WO2002032401A1 - Produit a injecter sous forme de poudre a base d'amifostine et son procede de preparation - Google Patents

Produit a injecter sous forme de poudre a base d'amifostine et son procede de preparation Download PDF

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Publication number
WO2002032401A1
WO2002032401A1 PCT/CN2001/000310 CN0100310W WO0232401A1 WO 2002032401 A1 WO2002032401 A1 WO 2002032401A1 CN 0100310 W CN0100310 W CN 0100310W WO 0232401 A1 WO0232401 A1 WO 0232401A1
Authority
WO
WIPO (PCT)
Prior art keywords
amifostine
powder injection
powder
preparing
water
Prior art date
Application number
PCT/CN2001/000310
Other languages
English (en)
Chinese (zh)
Inventor
Peiyuan Cheng
Guang Cheng
Original Assignee
Nanjing Zhenzhong Bioengineering Company Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Zhenzhong Bioengineering Company Ltd filed Critical Nanjing Zhenzhong Bioengineering Company Ltd
Priority to AU2001248229A priority Critical patent/AU2001248229A1/en
Publication of WO2002032401A1 publication Critical patent/WO2002032401A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an amifostine sterile powder injection and its preparation method, and more particularly to an amifostine non-lyophilized powder injection with improved stability and preparation thereof method.
  • Amifostine (dithiophosphoric acid S 2 (3-aminopropylamino) ethyl ester, English name amifostme) is a broad-spectrum cytoprotective agent.
  • a military anti-radiation agent it is now generally used as a protective agent for radiotherapy and chemotherapy. It is effective in reducing the side effects of anti-cancer drugs such as cyclophosphamide, chloraplatin, doxorubicin and anti-HIV drugs such as 3-azido-3-deoxythymidine, and does not affect the anti-cancer drugs or anti-HIV drugs. Curative effect.
  • the amifostine product on the market is exclusively produced by American Life Science Co., Ltd. under the trade name ETHY0L.
  • This product is currently only lyophilized powder for injection.
  • this amorphous form produced by lyophilization is thermally unstable. . Therefore, the lyophilized preparation must be maintained at a temperature of about 20 ° C and transported at a temperature of about 70 ° C to -2 ° C to avoid degradation of the formulated product, which is not only inconvenient, but also requires Special packaging and lots of freight.
  • amifostine non-frozen thousand powder injections are either 'dry' or '
  • the powder method involves a large number of practical problems when packing solid amifostine in bulk. Such problems include: the difficulty of manual operation of the powder, the need to grind the powder to an acceptable particle size and flowability, and to maintain Difficulties in dust, aseptic conditions, and the difficulty of loading precise doses of trimethoprim into each vial.
  • amifostine non-frozen mill powder which is generally regarded as a free-to-use ingredient, cannot be prepared and practically used.
  • One aspect of the present invention is to provide a stable, non-frozen amifostine sterile powder injection containing a crystalline composition of amifostine as a single component.
  • the second aspect of the wood invention is to provide a method for preparing a stable non-frozen amifostine amifostine-free powder injection consisting of crystals of amifostine mono-component.
  • the third object of the present invention is also to provide an industrial method for preparing a stable non-frozen amphotine ampoline sterile powder injection.
  • the obtained crystal has a moderate crystal length, has good fluidity without grinding, and can be accurately bottled.
  • the amifostine powder injection is composed of amifostine single-component crystals.
  • the crystal particles have a length of 300 to 700 microns and are non-lyophilized powder injections.
  • the amifostine crystal contains one to three molecules of crystal water, preferably the amifostine crystal contains three molecules of crystal water; water for injection includes Normal saline, distilled water and glucose.
  • the preparation method of amifostine powder injection of the present invention comprises dissolving the amifostine raw material drug in water for injection at a weight ratio of 1: 2 ⁇ 10, and mixing the solution with an alkaline solution to adjust the pH value to 6. 6 ⁇ 7. After 4 hours, then based on the amifostine raw material drug, add ethanol with a concentration of 75 to 98% in a weight ratio of 1: 1 to 5 to freeze and precipitate amifostine crystals with a particle length of 300 to 700 microns.
  • the method for preparing amifostine powder injection of the present invention comprises dissolving the amifostine raw material medicine in water for injection at a weight ratio of 1: 3 to 8, and after mixing, adjust the pH of the solution to 7 with an alkaline solution. After 0 ⁇ 7.2, 75% ethanol was added at a weight ratio of 1: 1 to 5 to 3 based on the amifostine raw material drug, and amifostine crystals having a particle length of 300 to 700 microns were frozen and precipitated.
  • the lye used may be a solution of sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate mixed with water, and one of them may be used alone You can also use any two or three of them together.
  • the freezing crystallization temperature is -16 to 23 ° C, and the freezing time is 5 to 10 hours. After freezing and crystallization, suction filtration, vacuum drying under reduced pressure, and 20 to 50 sieve, preferably 30 sieve after measuring the moisture content, and then divided into vials.
  • amifostine When used, amifostine is calculated as anhydrous. That is, intravenous injection of chemotherapy and radiotherapy drugs half an hour before the use of medicines, calculated based on body surface area, 800 mg per square meter during chemotherapy, 200 mg per square meter during radiotherapy, specific cases should be prescribed by your doctor.
  • the beneficial effect of the present invention is that the stability of the product is increased, no refrigeration is required, and it can be stored at room temperature for a year.
  • amifostine powder injection of the present invention no excipient is added, and the product is left to dry without being frozen and dried, thereby avoiding rabbits.
  • the frozen powdered injection can be repeatedly freeze-dissolved (ie, repeatedly cooled down and warmed up), which may cause the process.
  • the preparation is unstable.
  • the crystals of appropriate size were obtained by adjusting pH, temperature and time.
  • the particle length of the amifostine crystals was 300-700 microns.
  • the crystals of this size were sieved into 30-liter sieve bottles.
  • Amifost me amifostine crystals are colorless and transparent.
  • the experimental crystal size is 0.8 X 0.6 to 0.8.
  • the number of molecules in the cell is 7 4, Pinpinxiu # ⁇ V-1221.6 (6),
  • Figure 1 is a projection of its three-dimensional structure
  • Figure 2 is a diagram of its cell stack.
  • the product of the present invention (1, 3, 5, 12, 18, and 24) were sampled separately. J was sampled by j. ⁇ Each.
  • the item contains the requirements ⁇ wood ⁇ effect; ⁇ less ⁇ ⁇ I ⁇
  • the Z50 + CY group showed the effect of using Nanjing Zhenzhong Amifostine 200 mg / kg.
  • E200 + CY group shows the effect of using 200,200 mg / kg of foreign amifostine products.
  • the CY group indicates the effect of not using amifostine.
  • L color is similar to A color crystal ⁇ spot ⁇ 1.5 ° '. ⁇ 1.0% 99.0
  • silica gel H or silica gel GF254 (Qingdao Ocean Chemical Plant)
  • the color of the impurity spots in the sample is lighter than the color of the control sample, and the content of impurities in the sample can be determined to be less than 1.5%. If the color of the impurity spots in the sample is darker than the color of the control sample, the content of impurities in the sample can be determined to be greater than 1.5% 0
  • HPLC method is the method of amifostine content
  • Tailing factor ⁇ 2 Control ⁇ sheep preparation: Take about 50.0 mg of the reference substance, weigh it accurately, place it in a 25 ml measuring bottle, add 12.5 ml of water to dissolve it, and slowly add methanol to the mark to dilute to the mark.
  • Sample preparation Take about 50 mg of amifostine sample, weigh it accurately and place it in a 25 ml measuring bottle
  • the pH of the solution is measured at 7.0 ⁇ 7.2 Slowly add 125 ml of 98% ethanol, stir well and put it in a freezer (16 ⁇ 23 ° C) for 6 ⁇ 8 hours to precipitate a white crystalline powder with a crystal particle length of 300 ⁇ 7 00 microns, After suction filtration, vacuum drying under reduced pressure, after measuring the water content, sieved through a 30-mesh sieve, and aliquoted into vials.
  • the raw materials of azafotine were prepared according to the method described by Tong Zengshou and other Pharmacological Journals 1981, 16 (4), 302. Under aseptic conditions, at a room temperature of 18-22 ° C, 80 grams of the prepared amifostine drug substance was stirred and dissolved in 180 ml of water for injection. A few drops of a saturated solution of potassium hydroxide were added dropwise, and the pH of the solution was measured. The value is 6.6 ⁇ 6.7, slowly add 80ml of 98% ethanol, stir well and put it in the freezer (-16 ⁇ 23 ° C) for 5 ⁇ 6 hours to precipitate white crystalline powder and crystal particles The length is 300 ⁇ 700 micrometers. After suction filtration, vacuum drying under reduced pressure. After measuring the water content, it is passed through a 30-mesh sieve and divided into vials.
  • the amifostine raw material was prepared according to the method described by Tong Zengshou and other Pharmacological Journals 1981, 16 (4), 302. Under sterile conditions, at room temperature 18 to 22 ° C, 100 g of the prepared amifostine drug substance was stirred and dissolved in 500 ml of distilled water for injection, and a mixed saturated solution of sodium hydroxide and sodium bicarbonate was added dropwise so that The solution is completely dissolved. The pH of the solution is measured at 6.8 ⁇ 6.9. Slowly add 200ml of 98% ethanol. Stir evenly and put it in the freezer (-16 ⁇ 23 ° C) for 7 ⁇ 8 inches to make it white. A crystalline powder with a crystal particle length of 300 to 700 micrometers.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un agent à injecter sous forme de poudre à base d'amifostine non lyophilisée et son procédé de préparation. Le produit à injecter est obtenu à partir d'un seul ingrédient, à savoir l'amifostine, qui subit une cristallisation. La longueur du granulé cristallisé oscille entre 300 et 700 mm. Le procédé de préparation de ce produit à injecter sous forme de poudre à base d'amifostine consiste à ne pas ajouter d'excipients, à ne pas lyophiliser le produit mais à le sécher sous vide, ce qui permet d'éviter de soumettre le produit à injecter sous forme de poudre à des lyophilisations répétées, à savoir des congélations et des déshydratations alternées qui sont susceptibles de rendre le produit instable. Du reste, le produit à injecter obtenu dans cette invention présente une stabilité bien supérieure à celle des produits commercialisés actuellement dans le monde entier.
PCT/CN2001/000310 2000-10-19 2001-02-28 Produit a injecter sous forme de poudre a base d'amifostine et son procede de preparation WO2002032401A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001248229A AU2001248229A1 (en) 2000-10-19 2001-02-28 Amifostine powder injection and its method of process

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN00119038.5 2000-10-19
CNB001190385A CN1148192C (zh) 2000-10-19 2000-10-19 细胞保护剂氨磷汀制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2002032401A1 true WO2002032401A1 (fr) 2002-04-25

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PCT/CN2001/000310 WO2002032401A1 (fr) 2000-10-19 2001-02-28 Produit a injecter sous forme de poudre a base d'amifostine et son procede de preparation

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Country Link
CN (1) CN1148192C (fr)
AU (1) AU2001248229A1 (fr)
RU (1) RU2264808C2 (fr)
WO (1) WO2002032401A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096901A1 (fr) * 2006-02-24 2007-08-30 Natco Pharma Limited Nouvelle forme dihydrate d'amifostine et son procédé de préparation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101347412B (zh) * 2008-09-02 2011-07-27 大连美罗药业股份有限公司 三水合氨磷汀结晶冻干制剂及其制备方法
CN102286019B (zh) * 2011-07-11 2014-02-05 大连美罗大药厂 二水合3-氨基丙基胺乙基硫代磷酸的制备方法
CN109694386B (zh) * 2019-01-23 2021-03-23 美罗药业股份有限公司 氨磷汀三水合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5167947A (en) * 1989-10-26 1992-12-01 Southwest Research Institute Enhancement of absorption of radioprotective drugs
CN1092980A (zh) * 1992-07-31 1994-10-05 美国生物科学有限公司 结晶硫代磷酸二氢s-2-(3-氨丙氨基)乙酯组合物及其制备和使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5167947A (en) * 1989-10-26 1992-12-01 Southwest Research Institute Enhancement of absorption of radioprotective drugs
CN1092980A (zh) * 1992-07-31 1994-10-05 美国生物科学有限公司 结晶硫代磷酸二氢s-2-(3-氨丙氨基)乙酯组合物及其制备和使用方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHU ZHU: "Antiradiation agent: Amifostine", JOURNAL OF CHINESE PHARMACY, vol. 34, no. 1, 1999, pages 58 - 59 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096901A1 (fr) * 2006-02-24 2007-08-30 Natco Pharma Limited Nouvelle forme dihydrate d'amifostine et son procédé de préparation

Also Published As

Publication number Publication date
RU2264808C2 (ru) 2005-11-27
CN1148192C (zh) 2004-05-05
CN1291475A (zh) 2001-04-18
AU2001248229A1 (en) 2002-04-29

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