CN111377947B - Amoxicillin trihydrate pharmaceutical composition with low water activity and preparation method thereof - Google Patents
Amoxicillin trihydrate pharmaceutical composition with low water activity and preparation method thereof Download PDFInfo
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- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
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Abstract
The invention discloses an amoxicillin water activity control method, which comprises the step of controlling the water activity of amoxicillin trihydrate in a jet milling mode to obtain the amoxicillin trihydrate with the water activity value lower than 0.1aw. The pharmaceutical composition comprises the amoxicillin trihydrate and pharmaceutically acceptable auxiliary materials, and the amoxicillin trihydrate is pulverized in an air flow pulverization mode before use to control the water activity value to be lower than 0.1aw. Compared with the prior art, the amoxicillin trihydrate with low water activity obtained by jet milling treatment has the advantages of obviously improved stability, less time consumption of the jet milling method, simple process and low cost.
Description
Technical Field
The invention belongs to the technical field of antibiosis, and particularly relates to an amoxicillin trihydrate pharmaceutical composition with low water activity and a preparation method thereof.
Background
Amoxicillin, its chemical name is: (2S, 5R, 6R) -3,3-dimethyl-6- [ (R) - (-) -2-amino-2- (4-hydroxyphenyl) acetamido group]-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylic acid trihydrate. The molecular formula is: c 16 H 19 N 3 O 5 S·3H 2 O。
The chemical structural formula is as follows:
the amoxicillin is a penicillin antibiotic, and has good antibacterial activity on gram-negative bacteria such as streptococcus pneumoniae and hemolytic streptococcus, gram-positive bacteria such as penicillin-free staphylococcus and enterococcus faecalis, escherichia coli, aerobe-labile bacillus, salmonella, haemophilus influenzae and Neisseria gonorrhoeae, and gram-negative bacteria such as beta-lactamase-free strains and helicobacter pylori. In-vitro antibacterial experiments show that compared with ampicillin, amoxicillin and ampicillin are similar in terms of in-vitro antibacterial action and antibacterial spectrum, amoxicillin has strong penetrating power on bacterial cell walls, and can block the synthesis of the cell walls when acting on the cell walls, so that amoxicillin has stronger and quicker bactericidal action, and particularly has stronger action on enterococcus and salmonella. The beta-amide ring of amoxicillin is used as its basic structure to play the role of antibacterial activity, after oral administration, its lactam group is immediately hydrolyzed into peptide bond, which is quickly combined with transpeptidase in bacteria to inhibit the activity of bacterial mucopeptide synthetase, thus cutting off the only way for bacteria to build cell wall by means of transpeptidase to synthesize glycopeptide, causing the damage or destruction of bacterial cell wall, and promoting bacterial cell to become spherical body and dissolve. The cells of mammals have no cell walls, so that the amoxicillin has less toxicity to human bodies, but can also generate adverse reactions such as nausea, vomiting, diarrhea and the like.
The amoxicillin has been widely used in clinical medicine, and plays a positive role in a plurality of fields. In the specific treatment, the chronic bronchitis, skin and soft tissue infection, nasosinusitis, bronchitis, tonsillitis, pharyngitis, otitis media, pneumonia and the like caused by bacteria such as pneumococcus, hemolytic staphylococcus, penicillinase staphylococcus aureus and the like can be basically and completely cured. Meanwhile, the combination of amoxicillin and gentamicin also has certain efficacy on endocarditis, can treat cold injury caused by typhoid bacillus, and can be used for treating related inflammation of patients who cannot use chloramphenicol due to myelosuppression. However, the daily dosage of many existing amoxicillin preparations is relatively frequent, and the patient compliance is poor, so that an amoxicillin preparation capable of maintaining long-acting bioavailability needs to be prepared.
The prior art discloses various amoxicillin and related preparations thereof, such as improved solutions from the viewpoint of formulation prescription and preparation method:
WO9528927A1 discloses a coating process of amoxicillin and clavulanate potassium tablets. The prescription is as follows: amoxicillin trihydrate 1017.4mg, potassium clavulanate 152.45mg, magnesium stearate 14.5mg, sodium starch glycolate 29mg, colloidal silica 10.0mg, microcrystalline cellulose 226.65mg. After granulation was complete, the coating was applied with purified water and Opadry YS-1-7700. Compared with other patents, the pharmaceutical composition is additionally added with Xu Fuliao, such as diluent microcrystalline cellulose, disintegrant sodium starch glycolate, lubricant magnesium stearate, glidant colloidal silicon dioxide and the like, so that the dosage problem is effectively improved, the daily dosage is reduced from three times to two times, and the patient compliance is effectively improved; in addition, the weight of the granules can be effectively improved, and the tablet dosage of the active ingredients is ensured in the subsequent tabletting and encapsulating processes. In addition, in the patent, researchers have studied different prescriptions prepared by different ratios of amoxicillin and potassium clavulanate, and the antibacterial efficacy of amoxicillin is effectively improved by combining with potassium clavulanate. However, the patent uses too many kinds of auxiliary materials, which may affect the main drug and cause unnecessary side effects. In addition, the preparation process of the preparation with different proportions is complicated, and the workload is greatly increased.
WO9925343A1 discloses a granulation process for potassium clavulanate. Prescription: 100g of potassium clavulanate powder and microcrystalline cellulose
PH112 g and magnesium stearate 1g. The specific feeding time needs special attention, and is firstly used
And mixing the two materials for 10 minutes by using a T2C mixer, adding magnesium stearate when mixing for 2 minutes, continuously mixing, and directly tabletting by using a tabletting machine after uniformly mixing. It is known that beta-lactam antibiotic powders are not suitable for the preparation of tablets or capsules, mainly because the microcrystalline material itself has too poor flowability and too low density to effectively control the tablet amount of the drug during the preparation process of tablets or capsules. Therefore, the problems can be effectively avoided by mixing proper auxiliary materials, thereby reducing the process difficulty. The method reported in the patent has a simple preparation process, and the addition of the auxiliary materials effectively improves the fluidity of the mixture. And the potassium clavulanate prepared by the method has higher particle density, and the size of the tablets can be effectively reduced. It is also noteworthy thatIn the granulation process, the humidity control in the process is very important due to the moisture absorption characteristic of the potassium clavulanate. Therefore, the process used in the patent has higher requirements, and the conditions are difficult to control, so that the internal control in the production process has higher requirements.
EP0975342B1 discloses a process for preparing novel amoxicillin and potassium clavulanate tablets. The specific prescription is as follows: 46.3g of amoxicillin trihydrate, 24.3g of clavulanate potassium, 24.3g of silica gel and 1.38g of crospovidone. For the compound preparation, prescription screening of different proportions increases a large amount of workload for the preparation process, so in order to reduce process complexity and production cost, the patent firstly prepares a large amount of amoxicillin and potassium clavulanate granules respectively for later use, and adds different granules of corresponding amounts according to different proportions in subsequent prescription exploration, thereby greatly shortening the prescription screening period. However, the storage and stability of the active ingredient particles are to be investigated further.
US20030124187A1 discloses an amoxicillin and potassium clavulanate tablet and a preparation process thereof. The prescription is as follows: amoxicillin trihydrate 573.87mg, clavulanate potassium 148.93mg, silica gel 14.98mg, polyvinylpyrrolidone XL 17.21mg, colloidal silicon dioxide 1.7mg and magnesium stearate 3.00mg. Wherein the particle size of amoxicillin is required to be controlled to be 0.7-1.0mm, and the pressure of a rolling machine is required to be controlled to be 50KN. The size problem of tablet has mainly been solved to this patent, reduces the patient and swallows the degree of difficulty. Researchers investigate the prescription of the ratio of amoxicillin to potassium clavulanate from 2:1 to 14, screen out the ratio capable of stably controlling the medicine components, and provide reference for subsequent process exploration. However, the prior preparation work of the technical scheme is long, the raw materials need to be further processed, and the operation is complicated.
Therefore, an ideal pharmaceutical composition of amoxicillin and potassium clavulanate still needs to be found, so as to further obtain a composition preparation with good weight, stability and manufacturing cost superior to those of the prior art.
Disclosure of Invention
The invention aims to provide a method for controlling the water activity of amoxicillin and amoxicillin trihydrate with low water activity prepared by the method.
The second purpose of the invention is to provide a pharmaceutical composition consisting of the amoxicillin trihydrate with low water activity, which has good stability.
The third purpose of the invention is to provide a preparation made of the pharmaceutical composition.
It is a final object of the invention to provide a method for preparing said formulation.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for controlling water activity of amoxicillin, comprising the following steps: and (3) controlling the water activity of the amoxicillin trihydrate by using a jet milling mode to obtain the amoxicillin trihydrate with the water activity value lower than 0.1aw.
The equipment for jet milling is a jet mill, wherein the feeding pressure is 0.1-1.0MPa, preferably 0.2-0.7MPa, and the milling pressure is 0.1-1.0MPa, preferably 0.3-0.6MPa.
The number of jet milling is single or multiple.
The amoxicillin trihydrate prepared by the method for controlling the water activity of amoxicillin.
The pharmaceutical composition consisting of the amoxicillin trihydrate comprises the amoxicillin trihydrate and pharmaceutically acceptable auxiliary materials.
The composition also comprises potassium clavulanate and microcrystalline cellulose.
The weight ratio of the potassium clavulanate to the microcrystalline cellulose is 1:1, and the weight ratio of the crushed amoxicillin trihydrate to the total weight of the potassium clavulanate and the microcrystalline cellulose is (1-20): 1, preferably (1 to 10): 1, more preferably 2:1, 4:1 or 8:1.
The pharmaceutically acceptable auxiliary materials are excipient, filler, disintegrant or lubricant.
Preferably, the pharmaceutically acceptable excipients are microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide and magnesium stearate, and the weight ratio of amoxicillin trihydrate (calculated as amoxicillin) to microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide and magnesium stearate is 1: (0.1-0.3): (0.01-0.2): (0.01-0.2): (0.01-0.2): (0.01 to 0.05), preferably 1: (0.2-0.3): (0.05-0.1): (0.05-0.1): (0.01 to 0.02), more preferably 1.
The preparation prepared from the amoxicillin medicinal composition is a tablet or a dry suspension.
The preparation method of the preparation comprises the following steps: mixing the amoxicillin trihydrate after jet milling with auxiliary materials, adding a disintegrating agent and a lubricant after dry granulation, and tabletting after mixing to obtain the tablets.
The preparation method of the preparation comprises the following steps: mixing the amoxicillin trihydrate after the jet milling with the potassium clavulanate and the microcrystalline cellulose, then mixing with the auxiliary materials, adding the disintegrating agent and the lubricating agent after the dry granulation, mixing and tabletting to obtain the tablet.
Preferably, after the amoxicillin trihydrate, the clavulanate potassium and the microcrystalline cellulose which are subjected to jet milling and other auxiliary materials such as excipient and/or filler are subjected to dry granulation, the disintegrant and the lubricant magnesium stearate are added for mixing, and tabletting is carried out, thus obtaining the tablet.
Such as microcrystalline cellulose PH112.
Preferably, the mixture is dry granulated and tableted, and is coated by Opadry.
The preparation method of the preparation comprises the following steps: mixing the amoxicillin trihydrate after the air current pulverization with auxiliary materials to prepare the dry suspension.
The preparation method of the preparation comprises the following steps: mixing the amoxicillin trihydrate subjected to jet milling with the potassium clavulanate and the microcrystalline cellulose, and then mixing with the auxiliary materials to prepare the dry suspension.
Has the advantages that: compared with the prior art, the amoxicillin with low water activity obtained by adopting the airflow crushing treatment has obviously improved stability compared with the treatment mode of heating and drying. The amoxicillin and clavulanate potassium tablet product prepared by the pharmaceutical composition is more stable by using the air-jet milled amoxicillin trihydrate with low water activity, and the air-jet milling method has the advantages of less time consumption, simple process and low cost.
Detailed Description
The present invention will now be described in detail with reference to examples, which should not be construed as limiting the scope of the invention.
Example 1
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 150g (calculated as amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin with the prescription amount, using a Ma Xim butyl J-40 jet mill (0.5 g-100 g/h), setting the feeding speed at 50%, the feeding pressure at 0.7MPa and the crushing pressure at 0.6MPa, crushing the materials for 1 time, and collecting the crushed amoxicillin.
Water activity before pulverization is 0.174aw, particle size d (0.9) μm =49.365
After pulverization, the water activity is 0.064aw, the particle size d (0.9) mu m =25.657
Example 2
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 150g (calculated as amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin with the prescription amount, setting the feeding speed of a Ma Xim butyl J-40 jet mill (0.5 g-100 g/h) as 50 percent, the feeding pressure as 0.7MPa and the crushing pressure as 0.3MPa, crushing the materials for 2 times, and collecting the crushed amoxicillin.
Water activity before pulverization 0.174aw, particle size d (0.9) μm =49.365
Water activity after pulverization 0.062aw, particle size d (0.9) μm =19.759
Example 3
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 350g (calculated as amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin with the prescription amount, setting the feeding speed of a Ma Xim butyl J-40 jet mill (0.5 g-100 g/h) as 50%, the feeding pressure as 0.2MPa and the crushing pressure as 0.3MPa, crushing the materials for 3 times, and collecting the crushed amoxicillin.
Water activity before pulverization is 0.174aw, particle size d (0.9) μm =48.380
Water activity after pulverization is 0.082aw, particle size d (0.9) mum =24.779
Example 4
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 350g (calculated as amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin with the prescription amount, setting the feeding speed of a Ma Xim butyl J-40 jet mill (0.5 g-100 g/h) as 30 percent, the feeding pressure as 0.2MPa and the crushing pressure as 0.3MPa, crushing the materials for 3 times, and collecting the crushed amoxicillin.
Water activity before pulverization is 0.174aw, particle size d (0.9) μm =44.110
Water activity after pulverization 0.072aw, particle size d (0.9) mum =26.118
Comparative example 1
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 150g (calculated as amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin according to the prescription amount, drying by adopting a vacuum drying oven, drying for 8h at 35 +/-5 ℃, and collecting dried amoxicillin.
Water activity before drying was 0.174aw and after drying was 0.068aw
Comparative example 2
The prescription composition is as follows:
| composition (I) | Feed amount |
| Amoxicillin trihydrate | 150g (based on amoxicillin) |
The preparation process comprises the following steps:
weighing amoxicillin according to the prescription amount, drying by adopting a hot air circulation box, drying for 8h at 40 +/-5 ℃, and collecting dried amoxicillin.
The water activity before drying was 0.174aw and after drying was 0.075aw.
Example 5
High-temperature test:
taking 500g (calculated by amoxicillin) of the treated samples in examples 1 and 2 and comparative examples 1 and 2, mixing with 125g (calculated by clavulanic acid) of potassium clavulanate microcrystalline cellulose (weight ratio 1:1), 105g of microcrystalline cellulose, 42g of sodium carboxymethyl starch, 42g of colloidal silica and 8g of magnesium stearate, performing dry granulation and tabletting, and coating by Opadry. And (3) placing the finished product piece at the temperature of 60 ℃ for 10 days, sampling on the 5 th day and the 10 th day respectively, and inspecting the impurities and the content of the finished product piece.
The results are shown in Table 1:
TABLE 1
The results show that after the samples of the examples are placed at a high temperature of 60 ℃ for 10 days, the reduction of the potassium clavulanate content is less than 5%, which is superior to that of the comparative examples and achieves good stability results.
And (3) accelerated test:
taking the finished product piece (the preparation process is the same as the high temperature test), placing for 6 months under the condition of 40 ℃/75% RH, sampling in the 1 st, 2 nd, 3 rd and 6 th months respectively, and inspecting the impurities and the content of the sample. The results are as follows:
the results show that the samples of the examples of the present invention, after being left for 6 months at 40 ℃/75% RH, showed less than 3% reduction in potassium clavulanate, which is superior to the comparative examples and gives good stability results.
Dissolution test
Taking 6 finished tablets (the preparation process is the same as the high temperature test), taking 900ml of water as a dissolution medium according to a dissolution and release degree measuring method, and sampling, filtering and measuring dissolution curves at the rotating speed of 75 revolutions per minute for 5min, 10 min, 15 min, 30 min, 45 min and 60min respectively.
The result shows that the dissolution results of the samples in the examples of the invention are similar to the dissolution results of the samples in the comparative examples, and the dissolution of amoxicillin is not affected by the reduction of the particle size after the amoxicillin is crushed.
Example 6
The weight ratio of the crushed amoxicillin trihydrate (obtained in example 3) to the total weight of the potassium clavulanate and the microcrystalline cellulose is 2:1, and the dosage and the components of other auxiliary materials are the same as those in example 5, and the amoxicillin trihydrate and the microcrystalline cellulose are prepared into tablets.
The stability results were substantially the same as those of examples 1 and 2, as determined by the above method.
Example 7
The weight ratio of the crushed amoxicillin trihydrate (obtained in example 4) to the total weight of potassium clavulanate and microcrystalline cellulose is 8:1, and the dosage and components of other auxiliary materials are the same as those in example 5, and tablets are prepared.
The stability results were substantially the same as those of examples 1 and 2, as determined by the above method.
Claims (13)
1. The method for controlling the water activity of the amoxicillin is characterized in that the water activity of the amoxicillin trihydrate is controlled in a jet milling mode to obtain the amoxicillin trihydrate with the water activity value lower than 0.1aw, and the jet milling equipment is a jet mill, wherein the feeding pressure is 0.1-1.0MPa, and the milling pressure is 0.1-1.0MPa.
2. The method according to claim 1, wherein the feeding pressure is 0.2 to 0.7MPa and the pulverizing pressure is 0.3 to 0.6MPa.
3. An amoxicillin trihydrate prepared according to the method for the control of amoxicillin water activity described in claim 1 or 2.
4. A pharmaceutical composition comprising amoxicillin trihydrate according to claim 3, characterised in that it comprises amoxicillin trihydrate according to claim 3 and pharmaceutically acceptable excipients.
5. The pharmaceutical composition of claim 4, further comprising potassium clavulanate and microcrystalline cellulose.
6. The pharmaceutical composition according to claim 5, wherein the weight ratio of the potassium clavulanate to the microcrystalline cellulose is 1:1, and the weight ratio of the crushed amoxicillin trihydrate to the total weight of the potassium clavulanate and the microcrystalline cellulose is (1-20): 1.
7. the pharmaceutical composition according to claim 6, wherein the weight ratio of the crushed amoxicillin trihydrate to the total weight of the potassium clavulanate and microcrystalline cellulose is (1-10): 1.
8. the pharmaceutical composition of claim 7, wherein the ratio of the weight of amoxicillin trihydrate after comminution to the total weight of potassium clavulanate and microcrystalline cellulose is 2:1, 4:1 or 8:1.
9. A formulation of amoxicillin pharmaceutical composition according to claim 4, characterized in that it is a tablet or a dry suspension.
10. A method of preparing the formulation of claim 9, comprising the steps of: mixing the amoxicillin trihydrate after jet milling with auxiliary materials, adding a disintegrating agent and a lubricant after dry granulation, and tabletting after mixing to obtain the tablets.
11. A method of preparing the formulation of claim 9, comprising the steps of: mixing the amoxicillin trihydrate after jet milling with potassium clavulanate and microcrystalline cellulose, then mixing with auxiliary materials, adding a disintegrating agent and a lubricant after dry granulation, mixing and tabletting to obtain the tablets.
12. A method of preparing the formulation of claim 9, comprising the steps of: mixing the amoxicillin trihydrate after the air current pulverization with auxiliary materials to prepare the dry suspension.
13. A method of preparing the formulation of claim 9, comprising the steps of: mixing the amoxicillin trihydrate subjected to jet milling with the potassium clavulanate and the microcrystalline cellulose, and then mixing with the auxiliary materials to prepare the dry suspension.
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| CN115671068B (en) * | 2022-11-24 | 2024-03-01 | 浙江巨泰药业有限公司 | Amoxicillin and clavulanate potassium tablet and preparation method thereof |
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| CN103059045A (en) * | 2013-01-29 | 2013-04-24 | 黄明芳 | Novel amoxicillin sodium and clavulanate potassium compound and pharmaceutical composition thereof |
| CN103145733A (en) * | 2013-03-20 | 2013-06-12 | 四川省惠达药业有限公司 | Amoxicillin compound and pharmaceutical composition of amoxicillin compound and potassium clavulanate |
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| CN111377947A (en) | 2020-07-07 |
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