A pharmaceutical polyacrylic resin material and a method for preparing the same

Abstract

The application discloses a kind of pharmaceutical polyacrylic resin materials and preparation method thereof, it is related to high polymer material field.The application is prepared when pharmaceutical polyacrylic resin material, N, N, N', N'-tetramethyl-1-acryl-1, 3-diamine, epoxy chloropropane is reacted to obtain modified crosslinking agent;Chitosan, modified crosslinking agent is reacted to obtain modified chitosan;Modified chitosan, acrylic acid is reacted to obtain.The pharmaceutical polyacrylic resin material prepared by the application has good enteric property and sustained-release performance.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of high molecular materials, in particular to a kind of medicinal polyacrylic resin material and preparation method thereof. BACKGROUND

[0002] Polyacrylic resin is a kind of high molecular material copolymerized by methacrylic acid and its ester monomer, which is mainly used as functional coating material and controlled release matrix material in pharmacy. Polyacrylic resin has excellent water absorption, biocompatibility and biodegradability, and has wide application prospect in the field of medicine, especially as drug carrier, sustained-release material, biomedical material, etc. However, during the preparation process of polyacrylic resin, there are problems such as uneven swelling and unstable drug release rate, which limit its application in high-end pharmaceutical field. In addition, in the prior art, the modification of polyacrylic resin usually uses simple crosslinking agent or modifier, which is difficult to meet the performance requirements of the material. Therefore, how to optimize the preparation process to obtain polyacrylic resin material with better performance and more suitable for pharmaceutical requirements is a technical challenge faced by the current field.

[0003] Chitosan is a natural polysaccharide obtained by deacetylation of chitin. Chitin is an important component of shellfish, crabs, shrimps and small crayfish, and is the second most abundant natural biological polymer after cellulose, so the source of chitosan is also very rich, and the price is low. Chitosan has become one of the representatives of multifunctional pharmaceutical excipients in modern drug preparations due to its natural source, biodegradability, good biocompatibility, positive charge and easy modification. In addition, chitosan also has the advantages of low toxicity, non-immunogenicity, good biocompatibility, and chitosan can be degraded in vivo, with outstanding safety. Therefore, in the past few decades, chitosan has been increasingly valued due to its commercial value in biomedical, food, chemical and other industries.

[0004] The medicinal polyacrylic resin material prepared by the present application has good enteric solubility and sustained-release performance, and has broad market prospect. SUMMARY

[0005] The present application aims to provide a kind of medicinal polyacrylic resin material and preparation method thereof to solve the problems in the prior art.

[0006] In order to solve the above technical problems, the present application provides the following technical scheme:

[0007] A kind of medicinal polyacrylic resin material, the medicinal polyacrylic resin material is modified crosslinking agent prepared by reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin;Modified chitosan is prepared by reaction of chitosan and modified crosslinking agent;Modified chitosan is prepared by reaction of modified chitosan and acrylic acid.

[0008] A method for preparing a pharmaceutical polyacrylic acid resin material mainly comprises the following preparation steps:

[0009] (1) uniformly mix tetrabutylammonium bromide, epichlorohydrin and anhydrous ethanol, add dropwise N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution with a mass of 180-220 times of tetrabutylammonium bromide at 8°C, after the dropwise addition is completed, warm up to 30°C, distill under reduced pressure at room temperature, then add acetone with a volume of half of the anhydrous ethanol, stir until the solid completely precipitates, separate the precipitate, wash the precipitate with acetone for 3-5 times, and freeze-dry to obtain a modified crosslinking agent;

[0010] (2) uniformly mix chitosan solution, modified crosslinking agent and deionized water, react at 60°C for 12h, centrifugally separate the solid, wash the solid with deionized water for 3-5 times, and freeze-dry to obtain modified chitosan;

[0011] (3) uniformly mix deionized water and isopropyl alcohol according to a mass ratio of 1:8, warm up to 90°C, and dropwise add acrylic acid, modified chitosan and ammonium persulfate aqueous solution respectively, remove impurities by rotary evaporation, and freeze-dry to obtain the product.

[0012] As an optimization, the mass ratio of tetrabutylammonium bromide, epichlorohydrin and anhydrous ethanol in step (1) is 0.1:(4-5):(45-55).

[0013] As an optimization, the preparation method of the N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution in step (1) is to uniformly mix N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and anhydrous ethanol according to a volume ratio of 1:5.

[0014] As an optimization, the chitosan in step (2) is chitosan with a deacetylation degree of 85%.

[0015] As an optimization, the preparation method of the chitosan solution in step (2) is to uniformly mix chitosan, urea, potassium hydroxide and deionized water according to a mass ratio of 3:15:8:74, and repeatedly freeze and thaw for 3 times at -25°C and room temperature.

[0016] As an optimization, the molar ratio of the modified crosslinking agent to chitosan in step (2) is 1:0.8.

[0017] As an optimization, the preparation method of the ammonium persulfate aqueous solution in step (2) is to uniformly mix ammonium persulfate and deionized water according to a mass ratio of 1:13.5.

[0018] As an optimization, in step (3), the mass of acrylic acid is 3-5 times of the mass of deionized water, the mass of modified chitosan is 0.4-0.8 times of the mass of deionized water, and the mass of the ammonium persulfate aqueous solution is 2.5-2.9 times of the mass of deionized water.

[0019] Compared with the prior art, the present application has the advantages that:

[0020] In the preparation of the pharmaceutical polyacrylic acid resin material, the modified crosslinking agent is prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin; the modified chitosan is prepared by the reaction of chitosan and the modified crosslinking agent; and the pharmaceutical polyacrylic acid resin material is prepared by the reaction of the modified chitosan and acrylic acid.

[0021] Firstly, the modified crosslinking agent is prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin, and generally, glutaraldehyde is used as the crosslinking agent for chitosan. However, the Schiff base reaction occurs between the aldehyde group on the glutaraldehyde and the amino group on the chitosan, and the generated Schiff base structure is easy to break under acidic conditions and easy to dissolve in the stomach, thereby affecting the enteric solubility. The modified crosslinking agent prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin is used as the crosslinking agent, and the ring-opening reaction occurs between the epoxy group and the amino group on the chitosan during crosslinking, thereby forming a more stable crosslinking structure and having good enteric solubility.

[0022] Secondly, the modified crosslinking agent is prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin, and the quaternary ammonium is generated by the reaction of epichlorohydrin and the tertiary amine on N,N,N',N'-tetramethyl-1-propylene-1,3-diamine. On the one hand, N,N,N',N'-tetramethyl-1-propylene-1,3-diamine has a double bond structure and can react with acrylic acid to form a crosslinking network, thereby having a better coating effect on the drug. On the other hand, the generated quaternary ammonium has good hydrophilicity and can effectively ensure the sustained release, so that the coated drug can be stably released in the intestinal tract. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0024] The chitosan used in the following examples and comparative examples is chitosan with a degree of deacetylation of 85%.

[0025] Example 1: A pharmaceutical polyacrylic acid resin material, comprising the following preparation steps:

[0026] (1) N,N,N',N'-tetramethyl-1-propylene-1,3-diamine, anhydrous ethanol were mixed in a volume ratio of 1:5 to prepare an N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution; tetrabutylammonium bromide, epichlorohydrin, anhydrous ethanol were mixed in a mass ratio of 0.1:4:45, and N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution with a mass of 180 times that of tetrabutylammonium bromide was added dropwise at 8°C; after the dropwise addition was completed, the temperature was raised to 30°C; the solution was distilled at room temperature under reduced pressure; then anhydrous ethanol with a volume of half of the original volume was added; the solution was stirred until the solid completely precipitated; the precipitate was separated; the precipitate was washed with acetone 3 times; and the precipitate was freeze-dried to obtain a modified crosslinking agent;

[0027] (2) Chitosan, urea, potassium hydroxide, and deionized water were mixed in a mass ratio of 3:15:8:74, and the mixture was repeatedly frozen and thawed 3 times at -25°C and room temperature to prepare a chitosan solution; the chitosan solution, the modified crosslinking agent, and deionized water were mixed, and the molar ratio of the modified crosslinking agent to chitosan was 1:0.8; the mixture was reacted at 60°C for 12 h; the solid was separated by centrifugation; the solid was washed with deionized water 3 times; and the solid was freeze-dried to obtain a modified chitosan;

[0028] (3) Ammonium persulfate and deionized water were mixed in a mass ratio of 1:13.5 to prepare an ammonium persulfate aqueous solution; deionized water and isopropyl alcohol were mixed in a mass ratio of 1:8, and the mixture was heated to 90°C; acrylic acid with a mass of 3 times that of the deionized water, the modified chitosan with a mass of 0.4 times that of the deionized water, and the ammonium persulfate aqueous solution with a mass of 2.5 times that of the deionized water were added dropwise, respectively; the mixture was distilled to remove impurities; and the mixture was freeze-dried to obtain a product.

[0029] Example 2: A pharmaceutical polyacrylic acid resin material, comprising the following preparation steps:

[0030] (1) N,N,N',N'-tetramethyl-1-propylene-1,3-diamine, anhydrous ethanol were mixed in a volume ratio of 1:5 to prepare an N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution; tetrabutylammonium bromide, epichlorohydrin, anhydrous ethanol were mixed in a mass ratio of 0.1:4.5:50, and N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution with a mass of 200 times that of tetrabutylammonium bromide was added dropwise at 8°C; after the dropwise addition was completed, the temperature was raised to 30°C; the solution was distilled at room temperature under reduced pressure; then anhydrous ethanol with a volume of half of the original volume was added; the solution was stirred until the solid completely precipitated; the precipitate was separated; the precipitate was washed with acetone 4 times; and the precipitate was freeze-dried to obtain a modified crosslinking agent;

[0031] (2) mixing chitosan, urea, potassium hydroxide and deionized water in a mass ratio of 3:15:8:74, repeatedly freezing and thawing 3 times at -25℃ and room temperature, to obtain a chitosan solution; mixing the chitosan solution, modified crosslinking agent and deionized water, the molar ratio of modified crosslinking agent to chitosan being 1:0.8, reacting at 60℃ for 12 hours, centrifugally separating the solid, washing the solid with deionized water 4 times, and freeze-drying to obtain modified chitosan;

[0032] (3) mixing ammonium persulfate and deionized water in a mass ratio of 1:13.5 to obtain an ammonium persulfate aqueous solution; mixing deionized water and isopropyl alcohol in a mass ratio of 1:8, heating to 90℃, and respectively adding acrylic acid with a mass of 4 times that of deionized water, modified chitosan with a mass of 0.6 times that of deionized water, and the ammonium persulfate aqueous solution with a mass of 2.7 times that of deionized water, rotary-evaporating impurities, and freeze-drying to obtain.

[0033] Example 3: A pharmaceutical polyacrylic acid resin material, comprising the following preparation steps:

[0034] (1) mixing N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and anhydrous ethanol in a volume ratio of 1:5 to obtain an N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution; mixing tetrabutylammonium bromide, epichlorohydrin and anhydrous ethanol in a mass ratio of 0.1:5:55, adding the N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution with a mass of 220 times that of tetrabutylammonium bromide dropwise at 8℃, heating to 30℃ after the addition is completed, rotary-evaporating impurities at room temperature and reduced pressure, adding acetone with a volume of half that of anhydrous ethanol, stirring until the solid completely precipitates, separating the precipitate, washing the precipitate with acetone 5 times, and freeze-drying to obtain a modified crosslinking agent;

[0035] (2) mixing chitosan, urea, potassium hydroxide and deionized water in a mass ratio of 3:15:8:74, repeatedly freezing and thawing 3 times at -25℃ and room temperature, to obtain a chitosan solution; mixing the chitosan solution, modified crosslinking agent and deionized water, the molar ratio of modified crosslinking agent to chitosan being 1:0.8, reacting at 60℃ for 12 hours, centrifugally separating the solid, washing the solid with deionized water 5 times, and freeze-drying to obtain modified chitosan;

[0036] (3) mixing ammonium persulfate and deionized water in a mass ratio of 1:13.5 to obtain an ammonium persulfate aqueous solution; mixing deionized water and isopropyl alcohol in a mass ratio of 1:8, heating to 90℃, and respectively adding acrylic acid with a mass of 5 times that of deionized water, modified chitosan with a mass of 0.8 times that of deionized water, and the ammonium persulfate aqueous solution with a mass of 2.9 times that of deionized water, rotary-evaporating impurities, and freeze-drying to obtain.

[0037] Comparative Example 1: A pharmaceutical polyacrylic acid resin material, comprising the following preparation steps:

[0038] (1) chitosan, urea, potassium hydroxide, deionized water were mixed according to the mass ratio of 3:15:8:74, and were repeatedly frozen and thawed at -25℃ and room temperature for 3 times to prepare a chitosan solution; the chitosan solution, modified crosslinking agent, and deionized water were mixed, and the molar ratio of 1,2,3,4-bis (epoxy butane) to chitosan was 1:0.8, and the mixture was reacted at 60℃ for 12h, and the solid was separated by centrifugation, and the solid was washed with deionized water for 4 times, and was freeze-dried to prepare a modified chitosan;

[0039] (2) ammonium persulfate and deionized water were mixed according to the mass ratio of 1:13.5 to prepare an ammonium persulfate aqueous solution; deionized water and isopropyl alcohol were mixed according to the mass ratio of 1:8, and were heated to 90℃, and then deionized water with a mass of 4 times, modified chitosan with a mass of 0.6 times of deionized water, and the ammonium persulfate aqueous solution with a mass of 2.7 times of deionized water were added dropwise respectively, and impurities were removed by rotary evaporation, and freeze-drying was performed to prepare.

[0040] Comparative Example 2: a kind of polyacrylic acid resin material for medicine, comprising the following preparation steps:

[0041] (1) chitosan, urea, potassium hydroxide, deionized water were mixed according to the mass ratio of 3:15:8:74, and were repeatedly frozen and thawed at -25℃ and room temperature for 3 times to prepare a chitosan solution; the chitosan solution, glutaraldehyde, and deionized water were mixed, and the molar ratio of modified crosslinking agent to chitosan was 1:0.8, and the mixture was reacted at 60℃ for 12h, and the solid was separated by centrifugation, and the solid was washed with deionized water for 4 times, and was freeze-dried to prepare a modified chitosan;

[0042] (2) ammonium persulfate and deionized water were mixed according to the mass ratio of 1:13.5 to prepare an ammonium persulfate aqueous solution; deionized water and isopropyl alcohol were mixed according to the mass ratio of 1:8, and were heated to 90℃, and then deionized water with a mass of 4 times, modified chitosan with a mass of 0.6 times of deionized water, and the ammonium persulfate aqueous solution with a mass of 2.7 times of deionized water were added dropwise respectively, and impurities were removed by rotary evaporation, and freeze-drying was performed to prepare.

[0043] Test Example: Test tablet preparation: potassium chloride tablets were taken as reagent tablets, and the polyacrylic acid resin materials prepared in each example and comparative example were used as coating materials to prepare test tablets. The coating method was as follows: the polyacrylic acid resin materials prepared in each example and comparative example and water were mixed according to the mass ratio of 1:0.8 to prepare a polyacrylic acid resin dispersion; talc powder, water, and dodecylbenzenesulfonic acid were mixed according to the mass ratio of 1:1.5:0.0025, and were stirred for 10min by a homogenizer to prepare a talc powder suspension; the talc powder suspension was poured into the polyacrylic acid resin dispersion, and was stirred uniformly, and was passed through a 40 mesh sieve, and the potassium chloride tablets were coated by a coating device. The distance between the nozzle and the material was 120mm, the air inlet temperature was 30℃, the air inlet amount was 7.5~9.5m 3The test tablets were prepared by coating the polyacrylic resin material prepared in Example 2 according to the following conditions: spray rate 2.5 g / min, spray air pressure 2 bar, infusion rate 45 g / min, and drying at 40℃ for 24 h after coating.

[0044] The test tablets coated with the polyacrylic resin material prepared in Example 2 were subjected to release rate determination according to the method specified in Chinese Pharmacopoeia 2010. The results are shown in Table 1.

[0045] The test tablets coated with the polyacrylic resin material prepared in Comparative Example 1 were subjected to release rate determination according to the method specified in Chinese Pharmacopoeia 2010. The results are shown in Table 2.

[0046] The test tablets coated with the polyacrylic resin material prepared in Comparative Example 2 were subjected to release rate determination according to the method specified in Chinese Pharmacopoeia 2010. The results are shown in Table 3.

[0047] Table 1

[0048]

[0049] Table 2

[0050]

[0051] Table 3

[0052]

[0053] As can be seen from the experimental data of Examples 1-3 and Comparative Examples 1 and 2 in Table 1, the polyacrylic resin material for pharmaceutical use prepared in the present application has good sustained release performance and enteric solubility.

[0054] The difference between Comparative Example 1 and Example 2 is that the modified crosslinking agent is replaced by 1,2,3,4-epoxybutane. By comparison, the test tablets prepared in Comparative Example 2 have a release rate greater than that of Example 2 in artificial gastric juice, indicating that the modified crosslinking agent prepared by the reaction of N,N,N',N'-tetramethyl-1-propen-1,3-diamine and epichlorohydrin generates quaternary ammonium by the reaction of epichlorohydrin with the tertiary amine on N,N,N',N'-tetramethyl-1-propen-1,3-diamine, and the generated quaternary ammonium has good hydrophilicity, which can effectively ensure the sustained release property, so that the coated drug can be stably released in the intestinal tract, thereby improving the sustained release performance of the polyacrylic resin material for pharmaceutical use.

[0055] The difference between Comparative Example 2 and Example 2 is that the modified crosslinking agent is replaced by glutaraldehyde. By comparison, the release rate of the test piece prepared in Comparative Example 2 in water, artificial gastric juice and artificial intestinal juice is greater than that of Example 2, which indicates that the modified crosslinking agent prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin is generally used as a crosslinking agent for chitosan. However, the aldehyde group on glutaraldehyde reacts with the amino group on chitosan to form a Schiff base structure, which is easy to break in an acidic condition and is easy to dissolve in the stomach first, thereby affecting the enteric solubility. The modified crosslinking agent prepared by the reaction of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and epichlorohydrin is used as a crosslinking agent. When crosslinking, the epoxy group reacts with the amino group on chitosan to form a more stable crosslinking structure, thereby having good enteric solubility.

[0056] The above specific embodiments further illustrate the purpose, technical solutions and beneficial effects of the present application. It should be understood that the above description is only a specific embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A pharmaceutical polyacrylic acid resin material, characterized by, The preparation steps include: (1) uniformly mix tetrabutylammonium bromide, epichlorohydrin and anhydrous ethanol, drop 180-220 times of N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution of tetrabutylammonium bromide at 8 DEG C, then warm to 30 DEG C, distill under reduced pressure at room temperature, add acetone with a volume of half of the anhydrous ethanol, stir until the solid completely precipitates, separate the precipitate, wash the precipitate with acetone for 3-5 times, and freeze dry to obtain the modified crosslinking agent; (2) uniformly mix chitosan solution, modified crosslinking agent and deionized water, react at 60 DEG C for 12 h, centrifugally separate the solid, wash the solid with deionized water for 3-5 times, and freeze dry to obtain the modified chitosan; (3) uniformly mix deionized water and isopropyl alcohol at a mass ratio of 1:8, warm to 90 DEG C, drop acrylic acid, modified chitosan and ammonium persulfate aqueous solution respectively, remove impurities by rotary evaporation, and freeze dry to obtain the product.

2. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (1), the mass ratio of tetrabutylammonium bromide, epichlorohydrin and anhydrous ethanol is 0.1:(4-5):(45-55).

3. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (1), the preparation method of the N,N,N',N'-tetramethyl-1-propylene-1,3-diamine ethanol solution is as follows: uniformly mix N,N,N',N'-tetramethyl-1-propylene-1,3-diamine and anhydrous ethanol at a volume ratio of 1:5 to obtain the solution.

4. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (2), the chitosan is chitosan with a deacetylation degree of 85%.

5. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (2), the preparation method of the chitosan solution is as follows: uniformly mix chitosan, urea, potassium hydroxide and deionized water at a mass ratio of 3:15:8:74, and repeat freezing and thawing at -25 DEG C and room temperature for 3 times to obtain the solution.

6. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (2), the molar ratio of the modified crosslinking agent to chitosan is 1:0.

8.

7. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (2), the preparation method of the ammonium persulfate aqueous solution is as follows: uniformly mix ammonium persulfate and deionized water at a mass ratio of 1:13.5 to obtain the solution.

8. The method for preparing a pharmaceutical-grade polyacrylic acid resin material according to claim 1, characterized in that, In step (3), the mass of acrylic acid is 3-5 times of the mass of deionized water, the mass of modified chitosan is 0.4-0.8 times of the mass of deionized water, and the mass of the ammonium persulfate aqueous solution is 2.5-2.9 times of the mass of deionized water.

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