CN113855630A - Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof - Google Patents
Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof Download PDFInfo
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- CN113855630A CN113855630A CN202111372944.8A CN202111372944A CN113855630A CN 113855630 A CN113855630 A CN 113855630A CN 202111372944 A CN202111372944 A CN 202111372944A CN 113855630 A CN113855630 A CN 113855630A
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- betamethasone
- sodium phosphate
- suspension injection
- suspension
- acetate
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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
- A61K9/10—Dispersions; Emulsions
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
Abstract
The invention discloses a betamethasone sodium phosphate and betamethasone acetate suspension injection composition. The suspension composition can be prepared into a preparation with excellent stability by adopting a high-pressure homogenization process, and is suitable for industrial production.
Description
Technical Field
The invention relates to a betamethasone sodium phosphate and betamethasone acetate suspension injection and a preparation method thereof, belonging to the technical field of medicines.
Background
Glucocorticoid (GC) is an extremely important regulatory molecule in the body, plays an important role in regulating development, growth, metabolism, immune function and the like of the body, is the most important regulatory hormone for stress response of the body, and is also the most widely and effectively anti-inflammatory and immunosuppressant in clinic. Glucocorticoids are often preferred in emergency or critical situations. The clinically common glucocorticoid medicaments comprise prednisone, methylprednisolone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone and the like. Has antiinflammatory, antitoxic, antiallergic, antishock, nonspecific immunity inhibiting and antipyretic effects, and can prevent and stop immune inflammatory reaction and pathological immune reaction, and is almost effective for allergic diseases of any type.
Glucocorticoids can be divided into short-acting, medium-acting and long-acting types, the short-acting and medium-acting types take effect quickly, but the in vivo action time is short, the water-sodium retention is serious, the long-acting type needs to be administrated every day or even every few hours, the in vivo action time of the long-acting type is long, but the symptom cannot be relieved rapidly, and the betamethasone sodium phosphate & betamethasone acetate suspension injection can effectively solve the problem.
The betamethasone sodium phosphate and betamethasone acetate suspension injection is a compound preparation of soluble betamethasone ester and slightly soluble betamethasone ester, and the soluble betamethasone sodium phosphate can be quickly absorbed and quickly takes effect after being injected. After being injected, the slightly soluble betamethasone acetate becomes a reservoir for slow absorption and continuously acts, thereby controlling symptoms for a long time. However, because of the two active ingredients, betamethasone sodium phosphate has poor thermal stability, betamethasone acetate needs to be in a suspension particle state for a long time in a preparation, and the two active ingredients need to overcome the problems of thermodynamic and kinetic instability of the suspension for preparing the suspension injection.
Disclosure of Invention
The invention aims to solve the technical problem of providing betamethasone sodium phosphate and betamethasone acetate suspension injection which has stable and uniform physicochemical properties, good pharmacodynamic performance and easy storage.
Another objective of the present invention is to provide a method for preparing the betamethasone sodium phosphate and betamethasone acetate suspension injection, which is simple, easy to control the process, capable of increasing the sedimentation time, easy to fill, and the formed suspension injection is uniform and stable in properties and can ensure sterility.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
firstly, controlling the granularity of betamethasone acetate to ensure that the particle diameter of 80-99 percent of betamethasone acetate particles is less than or equal to 10um and the surface charge number of the particles is uniform and flocculent;
secondly, a high-pressure homogenization method is adopted, so that the particles are uniformly dispersed, the settling time is prolonged, and the physical stability of the product and injection is improved;
and thirdly, preparing the betamethasone sodium phosphate and betamethasone acetate suspension injection by adopting a sterilization and filtration mode, preventing the betamethasone sodium phosphate in the main drugs from degrading and the betamethasone acetate from aggregating and agglomerating under the high-temperature condition, and ensuring the sterility of the product.
A suspension injection of betamethasone sodium phosphate and betamethasone acetate is characterized in that each milliliter of liquid medicine contains:
… … … … … … … 3.0.0 mg betamethasone sodium phosphate (calculated as betamethasone),
… … … … … … … … 3.0.0 mg of betamethasone acetate,
… … … … … … … … … 3.4.4 mg of sodium dihydrogen phosphate,
sodium phosphate dibasic … … … … … … … … … 7.1.1 mg,
… … … … … … … … … … 0.2.2 mg of benzalkonium chloride,
… … … … … … 0.1.1 mg of disodium ethylene diamine tetraacetate;
adjusting pH to 6.8-7.2 with inorganic acid or inorganic base;
the balance consisting of water.
The invention provides a preparation method of a betamethasone sodium phosphate and betamethasone acetate suspension injection, which is sequentially carried out according to the following steps:
(1) taking betamethasone acetate, crushing and sterilizing to obtain an aseptic raw material medicine;
(2) adding 30-60% of sterile injection water into the prescription amount of sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium edetate, benzalkonium chloride and betamethasone sodium phosphate for dissolving, adding inorganic acid or inorganic base to adjust pH, and filtering with 0.2um filter membrane to obtain betamethasone sodium phosphate sterile solution;
(3) mixing sterile raw materials with sterile solution, shearing and stirring at 15000-20000 rpm for 10-20 min, and adding injectable water to total amount to obtain suspension;
(4) and (4) homogenizing the suspension in the step (3) to obtain a finished product.
The method is characterized in that:
A. obtaining micro-powder betamethasone acetate sterile raw material medicine in the step (1);
B. in the step (2), the betamethasone sodium phosphate solution passes through a 0.2um filter membrane or a filter element;
C. the mixing and homogenizing in the steps (3) and (4) are carried out under hundred-grade aseptic conditions;
D. filling the product obtained in the step (4) into a penicillin bottle under a stirring state;
E. the steps (2) and (3) are not sterilized at high temperature.
Because the sterile products obtained in the step (1) and the step (2) are all sterile products, the subsequent process does not relate to a high-temperature sterilization process, and the difficulties of betamethasone sodium phosphate degradation and betamethasone acetate aggregation and agglomeration in the main drug are solved.
As a limitation of the process of the invention:
the betamethasone acetate particles are crushed to 80-99% of particles with the particle size less than or equal to 10 um;
in the step (4), the homogenizing pressure is 5.0-7.0MPa, and the time is 5-20 minutes.
Compared with the prior art, the invention has the advantages that the technical scheme is adopted, and the invention is as follows:
the invention provides a preparation method of a betamethasone sodium phosphate and betamethasone acetate suspension injection, which overcomes the technical problems caused by the dynamics and thermodynamics of the suspension injection, and the preparation has stable and uniform physical and chemical properties, good pharmacodynamic performance, easy storage, sedimentation time of more than 30 minutes, convenient filling and sterility guarantee.
The specific implementation mode is as follows:
the present invention will be further described with reference to the following specific examples, but the present invention is not limited to these examples.
Example 1:
the embodiment provides a suspension injection of betamethasone sodium phosphate and betamethasone acetate and a preparation method thereof.
The method comprises the following specific steps:
(1) taking 12g of betamethasone acetate, crushing to obtain 90% of betamethasone acetate particles with the particle size less than or equal to 10um, and sterilizing to obtain sterile raw material medicines;
(2) adding the sterile injection water with the total amount of 1600mL into the sodium dihydrogen phosphate, the disodium hydrogen phosphate, the ethylene diamine tetraacetic acid, the benzalkonium chloride and the betamethasone sodium phosphate with the prescription amount for dissolving, adding inorganic acid or inorganic base to adjust the pH value to 6.8-7.2, and filtering by using a 0.2um filter membrane to obtain a betamethasone sodium phosphate sterile solution;
(3) mixing the sterile raw material medicine with the sterile solution, shearing and stirring at the rotating speed of 15000 rpm for 20 minutes, and adding water for injection to 4000mL to obtain a suspension;
(4) homogenizing the suspension in the step (3) under the pressure of 5.0MPa for 15 minutes to obtain a finished product;
(5) the settling time of the product is more than 30 minutes.
Example 2:
the embodiment provides a suspension injection of betamethasone sodium phosphate and betamethasone acetate and a preparation method thereof.
The method comprises the following specific steps:
(6) taking 12g of betamethasone acetate, crushing to obtain 99% of betamethasone acetate particles with the particle size less than or equal to 10um, and sterilizing to obtain sterile raw material medicines;
(7) adding sterile injection water with the total amount of 2000mL into the prescription amount of sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium ethylene diamine tetraacetate, benzalkonium chloride and betamethasone sodium phosphate for dissolving, adding inorganic acid or inorganic base to adjust the pH value to 6.8-7.2, and filtering by using a 0.2um filter membrane to obtain a betamethasone sodium phosphate sterile solution;
(8) mixing the sterile raw material medicine with the sterile solution, shearing and stirring at 18000 rpm for 10 minutes, and adding water for injection to 4000mL to obtain a suspension;
(9) homogenizing the suspension in the step (3) under the pressure of 6.5MPa for 8 minutes to obtain a finished product;
(10) the settling time of the product is more than 30 minutes.
The betamethasone sodium phosphate and betamethasone acetate suspension injection obtained in example 1 and example 2 was investigated for content uniformity, sterility test, redispersion times and accelerated long-term stability of betamethasone acetate, and the results were as follows:
TABLE 1 betamethasone sodium phosphate & betamethasone acetate suspension injection with content uniformity results
TABLE 2 sterility and redispersion number test
| Test sample | Sterility testing | Detection of number of redispersion |
| Example 1 | Compliance with regulations | 5 times (twice) |
| Example 2 | Compliance with regulations | 3 times of |
TABLE 3 stability test results
The betamethasone sodium phosphate and betamethasone acetate suspension injection prepared by the invention has stable and uniform physical and chemical properties and good drug effect performance; the preparation method is simple, the process is easy to control, the settling time is more than 30 minutes, the filling is convenient, the sterility is ensured, and the method is suitable for industrial production.
Claims (9)
1. A suspension injection containing betamethasone sodium phosphate and betamethasone acetate is characterized in that: the betamethasone sodium phosphate and the betamethasone acetate are used as active ingredients, and the active ingredients comprise alkaline buffer salt, a bacteriostatic agent, a metal ion complexing agent and/or a pH regulator.
2. Suspension injection according to claim 1, characterized in that: the alkaline buffer salt is sodium dihydrogen phosphate and disodium hydrogen phosphate.
3. Suspension injection according to claim 1, characterized in that: the bacteriostatic agent is benzalkonium chloride.
4. Suspension injection according to claim 1, characterized in that: the metal ion complexing agent is disodium ethylene diamine tetraacetate.
5. Suspension injection according to claim 1, characterized in that: the pH regulator is inorganic acid or inorganic base.
6. Suspension injection according to claim 1, characterized in that the suspension injection per ml consists of:
… … … … … … … 3.0.0 mg betamethasone sodium phosphate (calculated as betamethasone),
… … … … … … … … 3.0.0 mg of betamethasone acetate,
… … … … … … … … … 3.4.4 mg of sodium dihydrogen phosphate,
sodium phosphate dibasic … … … … … … … … … 7.1.1 mg,
… … … … … … … … … … 0.2.2 mg of benzalkonium chloride,
… … … … … … 0.1.1 mg of disodium ethylene diamine tetraacetate;
adjusting pH to 6.8-7.2 with inorganic acid or inorganic base;
the balance consisting of water.
7. The aseptic process of suspension injection of betamethasone sodium phosphate and betamethasone acetate according to any one of claims 1-6, comprising the steps of:
(1) taking betamethasone acetate, crushing and sterilizing to obtain an aseptic raw material medicine;
(2) adding 30-60% of sterile injection water into the prescription amount of sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium edetate, benzalkonium chloride and betamethasone sodium phosphate for dissolving, adding inorganic acid or inorganic base to adjust pH, and filtering with 0.2um filter membrane to obtain betamethasone sodium phosphate sterile solution;
(3) mixing sterile raw materials with sterile solution, shearing and stirring at 15000-20000 rpm for 10-20 min, and adding injectable water to total amount to obtain suspension;
(4) and (4) homogenizing the suspension in the step (3) to obtain a finished product.
8. The method is characterized in that the final product is not sterilized at high temperature, and is characterized in that:
A. obtaining micro-powder betamethasone acetate sterile raw material medicine in the step (1);
B. in the step (2), the betamethasone sodium phosphate solution passes through a 0.2um filter membrane or a filter element;
C. the mixing and homogenizing in the steps (3) and (4) are carried out under hundred-grade aseptic conditions;
D. filling the product obtained in the step (4) into a container under the stirring state;
E. the steps (2) and (3) are not sterilized at high temperature
F. In the step (4), the homogenizing pressure is 5.0-7.0MPa, and the time is 5-20 minutes.
9. The process for preparing a suspension injection according to claim 7, characterized in that: the betamethasone acetate is crushed until the particle size of 99 percent of particles is less than or equal to 20 um.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111372944.8A CN113855630A (en) | 2021-11-19 | 2021-11-19 | Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111372944.8A CN113855630A (en) | 2021-11-19 | 2021-11-19 | Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114796109A (en) * | 2022-04-29 | 2022-07-29 | 遂成药业股份有限公司 | Method for preparing glucocorticoid suspension |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167730A (en) * | 2007-10-24 | 2008-04-30 | 严洁 | Compound betamethasone suspension injection |
| CN102526078A (en) * | 2010-12-15 | 2012-07-04 | 重庆华邦制药股份有限公司 | Compound betamethasone suspension injection and preparation method thereof |
-
2021
- 2021-11-19 CN CN202111372944.8A patent/CN113855630A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167730A (en) * | 2007-10-24 | 2008-04-30 | 严洁 | Compound betamethasone suspension injection |
| CN102526078A (en) * | 2010-12-15 | 2012-07-04 | 重庆华邦制药股份有限公司 | Compound betamethasone suspension injection and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| MERCK & CO., INC.: "CELESTONE® SOLUSPAN®*brand of betamethasone sodium phosphate and betamethasone acetate Injectable Suspension USP 6 mg per mL", 《HTTPS://WWW.FDA.GOV.CN》 * |
| 孙少平: "《高分子材料在纳米给药系统中的应用》", 31 August 2017 * |
| 李威等主编: "《药剂学》", 28 February 2014 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114796109A (en) * | 2022-04-29 | 2022-07-29 | 遂成药业股份有限公司 | Method for preparing glucocorticoid suspension |
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