CN113350272A - Betamethasone sodium phosphate injection and preparation method and application thereof - Google Patents
Betamethasone sodium phosphate injection and preparation method and application thereof Download PDFInfo
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- CN113350272A CN113350272A CN202110577105.3A CN202110577105A CN113350272A CN 113350272 A CN113350272 A CN 113350272A CN 202110577105 A CN202110577105 A CN 202110577105A CN 113350272 A CN113350272 A CN 113350272A
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- injection
- sodium phosphate
- betamethasone sodium
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- 238000002347 injection Methods 0.000 title claims abstract description 126
- 239000007924 injection Substances 0.000 title claims abstract description 126
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 title claims abstract description 116
- 229960005354 betamethasone sodium phosphate Drugs 0.000 title claims abstract description 116
- 238000002360 preparation method Methods 0.000 title claims abstract description 78
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 68
- 239000007788 liquid Substances 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 49
- 239000000243 solution Substances 0.000 claims abstract description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 34
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 34
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 33
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 21
- 230000001954 sterilising effect Effects 0.000 claims abstract description 18
- 238000011049 filling Methods 0.000 claims abstract description 16
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- 239000003708 ampul Substances 0.000 claims abstract description 11
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims abstract description 8
- 230000001502 supplementing effect Effects 0.000 claims abstract description 6
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- 239000001301 oxygen Substances 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 229960002537 betamethasone Drugs 0.000 claims description 18
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 6
- 201000004624 Dermatitis Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 201000009053 Neurodermatitis Diseases 0.000 claims description 4
- 206010039986 Senile pruritus Diseases 0.000 claims description 4
- 206010041303 Solar dermatitis Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims 1
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 1
- 239000003963 antioxidant agent Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000003078 antioxidant effect Effects 0.000 abstract description 9
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- 230000001276 controlling effect Effects 0.000 description 20
- 238000001914 filtration Methods 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
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- 238000004128 high performance liquid chromatography Methods 0.000 description 6
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
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- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
-
- 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
-
- 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
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Abstract
The invention belongs to the field of medicines, and particularly relates to a betamethasone sodium phosphate injection and a preparation method and application thereof, wherein each 1000ml of the injection comprises the following components: 5-6 g of betamethasone sodium phosphate; 0.09-0.15 g of edetate disodium; 6-8 g of disodium hydrogen phosphate; proper amount of 1% phosphoric acid solution; the water for injection is added to 1000 mL. The preparation method of the injection comprises the following steps: preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount; adding a proper amount of water for injection into the liquid preparation tank, introducing nitrogen for bubbling, sequentially adding and dissolving the components, and supplementing the water for injection to the formula amount to obtain a liquid medicine; and (3) enabling the liquid medicine to pass through a sterilizing filter, and filling the liquid medicine into a vial or an ampoule which is purged by nitrogen to obtain the injection. The injection does not contain an organic solvent and an antioxidant, has low safety risk, and can realize better stability on the premise of not containing the antioxidant.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a betamethasone sodium phosphate injection and a preparation method and application thereof.
Background
Betamethasone sodium phosphate is a corticoid drug, is suitable for treating eczema, contact dermatitis, neurodermatitis, solar dermatitis, senile pruritus and other symptoms, and is an injection in common dosage form. Betamethasone sodium phosphate injection was first marketed in belgium in 1962, specifications: 4mg/mL, and the certificate authority is MSD Belgium BVBA.
However, betamethasone sodium phosphate is susceptible to degradation reaction in aqueous solution to produce betamethasone and other impurities. In order to prevent the degradation, a large amount of organic solvent (such as propylene glycol) and antioxidant (such as sodium bisulfite) are added into the existing preparation, but researches show that the propylene glycol has certain irritation to skin and mucous membrane; sodium bisulfite is irritant to skin, eyes and respiratory tract, and can cause anaphylaxis, corneal injury, blindness and asthma; large amounts of oral administration cause nausea, abdominal pain, diarrhea, circulatory failure and central nervous depression.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a betamethasone sodium phosphate injection and a preparation method and application thereof, so as to solve the safety problem caused by adding an organic solvent and an antioxidant into the existing betamethasone sodium phosphate injection.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a betamethasone sodium phosphate injection, wherein each 1000ml of the betamethasone sodium phosphate injection comprises:
the pH value of the betamethasone sodium phosphate injection is 8.2-8.5.
The betamethasone sodium phosphate injection does not contain an organic solvent and an antioxidant, is high in safety, and can realize better stability on the premise of not containing the organic solvent and the antioxidant. By controlling the dosage of the disodium hydrogen phosphate and the 1% phosphoric acid solution, the pH value of the betamethasone sodium phosphate injection can be ensured to be within the range of 8.2-8.5, the stability of the injection is ensured, and the osmotic pressure of the injection is ensured to be consistent with that of a reference preparation.
Preferably, the betamethasone sodium phosphate injection comprises the following components in each 1000ml of betamethasone sodium phosphate injection:
in any of the above schemes, preferably, the dissolved oxygen of the betamethasone sodium phosphate injection is less than or equal to 2mg/L, and the headspace residual oxygen is less than or equal to 4%.
In a second aspect, the invention provides a preparation method of a betamethasone sodium phosphate injection according to the first aspect, comprising the following steps:
s1: preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount;
s2: adding 60-90% of injection water into a liquid preparation tank, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, and supplementing the injection water to the formula amount to obtain a liquid medicine;
s3: and (3) enabling the liquid medicine to pass through a sterilizing filter, and filling the liquid medicine into a bottle or an ampoule which is purged by nitrogen to obtain the injection with headspace residual oxygen of less than or equal to 4%, wherein the pH value of the injection is 8.2-8.5.
The preparation method of the betamethasone sodium phosphate injection provided by the invention effectively controls the increase of impurities and prevents the reduction of the content of effective substances on the premise of not containing organic solvents and antioxidants by controlling the dissolved oxygen in the liquid medicine, regulating the pH, filling the liquid medicine into a vial or an ampoule which is purged by nitrogen, controlling the headspace residual oxygen of the liquid medicine and the like, thereby improving the safety and ensuring the stability of the injection. The preparation method adopts a sterilizing filter for sterilizing and filtering, meets the relevant regulations in the pharmaceutical production quality management standard, meets the sterility assurance level, and is also beneficial to the stability of the betamethasone sodium phosphate injection.
Preferably, in step S2, the water for injection is degassed water for injection; the temperature of the prepared liquid is 20-50 ℃; the dissolved oxygen in the liquid medicine is less than or equal to 2 mg/L.
In any of the above embodiments, the solution preparation temperature is preferably 30 to 40 ℃ in step S2.
In any of the above embodiments, preferably, in step S2, the disodium edetate, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are continuously stirred and continuously charged with nitrogen for protection.
In any of the above embodiments, preferably, in step S3, the filter membrane size of the sterilizing filter is 0.22 μm; the headspace residual oxygen content of the injection is controlled to be 2-3%.
In a third aspect, the invention provides an application of the betamethasone sodium phosphate injection as described in the first aspect in preparing medicines for treating eczema, contact dermatitis, neurodermatitis, solar dermatitis and senile pruritus.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment and the like used in the following examples are either commercially available or available by existing methods; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, an embodiment of the present invention provides a betamethasone sodium phosphate injection, where each 1000ml of the betamethasone sodium phosphate injection includes:
the pH value of the betamethasone sodium phosphate injection is 8.2-8.5.
A1% phosphoric acid solution means that 1g of phosphoric acid is contained in 100g of phosphoric acid solution.
The betamethasone sodium phosphate injection does not contain an organic solvent and an antioxidant, is high in safety, and can realize better stability on the premise of not containing the organic solvent and the antioxidant. By controlling the dosage of the disodium hydrogen phosphate and the 1% phosphoric acid solution, the pH value of the betamethasone sodium phosphate injection can be ensured to be within the range of 8.2-8.5, the betamethasone sodium phosphate injection replaces the action of an organic solvent, the stability of the injection is ensured, and the osmotic pressure of the injection is ensured to be consistent with that of a reference preparation.
Because the packing material (bottle or ampoule) of the injection contains metal ions, the precipitation of the metal ions can cause great quality risk to the liquid medicine in the long-term standing process, and the clarity of the liquid medicine can be influenced by products formed by migration of calcium, zinc, barium, potassium, magnesium, iron and other components contained in the packing material into the liquid medicine and oxidation hydrolysis. The edetate disodium can form a stable water-soluble chelate with metal ions, can prevent calcium, zinc, barium, potassium, magnesium, iron and other components in the packing material from being oxidized, and is favorable for improving the stability of the liquid medicine in the preparation, storage and clinical preparation processes. If the dosage of the edetate disodium is too small, the stability of the injection cannot be guaranteed, and if the dosage of the edetate disodium is too large, adverse reaction occurs, so that the stability of the injection can be favorably realized only if the dosage is within the range.
Further, in each 1000ml betamethasone sodium phosphate injection comprises:
further, the dissolved oxygen of the betamethasone sodium phosphate injection is less than or equal to 2mg/L, the headspace residual oxygen is less than or equal to 4%, the dissolved oxygen is determined according to a conventional method, and the headspace residual oxygen can be determined by adopting a residual oxygen analyzer.
In a second aspect, an embodiment of the present invention provides a preparation method of a betamethasone sodium phosphate injection according to the first aspect, including the following steps:
s1: preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount;
s2: adding 60-90% of injection water into a liquid preparation tank, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, and supplementing the injection water to the formula amount to obtain a liquid medicine;
s3: and (3) enabling the liquid medicine to pass through a sterilizing filter, and filling the liquid medicine into a bottle or an ampoule which is purged by nitrogen to obtain the injection with headspace residual oxygen of less than or equal to 4%, wherein the pH value of the injection is 8.2-8.5.
According to the preparation method of the betamethasone sodium phosphate injection provided by the embodiment of the invention, by controlling the dissolved oxygen in the liquid medicine, regulating and controlling the pH, filling the liquid medicine into a vial or an ampoule which is purged by nitrogen, controlling the headspace residual oxygen amount of the liquid medicine and other means, on the premise of not containing an antioxidant, the increase of impurities is effectively controlled, the reduction of the content of effective substances is prevented, the safety is improved, and the stability of the injection is ensured.
Betamethasone sodium phosphate is unstable at high temperature, impurities such as betamethasone and the like can be generated, a terminal sterilization process cannot be adopted through the investigation of a sterilization process, and a circulating steam method is mostly adopted for sterilization in the prior art, so that the regulation of the existing regulation cannot be met, and the sterility guarantee level cannot be met. The preparation method provided by the embodiment of the invention adopts the sterilizing filter to perform sterilizing filtration, not only meets the relevant regulations in the drug production quality management standard and meets the sterility assurance level, but also is beneficial to the stability of betamethasone sodium phosphate.
Further, in step S2, the water for injection is deaerated water for injection; the temperature of the solution preparation is 20-50 ℃, for example, the temperature can be 20 ℃, 30 ℃, 40 ℃ or 50 ℃, and the like, in the solution preparation process, if the temperature is too low, the solubility of each component is low, the dissolution speed is slow, and if the temperature is too high, the stability of betamethasone sodium phosphate is reduced, preferably, the temperature is 30-40 ℃; the dissolved oxygen in the liquid medicine is less than or equal to 2mg/L, for example, the dissolved oxygen can be 2mg/L, 1.5mg/L, 1mg/L or 0.5mg/L, etc.
Further, in step S2, the disodium edetate, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are continuously stirred and continuously charged with nitrogen for protection during the addition and dissolution.
Further, in step S3, the filter membrane size of the sterilizing filter is 0.22 micron; the headspace residual oxygen content of the injection is controlled to be 2% to 3%, for example, 2%, 2.2%, 2.4%, 2.6%, 2.8%, or 3%.
In a third aspect, the embodiment of the invention provides an application of the betamethasone sodium phosphate injection as described in the first aspect in preparing a medicine for treating eczema, contact dermatitis, neurodermatitis, solar dermatitis and senile pruritus.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
Reference formulation: the support quotient is MSD Belgium BVBA, the specification is 4mg/mL (calculated by betamethasone), the pH value is 8.3, and the osmotic pressure is 140 mOsmol/kg.
The preparation method comprises the following steps: s1, preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount; s2, adding 600mL of injection water into a liquid preparation tank, controlling the temperature of the liquid preparation to be 30 ℃, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, stirring until the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are completely dissolved, supplementing the injection water to 1000mL to obtain a liquid medicine, controlling the dissolved oxygen amount in the liquid medicine to be 2mg/L, and controlling the pH value range to be 8.2-8.5; s3 filtering the medicinal liquid with 0.22 μm microporous membrane, and filling into ampoules (1.2 mL/ampoule) purged with nitrogen to obtain injection with headspace residual oxygen content of 2%.
The preparation method 2 comprises the following steps: s1, preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount; s2, adding 800mL of injection water into a liquid preparation tank, controlling the temperature of the liquid preparation to be 40 ℃, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, stirring until the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are completely dissolved, adding 1000mL of the injection water to obtain a liquid medicine, controlling the dissolved oxygen amount in the liquid medicine to be 2mg/L, and controlling the pH value range to be 8.2-8.5; s3 filtering the medicinal liquid with 0.22 μm microporous membrane, and filling into ampoules (1.2 mL/ampoule) purged with nitrogen to obtain injection with headspace residual oxygen content of about 3%.
The preparation method 3 comprises the following steps: s1, preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount; s2, adding 900mL of injection water into a liquid preparation tank, controlling the temperature of the liquid preparation to be 50 ℃, charging nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, stirring until the disodium edetate, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are completely dissolved, supplementing the injection water to 1000mL to obtain liquid medicine, controlling the dissolved oxygen amount in the liquid medicine to be 1.5mg/L, and controlling the pH value range to be 8.2-8.5; s3 filtering the medicinal liquid with 0.22 μm microporous membrane, and filling into ampoules (1.2 mL/ampoule) purged with nitrogen to obtain injection with headspace residual oxygen content of about 4%.
The preparation method 4 comprises the following steps: basically the same as in the preparation method 2, except that in step S2, the solution preparation temperature is controlled to 30 ℃.
The preparation method 5: basically the same as in the preparation method 2, except that in step S2, the solution preparation temperature is controlled to 50 ℃.
The preparation method 6 comprises the following steps: basically the same as in the preparation method 2, except that in step S2, the solution preparation temperature is controlled to 60 ℃.
The preparation method 7 comprises the following steps: basically the same as in the preparation method 2, except that in step S2, the solution preparation temperature is controlled to 70 ℃.
The preparation method 8 comprises the following steps: substantially the same as in production method 2, except that in step S3, the headspace residual oxygen amount is about 4%.
The preparation method 9: substantially the same as in production method 2, except that in step S3, the headspace residual oxygen amount is about 2%.
The preparation method 10: s1, preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount; s2, adding 800mL of injection water into a liquid preparation tank, controlling the temperature of the liquid preparation to be 40 ℃, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, stirring until the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution are completely dissolved, adding the injection water to 1000mL to obtain a liquid medicine, and controlling the pH value to be 8.2-8.5; s3 the liquid medicine is filtered by a 0.22 mu m microporous membrane and is directly filled into ampoules (1.2 mL/ampoule) without nitrogen purging to obtain the injection.
Referring to the Chinese pharmacopoeia, the detection items of the betamethasone sodium phosphate injection are controlled as follows:
the limit of unknown maximum single impurities is 3%, the limit of betamethasone is 2.6%, and the limit of total impurities is 5%.
Examples 1 to 4
The component contents of the betamethasone sodium phosphate injection provided in examples 1-4 are shown in table 1, calculated by 1000mL betamethasone sodium phosphate injection.
TABLE 1
The betamethasone sodium phosphate injection is prepared according to the preparation method 2, and as can be seen from table 1, when the dosage of the disodium hydrogen phosphate is 6.65-7.35 mg/mL, the osmotic pressure is consistent with that of the reference preparation, and when the dosage of the disodium hydrogen phosphate is 6mg/mL, the difference between the osmotic pressure and the reference preparation is large.
Examples 5 to 8
The component contents of the betamethasone sodium phosphate injection provided in examples 5 to 8 are shown in table 2, based on 1000mL of betamethasone sodium phosphate injection.
TABLE 2
Betamethasone sodium phosphate injection is prepared according to the preparation method 8, the betamethasone sodium phosphate injection prepared in the examples 5-8 is respectively taken and placed for 30 days under the conditions that the temperature is 40 ℃ plus or minus 2 ℃ and the relative humidity is 75 percent plus or minus 5 percent, an accelerated test is carried out, the contents of impurities and main drugs in the betamethasone sodium phosphate injection are measured according to a high performance liquid chromatography (0512 of the four-part general regulation of 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in table 3.
TABLE 3
As can be seen from Table 3, when the amount of edetate disodium is 0.095-0.105 mg/mL, the growth range of betamethasone and total impurities is small, the stability of the liquid medicine is good, and when the amount of edetate disodium is not added or is small, the growth of betamethasone and total impurities in the injection is obvious.
Example 9
The content of the betamethasone sodium phosphate injection provided in example 9 is the same as that in example 6 in terms of 1000mL of betamethasone sodium phosphate injection, betamethasone sodium phosphate liquid solutions are respectively prepared according to steps S1 and S2 in the above preparation method 2, preparation method 4, preparation method 5, preparation method 6 and preparation method 7, the obtained betamethasone sodium phosphate liquid solutions are respectively placed at the temperature of 40 ℃, 30 ℃, 50 ℃, 60 ℃ and 70 ℃, and the contents of impurities and main drugs in the betamethasone sodium phosphate liquid solutions are measured according to a high performance liquid chromatography (0512 of the fourth division of the 2020 edition of chinese pharmacopoeia), and the measurement results are shown in table 4.
TABLE 4
In the embodiment, the influence of the solution preparation temperature on the stability of the betamethasone sodium phosphate liquid is examined, because the amount of the betamethasone sodium phosphate liquid prepared in the embodiment is small, and the preparation process time is short, in order to fully explain the influence of the solution preparation temperature on the stability of the betamethasone sodium phosphate liquid, the prepared liquid is placed at the temperature consistent with the solution preparation temperature and is kept still for 10 hours, so that the influence time of the solution preparation temperature on the betamethasone sodium phosphate liquid is prolonged.
As can be seen from Table 4, after the betamethasone sodium phosphate solution is placed at the temperature of 30-50 ℃ for 10 hours, the betamethasone and the total impurities have no obvious change trend; after the betamethasone and the total impurities are placed at the temperature of between 60 and 70 ℃ for 10 hours, the betamethasone and the total impurities are obviously increased, which shows that the liquid medicine is more stable when the temperature of the prepared liquid is controlled within the range of between 30 and 50 ℃. In the industrial production process, because a large amount of betamethasone sodium phosphate liquid needs to be prepared, the preparation process is long, and the influence of the temperature of the prepared liquid on the stability of the betamethasone sodium phosphate liquid is larger.
Example 10
Based on 1000mL betamethasone sodium phosphate injection, the betamethasone sodium phosphate injection provided in example 10 has the same component content as in example 6, the betamethasone sodium phosphate injection is prepared according to the preparation method 2, the preparation method 8, the preparation method 9 and the preparation method 10, the prepared betamethasone sodium phosphate injection is taken and placed for 30 days under the conditions that the temperature is 40 ℃ +/-2 ℃ and the relative humidity is 75% +/-5%, an acceleration test is carried out, the contents of impurities and main drugs in the betamethasone sodium phosphate injection are measured according to a high performance liquid chromatography (0512 of the four-part general rule of 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in table 5.
TABLE 5
As can be seen from Table 5, the injection prepared by the preparation methods 2, 8 and 9 has slow growth of betamethasone and total impurities and is relatively stable; the injection prepared by the preparation method 10 has obvious increase of betamethasone and total impurities. Therefore, the dissolved oxygen content of the injection is controlled to be less than or equal to 2mg/L, and the headspace residual oxygen content is controlled to be less than or equal to 4%, so that the increase of related substances in the storage process can be greatly reduced, and the stability of the injection is ensured.
Comparative example 1
The formula of the betamethasone sodium phosphate injection provided in the comparative example 1 is as follows, calculated by 1000mL betamethasone sodium phosphate injection:
5.49g of betamethasone sodium phosphate; 0.1g of edetate disodium; 0.3g of sodium bisulfite; 7.35g of disodium hydrogen phosphate; 6.2g of 1% phosphoric acid solution; the water for injection is added to 1000 mL.
The preparation method comprises the following steps:
s1, preparing betamethasone sodium phosphate, edetate disodium, sodium bisulfite, hydrogen phosphate disodium and 1% phosphoric acid solution according to the formula amount; s2, adding 800mL of injection water into a liquid preparation tank, controlling the temperature of the liquid preparation to be 40 ℃, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the sodium bisulfite, the disodium hydrogen phosphate and the 1% phosphoric acid solution, stirring until the edetate disodium, the betamethasone sodium phosphate, the sodium bisulfite, the disodium hydrogen phosphate and the 1% phosphoric acid solution are completely dissolved, adding the injection water to 1000mL to obtain a liquid medicine, and controlling the dissolved oxygen amount in the liquid medicine to be 2 mg/L; s3 filtering the medicinal liquid with 0.22 μm microporous membrane, and filling into ampoules (1.2 mL/branch) to obtain the injection.
The prepared betamethasone sodium phosphate injection is taken and placed for 30 days under the conditions that the temperature is 40 ℃ plus or minus 2 ℃ and the relative humidity is 75 percent plus or minus 5 percent, an accelerated test is carried out, the contents of impurities and main drugs in the betamethasone sodium phosphate injection are measured according to a high performance liquid chromatography (0512 of the four ministry of communications in 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in table 6.
TABLE 6
| Time | Unknown maximum single impurity/%) | Betamethasone/%) | Total impurities/%) | pH value |
| Day 0 | 0.067 | 0.071 | 0.522 | 8.3 |
| 10 days | 0.179 | 0.091 | 1.084 | 8.3 |
| 30 days | 0.571 | 0.205 | 2.189 | 8.2 |
As shown in Table 6, the betamethasone sodium phosphate injection has the obvious increase of betamethasone and total impurities in the process of placing.
Examples 11 to 14
The component contents of the betamethasone sodium phosphate injection provided in examples 11 to 14 are shown in table 7, based on 1000mL of betamethasone sodium phosphate injection.
TABLE 7
Betamethasone sodium phosphate injection is prepared according to the preparation method 8, the betamethasone sodium phosphate injection prepared in the embodiments 11 to 14 is respectively taken and placed for 30 days under the conditions that the temperature is 40 ℃ plus or minus 2 ℃ and the relative humidity is 75 percent plus or minus 5 percent, an accelerated test is carried out, the contents of impurities and main drugs in the betamethasone sodium phosphate injection are measured according to a high performance liquid chromatography (0512 of the four-part general regulation of 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in table 8.
TABLE 8
As can be seen from Table 8, the lower the pH value is after 30 days of standing, the faster the growth rate of the betamethasone content is; the higher the pH value is, the faster the unknown maximum single impurity growth speed is, so that the variation amplitude of betamethasone and the unknown maximum single impurity in the injection is related to the pH value of the injection, and when the pH value is within the range of 8.2-8.5, the stability of the injection is the best.
Example 15
The content of the betamethasone sodium phosphate injection provided in example 15, calculated on the basis of 1000mL of betamethasone sodium phosphate injection, is the same as that in example 6, and the betamethasone sodium phosphate injection is prepared according to the preparation method 8. The prepared injection is respectively placed in a steam sterilization cabinet to be sterilized in steam at 115 ℃ for 32min, placed in the steam sterilization cabinet to be sterilized in steam at 121 ℃ for 8min and not sterilized, the content of impurities in the betamethasone sodium phosphate injection is determined according to a high performance liquid chromatography (China pharmacopoeia 2020 edition four parts general rule 0512), and the determination results are shown in table 9.
TABLE 9
| Sample (I) | Unknown maximum single impurity/%) | Betamethasone/%) | Total impurities/%) | pH value |
| Is not sterilized | 0.067 | 0.071 | 0.522 | 8.31 |
| 115℃、32min | 3.887 | 0.732 | 6.936 | 8.35 |
| 121℃、8min | 3.628 | 0.717 | 6.534 | 8.34 |
As can be seen from Table 9, after the product is sterilized at 115 ℃, 32min and 121 ℃ for 8min, betamethasone and total impurities are obviously increased, the maximum single impurities and total impurities are unknown and exceed the limit requirements, and the pH value is not obviously changed, so that the betamethasone sodium phosphate injection cannot be sterilized by a terminal sterilization method, and a 0.22 mu m filter element is required for sterilization and filtration.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (9)
1. A betamethasone sodium phosphate injection is characterized in that each 1000ml of the betamethasone sodium phosphate injection comprises:
5-6 g of betamethasone sodium phosphate;
0.09-0.15 g of edetate disodium;
6-8 g of disodium hydrogen phosphate;
proper amount of 1% phosphoric acid solution;
adding water for injection to 1000 mL;
the pH value of the betamethasone sodium phosphate injection is 8.2-8.5.
2. The betamethasone sodium phosphate injection according to claim 1, comprising per 1000ml of betamethasone sodium phosphate injection:
5.04-5.57 g of betamethasone sodium phosphate;
0.095-0.105 g of edetate disodium;
6.65-7.35 g of disodium hydrogen phosphate;
6.14-6.37 g of 1% phosphoric acid solution;
water for injection was added to 1000 mL.
3. The betamethasone sodium phosphate injection of claim 1, wherein the dissolved oxygen content of the betamethasone sodium phosphate injection is less than or equal to 2mg/L, and the headspace residual oxygen content is less than or equal to 4%.
4. The preparation method of betamethasone sodium phosphate injection according to any one of claims 1-3, comprising the following steps:
s1: preparing betamethasone sodium phosphate, edetate disodium, disodium hydrogen phosphate and 1% phosphoric acid solution according to the formula amount;
s2: adding 60-90% of injection water into a liquid preparation tank, filling nitrogen, sequentially adding and dissolving the edetate disodium, the betamethasone sodium phosphate, the disodium hydrogen phosphate and the 1% phosphoric acid solution, and supplementing the injection water to the formula amount to obtain a liquid medicine;
s3: and (3) enabling the liquid medicine to pass through a sterilizing filter, and filling the liquid medicine into a bottle or an ampoule which is purged by nitrogen to obtain the injection with headspace residual oxygen of less than or equal to 4%, wherein the pH value of the injection is 8.2-8.5.
5. The method for preparing betamethasone sodium phosphate injection according to claim 4, wherein in step S2:
the water for injection is degassed water for injection;
the temperature of the prepared liquid is 20-50 ℃;
the dissolved oxygen in the liquid medicine is less than or equal to 2 mg/L.
6. The preparation method of betamethasone sodium phosphate injection as claimed in claim 4, wherein in step S2, the temperature of the solution is 30-40 ℃.
7. The method of claim 4, wherein in step S2, the mixture is continuously stirred and continuously charged with nitrogen for protection during the process of adding and dissolving the disodium edetate, the sodium phosphate of betamethasone, the disodium hydrogen phosphate and the 1% phosphoric acid solution.
8. The method for preparing betamethasone sodium phosphate injection according to claim 4, wherein in step S3:
the size of the filter membrane of the sterilizing filter is 0.22 micron;
the headspace residual oxygen amount of the injection is 2-3%.
9. Use of betamethasone sodium phosphate injection as defined in claim 1 for preparing a medicament for treating eczema, contact dermatitis, neurodermatitis, solar dermatitis and senile pruritus.
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| CN103720643A (en) * | 2013-08-20 | 2014-04-16 | 天津药业集团新郑股份有限公司 | Preparation method of betamethasone sodium phosphate injection |
| CN112245386A (en) * | 2020-11-04 | 2021-01-22 | 北京鑫开元医药科技有限公司 | Dexamethasone sodium phosphate injection and preparation method thereof |
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| CN103720643A (en) * | 2013-08-20 | 2014-04-16 | 天津药业集团新郑股份有限公司 | Preparation method of betamethasone sodium phosphate injection |
| CN112245386A (en) * | 2020-11-04 | 2021-01-22 | 北京鑫开元医药科技有限公司 | Dexamethasone sodium phosphate injection and preparation method thereof |
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