WO2018096556A1 - Compositions pharmaceutiques lyophilisées de dalbavancine - Google Patents

Compositions pharmaceutiques lyophilisées de dalbavancine Download PDF

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Publication number
WO2018096556A1
WO2018096556A1 PCT/IN2017/050546 IN2017050546W WO2018096556A1 WO 2018096556 A1 WO2018096556 A1 WO 2018096556A1 IN 2017050546 W IN2017050546 W IN 2017050546W WO 2018096556 A1 WO2018096556 A1 WO 2018096556A1
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WO
WIPO (PCT)
Prior art keywords
dalbavancin
composition
lyophilized
pharmaceutical composition
lyophilized pharmaceutical
Prior art date
Application number
PCT/IN2017/050546
Other languages
English (en)
Inventor
Mitesh Natavarlal Patel
Mafatlal Tribhovandas DAVE
Beena Pourusashap ANKLESARIA
Pranavkumar Jayesh Choksi
Original Assignee
Gufic Biosciences Limited
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 Gufic Biosciences Limited filed Critical Gufic Biosciences Limited
Priority to RU2019119405A priority Critical patent/RU2019119405A/ru
Priority to EP17873284.8A priority patent/EP3544616A4/fr
Publication of WO2018096556A1 publication Critical patent/WO2018096556A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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

Definitions

  • the present invention relates to lyophilized stable pharmaceutical compositions of Dalbavancin. More particularly, the present invention relates to pharmaceutical compositions comprising dalbavancin and an amino acid.
  • VRE vancomycin resistant enterococci
  • Vancomycin has long been considered the drug of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Its modest efficacy, coupled with increasing reports of treatment failures as a result of elevated vancomycin MICs seen in a proportionally greater number of isolates, has made it increasingly important to find an alternative agent which is effective in the treatment of resistant Gram-positive infections.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Dalbavancin (formerly BI397) is a novel semisynthetic glycopeptide that was engineered to be an improved alternative to the naturally available glycopeptides, vancomycin and teicoplanin. Preliminary in vitro assays and animal models have demonstrated it to be more active than vancomycin or Teicoplanin against Gram- positive bacteria. It is anticipated to be approved by the Food and Drug Administration in the 1st quarter of 2007(International journal of clinical practice., May 2007,61, 5, 853-863).
  • Dalbavancin is a lipoglycopeptide synthesized from a fermentation product of Nonomuraea species.
  • Dalbavancin is a mixture of five closely related active homologs (AO, Al, BO, B l, and B2); the component BO is the major component of dalbavancin.
  • the homologs share the same core structure and differ in the fatty acid side chain of the N- acylaminoglucuronic acid moiety (Rl) structure and/or the presence of an additional methyl group (R2) on the terminal amino group.
  • the BO INN chemical name is: 5,31-dichloro-38-de(methoxycarbonyl)-7- demethyl-19-deoxy-56-O-[2-deoxy-2-[(10-methylundecanoyl)amino]-P-D- glucopyranuronosyl]-38-[[3-(dimethylamino)propyl] carbamoyl]-42-0-a-D- mannopyranosyl-15-N-methyl(ristomycin A aglycone) hydrochloride.
  • Formulal Dalbavancin is marketed as lyophilized product for intravenous infusion by Durata Therapeutics US Limited under the trade name Dalvance® (Dalbavancin) for injection.
  • DALVANCE® (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI), caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus) and Enterococcus faecalis (vancomycin susceptible strains).
  • Staphylococcus aureus including methicillin-susceptible and methicillin-resistant strains
  • Streptococcus pyogenes Streptococcus agalactiae
  • Streptococcus dysgalactiae Streptococcus
  • Dalbavancin is generally unstable to light, heat, humidity and hence it is necessary to develop a pharmaceutical composition for stabilizing the Dalbavancin compound and the salts thereof for parenteral administration.
  • Indian patent number 235498 disclose a dry pharmaceutical composition
  • a dry pharmaceutical composition comprising: i) dalbavancin, ii) at least one stabilizer that is a sugar selected from the group consisting of mannitol, lactose, sucrose, sorbitol, glycerol, cellulose, trehalose, maltose and dextrose, iii) the ratio of dalvabancin to stabilizer is 2: 1 by weight, iv) said formulation has a pH in the range of 4-5, v) said formulation contains no more than about 5% MAG by weight after three months at 40°C.
  • MAG is defined as non-homologous dalbavancin compound lacking an acylglucoronamine moiety and is said to be a decomposition product of one or more of the dalbavancin components.
  • Lactose intolerance is caused due to insufficient amount of enzyme lactase, which breaks lactose into glucose and galactose in the small intestines. The person who suffers from lactose intolerance cannot easily digest lactose.
  • Lactose has been attributed to transmission of certain stable viruses, prions or other infectious or pathogenic compounds, e.g., human transmissible spongiform encephalopathy (TSE). Consequently, there is increased regulatory scrutiny of pharmaceutical compositions containing lactose. Therefore, there is a need for a replacement for mammalian derived stabilizers such as lactose in the formulations.
  • TSE human transmissible spongiform encephalopathy
  • Dalbavancin injectable formulation having no more than about 1% MAG by weight for a storage period of over 3 months at 40°C and 75 % RH and a replacement for mammalian derived stabilizers such as lactose for the preparation of pharmaceutical compositions containing Dalbavancin.
  • the present invention provides pre-lyophilized pharmaceutical formulation comprising Dalbavancin or pharmaceutically acceptable salt thereof along with a suitable stabilizing agent in an aqueous vehicle, wherein, the formulation is free from sugars.
  • pharmaceutically acceptable salt of Dalbavancin is Dalbavancin Hydrochloride.
  • the Dalbavancin Hydrochloride is stabilized by adding an amino acid as a stabilizing agent selected from the group consisting of L-proline, L-arginine, L- serine,etc. in aqueous vehicle to obtain pre-lyophilized formulation.
  • an amino acid as a stabilizing agent selected from the group consisting of L-proline, L-arginine, L- serine,etc.
  • the stabilizing agent is L-proline.
  • the pre-lyophilized pharmaceutical formulation of Dalbavancin Hydrochloride and stabilizing agent is lyophilized and provided as a drug concentrate, suitable for parenteral administration.
  • the lyophilized formulation comprises an effective amount of stabilizer in the range of lOOmg to 1000 mg.
  • the pH of the formulation is maintained in the range of 5.1 to 6 using alkalizing agent such as sodium hydroxide solution.
  • the present invention provides a method for stabilization of Dalbavancin Hydrochloride in an aqueous solution which comprises combining Dalbavancin Hydrochloride in an aqueous vehicle with an amino acid as a stabilizing agent selected from the group consisting of L-proline, L-arginine, L- serine etc.
  • an amino acid as a stabilizing agent selected from the group consisting of L-proline, L-arginine, L- serine etc.
  • an amino acid as a stabilizing agent selected from the group consisting of L-proline, L-arginine, L- serine etc.
  • One preferred amino acid is L-proline.
  • Dalbavancin Hydrochloride is generally unstable to heat, humidity, acid, and the like, it is therefore necessary to develop a stable pharmaceutical composition for parenteral administration or for intravenous infusion.
  • the present invention provides stable pharmaceutically acceptable composition/formulation for parenteral administration or intravenous infusion comprising Dalbavancin Hydrochloride as the active and an amino acid as a suitable stabilizer by maintaining appropriate pH of the formulation.
  • the present invention provides pre-lyophilized pharmaceutical composition
  • a pharmaceutically acceptable amino acid as stabilizing agent selected from the group consisting of L- proline, L-arginine and L-serine in an aqueous vehicle and an alkalizing agent such as sodium hydroxide solution wherein, pH of said composition is in the range of 5.1 to 6.0 and wherein, the pre-lyophilized composition is devoid of sugars.
  • the aqueous vehicle according to the invention is water for injection.
  • Dalbavancin Hydrochloride is present in the composition in an amount ranging from lOOmg to 1000 mg/vial; more preferably 500mg to 1000 mg/vial.
  • Dalbavancin Hydrochloride is stabilized using a suitable stabilizing agent where Dalbavancin Hydrochloride can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Dalbavancin Hydrochloride.
  • the stabilizing agent is selected from the group consisting of an amino acid selected from the group consisting of L-proline, L-arginine, L-serine etc.
  • One preferred stabilizing agent is L-proline.
  • the pre-lyophilized pharmaceutical composition comprises Dalbavancin Hydrochloride in an amount ranging from lOOmg to 1000 mg/vial; an effective amount of L-prolinein the range of lOOmg to lOOOmg as a stabilizing agent in aqueous vehicle and 0.1N sodium hydroxide solution as alkalizing agent for pH adjustment.
  • the pre-lyophilized composition thus provided in aqueous vehicle is filtered to remove particulate matter, filled into vials and subjected to lyophilization cycle to obtain lyophilized composition.
  • the present invention provides lyophilized composition of Dalbavancin Hydrochloride with water content less than 1.5%w/w, preferably in the range of 0.5 to 1.5%w/w; most preferably the water content is in an amount of about 1.0%w/w.
  • the present inventors have observed during experimentation that there is an increase in total impurities on storage of the lyophilized composition of Dalbavancin at 70°C for 7 days and further conducted stability studies on various Dalbavancin compositions so as to provide a stable composition having MAG impurity levels not more than 1%.
  • composition 2 the lyophilized formulation of dalbavancin of the present invention (composition 2) is subjected to accelerated degradation studies at high temperature of 70°C for 7 days and compared the same with marketed formulation (composition 1) and presented the data in table 1, wherein the dalbavancin formulation of the present invention (Composition 2) exhibits more stability over the marketed formulation (composition 1) indicating the suitability of the amino acid over the lactose present in the marketed formulation.
  • the invention provides accelerated degradation studies of the present composition having dalbavancin and amino acid in variable ratio of 1 : 0.6 (composition 3) and l : l(composition 4) at 70 °C for 7 days to assess the minimum amount of the stabilizer required to provide the desired stability.
  • the results are tabulated under table 2. According to the results of table 2, composition 4 exhibits better stability when compared to composition 3.
  • the lyophilized formulation of dalbavancin of the present invention is subjected to accelerated degradation studies at 40°C with relative humidity of 75% moisture for three months and compared the same with marketed formulation and presented the data in table 3, wherein the dalbavancin formulation of the present invention (Composition 6 having dalbavancin to L- proline in a ratio of 1 :0.8) exhibits more stability over the marketed formulation (composition 5).
  • the present invention provides stable, lyophilized pharmaceutical composition for parenteral administration, which is free from sugars, comprising; i) dalbavancin hydrochloride or its pharmaceutically acceptable salt;
  • the composition has a pH in the range of 5.1-6.0 and whereby said composition contains no more than aboutl% MAG by weight after 3 Months at 40°C and 75% RH.
  • the ratio of dalvabancin base to stabilizer is preferably in a ratio of 1 :0.8 to 1 : 1.
  • the amino acid as a stabilizing agent is selected from the group consisting of L- proline, L-arginine, L-serine, etc.
  • the stabilizing agent is L-proline used in an amount of 100 to lOOOmg.
  • the present invention provides stable, lyophilized pharmaceutical composition for parenteral administration, which is free from sugars, comprising;
  • lOOmg to lOOOmg of L-proline in aqueous vehicle as a stabilizing agent iii) lOOmg to lOOOmg of L-proline in aqueous vehicle as a stabilizing agent; iii) Sodium Hydroxide solution as alkalizing agent to regulate pH of said composition in the range of 5.1 -6.0.
  • the lyophilized pharmaceutical composition for parenteral administration comprises Dalbavancin Hydrochloride equivalent to anhydrous Dalbavancinin in an amount of 500 mg/vial and the L-proline in an amount of 400 mg.
  • the lyophilized pharmaceutical composition for parenteral administration comprises Dalbavancin Hydrochloride equivalent to anhydrous Dalbavancinin in an amount of 500 mg/vial and the L-proline in an amount of 500 mg.
  • the invention provides lyophilzation process which involves cooling of pre-lyophilized pharmaceutical composition comprising dalbavancin at suitable temperature not less than -45°C, raising temperature to 0°C at suitable pressure of 500 mtorr to 100 mtorr in 30 hours, then at 50mtorr, further raising temperature to +30°C in 20hrs, to obtain lyophilized composition.
  • the secondary drying of the composition is carried at a temperature in the range of +25 to +35°C for 5 hours to obtain lyophilized composition comprising the water content less than 1.5 %w/w.
  • the lyophilized composition of Dalbavancin containing L-proline in aqueous vehicle as a stabilizing agent with water content less than 1.5 %w/w according to the present invention have total impurities less than the prior art formulations as illustrated in tables 1 and 3 below.
  • compositions after lyophilization is chemically and physically stable over an extended period of time and is suitable for intended pharmaceutical use after reconstitution with suitable vehicle/diluents such as water for injection or 5% dextrose injection.
  • the lyophilized Dalbavancin Hydrochloride composition provided in accordance with this invention when reconstituted with 25 ml of suitable vehicle contains final drug concentrate of 20 mg/ml and subsequently diluted with 5% Dextrose Injection, to a final concentration of 1 mg/mL to 5 mg/mL.
  • the invention provides a process for preparation of lyophilized pharmaceutical composition of the invention which comprises a) providing pre-lyophilized composition consisting of Dalbavancin Hydrochloride dissolved in aqueous vehicle containing stabilizing agent and alkalizing agent and b) lyophilizing the composition to obtain lyophilized pharmaceutical composition with water content less than 1.5%.
  • the lyophilized composition comprising Dalbavancin Hydrochloride may be diluted with suitable diluents before administration as IV injection.
  • the final concentration of solution may be reduced further to desired level using 5% Dextrose infusion prior to administration to a patient.
  • compositions of the present invention are administered to a patient according to a dosing regimen.
  • a dosing regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, specific disease being treated, and the severity of the condition among other factors and the judgment of the treating physician.
  • the present invention provides lyophilized pharmaceutical composition comprising Dalbavancin which is free from sugars without compromising on the stability of drug and its solution before Lyophilisation and as lyophilized composition with less than 1.5%w/w water content, with reduced amount of total impurities which is stable for the entire period of the shelf life.
  • the use of amino acid, viz., L-proline as stabilizing agent provides increased stability to Dalbavancin and eliminates significant drawbacks of the use of mammalian derived stabilizer such as lactose and thus the parenteral formulation of the present invention is suitable for administration to lactose sensitive patients as well as to normal patients providing the desired therapeutic activity with no side effects.
  • the lyophilized pharmaceutical composition comprising Dalbavancin Hydrochloride which is free from sugar is provided herewith without compromising stability of drug and its solution before Lyophilisation has a pH between 5.1 to 6.0.
  • the formulation is stable for the entire period of the shelf life.
  • the stability of the freeze dried composition is more stable than the prior art formulation.

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

Abstract

L'invention concerne une composition pharmaceutique lyophilisée comprenant : a) du chlorhydrate de dalbavancine ou son sel pharmaceutiquement acceptable; b) une quantité pharmaceutiquement acceptable d'acide aminé en tant que stabilisant, le rapport de dalbavancine au stabilisant est de 1:0,8 à 1:1 en poids, d) ladite formulation présente un pH dans la plage de 5,1 à 6, v) ladite formulation ne contient pas plus d'environ 1 % de MAG en poids après 3 mois dans un environnement ayant une température de 40°C et une humidité relative de 75 % RH.
PCT/IN2017/050546 2016-11-23 2017-11-21 Compositions pharmaceutiques lyophilisées de dalbavancine WO2018096556A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
RU2019119405A RU2019119405A (ru) 2016-11-23 2017-11-21 Лиофилизированные фармацевтические композиции далбаванцина
EP17873284.8A EP3544616A4 (fr) 2016-11-23 2017-11-21 Compositions pharmaceutiques lyophilisées de dalbavancine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201621039995 2016-11-23
IN201621039995 2016-11-23

Publications (1)

Publication Number Publication Date
WO2018096556A1 true WO2018096556A1 (fr) 2018-05-31

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EP (1) EP3544616A4 (fr)
RU (1) RU2019119405A (fr)
WO (1) WO2018096556A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023211501A1 (fr) * 2022-04-26 2023-11-02 Hikma Pharmaceuticals Usa Inc. Formulations aqueuses stables de dalbavancine prêtes à administrer
WO2024079224A1 (fr) * 2022-10-12 2024-04-18 Xellia Pharmaceuticals Aps Composition de dalbavancine liquide
WO2024079223A1 (fr) * 2022-10-12 2024-04-18 Xellia Pharmaceuticals Aps Composition de dalbavancine liquide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006078277A2 (fr) * 2004-04-27 2006-07-27 Vicuron Pharmaceuticals Inc. Compositions de dalbavancin pour le traitement d'infections bacteriennes
WO2016071495A1 (fr) * 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060074014A1 (en) * 2002-11-18 2006-04-06 Vicuron Pharmaceuticals Inc. Dalbavancin compositions for treatment of bacterial infections
BR112015012351A8 (pt) * 2012-11-29 2019-10-01 Insmed Inc composição de antibiótico de glicopeptídeo à base de lipídeo estabilizado e uso de um componente lipídico, um componente de antibiótico de glicopeptídeo e um aminoácido ou derivado do mesmo

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006078277A2 (fr) * 2004-04-27 2006-07-27 Vicuron Pharmaceuticals Inc. Compositions de dalbavancin pour le traitement d'infections bacteriennes
WO2016071495A1 (fr) * 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3544616A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023211501A1 (fr) * 2022-04-26 2023-11-02 Hikma Pharmaceuticals Usa Inc. Formulations aqueuses stables de dalbavancine prêtes à administrer
WO2024079224A1 (fr) * 2022-10-12 2024-04-18 Xellia Pharmaceuticals Aps Composition de dalbavancine liquide
WO2024079223A1 (fr) * 2022-10-12 2024-04-18 Xellia Pharmaceuticals Aps Composition de dalbavancine liquide

Also Published As

Publication number Publication date
EP3544616A1 (fr) 2019-10-02
RU2019119405A (ru) 2020-12-25
EP3544616A4 (fr) 2020-12-09
RU2019119405A3 (fr) 2020-12-30

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