EP3003265A1 - Parenteral formulation of triazole antifungal agent and method for preparation thereof - Google Patents

Parenteral formulation of triazole antifungal agent and method for preparation thereof

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Withdrawn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)
French (fr)
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/en
Withdrawn legal-status Critical Current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.

Abstract

The present invention relates to pharmaceutical compositions for parenteral administration comprising Voriconazole or pharmaceutical acceptable salt thereof as the active ingredient and a solubilizing agent such as hydroxypropyl beta cyclodextrin in order to achieve increased solubility of the active ingredient. The present invention also provides a method of preparation of such composition.

Description

PARENTERAL FORMULATION OF TRIAZOLE ANTIFUNGAL AGENT AND METHOD FOR PREPARATION THEREOF
TECHNICAL FIELD OF THE INVENTION
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. The present invention also provides a method of preparation of such formulation.
BACKGROUND OF THE INVENTION
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.
Like the other triazole antifungals, 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, have revolutionised the treatment of serious fungal infections. However, 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.
The chemical name of 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. Although each of the patents above represents an attempt to provide aqueous solutions of Voriconazole which overcome the related problems of low aqueous solubility of the active ingredient, there still exists the need for alternative formulations providing not only enhanced solubility of Voriconazole but also physically and chemically stable Voriconazole powder for infusion.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide a 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.
In accordance with the above objects of the present invention, an aqueous pharmaceutical formulation is provided 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.
According to another embodiment of the present invention, a process for the preparation of an aqueous pharmaceutical formulation containing a triazole antifungal agent such as Voriconazole is provided, comprising the following stages:
-adding hydroxypropyl beta cyclodextrin in water for injection;
-adding Voriconazole and dissolving;
-adding NaCl and dissolving;
-adjusting pH with HC1;
-adjusting to final volume with water for injection;
-vials filling;
-lyophillization of the above vials to produce powder for suspension.
Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, 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.
Conventional approaches for enhancement of solubility have limited applicability, especially when the drugs are poorly soluble simultaneously in aqueous and in non-aqueous media. Solubilization may be affected by cosolvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion and change in polymorph. Common technique for improving the solubility of poorly water soluble drugs such as 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.
Surprisingly, it has been found that 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.
Accordingly, 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 β- 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. In addition, 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.
In aqueous solutions 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.
The physicochemical properties of free drug molecules are different from those bound to the cyclodextrin molecules. Likewise, the physicochemical properties of free cyclodextrin molecules are different from those in the complex. Higuchi and Connors (Duchene D, Bochot A, Yu S-C, Pe'pin C, Seiller M. 2003. Cyclodextrins and emulsions. Int J Pharm 266:85-90) have classified complexes based their effect on substrate solubility as indicated by phase-solubility profiles. A-type phase-solubility profiles are obtained when the solubility of the substrate (i.e., drug) increases with increasing ligand (i.e., cyclodextrin) concentration. 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.
More specifically, the 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.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention. EXAMPLES Example 1 Table 1 : Composition 1 to 3 of example 1
Three aqueous pharmaceutical compositions were prepared using different solubilising agents. The manufacturing process was the same for all of them and comprised the following steps:
-adding the solubilizing agent in water for injection;
-adding Voriconazole and dissolving;
-adjusting to final volume by adding water for injection.
The 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.
In terms of Voriconazole solubilization neither one of the tested solubilizing agents proved to be able to solubilize Voriconazole.
Taking into account that Voriconazole exhibits pH-dependent solubilization, it was decided to prepare a new composition (Composition 4) where the active ingredient is dissolved in acidic pH, then the solubilizer is added and finally desirable pH and volume are adjusted. Example 2:
Table 2: Composition 4 of example 2
The manufacturing process used was the following:
-adding Voriconazole in water for injection;
-adding HC1 until complete dissolution of Voriconazole;
-adding polysorbate 80 and dissolving;
-adjusting solution pH to 6.3 by adding the necessary quantity of NaOH;
-adjusting final solution volume by adding water for injection.
Even after the changes to the manufacturing procedure, there was not observed any improvement as far as the increase of Voriconazole solubility is concerned. In particular, even though Voriconazole managed to be completely dissolved with the addition of HC1, during pH adjustment to 6.3 the active ingredient gradually precipitated.
New formulations were prepared using cyclodextrins as solubilizers; more specifically a- cyclodextrin and γ-cyclodextrin were tested while β-cyclodextrin was not tested because is nephrotoxic and should not be used in parenteral formulations.
Example 3:
Table 3: Composition 5 and 6 of example 3
The manufacturing process used for preparing Compositions 5 and 6 was the following:
-adding cyclodextrin in water for injection;
-adding Voriconazole and dissolving;
-adjusting final solution volume by adding water for injection.
Results show that neither a-cyclodextrin nor γ-cyclodextrin (which has larger cavity than a- cyclodextrin) managed to form complexation with Voriconazole and increase its solubility. Thus, new compositions were prepared comprising hydroxypropyl beta cyclodextrin.
Example 4:
Table 4: Composition 7 of example 4
The manufacturing process used was the following:
-adding hydroxypropyl beta cyclodextrin in water for injection;
-adding Voriconazole and dissolving;
-adjusting final solution volume by adding water for injection.
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:
Table 5: Results of Composition 7
Test parameters PH Osmolality (mOsm/Kg) Specific gravity LOD
Before lyophillization 4.6 271 1.030 -
Lyophilized product (powder) - - - 3.1%
After lyophillization 4.9 274 1.038 -
Target characteristics
(reconstitution with 18 ml 6.0
water for injection) (5.0-7.0) 510±5% 1.000-1.080 <5% The physical characteristics before and after lyophillization were not satisfying according to the above table. Thus, the addition of NaCl in order to adjust osmolality, as well as the use of HCl to obtain the desirable pH, was necessary.
Example 5:
Table 6: Compositions 8 and 9 of example 5
The manufacturing process used for both Compositions 8 and 9 was the following:
-adding hydroxypropyl beta cyclodextrin in water for injection;
-adding Voriconazole and dissolving;
-adding NaCl and dissolving;
-adjusting pH to 6 with HCl;
-adjusting final solution volume by adding water for injection;
-filling the vials with 20 ml bulk solution;
-lyophilizing the above vials in order to produce the final product (powder for suspension).
Although 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. On the other hand, in Composition 9 the quantity of NaCl was increased in order to accomplish osmolality specifications.
The physical characteristics of bulk solution, lyophilized and reconstituted product of Composition 9 are presented in the table below:
Table 7: Results of Composition 9
The values obtained were within the specification.
Stability results of Composition 9, after storage of vials at 25°C/60% RH , 30°C/65% RH and 40°C/75% RH for six months are presented in the table below:
Table 8: Stability results of Composition 9
The above results demonstrate the suitability of Composition 9 for parenteral administration.

Claims

1. Aqueous pharmaceutical composition for parenteral administration comprising Voriconazole or pharmaceutical acceptable salt thereof and an effective amount of a solubilizing agent that provides increased Voriconazole solubility.
2. The pharmaceutical composition according to claim 1, wherein the solubilizing agent forms a water-soluble complex with Voriconazole.
3. The pharmaceutical composition according to any preceding claim, wherein the solubilizing agent is hydroxypropyl beta cyclodextrin.
4. The pharmaceutical composition according to any preceding claim, wherein the solubilizing agent is hydroxypropyl beta cyclodextrin with molar substitution 0.65.
5. The pharmaceutical composition according to any preceding claim, comprising hydroxypropyl beta cyclodextrin in an amount of from 8% (w/v) to 16% (w/v).
6. The pharmaceutical composition according to any preceding claim, which is in the form of readily reconstitutable powder for parenteral administration.
7. A process for preparing an aqueous pharmaceutical composition for lyophillization comprising Voriconazole or pharmaceutical acceptable salt thereof and an effective amount of hydroxypropyl beta cyclodextrin that provides increased Voriconazole solubility comprising the steps of:
-adding hydroxypropyl beta cyclodextrin in water for injection;
-adding Voriconazole and dissolving;
-adding NaCl and dissolving;
-adjusting pH with HC1;
-adjusting final solution volume by adding water for injection;
-filling the vials;
-lyophilizing the above vials to produce powder for suspension.
EP14726076.4A 2013-05-27 2014-05-13 Parenteral formulation of triazole antifungal agent and method for preparation thereof Withdrawn EP3003265A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20130100315A GR1008234B (en) 2013-05-27 2013-05-27 Parenteral formulation of triazole antifungal agent and method for preparation thereof
PCT/EP2014/001285 WO2014191080A1 (en) 2013-05-27 2014-05-13 Parenteral formulation of triazole antifungal agent and method for preparation thereof

Publications (1)

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

Family

ID=50792404

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14726076.4A Withdrawn EP3003265A1 (en) 2013-05-27 2014-05-13 Parenteral formulation of triazole antifungal agent and method for preparation thereof

Country Status (3)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113975236A (en) * 2021-12-08 2022-01-28 海南鑫开源医药科技有限公司 Voriconazole dry suspension and preparation process thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015163488A1 (en) 2014-04-25 2015-10-29 Ajinomoto Co., Inc. Immunostimulating agent
EP3511318A1 (en) 2015-10-28 2019-07-17 Ajinomoto Co., Inc. Immunostimulating agent
CN116570558B (en) * 2023-06-21 2023-12-26 广州仁恒医药科技股份有限公司 Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2018866A1 (en) * 2007-07-27 2009-01-28 Sandoz AG Pharmaceutical compositions containing voriconazole
WO2011020605A1 (en) * 2009-08-19 2011-02-24 Ratiopharm Gmbh Process for the production of coevaporates and complexes comprising voriconazole and cyclodextrin
WO2012171561A1 (en) * 2011-06-15 2012-12-20 Synthon Bv Stabilized voriconazole composition
EP2561863A1 (en) * 2011-08-22 2013-02-27 Farmaprojects, S.A.U. Pharmaceutical compositions comprising 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 (en) * 2021-12-08 2022-01-28 海南鑫开源医药科技有限公司 Voriconazole dry suspension and preparation process thereof

Also Published As

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

Similar Documents

Publication Publication Date Title
EP2402008B1 (en) Formulations containing amiodarone and sulfoalkyl ether cyclodextrin
EP3391890B1 (en) Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
EA023208B1 (en) Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US20120142768A1 (en) Formulations including amiodarone and salts thereof and methods of their manufacture and use
WO2012171561A1 (en) Stabilized voriconazole composition
EP3003265A1 (en) Parenteral formulation of triazole antifungal agent and method for preparation thereof
US11141417B2 (en) Voriconazole inclusion complexes
WO2014108918A2 (en) An injectable antifungal formulation
US10342816B2 (en) Aqueous ophthalmic formulations based on azithromycin
RU2575768C2 (en) Formulations of intravenous solutions of posaconazole stabilised by substituted beta-cyclodextrine
WO2016079749A2 (en) Process for preparation of parenteral formulation of anidulafungin
KR20140119363A (en) Stable compositions of voriconazole
JP2005527615A (en) A novel formulation for parenteral application of sodium channel blockers

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20151218

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20200107

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20200603