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WO1993004671A1 - Compositions d'aerosol medicinal - Google Patents

Compositions d'aerosol medicinal Download PDF

Info

Publication number
WO1993004671A1
WO1993004671A1 PCT/US1992/007379 US9207379W WO9304671A1 WO 1993004671 A1 WO1993004671 A1 WO 1993004671A1 US 9207379 W US9207379 W US 9207379W WO 9304671 A1 WO9304671 A1 WO 9304671A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation according
drug
propellant
glycerol phosphatide
glycerol
Prior art date
Application number
PCT/US1992/007379
Other languages
English (en)
Inventor
Martin J. Oliver
Philip A. Jinks
Original Assignee
Minnesota Mining And Manufacturing Company
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 Minnesota Mining And Manufacturing Company filed Critical Minnesota Mining And Manufacturing Company
Priority to EP92920106A priority Critical patent/EP0602181A1/fr
Publication of WO1993004671A1 publication Critical patent/WO1993004671A1/fr

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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant

Definitions

  • This invention relates to medicinal aerosol formulations and in particular to formulations suitable for pulmonary, nasal, buccal, or topical administration which are at least substantially free of chlorofluorocarbons.
  • inhalation Since the metered dose pressurized inhaler was introduced in the mid 1950's, inhalation has become the most widely used route for delivering bronchodilator drugs and steroids to the airways of asthmatic patients. Compared with oral administration of bronchodilators, inhalation offers a rapid onset of action and a low instance of systemic side effects. More recently, inhalation from a pressurized inhaler has been a route selected for the administration of other drugs, e.g., ergotamine, which are not primarily concerned with treatment of a bronchial malady. The metered dose inhaler is dependent upon the propulsive force of a propellant system used in its manufacture.
  • the propellant generally comprises a mixture of liquified chlorofluorocarbons (CFC's) which are selected to provide the desired vapor pressure and stability of the formulation.
  • CFC's chlorofluorocarbons
  • Propellants 11, 12 and 114 are the most widely used propellants in aerosol formulations for inhalation administration.
  • the aerosol formulations are generally in the form of a suspension of drug in the propellant utilizing a surfactant.
  • a surfactant there are few drugs which are soluble in aerosol propellants and solution formulations have been prepared using a polar cosolvent, such as ethanol.
  • European Patent No. 209547 discloses solution formulations of drugs in chlorofluorocarbon propellants in the presence of a glycerol phosphatide.
  • Patent Application No. 89312270.5 discloses that 1,1,1,2- tetrafluoroethane (Propellant 134a) , may be employed as a propellant for aerosol formulations suitable for inhalation therapy when used in combination with a compound (hereinafter an "adjuvant") having a higher polarity than Propellant 134a.
  • the adjuvant should be miscible with Propellant 134a in the amounts employed.
  • Suitable adjuvants include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether.
  • Preferred adjuvants are liquids or gases at room temperature (22°C) at atmospheric pressure. The combination of one or more of such adjuvants with
  • Propellant 134a provides a propellant system which has comparable properties to those of propellant systems based on CFC's, allowing use of known surfactants and additives in the pharmaceutical formulations. This is particularly advantageous since the toxicity and use of such compounds in metered dose inhalers for drug delivery to the human lung is well established.
  • hydrocarbons such as n-butane, isobutane, and propane be considered as CFC replacements in aerosol formulations.
  • hydrocarbons have low densities relative to the drugs in the formulations and that suspension formulations sediment rapidly and are unacceptable.
  • solubility of many drugs in these hydrocarbons is not sufficient, and solution formulations therefore do not contain suitable amounts of drug.
  • an aerosol formulation which contains no dispersed phase, comprising: an aerosol propellant system comprising a propellant selected from n-butane, dimethylether, and mixtures thereof; a glycerol phosphatide; and a drug, in which the drug is dissolved in the composition in an amount greater than could be achieved in the absence of glycerol phosphatide.
  • the glycerol phosphatide may be any one of the following compounds; phosphatidylcholine (lecithin) , phosphatidylethanolamine (cephalin) , phosphatidyl- inositol, phosphatidylserine, diphosphatidylglycerol, or phosphatidic acid.
  • compositions of the invention appear visibly to be true solutions since there is no dispersed phase apparent, they are more correctly referred to as micellar solutions.
  • the formulations of the invention can be prepared by forming a concentrate of glycerol phosphatide with a drug and propellant.
  • the concentrate can be formed by simple admixture with agitation and optionally under heating, e.g., 50 ⁇ C, until complete dissolution of the drug has been attained.
  • the concentrate can then be mixed with the remainder of the propellant formulation.
  • Phosphatidylcholine is the most suitable glycerol phosphatide to use in view of its low toxicity and high drug solubilizing efficacy.
  • Commercial grades of lecithin vary widely in phosphatidylcholine content.
  • Purified phosphatidylcholine (e.g., having phosphatidylcholine content in excess of about 90% by weight) is preferred for use in this invention.
  • Phosphatidylcholine purified from soya bean lecithin is readily available commercially and suitable grades include EpikuronTM 200 (Lucas-Meyer) and LipoidTM S100 (Lipoid KG) . Both products have a phosphatidylcholine content in excess of 95%.
  • Suitable drugs for use in the invention include those which exhibit at least a very slight solubility in the propellant system.
  • the drug will be in a relatively non-polar form, e.g., the form of an ester, base, or free alcohol.
  • Highly polar ionic salts of drugs are generally less suitable since it is difficult to solubilize the drug in sufficient quantity even with the presence of a small amount of cosolvent.
  • the drug is generally present in the formulation in an amount in the range from 0.1 to 15 mg/mL, usually from 2 to 10 mg/mL based on the total volume of the formulation.
  • Suitable medicaments include those disclosed in European Patent Application No.
  • 89312270.5 and include, but are not limited to, albuterol, beclomethasone dipropionate, fentanyl citrate, isoprenaline, rimiterol, pirbuterol, adrenaline, disodium cromoglycate (DSCG) , histamine acid sulphate, morphine and its salts, ergotamine, atropine, captopril, propranolol, diazepam, glycerol trinitrate. isosorbide dinitrate, isosorbide mononitrate, and ipratropium bromide.
  • albuterol beclomethasone dipropionate
  • fentanyl citrate include, but are not limited to, albuterol, beclomethasone dipropionate, fentanyl citrate, isoprenaline, rimiterol, pirbuterol, adrenaline, disodium cromoglycate (DSCG) , histamine acid sulphate, morphine
  • the propellant system contains one or both of n- butane and dimethylether and can include copropellants such as isobutane and propane.
  • the propellant system may include minor amounts of other propellants, but preferably contains no more than 5% by weight of CFCs. More preferably the propellant system is free from CFCs.
  • the compositions comprising drug, glycerol phosphatide, and propellant system contain one to 500, preferably one to 30, more preferably 2 to 10, parts by weight drug based on 100 parts by weight glycerol phosphatide, and 0.01 to 20, preferably 0.01 to 10, more preferably 0.01 to 3, parts by weight glycerol phosphatide based on 100 parts by weight propellant system.
  • a concentrate was prepared by combining the drug, the phosphatidylcholine, and a portion of the n-butane in a pressure resistant vessel. Dissolution of this concentrate was achieved by heating for 1 hour in a water bath maintained at 55°C.
  • the solution was then cooled and the remainder of the n-butane was added.
  • the resulting formulation was in the form of a stable solution.
  • the drug, phosphatidylcholine, and n-butane were mixed in a pressure resistant vessel to form a concentrate. Dissolution was achieved by heating for 1 hour in a water bath maintained at 55°C.
  • the solution was then cooled and the dimethylether was added.
  • the resulting formulation was in the form of a stable solution.
  • the drug, phosphatidylcholine, and a portion of the dimethylether were mixed in a pressure resistant vessel to form a concentrate. Dissolution was achieved by agitation at room temperature.
  • the solution was then cooled to -40°C followed by addition of the other components of the propellant system.
  • the resulting formulation was in the form of a stable solution.
  • the components were introduced into a polyethyleneterephthalate vial (15 mL) and a non- metering valve was crimped in place. An n-butane overage of 0.300 g was present in the formulation to allow for evaporation in the head space in the vial. A solution was obtained after three hours immersion in a 55°C water bath. The formulation was allowed to stand and cool to room temperature. No precipitation or crystallization was observed.
  • the formulation was prepared as in Example 5.
  • EXAMPLE 7 The following materials were weighed into a polyethyleneterephthalate vial and a non-metering valve was crimped in place: lal
  • LipoidTM S100 phosphatidylcholine 0.700 n-Butane 5.600
  • the drug (atropine in Example 8 and captopril in Example 9) and the phosphatidylcholine were weighed into a plastic coated glass bottle which was then sealed with a non-metering valve. The required quantity of n-butane was then pressure-filled into the sealed bottle to form a concentrate. The sealed bottle was then heated for 1 hour at 55°C in a water bath. The sealed bottle was then allowed to cool to room temperature and the remaining propellants were filled into the bottle.
  • EXAMPLE 8 The drug, atropine (base) , was solubilized within 1 hour in the concentrate and remained in solution when the remaining propellants were added.
  • EXAMPLE 9 The drug, captopril, was solubilized within one hour in the concentrate and remained in solution when the remaining propellants were added.
  • EXAMPLES 10 AND 11 The following formulations were prepared:
  • the formulations were prepared by weighing the drug (propranolol hydrochloride in Example 10 and diazepam in Example 11) , the phosphatidylcholine, and the ethanol into a glass vial, sealing the vial with a non-metering valve and pressure filling the required amount of n-butane into the sealed vial to form a concentrate. Each vial was then heated at 55°C for 2 hours in a water bath. The vials were allowed to cool to room temperature and the remaining propellants were filled into the vials.

Landscapes

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

Abstract

Composition d'aérosol en solution contenant un médicament, un phosphatide de glycérol, et un système propulsif contenant du n-butane, du diméthyléther ou un mélange de ceux-ci.
PCT/US1992/007379 1991-09-03 1992-08-28 Compositions d'aerosol medicinal WO1993004671A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP92920106A EP0602181A1 (fr) 1991-09-03 1992-08-28 Compositions d'aerosol medicinal

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9118830.0 1991-09-03
GB919118830A GB9118830D0 (en) 1991-09-03 1991-09-03 Medical aerosol formulations

Publications (1)

Publication Number Publication Date
WO1993004671A1 true WO1993004671A1 (fr) 1993-03-18

Family

ID=10700844

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/007379 WO1993004671A1 (fr) 1991-09-03 1992-08-28 Compositions d'aerosol medicinal

Country Status (5)

Country Link
EP (1) EP0602181A1 (fr)
AU (1) AU2573892A (fr)
CA (1) CA2116862A1 (fr)
GB (1) GB9118830D0 (fr)
WO (1) WO1993004671A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5653961A (en) * 1995-03-31 1997-08-05 Minnesota Mining And Manufacturing Company Butixocort aerosol formulations in hydrofluorocarbon propellant
WO1997038663A3 (fr) * 1996-04-12 1998-02-05 Flemington Pharmaceutical Corp Pulverisateur ou capsule buccal non polaire
US5776432A (en) * 1990-10-18 1998-07-07 Minnesota Mining And Manufacturing Company Beclomethasone solution aerosol formulations
WO2000054748A1 (fr) * 1999-03-12 2000-09-21 Ig Sprühtechnik Gmbh & Co. Kg. Aerosols-doseurs contenant de l'isobutane comme agent propulseur
US6228346B1 (en) 1996-04-25 2001-05-08 Pari Gmbh Spezialisten Fur Effektive Inhalation Propellant mixtures and aerosols for micronizing medicaments with compressed gas
US6660715B2 (en) * 1998-11-19 2003-12-09 Massachusetts Institute Of Technology Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery
US6676931B2 (en) 1997-10-01 2004-01-13 Novadel Pharma Inc. Buccal, polar and non-polar spray or capsule
WO2004019903A1 (fr) * 2002-08-29 2004-03-11 Novadel Pharma Inc. Capsule ou vaporisateur buccal, polaire et non polaire, contenant des medicaments pour le traitement de troubles metaboliques
WO2004058221A1 (fr) * 2002-12-24 2004-07-15 IG Sprühtechnik GmbH & Co. KG Aerosols-doseurs contenant de la lecithine comme surfactant
WO2005000270A3 (fr) * 2003-06-27 2005-05-12 Merck Patent Gmbh Preparations inhalables destinees a traiter l'hypertension pulmonaire et procedes d'utilisation desdites preparations
US6969508B2 (en) 1997-10-01 2005-11-29 Novadel Pharma, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating pain
US6977070B2 (en) 1997-10-01 2005-12-20 Novadel Pharma, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system
US7632517B2 (en) 1997-10-01 2009-12-15 Novadel Pharma Inc. Buccal, polar and non-polar spray containing zolpidem
US7919131B2 (en) 2003-01-31 2011-04-05 Fonterra Co-Operative Group Limited Extraction of compounds from dairy products
US9078816B2 (en) 1997-10-01 2015-07-14 Suda Ltd. Buccal, polar and non-polar spray containing ondansetron
US20190015430A1 (en) * 2010-06-11 2019-01-17 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin d analogue and a corticosteroid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB970027A (en) * 1962-05-24 1964-09-16 Revlon Aerosol compositions
WO1986004233A1 (fr) * 1985-01-16 1986-07-31 Riker Laboratories, Inc. Composition de propulseurs aerosols a base de chlorofluorocarbone contenant des medicaments
GB2240271A (en) * 1990-01-17 1991-07-31 Euro Celtique Sa Atropine-salbutamol aerosol
WO1991011496A1 (fr) * 1990-02-03 1991-08-08 Boehringer Ingelheim Kg Nouveaux gaz propulseurs et leur utilisation dans des preparations medicamenteuses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB970027A (en) * 1962-05-24 1964-09-16 Revlon Aerosol compositions
WO1986004233A1 (fr) * 1985-01-16 1986-07-31 Riker Laboratories, Inc. Composition de propulseurs aerosols a base de chlorofluorocarbone contenant des medicaments
GB2240271A (en) * 1990-01-17 1991-07-31 Euro Celtique Sa Atropine-salbutamol aerosol
WO1991011496A1 (fr) * 1990-02-03 1991-08-08 Boehringer Ingelheim Kg Nouveaux gaz propulseurs et leur utilisation dans des preparations medicamenteuses

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6346232B1 (en) 1990-10-18 2002-02-12 3M Innovative Properties Company Method of forming conductive lines
US5776432A (en) * 1990-10-18 1998-07-07 Minnesota Mining And Manufacturing Company Beclomethasone solution aerosol formulations
US5653961A (en) * 1995-03-31 1997-08-05 Minnesota Mining And Manufacturing Company Butixocort aerosol formulations in hydrofluorocarbon propellant
WO1997038663A3 (fr) * 1996-04-12 1998-02-05 Flemington Pharmaceutical Corp Pulverisateur ou capsule buccal non polaire
US5955098A (en) * 1996-04-12 1999-09-21 Flemington Pharmaceutical Corp. Buccal non polar spray or capsule
US6228346B1 (en) 1996-04-25 2001-05-08 Pari Gmbh Spezialisten Fur Effektive Inhalation Propellant mixtures and aerosols for micronizing medicaments with compressed gas
US6969508B2 (en) 1997-10-01 2005-11-29 Novadel Pharma, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating pain
US6676931B2 (en) 1997-10-01 2004-01-13 Novadel Pharma Inc. Buccal, polar and non-polar spray or capsule
US9078816B2 (en) 1997-10-01 2015-07-14 Suda Ltd. Buccal, polar and non-polar spray containing ondansetron
US6977070B2 (en) 1997-10-01 2005-12-20 Novadel Pharma, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system
US6998110B2 (en) 1997-10-01 2006-02-14 Novadel Pharma, Inc. Buccal, polar and non-polar spray or capsule
US8236285B2 (en) * 1997-10-01 2012-08-07 Novadel Pharma Inc. Buccal, polar and non-polar spray containing zolpidem
EP1952802A3 (fr) * 1997-10-01 2009-06-17 Novadel Pharma Inc. Vaporisation ou capsule orale, polaire et non polaire
US7632517B2 (en) 1997-10-01 2009-12-15 Novadel Pharma Inc. Buccal, polar and non-polar spray containing zolpidem
US6660715B2 (en) * 1998-11-19 2003-12-09 Massachusetts Institute Of Technology Nonaqueous solutions and suspensions of macromolecules for pulmonary delivery
WO2000054748A1 (fr) * 1999-03-12 2000-09-21 Ig Sprühtechnik Gmbh & Co. Kg. Aerosols-doseurs contenant de l'isobutane comme agent propulseur
WO2004019903A1 (fr) * 2002-08-29 2004-03-11 Novadel Pharma Inc. Capsule ou vaporisateur buccal, polaire et non polaire, contenant des medicaments pour le traitement de troubles metaboliques
EP2283814A1 (fr) * 2002-08-29 2011-02-16 Novadel Pharma Inc. Spray buccal polaire d'un sédatif
EP2277506A1 (fr) * 2002-08-29 2011-01-26 Novadel Pharma Inc. Spray buccal non polaire d'un sédatif
WO2004058221A1 (fr) * 2002-12-24 2004-07-15 IG Sprühtechnik GmbH & Co. KG Aerosols-doseurs contenant de la lecithine comme surfactant
JP2006517190A (ja) * 2002-12-24 2006-07-20 イーゲー スプリューテクニーク ゲーエムベーハー ウント ツェーオー．カーゲー 界面活性物質としてレシチンを含む投与エーロゾル
US7919131B2 (en) 2003-01-31 2011-04-05 Fonterra Co-Operative Group Limited Extraction of compounds from dairy products
AU2004251014B2 (en) * 2003-06-27 2010-11-25 Mylan Specialty L.P. Inhalable formulations for treating pulmonary hypertension and methods of using same
AU2004251014B8 (en) * 2003-06-27 2011-02-10 Mylan Specialty L.P. Inhalable formulations for treating pulmonary hypertension and methods of using same
CN1822817B (zh) * 2003-06-27 2012-10-10 德医药有限合伙公司 用于治疗肺性高血压的可吸入制剂及其使用方法
WO2005000270A3 (fr) * 2003-06-27 2005-05-12 Merck Patent Gmbh Preparations inhalables destinees a traiter l'hypertension pulmonaire et procedes d'utilisation desdites preparations
US9498437B2 (en) 2003-06-27 2016-11-22 Mylan Specialty L.P. Inhalable formulations for treating pulmonary hypertension and methods of using same
US20190015430A1 (en) * 2010-06-11 2019-01-17 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin d analogue and a corticosteroid
US20190381074A1 (en) * 2010-06-11 2019-12-19 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamind d analogue and a corticosteroid
US20190388439A1 (en) * 2010-06-11 2019-12-26 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamind d analogue and a corticosteroid
US20200009160A1 (en) * 2010-06-11 2020-01-09 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamind d analogue and a corticosteroid
US10617698B2 (en) * 2010-06-11 2020-04-14 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamind D analogue and a corticosteroid
US10660908B2 (en) * 2010-06-11 2020-05-26 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid
US10682364B2 (en) * 2010-06-11 2020-06-16 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamind D analogue and a corticosteroid
US10688108B2 (en) * 2010-06-11 2020-06-23 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid
US10716799B2 (en) * 2010-06-11 2020-07-21 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid

Also Published As

Publication number Publication date
AU2573892A (en) 1993-04-05
GB9118830D0 (en) 1991-10-16
EP0602181A1 (fr) 1994-06-22
CA2116862A1 (fr) 1993-03-18

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