CN110522730B - Amoxicillin soluble powder and preparation method thereof - Google Patents
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Abstract
The invention provides an amoxicillin soluble powder, which comprises the following components in parts by weight: 30-65 wt% of amoxicillin trihydrate, 5-45 wt% of buffering agent, 5-45 wt% of water softener, 1-55 wt% of filler and 0.1-10 wt% of flavoring agent; the buffering agent can stabilize the pH value of the solution after the amoxicillin soluble powder is dissolved within 6.5-8.0. The amoxicillin soluble powder has the advantages of good water solubility, good stability in water and gastric acid, good palatability and no loss of curative effect during treatment, facilitates the requirement of intensive culture, and provides convenience and quality guarantee for clinical medication of animals.
Description
Technical Field
The invention belongs to the field of veterinary medicines, and particularly relates to amoxicillin soluble powder and a preparation method thereof.
Background
Amoxicillin (Amoxicillin), a broad-spectrum beta-lactam antibiotic of the most commonly used semisynthetic penicillins, was developed and developed by the company becham (becham) in the uk in 1968. Has strong bactericidal action, broad antibacterial spectrum and strong inhibition and killing action on most pathogenic gram-positive bacteria and gram-negative bacteria. As an antibiotic commonly used by human and animals, amoxicillin is quickly absorbed by oral administration, and has better prevention and treatment effects on upper respiratory tract infection, urinary system infection, intestinal infection and the like.
The amoxicillin preparation is available in the forms of capsule, tablet, granule, dispersible tablet, etc., and is mainly soluble powder in veterinary drug, which is convenient for transportation and administration. Standard amoxicillin has very limited maximum solubility (2g/L) and is also susceptible to water ions (Ca) during use2+、Mg2+Etc.) to form a precipitate. In addition, as the molecular structure of amoxicillin has a beta-lactam ring, the amoxicillin has extremely unstable chemical properties and is easy to degrade under acid or alkali conditions to form inactive molecules. The solubility and chemical stability of amoxicillin in water are contradictory: the amoxicillin has increased solubility in alkaline environment, but has poor stability.
In veterinary clinic, amoxicillin soluble powder is taken as drinking water, so that the requirements on the water solubility and the stability of the product are high in order to ensure the quality of the medicine; in addition, intensive cultivation is mostly carried out in the process of concentrated preparation → dilution → drinking, and aiming at the characteristic, the amoxicillin soluble powder product with high content specification, high solubility and good stability is a great demand in reality.
The amoxicillin soluble powder in the ' pharmacopoeia of the people's republic of China ' 2015 is a preparation formed by mixing amoxicillin and anhydrous glucose, and the soluble powder prepared by the method has poor water solubility and does not meet the requirement of intensive culture. CN201510298759.7 is prepared by changing the particle size of raw and auxiliary materials and adding an organic acid, a stabilizer and a cosolvent, and the method can improve the stability of amoxicillin to a certain extent but has biased solubility. In addition, in some prior arts, the water solubility and stability of amoxicillin are improved by adding polyethylene glycol, changing the particle size, and performing simple physical mixing (such as CN201010582327.6 and CN201710590905.2) or preparing solid dispersion (such as CN201510715068.2) or micelle wrappage (such as CN201510357400.2) and the like, which improve the water solubility of amoxicillin to some extent, but the effect is not ideal. And other stabilizers such as gelatin hydrolysate have complicated preparation method, improve the stability of amoxicillin to a certain extent, but have poor water solubility.
Disclosure of Invention
In order to overcome the defects of the prior art, through deep research on the self characteristics (low solubility and poor stability) of amoxicillin, a targeted measure is made from a prescription and a process, so that the water solubility and the stability of amoxicillin are improved, and the amoxicillin soluble powder provided by the invention meets the typical standard of veterinary drugs and the clinical medication requirements.
The invention provides amoxicillin soluble powder, which comprises the following components in parts by weight: 30-65 wt% of amoxicillin trihydrate, 5-45 wt% of buffering agent, 5-45 wt% of water softener, 1-55 wt% of filler and 0.1-10 wt% of flavoring agent; the buffering agent can stabilize the pH value of the solution after the amoxicillin soluble powder is dissolved within 6.5-8.0.
The amoxicillin soluble powder has high content specification, high solubility and good stability; has good indexes in both water solubility and stability, good stability in gastric acid, improved bioavailability, good storage stability, and long-term storage stability.
The amoxicillin trihydrate content may be selected from 30 wt%, 35wt%, 40wt%, 45 wt%, 50wt%, 55 wt%, 55.5 wt%, 56 wt%, 56.5 wt%, 57 wt%, 57.5 wt%, 58 wt%, 58.5 wt%, 59 wt%, 59.5 wt%, 60 wt%, 65 wt%.
The buffer content may be selected from 5wt%, 6 wt%, 7 wt%, 8wt%, 9 wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30 wt%, 35wt%, 40wt%, 45 wt%.
The water softener content may be selected from 5wt%, 6 wt%, 7 wt%, 8wt%, 9 wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30 wt%, 35wt%, 40wt%, 45 wt%.
The filler content may be selected from 1 wt%, 2wt%, 3 wt%, 4 wt%, 5wt%, 6 wt%, 7 wt%, 8wt%, 9 wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30 wt%, 35wt%, 40wt%, 45 wt%, 50wt%, 55 wt%.
The amount of flavoring agent can be selected from 0.1 wt%, 0.2wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt%, 5.0 wt%, 6.0 wt%, 7.0 wt%, 8.0 wt%, 9.0 wt%, 10 wt%.
In one embodiment of the invention, the amoxicillin soluble powder of the invention comprises a buffer selected from one or more of a phosphate buffer, a carbonate buffer, a citrate buffer and a borate buffer; the water softener is sodium metaphosphate at least comprising one of sodium hexametaphosphate and sodium polyphosphate; the filler is selected from one or more of polyethylene glycol 6000, beta-cyclodextrin, glucose and sucrose; the flavoring agent is vanillin.
The amoxicillin soluble powder has high solubility, the maximum solubility (calculated by amoxicillin trihydrate) in normal temperature water can reach 10mg/ml, which is more than 5 times of that of the traditional imitation pharmacy or bulk drug, and the amoxicillin soluble powder can be used in various drinking water systems, including a drug feeding pump; the stability is good, no precipitate exists in the drinking water treatment period (24 hours), the pipeline is not blocked, the reaction with acid, alkali, ions and the like in water is avoided, the device is suitable for different water qualities, no curative effect loss exists in pipeline transportation, and the requirement of intensive culture is met; the product is stable in gastric acid within 2 h; the palatability is good, and sufficient drinking water can be ensured during the treatment period; the storage is stable, and the finished product meets the quality standard after being stored for 6 months under the accelerated condition. As an embodiment of the present invention, the amoxicillin soluble powder of the present invention comprises: 35-57.5 wt% of amoxicillin trihydrate, 5-40 wt% of buffering agent, 5-40 wt% of water softener, 1-50 wt% of filler and 0.1-5 wt% of flavoring agent; the buffering agent can stabilize the pH value of the solution after the amoxicillin soluble powder is dissolved within 7.5-8.0.
As a preferred embodiment of the present invention, the amoxicillin soluble powder of the present invention comprises: 35wt% of amoxicillin trihydrate, 15wt% of anhydrous sodium dihydrogen phosphate, 35wt% of sodium polyphosphate, 600014.8 wt% of polyethylene glycol and 0.2wt% of vanillin.
As an embodiment of the present invention, the amoxicillin soluble powder of the present invention comprises: 35wt% of amoxicillin trihydrate, 10wt% of anhydrous sodium carbonate, 10wt% of anhydrous sodium dihydrogen phosphate, 25wt% of sodium hexametaphosphate, 19.8wt% of anhydrous glucose and 0.2wt% of vanillin.
As an embodiment of the present invention, the amoxicillin soluble powder of the present invention comprises: 50wt% of amoxicillin trihydrate, 15wt% of anhydrous sodium carbonate, 5wt% of anhydrous sodium dihydrogen phosphate, 20wt% of sodium hexametaphosphate, 9.8wt% of anhydrous glucose and 0.2wt% of vanillin.
As an embodiment of the present invention, the amoxicillin soluble powder of the present invention comprises: 50wt% of amoxicillin trihydrate, 5wt% of anhydrous disodium hydrogen phosphate, 40wt% of sodium polyphosphate, 60004.8 wt% of polyethylene glycol and 0.2wt% of vanillin.
The invention also provides a method for preparing the amoxicillin soluble powder, wherein the method comprises the following steps: step (1), respectively crushing and sieving amoxicillin trihydrate, a buffering agent, a water softener, a filling agent and a flavoring agent, wherein the mesh number of a screen is 100-120 meshes; mixing the amoxicillin trihydrate crushed and sieved in the step (1) with a buffering agent and a water softener for 30-60 min, adding a filling agent and a flavoring agent, and mixing for 30-60 min; and (4) mixing the materials to obtain the amoxicillin soluble powder.
The preparation method has simple and convenient operation of the technical process and strong operability, and is suitable for industrial production. The pH value of the amoxicillin soluble powder prepared by the preparation method is determined according to the pH value of an appendix 0631 of the 2015 edition of Chinese veterinary pharmacopoeia, and the pH value of the solution ranges from 7.5 to 8.0.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The chemical reagents used in the examples of the present invention are all analytical reagents and purchased from the national pharmaceutical group. The experimental methods are conventional methods unless specified otherwise; the biomaterial is commercially available unless otherwise specified.
The effects of the present invention will be described below with reference to examples.
Preparation example 1 composition and preparation of an embodiment of the Amoxicillin soluble powder of the invention
The composition of amoxicillin soluble powder in this example is shown in table 1:
TABLE 1A composition of the Amoxicillin soluble powder of the invention
| Composition (I) | Content (wt.) |
| Amoxicillin trihydrate | 35g |
| Anhydrous sodium dihydrogen phosphate | 15g |
| Sodium polyphosphate | 35g |
| Polyethylene glycol 6000 | 14.8g |
| Vanillin | 0.2g |
The preparation method comprises the following steps:
(1) the amoxicillin trihydrate, the anhydrous sodium dihydrogen phosphate, the sodium polyphosphate, the polyethylene glycol and the vanillin are respectively crushed and sieved, and the mesh number of the mesh is 100.
(2) Mixing the pulverized and sieved amoxicillin trihydrate with anhydrous sodium dihydrogen phosphate and sodium polyphosphate for 35min, adding polyethylene glycol 6000 and vanillin, continuously mixing for 35min, and mixing uniformly for later use.
(3) And (3) subpackaging the uniformly mixed materials, and checking to obtain the finished product of the amoxicillin soluble powder.
Preparation example 2 composition and preparation of another embodiment of amoxicillin soluble powder of the present invention
The composition of amoxicillin soluble powder in this example is shown in table 2:
table 2 another composition of amoxicillin soluble powders of the present invention
| Composition (I) | Content (wt.) |
| Amoxicillin trihydrate | 35g |
| Anhydrous sodium carbonate | 10g |
| Anhydrous sodium dihydrogen phosphate | 10g |
| Sodium hexametaphosphate | 25g |
| Anhydrous glucose | 19.8g |
| Vanillin | 0.2g |
The preparation method comprises the following steps:
(1) pulverizing amoxicillin trihydrate, anhydrous sodium carbonate, anhydrous sodium dihydrogen phosphate, sodium hexametaphosphate, anhydrous glucose, and vanillin respectively, and sieving with 100 mesh sieve
(2) Mixing the pulverized and sieved amoxicillin trihydrate with anhydrous sodium carbonate, anhydrous sodium dihydrogen phosphate and sodium hexametaphosphate for 35min, adding polyethylene glycol 6000 and vanillin, continuously mixing for 35min, and mixing well for use.
(3) And (3) subpackaging the uniformly mixed materials, and checking to obtain the finished product of the amoxicillin soluble powder.
Preparation example 3 composition and preparation of another embodiment of amoxicillin soluble powder of the present invention
The composition of amoxicillin soluble powder in this example is shown in table 3:
table 3 another composition of amoxicillin soluble powder of the present invention
| Composition (I) | Content (wt.) |
| Amoxicillin trihydrate | 50g |
| Anhydrous sodium carbonate | 15g |
| Anhydrous sodium dihydrogen phosphate | 5g |
| Sodium hexametaphosphate | 20g |
| Anhydrous glucose | 9.8g |
| Vanillin | 0.2g |
The preparation method comprises the following steps:
(1) respectively pulverizing amoxicillin trihydrate, anhydrous sodium carbonate, anhydrous sodium dihydrogen phosphate, sodium hexametaphosphate, anhydrous glucose and vanillin, and sieving with 100 mesh sieve.
(2) Mixing the pulverized and sieved amoxicillin trihydrate with anhydrous sodium carbonate, anhydrous sodium dihydrogen phosphate and sodium hexametaphosphate for 35min, adding anhydrous glucose and vanillin, continuously mixing for 35min, and mixing well for later use.
(3) And (3) subpackaging the uniformly mixed materials, and checking to obtain the finished product of the amoxicillin soluble powder.
Preparation example 4 composition and preparation of an embodiment of the Amoxicillin soluble powder of the invention
The composition of amoxicillin soluble powder in this example is shown in table 4:
table 4 another composition of amoxicillin soluble powders of the present invention
| Composition (I) | Content (wt.) |
| Amoxicillin trihydrate | 50g |
| Anhydrous disodium hydrogen phosphate | 5g |
| Sodium polyphosphate | 40g |
| Polyethylene glycol 6000 | 4.8g |
| Vanillin | 0.2g |
The preparation method comprises the following steps:
(1) the amoxicillin trihydrate, the anhydrous sodium dihydrogen phosphate, the sodium polyphosphate, the polyethylene glycol and the vanillin are respectively crushed and sieved, and the mesh number of the mesh is 100.
(2) Mixing the pulverized and sieved amoxicillin trihydrate with anhydrous sodium dihydrogen phosphate and sodium polyphosphate for 35min, adding polyethylene glycol 6000 and vanillin, continuously mixing for 35min, and mixing uniformly for later use.
(3) And (3) subpackaging the uniformly mixed materials, and checking to obtain the finished product of the amoxicillin soluble powder.
Comparative example 1
The prescription composition comprises 35g of amoxicillin trihydrate and 75g of anhydrous glucose.
The preparation method comprises the following steps: the amoxicillin trihydrate and the anhydrous glucose are respectively crushed and sieved, the mesh number of the screen is 100 meshes, and the crushed and sieved amoxicillin trihydrate and the anhydrous glucose are mixed for 35 min.
Comparative example 2
The prescription comprises 80g of amoxicillin trihydrate, 600015 g of polyethylene glycol and 5g of beta-cyclodextrin.
The preparation method comprises the following steps: respectively pulverizing and sieving amoxicillin trihydrate, polyethylene glycol and betacyclodextrin with a mesh number of 100 meshes, mixing the pulverized and sieved amoxicillin trihydrate, polyethylene glycol and betacyclodextrin for 35 min.
Example 5 preparation of Amoxicillin soluble powder prepared in examples 1-4 and comparative solubility and stability testing tests
In order to verify the advantages of the amoxicillin soluble powder prepared by the invention, especially the solubility in water at normal temperature, the stability in tap water and gastric acid solution and the stability in the storage process, the following samples are selected for comparison tests, which comprise: the samples prepared in examples 1 to 4, amoxicillin starting material, and the samples prepared in comparative examples 1 and 2 were prepared.
5.1 solubility test
Experimental methods and conditions: weighing a proper amount of test sample powder, placing the test sample powder into 200ml of aqueous solution at the temperature of 25 +/-2 ℃, shaking for 30s every 5min, observing the dissolution condition after 15min, and if no precipitate exists, continuing to add the test sample until the precipitate exists, and taking the final completely dissolved amount as the maximum solubility so as to calculate the apparent solubility of each sample. The results are shown in Table 5.
Table 5 solubility test results
| Sample (I) | Solubility g/L | pH |
| Example 1 sample (35% amoxicillin trihydrate) | 30 | 7.8 |
| Example 2 sample (35% amoxicillin trihydrate) | 35 | 8.0 |
| Example 3 sample (containing 50% amoxicillin trihydrate) | 25 | 8.0 |
| Example 4 sample (containing 50% amoxicillin trihydrate) | 20 | 7.9 |
| Amoxicillin trihydrate raw material | 1.4 | 6.0 |
| Comparative example 1 sample (35% amoxicillin trihydrate) | 6.0 | 7.5 |
| Comparative example, 2 sample (containing 80% amoxicillin trihydrate) | 1.3 | 6.9 |
As can be seen from Table 5, the solubility of the samples prepared in preparation examples 1 to 4 was greatly improved as compared with the amoxicillin starting material and the samples prepared in comparative examples 1 and 2.
5.2 aqueous solution stability
Experimental methods and conditions: based on the solubility measurement results in Table 5, the sample is selected to have the highest solubility, precisely weighed, dissolved in 500ml of tap water, shaken up, placed in a 25 +/-2 ℃ water bath, sampled for 3h, 6h, 9h, 12h and 24h, the content is measured according to the method for measuring the content of amoxicillin soluble powder in the first part of the pharmacopoeia of Chinese animal pharmacopoeia 2015, and compared with the content of amoxicillin in the first part of the pharmacopoeia of China, and the degradation rate is calculated. Synchronously, weighing a certain amount of test sample powder, and preparing a solution with amoxicillin concentration of 0.5g/L (2.5 times of clinical dosage) by using tap water for water stability determination. The experimental results are shown in tables 6 to 7.
TABLE 6 degradation in water at maximum solubility of the samples (compare with 0h content)
TABLE 7 degradation in water (vs. Amoxicillin 0.5 g/L) at low concentrations for each sample
0h content comparison)
As can be seen from tables 6 to 7, the samples prepared in preparation examples 1 to 4 had much improved stability in water compared to the amoxicillin raw material and the samples prepared in comparative examples 1 and 2, and could satisfy the process of concentration → dilution → drinking in intensive cultivation, with stability within 6h at maximum solubility and stability within 24h at low concentration.
5.3 gastric acid solution stability
Stability in gastric acid solution mainly considers the content of different amoxicillin soluble powders in artificial gastric acid (0.1mol/L hydrochloric acid solution) for 2 hours.
Experimental methods and conditions: weighing a certain amount of test sample powder, preparing a solution with amoxicillin concentration of 0.5g/L (2.5 times of clinical dosage) by using 0.1mol/L hydrochloric acid solution, placing the solution in a water bath kettle at 37 +/-2 ℃, sampling for 0.5h, 1h and 2h respectively, measuring the content according to a method for measuring the content of amoxicillin soluble powder in the first part of the 2015 edition of Chinese veterinary pharmacopoeia, comparing the content with the configured content of 0h, and calculating the degradation rate. The results of the experiment are shown in Table 8.
TABLE 8 degradation in gastric acid (vs. 0 h) at low concentration (measured as amoxicillin at 0.5 g/L) for each sample
As can be seen from table 8, the stability in gastric acid solution of the samples prepared in preparation examples 1 to 4 is greatly improved compared to that of amoxicillin raw material and the samples prepared in comparative examples 1 and 2, and the in vivo bioavailability can be improved to a certain extent.
5.5 storage stability
Experimental methods and conditions: in order to predict the stability of each sample in the storage process, the samples are packaged by aluminum foil bags, an accelerated stability test is carried out according to relevant regulations of 'Chinese veterinary pharmacopoeia' 2015 edition, and the content reduction degree of 1, 2, 3 and 6 months accelerated is examined under the conditions of 40 +/-2 ℃/75 +/-5% RH. The results are shown in Table 9.
TABLE 9 degradation of the samples under accelerated conditions
As can be seen from table 9, amoxicillin raw material is more stable in the presence of solid, and the stability under accelerated conditions of preparation examples 1-4 is better than that of samples prepared in comparative examples 1 and 2, and the content still meets the quality standard.
The five comparative experiment results show that the amoxicillin soluble powder prepared by the invention has the advantages of good water solubility, good stability in water and gastric acid, and no loss of curative effect during treatment, facilitates the requirement of intensive culture, and provides convenience and quality guarantee for clinical medication of animals.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (2)
1. An amoxicillin soluble powder, wherein the amoxicillin soluble powder comprises: amoxicillin trihydrate, a buffering agent, sodium hexametaphosphate or sodium polyphosphate as a water softener, polyethylene glycol 6000 as a filling agent or anhydrous glucose and vanillin as a flavoring agent; the buffering agent is anhydrous sodium dihydrogen phosphate, anhydrous sodium carbonate or anhydrous disodium hydrogen phosphate, and can stabilize the pH value of the solution after the amoxicillin soluble powder is dissolved within 6.5-8.0;
the amoxicillin soluble powder comprises: 35wt% of amoxicillin trihydrate, 15wt% of anhydrous sodium dihydrogen phosphate, 35wt% of sodium polyphosphate, 600014.8 wt% of polyethylene glycol and 0.2wt% of vanillin; or
The amoxicillin soluble powder comprises: 35wt% of amoxicillin trihydrate, 10wt% of anhydrous sodium carbonate, 10wt% of anhydrous sodium dihydrogen phosphate, 25wt% of sodium hexametaphosphate, 19.8wt% of anhydrous glucose and 0.2wt% of vanillin; or
The amoxicillin soluble powder comprises: 50wt% of amoxicillin trihydrate, 15wt% of anhydrous sodium carbonate, 5wt% of anhydrous sodium dihydrogen phosphate, 20wt% of sodium hexametaphosphate, 9.8wt% of anhydrous glucose and 0.2wt% of vanillin; or
The amoxicillin soluble powder comprises: 50wt% of amoxicillin trihydrate, 5wt% of anhydrous disodium hydrogen phosphate, 40wt% of sodium polyphosphate, 60004.8 wt% of polyethylene glycol and 0.2wt% of vanillin.
2. A process for preparing an amoxicillin soluble powder as claimed in claim 1, wherein the process comprises the steps of:
step (1), respectively crushing and sieving amoxicillin trihydrate, a buffering agent, a water softener, a filling agent and a flavoring agent, wherein the mesh number of a screen is 100-120 meshes;
mixing the amoxicillin trihydrate crushed and sieved in the step (1) with a buffering agent and a water softener for 30-60 min, adding a filling agent and a flavoring agent, and mixing for 30-60 min; and (4) mixing the materials to obtain the amoxicillin soluble powder.
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| EP1602361A2 (en) * | 2004-06-01 | 2005-12-07 | Vaccifar BV | Antibiotic in the form of a water-soluble powder for veterinary and human use |
| CN106176617A (en) * | 2016-08-31 | 2016-12-07 | 中牧南京动物药业有限公司 | Amoxicillin soluble powder and preparation method thereof |
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| SI20411A (en) * | 1999-12-22 | 2001-06-30 | LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. | Watersoluble powders for peroral solution and their use |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1602361A2 (en) * | 2004-06-01 | 2005-12-07 | Vaccifar BV | Antibiotic in the form of a water-soluble powder for veterinary and human use |
| CN106176617A (en) * | 2016-08-31 | 2016-12-07 | 中牧南京动物药业有限公司 | Amoxicillin soluble powder and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| THE STABILITY OF AMOXICILLIN TRIHYDRATE AND POTASSIUM CLAVULANATE COMBINATION IN AQUEOUS SOLUTIONS;Akos JERZSELE等;《Acta Veterinaria Hungarica》;20091231;第57卷(第4期);第485-493页 * |
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