CN108272756B - Amoxicillin soluble powder and preparation method thereof - Google Patents
Amoxicillin soluble powder and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to an amoxicillin soluble powder and a preparation method thereof, wherein the soluble powder contains amoxicillin, gelatin hydrolysate with average molecular weight of 1500Da-3000Da, and a diluent, and preferably consists of 10wt% -30wt% of amoxicillin, 20wt% -50wt% of gelatin hydrolysate with average molecular weight of 1500Da-2000Da, and 20wt% -60wt% of sorbitol. The soluble powder can form a uniform solution in water, the solution has high stability, and most importantly, the soluble powder can provide effective drug efficacy for a long time, and the treatment effect is durable and reliable.
Description
Technical Field
The invention relates to the technical field of veterinary medicine preparations, and particularly relates to amoxicillin soluble powder and a preparation method thereof.
Background
Amoxicillin, also known as amoxicillin or amoxicillin, is the most commonly used semisynthetic penicillin broad-spectrum beta-lactam antibiotics, has the characteristics of strong bactericidal action and strong ability of penetrating cell membranes, and can be used for treating gram-positive bacteria and gram-negative bacteria infection sensitive to amoxicillin, such as staphylococcus aureus, colibacillosis, pullorum disease, infectious rhinitis, calf pneumonia, bovine pasteurellosis, mastitis, porcine infectious pleuropneumonia, fowl typhoid, and the like. For animal administration, it is usually prepared into soluble powder, and the powder is dissolved in water for administration via animal drinking process.
However, the amoxicillin soluble powder has the following defects in use:
(1) Amoxicillin is metabolized very rapidly and has short half-life, so the drug effect of the drug is not durable and needs to be repeatedly and continuously administrated.
(2) The addition of amoxicillin soluble powders to water often results in an inhomogeneous turbid solution that may precipitate over time, resulting in an inability to ensure that the animal is administered a therapeutically effective dose.
(3) The amoxicillin has extremely poor stability and is easy to degrade, the effective content is greatly reduced especially under the environment of high temperature, high humidity and the like, and particularly, the aqueous solution of the amoxicillin has quicker failure, so that the curative effect is often difficult to ensure.
The method for solving the defects in the prior art comprises the step of preparing amoxicillin and sustained-release materials into sustained-release preparations to prolong the drug effect, but the sustained-release materials are usually not easy to dissolve in water and have poor water solubility, such as ethyl cellulose, crospovidone and the like, the prepared preparations are still difficult to dissolve in water to form uniform solutions finally, and the sustained-release preparations are difficult to prepare, and some of the sustained-release preparations are too slow to release, thereby affecting the drug effect.
The prior art also has the problems that amoxicillin is prepared into solid dispersion, or ultramicro pulverization technology is utilized, or suspending agents such as glycerol and Arabic gum are added, or stabilizing agents such as sodium hexametaphosphate and citric acid are added, or beta cyclodextrin is used for preparing an inclusion compound, so as to solve the defects, but the methods generally have the problems of complex preparation process, great toxic and side effects and the like.
Therefore, the art still desires to obtain an amoxicillin soluble powder which has powerful and durable drug effect, can form a uniform solution in water, and has better high-temperature and high-humidity resistance and stronger aqueous solution stability.
Disclosure of Invention
The invention aims to provide amoxicillin soluble powder with lasting efficacy, good water solubility and high stability (particularly aqueous solution). The soluble powder is resistant to high temperature and high humidity, can form a uniform solution when added into water at normal temperature, has stable drug content and low degradation rate in 24 hours, can provide long-term effective drug efficacy, and is very convenient to use.
The invention provides an amoxicillin soluble powder, which contains amoxicillin, gelatin hydrolysate with average molecular weight of 1500Da-3000Da, and a diluent.
In one embodiment, the gelatin hydrolysate is obtained by acid hydrolysis of gelatin. In another alternative embodiment, the gelatin hydrolysate is obtained by alkaline hydrolysis.
In a preferred embodiment, the gelatine hydrolysate is obtained by protease hydrolysis.
In one embodiment, the average molecular weight of the gelatine hydrolysate is between 1500Da and 3000Da.
In a preferred embodiment, the average molecular weight of the gelatine hydrolysate is between 1500Da and 2000Da.
In one embodiment, the diluent is selected from one of mannitol, sorbitol and glucose.
In a preferred embodiment, the diluent is sorbitol.
In one embodiment, the gelatin hydrolysate may be commercially available.
In another embodiment, the gelatine hydrolysate may be obtained by self-production, for example by sequential hydrolysis using one to three proteases commonly used, such as serine proteases, cysteine proteases, aspartic proteases, metallo-proteases, aminopeptidases and the like, provided that the gelatine hydrolysate has an average molecular weight of 1500Da to 3000Da for the purposes of the present invention.
In a preferred embodiment, the gelatin hydrolysate can be prepared by the following method:
preparing aqueous solution from raw material gelatin, adjusting the pH value of the aqueous solution of gelatin to 5-7 by using a citric acid and phosphate buffer system, heating to 40-60 ℃, adding trypsin into the aqueous solution of gelatin, stirring, reacting for 2-3 hours, adding bacillus licheniformis into the solution, reacting for 2-3 hours, heating the solution to 90 ℃ to kill enzyme, filtering, concentrating and drying to obtain gelatin hydrolysate.
In one embodiment, the starting gelatin is type a gelatin or type B gelatin. In another alternative embodiment, the starting gelatin is a mixture of type a gelatin and type B gelatin.
In another preferred embodiment, the gelatin hydrolysate can be prepared by the following method:
preparing a raw material gelatin into an aqueous solution, adjusting the pH value of the aqueous solution of the gelatin to 5-7 by using a citric acid and phosphate buffer system, heating to 40-60 ℃, adding trypsin into the aqueous solution of the gelatin, stirring, reacting for 2-3 hours, adding bacillus licheniformis into the solution, reacting for 2-3 hours, adding protease obtained by fermentation of aspergillus niger into the solution, reacting for 1-2 hours, heating the solution to 90 ℃ to kill enzyme, filtering, concentrating and drying to obtain a gelatin hydrolysate.
In a preferred embodiment, the amoxicillin soluble powder has the composition:
10 to 30 weight percent of amoxicillin, 20 to 50 weight percent of gelatin hydrolysate with average molecular weight of 1500Da to 2000Da and 20 to 60 weight percent of sorbitol.
In another preferred embodiment, the amoxicillin soluble powder has the following composition:
30wt% of amoxicillin, 30wt% of gelatin hydrolysate with average molecular weight of 1500Da-2000Da and 40wt% of sorbitol.
The invention also provides a preparation method of amoxicillin soluble powder, and in one embodiment, the preparation method of the soluble powder comprises the following steps: sieving amoxicillin, diluent and gelatin hydrolysate with 80 mesh sieve respectively, mixing, packaging, and packaging.
In a preferred embodiment, the soluble powder is prepared as follows:
(1) Dissolving amoxicillin, gelatin hydrolysate and diluent in water, and stirring uniformly;
(2) And (2) carrying out spray drying on the mixed solution obtained in the step (1), and subpackaging and packaging the obtained powder.
In another more preferred embodiment, the soluble powder is prepared by the following method:
(1) Sieving amoxicillin and diluent with 80 mesh sieve respectively, and mixing well;
(2) Adding the gelatin hydrolysate into water to prepare an aqueous solution, adding into the mixed powder obtained in the step (1), stirring, granulating, drying, grading, subpackaging and packaging.
According to the invention, the amoxicillin is embedded in the gelatin hydrolysate with a specific molecular weight by utilizing a special net structure of the gelatin hydrolysate, so that on one hand, the solubility of the amoxicillin is improved, and the physical and chemical stability of the amoxicillin is improved, and the soluble powder is moisture-resistant and high-temperature-resistant, particularly, the aqueous solution of the soluble powder is uniform and stable, does not generate precipitate, and has a low degradation rate; on the other hand, the medicine can maintain the efficacy for a long time and provide a more durable treatment effect.
Detailed Description
The present invention will be further described with reference to the following examples. In practice, the amounts and proportions of the components of the compositions of the present invention should be limited to the ranges of ingredients set forth above, including but not limited to those set forth in the examples below.
Comparative example 1 soluble powder prepared by micronization technique
| Components | Weight (D) |
| Amoxicillin | 30g |
| Anhydrous sodium carbonate | 5g |
| Sodium dodecyl sulfate | 10g |
| Sodium hexametaphosphate | 5g |
| Sucrose | 50g |
Carrying out ultramicro crushing (the particle size is below 50 um) on amoxicillin, carrying out jet milling on other raw materials, and sieving by using a 300-mesh sieve; and then mixing the crushed sodium hexametaphosphate, the anhydrous sodium carbonate and the sodium dodecyl sulfate, uniformly mixing the mixed powder and the crushed amoxicillin, finally uniformly mixing the mixed powder and the crushed cane sugar, sieving by a 150-mesh sieve, and subpackaging to obtain the amoxicillin-sodium composite material.
Comparative example 2 soluble powder prepared by solid dispersion technique
Mixing amoxicillin and polyethylene glycol 6000, heating, stirring and melting in a tray, taking out after complete melting, cooling rapidly, ultra-low temperature pulverizing the obtained coagulum, sieving with 80 mesh sieve to obtain solid dispersion, mixing with PVPk30 sieved with 80 mesh sieve, dripping Tween 80 during mixing, and stirring uniformly to obtain the final product.
Comparative example 3 preparation of soluble powder with gelatin and Arabic gum
| Components | Weight (D) |
| Amoxicillin | 30g |
| Gelatin | 20g |
| Arabic gum | 20g |
| Disodium hydrogen phosphate | 15g |
| Trehalose | 10g |
| Glycerol | 5g |
Dissolving gelatin and Arabic gum in water, adding amoxicillin, glycerol, trehalose and disodium hydrogen phosphate, and mixing uniformly; spray drying the mixed solution to obtain mixed powder; heating the obtained mixed powder at 90 deg.C for 5 hr, cooling, and packaging.
Comparative example 4 preparation of soluble powder with gelatin hydrolysate having average molecular weight of 6000-9000Da
Respectively sieving amoxicillin and sorbitol by a 80-mesh sieve, and uniformly mixing to obtain mixed powder; adding water into the gelatin hydrolysate to obtain water solution, adding into the mixed powder, stirring, granulating, drying, grading, and packaging.
Comparative example 5 preparation of soluble powder with gelatin hydrolysate having average molecular weight of 3000-6000Da
Prepared according to the method of comparative example 4.
Comparative example 6 preparation of soluble powder with gelatine hydrolysate having average molecular weight of 1000-1500Da
Prepared according to the method of comparative example 4.
EXAMPLE 1 preparation of soluble powders with gelatine hydrolysates with average molecular weights of 1500Da-3000Da
Respectively sieving amoxicillin and sorbitol by a sieve of 80 meshes, and uniformly mixing to obtain mixed powder; adding water into the gelatin hydrolysate to obtain water solution, adding into the mixed powder, stirring, granulating, drying, grading, and packaging.
1. Water solubility test and aqueous solution stability test
Taking 1g of the soluble powder of comparative examples 1-6 and example 1 in terms of amoxicillin, putting the soluble powder in 150ml of water with the temperature of 25 +/-2 ℃, shaking for 2 minutes, standing for 30 minutes, observing the condition of the solution, and simultaneously sampling to determine the content (recorded as 0h content); then each solution is placed at 40 ℃ for 4h, 12h and 24h, the solution condition is observed and recorded, and the solution is sampled to determine the content, and the loss rate is calculated by comparing with the content at 0 hour, and the result is shown in the following table.
Physical stability results in aqueous solutions
| Comparative example | Aqueous solution (0 h) | Aqueous solution (4 h) | Aqueous solution (12 h) | Aqueous solution (24 h) |
| Comparative example 1 | With a small amount of precipitation | With a small amount of precipitation | With a small amount of precipitation | There is a little precipitation |
| Comparative example 2 | No precipitation | No precipitation | Without precipitation | No precipitation |
| Comparative example 3 | Without precipitation | No precipitation | Without precipitation | No precipitation |
| Comparative example 4 | With a small amount of precipitation | With a small amount of precipitation | With a small amount of precipitation | Has obvious precipitation |
| Comparative example 5 | Without precipitation | There is a little precipitation | With a small amount of precipitation | Has obvious precipitation |
| Comparative example 6 | Has obvious precipitation | Has obvious precipitation | Has obvious precipitation | Has obvious precipitation |
| Example 1 | Without precipitation | No precipitation | No precipitation | No precipitation |
The solubility of the amoxicillin is very low, about 1mg of the drug is dissolved in 1ml of water, and as shown in the table, at 0 hour, the solubility of the amoxicillin is greatly improved in comparative examples 1 and 2 by adopting an ultra-micro crushing technology and a solid dispersion technology respectively, but a small amount of undissolved drug still appears in a precipitation form in comparative example 1; comparative example 3 a drug was coated in dispersion with gelatin, gum arabic, etc., which formed a precipitate-free uniform suspension in water; comparative examples 4 to 6 and example 1 used gelatin hydrolysates of different molecular weights having amoxicillin embedded therein by virtue of their specific structure, but only gelatin hydrolysates with an average molecular weight of 1500Da to 3000Da were found to form a precipitate-free homogeneous solution with amoxicillin and the solution maintained good physical stability at elevated temperatures for 24 h. In the process of free drinking water administration of animals, if the formed solution is inhomogeneous and has precipitate, the dosage of animals can be affected, so that the drug effect cannot be exerted effectively in time, and specific animal administration experimental results will be given below for reference.
Chemical stability results of aqueous solutions
From the chemical stability of the aqueous solution, the amoxicillin soluble powder of the comparative examples 1 to 6 loses 7 to 13 percent of content after being prepared into the solution and being placed at high temperature for 12 hours, and the content is increased to 12 to 22 percent after the amoxicillin soluble powder is prepared into the solution, on one hand, the stability of the solution system is poor in the placing process, the amoxicillin is separated out, on the other hand, the drug is degraded at high temperature, and the water soluble powder prepared by adopting the gelatin hydrolysate with specific molecular weight in the example 1 has higher physical and chemical stability and extremely small drug content loss.
2. Accelerated test
The soluble powders of comparative examples 1 to 6 and example 1 were accelerated at 40 ℃ and 75% humidity for 6 months, and then the properties were observed and the content was measured, and the content loss rate was calculated as compared with 0h, and the results are shown in the following table.
Accelerated stability test (6 months) results
| Comparative example | Traits | Content loss rate |
| Comparative example 1 | Yellow lump | 14.1％ |
| Comparative example 2 | Dark yellow agglomerates | 16.3％ |
| Comparative example 3 | Yellow lump | 17.9％ |
| Comparative example 4 | Dark yellow lump | 20.4％ |
| Comparative example 5 | Pale yellow powder | 10.5％ |
| Comparative example 6 | Dark yellow agglomerates | 25.7％ |
| Example 1 | White-like powder | 4.1％ |
As shown in the table, the soluble powder prepared by adopting the superfine grinding technology in the comparative example 1 is easy to absorb moisture and degrade due to the extremely small particle size, large hygroscopicity and large specific surface area of the medicament; the solid dispersion prepared in comparative example 2 has poor system stability at high temperature, and the powder is seriously bonded due to the aging phenomenon that the solid dispersion is easy to appear; comparative example 3 discoloration occurred due to aging denaturation of gelatin in the formulation; comparative examples 4-6 and example 1 show that soluble powders prepared from 1500Da-3000Da gelatin hydrolysate resist high temperature and high humidity, have less drug loss, better stability and are less prone to deterioration during storage.
3. Animal metabolism test
Selecting 30 healthy pigs with the weight of 20-30kg, weighing and recording, controlling water for 2 hours before the test, prohibiting food intake during the test, dividing the pigs into 6 groups, 5 groups in each group, dissolving the soluble powder of the comparative examples 1-5 and the soluble powder of the example 1 in water, filling the pigs with the soluble powder of 10mg amoxicillin per 1kg of body weight, taking blood from the vena cava before filling as a control, taking blood from the vena cava after filling for 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h and 12h, taking 3ml of blood by vein, measuring the amoxicillin content in blood plasma, and taking the average value of the blood concentration of each comparative example at different times as shown in the table below.
As seen from the table above, comparative examples 1-2 reach the highest blood concentration within 45min-1h, and rapidly decrease within 4h, and the drug effect rapidly decreases after 4h, and can be maintained only by re-administration; comparative example 3 in the first 3h, the drug release speed is slow, the blood concentration is maintained at a lower level, and the higher blood concentration is not reached until 12h, but the blood concentration is at the lower level for a long time, which affects the onset time and the drug efficacy of the drug; comparative examples 4 and 5 reach the highest blood concentration within 1 hour after being taken, and rapidly decrease within 4 hours, the drug effect is reduced after 4 hours, and the overall maintenance time of the drug effect is shorter; while the embodiment 1 can reach higher blood concentration within 30min after being taken, and maintain higher blood concentration within 30min-8h until the blood concentration is gradually reduced after 12h, and the highest blood concentration is higher than that of other comparative examples, so that the soluble powder of the embodiment 1 can play the drug effect within 30min after being taken, and the drug effect can be maintained for 8h, the drug stays in the blood for a longer time, the drug efficiency is extremely high, and the drug does not need to be taken again within 8h-12h or even within 16 h.
4. Therapeutic effect on artificially induced colibacillosis
180 healthy chicks of 30 days old are taken and randomly divided into 6 groups of 30 chicks. Each chicken orally and artificially infected with 0.3ml of mixed solution of chicken colibacillus culture solution and parachicken haemophilus culture solution (containing 5 hundred million escherichia coli and 7 hundred million haemophilus paragallinarum), and most of the chickens have obvious clinical symptoms after 48 hours. At this time, the soluble powder of comparative examples 1 to 5 and example 1 was added to water to prepare 50mg/L of drinking water (based on the weight of the soluble powder), and the drinking water was administered in a free-drinking manner, and was newly prepared every 24 hours for 5 days.
After 5 days of continuous administration, the patients were observed for 7-14 days, and the onset and cure of each group were recorded, and the results are shown in the following table.
| Comparative example | Number of tests | The onset of disease | Number of deaths | Effective number of | Number of cure | Cure rate | Effective rate of |
| Comparative example 1 | 30 | 28 | 10 | 14 | 10 | 35％ | 50％ |
| Comparative example 2 | 30 | 27 | 9 | 12 | 7 | 26％ | 44％ |
| Comparative example 3 | 30 | 28 | 14 | 10 | 7 | 25％ | 36％ |
| Comparative example 4 | 30 | 30 | 12 | 15 | 8 | 27％ | 50％ |
| Comparative example 5 | 30 | 26 | 10 | 14 | 10 | 38％ | 54％ |
| Example 1 | 30 | 28 | 0 | 26 | 23 | 82％ | 93％ |
As can be seen from the above table, the curative ratio and the effective rate of example 1 are much higher than those of other comparative examples due to the provision of sustained drug efficacy. The gelatin hydrolysate with a specific molecular weight range is selected, and due to the special structure of the gelatin hydrolysate, amoxicillin can be embedded into the gelatin hydrolysate, so that the soluble powder which forms a uniform and stable solution with water can be prepared, the physical and chemical stability of the aqueous solution can be kept for a long time, the soluble powder is moisture-proof and high-temperature resistant, the long-time drug efficacy can be maintained, and the treatment effect of the drug is greatly exerted.
Example 2 preparation of a gelatine hydrolysate having an average molecular weight of 1500Da to 3000Da
1kg of type A gelatin was added to 2kg of water, heated to 55 ℃ for dissolution, the pH of the aqueous gelatin solution was adjusted to 6.5 with a sodium hydrogen phosphate solution, heated to 60 ℃, 0.1 w/w% trypsin was added to the aqueous gelatin solution and stirred, after 2 hours of reaction, 0.1 w/w% Bacillus licheniformis was added to the solution, after 2 hours of reaction, the solution was heated to 90 ℃ for enzyme deactivation, filtered, concentrated and dried to obtain a gelatin hydrolysate. The average molecular weight was determined to be 2488Da.
Example 3 preparation of a gelatine hydrolysate having an average molecular weight of 1500Da-2000Da
1kg of type B gelatin was added to 2kg of water, heated to 55 ℃ for dissolution, the pH of the aqueous gelatin solution was adjusted to 6.5 with a disodium hydrogen phosphate solution, heated to 60 ℃, 0.1 w/w% trypsin was added to the aqueous gelatin solution and stirred, after 3 hours of reaction, 0.1 w/w% Bacillus licheniformis was added to the solution, after 3 hours of reaction, 0.08 w/w% protease from Aspergillus niger fermentation was added to the solution, after 1.5 hours of reaction, the solution was heated to 90 ℃ for enzyme deactivation, filtered, concentrated and dried to obtain a gelatin hydrolysate. The average molecular weight was determined to be 1623Da.
EXAMPLE 4 preparation of Amoxicillin Water soluble powder
Respectively sieving amoxicillin and glucose with a 80-mesh sieve, and uniformly mixing to obtain mixed powder; adding water into the gelatin hydrolysate to obtain water solution, adding into the mixed powder, stirring, granulating, drying, grading, adding magnesium stearate, and packaging.
EXAMPLE 5 preparation of Amoxicillin Water soluble powder
Respectively sieving amoxicillin and mannitol with a 80-mesh sieve, and uniformly mixing to obtain mixed powder; adding water into the gelatin hydrolysate to obtain water solution, adding into the mixed powder, stirring, granulating, drying, grading, adding pulvis Talci, and packaging.
EXAMPLE 6 preparation of Amoxicillin Water-soluble powder
Respectively sieving amoxicillin and sorbitol by a sieve of 80 meshes, and uniformly mixing to obtain mixed powder; adding the gelatin hydrolysate into water to obtain water solution, adding into the mixed powder, stirring, granulating, drying, grading, and packaging.
EXAMPLE 7 preparation of Amoxicillin Water-soluble powder
Prepared as described in example 6.
EXAMPLE 8 preparation of Amoxicillin Water soluble powder
Prepared as described in example 6.
EXAMPLE 9 preparation of Amoxicillin Water soluble powder
Prepared as described in example 6.
The results of the physical stability of the aqueous solutions and the accelerated test of the soluble powders at high temperature and high humidity (40 ℃, 75%) of examples 4-9 are shown in the following table.
Physical stability results in aqueous solution
| Examples | Aqueous solution (0 h) | Aqueous solution (4 h) | Aqueous solution (12 h) | Aqueous solution (24 h) |
| Example 4 | No precipitation | No precipitation | No precipitation | No precipitation |
| Example 5 | No precipitation | No precipitation | No precipitation | Without precipitation |
| Example 6 | Without precipitation | Without precipitation | Without precipitation | Without precipitation |
| Example 7 | Without precipitation | No precipitation | No precipitation | Without precipitation |
| Example 8 | Without precipitation | No precipitation | No precipitation | No precipitation |
| Example 9 | No precipitation | No precipitation | Without precipitation | No precipitation |
Accelerated stability test (6 month) results
| Examples | Traits | Content loss rate |
| Example 4 | White-like powder | 5.7％ |
| Example 5 | White-like powder | 4.5％ |
| Example 6 | White-like powder | 3.8％ |
| Example 7 | White-like powder | 3.6％ |
| Example 8 | White-like powder | 3.5％ |
| Example 9 | White-like powder | 3.2％ |
Claims (8)
1. An amoxicillin soluble powder, which is characterized in that the soluble powder contains amoxicillin, gelatin hydrolysate with average molecular weight of 1500Da-3000Da, and diluent; the preparation method of the soluble powder comprises the following steps:
(1) Dissolving amoxicillin, gelatin hydrolysate and diluent in water, and uniformly stirring;
(2) Spray drying the mixed solution obtained in the step (1), and subpackaging and packaging the obtained powder;
or the preparation method of the soluble powder comprises the following steps:
(1) Sieving amoxicillin and diluent with 80 mesh sieve respectively, and mixing well;
(2) Adding the gelatin hydrolysate into water to prepare an aqueous solution, adding into the mixed powder obtained in the step (1), stirring, granulating, drying, grading, subpackaging and packaging.
2. Soluble powder of amoxicillin according to claim 1, characterized in that said gelatine hydrolysate is obtained by protease hydrolysis.
3. An amoxicillin soluble powder according to claim 1, characterized in that said diluent is selected from one of mannitol, sorbitol and glucose.
4. An amoxicillin soluble powder according to claim 1, characterized in that the average molecular weight of the gelatine hydrolysate is 1500Da-2000Da.
5. An amoxicillin soluble powder according to claim 1, characterized in that the preparation of said gelatin hydrolysate comprises the following steps:
preparing a raw material gelatin into an aqueous solution, adjusting the pH value of the aqueous solution of the gelatin to 5-7 by using a citric acid and phosphate buffer system, heating to 40-60 ℃, adding trypsin into the aqueous solution of the gelatin, stirring, reacting for 2-3 hours, adding bacillus licheniformis into the solution, reacting for 2-3 hours, heating the solution to 90 ℃ to inactivate enzyme, filtering, concentrating and drying to obtain a gelatin hydrolysate.
6. An amoxicillin soluble powder according to claim 4, characterized in that the preparation of said gelatin hydrolysate comprises the following steps:
preparing a raw material gelatin into an aqueous solution, adjusting the pH value of the aqueous solution of the gelatin to 5-7 by using a citric acid and phosphate buffer system, heating to 40-60 ℃, adding trypsin into the aqueous solution of the gelatin, stirring, reacting for 2-3 hours, adding bacillus licheniformis into the solution, reacting for 2-3 hours, adding protease obtained by fermentation of aspergillus niger into the solution, reacting for 1-2 hours, heating the solution to 90 ℃ to kill enzyme, filtering, concentrating and drying to obtain a gelatin hydrolysate.
7. The amoxicillin soluble powder according to claim 4, characterized in that the composition of said amoxicillin soluble powder is: 10-30 wt% of amoxicillin, 20-50 wt% of gelatin hydrolysate with average molecular weight of 1500-2000 Da and 20-60 wt% of sorbitol.
8. An amoxicillin soluble powder according to claim 4, characterized in that it consists of: 30wt% of amoxicillin, 30wt% of gelatin hydrolysate with average molecular weight of 1500Da-2000Da and 40wt% of sorbitol.
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| US9504656B2 (en) * | 2013-10-21 | 2016-11-29 | Banner Life Sciences, LLC | Pharmaceutical compositions for poorly soluble active ingredients |
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