WO2014108918A2 - Formulation antifongique injectable - Google Patents

Formulation antifongique injectable Download PDF

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Publication number
WO2014108918A2
WO2014108918A2 PCT/IN2014/000016 IN2014000016W WO2014108918A2 WO 2014108918 A2 WO2014108918 A2 WO 2014108918A2 IN 2014000016 W IN2014000016 W IN 2014000016W WO 2014108918 A2 WO2014108918 A2 WO 2014108918A2
Authority
WO
WIPO (PCT)
Prior art keywords
voriconazole
cyclodextrin
formulation
ready
hydroxypropyl
Prior art date
Application number
PCT/IN2014/000016
Other languages
English (en)
Other versions
WO2014108918A3 (fr
Inventor
Indu Bhushan
Manoj Kumar Pananchukunnath
Subhash Gore
Ajeet Kumar Singh
Sandip MALI
Original Assignee
Mylan Laboratories 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 Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2014108918A2 publication Critical patent/WO2014108918A2/fr
Publication of WO2014108918A3 publication Critical patent/WO2014108918A3/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61P31/10—Antimycotics

Definitions

  • the invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
  • the invention also relates to a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
  • voriconazole is practically insoluble in water (0.61 mg/ml at a pH 7; 0.2 mg/ml at a pH 3), due to which development of aqueous intravenous formulations, with a sufficient shelf life has proved to be difficult.
  • US Patent No. 6,632,803 describes pharmaceutical composition comprising voriconazole and sulfobutyl ether ⁇ -cyclodextrin (SBECD).
  • SBECD is significantly costlier than hydroxpropyl ⁇ -cyclodextrin (HPBCD).
  • EP 2 018 866 Al describes a process for increasing solubility of voriconazle in aqueous solutions by complexation with beta-cyclodextrin.
  • EP 2 018 866 Al fails to disclose long term stability of its formulation in lyophilized form.
  • EP 2 409 699 Al discloses pharmaceutical formulation comprising voriconazole, cyclodextrin and glycine, wherein glycine is present in a stabilizing amount.
  • WO 2012/171561 discloses pharmaceutical formulation comprising voriconazole, hydroxpropyl ⁇ -cyclodextrin (HPpCD) and lactose, wherein lactose acts as a stabilizing agent.
  • Voriconazole is marketed as an intravenous solution, which is available as a lyophilized powder for solution for intravenous infusion and contains 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial. It is a single-dose, unpreserved product. Vials containing 200mg lyophilized voriconazole are intended for reconstitution with water for injection to produce a solution containing lOmg/ml voriconazole and 160mg/ml of sulfobutyl ether beta-cyclodextrin sodium.
  • the invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
  • Another object of the invention is to provide a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
  • Yet another object of the invention is to provide a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution, for the treatment of a fungal infections to a person in need thereof.
  • Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility or stability of the drug of interest, which in turn can severely limit its therapeutic application.
  • Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, chemical modifications, complexation etc. of the drugs with appropriate complexing agents such as cyclodextrins.
  • Cyclodextrins are classified upon their properties and pore sizes as - cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the available cyclodextrin in the invention includes derivatives of cyclodextrin, preferably ⁇ -cyclodextrin or derivatives thereof, having 6.0 - 6.5 A° of diameter for each pore size, and more preferably hydroxypropyl ⁇ -cyclodextrin (HPPCD).
  • HPPD hydroxypropyl ⁇ -cyclodextrin
  • the degree of molecular substitution of hydroxypropyl ⁇ -cyclodextrin (HPpCD) is preferably 0.2 - 1.0, and more preferably 0.4 - 1.0. If the degree of molecular substitution is too low, the solubility of HPpCD becomes low. In contrast, if it is too high, HP ⁇ CD becomes too viscous too handle.
  • a ready to reconstitute injectable voriconazole formulation wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution, preferably not more than 140 mg/ml of hydroxypropyl ⁇ - cyclodextrin after reconstitution.
  • hydroxypropyl ⁇ -cyclodextrin refers to a compound consisting of a ring of 7 D-glucose units linked by alpha- 1, 4 glycosidic bonds, wherein a certain proportion of the hydroxyl groups are substituted with a 2-hydroxypropyl functional group through an ether bond.
  • bioavailability refers to the amount of a biologically active agent within a specific body compartment (such as the blood of the systemic circulation), following administration of the biologically active agent, as a percentage of the amount of the biologically active agent administered.
  • present invention provides a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ - cyclodextrin after reconstitution comprising the steps of: i) preparing an aqueous solution of voriconazole and hydroxpropyl ⁇ - cyclodextrin at a temperature of atleast 35°C ii) adjusting the pH of the aqueous solution with one or more pH regulating agents iii) optionally adding required amount of one or more pharmaceutically acceptable excipients iv) freeze-drying the solution to provide a lyophilized product for reconstitution.
  • the suitable dose for the parenteral administration of voriconazole is between 0.1 to 25 mg/kg, preferably 0.5 to 20 mg/kg, more preferably 1 to 10 mg/kg.
  • a ready to reconstitute injectable voriconazole formulation according to the present invention wherein the molar ratio of voriconazole and hydroxypropyl ⁇ -cyclodextrin in the formulation is in the range from about 1 :2 to about 1 :4, more preferably is about 1 :3.
  • a ready to reconstitute injectable voriconazole formulation comprises 8 to 16 parts by weight of hydroxpropyl ⁇ -cyclodextrin with respect to voriconazole, more preferably 10 to 14 parts by weight of hydroxpropyl ⁇ -cyclodextrin in respect to voriconazole.
  • a ready to reconstitute injectable voriconazole formulation optionally comprises one or more pH regulating agents, wherein the pH of the formulation is from about 3.5 to 7.0, preferably at about pH 4.0 to 6.5.
  • one or more pH regulating agents include an acid, a base or a buffer or combinations thereof.
  • the acid can be a mineral acid or an organic acid such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid tartaric acid and the likes.
  • the base can be oxides, hydroxides, carbonates, bicarbonates and the likes.
  • a ready to reconstitute injectable voriconazole formulation according to the present invention can additionally comprise one or more pharmaceutically acceptable excipients such as a sugar alcohol, preferably mannitol, wherein the pH of the formulation is essentially maintained at a range of about 3 to 7, preferably at about pH 4.0 to 6.5.
  • Mannitol is a hexahydric alcohol related to mannose and is isomeric with sorbitol. It is a water soluble monomer having no film forming properties.
  • a ready to reconstitute injectable voriconazole formulation according to the present invention can be freeze dried to obtain lyophilized powder which can be reconstituted with water for injection prior to administration as an infusion.
  • a pharmaceutical kit comprising a ready to reconstitute injectable voriconazole formulation according to the present invention and sterile infusion solutions such as Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection, or Water for Injection.
  • the formulations are typically diluted or reconstituted and may be further diluted if necessary, prior to administration.
  • the present invention provides a method for treatment of a fungal infection comprising administration of an effective amount of a stable, injectable antifungal formulation comprising voriconazole as per the present invention to the person in need thereof.
  • Fungal infections which may be treated by voriconazole have been extensively described in the literature, including EP-A 440 372.
  • step (2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
  • Example 7 Preparation of ready to reconstitute injectable voriconazole formulation comprising mannitol
  • step (2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
  • the injectable voriconazole formulation according to present invention has better reconstitution properties such as reconstitution time, appearance of the resulting solution, etc. when the voriconazole, hydroxypropyl ⁇ -cyclodextrin complex according to the present invention is redissolved, in an aqueous medium, which is suitable for injection.
  • AUCiast The area under the plasma concentration versus time curve from time zero to the last measurable concentration.
  • AUC j nf The area under the plasma concentration versus time curve from time zero to infinity. This is calculated as the sum of the AUCO-t plus the ratio
  • a ready to reconstitute injectable voriconazole formulation according to the present invention comprising not more than 150 mg/mL of hydroxypropyl ⁇ - cyclodextrin

Landscapes

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

Abstract

L'invention porte sur une formulation de voriconazole injectable prête à reconstituer, la formulation ne comprenant pas plus de 150 mg/ml d'hydroxypropyl-β-cyclodextrine après reconstitution.
PCT/IN2014/000016 2013-01-08 2014-01-07 Formulation antifongique injectable WO2014108918A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN120CH2013 2013-01-08
IN120/CHE/2013 2013-01-08

Publications (2)

Publication Number Publication Date
WO2014108918A2 true WO2014108918A2 (fr) 2014-07-17
WO2014108918A3 WO2014108918A3 (fr) 2014-12-04

Family

ID=51167477

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000016 WO2014108918A2 (fr) 2013-01-08 2014-01-07 Formulation antifongique injectable

Country Status (1)

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WO (1) WO2014108918A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019504042A (ja) * 2015-12-21 2019-02-14 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． 経口製剤およびその製造方法
JP2019506377A (ja) * 2015-12-21 2019-03-07 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． 薬物包接化合物、その製剤、およびそのための製造方法
TWI738100B (zh) * 2018-10-31 2021-09-01 法商施維雅藥廠 Bcl-2抑制劑之基於環糊精之調配物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1788725A (zh) * 2004-12-15 2006-06-21 北京博尔达生物技术开发有限公司 注射用伏立康唑冻干粉针剂及其制备方法
EP2018866A1 (fr) * 2007-07-27 2009-01-28 Sandoz AG Compositions pharmaceutiques contenant du voriconazole
EP2409699A1 (fr) * 2010-07-23 2012-01-25 Combino Pharm, S.L. Compositions stables de voriconazole
WO2012171561A1 (fr) * 2011-06-15 2012-12-20 Synthon Bv Composition de voriconazole stabilisée

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1788725A (zh) * 2004-12-15 2006-06-21 北京博尔达生物技术开发有限公司 注射用伏立康唑冻干粉针剂及其制备方法
EP2018866A1 (fr) * 2007-07-27 2009-01-28 Sandoz AG Compositions pharmaceutiques contenant du voriconazole
EP2409699A1 (fr) * 2010-07-23 2012-01-25 Combino Pharm, S.L. Compositions stables de voriconazole
WO2012171561A1 (fr) * 2011-06-15 2012-12-20 Synthon Bv Composition de voriconazole stabilisée

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019504042A (ja) * 2015-12-21 2019-02-14 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． 経口製剤およびその製造方法
JP2019506377A (ja) * 2015-12-21 2019-03-07 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． 薬物包接化合物、その製剤、およびそのための製造方法
US11007141B2 (en) 2015-12-21 2021-05-18 Guangzhou Xiangxue Pharmaceutical Co., Ltd. Oral preparation and preparation method thereof
US11071737B2 (en) 2015-12-21 2021-07-27 Guangzhou Xiangxue Pharmaceutical Co., Ltd. Drug inclusion complex, preparation thereof, and preparation method thereof
TWI738100B (zh) * 2018-10-31 2021-09-01 法商施維雅藥廠 Bcl-2抑制劑之基於環糊精之調配物

Also Published As

Publication number Publication date
WO2014108918A3 (fr) 2014-12-04

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