CN113694036B - 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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- CN113694036B CN113694036B CN202111097690.3A CN202111097690A CN113694036B CN 113694036 B CN113694036 B CN 113694036B CN 202111097690 A CN202111097690 A CN 202111097690A CN 113694036 B CN113694036 B CN 113694036B
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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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 provides amphotericin B vaginal effervescent tablets and a preparation method thereof, wherein the effervescent tablets comprise the following components in parts by weight: 40-60 parts of amphotericin B, 1500-2500 parts of acid particles, 1500-3750 parts of alkali particles, 60.8-315.5 parts of sodium carboxymethyl starch, 15.2-126.2 parts of silicon dioxide and 15.2-94.65 parts of magnesium stearate; 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 industrial production is facilitated, 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 amphotericin B vaginal effervescent tablet and a preparation method thereof.
Background
Amphotericin is a multi-olefinic antibiotic produced by streptomyces tuberosus (Streptomyces nodosus) M4575. Amphotericin contains A, B components, component A has low toxicity and weak antifungal effect, and component B has strong effect, namely amphotericin B. Amphotericin B belongs to polyene antibiotics, is one of the most powerful invasive mycosis preventing and treating medicines with the widest antibacterial spectrum, is also the first choice medicine for treating a plurality of serious deep mycotic infections, and has wide market application prospect. Fungal vaginitis is a vaginal inflammation caused by candida albicans, also known as candida, which is the most common conditional pathogenic bacteria in fungi. Candida albicans has very high sensitivity to amphotericin B, and thus amphotericin B is effective in treating mycotic vaginitis. The amphotericin B vaginal effervescent tablet of our company is an external antifungal product, is applied to colpitis caused by fungi through local administration, has the characteristics of quick effect, complete absorption, no damage to mucous membrane, less systemic side effect and the like, has great market potential, but has high application and cost due to the application of new dosage forms, and the market of effervescent tablet products also needs to be cultivated and guided.
The amphotericin B molecule is formed by connecting 7 pairs of conjugated double bond macrolide and a deoxyaminohexose of trehalose amine through glycosidic bond, and has amino, carboxyl and ester bond structurally, so that the amphotericin B molecule is unstable, has hygroscopicity and is easy to damage by light, heat and acid. The existing amphotericin B vaginal effervescent tablet is very unstable and has the following technical problems: 1. the preparation process has strict requirements on production environment, is limited in production batch, and cannot be produced in large batch; 2. the effervescent tablet is invalid due to effervescence when meeting water, and the production process is easy to absorb moisture and stick, so that the effervescent tablet needs severe environmental temperature and humidity; 3. the problems of expansion board appearance, content reduction and the like occur in the effective period. The product is aluminum-plastic-aluminum package, is a luxury plate in the package, has higher cost, even so, the quality problem is still worry, the stability reserved sample display content is obviously reduced, and the problem of customer complaints caused by plate expansion sometimes occurs. A series of problems severely restrict the production and use of the variety and must be studied and solved.
Disclosure of Invention
The invention aims to provide amphotericin B vaginal effervescent tablets and a preparation method thereof, which are used for solving the problems of poor stability, high production process requirement, easy expansion of plates during storage, reduced content and the like in the prior art.
The technical scheme of the invention is as follows: the amphotericin B vaginal effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 1500-2500 parts of acid particles, 1500-3750 parts of alkali particles, 60.8-315.5 parts of sodium carboxymethyl starch, 15.2-126.2 parts of silicon dioxide and 15.2-94.65 parts of magnesium stearate; 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: 580-780 parts of citric acid, 500-1400 parts of mannitol, 500-900 parts of pregelatinized starch and 30-50 parts of povidone K.
The alkali particles comprise the following components in parts by weight: 500-1000 parts of sodium bicarbonate, 900-1500 parts of mannitol and 30-80 parts of povidone K.
A preparation method of amphotericin B vaginal effervescent tablet comprises the following steps:
(1) Acid particle preparation: the acid granule comprises the following components in parts by weight: 580-780 parts of citric acid, 500-1400 parts of mannitol, 500-900 parts of pregelatinized starch and 30-50 parts of povidone K; dissolving povidone K30 in absolute ethanol to obtain povidone K30 solution, adding citric acid, mannitol and pregelatinized starch into boiling granulator, mixing for 5-15min, spraying povidone K30 solution, granulating, and controlling air volume at 2000-3000m 3 And (3) carrying out granulation at the atomization pressure of 1.2-2.0bar and the liquid inlet speed of 0.8-1.2kg/min, keeping the temperature of the material at 38-45 ℃, and continuously boiling and drying at 45-50 ℃ until the moisture content of the final particles is less than or equal to 2% when the passing rate of the material through a 40-mesh sieve is less than or equal to 85%;
(2) Alkali particle preparation: weighing raw materials according to the component proportion of the alkali particles, wherein the alkali particles comprise the following components in parts by weight: 500-1000 parts of sodium bicarbonate and 900 parts of mannitol1500 parts of povidone K30-80 parts; dissolving povidone K30 in absolute ethanol to obtain povidone K30 solution, adding sodium bicarbonate and mannitol into boiling granulator, mixing for 5-15min, spraying povidone K30 solution, granulating, and controlling air volume at 2000-3000m 3 And (3) carrying out granulation at the atomization pressure of 1.2-2.0bar and the liquid inlet speed of 0.8-1.2kg/min, keeping the temperature of the material at 38-45 ℃, and continuously boiling and drying at 45-50 ℃ until the moisture content of the final particles is less than or equal to 2% when the passing rate of the material through a 40-mesh sieve is less than or equal to 85%;
(3) The effervescent tablet is prepared by the following steps: the effervescent tablet is prepared from the following raw materials in parts by weight: 40-60 parts of amphotericin B, 1500-2500 parts of acid particles, 1500-3750 parts of alkali particles, 60.8-315.5 parts of sodium carboxymethyl starch, 15.2-126.2 parts of silicon dioxide and 15.2-94.65 parts of magnesium stearate; the weight ratio of the acid particles to the alkali particles is 1:1-1.5; adding alkali particles and amphotericin B into hopper, mixing for 5-15min, adding acid particles, carboxymethyl starch sodium, silicon dioxide and magnesium stearate, mixing for 10-30min, tabletting, and packaging to obtain the final 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 pressure is 8-15KN, the main pressure thickness is 1.5-2.5mm, the pre-pressing thickness is 2.0-3.0mm, the tablet thickness is more than 5mm, the rotating speed is 50000-80000 tablets/hour, and the tabletting process is controlled to be completed within 12 hours.
The obtained effervescent tablet is stored at 2-10deg.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 industrial production is facilitated, the production efficiency is improved, the exertion of the drug effect is ensured, and the safety of clinical medication is improved.
The mannitol is used for effectively improving the hygroscopicity, meanwhile, the acid-base granulating process is improved, the fluidized drying granulating mode is adopted, the 40-mesh passing rate of the terminal material is controlled to be less than or equal to 85%, and meanwhile, the terminal moisture is strictly controlled, so that the moisture absorption problem in the production process is solved, and the stability of the production process is further ensured. The invention optimizes the total mixing process, mixes the main medicine and the alkali particles firstly, then mixes the main medicine and other auxiliary materials, and simultaneously controls the weight ratio of the acid particles to the alkali particles to be 1:1-1.5, so that the acid-alkali balance degree of the final product is good, and the effective components are not adversely affected. The control parameters of the tabletting process are as follows: the main pressure is 8-15KN, the thickness of the main pressure is 1.5-2.5mm, the pre-pressing thickness is 2.0-3.0mm, the thickness of the sheet is more than 5mm, and the rotating speed is 50000-80000 sheets/hour. The process is controlled to be completed within 12 hours, and the packaged finished product is stored at 2-10 ℃, so that the stability of the product in the service life is ensured to the greatest extent, the quality and the safety of the product are improved, and meanwhile, the mass production is realized.
Detailed Description
The invention is further illustrated by the following examples, in which the processes and methods not described in detail are conventional and well known in the art, and in which the starting materials or reagents used are commercially available unless otherwise indicated.
Comparative example 1 (1 ten thousand tablets)
Acid granule formulation:
| citric acid | 680g |
| Microcrystalline cellulose | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Microcrystalline cellulose | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
the preparation process comprises the following steps:
alkali particle preparation: adding auxiliary materials into a wet granulation machine, starting stirring at a speed of 100r/min, mixing for 10min, starting cutting at a speed of 1500r/min while stirring, adding 10.0% of K30 absolute ethanol solution, granulating, and observing the preparation condition of the granules at any time. Drying in an oven at 80 ℃ after granulating until the water content of the final granules is less than or equal to 2%, and sieving with a 1.2mm sieve to obtain the final product.
Acid particle preparation: adding auxiliary materials into a wet granulation machine, starting stirring at a speed of 100r/min, mixing for 10min, starting cutting at a speed of 1500r/min while stirring, adding 8.0% of K30 absolute ethanol solution, granulating, and observing the preparation condition of the granules at any time. Drying in an oven at 80 ℃ after granulating until the water content of the final granules is less than or equal to 2%, and sieving with a 1.2mm sieve to obtain the final product.
Total mixing: adding the acid-base particles (weight ratio of 1:1.3), amphotericin B raw material and other auxiliary materials into a hopper, and mixing for 20min. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 11KN, the thickness of the main pressure 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 completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Example 1 (1 ten thousand tablets)
Acid granule formulation:
| citric acid | 680g |
| Mannitol (mannitol) | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Mannitol (mannitol) | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
| amphotericin B | 50g |
| Acid particles | 2455g |
| Alkali particles | 2455g |
| Carboxymethyl starch sodium (immediately disintegrating) | 160g |
| Silica dioxide | 50g |
| Magnesium stearate | 30g |
The preparation process comprises the following steps:
alkali particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 10.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2500m 3 And/h, atomizing pressure is 1.5bar, liquid inlet speed is 1.0kg/min, material temperature is set to 40 ℃ for granulation, and particles are observed at any timeThe uniformity and fluidization state are suitable, and the air quantity and the liquid inlet speed are timely adjusted. And (3) finishing granulating after sieving the granules with the 40-mesh passing rate of 75.1%, continuously setting the boiling drying at 47 ℃ until the water content of the final granules is 1.95%, and finishing the granules by using a 1.2mm screen.
Acid particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 8.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2500m 3 And (3) carrying out granulation at the temperature of 40 ℃ under the conditions of atomizing pressure of 1.5bar and liquid inlet speed of 1.0kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. And (3) finishing granulating after sieving the granules with the 40-mesh passing rate of 65.0%, continuously setting the boiling drying at 47 ℃ until the water content of the final granules is 1.76%, and finishing the granules by using a 1.2mm screen.
Total mixing: adding the acid particles, the alkali particles, the amphotericin B raw material and other auxiliary materials into a hopper, and mixing for 15min. The weight ratio of the acid to the alkali particles is 1:1. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 10KN, the thickness of the main pressure 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 completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Example 2 (1 Wan tablet)
Acid granule formulation:
| citric acid | 680g |
| Mannitol (mannitol) | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Mannitol (mannitol) | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
| amphotericin B | 50g |
| Acid particles | 2135g |
| Alkali particles | 2775g |
| Carboxymethyl starch sodium (immediately disintegrating) | 160g |
| Silica dioxide | 50g |
| Magnesium stearate | 30g |
The preparation process comprises the following steps:
alkali particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 10.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2000m 3 And (3) carrying out granulation at the temperature of 38 ℃ under the conditions of atomizing pressure of 1.2bar and liquid inlet speed of 0.8kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain granule with 40 mesh passing rate of 79%, and boiling and drying at 45deg.C until the final granule moisture is 1.82%, and finishing with 1.2mm sieve.
Acid particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 8.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2000m 3 And (3) carrying out granulation at the temperature of 38 ℃ under the conditions of atomizing pressure of 1.2bar and liquid inlet speed of 0.8kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. And (3) finishing the sieving of the 40-mesh particles by 71%, continuing to carry out boiling drying at 45 ℃ until the water content of the final particles is 1.99%, and finishing the particles by using a 1.2mm screen.
Total mixing: adding the acid particles, the alkali particles, the amphotericin B raw material and other auxiliary materials into a hopper, and mixing for 15min. The weight ratio of the acid to the alkali particles is 1:1.3. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 11KN, the thickness of the main pressure 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 completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Example 3 (1 ten thousand tablets were made) the same recipe as example 2.
Acid granule formulation:
| citric acid | 680g |
| Mannitol (mannitol) | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Mannitol (mannitol) | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
the preparation process comprises the following steps:
alkali particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 10.0% of K30 absolute ethanol solution, and granulating. Process control air quantity 3000m 3 And (3) carrying out granulation at the temperature of 43 ℃ under the conditions of atomizing pressure of 1.8bar and liquid inlet speed of 1.0kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain granule with 40 mesh passing rate of 72%, and boiling and drying at 50deg.C until the final granule moisture is 1.87%, and grading with 1.2mm sieve.
Acid particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 8.0% of K30 absolute ethanol solution, and granulating. Process control air quantity 3000m 3 And (3) carrying out granulation at the temperature of 43 ℃ under the conditions of atomizing pressure of 1.8bar and liquid inlet speed of 1.0kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain 40 mesh granules with a passing rate of 68%, and boiling and drying at 50deg.C until the final granule moisture is 1.88%, and finishing with 1.2mm sieve.
Total mixing: adding the alkali particles and amphotericin B raw materials with the prescription amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10min. The weight ratio of the acid to the alkali particles is 1:1.3. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 11KN, the thickness of the main pressure 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 completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Example 4 (1 Wan tablet)
Acid granule formulation:
| citric acid | 680g |
| Mannitol (mannitol) | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Mannitol (mannitol) | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
the preparation process comprises the following steps:
alkali particle preparation: adding adjuvants into boiling granulator, mixing for 10min, and sprayingGranulating with 10.0% K30 absolute ethanol solution. Process control air quantity 3000m 3 And (3) carrying out granulation at the temperature of 45 ℃ under the conditions of atomizing pressure of 2.0bar and liquid inlet speed of 1.2kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain granules with 40 mesh passing rate of 70%, and boiling and drying at 50deg.C until the final granule moisture is 1.56%, and grading with 1.2mm sieve.
Acid particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 8.0% of K30 absolute ethanol solution, and granulating. Process control air quantity 3000m 3 And (3) carrying out granulation at the temperature of 45 ℃ under the conditions of atomizing pressure of 2.0bar and liquid inlet speed of 1.2kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain granules with 40 mesh passing rate of 66%, and boiling and drying at 50deg.C until the final granule moisture is less than or equal to 1.77%, and finishing with 1.2mm screen.
Total mixing: adding the alkali particles and amphotericin B raw materials with the prescription amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10min. The weight ratio of the acid to the alkali particles is 1:1.5. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 12KN, the thickness of the main pressure is 1.7mm, the pre-pressing thickness is 2.3mm, the sheet thickness is 5.2mm, and the rotating speed is 60000 sheets/hour. The process is controlled to be completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Example 5 (1 ten thousand tablets) the recipe is the same as example 3
Acid granule formulation:
| citric acid | 680g |
| Microcrystalline cellulose | 1000g |
| Pregelatinized starch | 500g |
| Povidone K30 | 40g |
Alkali granule prescription:
| sodium bicarbonate | 750g |
| Mannitol (mannitol) | 1400g |
| Povidone K30 | 60g |
Total mix prescription:
the preparation process comprises the following steps:
alkali particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 10.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2500m 3 And/h, atomizing pressure is 1.5bar, liquid inlet speed is 1.0kg/min, material temperature is set to 45 ℃ for granulation, whether particle uniformity and fluidization state are proper or not is observed at any time,and the air quantity and the liquid inlet speed are timely adjusted. Granulating after sieving to obtain granule with 40 mesh passing rate of 73%, boiling and drying at 50deg.C until the final granule moisture is 1.88%, and finishing with 1.2mm screen.
Acid particle preparation: adding the auxiliary materials into a boiling granulator, mixing for 10min, spraying 8.0% of K30 absolute ethanol solution, and granulating. Process control air volume 2500m 3 And (3) carrying out granulation at the temperature of 45 ℃ under the conditions of atomizing pressure of 1.5bar and liquid inlet speed of 1.0kg/min, observing whether the particle uniformity and fluidization state are proper or not at any time, and adjusting the air quantity and liquid inlet speed in time. Granulating after sieving to obtain 40 mesh granules with a passing rate of 69%, boiling and drying at 50deg.C until the final granule moisture is 1.76%, and finishing with 1.2mm sieve.
Total mixing: adding the alkali particles and amphotericin B raw materials with the prescription amount into a hopper, mixing for 10min, adding the acid particles and other auxiliary materials, and mixing for 10min. The weight ratio of the acid to the alkali particles is 1:1.3. The control parameters of the particle tabletting after total mixing are as follows: the main pressure is 11KN, the thickness of the main pressure is 1.8mm, the pre-pressing thickness is 2.2mm, the sheet thickness is 5.1mm, and the rotating speed is 60000 sheets/hour. The process is controlled to be completed within 12 hours, and the finished product is obtained after packaging. The finished product is stored at 4 ℃.
Examples and comparative examples analysis
Table 1 shows the analysis of the production process of examples and comparative examples. As can be seen from table 1, the control index in the examples is good: uniform particles, small difference in tablet weight and friability meeting the regulations.
TABLE 1 analysis of the production process of examples and comparative examples
Comparison of long-term investigation results: (investigation conditions 25 ℃ + -2 ℃,60% + -5%)
1. Appearance and trait analysis
Table 2 shows the appearance and property analysis of examples and comparative examples. As can be seen from Table 2, the appearance and color of the comparative example product are obviously changed, the tablet swells from yellow to dark yellow for a long period of 6 months, and the long-term stability is poor; examples 2, 3 and 4 have no expansion plate and obvious color change phenomenon, and have good long-term stability.
TABLE 2 appearance and Property analysis of 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 was evident in the comparative examples, and the decrease in the foaming amount was alleviated by examining the long-term stability in all examples, and examples 2, 3 and 4 were preferable.
TABLE 3 analysis of foaming amount of examples and comparative examples
3. Acidity comparison:
the amphotericin B raw material is unstable and is easily influenced by acid and alkali, the content of the amphotericin B raw material is reduced, and the amphotericin B raw material is more easily influenced by acid particles aiming at the pH value of acid particles and alkali particles of the product, so that the proportion of total mixed acid and alkali particles needs to be strictly controlled. And (3) detecting the acidity value of the finished tablet in the later period, wherein the method comprises the following steps of: taking 2 tablets of finished product, adding 10ml of new boiling cold water into a small beaker, and immediately measuring by using an acidometer after the tablets react completely. The results are shown in Table 4, and all the acidity values of the comparative examples and examples are stable under accelerated examination, and the acidity values of the examples are increased compared with the acidity values of the comparative examples due to the fact that the acid-base ratio of the prescription is different.
TABLE 4 results of long-term investigation of acidity values for examples and comparative examples
4. Content analysis
Table 5 shows the content analysis of examples and comparative examples. As is clear from Table 5, the decrease in the content of the comparative examples was significantly changed, and the long-term content stability of all examples was better than that of the comparative examples, with example 3 being optimal.
TABLE 5 analysis of the contents of examples and comparative examples
Comparison of acceleration investigation results: (investigation conditions 30 ℃ + -2 ℃,65% + -5%)
1. Appearance and trait analysis
Table 6 shows the appearance and property analysis of examples and comparative examples. As can be seen from Table 6, the appearance and color of the comparative example product are obviously changed, the tablet is expanded after accelerating for 1 month, the color of the tablet is changed from yellow to dark yellow after accelerating for 3 months, and the stability is poor; examples 2, 3 and 4 have no expansion plate and obvious color change phenomenon, and have good acceleration stability and meet the regulations.
TABLE 6 appearance and Property analysis of examples and comparative examples
2. Analysis of foaming amount
Table 7 shows the foaming amount analysis of examples and comparative examples. As is clear from Table 7, the foaming amount of the comparative example was remarkably decreased, and the addition of 6 was not acceptable, and the long-term stability of the foaming amount of the examples was gradually decreased as compared with the foaming amount, and the foaming amount was acceptable after 6 months.
Table 7 analysis of foaming amount of examples and comparative examples
3. Acidity comparison:
the acidity value detection method comprises the following steps: taking 2 tablets of finished product, adding 10ml of new boiling cold water into a small beaker, and immediately measuring by using an acidometer after the tablets react completely, wherein the result is shown in Table 8. As can be seen from table 8, all the acidity values of the comparative examples and examples are stable under accelerated examination, and are the same as the acidity values under long-term examination; the acidity value of the examples is increased compared with the comparative examples due to the different proportions of the acid and the base prescribed.
TABLE 8 accelerated investigation of acidity values for 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 content of the comparative examples was significantly reduced, and the content stability was improved in all the examples as compared with the comparative examples, and the best example was example 3.
TABLE 9 analysis of the contents of examples and comparative examples
As can be seen from tables 1-9, all the examples of the present invention have good production conditions, the appearance color of the prepared product and the condition of the expansion plate of the finished product are improved, the foaming amount and the acidity value meet the requirements, and the content is stable and good. Wherein examples 2, 3, 4 have significant advantages over the comparative examples, example 3 is optimal.
The vaginal effervescent tablet prepared by the invention has good appearance, high content and foaming, good long-term and accelerated stability, high clinical use safety and meets the requirement on acidity value. Compared with the existing products, the color, the expansion plate condition, the content, the foaming quantity, the quality stability and the like of the products produced under the new prescription and process are better than those of the products produced at present, the problems of the expansion plate and the unstable content of the products in the effective period are solved, and the mass production is realized.
Claims (4)
1. The preparation method of the amphotericin B vaginal effervescent tablet is characterized by comprising the following steps:
(1) Acid particle preparation: the acid granule comprises the following components in parts by weight: 580-780 parts of citric acid, 500-1400 parts of mannitol, 500-900 parts of pregelatinized starch and 30-50 parts of povidone 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 the povidone K30 solution for granulation, controlling the air quantity to be 2000-3000 m/h, the atomization pressure to be 1.2-2.0bar and the liquid inlet speed to be 0.8-1.2kg/min, keeping the temperature of the material to be 38-45 ℃, and when the passing rate of the material through a 40-mesh sieve is less than or equal to 85%, finishing the granulation, and continuously boiling and drying at 45-50 ℃ until the moisture of the final particles is less than or equal to 2%;
(2) Alkali particle preparation: weighing raw materials according to the component proportion of the alkali particles, wherein the alkali particles comprise the following components in parts by weight: 500-1000 parts of sodium bicarbonate, 900-1500 parts of mannitol and 30-80 parts of povidone K; 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 to be 2000-3000 m/h, atomizing pressure to be 1.2-2.0bar and liquid inlet speed to be 0.8-1.2kg/min in the granulation process, keeping material temperature to be 38-45 ℃, finishing granulation when the 40-mesh sieving passing rate of the material is less than or equal to 85%, and continuously boiling and drying under the condition of 45-50 ℃ until the water content of the final particles is less than or equal to 2%;
(3) The effervescent tablet is prepared by the following steps: the effervescent tablet is prepared from the following raw materials in parts by weight: 40-60 parts of amphotericin B, 1500-2500 parts of acid particles, 1500-3750 parts of alkali particles, 60.8-315.5 parts of sodium carboxymethyl starch, 15.2-126.2 parts of silicon dioxide and 15.2-94.65 parts of magnesium stearate; the weight ratio of the acid particles to the alkali particles is 1:1.3-1.5; adding alkali particles and amphotericin B into a hopper, mixing for 5-15min, adding acid particles, carboxymethyl starch sodium, silicon dioxide and magnesium stearate, continuously mixing for 10-30min, tabletting under the conditions of main pressure of 8-15KN, main pressure thickness of 1.5-2.5mm, pre-compression thickness of 2.0-3.0mm, tablet thickness of > 5mm and rotation speed of 50000-80000 tablets/hr, controlling the tabletting process to be completed within 12 h, and packaging to obtain the finished effervescent tablet.
2. The preparation method according to claim 1, wherein in the steps (1) and (2), the povidone K30 solution has a mass concentration of 8.0 to 10.0%.
3. The method according to claim 1, wherein the obtained effervescent tablet is stored at 2-10 ℃.
4. The amphotericin B vaginal effervescent tablet obtained by the preparation method according to claim 1, wherein said effervescent tablet comprises the following components in parts by weight: 40-60 parts of amphotericin B, 1500-2500 parts of acid particles, 1500-3750 parts of alkali particles, 60.8-315.5 parts of sodium carboxymethyl starch, 15.2-126.2 parts of silicon dioxide and 15.2-94.65 parts of magnesium stearate; wherein the weight ratio of the acid particles to the alkali particles is 1:1.3-1.5;
the acid particles comprise the following components: 580-780 parts of citric acid, 500-1400 parts of mannitol, 500-900 parts of pregelatinized starch and 30-50 parts of povidone K;
the alkali particles comprise the following components: 500-1000 parts of sodium bicarbonate, 900-1500 parts of mannitol and 30-80 parts of povidone K.
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| 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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| 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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| Title |
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| 《微生物工程》编写组.沸腾造粒干燥.《微生物工程 下》.1982, * |
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