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EP3003265A1 - Formulation parentérale d'agent antifongique à base de triazole et son procédé de préparation - Google Patents

Formulation parentérale d'agent antifongique à base de triazole et son procédé de préparation

Info

Publication number
EP3003265A1
EP3003265A1 EP14726076.4A EP14726076A EP3003265A1 EP 3003265 A1 EP3003265 A1 EP 3003265A1 EP 14726076 A EP14726076 A EP 14726076A EP 3003265 A1 EP3003265 A1 EP 3003265A1
Authority
EP
European Patent Office
Prior art keywords
voriconazole
pharmaceutical composition
beta cyclodextrin
hydroxypropyl beta
solubility
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP14726076.4A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthimios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Morfis Abatzis
Christina KIZIRIDI
Efstathia MILOULI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP3003265A1 publication Critical patent/EP3003265A1/fr
Withdrawn legal-status Critical Current

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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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

Definitions

  • the present invention relates to an aqueous pharmaceutical formulation for parenteral administration comprising a triazole antifungal agent such as Voriconazole or pharmaceutical acceptable salt thereof and an effective amount of a solubilizing agent such as hydroxypropyl beta cyclodextrin, in order to improve the solubility of the poorly water soluble active ingredient.
  • a triazole antifungal agent such as Voriconazole or pharmaceutical acceptable salt thereof
  • a solubilizing agent such as hydroxypropyl beta cyclodextrin
  • Voriconazole is a broad spectrum, triazole antifungal agent that is generally used to treat serious, invasive fungal infections including invasive aspergillosis, esophageal candidiasis, and infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani.
  • Voriconazole exerts its antifungal activity by inhibition of 14-alpha-lanosterol demethylation, which is mediated by fungal cytochrome P450 enzymes. This inhibition is more selective for fungal than for mammalian enzyme systems.
  • the accumulation of 14-alphamethyl sterols results in a decrease in ergosterol, which is an essential component of fungal cell wall formation.
  • First generation triazole agents such as fluconazole and itraconazole
  • fluconazole and itraconazole have revolutionised the treatment of serious fungal infections.
  • neither was an ideal agent Itraconazole was plagued by absorption problems; fluconazole had a limited spectrum of antifungal activity and resistance was soon noted in immunosuppressed hosts who received long-term treatment.
  • Voriconazole is a second generation triazole agent. Replacement of one of the triazole rings with a fluorinated pyrimidine and the addition of an a-methyl group resulted in expanded activity, compared with that of fluconazole and itraconazole.
  • Voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fiuoropyrimidin- 4-yl)-l-(l H-l,2,4-triazol-l-yl)butan-2-ol and its molecular formula is C 16.H14F3N5O corresponding to a molecular weight of 349.31. It is a white to almost white powder. It is very slightly soluble in water and freely soluble in acetone and in dichloromethane.
  • US 6165484 Bl discloses a pharmaceutical composition comprising at least one antifungal agent and at least one chelator.
  • WO 2005/051353 A2 discloses an aqueous micellar poloxamer formulation comprising Voriconazole.
  • WO 2009/126950 A2 discloses a method for enhancing the solubility of an organic compound which is insoluble or sparingly soluble in water, said method comprising mixing said compound with water and with a diterpene glycoside.
  • thermodynamically stable and efficient product comprising a triazole antifungal agent such Voriconazole or pharmaceutical acceptable salt thereof suitable for intravenous administration.
  • the present invention aims at developing a formulation that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions.
  • Another object of the present invention is to provide an aqueous pharmaceutical formulation comprising Voriconazole or pharmaceutical acceptable salt thereof for parenteral use that effectively address issues related to the solubility of the active substance, stability of the dosage form as well as physiological acceptability by the patient.
  • Another aspect of the present invention is to provide a solid composition prepared by a process comprising lyophillization of an aqueous solution containing Voriconazole or pharmaceutical acceptable salt thereof and a pharmaceutically acceptable solubilizing agent and optionally other excipients to form a readily reconstitutable powder.
  • an aqueous pharmaceutical formulation comprising a triazole antifungal agent such as Voriconazole or pharmaceutical acceptable salt thereof as an active ingredient and an effective amount of a pharmaceutically acceptable solubilizing agent such as hydroxypropyl beta cyclodextrin in order to achieve increased solubility of the active ingredient.
  • a triazole antifungal agent such as Voriconazole or pharmaceutical acceptable salt thereof
  • a pharmaceutically acceptable solubilizing agent such as hydroxypropyl beta cyclodextrin
  • a process for the preparation of an aqueous pharmaceutical formulation containing a triazole antifungal agent such as Voriconazole comprising the following stages:
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • Parenteral pharmaceutical dosage forms bypass normal defence barriers of the human body due to the route of administration Thus, the preparation should be made with high degree of care and cautiousness.
  • Such products should be sterile, pyrogen free, isotonic, with physiological pH value or a pH that can be adjusted easily by the body upon administration and stable both chemically and physically. There should be absence of any particulate matter after manufacture as well as after storage of the product.
  • Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility is the most important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown.
  • Solubilization may be affected by cosolvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion and change in polymorph.
  • Voriconazole is the use of solubilizing agents such as benzyl alcohol, hydroxypropyl betadex, macrogol 15 hydroxystearate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, povidone, sulfobutylether betacyclodextrin, tricaprylin, triolein, polyoxyethylene sorbitan fatty acid esters, polyethylene-propylene glycol copolymers.
  • solubilizing agents such as benzyl alcohol, hydroxypropyl betadex, macrogol 15 hydroxystearate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, povidone, sulfobutylether betacyclodextrin, tricaprylin, triolein, polyoxyethylene sorbitan fatty acid esters, polyethylene-propylene glycol copolymers.
  • the main object of the present invention which is providing increased solubility of Voriconazole in aqueous solutions, is satisfied when hydroxypropyl betacyclodextrin is comprised in such solutions.
  • Hydroxypropyl betacyclodextrin forms a complex with Voriconazole that greatly modifies its physical and chemical properties, mostly in terms of water solubility.
  • the present invention provides an aqueous parenteral formulation of Voriconazole comprising 8% (w/v) to 16% (w/v) of hydroxypropyl betacyclodextrin. Preferably, 10% (w/v) to 15% (w/v) and most preferably 12% (w/v) of hydroxypropyl betacyclodextrin.
  • Cyclodextrins are useful formulation vehicles, which increase the amount of drug that can be solubilized in aqueous media.
  • Cyclodextrins are cyclic amylose-derived oligomers composed of a varying number of a- 1-4 linked glucose units. These glucose chains form a cone-like cavity into which compounds may enter and form a water-soluble complex and thus change the drug's physical-chemical properties
  • Drug-cyclodextxin complexation can be regarded as molecular encapsulation, i.e., encapsulation of drug at the molecular level.
  • the cyclodextrin molecule shields, at least partly, the drug molecule from attack by various reactive molecules.
  • the cyclodextrin can insulate a labile compound from a potentially corrosive environment and in this way, reduce or even prevent drug hydrolysis, oxidation, steric rearrangement, racemization, and other forms of isomerization, polymerization, and even enzymatic decomposition of drugs.
  • Hydroxypropyl beta cyclodextrin is a partially substituted poly(hydroxypropyl) ether of ⁇ - cyclodextrin with improved water solubility properties.
  • the number of hydroxypropyl groups per anhydro glucose unit is expressed as molar substitution (MS) and is not less than 0.40 and not more than 1.50.
  • Hydroxypropyl beta cyclodextrins are prepared by reacting beta cyclodextrin with propylene oxide in alkaline aqueous solutions.
  • the high alkali concentration favours alkylation at 0-6, while the low alkali concentration favours alkylation at 0-2.
  • the products are always substituted randomly when it comes to distribution among the different glucose units.
  • the ratio of reactants, reaction time and the temperature affect the average degree of substitution (DS). It follows that the composition of hydroxypropyl beta cyclodextrin samples show high variability, which is also reflected in the chemical and physical properties.
  • cyclodextrins are able to form complexes with many drugs by taking up a drug molecule or more frequently some lipophilic moiety of the molecule, into the central cavity. No covalent bonds are formed or broken during the complex formation, and drug molecules in the complex are in rapid equilibrium with free molecules in the solution.
  • the driving forces for the complex formation include release of enthalpy-rich water molecules from the cavity, electrostatic interactions, van der Waals' interactions, hydrophobic interactions, hydrogen bonding, release of conformational strain and charge-transfer interactions.
  • phase-solubility profiles When the complex is first order with respect to ligand and first or higher order with respect to substrate then AL-type phase-solubility profiles are obtained. If the complex is first order with respect to the substrate, but second or higher order with respect to the ligand then AP- type phase-solubility profiles are obtained. AN-type phase-solubility profiles can be difficult to interpret. B-type phase-solubility profiles indicate formation of complexes with limited solubility in the aqueous complexation medium. In general, the water-soluble cyclodextrin derivatives form A-type phase-solubility profiles, whereas the less soluble natural cyclodextrins frequently form B-type profiles.
  • phase solubility profile of Voriconazole-Hydroxypropyl beta cyclodextrin MS 0.98 and MS 0.65 complex is of AL-type, indicating that the formed complex is first order with respect to hydroxypropyl beta cyclodextrin MS 0.98 and MS 0.65 respectively.
  • the aqueous pharmaceutical composition according to the present invention may optionally comprise other common excipients used for parenteral administration such as pH adjusting agents, antioxidants and preservatives.
  • pH adjusting agents may be, for example, acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate , sodium borate, sodium citrate, sodium acetate, sodium lactate.
  • Such agents are included in an amount necessary to maintain the pH of the aqueous pharmaceutical formulation in a physiologically acceptable range.
  • aqueous pharmaceutical compositions were prepared using different solubilising agents. The manufacturing process was the same for all of them and comprised the following steps:
  • solubilizing agents polysorbate 80 (polyoxyethylene sorbitan fatty acid ester), solutol HS-15 (macrogol 15 hydroxystearate) and poloxamer 188 (polyethylene-propylene glycol copolymer) of Compositions 1, 2 and 3 respectively, were used at the maximum quantity according to bibliography references for injectable products.
  • composition 4 a new composition where the active ingredient is dissolved in acidic pH, then the solubilizer is added and finally desirable pH and volume are adjusted.
  • Composition 4 a new composition where the active ingredient is dissolved in acidic pH, then the solubilizer is added and finally desirable pH and volume are adjusted.
  • the manufacturing process used was the following:
  • New formulations were prepared using cyclodextrins as solubilizers; more specifically a- cyclodextrin and ⁇ -cyclodextrin were tested while ⁇ -cyclodextrin was not tested because is nephrotoxic and should not be used in parenteral formulations.
  • compositions 5 and 6 The manufacturing process used for preparing Compositions 5 and 6 was the following:
  • the manufacturing process used was the following:
  • Voriconazole was completely diluted with the use of hydroxypropyl beta cyclodextrin with molar substitution 0.98 and lyophillization of bulk solution was followed.
  • the physical characteristics of bulk solution, lyophilized and reconstituted product are presented in table 5 below:
  • hydroxypropyl beta cyclodextrin with molar substitution 0.98 proved to be an excellent solubilizer for Voriconazole, forming a complex of first order with respect to hydroxypropyl beta cyclodextrin, hydroxypropyl beta cyclodextrin with molar substitution 0.65 was also tested because according to bibliography cyclodextrin derivatives of lower molar substitution are better solubilizers than the same type of derivatives of higher molar substitution.
  • Results confirmed the theory as the required quantity of hydroxypropyl beta cyclodextrin with molar substitution 0.65 for the solubilization of Voriconazole was lower than the required quantity of hydroxypropyl beta cyclodextrin with molar substitution 0.98.
  • the quantity of NaCl was increased in order to accomplish osmolality specifications.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques à administrer par voie parentérale, comprenant du voriconazole ou un sel pharmaceutiquement acceptable de celui-ci comme principe actif et un agent de solubilisation tel que l'hydroxypropyl-bêta-cyclodextrine pour obtenir une solubilité accrue du principe actif. La présente invention concerne également un procédé de préparation de cette composition.
EP14726076.4A 2013-05-27 2014-05-13 Formulation parentérale d'agent antifongique à base de triazole et son procédé de préparation Withdrawn EP3003265A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20130100315A GR1008234B (el) 2013-05-27 2013-05-27 Παρεντερικο σκευασμα ενος αντιμυκητιασικου παραγοντα τριαζολης και μεθοδος για την παρασκευη αυτου
PCT/EP2014/001285 WO2014191080A1 (fr) 2013-05-27 2014-05-13 Formulation parentérale d'agent antifongique à base de triazole et son procédé de préparation

Publications (1)

Publication Number Publication Date
EP3003265A1 true EP3003265A1 (fr) 2016-04-13

Family

ID=50792404

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14726076.4A Withdrawn EP3003265A1 (fr) 2013-05-27 2014-05-13 Formulation parentérale d'agent antifongique à base de triazole et son procédé de préparation

Country Status (3)

Country Link
EP (1) EP3003265A1 (fr)
GR (1) GR1008234B (fr)
WO (1) WO2014191080A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113975236A (zh) * 2021-12-08 2022-01-28 海南鑫开源医药科技有限公司 一种伏立康唑干混悬剂及其制备工艺

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160147960A (ko) 2014-04-25 2016-12-23 아지노모토 가부시키가이샤 면역자극제
EP3511318A1 (fr) 2015-10-28 2019-07-17 Ajinomoto Co., Inc. Agent immunostimulant
CN116570558B (zh) * 2023-06-21 2023-12-26 广州仁恒医药科技股份有限公司 一种伏立康唑眼用纳米缓释组合物及其制备方法和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2018866A1 (fr) * 2007-07-27 2009-01-28 Sandoz AG Compositions pharmaceutiques contenant du voriconazole
EA201270283A1 (ru) * 2009-08-19 2012-12-28 Рациофарм Гмбх Способ получения соэвапоратов и комплексы, содержащие вориконазол и циклодекстрин
KR101731155B1 (ko) * 2011-06-15 2017-04-27 신톤 비.브이. 안정화된 보리코나졸 조성물
EP2561863A1 (fr) * 2011-08-22 2013-02-27 Farmaprojects, S.A.U. Compositions pharmaceutiques comportant du voriconazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014191080A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113975236A (zh) * 2021-12-08 2022-01-28 海南鑫开源医药科技有限公司 一种伏立康唑干混悬剂及其制备工艺

Also Published As

Publication number Publication date
WO2014191080A1 (fr) 2014-12-04
GR1008234B (el) 2014-06-24

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