WO1997019690A1 - Solutions stables d'hydrochlorure de vancomycine - Google Patents

Solutions stables d'hydrochlorure de vancomycine Download PDF

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Publication number
WO1997019690A1
WO1997019690A1 PCT/US1996/018898 US9618898W WO9719690A1 WO 1997019690 A1 WO1997019690 A1 WO 1997019690A1 US 9618898 W US9618898 W US 9618898W WO 9719690 A1 WO9719690 A1 WO 9719690A1
Authority
WO
WIPO (PCT)
Prior art keywords
vancomycin hydrochloride
ethanol
ppt
solutions
vancomycin
Prior art date
Application number
PCT/US1996/018898
Other languages
English (en)
Inventor
Robert L. Robison
Original Assignee
Eli Lilly And Company
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
Priority claimed from GBGB9600213.4A external-priority patent/GB9600213D0/en
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU14071/97A priority Critical patent/AU1407197A/en
Publication of WO1997019690A1 publication Critical patent/WO1997019690A1/fr

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Classifications

    • 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

Definitions

  • This invention relates to aqueous solutions of the antibiotic vancomycin hydrochloride and to a method for improving the stability thereof.
  • Vancomycin is described in U.S. Patent No. 3,067,099. It is a well known antibiotic, often prescribed for the treatment of staphylococcal infections, particularly infections caused by methicillin-resistant strains of staphylococcus . Vancomycin is a fermentation product isolated from the culture broth of Norcardia oi entalis , which produces a mixture of closely related co-fermentation factors, "Factor B" being identified as the manor antibacterial agent in the mixture.
  • vancomycin itself degrades to a number of products including its predominant degradation product, vancomycin
  • Vancomycin is formulated for pharmaceutical use as the hydrochloride salt, vancomycin hydrochloride, which has previously been supplied for oral and parenteral use as a dry- solid or as a frozen liquid preparation.
  • liquid solutions of vancomycin hydrochloride have been impractical as pharmaceutical preparations because of the limited stability of the vancomycin hydrochloride agent in solution. Nevertheless, it is desirable to provide vancomycin hydrochloride in solution so as to reduce the manufacturing costs associated with lyophilization and to reduce hospital labor costs required for reconstitution of the lyophilized product and transfer of the reconstituted material .
  • the present invention provides stable solutions of vancomycin hydrochloride and a method for inhibiting physical and chemical degradation of vancomycin hydrochloride in a solution.
  • the present invention provides stable solutions of vancomycin hydrochloride comprising between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30% v/v ethanol. These solutions are particularly useful for storage in a liquid state not requiring either freezing or freeze drying in order to maintain stability of the active agent.
  • the present invention also provides a method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin hydrochloride, said method comprising including between about 0.5% and about 30% v/v ethanol in said solution.
  • the vancomycin hydrochloride solutions of this invention comprise between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30% v/v of ethanol .
  • Preferred solutions comprise between about 5% and about 12% w/v vancomycin hydrochloride.
  • Solutions comprising between about 10% and 30% v/v ethanol are likewise preferred.
  • Especially preferred solutions comprise 10% w/v vancomycin hydrochloride with either 10% or 20% v/v ethanol.
  • Especially preferred methods comprise including either 10% or 20% v/v ethanol with 10% w/v vancomycin hydrochloride. Cooling vancomycin hydrochloride solutions containing ethanol to 10°C or less further inhibits degradation of vancomycin and thus results in preferred methods. Temperatures of 0°C to 5°C are especially preferred. Vancomycin hydrochloride solutions of the current invention are prepared by slurrying the calculated amount of vancomycin base in a suitable diluent, for example, water or commercially available preparations used for intravenous administration, in which sufficient alcohol to achieve the desired concentration has been included. Many other suitable diluents are known in the art. Hydrochloric acid is then added to form the soluble hydrochloride salt. The solution of vancomycin hydrochloride is adjusted to a final pH of 2.5- 4.5, preferrably 3.1-3.3 and brought to final volume with the diluent.
  • a substantial portion of the hydrochloric acid necessary to convert the base to the salt can be added to a suitable diluent containing sufficient alcohol to achieve the desired concentration prior to adding the vancomycin base.
  • the resulting solution is adjusted to a final pH of 2.5-4.5, preferrably 3.1-3.3, and brought to final volume with the diluent.
  • the solutions thus prepared are filtered through 0.2 micron membranes to clarify them and render them particulate free. Filtration may also be used to sterilize solutions.
  • the filtered solutions can then be filled into a variety of pharmaceutically appropriate packages, such as, for example, ampoules, vials, syringes, and bulk packages.
  • Example 1 In order to assess the effect of ethanol on stability of vancomycin hydrochloride solutions, three lots of vancomycin base were converted to vancomycin hydrochloride in a 10% w/v concentrate solution according to the procedures outlined above. Varying concentrations of ethanol were included in the solutions, which were then stored either at room (about 23°C) or refrigerated (about 5°C) temperatures. The solutions were evaluated for purity, retention of potency, appearance of degradation products, and physical stability at various time points.
  • vancomycin hydrochloride can be formulated according to the current invention as a liquid that can be easily stored for immediate use.
  • vancomycin hydrochloride solutions can be prepared as a concentrate that is readily diluted or as a solution that is ready for direct administration.
  • formulations of the current invention may be made sufficiently concentrated to eliminate any concern over the ethanolic content of the diluted product.
  • a liquid concentrate containing 100 mg/ml vancomycin hydrochloride and 10% ethanol can be diluted twenty-fold to 5 mg/ml vancomycin hydrochloride and 0.5% ethanol.
  • a typical 500 mg dose of vancomycin hydrochloride could be administered in a 100 ml intravenous solution containing 0.5 ml ethanol.
  • a 1 g dose of vancomycin hydrochloride could be administered in a 200 ml intravenous solution.
  • ethanol occurs at very low ethanol concentrations and may be included in concentrations as low as 0.5% to improve stability of dilute vancomycin hydrochloride solutions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des solutions stables d'hydrochlorure de vancomycine comportant entre environ 0,5 % et environ 12 % en poids/volume d'hydrochlorure de vancomycine et entre environ 0,5 % et environ 30 % en pourcentage volumique d'éthanol. Ces solutions sont particulièrement utiles au stockage à l'état liquide sans que la congélation ou la lyophilisation soient nécessaires pour maintenir la stabilité de l'agent actif. Est également décrit un procédé d'inhibition de la dégradation d'hydrochlorure de vancomycine dans une solution contenant entre environ 0,5 % et environ 12 % en poids/volume d'hydrochlorure de vancomycine, ce procédé consistant à inclure entre environ 0,5 % et environ 30 % en pourcentage volumique d'éthanol dans cette solution.
PCT/US1996/018898 1995-12-01 1996-11-25 Solutions stables d'hydrochlorure de vancomycine WO1997019690A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14071/97A AU1407197A (en) 1995-12-01 1996-11-25 Stable vancomycin hydrochloride solutions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US782495P 1995-12-01 1995-12-01
US60/007,824 1995-12-01
GBGB9600213.4A GB9600213D0 (en) 1996-01-05 1996-01-05 Stable vancomycin hydrochloride solutions
GB9600213.4 1996-01-05

Publications (1)

Publication Number Publication Date
WO1997019690A1 true WO1997019690A1 (fr) 1997-06-05

Family

ID=26308428

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/018898 WO1997019690A1 (fr) 1995-12-01 1996-11-25 Solutions stables d'hydrochlorure de vancomycine

Country Status (3)

Country Link
AU (1) AU1407197A (fr)
CA (1) CA2238872A1 (fr)
WO (1) WO1997019690A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999017793A1 (fr) * 1997-10-03 1999-04-15 Fujisawa Pharmaceutical Co., Ltd. Chlorhydrates de vancomycines antibiotiques et leur procede de production
WO2015138983A1 (fr) 2014-03-14 2015-09-17 Cutispharma, Inc. Composition de vancomycine orale liquide et procédé associé
WO2016071495A1 (fr) 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides
WO2016127087A1 (fr) * 2015-02-06 2016-08-11 Latitude Pharmaceuticals, Inc. Formulations de solutions aqueuses de vancomycine
WO2017194385A1 (fr) 2016-05-09 2017-11-16 Xellia Pharmaceuticals Aps Formulations stabilisées d'antibiotiques glycopeptidiques
WO2020185518A1 (fr) 2019-03-08 2020-09-17 Emphascience, Inc. Formulations pharmaceutiques stables de médicaments peptidiques et protéiques
EP4014969A1 (fr) 2020-12-16 2022-06-22 EVER Valinject GmbH Solution aqueuse
EP4014965A1 (fr) 2020-12-16 2022-06-22 EVER Valinject GmbH Solution aqueuse
US11433115B2 (en) 2020-10-30 2022-09-06 Somerset Therapeutics, Llc Glycopeptide antibiotics liquid formulations and methods and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4885275A (en) * 1987-10-15 1989-12-05 Eli Lilly And Company Vancomycin-HCL solutions and the lyophilization thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4885275A (en) * 1987-10-15 1989-12-05 Eli Lilly And Company Vancomycin-HCL solutions and the lyophilization thereof

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999017793A1 (fr) * 1997-10-03 1999-04-15 Fujisawa Pharmaceutical Co., Ltd. Chlorhydrates de vancomycines antibiotiques et leur procede de production
US10688046B2 (en) 2014-03-14 2020-06-23 Cutispharma, Inc. Composition and method for vancomycin oral liquid
US10959947B2 (en) 2014-03-14 2021-03-30 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid
US10959946B2 (en) 2014-03-14 2021-03-30 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid
US10959948B2 (en) 2014-03-14 2021-03-30 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid
WO2015138983A1 (fr) 2014-03-14 2015-09-17 Cutispharma, Inc. Composition de vancomycine orale liquide et procédé associé
US10959949B2 (en) 2014-03-14 2021-03-30 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid
EP3145527A4 (fr) * 2014-03-14 2018-01-03 Cutispharma, Inc. Composition de vancomycine orale liquide et procédé associé
US10493028B2 (en) 2014-03-14 2019-12-03 Cutispharma, Inc. Composition and method for vancomycin oral liquid
JP2017508807A (ja) * 2014-03-14 2017-03-30 キューティスファーマ インコーポレーテッドＣｕｔｉｓｐｈａｒｍａ， Ｉｎｃ． バンコマイシン経口液体のための組成物および方法
EP4000628A1 (fr) * 2014-03-14 2022-05-25 Azurity Pharmaceuticals, Inc. Composition de vancomycine orale liquide et procédé associé
US11638692B2 (en) 2014-03-14 2023-05-02 Azurity Pharmaceuticals, Inc. Composition and method for vancomycin oral liquid
US11628200B2 (en) 2014-11-06 2023-04-18 Xellia Pharmaceuticals Aps Glycopeptide compositions
US10039804B2 (en) 2014-11-06 2018-08-07 Xellia Pharmaceuticals Aps Glycopeptide compositions
US11517609B2 (en) 2014-11-06 2022-12-06 Xellia Pharmaceuticals Aps Glycopeptide compositions
EP4147710A1 (fr) 2014-11-06 2023-03-15 Xellia Pharmaceuticals ApS Compositions glycopeptidiques en solution
US11000567B2 (en) 2014-11-06 2021-05-11 Xellia Pharmaceuticals Aps Glycopeptide compositions
WO2016071495A1 (fr) 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides
EP3834837A1 (fr) 2014-11-06 2021-06-16 Xellia Pharmaceuticals ApS Compositions de glycopeptide
US10849956B2 (en) 2014-11-06 2020-12-01 Xellia Pharmaceuticals Aps Glycopeptide compositions
EP3542812A1 (fr) 2014-11-06 2019-09-25 Xellia Pharmaceuticals ApS Compositions de glycopeptide
US10188697B2 (en) 2014-11-06 2019-01-29 Xellia Pharmaceuticals Aps Glycopeptide compositions
AU2016215070B2 (en) * 2015-02-06 2020-09-24 Latitude Pharmaceuticals, Inc. Aqueous solution formulations of vancomycin
JP2018507848A (ja) * 2015-02-06 2018-03-22 ラティチュード ファーマシューティカルズ インコーポレイテッド バンコマイシンの水溶液製剤
WO2016127087A1 (fr) * 2015-02-06 2016-08-11 Latitude Pharmaceuticals, Inc. Formulations de solutions aqueuses de vancomycine
US10376560B2 (en) 2015-02-06 2019-08-13 Latitude Pharmaceuticals, Inc. Aqueous solution formulations of vancomycin
CN107106585A (zh) * 2015-02-06 2017-08-29 杭州美南医药科技有限公司 万古霉素的水溶液制剂
CN109069580A (zh) * 2016-05-09 2018-12-21 埃克斯利亚制药有限公司 稳定化的糖肽抗生素配制品
WO2017194385A1 (fr) 2016-05-09 2017-11-16 Xellia Pharmaceuticals Aps Formulations stabilisées d'antibiotiques glycopeptidiques
US10729708B2 (en) 2016-05-09 2020-08-04 Xellia Pharmaceuticals Aps Stabilized glycopeptide antibiotic formulations
WO2020185518A1 (fr) 2019-03-08 2020-09-17 Emphascience, Inc. Formulations pharmaceutiques stables de médicaments peptidiques et protéiques
US11433115B2 (en) 2020-10-30 2022-09-06 Somerset Therapeutics, Llc Glycopeptide antibiotics liquid formulations and methods and uses thereof
EP4014965A1 (fr) 2020-12-16 2022-06-22 EVER Valinject GmbH Solution aqueuse
WO2022129264A1 (fr) 2020-12-16 2022-06-23 Ever Valinject Gmbh Solution aqueuse
WO2022129263A1 (fr) 2020-12-16 2022-06-23 Ever Valinject Gmbh Solution aqueuse
EP4014969A1 (fr) 2020-12-16 2022-06-22 EVER Valinject GmbH Solution aqueuse

Also Published As

Publication number Publication date
CA2238872A1 (fr) 1997-06-05
AU1407197A (en) 1997-06-19

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