EP0467916A1 - Fongicides au pyrrol en aerosol - Google Patents

Fongicides au pyrrol en aerosol

Info

Publication number
EP0467916A1
EP0467916A1 EP90905606A EP90905606A EP0467916A1 EP 0467916 A1 EP0467916 A1 EP 0467916A1 EP 90905606 A EP90905606 A EP 90905606A EP 90905606 A EP90905606 A EP 90905606A EP 0467916 A1 EP0467916 A1 EP 0467916A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
microns
propellant
formulation according
weight
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Withdrawn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
EP90905606A
Other languages
German (de)
English (en)
Inventor
Thomas Samuel Campbell Crespina Orr
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.)
Fisons Ltd
Original Assignee
Fisons Ltd
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 Fisons Ltd filed Critical Fisons Ltd
Publication of EP0467916A1 publication Critical patent/EP0467916A1/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Withdrawn legal-status Critical Current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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to novel pharmaceutical formulations and a novel therapeutic method of using them.
  • Invasive fungal infections cause significant morbidity and mortality especially in patients with impaired immune defenses.
  • the development of the azole group of antifungal agents has contributed greatly to the treament of fungal infections.
  • Such compounds are normally administered in suitable formulations orally, topically to the skin, or by pessary or suppository. When administered by such routes, however, even the potent azole antifungal agents have little or no effect on an established, invasive fungal infection of the lung of an immunocompromised patient.
  • a pharmaceutical formulation comprising, as active ingredient, an azole antifungal in a form suitable for administration by inhalation.
  • the prophylactic administration of azole antifungal agents to the lung will be particularly effective in the prevention of fungal infections whose main portal of entry is the respiratory system, especially those caused by asper ⁇ illus and cryptococcus species.
  • use of low doses applied directly to the lungs will minimise the risks of the side effects seen with systemic antifungal agents.
  • azole antifungal agents which may be mentioned are, for example, clotrimazole, econazole nitrate, fluconazole, itraconazole, ketoconazole, miconazole nitrate and saperconazole.
  • aqueous solutions/suspensions for use with a nebuliser device; dry powder and pressurised dry powder aerosol.
  • Suitable nebuliser solutions/suspensions may be prepared by adding the azole antifungal agent to water, which has preferably been distilled or sterilised.
  • the aqueous medium may include suspending agents, solubilising agents, stabilisers and/or preservatives.
  • the formulation may additionally contain another prophylactic agent, such as pentamidine, or a bronchodilator.
  • the active ingredients in finely divided form may be used in admixture with a larger sized carrier comprising particles, eg of up to 400 microns diameter.
  • a larger sized carrier comprising particles, eg of up to 400 microns diameter.
  • Effective particle size for particles below 30 microns may be measured by a Coulter counter.
  • Effective particle size for particles above 30 microns may be measured by an Alpine air jet sieve.
  • At least 95% by weight of the particles of the active ingredients have an effective particle size in the range 0.1 to 10 microns.
  • at least 90% and more desirably at least 95% by weight thereof have an effective particle size in the range 1 to 10 microns.
  • at least 50% by weight of the particles of the active ingredients have an effective particle size in the range 1 to 5 microns.
  • the particle size spectrum of the carrier will depend on the particular inhalation device from which the formulation is to be dispersed. It is however desirable to avoid carrier particles of less than 10 microns in size, thus minimising the number of non-drug particles which penetrate deep into the lung. A large proportion of very large particles may also cause a gritty feel in the mouth of the user and is therefore less preferred.
  • Use of a carrier of large particle size may also cause problems in filling- when using filling machines which involve a dosator which picks up powder by dipping into a powder bed from above.
  • use of a carrier of large particle size may ease filling when using machines in which a die is filled from above, but may incline the composition to segregate during transport or storage.
  • At least 95% by weight of the particles of the carrier have an effective particle size below 400 microns.
  • Preferably at least 50%, and more desirably at least 70%, by weight of the carrier particles have an effective particle size in the range 30 to 150, especially 30 to 80 microns.
  • the composition preferably contains from 2 to 50% by weight, more especially from 5 to 25% by weight and particularly from 10 to 15% by weight of the active ingredient, and from 50 to 98% by weight, more especially from 75 to 95% by weight and particularly from 85 to 90% by weight of the carrier.
  • the finely divided active ingredients may be prepared in the desired particle size range for example using a ball mill, a fluid energy mill, by precipitation or by spray drying.
  • the carrier may be prepared by spray drying or grinding and subsequently separating out the desired fraction, for example by air classification and/or seiving.
  • the powder compositions may be prepared by mixing the ingredients together in one or, preferably, more (eg two) steps in a mixer, such as a planetary or other stirred mixer.
  • the carrier may be any non-toxic material which is chemically inert to the active ingredients and is acceptable for inhalation.
  • carriers which may be used include inorganic salts, eg sodium chloride or calcium carbonate; organic salts, eg sodium tartrate or calcium lactate; organic compounds, eg urea or propylidone; monosaccharides, eg lactose, mannitol, arabinose or dextrose monohydrate; disaccharides, eg maltose or sucrose; polysaccharides, eg starches, dextrins or dextrans.
  • a particularly preferred carrier is lactose, eg crystalline lactose.
  • the powder compositions will generally be put in sealed gelatine, plastic or other capsules.
  • the container is preferably loosely filled to less than about 80% by volume, preferably less than about 50% by volume with the powder composition.
  • the active ingredients may be used in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1,000, preferably from 30 to 500 microns in diameter and comprises an agglomeration of individual medicament particles, at least 90% by weight of which have a diameter of less than 10 microns.
  • the soft pellet or granule preferably has an internal coherence such that the pellet or granule remains intact when filled into a container, eg a capsule, using automatic or semi-automatic filling machines, under conditions of transport and storage, and when fluidised within a container in the device from which it is intended to dispense the pellets or granules and yet may be broken up into particles of a therapeutically effective size outside the container as it discharges from the container.
  • the active ingredients are preferably finely divided, eg at least 95% by weight of the paticles of the active ingredient have an effective particle size of from 1 to 10 microns (and these finely divided forms of the active ingredients are a feature of the invention) .
  • the active ingredient to have a mass median diameter of less than 5 microns and especially of less than 4 microns and most preferably of less than 3.5 microns.
  • w e prefer the composition to contain from 0.1 to 12%, more preferably from 0.2 to 5%, eg about 1 to 3.5% by weight of the finely divided active ingredients.
  • mass median diameter we mean the diameter such that half the particulate mass is in particles of lesser diameter and half in particles of greater diameter.
  • the mass median diameter is essentially a Stokes diameter and may be determined using a Joyce Loebl sedimentation disc centrifuge either in a two layer or line start photometric mode (Bagness J and Ottaway A, Proc. Soc. Analyt. Chem. Part 4, Vol 9, 1972 pages 83 -86).
  • the active ingredients of mass median diameter less than 4 microns when formulated as aerosol units and when the units are examined using a single stage liquid impinger (modification of that described in J. Pharm. Pharmac. 1973,
  • the invention enables effective lung penetration to potential sites of organism colonisation.
  • the fine active ingredient(s) may be made by grinding or milling and is (are) preferably dried thoroughly before they are incorporated into the liquefied propellant medium.
  • the liquefied propellant is preferably a gas at room temperature (20°C) and atmospheric pressure ie it should have a boiling point below 20°C at atmospheric pressure.
  • the liquefied propellant should also be non-toxic.
  • suitable liquefied propellants which may be employed are dimethyl ether and alkanes containing up to 5 carbon atoms, eg butane or pentane, or a lower alkyl chloride, eg methyl, ethyl or propyl chlorides.
  • the most suitable liquefied propellants are the fluorinated and fluorochlorinated lower alkanes such as those sold under the Registerd Trade Mark "Freon”. Mixtures of the above mentioned propellants may be suitably employed.
  • propellant 12 dichlorodifluoromethane
  • propellant 114 1,2-dichlorotetrafluoroethane
  • trichloromonofluoromethane Propellant 11
  • dichloromonofluoromethane Propellant 21
  • monochlorodifluoromethane Propellant 22
  • trichlorotrifluoroethane Propellant 113
  • monochlorotrifluoromethane Propellant 13
  • Propellants with improved vapour pressure characteristics may be obtained by using certain mixtures of these compounds, eg "Propellant 11" with “Propellant 12” or “Propellant 12” with “Propellant 114".
  • “Propellant 12” which has a vapour pressure of about 570kPa (absolute) at 20°C, may be mixed in various proportions to form a propellant having a desired intermediate vapour pressure.
  • the vapour pressure of the propellant employed be between 380 and 500, and preferably between 410 and 470kPa (absolute) at 20°C.
  • Such a propellant mixture is usable safely with metallic containers.
  • the composition may also contain a surface active agent.
  • the surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent.
  • the preferred solid anionic surface active agent is sodium dioctylsulphosuccinate.
  • the amount of the surface active agent required is related to the solids content of the suspension and to the particle size of the solids. In general it is only necessary to use 5-15%, and preferably 5-8% of the solid surface active agent by weight of the solids content of the suspension.
  • HLB hydrophile-lipophile balance
  • the HLB ratio is an empirical number which provides a guide to the surface active properties of a surface active agent. The lower the HLB ratio, the more lipophilic is the agent and, conversely, the higher the HLB ratio, the more hydrophilic is the agent.
  • the HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W C Griffin in the Journal of the Society of Cosmetic Chemists, Vol 1, No 5, pages 311-326 (1949).
  • the surface active agent employed should have an HLB ratio of 1 to 5. It is possible to employ mixtures of surface active agents, the mixture having an HLB ratio within the prescribed range.
  • liquid non-ionic surface active agent to comprise from 0.1 to 2%, and more preferably from 0.2 to 1% by weight of the total composition. Such compositions tend to be more physically stable on storage.
  • liquid non-ionic surface active agents which may be employed are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, oleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the Registered Trade Mark "span”) and the polyoxyethylene and polyoxypropylene derivatives of these esters.
  • an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannito
  • liquid non-ionic surface active agents are the oleates of sorbitan, eg those sold under the Registered Trade Marks "Arlacel C” (sorbitan sesquioleate) , "Span 80" (sorbitan monooleate) and “Span 85” (Sorbitan trioleate) .
  • Specific examples of other liquid non-ionic surface active agents which may be employed are sorbitan monolaurate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol pentaoleate and polyoxypropylene mannitol dioleate.
  • a solid non-ionic surface active agent which may be mentioned is lecithin, eg soya lecithin, a vegetable lecithin extracted from soya beans, but lecithin is not preferred.
  • lecithin eg soya lecithin, a vegetable lecithin extracted from soya beans, but lecithin is not preferred.
  • We prefer the ratio of propellant 12 to 114 to be in the range 2 to 1:1 and preferably 1.5:1 by weight, ie we prefer an excess of propellant 12 over propellant 114.
  • the preferred dosages of active drug will be dependent on several factors including the particular azole antifungal agent used and the patient's diagnosis. However, when the treatment is to be used prophylactically, we prefer that adequate levels of the drug are maintained in the lung to prevent invasive fungal colonisation.
  • a unit dose of active ingredient may be from 0.05 to 40 g, more preferably 1 to 30 mg, particularly 5 to 20 mg.
  • the aerosol dispensing pack is preferably provided with a valve adapted to deliver unit dosages of between 0.025 and 0.25mls, and preferably 0.05 or O.lmls of composition.
  • a valve adapted to deliver unit dosages of between 0.025 and 0.25mls, and preferably 0.05 or O.lmls of composition.
  • the pressurised aerosol formulations of the invention may be made by mixing the various components at a temperature and pressure at which the propellant is in the liquid phase and the active ingredients are in the solid phase.
  • a container equipped with a valve is filled with a propellant containing the finely divided active ingredient in suspension.
  • a container may first. e charged with a weighed amount of dry active ingredients which have been ground to a predetermined particle size, or with a slurry of powder in the cooled liquid propellant.
  • a container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle.
  • a bulk of the total composition may be made and portions of this bulk compositon may be filled into the container through the valve.
  • the powder will be dispensed in a stream of propellant which will vaporise providing an aerosol of dry powder.
  • finely divided powdered azole antifungal may be used as inhalation medicaments.
  • finely divided powdered azole antifungal is novel.
  • finely divided powdered azole antifungal with a mass median diameter in the range 0.1 to 10 microns. We prefer at least 95% of such powdered antifungal to have a mass median diameter in this range.
  • compositions of the invention may be used in the remedial treatment or, more preferably, in the prophylaxis of fungal infections of the airways.
  • the compositions of the invention, when administered via inhalation, will be particularly useful for the prophylaxis of systemic fungal infections whose portal of entry is the respiratory system.
  • compositions for the prophylaxis of fungal infections whose main portal of entry is the respiratory system.
  • formulations of the invention are advantageous in that they are less toxic, more efficacious, give rise to fewer side effects are better tolerated or have other useful properties compared to known therapies.
  • compositions of the invention may, therefore, be used for the prophylaxis and/or treatment of aspergillosis and cryptococcosis.
  • Patients particularly susceptible to invasive aspergillosis are those with defective neutrophil function and/or neutropenia, for example those with hematologic and lymphoreticular malignancy, organ transplants, or high dose steroid use.
  • Some asthmatic patients are also predisposed to allergic bronchopulmonary aspergillosis (ABPA) for which there is no established therapy. Treatment of the symptoms of asthma and/or ABPA using steroids increases the risk of developing invasive disease.
  • ABPA allergic bronchopulmonary aspergillosis
  • Patients particularly at risk of developing cryptococcosis are those with AIDS, lymphoreticular malignancies, organ transplants, chronic steroid use, sarcoidosis,. chronic active hepatitis, connective tissue disorders or severe diabetes mellitus.
  • the treatment may be administered by nasal inhalation; however we prefer oral inhalation.
  • the dosage to be given will clearly vary with the patient and with their condition. In general, however, relatively low doses administered at an interval to maintain adequate pulmonary drug concentration are indicated.
  • a method of prophylaxis of a fungal pulmonary infection especially infections caused by aspergillosis or cryptococcosis, which comprises administering by inhalation a therapeutically effective amount of an azole antifungal agent to a patient predisposed to such an infection.

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

Abstract

Formules pharmaceutiques ayant pour composant actif un fongicide au pyrrol aministrable par inhalation. Ces formules comprennent des formules par aérosol pressurisé, des formules par aérosol non pressurisé, et des solutions/suspensions à utiliser au moyen d'un nébulisateur. La présente invention décrit aussi un fongicide au pyrrol pulvérisé finement divisé, avec un diamètre moyen de masse variant entre 0.1 et 10 microns, ainsi qu'une méthode de prophylaxie des infections fongiques pulmonaires comprenant l'administration par inhalation d'une quantité thérapeutiquement efficace de fongicide au pyrrol à un patient prédisposé à ces infections.
EP90905606A 1989-04-12 1990-04-05 Fongicides au pyrrol en aerosol Withdrawn EP0467916A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898908250A GB8908250D0 (en) 1989-04-12 1989-04-12 Formulations
GB8908250 1989-04-12

Publications (1)

Publication Number Publication Date
EP0467916A1 true EP0467916A1 (fr) 1992-01-29

Family

ID=10654880

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90905606A Withdrawn EP0467916A1 (fr) 1989-04-12 1990-04-05 Fongicides au pyrrol en aerosol

Country Status (7)

Country Link
EP (1) EP0467916A1 (fr)
JP (1) JPH04504419A (fr)
CA (1) CA2014401A1 (fr)
GB (1) GB8908250D0 (fr)
GR (1) GR900100280A (fr)
PT (1) PT93739A (fr)
WO (1) WO1990011754A1 (fr)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000061A1 (fr) * 1990-06-29 1992-01-09 Fisons Plc Compositions d'aerosol pressurisees
ATE339952T1 (de) 1991-06-10 2006-10-15 Schering Corp Fluorchlorkohlenwasserstofffreie aerosolformulierungen
IT1253711B (it) * 1991-12-17 1995-08-23 Alfa Wassermann Spa Formulazioni farmaceutiche vaginali contenenti rifaximin e loro uso nel trattamento delle infezioni vaginali
US7105152B1 (en) 1991-12-18 2006-09-12 3M Innovative Properties Company Suspension aerosol formulations
US7101534B1 (en) 1991-12-18 2006-09-05 3M Innovative Properties Company Suspension aerosol formulations
RU2127733C1 (ru) * 1992-03-18 1999-03-20 Жансен Фармасетика Н.В. Стереоизомеры итраконазола или саперконазола, способ их получения, их комплексы и фармацевтическая композиция на их основе
CA2154777A1 (fr) * 1993-01-27 1994-08-04 Nancy M. Gray Methode et composition utilisant le (2r,4s)-itraconazole
DE4323636A1 (de) * 1993-07-15 1995-01-19 Hoechst Ag Arzneistoffzubereitungen aus umhüllten, schwerstwasserlöslichen Arzneistoffen für Inhalationsarzneiformen und Verfahren zu ihrer Herstellung
JP2875140B2 (ja) * 1993-08-16 1999-03-24 明治製菓株式会社 抗ｍｒｓａ組成物
NL1006103C2 (nl) * 1997-05-21 1998-11-25 Nutricia Nv Huidspray op poederbasis.
WO1999029522A1 (fr) 1997-12-09 1999-06-17 The Goodyear Tire & Rubber Company Pneumatique muni d'une antenne pour repeteur radio
PT1039909E (pt) 1997-12-31 2003-02-28 Choongwae Pharma Corp Metodo de producao e composicao de uma preparacao oral de itraconazole
US6086376A (en) * 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
US6932861B2 (en) 2000-11-28 2005-08-23 Fmc Corporation Edible PGA coating composition
KR100743404B1 (ko) 2000-12-21 2007-07-30 넥타르 테라퓨틱스 폴리엔 항균제의 폐 전달
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
US7582284B2 (en) 2002-04-17 2009-09-01 Nektar Therapeutics Particulate materials
WO2006026502A1 (fr) * 2004-08-27 2006-03-09 The Dow Chemical Company Administration amelioree de compositions medicamenteuses pour le traitement d'infections parfois mortelles
WO2008097664A1 (fr) 2007-02-11 2008-08-14 Map Pharmaceuticals, Inc. Procédé d'administration thérapeutique de dhe pour procurer un soulagement rapide de la migraine tout en minimisant le profil des effets secondaires
WO2008124131A1 (fr) * 2007-04-05 2008-10-16 The John Hopkins University Agents antifongiques comme neuroprotecteurs
CN102065842A (zh) * 2008-04-15 2011-05-18 先灵公司 优选含有泊沙康唑和hpmcas的固体分散体形式的口服药物组合物
EP2601973A1 (fr) 2011-12-09 2013-06-12 Laboratoires SMB SA Formulation de poudre sèche de dérivé d'azole pour inhalation
WO2014106727A1 (fr) 2013-01-03 2014-07-10 Vectura Limited Inhalateur et formulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1241602A (fr) * 1984-02-23 1988-09-06 Ortho Pharmaceutical Corporation Solution fongifuge en aerosol
JPH01153634A (ja) * 1987-12-10 1989-06-15 Kyorin Pharmaceut Co Ltd 吸入剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9011754A1 *

Also Published As

Publication number Publication date
WO1990011754A1 (fr) 1990-10-18
GB8908250D0 (en) 1989-05-24
JPH04504419A (ja) 1992-08-06
GR900100280A (el) 1991-09-27
PT93739A (pt) 1990-11-20
CA2014401A1 (fr) 1990-10-12

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