is 3-5% of the total mass of the polyethylene glycol derivative and chitosan quaternary ammonium salt. During post-treatment, sodium ions, potassium ions, and p-toluenesulfonate ions introduced into the matrix by the catalyst can be removed by washing with water.

[0012] Furthermore, the cross-linking reaction is carried out at a temperature of 50-60°C for a time of 5-12 hours.

[0013] Furthermore, the heating and mixing temperature is 50~60℃, and the time is 0.5~1 h.

[0014] A second objective of this invention is to provide a medical biological dressing plug matrix prepared by the aforementioned preparation method.

[0015] The beneficial effects of this invention are as follows: This invention uses gelatin, glycerin, polyethylene glycol derivatives, and chitosan quaternary ammonium salt as raw materials to prepare a medical biological dressing suppository matrix. This suppository matrix has good biocompatibility and will not cause irritation or allergic reactions to the medication cavity. Furthermore, after the suppository matrix dissolves in the cavity, it forms a thin film with good adhesion on the cavity mucosa, allowing the released drug to fully and for a long time contact the lesion, improving the efficacy and bioavailability of the drug. It is suitable for preparing suppositories for the treatment of gynecological diseases, anorectal diseases, and prostate diseases. Attached Figure Description

[0016] Figure 1 The adhesion test results are for the matrices prepared in Examples 1-5 and Comparative Examples 1-4 of this invention. Figure 2 The results are the adhesion test results of the matrices prepared in Examples 6-8 and Comparative Examples 5-6 of this invention. Detailed Implementation

[0017] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0018] The following examples and comparative examples illustrate the sources of raw materials: Methoxylated polyethylene glycol-glycidyl ether was purchased from Hunan Huateng Pharmaceutical Co., Ltd. Chitosan quaternary ammonium salt was purchased from Shanghai Tengzhun Biotechnology Co., Ltd. The gelatin was pharmaceutical grade and purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0019] Example 1 S1. Add 20 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 5000), 10 g of chitosan quaternary ammonium salt (molecular weight 100000, degree of substitution 98%) and 1 g of sodium hydroxide to 500 g of water. Stir and react at 50 °C for 8 h. Concentrate under reduced pressure to a solid content of 88%. Dry under vacuum at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0020] S2. Mix 10 g gelatin, 40 g glycerin, 10 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 10 g water at 50°C for 1 h to obtain a medical biological dressing plug matrix.

[0021] Example 2 S1. Add 25 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 5000), 10 g of chitosan quaternary ammonium salt (molecular weight 200000, degree of substitution 98%) and 1.5 g of potassium hydroxide to 500 g of water. Stir and react at 60 °C for 5 h. Concentrate under reduced pressure to a solid content of 85%. Dry under vacuum at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0022] S2. Mix 10 g gelatin, 30 g glycerin, 15 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 5 g water at 60°C for 0.5 h to obtain a medical biological dressing plug matrix.

[0023] Example 3 S1. Add 30 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 10000), 20 g of chitosan quaternary ammonium salt (molecular weight 100000, degree of substitution 98%) and 2 g of p-toluenesulfonic acid to 500 g of water, stir and react at 55 °C for 8 h, concentrate under reduced pressure to a solid content of 80%, and vacuum dry at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0024] S2. Mix 10 g gelatin, 35 g glycerin, 10 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 0.5 h to obtain a medical biological dressing plug matrix.

[0025] Example 4 S1. Add 20 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 5000), 20 g of chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) and 2 g of sodium hydroxide to 500 g of water. Stir and react at 60 °C for 5 h. Concentrate under reduced pressure to a solid content of 85%. Dry under vacuum at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0026] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0027] Example 5 S1. Add 25 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 10000), 20 g of chitosan quaternary ammonium salt (molecular weight 100000, degree of substitution 98%) and 1.5 g of sodium hydroxide to 500 g of water. Stir and react at 60 °C for 8 h. Concentrate under reduced pressure to a solid content of 85%. Dry under vacuum at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0028] S2. Mix 10 g gelatin, 40 g glycerin, 20 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 5 g water at 60°C for 0.5 h to obtain a medical biological dressing plug matrix.

[0029] Comparative Example 1 The medical biological dressing matrix was prepared according to the method of Example 4, except that methoxy polyethylene glycol-glycidyl ether was replaced with polyethylene glycol.

[0030] S1. Add 20 g of polyethylene glycol (molecular weight 5000), 20 g of chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) and 2 g of sodium hydroxide to 500 g of water. Stir and react at 60 °C for 5 h. Concentrate under reduced pressure to a solid content of 85%. Dry under vacuum at 60 °C for 12 h to obtain polyethylene glycol / chitosan quaternary ammonium salt composite.

[0031] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0032] Comparative Example 2 The medical biological dressing matrix was prepared according to the method of Example 4, except that sodium hydroxide was not added.

[0033] S1. Add 20 g of methoxy polyethylene glycol-glycidyl ether (molecular weight 5000) and 20 g of chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) to 500 g of water, stir and react at 60 °C for 5 h, concentrate under reduced pressure to a solid content of 85%, and vacuum dry at 60 °C for 12 h to obtain polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0034] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol derivative / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0035] Comparative Example 3 The medical biological dressing matrix was prepared according to the method of Example 4, except that chitosan quaternary ammonium salt was used instead of polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0036] 10 g gelatin, 30 g glycerin, 20 g chitosan quaternary ammonium salt and 10 g water were stirred and mixed at 55°C for 1 h to obtain the matrix of medical biological dressing plugs.

[0037] Comparative Example 4 The medical biological dressing matrix was prepared according to the method of Example 4, except that methoxy polyethylene glycol-glycidyl ether was used instead of polyethylene glycol derivative / chitosan quaternary ammonium salt complex.

[0038] 10 g gelatin, 30 g glycerin, 20 g methoxy polyethylene glycol-glycidyl ether and 10 g water were stirred and mixed at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0039] The substrates prepared in Examples 1-5 and Comparative Examples 1-4 were subjected to adhesion tests, and the test results are shown in Table 1.

[0040] The substrate (50 mm × 20 mm × 5 mm) was placed flat on a glass slide and placed at 37°C for 30 min. The peel strength was then tested at a peel speed of 5 mm / min.

[0041] Table 1

[0042] As shown in Table 1, the polyethylene glycol derivative / chitosan quaternary ammonium salt complex prepared by the present invention through crosslinking reaction of polyethylene glycol derivative and chitosan quaternary ammonium salt can significantly improve the adhesion of the matrix.

[0043] Skin contact experiments were conducted on the matrices prepared in Examples 1-5 above. 100 volunteers were selected and randomly divided into 5 groups of 20 each. The results showed that no adverse reactions occurred to the matrices in any of the volunteers.

[0044] The biocompatibility of the matrices prepared in Examples 1 to 5 above was tested according to Appendix C of GB / T 16886.5-2017 "Biological evaluation of medical devices - Part 5: In vitro cytotoxicity test". The results showed that the in vitro cytotoxicity of the matrices was all grade 1, indicating that the matrices have good biocompatibility.

[0045] A third objective of this invention is to provide a method for preparing a matrix for a medical biological dressing plug, comprising the following steps: S1. Under the action of a crosslinking agent, polyethylene glycol and chitosan quaternary ammonium salt are crosslinked to obtain a polyethylene glycol / chitosan quaternary ammonium salt complex. S2. Gelatin, glycerin and polyethylene glycol / chitosan quaternary ammonium salt complex are heated and mixed to obtain the matrix of medical biological dressing plug.

[0046] Further, the crosslinking agent is 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione. The use of 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione as the crosslinking agent in this invention aims to further optimize the performance of the matrix.

[0047] Furthermore, the amount of the crosslinking agent is 1-3% of the total mass of polyethylene glycol and chitosan quaternary ammonium salt.

[0048] Furthermore, the average molecular weight of the polyethylene glycol is 6000~10000.

[0049] Furthermore, the chitosan quaternary ammonium salt has a molecular weight of 100,000 to 300,000 and a degree of substitution ≥90%. The chitosan quaternary ammonium salt can impart certain antibacterial properties to the matrix, while its chitosan molecular structure undergoes a cross-linking reaction with polyethylene glycol.

[0050] Furthermore, the mass ratio of polyethylene glycol to chitosan quaternary ammonium salt is (20~30): (10~20).

[0051] Furthermore, the mass ratio of the gelatin, glycerin and polyethylene glycol / chitosan quaternary ammonium salt complex is 10 : (30~40) : (10~20).

[0052] Furthermore, the cross-linking reaction is carried out at a temperature of 50-60°C for a time of 5-12 hours.

[0053] Furthermore, the heating and mixing temperature is 50~60℃, and the time is 0.5~1 h.

[0054] A fourth objective of this invention is to provide a medical biological dressing plug matrix prepared by the aforementioned preparation method.

[0055] Example 6 S1. Add 20 g of polyethylene glycol (molecular weight 6000), 20 g of chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) and 1.2 g of 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione to 500 g of water. Stir the reaction at 60 °C for 5 h, concentrate under reduced pressure to a solid content of 85%, and dry under vacuum at 60 °C for 12 h to obtain the polyethylene glycol / chitosan quaternary ammonium salt complex.

[0056] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0057] Example 7 S1. Add 25 g of polyethylene glycol (molecular weight 8000), 20 g of chitosan quaternary ammonium salt (molecular weight 100000, degree of substitution 98%) and 1 g of 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione to 500 g of water, stir and react at 60 °C for 8 h, concentrate under reduced pressure to a solid content of 85%, and vacuum dry at 60 °C for 12 h to obtain polyethylene glycol / chitosan quaternary ammonium salt composite.

[0058] S2. Mix 10 g gelatin, 40 g glycerin, 20 g polyethylene glycol / chitosan quaternary ammonium salt complex and 5 g water at 60°C for 0.5 h to obtain a medical biological dressing plug matrix.

[0059] Example 8 S1. Add 25 g of polyethylene glycol (molecular weight 10000), 10 g of chitosan quaternary ammonium salt (molecular weight 200000, degree of substitution 98%) and 1 g of 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione to 500 g of water. Stir the reaction at 60 °C for 5 h, concentrate under reduced pressure to a solid content of 85%, and dry under vacuum at 60 °C for 12 h to obtain the polyethylene glycol / chitosan quaternary ammonium salt complex.

[0060] S2. Mix 10 g gelatin, 30 g glycerin, 15 g polyethylene glycol / chitosan quaternary ammonium salt complex and 5 g water at 60°C for 0.5 h to obtain a medical biological dressing plug matrix.

[0061] Comparative Example 5 The matrix was prepared according to the method of Example 6, except that 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione was replaced with diglycidyl ether.

[0062] S1. Add 20 g polyethylene glycol (molecular weight 6000), 20 g chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) and 1.2 g diglycidyl ether to 500 g water, stir and react at 60 °C for 5 h, concentrate under reduced pressure to a solid content of 85%, and vacuum dry at 60 °C for 12 h to obtain polyethylene glycol / chitosan quaternary ammonium salt complex.

[0063] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0064] Comparative Example 6 The coagulating matrix was prepared according to the method of Example 8, except that 5,5-dimethyl-1,3-bis(epoxyethylenemethyl)imidazolidine-2,4-dione was replaced with N,N-methylenebisacrylamide.

[0065] S1. Add 20 g of polyethylene glycol (molecular weight 6000), 20 g of chitosan quaternary ammonium salt (molecular weight 300000, degree of substitution 98%) and 1.2 g of N,N-methylenebisacrylamide to 500 g of water, stir and react at 60 °C for 5 h, concentrate under reduced pressure to a solid content of 85%, and vacuum dry at 60 °C for 12 h to obtain polyethylene glycol / chitosan quaternary ammonium salt composite.

[0066] S2. Mix 10 g gelatin, 30 g glycerin, 20 g polyethylene glycol / chitosan quaternary ammonium salt complex and 10 g water at 55°C for 1 h to obtain a medical biological dressing plug matrix.

[0067] The substrates prepared in Examples 6-8 and Comparative Examples 5-6 were subjected to adhesion tests, and the test results are shown in Table 2.

[0068] The substrate (50 mm × 20 mm × 5 mm) was placed flat on a glass slide and placed at 37°C for 30 min. The peel strength was then tested at a peel speed of 5 mm / min.

[0069] Table 2

[0070] As shown in Table 2, the polyethylene glycol / chitosan quaternary ammonium salt composite prepared by using 5,5-dimethyl-1,3-di(epoxyethylenemethyl)imidazolidine-2,4-dione as a crosslinking agent in this invention can improve the adhesion of the matrix.

[0071] Skin contact experiments were conducted on the matrices prepared in Examples 6-8 above. Sixty volunteers were selected and randomly divided into three groups of 20 each. The results showed that none of the volunteers experienced any adverse reactions to the matrices.

[0072] The biocompatibility of the matrices prepared in Examples 6-8 above was tested according to Appendix C of GB / T 16886.5-2017 "Biological evaluation of medical devices - Part 5: In vitro cytotoxicity test". The results showed that the in vitro cytotoxicity of the gel matrices was all grade 1, indicating that the matrices have good biocompatibility.

[0073] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for the preparation of a medical biological dressing plug matrix, characterized in that, The method comprises the following steps: S1. Cross-linking polyethylene glycol derivative and chitosan quaternary ammonium salt to obtain a polyethylene glycol derivative / chitosan quaternary ammonium salt complex; S2. Heating and mixing gelatin, glycerol and the polyethylene glycol derivative / chitosan quaternary ammonium salt complex to obtain a medical biological dressing plug matrix.

2. The method of claim 1, wherein: The polyethylene glycol derivative is methoxyl polyethylene glycol-glycidyl ether.

3. The method of claim 2, wherein: The molecular weight of the methoxyl polyethylene glycol-glycidyl ether is 5000-10000.

4. The method of claim 1, wherein: The molecular weight of the chitosan quaternary ammonium salt is 100000-300000, and the degree of substitution is greater than or equal to 90%.

5. The method of claim 2, wherein: The mass ratio of the polyethylene glycol derivative to the chitosan quaternary ammonium salt is (20-30):(10-20).

6. The method of claim 1, wherein: The mass ratio of the gelatin, glycerol and the polyethylene glycol derivative / chitosan quaternary ammonium salt complex is 10:(30-40):(10-20).

7. The method of claim 1, wherein: The cross-linking reaction is carried out in the presence of a catalyst, which is one of sodium hydroxide, potassium hydroxide and p-toluene sulfonic acid.

8. The method of claim 7, wherein: The amount of the catalyst is 3-5% of the total mass of the polyethylene glycol derivative and the chitosan quaternary ammonium salt.

9. The method of claim 1, wherein: The temperature of the cross-linking reaction is 50-60℃, and the time is 5-12 h; the temperature of the heating and mixing is 50-60℃, and the time is 0.5-1 h.

10. A medical biological dressing plug matrix prepared by the preparation method in any one of claims 1-9.

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