EP0282537A1 - Nouveau systeme d'administration de liposomes a des mammiferes - Google Patents

Nouveau systeme d'administration de liposomes a des mammiferes

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Publication number
EP0282537A1
EP0282537A1 EP87906023A EP87906023A EP0282537A1 EP 0282537 A1 EP0282537 A1 EP 0282537A1 EP 87906023 A EP87906023 A EP 87906023A EP 87906023 A EP87906023 A EP 87906023A EP 0282537 A1 EP0282537 A1 EP 0282537A1
Authority
EP
European Patent Office
Prior art keywords
solid material
liposomes
lipid
propellant
powder
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.)
Pending
Application number
EP87906023A
Other languages
German (de)
English (en)
Inventor
Bengt Ingemar Axelsson
Ulla Katarina BYSTRÖM
Carl Magnus Olof DAHLBÄCK
Leif Arne KÄLLSTRÖM
Per-Gunnar Nilsson
Jan William Trofast
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.)
Draco AB
Original Assignee
Draco AB
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 Draco AB filed Critical Draco AB
Publication of EP0282537A1 publication Critical patent/EP0282537A1/fr
Pending legal-status Critical Current

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes

Definitions

  • the present invention provides a new system to administer liposomal formulations to mammals, including man, compris ⁇ ing a dry lipid-based solid material, which in an aqueous milieu spontaneously form or reconstitute liposomes, and a device for aerosolizing a selected quantity of the dry lipid-based solid material in a suitable form.
  • the inven- tion is particularly concerned with breath-actuated powder-inhalators and self-propelling powder-dispensing compositions capable of dispensing in aerosol form a powder of said dry lipid-based solid materials.
  • liposomal formulations have been administered to mammals as aqueous dispersions or as compositions consis ⁇ ting of dissolved lipids. It is an object of the present invention to provide a new improved system to administer liposomal formulations.
  • the invention is based on the fact that certain lipid-based solid materials hydrate to form or reconstitute liposomes in an aqueous milieu.
  • the lipid- based solid materials are administered to the body in aerosol from by a suitable device and the hydration to liposomes occurs in vivo, either at the site of action or elsewhere.
  • the aerosolized lipid-based solid material can be administered to various parts of the body applications where it is inhaled as a finely-divided powder and hydrated in the respiratory tract are particularly suitable. It is therefore a further object of the present invention to provide a pharmaceutical package suitable for inhalation therapy.
  • Liposomes are widely described in the literature and their general structure is well known, they are structures com ⁇ posed of concentric rings of lipid bilayers. Liposomes have been used as carriers for different kinds of pharmacologi ⁇ cally active substances in order to improve their thera ⁇ Therapeutic efficacy.
  • Liposomes can be used as carriers both for hydrophilic and lipophilic substances. Hydrophilic substances are encapsu ⁇ lated in the aqueous space between the lipid bilayers while lipophilic substances are incorporated into the lipid bilayers.
  • Liposomes can be made from a range of lipids, both neutral and charged, including phophatidylcholines, and can be manufactured in a number of different ways resulting in liposomes with various properties. Liposomes can therefore to some extent be taylored to suit a specific application. Examples of parameters which can be controlled are liposome size (20 nm - 10 ⁇ m) , type [SUV (small unilamellar vesic ⁇ les), LUV (large unilamellar vesicles), MLV (multilamellar vesicles) etc], phase-transition temperature, Tc (and hence the rate of release of encapsulated substance) and liposome charge.
  • SUV small unilamellar vesic ⁇ les
  • LUV large unilamellar vesicles
  • MLV multilamellar vesicles
  • Aqueous liposome dispersions have a limited physical sta ⁇ bility since the liposomes can aggregate resulting in a change in the size distribution. Furthermore, if the en ⁇ capsulated drug is hydrophilic it may be lost into the external aqueous phase. In addition, there is a potential risk for chemical degradation of the lipid components and the pharmacologically active substance in an aqueous milieu.
  • dry solid composition The problem concerning stability can to large extent be solved if a dry solid composition is developed.
  • dry implies a virtually water-free formulation but does not imply the absence of a liquid in which the solid com ⁇ position is virtually insoluble.
  • a dry solid composition is stable during long time at room temperature and under moi ⁇ sture protection in a closed container.
  • the first approach is by liposome pre ⁇ cursors, proliposomes.
  • Proliposomes are formulations from which liposomes readily can be prepared, usually by dis- persing the proliposome material in an aqueous solution and, if necessary, heating the dispersion to a temperature above the phase-transition temperature of the lipid mate ⁇ rial (UK Patent Specification 1 575 343, UK Patent Appli ⁇ cation GB 2 135 268 A).
  • the second approach to obtain a dry solid composition is to dehydrate a liposome dispersion in the presence of a filler material intended to impede agglomeration of the dehydrated product (UK Patent Application GB 2 002 319 A).
  • the dehy- dration can for example be performed by lyophilization or by spray-drying.
  • the liposomes are reconstituted by rehyd- ration of the dry product.
  • the dry solid products of the both approaches discussed above can be used in the present invention. Instead of hydrating the dry solid material before administration as in previous methods, it is in the present invention admi ⁇ creamyred to the body in aerosol form by a suitable device. In the body the dry lipid-based solid material is hydrated to liposomes.
  • a powder-inhalator provides a selected quantity of a dry powder in a form suitable for inhalation.
  • the pressurized dose-aerosol is a pressure-tight container having a valve-controlled opening and containing a self- propelling composition capable of providing drug in aerosol form.
  • the self-propelling composition comprises a propel- lant in which the pharmacologically active substance is dissolved or dispersed.
  • adjuvants such as ethanol, nonionic surfactants, taste maskers, etc are added to improve the formulation.
  • the active material is dispensed in a stream of propellant.
  • Pressurized dose-aerosols con- taining lipid materials exist on the market. However, these materials are present as suspending agents for the drug particles in the propellant and as valve lubricants.
  • UK Patent Application GB 2 145 107 A provides a method and a pack for in situ formation of liposomes in which at least two separate components are brought together under pres ⁇ sure, the first component comprising water and the second component comprising a dissolved lipid material.
  • the com ⁇ ponents are passed as a mixture through a nozzle or other arrangement to produce an aerosol spray containing liposomes.
  • European Patent Application 158 441 provides aerosol compositions comprising in a volatile liquid propellant
  • the propellant volatili ⁇ ses, leaving an aerosol of the remaining components as a proliposome composition in the form of droplets. In the presence of water, these droplets spontaneously form liposomes.
  • PCT application WO 86/01714 describes 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 volatile liquid carrier is preferably a solvent for the phospholipid and the drug molecules must be dissolved in the formulation.
  • the aerosol compositions described above differ from the present invention in that the lipid material and/or the biologically active material are not in a particulate solid state, but dissolved in a solvent.
  • chemical stability can be a large problem when the lipid material and or the biologically active substances are in a dissolved state.
  • the present invention provides a new system to administer liposomal formulations to mammals, including man.
  • the system comprises a dry lipid-based solid material and a device for aerosolizing said material.
  • the said material can either be manufactured by dehydration of a liposome dispersion in the presence of a filler material or be a proliposome material.
  • the said materials spontaneously hydrate to form or reconstitute liposomes at the target organ or elsewhere in the body.
  • the device is preferable a breath-actuated powder-inhalator or a pressurized dose- aerosol.
  • the present method is distinguished from previous methods to administer liposomal formulations in that the lipid-based composition is, not dissolved in a solvent or dispersed in water, but in a particulate solid state. The problems concerning chemical stability are therefore eliminated.
  • the dry lipid-based solid materials used in the present invention contain lipid material and optionally a pharma ⁇ cologically active substance. They can also contain at least one adjuvant which imparts advantageous properties.
  • the lipid material can be any of those conventionally used in liposomal formulations.
  • the main liposome-form- ing component is a phospholipid, including synthetic leci ⁇ thins and natural lecithins.
  • other lipids may be used to optimize the properties of the formulation. Examples of such addi ⁇ tives are sterols such as cholesterol or derivatives thereof or components with a positive or negative charge.
  • Cholesterol or derivatives thereof may be incorporated, preferably in a proportion of 0.1 to 50 % w/w of the total lipids, to modify the membrane structure rendering it more fluid or more rigid and thereby influence the release pro- perties of the entrapped pharmacologically active material. Cholesterol also has a positive effect on the stability of the liposomes during lyophilization.
  • Components with a negative or positive charge will provide an electrostatic stabilization of the liposomes and may also improve the uptake of the liposomes in the target cells.
  • negatively charged lipophilic substances are phosphatic acid, dicetyl phosphoric acid, phosphatidyl serine, phosphatidyl inositol and phosphatidyl glycerol.
  • positively charged lipophilic substances are stearylamine, stearylamine acetate and cetylpyridinium chloride.
  • liposomes can be made without any encapsulated substance.
  • Suitable adjuvants are filler substances such as carbohy- drates, for example lactose, sucrose or trehalose. These materials facilate the dispersion of a proliposome material and impede agglomeration of a " dehydrated product.
  • the proliposome formulation used in the present invention can be any which in an aqueous milieu forms liposomes in the temperature range of current interest. Some care must be taken to ensure that liposomes and not other structures are formed when a proliposome material is used.
  • a material obtained from a dehydrated liposome dispersion gives larger opportunities to taylor the formulation.
  • the liposome dispersion from which the dry solid material is made can be prepared according to any of the numerous meth ⁇ ods known in the art.
  • the dehydration can be performed with any method which does not destroy the liposomal structure.
  • the dehydration will be carried out by lyophi- lization or spray-drying in the presence of a filler material,
  • the system described in the present invention can be used to administer liposomes to various parts of the body.
  • the following routes of administration should be mentioned; oral, rectal, vaginal, in open wounds, and by inhalation.
  • the system For each application the system must be optimized both with respect to the lipid-based solid composition (components, method of manufacture etc) and the device (breath-actuater powder-inhalato , pressurized, aerosol etc).
  • Inhalation therapy is an attractive application of the present invention.
  • the respiratory tract there is a large area with high humidity where the lipid-based solid material can be hydrated.
  • Various powder-dispensing devices such as powder-inhalators and pressurized dose-aerosols which can deliver a powder of the material to the respi ⁇ ratory tract exist.
  • Pharmacologically active substances which are particularly useful for inhalation are 0 2 -receptor active substances, xanthines, glucocorticoids, other antiallergic or antiin- flammatory substances or derivatives of the substances mentioned.
  • Suitable ⁇ .-receptor active substances are terbutaline, salbutamol, mabuterol, fenoterol, formoterol, orciprena- line, isoprenaline, isoetharine, clenbuterol, hexoprena- line, procaterol, l-(4-hydroxyphenyl)-2-[1,l-dimethyl-3- -(2-methoxyphenyl) propylamino]-ethanol, l-(3,5-dihydroxy- phenyl)-2-[1,l-dimethyl-3-(2-methoxyphenyl) propylamino]- -ethanol, 1-3,4-dihydroxyphenyl)-2-[1,l-dimeth l-3-(2- -methoxyphenyl) propylamino]-ethanol, (4-hydroxy- ⁇ , -[ [ [6 -(4-phenylbutoxy)-hexyl]-ami o]-methyl]-
  • theophylline and enprofylline and pharmacologically acceptable salts and derivatives thereof and compounds of similar pharmacological properties are the most suitable.
  • Suitable glucocorticoids are compounds like budesonide, beclomethasone, dexamethasone, flumethasone, flunisolide, triamcinolone acetonide, 17- and/or 21-esters of these steroids, pharmacologically acceptable salts thereof and compounds of similar pharmacological properties.
  • cromoglycate lidocaine, indometacin, diclofenac, ibuprofen, piroxicam, sulindac, derivatives thereof and compounds of similar pharmacological properties.
  • Breath-actuated powder-inhalers are suitable devices to administer the lipid-based solid material to the respira- tory tract.
  • said material may be sensitive to moisture it may be necessary to ensure moisture protection. This is also the case for certain other inhalation materials on the market, for example sodium cromoglycate, and can therefore easily be ensured also for said solid-based lipid material.
  • the pressurized dose-aerosol is for several reasons, which will be discussed below, a particular suitable device. Considerations which must be taken into account when a pressurized dose-aerosol is developed are therefore discus- sed below.
  • the pressurized dose-aerosol can be manufactured according to known technique i.e. a powder of a defined particle-size is suspended in a suitable propellant mixture.
  • the disper ⁇ sion is filled on containers which are sealed with a meter- ing valve.
  • the water content should be kept as low as poss ⁇ ible.
  • the components making up the lipid-based solid com ⁇ position must be virtually insoluble in the propellant. Further they must of course be chemically stable during storage in the aerosol container.
  • propellant 11 (C1 3 F)
  • propellant 11 CC1 3 F
  • propellant 12 CCl 2 2
  • propellant 114 C1F 2C C1F
  • propellant 115 ClF 2 CF 3
  • propellant C-318 C F
  • the solid material is suspended in a concentration between 0.001 and 20 % by weight, in the liquified propellant.
  • the pressurized dose-aerosol can also contain at least one adjuvant which imparts advantageous properties.
  • adju ⁇ vants may be surfactants, taste-maskers or modifiers of the solubility of the lipid-based solid material in the propel ⁇ lant.
  • Preferred surfactants are those which are soluble in the propellant and constitutes between 0.001 % and 20 % by weight of the total composition.
  • DMPC diristoyl ⁇ 2 phosphatidylcholine
  • DPPA dipalmitoyl ⁇ 10 phosphatic acid
  • the pressurized dose-aerosol described above shows advan ⁇ tages compared to other ways of storing and delivering liposomal formulations. It comprises a package where the material is protected during storage from air, light, moi- sture etc, which may affect the material. It is easy to administer a dose of the formulation without affecting the rest of the material. The lipid material is in a solid state and therefore there is minimal risk for chemical degradation and for changes in the physical structure.
  • the liposomes can be manufactured to have specific properties (liposome size, drug-loading etc) which may be difficult to obtain when the liposomes are generated in situ.
  • the present invention is exemplified but In no way limited by the following examples. A variety of other materials and other methods could be used to obtain the desired lipid- based solid composition. Further, other routes and devices could be used to administer the lipid-based solid material. In all examples care was taken to avoid that the dry solid formulation ⁇ came into contact with moisture.
  • gelatine capsules were filled with 20 mg of micronized lactose.
  • the capsules were used to determine the tolerance of inhaling the lipid-based solid composition in man using a randomized, single blind cross-over study.
  • the powders were administered by inhalation using Spin- matic R inhalator to 10 healthy volunteers. Each volunteer received 3 single doses of the two formulations. There was a wash-out period of at least 2 days between the treat ⁇ ments. No adverse drug experiences (ADE) were found in the study.
  • ADE adverse drug experiences
  • the particle size of the spray-dried powder was suitable for inhalation therapy (MMD ⁇ 3 ⁇ m. according to image-analysis). 100 mg of the powder was dispersed in 10 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114. The mixture was sealed
  • the resulting pressurized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Liposomes were formed by heating (maximum temperature 70 °C) the sample for 45 minutes during stirring. The lipo ⁇ some dispersion was spray-dried with a Buchi 190 Mini Spray-Dryer using an inlet temperature of 155 °C. The final traces of water were eliminated by over-night storage under
  • the particle size of the spray-dried powder was suitable for inhalation therapy (MMD ⁇ 3 ⁇ according to image-analysis). 100 mg of the powder was dispersed in 10 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114. The mixture was sealed in an glass container fitted with a 50 ⁇ l metering valve. The resulting pressurized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Example 4 The procedure of example 4 was repeated except that 3.33 g of lyophilized Epikuron R 200 H powder was dispersed in 500 g of an aqueous solution of lactose containing 6.67 g lactose. The resulting pressurized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • 5.0 g of the lyophilized and micronized powder was dispersed in 340 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114.
  • Containers were filled with approximately 10 g each of the suspension and sealed. Both Al-containers and glass containers were used. 50 ⁇ l valves with steam of stainless steel, 50 ⁇ l valves with steam of plastic and non-metering valves were used to seal the containers. The resulting pressurized dose-aerosols were used to produce an aerosol which formed liposomes in an aqueous milieu.
  • the dry powder was micronized to a par- ticle-size suitable for inhalation therapy (MMD ⁇ 3 ⁇ m according to image-analysis). 16.3 g of the lyophilized and micronized powder was dispersed in 1100 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114. Con ⁇ tainers were filled with approximately 8.7 g each of the suspension and sealed. Both Al-containers and glass contai ⁇ ners were used. 50 ⁇ l valves with steam of stainless steel, 50 ⁇ l valves with steam of plastic and non-metering valves were used to seal the containers. The resulting pressurized dose-aerosols were used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Containers were filled with approximately 8.7 g each of the suspension and sealed. Both Al-containers and glass con ⁇ tainers were used. 50 ⁇ l valves with steam of stainless steel, 50 ⁇ l valves with steam of plastic and non-metering valves were used to seal the containers. The resulting pressurized dose-aerosols were used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Example 8 The procedure of Example 8 was repeated except that 7.5 g of the dry powder resulting from the lyophilization of the t-butanol solution in that example was dispersed in 314 g of an aqueous solution of lactose (4.78 weight %). Further ⁇ more, 7 g of the lyophilized and micronized powder was dis ⁇ persed in the propellant mixture. The resulting pressurized dose-aerosols were used to produce an aerosol which formed liposomes in an aqueous milieu.
  • 6.0 g of the lyophilized and micronized powder manufactured in example 10 was dispersed in 1100 g of a chilled 65:35 w/w mixture of propellant 114 and propellant 115. Contai ⁇ ners were filled with approximately 8.7 g each of the sus ⁇ pension and sealed. Both Al-containers and glass containers were used. 50 ⁇ l valves with steam of stainless steel, 50 ⁇ l valves with steam of plastic and non-metering valves were used to seal the containers. The resulting pressurized dose-aerosols were used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Eplkuron R 200 H was dissolved in 135 g t-butanol under gentle heating. The solution was frozen and lyophilized. 4 g of the dry lyophilized powder was dispersed in 200 g distilled water. Liposomes were formed by heating (maximum temperature 70 °C) the sample for 1 hour during stirring. 2 g terbutaline sulphate was dissolved in 100 g distilled water. The both preparations were mixed, frozen and lyo- philized. 5 g of the dried product was dispersed in 27 ml distilled water. Liposomes were formed by heating (maximum temperature 70 °C) the samples for 30 minutes under stir ⁇ ring.
  • the dispersion was diluted with 350 g of an aqueous solution of lactose (6.67 weight %).
  • the liposome disper ⁇ sion was flash-frozen by dripping it into liquid nitrogen and was then lyophilized.
  • the dry powder was micronized to a particle-size suitable for inhalation therapy (MMD ⁇ 3 ⁇ m according to image-analysis).
  • MMD ⁇ 3 ⁇ m a particle-size suitable for inhalation therapy
  • the encapsulation of terbu- taline sulphate into the liposomes was measured spectro- photometically at 280 nm. It was found to be 33 % both before and after icronization.
  • the liposome dispersion was flash-frozen by dripping it into liquid nitrogen and was then lyophilized.
  • the encapsulation of catalase into the liposomes was determined spectrophotometically at 280 nm to 25 %.
  • 100 mg of the powder was dispersed in 10 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114. The mixture was sealed in a glass container fitted with a 50 ⁇ l metering valve. The resulting pressurized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • Example 14 The procedure of example 14 was repeated except that DPPC was used instead of DMPC and a xantine (caffeine) was used instead of catalase. Furthermore, the temperature was 60 °C during formation of the liposomes. The resulting pressur ⁇ ized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • DMPC 4*0 mg DMPC was dissolved in 5 g t-butanol under gentle heating. The solution was frozen and lyophilized. The resulting powder was dispersed in 15 g of a chilled 50:50 w/w mixture of propellant 12 and propellant 114. The mixture was sealed in a glass container fitted with a 50 ⁇ l metering valve. The resulting pressurized dose-aerosol was used to produce an aerosol which formed liposomes in an aqueous milieu.
  • the resulting pressurized dose-aerosols were used to pro ⁇ cute an aerosol which groups of Sprague Dawley rats were exposed to nose-only in a Battelle inhalation chamber.
  • the animals were given Sephadex beeds by intratracheal instillation. The animals were then exposed to the aerosol daily for three consecutive days. On the fifth day the animals were sacrificed and the lung weights were examined.

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

Abstract

Un nouveau système, servant à administrer des compositions de liposomes à des mammifères y compris l'homme, utilise une substance solide sèche à base de lipides qui dans un milieu aqueux forme ou reconstitue spontanément les liposomes, et un dispositif permettant de disperser en aérosol une quantité choisie de la substance solide à base de lipides sous une forme appropriée. La présente invention est particulièrement destinée à des applications dans lesquelles la composition solide à base de lipides est inhalée en poudre très fine sous une forme d'aérosol et hydratée dans les voies respiratoires.
EP87906023A 1986-09-12 1987-09-08 Nouveau systeme d'administration de liposomes a des mammiferes Pending EP0282537A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8603812 1986-09-12
SE8603812A SE8603812D0 (sv) 1986-09-12 1986-09-12 Administration of liposomes to mammals

Publications (1)

Publication Number Publication Date
EP0282537A1 true EP0282537A1 (fr) 1988-09-21

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Family Applications (2)

Application Number Title Priority Date Filing Date
EP87906023A Pending EP0282537A1 (fr) 1986-09-12 1987-09-08 Nouveau systeme d'administration de liposomes a des mammiferes
EP87850273A Withdrawn EP0260241A1 (fr) 1986-09-12 1987-09-08 Système pour l'administration de liposomes aux mammifères

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP87850273A Withdrawn EP0260241A1 (fr) 1986-09-12 1987-09-08 Système pour l'administration de liposomes aux mammifères

Country Status (13)

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EP (2) EP0282537A1 (fr)
JP (1) JPH01500668A (fr)
KR (1) KR880701540A (fr)
AU (1) AU603139B2 (fr)
CA (1) CA1256798A (fr)
DK (1) DK247388A (fr)
FI (1) FI882221L (fr)
HU (1) HU198835B (fr)
IE (1) IE872453L (fr)
NZ (1) NZ221732A (fr)
SE (1) SE8603812D0 (fr)
WO (1) WO1988001862A1 (fr)
ZA (1) ZA876641B (fr)

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JPH01500668A (ja) 1989-03-09
FI882221A7 (fi) 1988-05-11
FI882221A0 (fi) 1988-05-11
SE8603812D0 (sv) 1986-09-12
WO1988001862A1 (fr) 1988-03-24
CA1256798A (fr) 1989-07-04
HUT47840A (en) 1989-04-28
DK247388D0 (da) 1988-05-06
FI882221L (fi) 1988-05-11
AU603139B2 (en) 1990-11-08
EP0260241A1 (fr) 1988-03-16
NZ221732A (en) 1990-08-28
DK247388A (da) 1988-05-06
AU7913387A (en) 1988-04-07
IE872453L (en) 1988-03-12
ZA876641B (en) 1988-03-14
HU198835B (en) 1989-12-28
KR880701540A (ko) 1988-11-03

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