WO1996013254A1 - Composition pharmaceutique contenant l'atovaquone - Google Patents

Composition pharmaceutique contenant l'atovaquone Download PDF

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Publication number
WO1996013254A1
WO1996013254A1 PCT/GB1995/002523 GB9502523W WO9613254A1 WO 1996013254 A1 WO1996013254 A1 WO 1996013254A1 GB 9502523 W GB9502523 W GB 9502523W WO 9613254 A1 WO9613254 A1 WO 9613254A1
Authority
WO
WIPO (PCT)
Prior art keywords
atovaquone
composition according
pulmonary surfactant
protein
composition
Prior art date
Application number
PCT/GB1995/002523
Other languages
English (en)
Inventor
Walker Anderson Long
Craig William Davis
Kevin Alexander Miller
Jeffrey Scott Staton
Original Assignee
Glaxo Wellcome House
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 Glaxo Wellcome House filed Critical Glaxo Wellcome House
Priority to AU37056/95A priority Critical patent/AU3705695A/en
Publication of WO1996013254A1 publication Critical patent/WO1996013254A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical formulation containing a non-protein pulmonary surfactant and atovaquone and its use, particularly for lung infections.
  • Atovaquone (2-[4-(4-chlorophenyI)cyclohexyl]-3-hydroxy- 1 ,4-naphthoquinone) is described in US Patent No. 5053432. It has been described as being useful in the treatment of Pneumocystis carinii, malaria and a number of other protozoal infections. Unfortunately, atovaquone is poorly soluble and poorly bioavailable and its efficacy is limited by its bioavailability. This makes formulation using standard formulatory techniques difficult, particularly for the treatment of Pneumocystis carinii which requires relatively high plasma concentrations of atovaquone.
  • the present invention provides a pharmaceutical composition for use in the preparation of pharmaceutical formulations which comprises 2 to 50% of atovaquone by weight and 50 to 98% of a non-protein pulmonary surfactant.
  • the composition comprises 10 to 30% atovaquone by weight and 70 to 90% non-protein pulmonary surfactant by weight.
  • a preferred composition comprises 17.4% atovaquone by weight and 82.6% non protein pulmonary surfactant.
  • non-protein pulmonary surfactant a synthetic material useful for assisting respiration when natural pulmonary surfactant is deficient or dysfunctional.
  • non-protein pulmonary surfactants include a phospholipid such as dipalmitoylphosphatidylcholine DPPC.
  • a preferred synthetic pulmonary surfactant contains 50-60% of a phospholipid, such as DPPC, 20-40% sodium chloride, and 4-10% of an agent that provides mobility for the phospholipid film such as cetyl alcohol and optionally 4-10% tyloxapol.
  • Phospholipids that may be substituted for DPPC include phoshatidylglycerols.
  • phosphatidylinositols examples include C 14.13 fatty acid type alcohols such as stearyl alcohol or myristyl alcohol.
  • Other formulation agents that can be incorporated in the compositions of the present invention include non-ionic surfactants such as polyoxyethylene stearates; and other typical tonicity adjusters such as dextrose, mannitol and calcium salts.
  • Such a synthetic pulmonary surfactant is marketed by the Wellcome Foundation Limited under the trade mark EXOSURF.
  • the composition is suitably manufactured to a median particle size of 1-5 microns and preferably to a median particle size of 2 microns.
  • This particle size enables administration of respirable particles via nebulization or aerosolization without additional energy input to obtain the desired particle size.
  • This small particle size also facilitates administration by instillation in minimizing the potential for airway obstruction.
  • Manufacturing techniques utilized to obtain this particle size include, but are not limited to, homogenization, microfluidization, micronization, milling, re-crystallization, spray-drying, etc. It is recognized that those skilled in the art may be aware of additional techniques to obtain this particle size and these techniques are therefore included within this embodiment.
  • the compositions of the present invention are also particularly suitable for dilution with water to give aqueous pharmaceutical formulations.
  • Spray drying followed by microfluidization has been found to be particularly advantageous in preparing compositions of the present invention having the required particle size and a sufficient concentration of atovaquone. Accordingly, there is also provided a method for preparing compositions of the present invention which method comprises spray drying atovaquone with the non-protein pulmonary surfactant followed by microfluidizing a suspension of the spray dried material.
  • atovaquone and the non-protein pulmonary surfactant are dissolved in tetrafuran prior to spray drying.
  • the spray dried atovaquone and surfactant are added to a saline solution at a non-extreme elevated temperature, for example 65-70°C, prior to microfluidizing.
  • the present invention provides a method for the treatment and/or prophylaxis of a parasitic infection in mammals, including humans, which comprises administering an effective amount of a composition of the present invention.
  • the composition is administered by the pulmonary route or orally.
  • Parasitic infections that can be treated by compositions of the present invention include malaria, toxoplasmosis and other protozoal infections and pneumocystis carinii.
  • the amount of atovaquone and non-protein pulmonary surfactant required to be effective as an anti-parasitic agent will, of course, vary and is ultimately at the discretion of the medical practitioner.
  • a suitable effective dose for administration to man for treatment of a protozoal parasitic disease is in the range of 0.5 mg to 30 mg of atovaquone per kilogram bodyweight per day, and 0.5 to 1500 mg of DPPC per kilogram bodyweight per day, for example 1 to 20 mg/kg/day of atovaquone and 1 to 1000 mg/kg/day of DPPC, particularly 3 to 15mg/kg/day of atovaquone and 3 to 750 mg kg/day of DPPC.
  • a suitable effective dose for administration to man for prophylaxis of parasitic diseases is in the range of from 3 to 20 mg kg/week of atovaquone and 3 to 1000 of DPPC, for example from 6 to lOmg/kg/week of atovaquone and 6 to 500 of DPPC.
  • compositions of the present invention may conveniently be presented as pharmaceutical formulations in unit dosage form.
  • a convenient unit-dose formulation contains the active ingredients in amounts of 200 mg to 1000 mg atovaquone and 200 to 10000 mg DPPC.
  • Suitable formulations within the scope of the present invention include, for example, solid dosage forms such as tablets and liquid dosage forms, such as suspensions.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared using methods known in the art of pharmacy.
  • compositions of the present invention may be administered to the lungs of a patient by any suitable means, but are preferably administered by generating an aerosol comprised of respirable particles containing atovaquone, which particles are inhaled by the patient.
  • the particles may optionally contain other therapeutic ingredients.
  • Aerosols of liquid particles comprising atovaquone may be produced by any suitable means, such as with a nebuliser. Nebulisers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air/oxygen, through a narrow venturi orifice or by means of ultrasonic agitation.
  • Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier, the active ingredient comprising up to 40% w/w of the formulation but preferably less than 20%.
  • the carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride.
  • Optional additives include preservatives if a formulation is not prepared sterile, for example methyl hydroxybenzoate. antioxidants, flavouring agents, volatile oils, and other surfactants.
  • An example of an aerosol generator comprises a metered dose inhaler.
  • Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution of the formulation of the active ingredient in a liquified propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume, typically firom 10-150 micro litres, to provide a fine particle spray containing the active ingredient.
  • Suitable propellants include chlorofluorocarbon compounds for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof.
  • the formulation may additionally contain one or more co-solvents for example ethanol, surfactants such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents.
  • the aerosol may be produced by the aerosol generator at a rate of from about 10-150 litres per minute, more preferably from about 30-150 litres per minute and most preferably about 60 litres per minute. Aerosols containing greater amounts of medicament may be administered more rapidly.
  • compositions for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of the active ingredients.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compression tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, or dispersing agent.
  • Moulded tablets may be made by moulding an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling the active ingredients, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein the active ingredients are sealed in a paper envelope.
  • the active ingredients may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged e.g. in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid or a non- aqueous liquid or as an oil-in-water liquid emulsion.
  • Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the active ingredients are formulated in an appropriate release-controlling matrix, or are coated with a suitable release-controlling film. Such formulations may be particularly convenient for prophylactic use.
  • Tests to measure the bioavailability of atovaquone in vivo indicate that formulations of atovaquone and non-protein pulmonary surfactants, for example Exosurf have improved bioavailability compared to prior art formulations of atovaquone.
  • the invention therefore provides in a further aspect, formulations comprising atovaquone and a non-protein pulmonary surfactant eg Exosurf, for use in therapy, in particular in the treatment and prophylaxis of protozoal parasitic infections, e.g. malaria and toxoplasmosis, and infections caused by P. carinii.
  • Tyloxapol (mg) 2.96 11.86 17.78 12.0 18.0 12.0
  • Formulation (h) was prepared by standard methods.
  • the spray dried DPPC/cetyl alcohol/tyloxapol/atovaquone material was added to a saline solution at 65-70°C comprising the appropriate amount of sodium chloride in water for injection, followed by mixing.
  • the pH was adjusted using hydrochloric acid and/or sodium hydroxide.
  • the resulting suspension was microfluidized at 10000 psig until 90% of the particles were less than three microns in size.
  • the microfluidized atovaquone/Exosurf suspension was filled into 50mL amber glass vials and terminally sterilized for fifteen minutes at 121 °C.

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

Abstract

La présente invention concerne une composition pharmaceutique contenant de l'atovaquone et un tensioactif pulmonaire non protéinique. Une composition appropriée comprend 10 à 30 % en poids d'atovaquone et 70 % à 90 % d'un tensioactif pulmonaire non protéinique. La composition convient à une administration orale ou pulmonaire et permet d'avoir une atovaquone avec une biodisponibilité améliorée.
PCT/GB1995/002523 1994-10-26 1995-10-25 Composition pharmaceutique contenant l'atovaquone WO1996013254A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37056/95A AU3705695A (en) 1994-10-26 1995-10-25 Pharmaceutical composition comprising atovaquone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9421585 1994-10-26
GB9421585.2 1994-10-26

Publications (1)

Publication Number Publication Date
WO1996013254A1 true WO1996013254A1 (fr) 1996-05-09

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/002523 WO1996013254A1 (fr) 1994-10-26 1995-10-25 Composition pharmaceutique contenant l'atovaquone

Country Status (2)

Country Link
AU (1) AU3705695A (fr)
WO (1) WO1996013254A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035660A1 (fr) * 1997-02-11 1998-08-20 Mse Pharmazeutika Gmbh Preparations transdermiques, orales et intraveineuses de 2,3-dimethoxy-5-methyle-6-decaprenyle-1,4-benzoquinone
WO2005037246A2 (fr) * 2003-10-15 2005-04-28 Pari Gmbh Preparation aqueuse sous forme d'aerosol
EP1712220A1 (fr) * 2005-04-15 2006-10-18 PARI GmbH Spezialisten für effektive Inhalation Composition d'aérosol pharmaceutique
EA016072B1 (ru) * 2005-05-18 2012-01-30 Палметрикс Инк. Применение состава соли кальция для изменения биофизических свойств слизистой оболочки
CN109640948A (zh) * 2016-06-16 2019-04-16 利物浦大学 化学组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362996A2 (fr) * 1988-08-16 1990-04-11 The Wellcome Foundation Limited Naphtoquinones pour le traitement et prophylaxe des infections de pneumocystis carinii
WO1994014426A1 (fr) * 1992-12-24 1994-07-07 The Wellcome Foundation Limited Compositions pharmaceutiques a base d'atovaquone
WO1995015182A1 (fr) * 1993-12-02 1995-06-08 Emory University Compositions anti-infectieuses et procedes d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362996A2 (fr) * 1988-08-16 1990-04-11 The Wellcome Foundation Limited Naphtoquinones pour le traitement et prophylaxe des infections de pneumocystis carinii
WO1994014426A1 (fr) * 1992-12-24 1994-07-07 The Wellcome Foundation Limited Compositions pharmaceutiques a base d'atovaquone
WO1995015182A1 (fr) * 1993-12-02 1995-06-08 Emory University Compositions anti-infectieuses et procedes d'utilisation

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035660A1 (fr) * 1997-02-11 1998-08-20 Mse Pharmazeutika Gmbh Preparations transdermiques, orales et intraveineuses de 2,3-dimethoxy-5-methyle-6-decaprenyle-1,4-benzoquinone
WO2005037246A2 (fr) * 2003-10-15 2005-04-28 Pari Gmbh Preparation aqueuse sous forme d'aerosol
WO2005037246A3 (fr) * 2003-10-15 2005-12-08 Pari Gmbh Preparation aqueuse sous forme d'aerosol
US7758886B2 (en) 2003-10-15 2010-07-20 Pari Gmbh Pharmaceutical aerosol composition
EP1712220A1 (fr) * 2005-04-15 2006-10-18 PARI GmbH Spezialisten für effektive Inhalation Composition d'aérosol pharmaceutique
WO2006108556A3 (fr) * 2005-04-15 2007-05-03 Pari Gmbh Composition pharmaceutique sous forme d'aerosol
EA016072B1 (ru) * 2005-05-18 2012-01-30 Палметрикс Инк. Применение состава соли кальция для изменения биофизических свойств слизистой оболочки
CN109640948A (zh) * 2016-06-16 2019-04-16 利物浦大学 化学组合物

Also Published As

Publication number Publication date
AU3705695A (en) 1996-05-23

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