CN116407508A - Preparation method of hydrocortisone sodium succinate for injection - Google Patents
Preparation method of hydrocortisone sodium succinate for injection Download PDFInfo
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- CN116407508A CN116407508A CN202111671325.9A CN202111671325A CN116407508A CN 116407508 A CN116407508 A CN 116407508A CN 202111671325 A CN202111671325 A CN 202111671325A CN 116407508 A CN116407508 A CN 116407508A
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- QTQGHKVYLQBJLO-UHFFFAOYSA-N 4-methylbenzenesulfonate;(4-methyl-1-oxo-1-phenylmethoxypentan-2-yl)azanium Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)CC(N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960001401 hydrocortisone sodium succinate Drugs 0.000 title claims abstract description 70
- 238000002347 injection Methods 0.000 title claims abstract description 64
- 239000007924 injection Substances 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000001035 drying Methods 0.000 claims abstract description 74
- 238000004108 freeze drying Methods 0.000 claims abstract description 54
- 238000000859 sublimation Methods 0.000 claims abstract description 37
- 230000008022 sublimation Effects 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 35
- 239000007788 liquid Substances 0.000 claims abstract description 32
- 239000000337 buffer salt Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000008215 water for injection Substances 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 230000001105 regulatory effect Effects 0.000 claims abstract description 7
- 238000011049 filling Methods 0.000 claims abstract description 6
- 238000004458 analytical method Methods 0.000 claims description 35
- 238000007710 freezing Methods 0.000 claims description 34
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 34
- 238000000137 annealing Methods 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 22
- 229960000890 hydrocortisone Drugs 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 12
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 abstract 1
- 230000008014 freezing Effects 0.000 description 22
- 238000001816 cooling Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 9
- HHZQLQREDATOBM-CODXZCKSSA-M Hydrocortisone Sodium Succinate Chemical compound [Na+].O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC([O-])=O)[C@@H]4[C@@H]3CCC2=C1 HHZQLQREDATOBM-CODXZCKSSA-M 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000004321 preservation Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 238000012792 lyophilization process Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KMCRQJMZUHNLKJ-NSCUHMNNSA-N (e)-4-(4-nitrophenyl)but-3-en-2-one Chemical compound CC(=O)\C=C\C1=CC=C([N+]([O-])=O)C=C1 KMCRQJMZUHNLKJ-NSCUHMNNSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- VWQWXZAWFPZJDA-CGVGKPPMSA-N hydrocortisone succinate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 VWQWXZAWFPZJDA-CGVGKPPMSA-N 0.000 description 2
- 229950006240 hydrocortisone succinate Drugs 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- -1 salt compound Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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]
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of hydrocortisone sodium succinate for injection, and relates to the technical field of pharmaceutical preparations. A preparation method of hydrocortisone sodium succinate for injection comprises the following steps: dissolving hydrocortisone sodium succinate and buffer salt in water for injection to form a liquid medicine, regulating the pH value to 7.5-7.9, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection, wherein the freeze-drying step comprises prefreezing, sublimation drying and resolution drying. The freeze-drying process of hydrocortisone sodium succinate for injection provided by the invention has the advantages of good product stability and short redissolution time by controlling the temperature and time of each step.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to hydrocortisone sodium succinate for injection and a preparation method thereof.
Background
Hydrocortisone is an endogenous corticosteroid, belongs to a short-acting corticosteroid, has the action time of 8-12 hours, has the anti-inflammatory effect which is 1.25 times that of cortisone, can be directly injected into veins without being activated by liver medicine enzyme to quickly play a role, so that the hydrocortisone gradually replaces the cortisone which needs to be activated by the liver medicine enzyme, is widely used for clinical treatment, and is used for substitution therapy of acute adrenal cortex insufficiency, asthma, shock, sepsis shock and the like and treatment of allergic diseases such as anaphylaxis, autoimmunity, rheumatism and the like, especially acute attack.
Sodium hydrocortisone succinate (salt compound of hydrocortisone) has the same metabolic and anti-inflammatory effects as hydrocortisone. Because the medicine is easy to dissolve in water, has quick response and less adverse reaction, is suitable for diseases requiring quick improvement of blood concentration of hydrocortisone, is the first choice medicine for treating certain diseases, and has irreplaceability in clinic. The structural formula is as follows:
the sodium hydrocortisone succinate is relatively unstable in water and is easily degraded into hydrocortisone and 17-succinic acid hydrocortisone. Therefore, the hydrocortisone sodium succinate needs to be prepared into powder injection to meet the production, storage and use requirements. Sodium hydrocortisone succinate for injection was originally developed by PHARMACIAAND UPJOHN (later purchased as a pyroxene) and marketed in the United states at month 4 of 1955 under the trade name SOLU-
The marketing specifications include: 100 mg/bottle, 250 mg/bottle, 500 mg/bottle and 1 g/bottle (calculated as hydrocortisone) were then marketed in various countries in japan and europe. The original preparation is not imported into China, and domestic pharmaceutical enterprises develop and market the hydrocortisone sodium succinate for injection with the specification of 50 mg/bottle and 100 mg/bottle (calculated by hydrocortisone).
There are few documents or patent reports on the preparation process of hydrocortisone sodium succinate freeze-dried powder injection for injection at home and abroad. CN103550251a discloses a freeze-dried powder injection of hydrocortisone sodium succinate magnesium sulfate compound pharmaceutical composition and a preparation process thereof. The influence of excipient added in the prescription on the appearance, moisture, re-dissolution characteristics and stability of the freeze-dried preparation product is examined. The lyophilization process is not described in detail, but only the low-temperature lyophilization for 30 to 40 hours is described briefly.
CN112220761a discloses a method for preparing sodium hydrocortisone succinate for injection from hydrocortisone succinate as a starting material. Firstly preparing sodium bicarbonate and phosphate into mixed salt solution, then adding the mixed salt solution into acetone suspension of hydrocortisone succinate for neutralization reaction, sterilizing and filtering the liquid medicine, and then preparing the liquid medicine into powder injection by freeze drying or spray drying (sterile split charging). The lyophilization process is not described in detail.
CN103371978A discloses a method for preparing freeze-dried powder injection by ethanol solvent. The injection water containing a certain amount of ethanol is used for preparing the liquid medicine, so that the freeze-drying production efficiency can be improved, and the stability of the powder injection can be improved. However, in the industrial application, the technology needs to be provided with an explosion-proof workshop to meet the requirement of safe production.
At present, the hydrocortisone sodium succinate for injection which is marketed in China has the problems of high moisture and high impurity content. The conventional practice of reducing the moisture content is to increase the drying temperature and/or extend the drying time of the lyophilization process, but in most cases, the product moisture cannot be reduced to such a low level by one or both of the above, so that the stability of the storage process is not ensured and there is also a risk of an increase in degradation impurities; in addition, the product prepared by adopting the conventional freeze-drying process is easy to have harder texture and difficult to redissolve, and the clinical use is influenced.
Therefore, the hydrocortisone sodium succinate freeze-dried powder injection for injection and the preparation method thereof are needed to solve the problems that the quality of the hydrocortisone sodium succinate freeze-dried powder injection for injection is poor, the freeze-drying period is long and the production efficiency is low due to the adoption of the conventional freeze-drying process.
In view of this, the present invention has been made.
Disclosure of Invention
The main object of the present invention is to provide a method for preparing hydrocortisone sodium succinate for injection, which aims to at least partially solve at least one of the above technical problems.
As a first aspect of the present invention, the present invention provides a method for preparing hydrocortisone sodium succinate for injection, comprising the steps of: dissolving hydrocortisone sodium succinate and buffer salt in water for injection to form a liquid medicine, regulating the pH value to 7.5-7.9, filtering the liquid medicine, sub-packaging the liquid medicine into bottles, and freeze-drying to obtain the hydrocortisone sodium succinate for injection, wherein the freeze-drying step comprises the following steps of:
(a) Pre-freezing: the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 2 to 8 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 20 ℃ to minus 3 ℃, and the temperature is kept for 8 hours to 72 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ to 50 ℃, and the temperature is kept for 2 hours to 15 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 2 hours.
Further, the freeze-drying step includes:
(a) Pre-freezing: the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 2 to 8 hours;
(b) Annealing: raising the oil temperature to-30 to-3 ℃ and preserving the heat for 0.5 to 3 hours; then the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 1 to 6 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 20 ℃ to minus 3 ℃, and the temperature is kept for 8 hours to 72 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ to 50 ℃, and the temperature is kept for 2 hours to 15 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 2 hours.
Further, the freeze-drying comprises the following steps:
(a) Pre-freezing: the temperature of the oil is reduced to minus 60 ℃ to minus 40 ℃ and the temperature is kept for 3 to 6 hours;
(b) Annealing: raising the temperature of oil to-20 to-5 ℃ and preserving heat for 0.5 to 2 hours; then the temperature of the oil is reduced to minus 60 ℃ to minus 40 ℃ and the temperature is kept for 2 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 15 ℃ to minus 5 ℃ for 1 hour to 2 hours, and the temperature is kept for 8 hours to 55 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 35 ℃ to 45 ℃, and the temperature is kept for 4 hours to 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1.5 hours.
Further, the buffer salt is selected from a phosphate buffer system, a citrate buffer system or an acetate buffer system.
Further, the buffer salt is selected from phosphate buffer systems.
Further, the raw and auxiliary materials of hydrocortisone sodium succinate for injection are as follows: hydrocortisone sodium succinate: sodium dihydrogen phosphate monohydrate: the mass ratio of anhydrous disodium hydrogen phosphate is 66.84: (0.44-0.48): (4.15-4.58), regulating the pH value to 7.5-7.9 by sodium hydroxide or hydrochloric acid, and fixing the volume of the water for injection.
Further, when the specification of the sodium hydrocortisone succinate for injection is 50 mg/bottle based on hydrocortisone, the freeze-drying step comprises:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 3 to 4 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 3 to 4 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 8 hours to 12 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 4 hours to 6 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
Further, when the specification of the sodium hydrocortisone succinate for injection is 100 mg/bottle based on hydrocortisone, the freeze-drying step comprises:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 8 hours to 15 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 5 hours to 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
Further, when the specification of the sodium hydrocortisone succinate for injection is 500 mg/bottle based on hydrocortisone, the freeze-drying step comprises:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 40 hours to 55 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 8 hours to 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
Further, the preparation method of hydrocortisone sodium succinate for injection comprises the following steps: weighing hydrocortisone sodium succinate, sodium dihydrogen phosphate monohydrate and anhydrous disodium hydrogen phosphate, dissolving the sodium dihydrogen phosphate monohydrate and the anhydrous disodium hydrogen phosphate in water for injection to form a buffer salt solution, adjusting the temperature of the buffer salt solution to 5-20 ℃, adding the hydrocortisone sodium succinate into the buffer salt solution, stirring and dissolving, adjusting the pH to 7.5-7.9, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection.
Further, the preparation method of hydrocortisone sodium succinate for injection comprises the following steps: weighing hydrocortisone sodium succinate, sodium dihydrogen phosphate monohydrate and anhydrous disodium hydrogen phosphate, dissolving the sodium dihydrogen phosphate monohydrate and the anhydrous disodium hydrogen phosphate in water for injection to form a buffer salt solution, adjusting the temperature of the buffer salt solution to 5-20 ℃, adding the hydrocortisone sodium succinate into the buffer salt solution, stirring and dissolving, adjusting the pH to 7.6-7.8, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection.
Further, the liquid medicine is filtered by a microporous filter membrane with the size of 0.22 microns.
Compared with the prior art, the invention has the following beneficial effects:
(1) The preparation method of hydrocortisone sodium succinate for injection provided by the invention controls the temperature and time of each step in the freeze-drying process, and has the advantages of good product stability, low moisture content and short redissolution time;
(2) According to the invention, an annealing process is further introduced in the development of the freeze-drying process, the size of ice crystal particles is increased in the annealing process, the pore diameter remained after the sublimation of water vapor is increased, and the resistance is reduced, so that the sublimation drying efficiency is improved, and the mass transfer control problem is relieved; the annealing process is introduced to ensure that the product has low moisture content, good stability and short redissolution time, improves the quality of hydrocortisone sodium succinate for injection and ensures the medication safety of patients.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The examples were conducted under conventional conditions, except that the specific conditions were not specified. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The raw materials and the auxiliary materials related to each embodiment and the comparative embodiment of the invention are all from the same batch number.
Example 1 (50 mg/bottle gauge in hydrocortisone)
This example provides a 50 mg/bottle specification injection hydrocortisone sodium succinate prescription process wherein the dosing ratio is as follows:
the preparation method comprises the following steps:
(1) 66.84g of hydrocortisone sodium succinate, 0.44mg of sodium dihydrogen phosphate monohydrate and 4.58mg of anhydrous disodium hydrogen phosphate are accurately weighed, the sodium dihydrogen phosphate monohydrate and the anhydrous disodium hydrogen phosphate are dissolved by water for injection with the preparation amount of below 70 ℃, the mixture is stirred until the mixture is dissolved to obtain a buffer salt solution, the temperature of the buffer salt solution is adjusted to 5 ℃, then the hydrocortisone sodium succinate is added and stirred for dissolving, finally the pH value is adjusted to 7.7 by sodium hydroxide solution, and the volume is fixed to 1000mL by water for injection.
(2) Filtering the liquid medicine obtained in the step (1) by using a microporous filter membrane with the diameter of 0.22 microns, sub-packaging the liquid medicine into penicillin bottles, and half-tamponade.
(3) And (3) freeze-drying the liquid medicine liquid split-packed in the step (2), and pressing and capping to obtain the hydrocortisone sodium succinate for injection.
Example 1-1
Wherein the freeze-drying operation:
(1) pre-freezing: 3 hours to reduce the oil temperature to-32 ℃ and keep the temperature for 2 hours;
(2) annealing: raising the oil temperature to-3 ℃ for 0.5 hour, and preserving the heat for 3 hours; then the oil temperature is reduced to minus 30 ℃ for 0.5 hour, and the temperature is kept for 6 hours;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is raised to-20 ℃ for 3 hours, and heat preservation is carried out for 8 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ for 0.5 hour, and the temperature is kept for 15 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 hour.
Examples 1 to 2
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 3 hours;
(2) annealing: heating the oil temperature to-8 ℃ for 1 hour, and preserving the heat for 1 hour; then the oil temperature is reduced to-50 ℃ for 1 hour, and the temperature is kept for 3 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 9 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 5 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 1 to 3
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-45 ℃ for 2 hours, and preserving the heat for 4 hours;
(2) annealing: heating the oil temperature to-10 ℃ for 1 hour, and preserving the heat for 1.5 hours; then the oil temperature is reduced to-45 ℃ for 2 hours, and the temperature is kept for 4 hours;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is increased to-12 ℃ for 1 hour, and heat preservation is carried out for 8 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 42 ℃ for 2 hours, and the temperature is kept for 4 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 hour.
Examples 1 to 4
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-55 ℃ for 1 hour, and preserving the heat for 3.5 hours;
(2) annealing: raising the oil temperature to-5 ℃ for 2 hours, and preserving the heat for 0.5 hour; then the oil temperature is reduced to-55 ℃ for 1 hour, and the temperature is kept for 3.5 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-7 ℃ for 2 hours, and the temperature is kept for 12 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 45 ℃ for 1 hour, and the temperature is kept for 6 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 1 to 5
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 3 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 9 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 5 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 1 to 6
Wherein the freeze-drying operation:
(1) pre-freezing: the oil temperature was reduced to-50℃for 1 hour and kept for 4 hours.
(2) Sublimation drying: vacuum degree is controlled at 10-30 Pa, oil temperature is raised to-12 ℃ for 2 hours, and heat preservation is carried out for 14 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 8 hours; finally, maintaining the analysis drying temperature unchanged, setting the vacuum degree to be less than or equal to 10Pa, and preserving the heat for 1 hour.
Example 2 (100 mg/bottle gauge in hydrocortisone)
This example provides a 100 mg/bottle specification injection hydrocortisone sodium succinate prescription process wherein the dosing ratio is as follows:
the preparation method comprises the following steps:
(1) 133.68g of hydrocortisone sodium succinate, 0.96g of sodium dihydrogen phosphate monohydrate and 8.60g of anhydrous disodium hydrogen phosphate are accurately weighed, the sodium dihydrogen phosphate monohydrate and the anhydrous disodium hydrogen phosphate are dissolved by using water for injection with the preparation amount of below 70 ℃ of 90 percent, after stirring until the solution is clear, the temperature is adjusted to 15 ℃, then the hydrocortisone sodium succinate is added and the solution is stirred, finally the pH is adjusted to 7.5 by using sodium hydroxide solution, and the volume is fixed to 1000mL by using water for injection.
(2) Filtering the liquid medicine obtained in the step (1) by using a microporous filter membrane with the diameter of 0.22 microns, sub-packaging the liquid medicine into penicillin bottles, and half-tamponade.
(3) And (3) freeze-drying the liquid medicine liquid split-packed in the step (2), and pressing and capping to obtain the hydrocortisone sodium succinate for injection.
Example 2-1
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-40 ℃ for 2 hours, and preserving the heat for 3 hours;
(2) annealing: heating the oil temperature to-20 ℃ for 1 hour, and preserving heat for 2 hours; then the oil temperature was reduced to-40℃for 2 hours and incubated for 2 hours.
(3) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-5 ℃ for 2 hours, and the temperature is kept for 8 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 45 ℃ for 1 hour, and the temperature is kept for 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1.5 hours.
Example 2-2
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) annealing: heating the oil temperature to-6 ℃ for 1 hour, and preserving the heat for 1 hour; then the oil temperature is reduced to-50 ℃ for 1 hour, and the temperature is kept for 4 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 10 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 6 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 2 to 3
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-45 ℃ for 2 hours, and preserving the heat for 5 hours;
(2) annealing: heating the oil temperature to-10 ℃ for 1 hour, and preserving the heat for 1.5 hours; then the oil temperature is reduced to-45 ℃ for 2 hours, and the temperature is kept for 5 hours;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is increased to-12 ℃ for 1 hour, and heat preservation is carried out for 8 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 2 to 4
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-55 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) annealing: raising the oil temperature to-5 ℃ for 2 hours, and preserving the heat for 0.5 hour; then the oil temperature is reduced to-55 ℃ for 1 hour, and the temperature is kept for 4 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-7 ℃ for 2 hours, and the temperature is kept for 15 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 45 ℃ for 1 hour, and the temperature is kept for 5 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 hour.
Examples 2 to 5
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 10 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 6 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 2 to 6
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 5 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ for 2 hours, and the temperature is kept for 16 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Example 3 (500 mg/bottle gauge in hydrocortisone)
This example provides a 500 mg/bottle specification injection hydrocortisone sodium succinate prescription process wherein the dosing ratio is as follows:
the preparation method comprises the following steps:
(1) 133.68g of hydrocortisone sodium succinate, 0.92g of sodium dihydrogen phosphate monohydrate and 8.30g of anhydrous disodium hydrogen phosphate are accurately weighed, 80% of the preparation amount of water for injection below 70 ℃ is used for dissolving the sodium dihydrogen phosphate monohydrate and the anhydrous disodium hydrogen phosphate, after stirring until the solution is clear, the temperature is adjusted to 20 ℃, then the hydrocortisone sodium succinate is added and the solution is stirred, finally the pH is adjusted to 7.9 by using a sodium hydroxide solution, and the volume is fixed to 1000mL by using water for injection.
(2) Filtering the liquid medicine obtained in the step (1) by using a microporous filter membrane with the diameter of 0.22 microns, sub-packaging the liquid medicine into penicillin bottles, and half-tamponade.
(3) And (3) freeze-drying the liquid medicine after the split charging in the step (2), and pressing and capping to obtain the hydrocortisone sodium succinate for injection.
Example 3-1
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-65 ℃ for 0.5 hour, and preserving the heat for 8 hours;
(2) annealing: raising the oil temperature to-30 ℃ for 3 hours, and preserving the heat for 0.5 hour; then the oil temperature is reduced to-65 ℃ for 3 hours, and the temperature is kept for 1 hour;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is increased to-3 ℃ for 2 hours, and heat preservation is carried out for 72 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 50 ℃ for 3 hours, and the temperature is kept for 2 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 2 hours.
Example 3-2
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) annealing: heating the oil temperature to-6 ℃ for 1 hour, and preserving the heat for 1 hour; then the oil temperature is reduced to-50 ℃ for 1 hour, and the temperature is kept for 4 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 50 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 3 to 3
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-45 ℃ for 2 hours, and preserving the heat for 5 hours;
(2) annealing: heating the oil to-5 ℃ for 1 hour, and preserving the heat for 1.5 hours; then the oil temperature is reduced to-45 ℃ for 2 hours, and the temperature is kept for 5 hours;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is increased to-12 ℃ for 1 hour, and heat preservation is carried out for 55 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 9 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 3 to 4
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-55 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) annealing: raising the oil temperature to-10 ℃ for 2 hours, and preserving the heat for 0.5 hour; then the oil temperature is reduced to-55 ℃ for 1 hour, and the temperature is kept for 4 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-7 ℃ for 2 hours, and the temperature is kept for 40 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 45 ℃ for 1 hour, and the temperature is kept for 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 hour.
Examples 3 to 5
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-60 ℃ for 1 hour, and preserving the heat for 6 hours;
(2) annealing: raising the oil temperature to-5 ℃ for 2 hours, and preserving the heat for 0.5 hour; then the oil temperature is reduced to minus 60 ℃ for 1 hour, and the temperature is kept for 5 hours;
(3) sublimation drying: vacuum degree is controlled to be 10-30 Pa, oil temperature is raised to-15 ℃ for 1 hour, and heat preservation is carried out for 55 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 35 ℃ for 2 hours, and the temperature is kept for 4 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 hour.
Examples 3 to 6
Wherein the freeze-drying operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 50 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Examples 3 to 7
Wherein the freeze-drying operation:
(1) pre-freezing: the oil temperature is reduced to-50 ℃ for 1 hour, and the temperature is kept for 6 hours.
(2) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ for 2 hours, and the temperature is kept for 60 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 12 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Comparative example 1
The comparative example specifications, recipe and example 1 were identical, with the preparation method differing only in the lyophilization operation:
(1) pre-freezing: cooling the oil temperature to-40 ℃ for 0.5 hour, and preserving the heat for 2 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-10 ℃ for 2 hours, and the temperature is kept for 2 hours; heating the oil to-5 ℃, and preserving the heat for 5 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be less than or equal to 10Pa, the oil temperature is increased to 35 ℃ for 2 hours, and the temperature is kept for 2 hours.
Comparative example 2
The comparative example specifications, recipe and example 2 were identical, with the preparation method differing only in the lyophilization operation:
(1) pre-freezing: cooling the oil temperature to-70 ℃ for 2 hours, and preserving the heat for 7 hours;
(2) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 28 ℃ for 2 hours, and the temperature is kept for 12 hours;
(3) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ for 1 hour, and the temperature is kept for 2 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Comparative example 3
The comparative example specifications, recipe and example 3 were identical, with the preparation method differing only in the lyophilization operation:
(1) pre-freezing: cooling the oil temperature to-50 ℃ for 1 hour, and preserving the heat for 4 hours;
(2) annealing: heating the oil temperature to 10 ℃ for 1 hour, and preserving the heat for 1 hour; then the oil temperature is reduced to-50 ℃ for 1 hour, and the temperature is kept for 4 hours;
(3) sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 8 ℃ below zero for 2 hours, and the temperature is kept for 50 hours;
(4) and (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ for 2 hours, and the temperature is kept for 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 1 hour.
Test example 1 quality comparison test
The mass comparison of the hydrocortisone sodium succinate for injection provided in examples 1-1 to 3-7 and comparative examples 1-3 with the original developer for 0 hour and 10 days (60 ℃ C.) is shown in the following table:
note that: the data of the original developer at the time of 0 cannot be obtained, which is calculated by the data of the original developer after leaving the factory for 6 months.
The properties, moisture and reconstitution time of the hydrocortisone sodium succinate for injection provided in examples 1-1 to 3-7 and comparative examples 1-3 under the illumination condition (4500 Lx+/-500 Lx is placed for 10 days) show similar trend with the high temperature condition of 60 ℃, and the quality of the hydrocortisone sodium succinate for injection is better than that of the comparative examples and similar to that of the original preparation.
Test example 2 investigation of substances
The sodium hydrocortisone succinate for injection provided in examples 1-1 to 3-7 and comparative examples 1-3 was examined with respect to the original developer at 0 hour and 10 days (60 ℃ C.), and the results are shown in the following table:
the inspection results of the relevant substances of the hydrocortisone sodium succinate for injection provided in examples 1-1 to 3-7 and comparative examples 1-3 under the illumination condition (4500 Lx+/-500 Lx is placed for 10 days) show similar trend with the high temperature condition of 60 ℃, and the stability of the examples is better than that of the comparative examples and is similar to that of the original preparation.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The preparation method of hydrocortisone sodium succinate for injection is characterized by comprising the following steps of: dissolving hydrocortisone sodium succinate and buffer salt in water for injection to form a liquid medicine, regulating the pH value to 7.5-7.9, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection, wherein the freeze-drying step comprises the following steps of:
(a) Pre-freezing: the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 2 to 8 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 20 ℃ to minus 3 ℃, and the temperature is kept for 8 hours to 72 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ to 50 ℃, and the temperature is kept for 2 hours to 15 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 2 hours.
2. The method for preparing hydrocortisone sodium succinate for injection according to claim 1, wherein the freeze-drying step comprises:
(a) Pre-freezing: the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 2 to 8 hours;
(b) Annealing: raising the oil temperature to-30 to-3 ℃ and preserving the heat for 0.5 to 3 hours; then the temperature of the oil is reduced to-65 ℃ to-32 ℃ and the temperature is kept for 1 to 6 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 20 ℃ to minus 3 ℃, and the temperature is kept for 8 hours to 72 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 30 ℃ to 50 ℃, and the temperature is kept for 2 hours to 15 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 2 hours.
3. The method for preparing hydrocortisone sodium succinate for injection according to claim 2, wherein the freeze-drying comprises the following steps:
(a) Pre-freezing: the temperature of the oil is reduced to minus 60 ℃ to minus 40 ℃ and the temperature is kept for 3 to 6 hours;
(b) Annealing: raising the temperature of oil to-20 to-5 ℃ and preserving heat for 0.5 to 2 hours; then the temperature of the oil is reduced to minus 60 ℃ to minus 40 ℃ and the temperature is kept for 2 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to minus 15 ℃ to minus 5 ℃ for 1 hour to 2 hours, and the temperature is kept for 8 hours to 55 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 35 ℃ to 45 ℃, and the temperature is kept for 4 hours to 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1.5 hours.
4. A process for the preparation of hydrocortisone sodium succinate for injection according to claim 3 wherein the buffer salt is selected from phosphate buffer system, citrate buffer system or acetate buffer system.
5. The preparation method of hydrocortisone sodium succinate for injection according to claim 4, wherein the raw and auxiliary materials of the hydrocortisone sodium succinate for injection comprise the following proportions: hydrocortisone sodium succinate: sodium dihydrogen phosphate monohydrate: the mass ratio of anhydrous disodium hydrogen phosphate is 66.84: (0.44-0.48): (4.15-4.58), regulating the pH value to 7.5-7.9 by sodium hydroxide or hydrochloric acid, and fixing the volume of the water for injection.
6. The method for preparing hydrocortisone sodium succinate for injection according to claim 5, wherein the freeze-drying step comprises, when the specification of the hydrocortisone sodium succinate for injection is 50 mg/bottle in terms of hydrocortisone:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 3 to 4 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 3 to 4 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 8 hours to 12 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 4 hours to 6 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
7. The method for preparing hydrocortisone sodium succinate for injection according to claim 5, wherein the freeze-drying step comprises, when the specification of the hydrocortisone sodium succinate for injection is 100 mg/bottle in terms of hydrocortisone:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 8 hours to 15 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 5 hours to 8 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
8. The method for preparing hydrocortisone sodium succinate for injection according to claim 5, wherein the freeze-drying step comprises, when the specification of the hydrocortisone sodium succinate for injection is 500 mg/bottle in terms of hydrocortisone:
(a) Pre-freezing: the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(b) Annealing: raising the oil temperature to-10 ℃ to-5 ℃ and preserving the heat for 0.5-1.5 hours; then the temperature of the oil is reduced to minus 55 ℃ to minus 45 ℃ and the temperature is kept for 4 to 5 hours;
(c) Sublimation drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to-12 ℃ to-7 ℃, and the temperature is kept for 40 hours to 55 hours;
(d) And (5) analysis and drying: the vacuum degree is controlled to be 10Pa to 30Pa, the oil temperature is increased to 40 ℃ to 45 ℃, and the temperature is kept for 8 hours to 10 hours; the temperature is unchanged, the vacuum degree is less than or equal to 10Pa, and the temperature is kept for 0.5 to 1 hour.
9. The method for preparing hydrocortisone sodium succinate for injection according to any one of claims 1-8, comprising the following steps: weighing hydrocortisone sodium succinate and buffer salt, dissolving the buffer salt in water for injection to form a buffer salt solution, regulating the temperature of the buffer salt solution to 5-20 ℃, adding the hydrocortisone sodium succinate into the buffer salt solution, stirring for dissolving, regulating the pH value to 7.5-7.9, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection.
10. The method for preparing hydrocortisone sodium succinate for injection according to claim 9, comprising the following steps: weighing hydrocortisone sodium succinate and buffer salt, dissolving the buffer salt in water for injection to form a buffer salt solution, adjusting the temperature of the buffer salt solution to 5-20 ℃, adding the hydrocortisone sodium succinate into the buffer salt solution, stirring for dissolving, adjusting the pH to 7.6-7.8, filtering the liquid medicine, filling the liquid medicine into a bottle, and freeze-drying to obtain the hydrocortisone sodium succinate for injection.
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