WO2001047542A1 - Preparations de vancomycine - Google Patents

Preparations de vancomycine Download PDF

Info

Publication number
WO2001047542A1
WO2001047542A1 PCT/JP2000/009438 JP0009438W WO0147542A1 WO 2001047542 A1 WO2001047542 A1 WO 2001047542A1 JP 0009438 W JP0009438 W JP 0009438W WO 0147542 A1 WO0147542 A1 WO 0147542A1
Authority
WO
WIPO (PCT)
Prior art keywords
vancomycin
solution
polyethylene glycol
injection
water
Prior art date
Application number
PCT/JP2000/009438
Other languages
English (en)
Japanese (ja)
Inventor
Tomio Watanabe
Rieko Hamano
Norifumi Miyamoto
Original Assignee
Meiji Seika Kaisha, 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 Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.
Priority to AU22316/01A priority Critical patent/AU2231601A/en
Publication of WO2001047542A1 publication Critical patent/WO2001047542A1/fr

Links

Classifications

    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a 'preparation, and more particularly, to a freeze-dried vancomycin preparation having excellent stability and solubility, and further having reduced renal toxicity.
  • Vancomycin is a glycopeptide antibiotic derived from Streptomyces orien talis and is mainly effective against Gram-negative bacteria. When vancomycin is used as an injection, its mineral acid salt is often used in the form of a powder or lyophilized form and dissolved before administration.
  • vancomycin hydrochloride may cause renal disorders such as acute renal failure and interstitial nephritis as side effects, and it is necessary to administer it carefully, such as by conducting periodic tests. Was.
  • the present invention relates to a vancomycin preparation which suppresses the chemical decomposition of vancomycin by a normal production method that does not use an organic solvent or the like in which a residual solvent is problematic, has stable and good solubility, and further has reduced toxicity to kidneys.
  • it aims to provide a freeze-dried preparation of vancomycin.
  • the present inventors have surprisingly found that combining vancomycin with polyethylene glycol stabilizes vancomycin and improves the solubility of the preparation. We have also surprisingly found that the resulting composition has reduced kidney toxicity. The present invention is based on these findings.
  • a formulation according to the present invention is a vancomycin formulation comprising vancomycin or a pharmaceutically acceptable salt thereof and polyethylene glycol.
  • the formulation according to the present invention is advantageous in that it can be easily prepared, the chemical degradation of vancomycin during storage is suppressed, the stability and solubility are excellent, and the toxicity to the kidney is reduced.
  • Vancomycin used in the present invention can be produced, for example, by the method described in US Pat. No. 3,670,999. Alternatively, commercially available pharmaceutical grade drug substances can be used. Since the free base of vancomycin is poorly soluble in water, it is not preferable as it is as an API for injection. The free base is converted into a water-soluble salt and then supplied as an API for injection. Accordingly, the pharmaceutically acceptable salts of vancomycin used in the present invention include water-soluble salts, for example, water-soluble inorganic salts such as hydrochloride and sulfate, and water-soluble organic salts. Particularly, hydrochloride is preferable.
  • the average molecular weight of the polyethylene glycol used in the present invention is from 300 to 200,000.
  • those having an average molecular weight of 300 to 200, more preferably those having an average molecular weight of 400 are preferably used.
  • the amount of polyethylene glycol is usually 4 to 50 parts by weight, preferably 6 to 40 parts by weight, and more preferably 8 to 25 parts by weight, based on 100 parts by weight of vancomycin. Although the stability increases with the increase in the amount of polyethylene glycol, sufficient stability can be ensured by adding up to 50 parts.
  • additives can be added to increase the solubility of the lyophilized preparation or to adjust the pH or osmotic pressure as an injection.
  • additives are not particularly limited as long as they are substances and addition amounts usually used as additives for pharmaceuticals.
  • the following additives may be added as needed.
  • pH adjuster examples include hydrochloric acid, phosphoric acid, citric acid, malic acid, tartaric acid, succinic acid or salts thereof, sodium hydroxide, potassium hydroxide and the like.
  • salts such as sodium chloride and chlorinated glucose
  • sugars such as sucrose and glucose
  • sugar alcohols such as mannitol, sorbitol and xylitol
  • vancomycin or a pharmaceutically acceptable salt thereof, polyethylene glycol, a sugar alcohol, and various additives such as a pH adjuster, if necessary, are dissolved in an aqueous medium, Perform aseptic filtration using a membrane filter.
  • the sterile solution is dispensed into vials, trays, etc., and prepared by the usual freeze-drying method.
  • a vancomycin infusion kit that can be stably stored and can be easily prepared at the time of use can also be provided.
  • a 5 OmL solution was prepared by adding 500 mg of vancomycin hydrochloride and 10 Omg of polyethylene glycol (Macrogol 400) as a stabilizer per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22 m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. Following the normal freeze-drying method, cool to --40 ° C, freeze and hold for 2 hours, then reduce the water content under 10 OmT 0 rr or less, at -10 ° C for 20 hours, and at 40 ° C for 10 hours. Was dried by sublimation, the vacuum was released with nitrogen gas, and the mixture was sealed to give a freeze-dried preparation.
  • Macrogol 400 polyethylene glycol
  • 5 OmL was prepared by adding 50 Omg of vancomycin hydrochloride and 10 Omgs of polyethylene glycol (Macrogol 400) as a stabilizer per 100 mL of mannitol per 5 mL of water for injection.
  • the solution was aseptically filtered through a membrane filter one (0. 22 urn), this c filled with each drug solution 5mL vial having an inner volume of about 15 mL, in accordance with conventional freeze drying method, freeze and cooled to one 40 ° C And hold for 2 hours, under reduced pressure of 10 OmTorr or less, — Sublimate moisture at 10 ° C for 20 hours and further at 40 ° C for 10 hours, dry, release the vacuum with nitrogen gas, stopper tightly and freeze-dried It was decided.
  • a 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 40 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 10 Omg of mannitol per 5 mL of water for injection.
  • This solution was aseptically filtered through a membrane filter (0.22 IJL m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This was subjected to the same operation as in Example 1 to obtain a lyophilized preparation.
  • a 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride per 5 mL of water for injection and 80 mg of polyethylene glycol (Macrogol 400) 80 mg s mannitol as a stabilizer. This solution was aseptically filtered through a membrane filter (0.22 ⁇ m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This was subjected to the same operation as in Example 1 to obtain a lyophilized preparation. 0 Example 5
  • a 5 OmL solution was prepared by adding 500 mg of vancomycin hydrochloride, 120 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 100 mg of mannitol per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22 Mm), and 5 mL each of the drug solution was filled into a vial having an internal volume of about 15 mL. C This was obtained in the same manner as in Example 1 to obtain a freeze-dried preparation.
  • a 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 100 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 300 mg of mannitol per 5 mL of water for injection.
  • the solution was aseptically filtered through a membrane filter evening scratch (0. 22 um), this c filled by chemical 5 mL of the vial having an inner volume of about 15 mL, to give a freeze-dried preparation in the same manner as in Example 1 Was.
  • a 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 100 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 200 mg of mannitol per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22; m), and 5 mL each of the drug solution was filled into a vial with an internal volume of about 15 mL. C This was then freeze-dried in the same manner as in Example 1. I got
  • a 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride and 10 Omg of polyethylene glycol (Macrogol 400) as a stabilizer per 150 mL of water for injection. This solution was aseptically filtered through Yuichi Membrane Filler (0.22 ⁇ m), and 5 mL each of the drug solution was filled into a vial with an internal volume of about 15 mL. C The freeze-dried preparation was obtained in the same manner as in Example 1. .
  • Vancomycin hydrochloride (50 Omg) and L-arginine (18 Omg) as a stabilizer were dissolved per 5 mL of water for injection, and hydrochloric acid was added to adjust the pH to 4, to thereby prepare 5 OmL.
  • This solution was aseptically filtered through a membrane filter (0.22 ⁇ m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This is the same as in Example 1.
  • a freeze-dried preparation was obtained in the same manner as in b.
  • Example 2 50 mL of a solution in which 50 Omg of vancomycin hydrochloride was dissolved per 5 mL of water for injection was prepared. This solution was aseptically filtered through a membrane filter (0.22 / m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. A lyophilized preparation was obtained in the same manner as in Example 1.
  • Triethylamine buffer Add 2000 mL of water to 4 mL of triethylamine, mix and adjust the pH to 3.2 with phosphoric acid.
  • Solution A and Solution B are sent according to Table 1 below. The linear gradient was performed for 12 to 20 minutes and 22 to 23 minutes.
  • Test medium composition Mobile phase A Triethylamine buffer / acetonitrile
  • Vancomycin B (%) X 100
  • Comparative Example 1 formulation containing arginine as a stabilizer
  • Comparative Example 2 formulation containing D-mannitol as a stabilizer
  • Comparative Example 3 formulation without additives
  • Comparative Example 1 (formulation containing arginine as stabilizer), Comparative Example 2 (formulation containing D-mannitol as stabilizer), and Comparative Example 3 ( It was confirmed that the solubility of each of the formulations containing the polyethylene glycol of the present invention was improved as compared with the formulation without the additive.
  • Example 1 In male SD rats (6 weeks of age), the formulation of Example 1 and the formulation of Comparative Example 3 were prepared with physiological saline so that the dose was 1 OmL / kg, and 40 Omg / kg was intravenously administered. After 24 hours, renal light microscopy was performed. Table 4 shows the results.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des préparations de vancomycine (en particulier des préparations lyophilisées) produites à l'aide d'un procédé de fabrication classique n'utilisant pas de solvant organique afin d'éviter une décomposition chimique de la vancomycine. Ces préparations présentent une stabilité et une solubilité élevées, et une toxicité rénale réduite. Elles contiennent de la vancomycine ou des sels pharmaceutiquement acceptables de celle-ci, et du polyéthylène glycol.
PCT/JP2000/009438 1999-12-28 2000-12-28 Preparations de vancomycine WO2001047542A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22316/01A AU2231601A (en) 1999-12-28 2000-12-28 Vancomycin preparations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/375258 1999-12-28
JP37525899 1999-12-28

Publications (1)

Publication Number Publication Date
WO2001047542A1 true WO2001047542A1 (fr) 2001-07-05

Family

ID=18505231

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/009438 WO2001047542A1 (fr) 1999-12-28 2000-12-28 Preparations de vancomycine

Country Status (2)

Country Link
AU (1) AU2231601A (fr)
WO (1) WO2001047542A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009004592A1 (fr) * 2007-07-03 2009-01-08 Wockhardt Research Centre Compositions de vancomycine
JP2009149619A (ja) * 2007-11-28 2009-07-09 Nichi-Iko Pharmaceutical Co Ltd グリコペプチド類含有凍結乾燥組成物及びその製造方法
JP2010105965A (ja) * 2008-10-30 2010-05-13 Taiyo Yakuhin Kogyo Kk バンコマイシン製剤
US20100286031A1 (en) * 2005-09-29 2010-11-11 Charan Chatan K Antibiotic Formulations, Unit Doses, Kits and Methods
JP2011153119A (ja) * 2010-01-27 2011-08-11 Mylan Seiyaku Ltd バンコマイシンまたはその塩を含有する錠剤
JP2014501781A (ja) * 2011-01-05 2014-01-23 ホスピラ・インコーポレイテツド バンコマイシンの噴霧乾燥
US9428291B2 (en) 2013-03-15 2016-08-30 Choon Teo Method and system for producing high purity vancomycin hydrochloride
US11638692B2 (en) 2014-03-14 2023-05-02 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50148594A (fr) * 1974-05-20 1975-11-28
EP0095897A2 (fr) * 1982-05-28 1983-12-07 Beecham Group Plc Formulations pharmaceutiques
US5756552A (en) * 1994-10-13 1998-05-26 Wakamoto Pharmaceutical Co., Ltd. Lyophilized pharmaceutical preparations capable of providing aqueous drug composition having property of reversible thermosetting gelation
JPH1180022A (ja) * 1997-07-10 1999-03-23 Meiji Seika Kaisha Ltd バンコマイシンの凍結乾燥製剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50148594A (fr) * 1974-05-20 1975-11-28
EP0095897A2 (fr) * 1982-05-28 1983-12-07 Beecham Group Plc Formulations pharmaceutiques
US5756552A (en) * 1994-10-13 1998-05-26 Wakamoto Pharmaceutical Co., Ltd. Lyophilized pharmaceutical preparations capable of providing aqueous drug composition having property of reversible thermosetting gelation
JPH1180022A (ja) * 1997-07-10 1999-03-23 Meiji Seika Kaisha Ltd バンコマイシンの凍結乾燥製剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOWTLE W.: "A new approach to vancomycin formulation using filling technology for semi-solid matrix capsules", PHARM. TECHNOL., vol. 12, no. 6, June 1988 (1988-06-01), XP002938041 *
BOWTLE W.: "The application of semi-solid capsule technology to antibiotic formulation", BOLL. CHIM. FARM., vol. 125, no. 2, 1986, pages 72 - 74, XP002938042 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100286031A1 (en) * 2005-09-29 2010-11-11 Charan Chatan K Antibiotic Formulations, Unit Doses, Kits and Methods
US9351930B2 (en) 2005-09-29 2016-05-31 Bayer Intellectual Property Gmbh Antibiotic formulations, unit doses, kits, and methods
US9351929B2 (en) 2005-09-29 2016-05-31 Bayer Intellectual Property Gmbh Antibiotic formulations, unit doses, kits, and methods
US9205050B2 (en) * 2005-09-29 2015-12-08 Bayer Intellectual Property Gmbh Antibiotic formulations, unit doses, kits and methods
WO2009004592A1 (fr) * 2007-07-03 2009-01-08 Wockhardt Research Centre Compositions de vancomycine
JP2009149619A (ja) * 2007-11-28 2009-07-09 Nichi-Iko Pharmaceutical Co Ltd グリコペプチド類含有凍結乾燥組成物及びその製造方法
JP2010105965A (ja) * 2008-10-30 2010-05-13 Taiyo Yakuhin Kogyo Kk バンコマイシン製剤
JP2011153119A (ja) * 2010-01-27 2011-08-11 Mylan Seiyaku Ltd バンコマイシンまたはその塩を含有する錠剤
US9023258B2 (en) 2011-01-05 2015-05-05 Hospira, Inc. Spray drying vancomycin
EP2661254A4 (fr) * 2011-01-05 2015-01-28 Hospira Inc Séchage par atomisation de la vancomycine
US8709310B2 (en) 2011-01-05 2014-04-29 Hospira, Inc. Spray drying vancomycin
JP2014501781A (ja) * 2011-01-05 2014-01-23 ホスピラ・インコーポレイテツド バンコマイシンの噴霧乾燥
US9763997B2 (en) 2011-01-05 2017-09-19 Hospira, Inc. Spray drying vancomycin
US9428291B2 (en) 2013-03-15 2016-08-30 Choon Teo Method and system for producing high purity vancomycin hydrochloride
US10799458B2 (en) 2013-03-15 2020-10-13 Zhejiang Medicine Co., Ltd Method and system for producing high purity vancomycin hydrochloride
US11638692B2 (en) 2014-03-14 2023-05-02 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid

Also Published As

Publication number Publication date
AU2231601A (en) 2001-07-09

Similar Documents

Publication Publication Date Title
JP3576180B2 (ja) 改良イフォスファミド凍結乾燥組成物
US11766405B2 (en) Process for the preparation of a freeze-dried pharmaceutical composition containing mitomycin C
JPH08500104A (ja) 結晶質アミホスチン組成物及びその調製方法並びに使用
JP6832281B2 (ja) バンコマイシンの水溶液製剤
JP4142149B2 (ja) バンコマイシンの凍結乾燥製剤
US20160143911A1 (en) Stable and water soluble pharmaceutical compositions comprising pemetrexed
CN110876259B (zh) 注射用组合物
US20080103121A1 (en) Cephalosporin derivative formulation
EP3008064B1 (fr) Sel stable d'arginine de pemetrexed et compositions le comprenant
EP2052723A1 (fr) Préparation lyophilisée stable
EP2958554B1 (fr) Composition stable de bendamustine
JPH03193735A (ja) グリコペプチド系抗生物質の安定化組成物
KR100700963B1 (ko) 켐토테신의 다당체 유도체를 함유하는 동결건조된 액상제제
WO2001047542A1 (fr) Preparations de vancomycine
JP2010105965A (ja) バンコマイシン製剤
WO2008026556A1 (fr) Préparation lyophilisée de 1-méthylcarbapenem
JP2017001995A (ja) 凍結乾燥製剤
US5703111A (en) Stable injectable formulation of BMY-25067
JP6665057B2 (ja) ボルテゾミブを含有する医薬製剤
US20140275122A1 (en) Voriconazole Formulations
WO2017037737A1 (fr) Formulations parentérales de lévosimendan
JP6706988B2 (ja) ボルテゾミブを含有する医薬組成物
WO2022169582A1 (fr) Compositions et procédés d'administration parentérale claire concentrée d'agents thérapeutiques de dantrolène
JP2018095593A (ja) 凍結乾燥製剤及びその製造方法
WO2016079749A2 (fr) Procédé de préparation de formulation parentérale d'anidulafungine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 548134

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase