Water-soluble amoxicillin powder and preparation method thereof

Abstract

The invention belongs to the field of veterinary drugs, and particularly relates to water-soluble amoxicillin powder which comprises the following components: 50-60 parts of amoxicillin, 5-10 parts of polyvinyl alcohol modified beta-cyclodextrin, 1-3 parts of tryptophan, 20-30 parts of a filler and 0.5-1 part of a flavoring agent. The water-soluble amoxicillin powder disclosed by the invention has an excellent slow-release effect and storage stability.

Description

Technical Field

[0001] The present invention belongs to the field of veterinary drugs, and particularly relates to a water-soluble amoxicillin powder and a preparation method thereof. Background Art

[0002] Amoxicillin is a semi-synthetic antibiotic artificially synthesized on the basis of natural penicillin and is a p-hydroxy homolog of ampicillin. Amoxicillin is more widely used than traditional injectable penicillin and has stronger antibacterial activity against Gram-negative bacteria. Due to the advantages of strong acid resistance, high bactericidal activity, broad antibacterial spectrum, and diverse dosage forms, this preparation product is widely used in the veterinary field by farmers.

[0003] Amoxicillin has disadvantages such as poor stability, easy degradation in water, and short maintenance time in water. In actual use, to make up for these disadvantages, the method of increasing the dosage or dosing frequency is often used to deal with them, which brings problems of overuse of antibiotics and environmental pollution caused by the discharge of residual antibiotics in drinking water. To solve these problems, only by starting from the manufacturing technology of antibiotic preparations, improving the efficacy of antibiotics, reducing the degradation of antibiotics, and making antibiotics convenient to use and waste-free and zero-emission at the breeding end. Therefore, how to improve the sustained-release effect of amoxicillin and reduce the number of medication times has become a research hotspot. In addition, traditional amoxicillin is slightly soluble in water. To improve the solubility of amoxicillin powder, cosolvents such as sodium carbonate are generally added during the powder-making process to increase its water solubility. However, the addition of these substances will cause the amoxicillin powder to easily turn yellow and deteriorate during storage, which is not conducive to long-term storage and affects the product quality to a certain extent. Therefore, how to improve storage stability is also a current research hotspot.

[0004] Based on this, there is an urgent need to develop a water-soluble amoxicillin powder with excellent sustained-release effect and storage stability. Summary of the Invention

[0005] Aiming at the deficiencies in the prior art, the present invention aims to provide a water-soluble amoxicillin powder with excellent sustained-release effect and storage stability. To achieve the above object, the present invention adopts the following technical solutions: A water-soluble amoxicillin powder, calculated by weight, comprises the following components: 50 - 60 parts of amoxicillin; 20 - 30 parts of polyvinyl alcohol-modified β-cyclodextrin; 3 - 5 parts of tryptophan; 20 - 30 parts of filler; 0.5 - 1 part of flavoring agent; The preparation method of the polyvinyl alcohol-modified β-cyclodextrin is as follows: Step 1: React β-cyclodextrin with p-toluenesulfonyl chloride in the presence of sodium hydroxide to obtain mono-6-p-toluenesulfonyl-β-cyclodextrin ester; Step 2: React mono-6-p-toluenesulfonyl-β-cyclodextrin ester, triethylamine and DMSO at 120 - 140 °C to obtain mono-6-formyl-β-cyclodextrin ester; Step 3: React polyvinyl alcohol and mono-6-formyl-β-cyclodextrin ester in the presence of p-toluenesulfonic acid to obtain polyvinyl alcohol-modified β-cyclodextrin.

[0006] In some embodiments, in Step 1, the molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride is 1:(1.1 - 1.5); the molar ratio of β-cyclodextrin to sodium hydroxide is 1:(2 - 5).

[0007] In some embodiments, in Step 2, the molar ratio of mono-6-p-toluenesulfonyl-β-cyclodextrin ester to triethylamine is 1:(5 - 10).

[0008] In some embodiments, in Step 3, the mass ratio of polyvinyl alcohol to mono-6-formyl-β-cyclodextrin ester is 1:(2 - 5); the mass ratio of polyvinyl alcohol to p-toluenesulfonic acid is 1:(0.1 - 0.15).

[0009] In some embodiments, the flavoring agent is selected from one or more of citric acid, acesulfame potassium, aspartame, aspartame, vanillin, sorbitol, sucralose.

[0010] In some embodiments, the filler is selected from one or more of glucose, lactose, soluble starch, mannitol.

[0011] In some embodiments, the filler consists of 70 wt% lactose and 30 wt% water-soluble starch.

[0012] In some embodiments, a water-soluble amoxicillin powder, by weight, comprises the following components: Amoxicillin 60 parts; Polyvinyl alcohol-modified β-cyclodextrin 25 parts; Tryptophan 5 parts; Filler 25 parts; Vanillin 1 part; The filler consists of 70 wt% lactose and 30 wt% water-soluble starch.

[0013] The present invention also provides a method for preparing a water-soluble amoxicillin powder, comprising the following steps: Step S1: Weigh each raw material accurately. First, add polyvinyl alcohol modified β-cyclodextrin and tryptophan into an appropriate amount of water, heat it to 50 - 60 °C, stir until the polyvinyl alcohol modified β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant-temperature stirring, and stir to form a homogeneous viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and after drying, obtain the amoxicillin inclusion complex. Collect the inclusion complex, crush it, and sieve it through an 80 - 100 mesh sieve for standby; Step S2: Add the amoxicillin inclusion complex, filler, and flavoring agent obtained in Step 1 into a three-dimensional mixer for mixing. The mixing time is 20 - 30 min. Subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0014] The present invention also provides the application of the above-mentioned water-soluble amoxicillin powder in the preparation of veterinary antibacterial drugs.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The water-soluble amoxicillin powder of the present invention has excellent sustained-release effect. It bursts and releases within 2 hours, and then slowly and continuously releases in an incremental form. The sustained-release effect can extend its action time, greatly improve the bioavailability of the drug, and reduce the environmental pollution caused by antibiotics.

[0016] 2) The water-soluble amoxicillin powder of the present invention has excellent storage stability. After 6 months of accelerated test, the content of amoxicillin is still as high as more than 99.9%. Specific Embodiments

[0017] The following non-limiting embodiments can enable those of ordinary skill in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. The following content is only an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the present invention according to the disclosed content, and it should also fall within the scope claimed by the present invention.

[0018] When the embodiments give numerical ranges, it should be understood that unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0019] The present invention will be further described below by way of specific embodiments. All kinds of chemical reagents used in the embodiments of the present invention are obtained through conventional commercial channels unless otherwise specified.

[0020] Preparation Example 1 Preparation of Polyvinyl Alcohol Modified β-Cyclodextrin (PVA-β-CD) Step 1: Synthesis of Mono-6-p-toluenesulfonyl-β-cyclodextrin Ester (β-CD-6-OTs) β-cyclodextrin (β-CD, 0.1 mol) was added to water (200 mL), and then sodium hydroxide (0.4 mol) was added and stirred evenly. p-Toluenesulfonyl chloride (0.15 mol) was dissolved in acetonitrile (50 mL) and added dropwise to the mixed solution of β-cyclodextrin at 0 °C, and the temperature was raised to 35 °C and stirred for reaction for 2 h. After the reaction was completed, the mixed solution was neutralized with dilute HCl to pH = 6, the precipitate was filtered, the filtrate was left standing overnight at 4 °C, and the precipitate was collected again. The precipitate obtained twice was recrystallized and dried to obtain mono-6-p-toluenesulfonyl-β-cyclodextrin ester with a yield of 36.4%.

[0021] Step 2: Synthesis of Mono-6-formyl-β-cyclodextrin Ester (β-CD-6-CHO) β-CD-6-OTs (0.1 mol), triethylamine (1.0 mol), and DMSO (200 mL) were added to the reactor, and the temperature was raised to 135 °C with stirring for reaction for 2.0 h. After the reaction was completed, the dark brown product was added to anhydrous ethanol to precipitate the product, and the product was purified by the method of dissolving and precipitating with distilled water-acetone for many times. After drying, β-CD-6-CHO was obtained with a yield of 55.6%.

[0022] Step 3: Synthesis of Polyvinyl Alcohol Modified β-cyclodextrin (PVA-β-CD) Polyvinyl alcohol (PVA, 0.5 g) was dissolved in DMSO (10 mL), then β-CD-6-CHO (2.0 g) and p-toluenesulfonic acid (0.05 g) were added, and the temperature was raised to 80 °C and stirred for reaction for 2 h. After the reaction was completed, the reaction mixture was poured into a dialysis bag, and distilled water was changed once every 12 h. After dialysis for one week, the product in the bag was dried to obtain polyvinyl alcohol modified β-cyclodextrin PVA-β-CD.

[0023] Example 1 A water-soluble amoxicillin powder, by weight, comprises the following components: 60 parts of amoxicillin; 25 parts of polyvinyl alcohol modified β-cyclodextrin (obtained from Preparation Example 1); 5 parts of tryptophan; 25 parts of filler; 1 part of flavoring agent vanillin; The filler consists of 70 wt% lactose and 30 wt% water-soluble starch.

[0024] The preparation method of the above water-soluble amoxicillin powder comprises the following steps: Step 1: Weigh accurately each raw material according to the above ratios. First, add polyvinyl alcohol modified β-cyclodextrin and tryptophan into an appropriate amount of water, heat to 60 °C, stir until the polyvinyl alcohol modified β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant temperature stirring, stir for 2 h to form a homogeneous viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and obtain amoxicillin inclusion complex after drying. Collect the inclusion complex, crush it, and sieve it through a 100-mesh sieve for standby.

[0025] Step 2: Add the amoxicillin inclusion complex, filler, and flavoring agent vanillin obtained in Step 1 into a three-dimensional mixer for mixing. The mixing time is 30 min. Subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0026] Example 2 A water-soluble amoxicillin powder, by weight, comprises the following components: Amoxicillin 50 parts; Polyvinyl alcohol modified β-cyclodextrin (obtained from Preparation Example 1) 20 parts; Tryptophan 4 parts; Filler 30 parts; Flavoring agent aspartame 0.5 part; The filler consists of 70 wt% lactose and 30 wt% water-soluble starch.

[0027] The preparation method of the above water-soluble amoxicillin powder comprises the following steps: Step 1: Weigh accurately each raw material according to the above ratios. First, add polyvinyl alcohol modified β-cyclodextrin and tryptophan into an appropriate amount of water, heat to 60 °C, stir until the polyvinyl alcohol modified β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant temperature stirring, stir for 2 h to form a homogeneous viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and obtain amoxicillin inclusion complex after drying. Collect the inclusion complex, crush it, and sieve it through a 100-mesh sieve for standby.

[0028] Step 2: Add the amoxicillin inclusion complex, filler, and flavoring agent aspartame obtained in Step 1 into a three-dimensional mixer for mixing. The mixing time is 30 min. Subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0029] Example 3 A water-soluble amoxicillin powder, by weight, comprises the following components: Amoxicillin 60 parts; Polyvinyl alcohol modified β-cyclodextrin (obtained from Preparation Example 1) 25 parts; Tryptophan 5 parts; Filler lactose 25 parts; 1 part of vanillin, a flavoring agent; The preparation method of the above water-soluble amoxicillin powder comprises the following steps: Step 1: Weigh each raw material accurately according to the above ratio. First, add polyvinyl alcohol-modified β-cyclodextrin and tryptophan into an appropriate amount of water, heat to 60°C, stir until the polyvinyl alcohol-modified β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant-temperature stirring, and stir for 2 h to form a uniform viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and after drying, obtain the amoxicillin inclusion complex. Collect the inclusion complex, crush it, and sieve it through a 100-mesh sieve for standby.

[0030] Step 2: Add the amoxicillin inclusion complex, filler lactose and flavoring agent vanillin obtained in Step 1 into a three-dimensional mixer for mixing. The mixing time is 30 min. Subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0031] Comparative Example 1 On the basis of Example 1, tryptophan is omitted, and the specific conditions are as follows: A water-soluble amoxicillin powder, by weight, comprises the following components: 60 parts of amoxicillin; 25 parts of polyvinyl alcohol-modified β-cyclodextrin (obtained from Preparation Example 1); 25 parts of filler; 1 part of vanillin, a flavoring agent; The filler consists of 70 wt% lactose and 30 wt% water-soluble starch.

[0032] The preparation method of the above water-soluble amoxicillin powder comprises the following steps: Step 1: Weigh each raw material accurately according to the above ratio. First, add polyvinyl alcohol-modified β-cyclodextrin into an appropriate amount of water, heat to 60°C, stir until the polyvinyl alcohol-modified β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant-temperature stirring, and stir for 2 h to form a uniform viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and after drying, obtain the amoxicillin inclusion complex. Collect the inclusion complex, crush it, and sieve it through a 100-mesh sieve for standby.

[0033] Step 2: Add the amoxicillin inclusion complex, filler and flavoring agent vanillin obtained in Step 1 into a three-dimensional mixer for mixing. The mixing time is 30 min. Subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0034] Comparative Example 2 On the basis of Example 1, polyvinyl alcohol-modified β-cyclodextrin is replaced by unmodified β-cyclodextrin, and the specific conditions are as follows: A water-soluble amoxicillin powder, by weight, comprises the following components: 60 parts of amoxicillin; 25 parts of β-cyclodextrin; 5 parts of tryptophan; 25 parts of filler; 1 part of vanillin as flavoring agent; The filler consists of 70wt% lactose and 30wt% water-soluble starch.

[0035] The preparation method of the above water-soluble amoxicillin powder comprises the following steps: Step 1: Weigh each raw material accurately according to the above ratio. First, add β-cyclodextrin and tryptophan into an appropriate amount of water, heat to 60 °C, stir until β-cyclodextrin is completely dissolved, then add amoxicillin under the condition of constant-temperature stirring, and stir for 2 h to form a homogeneous viscous liquid, that is, the inclusion complex solution. Add the inclusion complex solution into the drying system, and after drying, obtain the amoxicillin inclusion complex. Collect the inclusion complex, pulverize it, and sieve it through a 100-mesh sieve for standby.

[0036] Step 2: Add the amoxicillin inclusion complex, filler and vanillin as flavoring agent obtained in Step 1 into a three-dimensional mixer for mixing, and the mixing time is 30 min. Then subpackage and inspect the uniformly mixed material to obtain the water-soluble amoxicillin powder.

[0037] Performance test (1) Sustained-release performance test According to the dissolution and release determination method in the first part of the Pharmacopoeia of the People's Republic of China - General Rule 0931, put 30 g of soluble powder sample into each dissolution cup, with 6 as a group, and take the average value of the test; test the dissolution amount of amoxicillin in the water-soluble amoxicillin powder.

[0038] The specific operation is as follows: Measure 150 mL of phosphate buffer solution (pH = 6.8) into each of the 6 dissolution cups, and add water to 900 mL to obtain the dissolution medium; after the temperature of the dissolution medium is constant at 37 °C, put the samples into the 6 dissolution cups respectively, and stir at room temperature and a rotation speed of 100 r / min; at 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h respectively, take out 5 mL of the solution and filter it through a microporous filter membrane. The time from sampling to filtration should be completed within 30 seconds. Take the clarified filtrate, detect the content by LCMS, and calculate the cumulative release percentage of the drug. The results are shown in Table 1.

[0039] Table 1 Results of sustained-release performance test As can be seen from Table 1, the water-soluble amoxicillin powder of the present invention has excellent sustained-release effect. It bursts and releases within 2 hours, and then slowly and continuously releases in an incremental form. The sustained-release effect can extend its action time and improve the bioavailability of the drug. The main reason is that: the present invention modifies cyclodextrin with polyvinyl alcohol to form a stable and complex network structure, which can reduce the diffusion rate of amoxicillin and achieve the sustained-release effect. From Example 1 and Comparative Example 1, it can be seen that adding a certain amount of tryptophan can improve the dissolution rate of amoxicillin, making the final cumulative sustained-release rate reach 99.8%.

[0040] (2) Stability test Detection method: Detect according to Part I of the "Chinese Veterinary Pharmacopoeia" (2020). The detection temperature is 40°C ± 2°C, and the humidity is 75% ± 5%. Accelerated tests are carried out on the samples prepared in Examples 1-3 and Comparative Examples 1-2. Place them under constant temperature and humidity conditions for 6 months. Sampling is carried out at 0 month, 1 month, 2 months, 3 months and 6 months respectively, and the content of amoxicillin is determined. The results are shown in Table 2.

[0041] Table 2 Results of accelerated stability test As can be seen from Table 2, the water-soluble amoxicillin powder of the present invention has excellent storage stability. The content of amoxicillin is still as high as over 99.9% after being placed for 6 months. The possible reason is that: the present invention modifies cyclodextrin with polyvinyl alcohol to form a stable and complex network structure, which has a good binding property with amoxicillin molecules.

[0042] The above embodiments are merely examples clearly described and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or alterations can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. And the obvious changes or alterations thus extended are still within the protection scope of the present invention.

Claims

1. A water-soluble amoxicillin powder, comprising the following components by weight: Amoxicillin 50~60 parts; 20-30 parts of polyvinyl alcohol modified β-cyclodextrin; 3-5 parts of tryptophan; 20~30 parts of filler; 0.5~1 part of flavoring agent; The preparation method of the polyvinyl alcohol modified β-cyclodextrin is: Step 1: In the presence of sodium hydroxide, β-cyclodextrin and p-toluenesulfonyl chloride react to obtain mono-6-p-toluenesulfonyl-β-cyclodextrin ester; Step 2: Mono-6-p-toluenesulfonyl-β-cyclodextrin ester, triethylamine and DMSO react at 120-140° C. to obtain mono-6-formyl-β-cyclodextrin ester; Step 3: Polyvinyl alcohol and mono-6-formyl-β-cyclodextrin ester react in the presence of p-toluenesulfonic acid to obtain polyvinyl alcohol-modified β-cyclodextrin.

2. The method according to claim 1, characterized in that: In step 1, the molar ratio of the β-cyclodextrin to p-toluenesulfonyl chloride is 1:(1.1-1.5); the molar ratio of the β-cyclodextrin to sodium hydroxide is 1:(2-5).

3. The method according to claim 1, characterized in that In step 2, the molar ratio of the mono-6-p-toluenesulfonyl-β-cyclodextrin ester to triethylamine is 1:(5-10).

4. The method according to claim 1, characterized in that: In step 3, the mass ratio of the polyvinyl alcohol to mono-6-formyl-β-cyclodextrin ester is 1:(2-5); the mass ratio of the polyvinyl alcohol to p-toluenesulfonic acid is 1:(0.1-0.15).

5. The method according to claim 1, characterized in that The flavoring agent is selected from one or more of citric acid, acesulfame potassium, aspartame, aspartame, vanillin, sorbitol, and sucralose.

6. The method according to claim 1, characterized in that The filler is selected from one or more of glucose, lactose, water-soluble starch and mannitol.

7. The method according to claim 6, characterized in that The filler consists of 70 wt % lactose and 30 wt % water-soluble starch.

8. The method according to claim 1, characterized in that By weight, it includes the following components: Amoxicillin 60 parts; 25 parts of polyvinyl alcohol modified β-cyclodextrin; Tryptophan 5 parts; Filler 25 parts; 1 part of vanillin; The filler consists of 70 wt % lactose and 30 wt % water-soluble starch.

9. The method for preparing the water-soluble amoxicillin powder according to any one of claims 1 to 8, comprising the following steps: Step S1: Accurately weigh each raw material, first add polyvinyl alcohol-modified β-cyclodextrin and tryptophan to an appropriate amount of water, heat to 50~60°C, stir until the polyvinyl alcohol-modified β-cyclodextrin is completely dissolved, then add amoxicillin under constant temperature stirring conditions, stir to form a uniform viscous liquid, i.e., inclusion complex solution, add the inclusion complex solution to a drying system, dry to obtain an amoxicillin inclusion complex, collect the inclusion complex, crush, and pass through an 80~100 mesh sieve for later use; Step S2: adding the amoxicillin inclusion compound, filler and flavoring agent obtained in step 1 into a three-dimensional mixer for mixing for 20 to 30 minutes, packaging and inspecting the uniformly mixed materials to obtain water-soluble amoxicillin powder.

10. Use of the water-soluble amoxicillin powder according to any one of claims 1 to 8 in the preparation of veterinary antibacterial drugs.

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