WO2017060923A1 - Formulation parentérale lyophilisée de micafungine sodique et son procédé - Google Patents

Formulation parentérale lyophilisée de micafungine sodique et son procédé Download PDF

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Publication number
WO2017060923A1
WO2017060923A1 PCT/IN2016/050341 IN2016050341W WO2017060923A1 WO 2017060923 A1 WO2017060923 A1 WO 2017060923A1 IN 2016050341 W IN2016050341 W IN 2016050341W WO 2017060923 A1 WO2017060923 A1 WO 2017060923A1
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WO
WIPO (PCT)
Prior art keywords
composition
micafungin
agent
sodium
pharmaceutical composition
Prior art date
Application number
PCT/IN2016/050341
Other languages
English (en)
Inventor
Mitesh Natavarlal Patel
Mafatlal Tribhovandas DAVE
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
Publication of WO2017060923A1 publication Critical patent/WO2017060923A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • the present invention relates to freeze dried, pharmaceutical formulation of Micafungin sodium along with a suitable stabilizing agent and alkalizing agent for parenteral administration wherein said formulation is free from polysaccharide, di saccharide or mammalian derived stabilizing agent Lactose.
  • the pharmaceutical formulation provides sufficient stabilization of Micafungin sodium thus improving the shelf life during storage.
  • the invention further relates to a process of preparation thereof.
  • Fungal infections are an important problem, particularly in immune compromised patients, resulting from A IDS infections, aggressive cancer treatment the growing use of organ transplants, and othernosocomial situations.
  • Advanced medical therapies have created a critical need for new safe fungi cidalagents that can be used to treat disseminated infections.
  • Systemic mycoses are not easily diagnosed; andthe patient has usually been infected for quite some time before symptoms appear. Thus, empiric therapyneeds to begin immediately, but currently available treatments have posed problems with toxicity or resistance.
  • hese agents interfere with cell wall biosynthesis by non-competitive inhibition of 1, 3- d-glucan Synthase, an enzyme present in fungi but absent in mammalian cells (Walsh et al., 2000; E rnst, 2001). They are used to treat a variety of fungal infections, including invasive infections due to either Candida or Aspergillus. These antifungals have shown clinical efficacy and a more favourable adverse- event (A E) profile compared with those of conventional antifungal agents.
  • a E adverse- event
  • Micafungin sodium is a semi synthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product of Coleophomaempetri F- 11899. Micafungin inhibits the synthesis of 1,3- beta- D-glucan, an integral component of the fungal cell wall.
  • Micafungin sodium is Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4'(pentyloxy)phenyl]-3- isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-[4- hydroxy- 3- (sulfooxy) phenyl] -L -threonine]-, monosodium sal t( Formulal).
  • Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, ⁇ , ⁇ -dimethylformamide and dimethyl sulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane).
  • Micafungin sodium is marketed as lyophilized product for intravenous infusion by AstellasPharma US, Inc. under the trade name MY CA MINE ⁇ .
  • Micafungin sodium is indicatedfor the treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis, A bscesses, Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation.
  • lactose as stabilizing agent which does not provide desirable stability due to the sensitivity of Micafungin sodium against environmental stress.
  • a lso the formulation containing lactose is not suitable for patients with lactose intolerance.
  • 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.
  • TSE human transmissible spongiform encephalopathy
  • Indian patent number 215552 disclose a pharmaceutical composition of Micafungin in lyophilized form comprising lactose as stabilizing agent.
  • Micafungin Sodium is generally unstable to light, heat, humidity, acid, and the like, it is necessary to develop a pharmaceutical composition for stabilizing the compound and the salts thereof for parenteral administration.
  • the present invention provides pre- lyophilized pharmaceutical formulation comprising Micafungin or pharmaceutically acceptable salt thereof along with a suitable stabilizing agent in an aqueous vehicle, wherein, the formulation is free from polysaccharide and disaccharide.
  • pharmaceutically acceptable salt of Micafungin is Micafungin sodium.
  • the Micafungin sodium is stabilized by adding stabilizing agents selected from the group consisting of a polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose and mixture thereof in aqueous vehicle to obtain pre-lyophilized formulation.
  • the stabilizing agent is polyvinyl pyrrolidone (K ollidon PF 12).
  • the pre-lyophilized pharmaceutical formulation of Micafungin sodium and stabilizing agent is freeze dried and provided as a drug concentrate, suitable for parenteral administration.
  • the freeze dried formulation comprises an effective amount of stabi I izer i n the range of 10Omg to 1000 mg.
  • the pH of the formulation is maintained in the range of 5 to 7 using alkalizing agent.
  • the present invention provides a method for stabilization of Micafungin sodium in an aqueous solution which comprises combining Micafungin sodium in an aqueous vehicle with a stabilizing agent selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose and mixture thereof; preferably polyvinyl pyrrolidone (Kollidon PF 12).
  • a stabilizing agent selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose and mixture thereof; preferably polyvinyl pyrrolidone (Kollidon PF 12).
  • Micafungin Sodium is generally unstable to light, heat, humidity, acid, and the like, it is therefore necessary to develop a pharmaceutical composition for stabilizing the compound and the salts thereof for parenteral administration.
  • the present invention provides stable pharmaceutically acceptable composition/formulation for parenteral administration or intravenous infusion comprising of Micafungin sodium as the active using a suitable stabilizer and maintaining appropriate pH of the formulation.
  • the present invention provides pre-lyophilized pharmaceutical composition
  • a pharmaceutically acceptable stabilizing agent selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose or mixture thereof in an aqueous vehicle and an alkalizing agent, wherein, pH of said composition is in the range of 5.0 to 7.0 and wherein, the pre-lyophilized composition is devoid of polysaccharide and disaccharide.
  • the aqueous vehicle according to the invention is water for injection.
  • Micafungin sodium is present in the composition in an amount ranging from 1 mg to 100 mg/vial; more preferably 50mg to 100 mg/vial.
  • Micafungin sodium is stabilized using a suitable stabilizing agent where Micafungin sodium can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Micafungin sodium.
  • the stabilizing agent is selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose or mixture thereof.
  • the stabilizing agent is polyvinyl pyrrolidone (Kollidon PF 12).
  • the pre-lyophilized pharmaceutical composition comprises Micafungin sodium in an amount ranging from 1 mg to 100 mg/vial; an effective amount of polyvinyl pyrrolidone (Kollidon PF 12) in the range of 100mg to 1000mg as a stabilizing agent in aqueous vehicle and 0.1 N 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 freeze drying cycle to obtain freeze dried composition.
  • the present inventors observed during experimentation that there is an increase in total impurities on storage of the lyophilized composition at 403 ⁇ 43 for 3 months. Since, Micafungin is not stable to humidity it was necessary to reduce the water content to the desirable extent to obtain the freeze dried product with reduced total impurities and increased stability.
  • the present invention provides freeze dried composition of Micafungin sodium with water content less than 2.0%w/w, preferably in the range of 1.0 to 1.5%w/w; most preferably the water content is in an amount of about 1.2%w/w.
  • the present invention provides stable, freeze dried, pharmaceutical composition for parenteral administration, which is free from polysaccharide and disaccharide, comprising;
  • a pharmaceutically acceptable stabilizing agent selected from the group consisting of a polyvinyl pyrrol i done (Kollidon PF 12), Dextrose, Galactose or mixture thereof; and
  • the stabilizing agent is preferably polyvinyl pyrrol i done (K ollidon PF 12) used in an amount of 100 to 10OOmg.
  • the stable freeze dried pharmaceutical composition for parenteral administration comprising;
  • mice i. Micafungin sodium in an amount of 50 nrgA ial;
  • the stable freeze dried pharmaceutical composition for parenteral administration comprising;
  • mice i. Micafungin sodium in an amount of 100 mg/vial
  • the invention provides freeze drying process which involves cooling of pre-lyophilized pharmaceutical composition at suitable temperature not less than -50eC, raising temperature to OeCat suitable pressure of 150 mtorr to 100 mtorr in 30 hours, then at 75 mtorr, further raising temperature to +15eC in 20 hrs, to obtain freeze-dried composition.
  • the secondary drying of the composition is carried at a temperature in the range of +12 to +18 3 ⁇ 43 for 3 hours.
  • the freeze dried composition of Micafungin containing Kollidon PF-12 in aqueous vehicle as a stabilizing agent with water content less than 2.0%w/w have total impurities less than the prior art formulations as illustrated in example 3 below.
  • composition after freeze drying 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, sodium chloride injection or 5% dextrose injection.
  • the freeze dried Micafungin sodium provided in accordance with the invention when reconstituted with 5 ml of suitable vehicle contains final drug concentrate of 10 mg/ml.
  • the invention provides a process for preparation of freeze dried pharmaceutical composition of the invention which comprises a)providing pre-lyophilized composition consisting of Micafungin sodium dissolved in aqueous vehicle containing stabilizing agent and alkalizing agent and b) lyophilizing the composition to obtain freeze dried pharmaceutical composition with water content less than 2%.
  • the freeze dried composition comprising Micafungin sodium may be diluted with suitable diluents before administration as IV injection. The final concentration of solution may be reduced to further 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 freeze dried pharmaceutical composition comprising Micafungin sodium which is free from polysaccharide and disaccharide without compromising the stability of drug and its solution before Lyophilisation and as freeze dried composition with less than 2%w/w water content, with reduced amount of total impurities which is stable for the entire period of the shelf life.
  • the use of Kollidon PF-12 as stabilizing agent eliminates significant drawbacks of the use of mammalian derived stabilizer such as lactose and 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.
  • example 1 and example 2 showed increase in total impurities i.e. 4.93% and 3.86% respectively after 3 months at 403 ⁇ 43, the present inventors further carried changes in lyophilisation to get desired water content and modification in pH for reducing the impurities content.
  • the invention provides freeze drying process which involves cooling of pre-lyophilized pharmaceutical composition at suitable temperature not less than -50eC, raising temperature to OeCat suitable pressure of 150 mtorr to 100 mtorr in 30 hours, then at 75 mtorr, further raising temperature to +15eC in 20 hrs, to obtain freeze-dried composition. This was followed by secondary drying of the freeze dried composition to a temperature in the range of +12 to +18 ⁇ ] for 3 hours. The resulting freeze dried or lyophilized preparation was stored at 40eC and 75% humidity up to 3 months.

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

Abstract

La présente invention concerne des formulations pharmaceutiques lyophilisées stables de micafungine qui comprend de la micafungine sodique ; un agent stabilisant et un agent alcalifiant appropriés pour une administration parentérale, la formulation étant dépourvue d'agent de stabilisation lactose dérivé de polysaccharide, de disaccharide ou de mammifère. La formulation pharmaceutique permet d'obtenir une stabilisation suffisante de la micafungine sodique, améliorant ainsi la durée de conservation du produit au cours du stockage.
PCT/IN2016/050341 2015-10-10 2016-10-07 Formulation parentérale lyophilisée de micafungine sodique et son procédé WO2017060923A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3858/MUM/2015 2015-10-10
IN3858MU2015 IN2015MU03858A (fr) 2015-10-10 2016-10-07

Publications (1)

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WO2017060923A1 true WO2017060923A1 (fr) 2017-04-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112330A1 (fr) * 2016-12-16 2018-06-21 Baxter International Inc. Compositions de micafungine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089214A1 (fr) * 2010-01-22 2011-07-28 Ascendis Pharma As Lieurs de précurseurs à base de carbamates liés à des supports
US20130331312A1 (en) * 2011-01-31 2013-12-12 Yunhai Hong Medicinal composition containing echinocandin antifungal agent micafungin and preparation method and use thereof
WO2014173205A1 (fr) * 2013-04-26 2014-10-30 江苏豪森药业股份有限公司 Composition pharmaceutique contenant de la micafungine ou un sel de celle-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089214A1 (fr) * 2010-01-22 2011-07-28 Ascendis Pharma As Lieurs de précurseurs à base de carbamates liés à des supports
US20130331312A1 (en) * 2011-01-31 2013-12-12 Yunhai Hong Medicinal composition containing echinocandin antifungal agent micafungin and preparation method and use thereof
WO2014173205A1 (fr) * 2013-04-26 2014-10-30 江苏豪森药业股份有限公司 Composition pharmaceutique contenant de la micafungine ou un sel de celle-ci

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112330A1 (fr) * 2016-12-16 2018-06-21 Baxter International Inc. Compositions de micafungine

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