WO1986001714A1 - Systeme d'administration aerosol de liposomes pour la liberation entretenue de medicaments - Google Patents

Systeme d'administration aerosol de liposomes pour la liberation entretenue de medicaments Download PDF

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Publication number
WO1986001714A1
WO1986001714A1 PCT/GB1985/000430 GB8500430W WO8601714A1 WO 1986001714 A1 WO1986001714 A1 WO 1986001714A1 GB 8500430 W GB8500430 W GB 8500430W WO 8601714 A1 WO8601714 A1 WO 8601714A1
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WO
WIPO (PCT)
Prior art keywords
liposomes
phospholipid
active substance
therapeutically active
propellent
Prior art date
Application number
PCT/GB1985/000430
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English (en)
Inventor
Brian Carman-Meakin
Ian Walter; Kellaway
Stephen James; Farr
Original Assignee
Riker Laboratories, Inc.
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 Riker Laboratories, Inc. filed Critical Riker Laboratories, Inc.
Publication of WO1986001714A1 publication Critical patent/WO1986001714A1/fr

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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
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • a liposomal sustained-release aerosol delivery system A liposomal sustained-release aerosol delivery system
  • This invention relates to a process for the preparation of liposomes and in particular to a simple, rapid method of forming liposomes using a fluoro- chlorocarbon propellent-based pressurised aerosol device.
  • the liposomes formed following delivery by the pressurised aerosol device provide sustained-release of medicament.
  • Liposomes are artificial spherules of phospholipids composed of a series of concentric layers alternated with aqueous compartments. Bangham et al (J. Mol. Biol. 13. (1) 238-59, 1965) first described the preparation of such multi-lamellar lipid vesicles and since then a wide variety of methods have been reported for the preparation of synthetic liposomes. Liposomes were originally used as artificial models to study the properties of biological membranes. However, the practical potential of liposomes is that they are capable of englobing or entrapping a wide range of substances, e.g. drugs, to protect them from degradation and/or to target them toward specific organs. Drugs and other molecules may be encapsulated by two processes.
  • Liposomes have been prepared using a method based on the evaporation of volatile solvent from an ether/lipid/water dispersion. By ultrasonication, a water in lipophilic solvent dispersion was produced, from which the volatile solvent was removed by either evaporation under reduced pressure or by bubbling nitrogen through the mixture.
  • the small unilamellar vesicles produced by ultrasonication possessed only a small aqueous compartment (25 nm diameter) and showed a low efficiency in capturing biologically active molecules.
  • a modified method was based on the removal of organic solvent under reduced pressure to produce a lipid gel which, on addition of excess aqueous phase, formed vesicles of large volume capable of retaining macromolecules with a high capture efficiency.
  • Similar large unilamellar vesicles were also prepared by utilising a calcium-induced structural change in the lipid vesicles. However, this technique was limited to a single phospholipid (phosphatidyl serine) and again had a relatively low efficiency of encapsulation.
  • British Patent Specification No. 2 145 107 A discloses a method for the preparation of liposomes in which at least two separate components are brought together under pressure, a first component comprising water and a second component comprising a lipid material. The components are then passed as a mixture under pressure through a nozzle or other arrangement to produce an aerosol spray containing liposomes.
  • at least one of the first or second components preferably includes a separate active material, e.g. a drug molecule.
  • the specification also discloses a pack for use in preparing a liposomal aerosol comprising at least a first and a second chamber, one chamber containing a first component comprising water and the other chamber containing a second component comprising a lipid material, and one or both of the chambers and/or a third chamber including a propellent material.
  • the pack also includes an arrangement for dispensing as a spray a mixture of the first and second components fed from their respective chambers under pressure developed by the propellent material or materials.
  • the present invention provides an alternative method for the preparation of liposomes.
  • a process for the preparation of liposomes which comprises spraying micro-fine droplets of substantially pure phospholipid in a volatile liquid carrier to impinge either upon or below an aqueous surface thereby forming liposomes.
  • the micro-fine droplets are generated using a propellent-based pressurised aerosol delivery system, the liquid carrier comprising the aerosol propellent which is conveniently a fluorochlorocarbon.
  • the aerosol propellent which is conveniently a fluorochlorocarbon.
  • This system can be utilised to deliver drugs to the mucosal surfaces within the lung and achieve sustained-release from the liposomes which are produced in-situ.
  • the process of the invention provides a simple rapid method for producing liposomes.
  • Discrete micro-fine droplets generally having a diameter in the range 0.5 to 50 micron, of phospholipid in a volatile liquid carrier are sprayed onto or below an aqueous surface.
  • the liquid carrier evaporates and the contact of the resulting solid phospholipid with the water surface results in the spontaneous formation of liposomes.
  • the process may be used to prepare entrapped molecules, e.g. therapeutically active molecules within the liposomes by simple admixture of the desired compound with the phospholipid and lipid carrier.
  • the drug may be dissolved either in the propellent alone or in the presence of a small proportion of a co-solvent, e.g. alcohols, particularly ethanol.
  • a co-solvent e.g. alcohols, particularly ethanol.
  • An alternative method of increasing the solubility of hydrophilic drug molecules in fluorocarbon propellents is to use an excipient which forms an ion-pair with the drug molecule. Examples of such excipients include dicetyl phosphate, benzalkonium chloride, cetyl pyridinium chloride, etc.
  • the process of the invention may be used to entrap any drug molecule which may be solubilised in the composition to entrap drug molecules within liposomes.
  • the entrapped drug molecules are gradually released from liposomes and accordingly these may be used as a method of obtaining sustained release of drug molecules.
  • the rate of release of the drug molecule is dependent upon the molecule itself, the amount of drug entrapped and the particular formulation utilised.
  • the use of a propellent-based pressurised aerosol delivery system allows preparation of the liposomes spontaneously during use or immediately prior to use thereby avoiding problems of poor stability on prolonged storage.
  • the aerosol system is capable of use in inhalation therapy to allow in situ formation of liposomes entrapping therapeutically active molecules on the moist surfaces of the lungs.
  • the process of the invention has significant advantages in its application to inhalation therapy compared to liposomes produced by contacting water with ⁇ pid material and drug prior to the production of an aerosol spray.
  • the mean particle size of droplets issuing from the valve orifice of a pressurised aerosol pack is typically in the range 30 to 50 microns. Only particles in the range 2 to 7 microns are capable of reaching the lower regions of the lung and aerosols for use in inhalation therapy rely upon the rapid evaporation of the fluorochlorocarbon propellent from the droplets to produce a particle size reduction into the range 2 to 7 microns as the droplets are inhaled.
  • the present invention -relies predominantly upon the use of propellents in the formulations thereby producing droplets within the respirable range and liposomes are formed in-situ when the droplets contact an aqueous surface, e.g. the moist surface of the lungs.
  • a pack for use in preparing an aerosol which comprises a single chamber containing a solution of substantially pure phospholipid and a therapeutically active substance dissolved in a propellent material, the molar ratio of phospholipid to the therapeutically active substance being greater than 1:1, the pack including an arrangement for dispensing said solution as a spray under pressure developed by the propellent material.
  • the molar ratio of phospholipid to the therapeutically active substance is generally at least 5:1 and normally within the range 10:1 to 20:1.
  • the solution is anhydrous.
  • the phospholipids used in the invention may be selected from a wide range including: phosphatidylcholine (lecithin) (PC) phosphatidylglycerol (PG) phosphatidylserine (PS) phosphatidic acid (PA) phosphatidylinositol (PI) phosphatidylethanola ine (PE) dipalmitoylphosphatidylglycerol (DPPG) and diacylphosphatidylcholine (DAPC) .
  • PC phosphatidylcholine
  • PG phosphatidylglycerol
  • PS phosphatidylserine
  • PA phosphatidic acid
  • PI phosphatidylinositol
  • PE dipalmitoylphosphatidylglycerol
  • DAPC diacylphosphatidylcholine
  • DCP dicetylphosphate
  • SA stearyla ine
  • SM sphingomyelin
  • C distearyldimethyl ammonium chloride
  • the phospholipids must be substantially pure in order to ensure uniform liposome formation.
  • the phospholipid is at least 80% pure, more preferably 90% to 100% pure.
  • a preferred phospholipid is purified egg phosphatidylcholine (lecithin) .
  • the volatile liquid carrier is preferably a solvent for the phospholipid.
  • Convenient carriers are aerosol propellents, in particular fluorochlorocarbon propellents, e.g. Propellent 11 (trichloro ono- fluoromethane) , Propellent 12 (dichlorodifluoromethane) and Propellent 114 (dichlorotetrafluoroethane) .
  • Suitable formulations for use with a pressurised aerosol delivery system comprise 90 to 99.9% of one or more fluorochlorocarbon propellents and 0.1 to 10% by weight of one or more phospholipids plus formulation aids if required.
  • Example 1 In vitro evidence to show the in-situ production of liposomes from a fluorochlorocarbon propellent-based aerosol device.
  • PC Purified egg phosphatidyl choline
  • Crude egg lecithin BDH Chemicals, England
  • the egg PC was purified and recrystallised as described by Bangham et al. Methods in Membrane Biology, editor E.D. Korn, 1_, page 68, Plenum Press 1974, and was stored under acetone at 4°C.
  • the recrystallised egg PC was shown to be chromatographically pure using a solvent system of chloroform/methanol/water (14/6/1) .
  • a pre-requisite for phospholipids to orientate into a liposomal configuration is the presence of an aqueous environment.
  • An aerosol sampling device was therefore designed to provide humid conditions into which the aerosol dose could be fired and is illustrated in Figure 1 of the accompanying drawings.
  • the apparatus consisted of a 1 litre filtering flask 1, containing a beaker partly filled with a known volume of aqueous receptor fluid 10.
  • An intake tube 2 protruded through its neck with one end 3 located just above the receptor fluid surface and the other end 4 fitted with a medicinal aerosol oral adaptor 5 and aerosol device 6.
  • a means of sampling the receptor fluid was included.
  • the receptor fluid was glass distilled water (pH 5.8) filtered -through a 0.2 micron membrane filter. To attain conditions within the flask of a high relative humidity and 37°C the flask was immersed up to the height of the side arm in a water bath 7 maintained at 37°C. To ensure delivery of the majority of the aerosolised dose into the receptor fluid, air flow through the apparatus was achieved via a tube 8 connected to a vacuum pump (Speedivac). A flow rate of 50 litre/min was monitored by a flow meter (Gap Ltd.). A sampling syringe 9 was provided for obtaining samples of liposome. To permit air flow, the aerosol adaptor had an orifice 11 at the rear. The assembled apparatus was positioned in a pre-equilibrated laminar air flow cabinet to avoid contamination of the receptor fluid with airborne particles.
  • Aerosols containing 1% w/w egg PC at vapour pressures of 3.43 x 10 5 N/m 2 and 4.79 x 10 5 N/m 2 (50 and 70 psia) (21°c) were examined. 100 ml of receptor fluid was dispensed into the flask and the apparatus assembled. Sufficient time was allowed for equilibration. The aerosol unit was shaken, primed and placed in the oral adaptor. Air was drawn through the apparatus and the valve actuated at 10 second intervals for a previously determined number of times.
  • Figure 3 of the accompanying drawings shows the effect of time on the particle size of particles generated from aerosols containing 1% w/w pure egg PC and possessing vapour pressures of 3.43 x 10 5 N/m 2 and 4.79 x 105 N/m 2 (50 or 70 psia) at 21°C, each point representing the mean of three determinations with standard error bars.
  • the initial particle size was dependent on vapour pressure; 882 nm for 3.43 x 10 5 N/m 2 (50 psia) and 560 nm for 4.79 x 10 5 N/m 2 (70 psia) .
  • the particle size decreased with time equilibrating at approximately 90 to 100 minutes to a size of 250 to 290 nm.
  • the 250 nm particles produced after loss of propellent by evaporation were of similar particle size and structural characteristics to the multi-lamellar vesicles produced by a variety of methods of the prior art.
  • Figure 4 of the accompanying drawings is an electron micrograph and reveals clusters of aggregated multilamellar vesicles ranging in size from 150 to 400 nm but collectively in aggregates below 1 micron in size.
  • MLVs multi-lamellar vesicles
  • the aqueous phase used was either (a) 0.9% w/v saline adjusted to pH 7.4 with 0.1M sodium hydroxide or (b) physiologically iso-osmotic, phosphate buffered saline (PBS) at pH 7.4.
  • PBS physiologically iso-osmotic, phosphate buffered saline
  • Salbutamol hemisulphate being practically insoluble in ethanol was added to the aqueous phase.
  • Salbutamol base was sufficiently soluble in ethanol to permit incorporation into the lipid film prior to hydration.
  • the final concentration of lipid was 10 mg/ml and drug 1 mg/ml.
  • the liposome/drug suspensions were shaken at 37°C for sufficient time to permit equilibration before separation of liposomes by centrifugation and assay for drug content in the supernatent by HPLC.
  • Hydrophobic species generally partition into liposomes to a greater extent than hydrophilic species. Formation of an ion-pair complex with a lipophilic moiety represented a method of conferring hydrophobicity to the salbutamol molecule. Dicetyl phosphate (DCP) incorporates into lecithin bilayers and is routinely used at concentrations below 10 mole % to confer a negative charge to liposomes (szoka, F., Papahadjopoulos, D. , Am. Rev. Biophys. Bioeng. 9:467, 1980).
  • DCP Dicetyl phosphate
  • Figure 6 represents a. plot of entrapment of salbutamol (mg/mg %) in DCP/PC liposomes at 37°C against time for varying DCP concentrations.
  • Figure 7 represents a plot of the partition coefficient for salbutamol in liposome (DCP/PC) against molar ratio DCP/salbutamol.
  • DCP/PC partition coefficient for salbutamol in liposome
  • the inclusion of 30% DCP caused a 175% increase in entrapment from 1.4 to 2.45 mg/mg %.
  • FIG. 8 of the accompanying drawings shows a multi-stage liquid impinger which comprises a glass container 80 divided into four sections (Stages 1 to 4) by glass separation plates 82, each section being in communication with adjacent sections via conduits 84.
  • the pressurised aerosol container 86 is positioned at the throat 88 of the apparatus.
  • Sintered glass collection plates 89 are positioned on each separation plate.
  • a fixed volume (10 ml) of pre-filtered (0.05 micron) water was added to each stage to ensure that a moist sintered glass surface was presented to the air flowing through the conduits 84.
  • An outlet 90 is provided in Stage 4 for communication, via a filter 92, to a pump. In practice, air is drawn through the apparatus by the pump so that 60 litres/minute enters the throat 88.
  • the MLI was calibrated in terms of effective cut-off diameter by monitoring an aerosol cloud of methylene blue particles produced from a 0.5% ethanolic solution using a spinning disc aerosol generator.
  • the particles were directed either into a calibrated 8-stage impactor (Andersen Samplers, Inc., Georgia, U.S.A.) or into the MLI by an airstream generated by a vacuum situated downstream of the sampling device.
  • Table 1 Deposition of aerosol emitted from pressurised packs containing egg PC at 3.43 or 4.79 x 10 5 N/m 2 (50 or 70 psia) at 21°c in the multistage liquid impinger apparatus. Each result (expressed as a % retention of the total aerosol) is a mean of three determinations.
  • Effective cut off diameter was assumed as 20 micron for the glass throat (Hallworth, G.W., Andrews, G., J. Pharm. Pharmacol., 28:898, 1976) and determined as 10.47 micron for Stage 1, 5.51 micron for Stage 2, 3.59 micron for Stage 3 and 1.25 micron for Stage 4.
  • hydrophobic drugs are incorporated into liposomes to a higher degree than hydrophilic moieties (Juliano, R.L., Stamp. D., Biochem. Pharmacol. 27:21, 1976).
  • degree of liposomal incorporation of steroidal esters can be increased by extending the degree of liposomal incorporation of steroidal esters
  • Radiolabelled compound (Amersham International, U.K.; specific activity 83 Ci/mmol) was used to permit measurement of the drug efflux rate from liposomes produced in-situ using a pressurised aerosol delivery system.
  • Pressure packs (10 ml) containing 1% w/w egg PC (spiked with 1.59 Ci 1 C-DPPC) and 1 mg of hydrocortisone 21-octanoate (spiked with 4.15 ⁇ Ci of the tritiated steroid ester) in P11/P12, 23/77 blend were prepared. Following shaking and priming, the pressure packs were secured in an inverted position in an oral adaptor and depressed at 5 s intervals for 40 actuations. The emitted aerosol was directed into a calibrated multistage liquid impinger as described in Example 2, each stage containing 10 ml of sterile 0.9% w/v saline, at 60 litre/min via a glass throat.
  • Table 2 reports the partitioning of hydrocortisone 21-octanoate between egg PC liposomes and water at 37°C.

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Abstract

Procédé de préparation de liposomes, consistant à pulvériser des micro-gouttelettes d'une composition comprenant un phospholipide sensiblement pur dans un véhicule liquide volatil, de sorte que les micro-gouttelettes entrent en collision avec une surface aqueuse soit par le haut soit par le bas, formant ainsi des liposomes au niveau de ladite surface. Les compositions peuvent comprendre des molécules de médicaments dissous, qui sont emprisonnées lors de la formation des liposomes. L'emprisonnement ainsi obtenu des molécules de médicaments en assure la libération entretenue.
PCT/GB1985/000430 1984-09-17 1985-09-17 Systeme d'administration aerosol de liposomes pour la liberation entretenue de medicaments WO1986001714A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8423436 1984-09-17
GB848423436A GB8423436D0 (en) 1984-09-17 1984-09-17 Preparation of liposomes

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EP (1) EP0195809A1 (fr)
JP (1) JPS62500643A (fr)
AU (1) AU4866885A (fr)
CA (1) CA1256801A (fr)
ES (1) ES8707859A1 (fr)
GB (1) GB8423436D0 (fr)
NZ (1) NZ213459A (fr)
WO (1) WO1986001714A1 (fr)
ZA (1) ZA856969B (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987001586A1 (fr) * 1985-09-17 1987-03-26 Biocompatibles Limited Aerosol
WO1987005803A1 (fr) * 1986-04-01 1987-10-08 Aktiebolaget Draco COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES beta2-RECEPTRICES
JPS63211223A (ja) * 1986-11-06 1988-09-02 リサーチ　デベロップメント　ファウンデイション 医療用のリポソームおよび薬物含有リポソームのエアゾールの小粒子
EP0293465A4 (fr) * 1986-11-28 1988-11-28 Liposome Co Inc Composition a base de phospholipides.
US4804678A (en) * 1982-01-22 1989-02-14 Fisons Plc Method for treating allergic conditions
EP0310984A2 (fr) * 1987-10-05 1989-04-12 Abnoba Heilmittel Gmbh Procédé et appareil pour la fabrication de colloides aqueux
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
EP0382619A1 (fr) * 1989-02-09 1990-08-16 L'oreal Procédé de fabrication de mousses utilisables dans les domaines cosmétique et pharmaceutique et mousses obtenues par ce procédé
US5049388A (en) * 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US5141674A (en) * 1984-03-08 1992-08-25 Phares Pharmaceutical Research N.V. Methods of preparing pro-liposome dispersions and aerosols
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
US5340587A (en) * 1985-05-22 1994-08-23 Liposome Technology, Inc. Liposome/bronchodilator method & System
WO1994027581A1 (fr) * 1993-05-28 1994-12-08 Aphios Corporation Procedes et appareil destines a la production de liposomes
WO1995001164A1 (fr) * 1993-06-30 1995-01-12 Genentech, Inc. Procede de preparation de liposomes
US5384133A (en) * 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
WO2009073843A1 (fr) * 2007-12-06 2009-06-11 Cytotech Labs, Llc Compositions inhalables présentant une meilleure biodisponibilité
US10973763B2 (en) 2011-06-17 2021-04-13 Berg Llc Inhalable pharmaceutical compositions
US11400058B2 (en) 2010-03-12 2022-08-02 Berg Llc Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3594476A (en) * 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
EP0087993A1 (fr) * 1982-02-17 1983-09-07 Parfums Christian Dior Mélange pulvérulent de constituants lipidiques et de constituants hydrophobes, procédé pour le préparer, phases lamellaires lipidiques hydratées et procédé de fabrication, compositions pharmaceutiques ou cosmetiques comportant des phases lamellaires lipidiques hydratées
GB2145107A (en) * 1983-08-17 1985-03-20 Sterwin Ag Preparation of aerosol compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3594476A (en) * 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
EP0087993A1 (fr) * 1982-02-17 1983-09-07 Parfums Christian Dior Mélange pulvérulent de constituants lipidiques et de constituants hydrophobes, procédé pour le préparer, phases lamellaires lipidiques hydratées et procédé de fabrication, compositions pharmaceutiques ou cosmetiques comportant des phases lamellaires lipidiques hydratées
GB2145107A (en) * 1983-08-17 1985-03-20 Sterwin Ag Preparation of aerosol compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 97, No. 10, September 1982, Columbus, Ohio (US) W.D. SEUFERT et al.: "Dipalmitoyl-Phosphatidycholine Dissolved in Ethanol Forms Highly Elastic Monolayers" see page 414, Abstract 78826w, & Can. J. Physiol. Pharmacol. 1982, 60 (6), 862-4 (Eng). *
CHEMICAL ABSTRACTS, Volume 98, No. 26, June 1983, Columbus, Ohio (US) V.N. VASIL'CHENKO et al.: "Gasdispersion Method for Liposome Preparation", see pages 376, 377, Abstract 221752x, & Liposomy Ikh Vzaimodeistvie Kletkami Tkanyami, Mater. Vses. Simp. 1980 (pub. 1981) 86-91 (Russ). *
CHEMICAL ABSTRACTS, Volume 99, No. 22, November 1983, Columbus, Ohio (US) MARKS L.B. et al.: "Ultrasonic and Jet Aerosolization of Phospholipids and the Effects on Surface Activity", see page 343, Abstract 181351c, & Pediatr. Res. 1983, 17 (9), 742-7 (Eng). *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804678A (en) * 1982-01-22 1989-02-14 Fisons Plc Method for treating allergic conditions
US5141674A (en) * 1984-03-08 1992-08-25 Phares Pharmaceutical Research N.V. Methods of preparing pro-liposome dispersions and aerosols
US5340587A (en) * 1985-05-22 1994-08-23 Liposome Technology, Inc. Liposome/bronchodilator method & System
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
WO1987001586A1 (fr) * 1985-09-17 1987-03-26 Biocompatibles Limited Aerosol
WO1987005803A1 (fr) * 1986-04-01 1987-10-08 Aktiebolaget Draco COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES beta2-RECEPTRICES
US5384133A (en) * 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
US5049388A (en) * 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
JPS63211223A (ja) * 1986-11-06 1988-09-02 リサーチ　デベロップメント　ファウンデイション 医療用のリポソームおよび薬物含有リポソームのエアゾールの小粒子
EP0293465A4 (fr) * 1986-11-28 1988-11-28 Liposome Co Inc Composition a base de phospholipides.
EP0293465A1 (fr) * 1986-11-28 1988-12-07 Liposome Co Inc Composition a base de phospholipides.
EP0310984A3 (en) * 1987-10-05 1989-11-23 Abnoba Heilmittel Gmbh Process and apparatus for the preparation of aqueous colloids
EP0310984A2 (fr) * 1987-10-05 1989-04-12 Abnoba Heilmittel Gmbh Procédé et appareil pour la fabrication de colloides aqueux
US5171577A (en) * 1989-02-09 1992-12-15 L'oreal Process for the preparation of foams which can be used in the cosmetics and pharmaceutical field and foams obtained by this process
EP0382619A1 (fr) * 1989-02-09 1990-08-16 L'oreal Procédé de fabrication de mousses utilisables dans les domaines cosmétique et pharmaceutique et mousses obtenues par ce procédé
WO1994027581A1 (fr) * 1993-05-28 1994-12-08 Aphios Corporation Procedes et appareil destines a la production de liposomes
US5554382A (en) * 1993-05-28 1996-09-10 Aphios Corporation Methods and apparatus for making liposomes
WO1995001164A1 (fr) * 1993-06-30 1995-01-12 Genentech, Inc. Procede de preparation de liposomes
US5653996A (en) * 1993-06-30 1997-08-05 Genentech, Inc. Method for preparing liposomes
AU689786B2 (en) * 1993-06-30 1998-04-09 Genentech Inc. Method for preparing liposomes
WO2009073843A1 (fr) * 2007-12-06 2009-06-11 Cytotech Labs, Llc Compositions inhalables présentant une meilleure biodisponibilité
US11400058B2 (en) 2010-03-12 2022-08-02 Berg Llc Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof
US10973763B2 (en) 2011-06-17 2021-04-13 Berg Llc Inhalable pharmaceutical compositions

Also Published As

Publication number Publication date
ZA856969B (en) 1987-06-24
EP0195809A1 (fr) 1986-10-01
ES8707859A1 (es) 1987-09-01
ES547059A0 (es) 1987-09-01
GB8423436D0 (en) 1984-10-24
CA1256801A (fr) 1989-07-04
NZ213459A (en) 1989-07-27
AU4866885A (en) 1986-04-08
JPS62500643A (ja) 1987-03-19

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