CN113694036A - Amphotericin B vaginal effervescent tablet and preparation method thereof - Google Patents
Amphotericin B vaginal effervescent tablet and preparation method thereof Download PDFInfo
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Abstract
The invention provides an amphotericin B vaginal effervescent tablet and a preparation method thereof, wherein the amphotericin B vaginal effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 2500 parts of acid granules 1500-; wherein the weight ratio of the acid particles to the alkali particles is 1: 1-1.5. The acid-base particles are prepared by adopting a fluidized drying granulation method. The prescription, the process and the storage method of the amphotericin B vaginal effervescent tablet are optimized, so that the quality stability of the amphotericin B vaginal effervescent tablet is greatly improved, the amphotericin B vaginal effervescent tablet is beneficial to industrial production, the production efficiency is improved, the exertion of the drug effect is ensured, and the safety of clinical medication is improved.
Description
Technical Field
The invention relates to the technical field of effervescent tablet preparation, in particular to an amphotericin B vaginal effervescent tablet and a preparation method thereof.
Background
Amphotericin is a polyene antibiotic produced by Streptomyces nodosus (Streptomyces nodosus) M4575. Amphotericin contains A, B components, component A has low toxicity and weak antifungal effect, and is not used clinically, and component B has strong effect, and is called amphotericin B. Amphotericin B belongs to polyene antibiotics, is one of invasive mycosis preventing and treating medicines with the strongest action and the widest antibacterial spectrum, is also a first-choice medicine for treating a plurality of serious deep fungal infections, and has wide market application prospect. Mycotic vaginitis is vaginal inflammation caused by candida albicans, and the candida is also called candida and is the most common conditional pathogenic bacterium in fungi. Candida albicans has very high sensitivity to amphotericin B, and therefore amphotericin B can effectively treat mycotic vaginitis. The amphotericin B vaginal effervescent tablet is an external antifungal product, is used for treating vaginal inflammation caused by fungi through local administration, has the characteristics of quick response, complete absorption, no damage to mucosa, less systemic side effect and the like, has high market potential, but needs to be cultivated and guided in the market due to the problems of application and higher cost of a new formulation.
The amphotericin B molecule is formed by connecting a macrolide containing 7 pairs of conjugated double bonds and deoxyhexosamine of trehalose by glycosidic bonds, and has an amino group, a carboxyl group and an ester bond in the structure, so the amphotericin B molecule is very unstable, has hygroscopicity and is easy to damage by light, heat and acid. The existing amphotericin B vaginal effervescent tablet is extremely unstable and has the following technical problems: 1. the preparation process has strict requirements on production environment, the production batch is limited, and the mass production cannot be realized; 2. the effervescent tablet can effervesce when meeting water and lose efficacy, and the production process is easy to absorb moisture and adhere, so harsh environment temperature and humidity are required; 3. the problems of appearance expansion, content reduction and the like appear in the effective period. The product is an aluminum-plastic-aluminum package, is a luxury version in the package, has high cost, even if the product is packaged, the quality problem is still worried, the stability is remained, the content is obviously reduced, and in addition, the problem of customer complaints caused by board expansion sometimes occurs. A series of problems seriously restrict the production and the use of the variety and must be researched and solved.
Disclosure of Invention
The invention aims to provide an amphotericin B vaginal effervescent tablet and a preparation method thereof, and aims to solve the problems of poor stability, high production process requirement, easiness in plate expansion during storage, content reduction and the like in the prior art.
The technical scheme of the invention is as follows: an amphotericin B vaginal effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 2500 parts of acid granules 1500-; wherein the weight ratio of the acid particles to the alkali particles is 1: 1-1.5.
The acid particles comprise the following components in parts by weight: 780 parts of citric acid 580-containing organic solvent, 1400 parts of mannitol 500-containing organic solvent, 900 parts of pregelatinized starch 500-containing organic solvent and 3030-50 parts of polyvidone K.
The alkali particles comprise the following components in parts by weight: 1000 parts of sodium bicarbonate 500-.
A preparation method of amphotericin B vaginal effervescent tablets comprises the following steps:
(1) preparing acid particles: weighing the raw materials according to the component proportion of the acid particles, wherein the acid particles comprise the following components in parts by weight: 780 parts of citric acid 580-containing organic solvent, 1400 parts of mannitol 500-containing organic solvent, 900 parts of pregelatinized starch 500-containing organic solvent and 3030-50 parts of polyvidone K; dissolving polyvidone K30 in anhydrous ethanol to obtain polyvidone K30 solution, adding citric acid, mannitol and pregelatinized starch into boiling granulator, mixing for 5-15min, spraying polyvidone K30 solution for granulation, and controlling air flow rate to 2000-3000m3H, atomizing pressure of 1.2-2.0bar, liquid inlet speed of 0.8-1.2kg/min, keeping material temperature at 38-45 ℃, completing granulation when the passing rate of 40-mesh sieving of the material is less than or equal to 85%, and continuously carrying out fluidized drying at 45-50 ℃ until the water content of final granules is less than or equal to 2%;
(2) preparing alkali particles: weighing the raw materials according to the component proportion of the alkali particles, wherein the alkali particles comprise the following components in parts by weight: 1000 parts of sodium bicarbonate 500-; dissolving polyvidone K30 in anhydrous ethanol to obtain polyvidone K30 solution, adding sodium bicarbonate and mannitol into boiling granulator, mixing for 5-15min, spraying polyvidone K30 solution for granulation, and controlling air volume at 2000-3000m3H, atomizing pressure of 1.2-2.0bar, liquid inlet speed of 0.8-1.2kg/min, keeping material temperature at 38-45 ℃, completing granulation when the passing rate of 40-mesh sieving of the material is less than or equal to 85%, and continuously carrying out fluidized drying at 45-50 ℃ until the water content of final granules is less than or equal to 2%;
(3) preparing an effervescent tablet: weighing the raw materials according to the component proportion of the effervescent tablet, wherein the effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 2500 parts of acid granules 1500-; the weight ratio of the acid particles to the alkali particles is 1: 1-1.5; adding the alkali granules and the amphotericin B into a hopper, mixing for 5-15min, adding the acid granules, the sodium carboxymethyl starch, the silicon dioxide and the magnesium stearate, continuously mixing for 10-30min, tabletting and packaging to obtain the finished effervescent tablet.
In the steps (1) and (2), the mass concentration of the povidone K30 solution is 8.0-10.0%.
In the step (3), during tabletting, the main pressing is 8-15KN, the thickness of the main pressing is 1.5-2.5mm, the pre-pressing thickness is 2.0-3.0mm, the thickness of the tablet is more than 5mm, the rotating speed is 50000 and 80000 tablets per hour, and the tabletting process is controlled to be completed within 12 hours.
The obtained effervescent tablet is stored at 2-10 deg.C.
The prescription, the process and the storage method of the amphotericin B vaginal effervescent tablet are optimized, so that the quality stability of the amphotericin B vaginal effervescent tablet is greatly improved, the amphotericin B vaginal effervescent tablet is beneficial to industrial production, the production efficiency is improved, the exertion of the drug effect is ensured, and the safety of clinical medication is improved.
According to the invention, the mannitol is used, so that the hygroscopicity of the mannitol is effectively improved, meanwhile, the acid-base granulation process is improved, the fluidized drying granulation mode is adopted, the 40-mesh passing rate of the end-point material is controlled to be less than or equal to 85%, the end-point moisture is strictly controlled, the moisture absorption problem in the production process is solved, and the stability of the production process is further ensured. The invention also optimizes the total mixing process, the main drug and the alkaline granules are mixed firstly and then mixed with other auxiliary materials, and the weight ratio of the acid granules to the alkaline granules is controlled to be 1:1-1.5, so that the acid-base balance degree of the final product is good, and the adverse effect on the effective components is avoided. The tabletting process control parameters are as follows: the main pressure is 8-15KN, the main pressure thickness is 1.5-2.5mm, the pre-pressing thickness is 2.0-3.0mm, the slice thickness is more than 5mm, and the rotating speed is 50000 and 80000 slices/hour. The process control is finished within 12 hours, and the packaged finished product is stored at 2-10 ℃, so that the stability of the product within the expiration date is ensured to the maximum extent, the quality and the safety of the product are improved, and the mass production is realized.
Detailed Description
The present invention is further illustrated by the following examples in which the procedures and methods not described in detail are conventional and well known in the art, and the starting materials or reagents used in the examples are commercially available, unless otherwise specified, and are commercially available.
Comparative example 1 (made into 1 ten thousand tablets)
Acid particle prescription:
| citric acid | 680g |
| Microcrystalline cellulose | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Microcrystalline cellulose | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
the preparation process comprises the following steps:
preparing alkali particles: adding the auxiliary materials into a wet granulation machine, starting stirring at a rotating speed of 100r/min, mixing for 10min, then starting cutting at a rotating speed of 1500r/min while starting stirring, simultaneously adding 10.0% of K30 absolute ethanol solution for granulation, and observing the preparation condition of granules at any time. Drying in an oven at 80 ℃ after granulation is finished until the water content of the final granules is less than or equal to 2%, and sieving by a 1.2mm sieve for granulation.
Preparing acid particles: adding the auxiliary materials into a wet granulation machine, starting stirring at a rotating speed of 100r/min, mixing for 10min, then starting cutting at a rotating speed of 1500r/min while starting stirring, simultaneously adding 8.0% of K30 absolute ethanol solution for granulation, and observing the preparation condition of granules at any time. Drying in an oven at 80 ℃ after granulation is finished until the water content of the final granules is less than or equal to 2%, and sieving by a 1.2mm sieve for granulation.
Total mixing: adding the acid-base granules (weight ratio 1:1.3), amphotericin B raw material and other auxiliary materials into a hopper, and mixing for 20 min. The total mixed granule tabletting control parameters are as follows: the main pressing thickness is 11KN, the main pressing thickness is 1.8mm, the pre-pressing thickness is 2.2mm, the sheet thickness is 5.1mm, and the rotating speed is 70000 sheets/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Example 1 (made into 1 ten thousand tablets)
Acid particle prescription:
| citric acid | 680g |
| Mannitol | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Mannitol | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
| amphotericin B | 50g |
| Acid granules | 2455g |
| Alkali particle | 2455g |
| Carboxymethyl starch sodium (Liqian) | 160g |
| Silicon dioxide | 50g |
| Magnesium stearate | 30g |
The preparation process comprises the following steps:
preparing alkali particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 10.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 2500m3H, atomizing pressure of 1.5bar, liquid inlet speed of 1.0kg/min, granulating at 40 deg.C, observing whether particle uniformity and fluidization state are appropriate, and adjusting air quantity and liquid inlet speed in time. The granulation was terminated with a 40 mesh pass rate of 75.1% by sieving, and boiling-drying was continued at 47 ℃ until the moisture of the final granules became 1.95%, and the granules were granulated with a 1.2mm mesh sieve.
Preparing acid particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 8.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 2500m3H, atomizing pressure of 1.5bar, liquid inlet speed of 1.0kg/min, granulating at 40 deg.C, observing whether particle uniformity and fluidization state are appropriate, and adjusting air quantity and liquid inlet speed in time. The granulation was terminated by sieving the granules with a 40 mesh pass rate of 65.0%, and boiling-drying was continued at 47 ℃ until the moisture of the final granules was 1.76%, and the granules were granulated using a 1.2mm sieve.
Total mixing: adding the acid granules, the alkali granules, the amphotericin B raw materials and other auxiliary materials into a hopper according to the prescription amount, and mixing for 15 min. The weight ratio of the acid-base particles is 1:1. The total mixed granule tabletting control parameters are as follows: the main pressure is 10KN, the main pressure thickness is 1.7mm, the pre-pressing thickness is 2.2mm, the sheet thickness is 5.2mm, and the rotating speed is 60000 sheets/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Example 2 (made into 1 ten thousand tablets)
Acid particle prescription:
| citric acid | 680g |
| Mannitol | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Mannitol | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
| amphotericin B | 50g |
| Acid granules | 2135g |
| Alkali particle | 2775g |
| Carboxymethyl starch sodium (Liqian) | 160g |
| Silicon dioxide | 50g |
| Magnesium stearate | 30g |
The preparation process comprises the following steps:
preparing alkali particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 10.0% K30 anhydrous ethanol solution, and granulating. Process control air volume of 2000m3H, atomizing pressure of 1.2bar, liquid inlet speed of 0.8kg/min, granulation at 38 ℃, observation of proper particle uniformity and fluidization state, and timely adjustment of air quantity and liquid inlet speed. And (4) finishing granulation by sieving the granules with 40 meshes and passing through the rate of 79%, continuously carrying out boiling drying at 45 ℃ until the moisture of the final granules is 1.82%, and finishing granules by using a 1.2mm screen.
Preparing acid particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 8.0% K30 anhydrous ethanol solution, and granulating. Process control air volume of 2000m3At the atomization pressure of 1.2bar, feed liquidThe speed is 0.8kg/min, the material temperature is set to be 38 ℃ for granulation, whether the particle uniformity and the fluidization state are proper or not is observed at any time, and the air quantity and the liquid inlet speed are adjusted in time. The passing rate of the sieved granules of 40 meshes is 71 percent, boiling and drying are continued at 45 ℃ until the moisture of the final granules is 1.99 percent, and a sieve of 1.2mm is used for finishing the granules.
Total mixing: adding the acid granules, the alkali granules, the amphotericin B raw materials and other auxiliary materials into a hopper according to the prescription amount, and mixing for 15 min. The weight ratio of the acid-base particles is 1: 1.3. The total mixed granule tabletting control parameters are as follows: the main pressing thickness is 11KN, the main pressing thickness is 1.8mm, the pre-pressing thickness is 2.2mm, the sheet thickness is 5.1mm, and the rotating speed is 70000 sheets/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Example 3 (1 ten thousand tablets were made) the formulation was the same as in example 2.
Acid particle prescription:
| citric acid | 680g |
| Mannitol | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Mannitol | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
the preparation process comprises the following steps:
preparing alkali particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 10.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 3000m3H, atomizing pressure of 1.8bar, liquid inlet speed of 1.0kg/min, setting the temperature of the material to be 43 ℃ for granulation, observing whether the uniformity and the fluidization state of the particles are proper at any time, and adjusting the air quantity and the liquid inlet speed in time. And (4) finishing granulation by sieving granules with 40 meshes and passing rate of 72%, continuously boiling and drying at 50 ℃ until the moisture of the final granules is 1.87%, and finishing granules by using a 1.2mm sieve.
Preparing acid particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 8.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 3000m3H, atomizing pressure of 1.8bar, liquid inlet speed of 1.0kg/min, setting the temperature of the material to be 43 ℃ for granulation, observing whether the uniformity and the fluidization state of the particles are proper at any time, and adjusting the air quantity and the liquid inlet speed in time. Granulating after sieving the granules with a 40-mesh passing rate of 68 percent, continuously boiling and drying at 50 ℃ until the moisture of the final granules is 1.88 percent,the granules were sized using a 1.2mm sieve.
Total mixing: adding the alkali particles and the amphotericin B raw materials in the formula amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10 min. The weight ratio of the acid-base particles is 1: 1.3. The total mixed granule tabletting control parameters are as follows: the main pressing thickness is 11KN, the main pressing thickness is 1.8mm, the pre-pressing thickness is 2.2mm, the sheet thickness is 5.1mm, and the rotating speed is 70000 sheets/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Example 4 (made into 1 ten thousand pieces)
Acid particle prescription:
| citric acid | 680g |
| Mannitol | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Mannitol | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
the preparation process comprises the following steps:
preparing alkali particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 10.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 3000m3H, atomizing pressure of 2.0bar, liquid inlet speed of 1.2kg/min, granulation at 45 ℃, observation of proper particle uniformity and fluidization state, and timely adjustment of air quantity and liquid inlet speed. And (4) finishing granulation by sieving granules with 40 meshes and passing rate of 70%, continuously boiling and drying at 50 ℃ until the moisture of the final granules is 1.56%, and finishing granules by using a 1.2mm sieve.
Preparing acid particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 8.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 3000m3H, atomizing pressure of 2.0bar, liquid inlet speed of 1.2kg/min, granulation at 45 ℃, observation of proper particle uniformity and fluidization state, and timely adjustment of air quantity and liquid inlet speed. And (4) finishing granulation after sieving the granules with 40 meshes and passing rate of 66%, continuously boiling and drying at 50 ℃ until the moisture of the final granules is less than or equal to 1.77%, and finishing granules by using a 1.2mm sieve.
Total mixing: adding the alkali particles and the amphotericin B raw materials in the formula amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10 min. The weight ratio of the acid-base particles is 1: 1.5. The total mixed granule tabletting control parameters are as follows: the main pressure is 12KN, the main pressure thickness is 1.7mm, the pre-pressing thickness is 2.3mm, the slice thickness is 5.2mm, and the rotating speed is 60000 slices/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Example 5 (1 ten thousand tablets were made) the formulation was the same as in example 3
Acid particle prescription:
| citric acid | 680g |
| Microcrystalline cellulose | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali particle prescription:
| sodium bicarbonate | 750g |
| Mannitol | 1400g |
| Povidone K30 | 60g |
The total mixed formula comprises:
the preparation process comprises the following steps:
preparing alkali particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 10.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 2500m3H, atomizing pressure of 1.5bar, liquid inlet speed of 1.0kg/min, granulation at 45 ℃, observation of proper particle uniformity and fluidization state, and timely adjustment of air quantity and liquid inlet speed. The granulation was terminated by sieving the granules with a 40 mesh pass rate of 73%, boiling-drying was continued at 50 ℃ until the moisture of the final granules was 1.88%, and the granules were granulated with a 1.2mm sieve.
Preparing acid particles: adding adjuvants into boiling granulator, mixing for 10min, spraying 8.0% K30 anhydrous ethanol solution, and granulating. Process control air volume 2500m3H, atomizing pressure of 1.5bar, liquid inlet speed of 1.0kg/min, granulation at 45 ℃, observation of proper particle uniformity and fluidization state, and timely adjustment of air quantity and liquid inlet speed. The granulation was terminated by sieving the granules with a 40 mesh pass rate of 69%, boiling-drying was continued at 50 ℃ until the moisture of the final granules became 1.76%, and the granules were granulated with a 1.2mm sieve.
Total mixing: adding the alkali particles and the amphotericin B raw materials in the formula amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10 min. The weight ratio of the acid-base particles is 1: 1.3. The total mixed granule tabletting control parameters are as follows: the main pressure is 11KN, the main pressure thickness is 1.8mm, the pre-pressing thickness is 2.2mm, the slice thickness is 5.1mm, and the rotating speed is 60000 slices/hour. The process is controlled to be finished within 12 hours, and the finished product is obtained by packaging. The finished product is stored at 4 ℃.
Analysis of examples and comparative examples
Table 1 shows the production process conditions of examples and comparative examples. As can be seen from Table 1, the control indexes in the examples are good: uniform particles, small difference of tablet weight and friability meeting the specification.
TABLE 1 analysis of the production process of examples and comparative examples
And (3) comparing long-term examination results: (examination conditions 25 ℃ C. + -. 2 ℃ C., 60%. + -. 5%)
1. Appearance and character analysis
Table 2 shows the appearance and properties of the examples and comparative examples. As can be seen from Table 2, the finished product of the comparative example has obvious appearance and color change, and the tablet expands for 6 months, the color changes from yellow to dark yellow, and the long-term stability is poor; examples 2, 3 and 4 had no expansion plate and no apparent color change, and had good long-term stability.
TABLE 2 appearance and Properties of the examples and comparative examples
2. Analysis of foaming amount
Table 3 shows the foaming amount analysis of examples and comparative examples. As is clear from Table 3, the decrease in the foaming amount of the comparative examples is remarkable, and the decrease in the foaming amount is moderate in all the examples in long-term stability test, and examples 2, 3 and 4 are preferable.
TABLE 3 analysis of foaming amounts of examples and comparative examples
3. And (3) acidity comparison:
the amphotericin B raw material is unstable and is easily influenced by acid and alkali to reduce the content, and the pH value of the acid and alkali granules of the product is more easily influenced by acid granules, so the proportion of total mixed acid and alkali granules needs to be strictly controlled. And (3) detecting the acidity value of the finished tablet at the later stage by the following method: and (3) taking 2 finished products, adding 10ml of new boiling cold water into a small beaker, and immediately measuring by using an acidimeter after the tablets completely react. The results are shown in Table 4, and the acidity values of all the comparative examples and examples are stable in accelerated examination, and the acidity values of the examples are increased compared with those of the comparative examples due to the difference in the ratio of the acid to the base.
TABLE 4 Long-term evaluation of acidity values for examples and comparative examples
4. Content analysis
Table 5 shows the content analysis of examples and comparative examples. As can be seen from Table 5, the content of the comparative examples is reduced and changed remarkably, and the long-term content stability of all the examples is better than that of the comparative examples, wherein the example 3 is the most preferable.
TABLE 5 content analysis of examples and comparative examples
And (3) accelerating the comparison of the investigation results: (examination conditions 30 ℃ C. + -. 2 ℃ C., 65%. + -. 5%)
1. Appearance and character analysis
Table 6 shows the appearance and properties of the examples and comparative examples. As can be seen from Table 6, the finished product of the comparative example has obvious appearance and color change, the tablet expands after 1 month is accelerated, the color changes from yellow to dark yellow after 3 months is accelerated, and the stability is poor; examples 2, 3 and 4 had no expansion plate and no obvious color change, and were good in acceleration stability and in compliance with the regulations.
TABLE 6 appearance and Properties of examples and comparative examples
2. Analysis of foaming amount
Table 7 shows the foaming amount analysis of examples and comparative examples. As can be seen from Table 7, the comparative example showed a remarkable decrease in the foaming amount, and the addition of 6 failed, and the examples showed a slow decrease in the long-term stability of the foaming amount compared with the foaming amount, and the foaming amount was acceptable after accelerated for 6 months.
TABLE 7 analysis of foaming amounts of examples and comparative examples
3. And (3) acidity comparison:
the acidity value detection method comprises the following steps: 2 finished products were taken and put in a small beaker, 10ml of fresh boiling cold water was added, and immediately after the tablets reacted completely, the results were measured using an acidimeter, and are shown in Table 8. As can be seen from Table 8, all the comparative examples and examples showed a stability in accelerated pH examination, which was the same as the pH value observed for a long period of time; the acidity values of the examples are increased compared with those of the comparative examples due to the difference in the ratio of acid to base.
TABLE 8 acidity values accelerated examination of examples and comparative examples
4. Content analysis
Table 9 shows the content analysis of examples and comparative examples. As is clear from Table 9, the accelerated decrease in the content of the comparative examples is remarkably changed, and the content stability of all the examples is better than that of the comparative examples, and example 3 is the best.
TABLE 9 content analysis of examples and comparative examples
As can be seen from tables 1-9, the production conditions of all the examples of the invention are good, the appearance color of the prepared product and the condition of the finished expansion plate are improved, the foaming amount and the acidity value meet the requirements, and the content is stable and tends to be good. Of these, examples 2, 3, 4 have significant advantages over the comparative example, with example 3 being the most preferred.
The vaginal effervescent tablet prepared by the invention has good appearance, acidity value meeting the requirement, high content and foaming amount, good long-term and accelerated stability and high safety in clinical use. The comparison shows that the product produced under the new prescription and process is better than the product produced at present in the aspects of color, expansion plate condition, content, foaming amount, quality stability and the like, the problems of product expansion plate and unstable content in the period of validity are solved, and the mass production is realized.
Claims (7)
1. The amphotericin B vaginal effervescent tablet is characterized by comprising the following components in parts by weight: 40-60 parts of amphotericin B, 2500 parts of acid granules 1500-; wherein the weight ratio of the acid particles to the alkali particles is 1: 1-1.5.
2. The amphotericin B vaginal effervescent tablet of claim 1, wherein said acid granules comprise the following components in parts by weight: 780 parts of citric acid 580-containing organic solvent, 1400 parts of mannitol 500-containing organic solvent, 900 parts of pregelatinized starch 500-containing organic solvent and 3030-50 parts of polyvidone K.
3. The amphotericin B vaginal effervescent tablet of claim 1, wherein said base granules comprise the following components in parts by weight: 1000 parts of sodium bicarbonate 500-.
4. The preparation method of the amphotericin B vaginal effervescent tablet is characterized by comprising the following steps:
(1) preparing acid particles: weighing the raw materials according to the component proportion of the acid particles, wherein the acid particles comprise the following components in parts by weight: 780 parts of citric acid 580-containing organic solvent, 1400 parts of mannitol 500-containing organic solvent, 900 parts of pregelatinized starch 500-containing organic solvent and 3030-50 parts of polyvidone K; dissolving povidone K30 in absolute ethyl alcohol to prepare povidone K30 solution, adding citric acid, mannitol and pregelatinized starch into a boiling granulator, mixing for 5-15min, spraying povidone K30 solution for granulation, controlling air quantity at 2000m and 3000m, atomizing pressure at 1.2-2.0bar and liquid inlet speed at 0.8-1.2kg/min, keeping the temperature of the material at 38-45 ℃, completing granulation when the passing rate of 40-mesh sieving of the material is less than or equal to 85%, and continuously carrying out boiling drying at 45-50 ℃ until the moisture of the final granules is less than or equal to 2%;
(2) preparing alkali particles: weighing the raw materials according to the component proportion of the alkali particles, wherein the alkali particles comprise the following components in parts by weight: 1000 parts of sodium bicarbonate 500-; dissolving povidone K30 in absolute ethyl alcohol to prepare povidone K30 solution, adding sodium bicarbonate and mannitol into a boiling granulator, mixing for 5-15min, spraying povidone K30 solution for granulation, controlling air quantity of 2000 and 3000m and liquid inlet speeds of 1.2-2.0bar and 0.8-1.2kg/min in the granulation process, keeping the material temperature at 38-45 ℃, completing granulation when the passing rate of 40-mesh sieving of the material is less than or equal to 85%, and continuously carrying out boiling drying at 45-50 ℃ until the moisture of the final granules is less than or equal to 2%;
(3) preparing an effervescent tablet: weighing the raw materials according to the component proportion of the effervescent tablet, wherein the effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 2500 parts of acid granules 1500-; the weight ratio of the acid particles to the alkali particles is 1: 1-1.5; adding the alkali granules and the amphotericin B into a hopper, mixing for 5-15min, adding the acid granules, the sodium carboxymethyl starch, the silicon dioxide and the magnesium stearate, continuously mixing for 10-30min, tabletting and packaging to obtain the finished effervescent tablet.
5. The preparation method according to claim 4, wherein the mass concentration of the povidone K30 solution in steps (1) and (2) is 8.0-10.0%.
6. The process according to claim 4, wherein in the step (3), the main pressing is 8-15KN, the main pressing thickness is 1.5-2.5mm, the pre-pressing thickness is 2.0-3.0mm, the tablet thickness is more than 5mm, the rotation speed is 50000-80000 tablets/hour, and the tabletting process is controlled to be completed within 12 hours.
7. The process according to claim 4, wherein the effervescent tablet is stored at 2-10 ℃.
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| US20130266955A1 (en) * | 2010-12-31 | 2013-10-10 | Wensheng Xia | Effervescent compositions and uses thereof |
| CN108310364A (en) * | 2018-04-26 | 2018-07-24 | 霍尔果斯汉智医药科技有限公司 | A kind of amphotericin B vaginal expansion plug and preparation method thereof |
| CN110638744A (en) * | 2019-11-11 | 2020-01-03 | 哈尔滨欧替药业有限公司 | Vaginal effervescent suppository and preparation method and application thereof |
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| US20130266955A1 (en) * | 2010-12-31 | 2013-10-10 | Wensheng Xia | Effervescent compositions and uses thereof |
| CN108310364A (en) * | 2018-04-26 | 2018-07-24 | 霍尔果斯汉智医药科技有限公司 | A kind of amphotericin B vaginal expansion plug and preparation method thereof |
| CN110638744A (en) * | 2019-11-11 | 2020-01-03 | 哈尔滨欧替药业有限公司 | Vaginal effervescent suppository and preparation method and application thereof |
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