Amoxicillin dry granules and preparation method thereof

Abstract

The present invention relates to the technical field of medical, dental or cosmetic preparations, and specifically discloses an amoxicillin dry granule and a preparation method thereof. The amoxicillin dry granule comprises the following components: 70 to 90 parts by weight of nanoparticles loaded with amoxicillin, 5 to 10 parts by weight of a wetting agent, and 1 to 3 parts by weight of a flavoring agent. The present invention also provides a preparation method thereof. Compared with the prior art, the amoxicillin dry granule prepared by the present invention has the advantages of long drug efficacy maintenance time, less drug feeding times, and high drug utilization rate.

Description

Technical Field

[0001] The invention relates to the technical field of medical, dental or cosmetic preparations, and in particular to amoxicillin dry granules and a preparation method thereof. Background Art

[0002] Amoxicillin is a semi-synthetic penicillin antibiotic, also known as amoxicillin. It is a white or off-white crystalline powder, with both acidity and alkalinity. It is slightly soluble in water, insoluble in ethanol, and has a slightly bitter taste. The chemical structure of its raw material is adenine ribonucleotide, with an extra hydroxyl group on the side chain benzene ring. It has basically the same drug properties as adenine ribonucleotide, and is a penicillin with an amino side chain.

[0003] CN201810853396.2 relates to a kind of amoxicillin granules with stable quality and a preparation method thereof, belonging to the field of medical technology. The preparation is made of amoxicillin and excipients through wet granulation technology, including diluents, adhesives, disintegrants, colorants and taste masking agents, and does not contain ethanol. After 36 months of long-term stability test, the content of each specific impurity is not higher than 0.07%, ensuring the stability of the drug during storage. In terms of preparation technology, low-temperature drying technology is adopted to ensure the stability of amoxicillin granules during the production process.

[0004] CN202211099801.9 provides a kind of amoxicillin clavulanate potassium biphasic release granules for children and a preparation method thereof. The biphasic release granules are composed of quick-release granules and enteric-coated sustained-release granules; the quick-release granules are composed of the following raw materials in mass percentage: amoxicillin trihydrate and clavulanate potassium mixture 75-90%, disintegrant 2-10%, suspending agent 5-10%, glidant 0.2-5%, lubricant 0.5-2%, flavoring agent 1-3%; the enteric-coated sustained-release granules are composed of the following raw materials in mass percentage: amoxicillin trihydrate and clavulanate potassium mixture 65-80%, binder 5-10%, sustained-release coating layer material 5-10%, enteric coating layer material 10-20%; the mass ratio of amoxicillin trihydrate in the quick-release granules to amoxicillin trihydrate in the enteric-coated sustained-release granules is 1:1, which has the advantages of easy swallowing, rapid effect, long maintenance of drug effect time, and less number of doses.

[0005] At present, amoxicillin preparations are mainly oral preparations, including tablets, granules, and suspensions. However, for special groups, tablets are difficult to swallow, while granules and suspensions are relatively easy to take, but they still have the defects of difficult feeding and poor compatibility. The market urgently needs an amoxicillin preparation with a long duration of efficacy, less feeding times, good taste, and easy swallowing. In addition, amoxicillin enters the stomach from the mouth, then enters the intestine, is absorbed by the intestine and enters the systemic blood circulation, but its stagnation time in the intestine is only about 3-20 hours, so the utilization rate of the drug will be low. This will greatly increase the frequency of taking medicine and further increase the difficulty of taking medicine. Summary of the invention

[0006] In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is to provide an amoxicillin dry granule and a preparation method thereof.

[0007] Amoxicillin has a very significant oral absorption effect, and has the advantages of broad spectrum, acid resistance, and convenient preparation and use. However, in the prior art, amoxicillin granules can be released in the acidic environment of gastric juice, which can easily irritate the gastric mucosa, causing various adverse reactions such as abdominal pain and nausea, and are not suitable for patients with gastric diseases. In addition, it will lead to a decrease in intestinal absorption rate, thereby affecting the entry of drug components into the blood circulation, resulting in a decrease in utilization rate. The microstructure of polylysine has different responses to different pH environments. When pH <7, the amino group in the polylysine structure is positively charged, so that the long molecular chain is arranged in a disordered state. Under alkaline conditions, the positive charge of the amino group in the polylysine structure is weakened, and the main chain is wound into a stable spiral structure by relying on the intrachain hydrogen keyboard. Therefore, in the present invention, modified polylysine is obtained by modifying polylysine, and then the carboxyl group of amoxicillin is electrostatically bonded with the residual amino group of the polyamino acid main chain lysine, and the conjugation effect of the naphthalene ring is used to construct a pH-sensitive polylysine carrier. In gastric juice, the modified polylysine is wrapped around the periphery of amoxicillin, so that the drug cannot be released. With the increase of pH, the modified polylysine carboxyl group is ionized with negative charge, and its solubility and molecular internal repulsion increase, and the basic structure changes from disorder to ordered state, and the drug is released from the carrier. In addition, the electrostatic bonding between the drug and the carrier can produce an electrostatic effect with the intestinal surface, thereby extending the in vivo retention time. In this way, the bioavailability of amoxicillin is improved, the frequency of taking is reduced, and the difficulty of taking medicine is reduced.

[0008] To achieve the above object, the present invention provides an amoxicillin dry granule, comprising the following components: 70 to 90 parts by weight of nanoparticles loaded with amoxicillin, 5 to 10 parts by weight of a wetting agent, and 1 to 3 parts by weight of a flavoring agent.

[0009] Furthermore, the wetting agent includes 80wt% ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three is 10:2:1.

[0010] Furthermore, the flavor corrector is one of aspartame, cyclamate, strawberry flavor, and tartrazine.

[0011] The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0012] S1. Add 5,6,7-trihydroxy-2-naphthoic acid to an ethanol aqueous solution, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide, and stir at 0-5° C. for 10-40 minutes to obtain a solution A;

[0013] S2, adding polylysine to water to obtain solution B, adding sodium hydroxide to adjust the pH to weak alkalinity, then adding solution A to solution B, stirring at 0-5°C for 16-32h, dialyzing the mixture after the stirring, and freeze-drying after dialysis for 2-3d to obtain modified polylysine;

[0014] S3. Add amoxicillin and modified polylysine into dimethyl sulfoxide, stir and mix well, then add an equal volume of PBS buffer, mix well and dialyze. After dialysis for 2 to 3 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

[0015] Furthermore, in step S1, the ethanol aqueous solution is 50-70 wt %.

[0016] Furthermore, in step S2, pH=7-8.

[0017] Furthermore, the dialysis molecular weight is less than 3500Da.

[0018] Furthermore, the concentrations of amoxicillin and modified polylysine are 1-4 g / L and 2-8 g / L respectively.

[0019] Preferably, the method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0020] S1, adding 5 to 20 parts by weight of 5,6,7-trihydroxy-2-naphthoic acid to a 50 to 70 wt% ethanol aqueous solution, and then adding 5 to 20 parts by weight of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3 to 10 parts by weight of N-hydroxysuccinimide, and stirring at 0 to 5° C. for 10 to 40 minutes to obtain a solution A;

[0021] S2, adding 10 to 50 parts by weight of polylysine to 100 to 500 parts by weight of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7 to 8, and then adding solution A to solution B, stirring at 0 to 5°C for 16 to 32 hours, dialyzing the mixture (<3500Da) after the stirring, and freeze-drying after dialysis for 2 to 3 days to obtain modified polylysine;

[0022] S3. Add amoxicillin and modified polylysine to dimethyl sulfoxide, wherein the contents of amoxicillin and modified polylysine are 1-4 g / L and 2-8 g / L, respectively. Stir and mix well, then add an equal volume of PBS buffer solution, mix well, and dialyze (<3500Da). After dialysis for 2-3 days, freeze-dry to obtain amoxicillin-loaded nanoparticles.

[0023] A method for preparing amoxicillin dry granules comprises the following steps:

[0024] The nanoparticles loaded with amoxicillin are added to a wetting agent, and then a flavoring agent is added, and the nanoparticles are added to a granulator for granulation to prepare dry granules with a mesh size of 10 to 30.

[0025] Beneficial effects of the present invention:

[0026] 1. Compared with the prior art, the amoxicillin dry granules of the present invention can reduce the frequency of taking the medicine, reduce the difficulty of taking the medicine, and at the same time reduce the irritation of the medicine to the stomach, increase the sustained release time of the medicine in the intestine, and improve the utilization rate of the medicine.

[0027] 2. The present invention obtains modified polylysine by modifying polylysine, and then utilizes the carboxyl group of amoxicillin to electrostatically bond with the residual amino group of lysine in the main chain of the polyamino acid, and simultaneously utilizes the conjugation effect of the naphthalene ring to construct a pH-sensitive polylysine carrier, thereby achieving an ideal state in which the drug release amount is low in the stomach and high in the intestine. DETAILED DESCRIPTION

[0028] 5,6,7-Trihydroxy-2-naphthoic acid, 2-Naphthalenecarboxylic acid, 5,6,7-trihydroxy, CAS No.: 167409-11-2.

[0029] Polylysine, Mw=3500~5000.

[0030] PBS buffer, 0.01 mol / L, pH = 7.4.

[0031] Comparative Example 1

[0032] A method for preparing amoxicillin dry granules comprises the following steps:

[0033] 80 g of amoxicillin-loaded nanoparticles were added to 10 g of a wetting agent, wherein the wetting agent included 80 wt % ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three was 10:2:1, and then 3 g of tartrazine was added, and the mixture was added to a dry granulator for granulation to prepare 30 mesh dry granules.

[0034] The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0035] Amoxicillin and polylysine were added to dimethyl sulfoxide, the contents of amoxicillin and polylysine were 3 g / L and 6 g / L respectively, stirred and mixed evenly, then an equal volume of PBS buffer was added, and dialyzed (<3500Da) after mixing evenly. After dialysis for 2 days, freeze-dried to obtain nanoparticles loaded with amoxicillin.

[0036] Comparative Example 2

[0037] A method for preparing amoxicillin dry granules comprises the following steps:

[0038] 26 g of amoxicillin was added to 10 g of a wetting agent, wherein the wetting agent included 80 wt% ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three was 10:2:1, and then 3 g of tartrazine was added, and the mixture was added to a dry granulator for granulation to prepare 30 mesh dry granules.

[0039] Example 1

[0040] A method for preparing amoxicillin dry granules comprises the following steps:

[0041] 80 g of amoxicillin-loaded nanoparticles were added to 10 g of a wetting agent, wherein the wetting agent included 80 wt % ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three was 10:2:1, and then 3 g of tartrazine was added, and the mixture was added to a dry granulator for granulation to prepare 30 mesh dry granules.

[0042] The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0043] S1. Add 11 g of 5,6,7-trihydroxy-2-naphthoic acid to a 50 wt % ethanol aqueous solution, then add 11 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 6 g of N-hydroxysuccinimide, and stir at 0° C. for 20 min to obtain a solution A;

[0044] S2, adding 20 g of polylysine to 400 mL of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7.5, then adding solution A to solution B, stirring at 0°C for 26 h, dialyzing the mixture (<3500 Da) after the stirring, and freeze-drying after dialysis for 2 days to obtain modified polylysine;

[0045] S3. Add amoxicillin and modified polylysine to dimethyl sulfoxide, the contents of amoxicillin and modified polylysine are 3 g / L and 6 g / L respectively, stir and mix evenly, then add an equal volume of PBS buffer, mix evenly, and dialyze (<3500Da). After dialysis for 2 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

[0046] Example 2

[0047] A method for preparing amoxicillin dry granules comprises the following steps:

[0048] 80 g of amoxicillin-loaded nanoparticles were added to 10 g of a wetting agent, wherein the wetting agent included 80 wt % ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three was 10:2:1, and then 3 g of tartrazine was added, and the mixture was added to a dry granulator for granulation to prepare 30 mesh dry granules.

[0049] The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0050] S1. Add 8 g of gallic acid to a 50 wt % ethanol aqueous solution, then add 11 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 6 g of N-hydroxysuccinimide, and stir at 0° C. for 20 min to obtain solution A;

[0051] S2, adding 20 g of polylysine to 400 mL of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7.5, then adding solution A to solution B, stirring at 0°C for 26 h, dialyzing the mixture (<3500 Da) after the stirring, and freeze-drying after dialysis for 2 days to obtain modified polylysine;

[0052] S3. Add amoxicillin and modified polylysine to dimethyl sulfoxide, the contents of amoxicillin and modified polylysine are 3 g / L and 6 g / L respectively, stir and mix evenly, then add an equal volume of PBS buffer, mix evenly, and dialyze (<3500Da). After dialysis for 2 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

[0053] Example 3

[0054] A method for preparing amoxicillin dry granules comprises the following steps:

[0055] 80 g of amoxicillin-loaded nanoparticles were added to 10 g of a wetting agent, wherein the wetting agent included 80 wt % ethanol aqueous solution, hydroxypropyl cellulose, and polysorbate 80; the mass ratio of the three was 10:2:1, and then 3 g of tartrazine was added, and the mixture was added to a dry granulator for granulation to prepare 30 mesh dry granules.

[0056] The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps:

[0057] S1, adding 7.7 g of protocatechuic acid to a 50 wt% ethanol aqueous solution, and then adding 11 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 6 g of N-hydroxysuccinimide, and stirring at 0° C. for 20 min to obtain solution A;

[0058] S2, adding 20 g of polylysine to 400 mL of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7.5, then adding solution A to solution B, stirring at 0°C for 26 h, dialyzing the mixture (<3500 Da) after the stirring, and freeze-drying after dialysis for 2 days to obtain modified polylysine;

[0059] S3. Add amoxicillin and modified polylysine to dimethyl sulfoxide, the contents of amoxicillin and modified polylysine are 3 g / L and 6 g / L respectively, stir and mix evenly, then add an equal volume of PBS buffer, mix evenly, and dialyze (<3500Da). After dialysis for 2 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

[0060] Example 4

[0061] The same as Example 1, the only difference is that the nanoparticles loaded with amoxicillin are 70 g.

[0062] Example 5

[0063] The same as Example 1, the only difference is that the nanoparticles loaded with amoxicillin are 90 g.

[0064] Test Example 1

[0065] The amoxicillin dry granules in the control example and the embodiment were subjected to a simulated digestive tract gastric juice-intestinal juice release test. 5 mL of amoxicillin dry granule solution with a concentration of 0.1 g / mL was placed in a dialysis bag (Mw < 10000), immersed in a buffer solution simulating gastric juice, pH = 2.5, and oscillated at 37°C. After dialysis for 2-5 hours, the pH of the dialysate was adjusted to 6.4 to simulate the intestinal environment. After about 10 hours, the pH was adjusted to 7.4 to simulate the intestinal cell gap environment. The dialysate was taken at regular intervals to calculate the drug release rate.

[0066] Table 1 Release of amoxicillin dry granules in simulated gastrointestinal environment

[0067]

[0068]

[0069] By comparing Reference Example 2 with the embodiment, it can be found that when amoxicillin is not loaded, it begins to release in large quantities in the stomach, and the sustained release effect cannot be achieved. In Reference Example 2, since the microstructure of polylysine has different responses to different pH environments, when pH <7, the amino group in the polylysine structure is positively charged, so that the molecular long chain is arranged in a disordered state, and under alkaline conditions, the positive charge of the amino group in the polylysine structure is weakened, and the main chain is wound into a stable spiral structure by relying on the hydrogen keyboard in the chain. The increase in pH will accelerate the release of amoxicillin, and the localized release for the intestinal tract cannot be achieved. Therefore, in Example 1, modified polylysine is obtained by modifying polylysine, and then the carboxyl group of amoxicillin is electrostatically bonded to the residual amino group of the polyamino acid main chain lysine, and the conjugation effect of the naphthalene ring is used to construct a pH-sensitive polylysine carrier, and the modified polylysine is more responsive to pH. In gastric juice, the modified polylysine is wrapped around the periphery of amoxicillin, so that the drug cannot be released. As the pH increases, the modified polylysine carboxyl group is ionized and negatively charged, its solubility and internal molecular repulsion increase, the basic structure changes from disorder to order, and the drug is released from the carrier. In addition, the electrostatic binding between the drug and the carrier can produce electrostatic effects on the intestinal surface, thereby prolonging the in vivo retention time. In this way, the bioavailability of amoxicillin is improved, the frequency of administration is reduced, and the difficulty of taking the medicine is reduced. The poor sustained release effect in Examples 2 to 3 may be due to the lack of conjugation effect, which makes the binding between the carrier and amoxicillin weaker.

[0070] Test Example 2

[0071] The amoxicillin dry granules in the control example and the example were subjected to animal experiments respectively. Healthy experimental rabbits weighing about 2 kg were selected and the dosage was 25 mg per kg. The blood drug concentration was detected at 1 h, 4 h, 8 h, and 12 h after feeding.

[0072] Table 2 Sustained release test of amoxicillin dry granules

[0073]

[0074] From the blood drug concentration, it can be seen that the dry granules prepared in Examples 1 to 3 have a good sustained release effect and can maintain a long drug effect in the body, while the control example 2 has a short drug effect and a low drug utilization rate. This is because in Example 1, modified polylysine is obtained by modifying polylysine, and then the carboxyl group of amoxicillin is electrostatically bonded with the residual amino group of lysine in the main chain of the polyamino acid, and the conjugation effect of the naphthalene ring is used to construct a pH-sensitive polylysine carrier. The modified polylysine has better responsiveness to pH. In gastric juice, the modified polylysine is wrapped around the periphery of amoxicillin, making it impossible for the drug to be released. As the pH increases, the modified polylysine carboxyl group is ionized with a negative charge, its solubility and internal molecular repulsion increase, the basic structure changes from disorder to ordered state, and the drug is released from the carrier. In addition, the electrostatic binding between the drug and the carrier can produce an electrostatic effect with the intestinal surface, thereby prolonging the in vivo retention time. This is also mutually corroborated by the experimental data in Test Example 1.

[0075] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. An amoxicillin dry granule, characterized in that: The invention comprises the following components: 70-90 parts by weight of nanoparticles loaded with amoxicillin, 5-10 parts by weight of a wetting agent, and 1-3 parts by weight of a flavoring agent; The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps: S1, adding 5-20 parts by weight of 5,6,7-trihydroxy-2-naphthoic acid to a 50-70 wt% ethanol aqueous solution, and then adding 5-20 parts by weight of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3-10 parts by weight of N-hydroxysuccinimide, and stirring at 0-5° C. for 10-40 min to obtain a solution A; S2, adding 10-50 parts by weight of polylysine to 100-500 parts by weight of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7-8, and then adding solution A to solution B, stirring at 0-5°C for 16-32 hours, dialyzing the mixture after the stirring, the dialyzed molecular weight is <3500Da, and freeze-drying after dialysis for 2-3 days to obtain modified polylysine; S3. Add amoxicillin and modified polylysine into dimethyl sulfoxide. The contents of amoxicillin and modified polylysine are 1-4 g / L and 2-8 g / L, respectively. Stir and mix well. Then add an equal volume of PBS buffer solution. Mix well and dialyze. The dialyzed molecular weight is <3500Da. After dialysis for 2-3 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

2. The amoxicillin dry granules according to claim 1, characterized in that The wetting agent includes 80wt% ethanol aqueous solution, hydroxypropyl cellulose and polysorbate-80.

3. The amoxicillin dry granules according to claim 2, characterized in that: The mass ratio of the ethanol aqueous solution, hydroxypropyl cellulose and polysorbate 80 is 10:2:

1.

4. The amoxicillin dry granules according to claim 1, characterized in that The flavor corrector is one of aspartame, cyclamate, strawberry flavor essence and tartrazine.

5. The method for preparing the amoxicillin dry granules according to any one of claims 1 to 4, characterized in that: The steps include: The nanoparticles loaded with amoxicillin are added to a wetting agent, and then a flavoring agent is added, and the nanoparticles are added to a granulator for granulation to prepare dry granules of 10-30 meshes; The method for preparing the amoxicillin-loaded nanoparticles comprises the following steps: S1, adding 5-20 parts by weight of 5,6,7-trihydroxy-2-naphthoic acid to a 50-70 wt% ethanol aqueous solution, and then adding 5-20 parts by weight of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3-10 parts by weight of N-hydroxysuccinimide, and stirring at 0-5° C. for 10-40 min to obtain a solution A; S2, adding 10-50 parts by weight of polylysine to 100-500 parts by weight of water to obtain solution B, adding sodium hydroxide to adjust the pH to 7-8, and then adding solution A to solution B, stirring at 0-5°C for 16-32 hours, dialyzing the mixture after the stirring, the dialyzed molecular weight is <3500Da, and freeze-drying after dialysis for 2-3 days to obtain modified polylysine; S3. Add amoxicillin and modified polylysine into dimethyl sulfoxide. The contents of amoxicillin and modified polylysine are 1-4 g / L and 2-8 g / L, respectively. Stir and mix well. Then add an equal volume of PBS buffer solution. Mix well and dialyze. The dialyzed molecular weight is <3500Da. After dialysis for 2-3 days, freeze-dry to obtain nanoparticles loaded with amoxicillin.

Images