EP0298984A1 - COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES $g(b) 2?-RECEPTRICES - Google Patents

COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES $g(b) 2?-RECEPTRICES

Info

Publication number
EP0298984A1
EP0298984A1 EP19870902176 EP87902176A EP0298984A1 EP 0298984 A1 EP0298984 A1 EP 0298984A1 EP 19870902176 EP19870902176 EP 19870902176 EP 87902176 A EP87902176 A EP 87902176A EP 0298984 A1 EP0298984 A1 EP 0298984A1
Authority
EP
European Patent Office
Prior art keywords
liposomes
pharmaceutical composition
receptor active
active substance
terbutaline sulphate
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Withdrawn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
EP19870902176
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 EP0298984A1 publication Critical patent/EP0298984A1/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Withdrawn legal-status Critical Current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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

Definitions

  • compositions of liposomes and ß 2 -receptor active substances are provided.
  • the present invention relates to a novel pharmaceutical composition in dry powder form and is particularly concerned with liposomal formulations of ß 2 -receptor active substances for inhalation.
  • the object of the invention is to provide a pharmaceutical composition consisting of a dry powder comprising a ß 2 -receptor active substance encapsulated into liposomes.
  • a pharmaceutical composition consisting of a dry powder comprising a ß 2 -receptor active substance encapsulated into liposomes.
  • Aqueous liposome dispersions have a limited physical stability since the liposomes can aggregate resulting in a change in the size distribution. Furthermore, if the encapsulated 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. The problem concerning stability can to large extent be solved if a dry solid composition is developed.
  • ß 2 -receptor active substances are examples of substances which can be used in accordance with the present invention: terbutaline, salbutamol, mabuterol, fenoterol. orciprenaline, formoterol, isoprenaline, isoetharine, clenbuterol, hexoprenaline, procaterol, 1-(4-hydroxyphenyl-2-[1,1-dimethyl-3- ⁇ 2-methoxy-phenyl)propylamino]-ethanol, 1-(3,5-dihydroxy-phenyl)-2-[1,1-dimethyl-3-(2-methoxyphenyl)-propylamino]-ethanol, 1-(3,4-dihydroxyphenyl)-2-[1,1 ⁇ -dimethyl-3-(2-methoxyphenyl)propylamino]ethanol, (4-hydroxy- ⁇ -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
  • Preferred pharmacologically acceptable salts of B 2 -receptor substances are salts with physiologically acceptable acids. Suitable acids which may be used are, for example, hydrochloric, hydrobromic, sulfuric, fumaric, citric, tartaric, maleic or succinic acid.
  • the B 2 -receptor active substance which is particularly preferred is terbutaline sulphate.
  • Inhalation of ß 2 -receptor active substances is used for the treatment of allergic and inflammatory conditions in the respiratory tract, like asthma and airway hyperresponsiveness.
  • the treatment suffers from the disadvantage that it has a limited duration of action.
  • the bronchodilating effect of inhaled terbutaline sulphate administered during the evening is lost during the late night which might result in a new asthmatic attack during the sleeping period.
  • Liposomes are widely described in the litterature and their general structure is well known; they are structures composed of concentric rings of lipid bilayers. Dehydrated liposomes are described in International Application WO86/01103 (Liposome Co.). Liposomes have been used as carriers for different kinds of pharmacologically active drugs in order to improve the therapeutic efficacy. Drug-loaded liposomal formulations are however generally intended for subcutanous, intravenous or oral administration. Drug encapsulated into liposomes intended specifically for inhalation are for instance described in European Patent Applications 158441 (Phares), 84898 (Fison) and 0170642 (Draco) and in International Application WO86/01714 (Riker).
  • the lipid materials used in the present invention may be any of those conventionally used in liposomal formulations.
  • the main liposome-forming component is a phosholipid, including synthetic lecithins and natural lecithins, e.g. those derived from egg and soyabean.
  • the phase-transition temperature (Tc) of the phospholipid can have a marked influence on the retention of the liposome encapsulated substance in the target organ. It is therefore favourable to use well-defined synthetic phospholipids.
  • Dimyristoyl phosphatidylcholine, DMPC (Tc - 23 oC), dipalmitoyl phosphatidylcholine, DPPC (Tc - 41 oC) and distearoyl phosphatidylcholine, DSPC (Tc - 55 °C), either alone or in combination are preferred to the natural lecithins. It is known that DPPC is the main phospholipid in the natural lung-surfactant. By the use of pure synthetic phospholipids the risk of undesired immunological reactions is minimized.
  • main liposome-forming component In addition to the main liposome-forming component other lipids may be used to optimize the properties of the formulation.
  • examples of such additives are cholesterol and components which provide positive or negative charge.
  • Cholesterol, or carbohydrate derivatives thereof in a proportion up to 50 % w/w of the total lipids may be incorporated to modify the membrane structure rendering it more fluid or more rigid and thereby influence the release properties of the entrapped pharmacologically active material. Cholesterol also has a positive effect on the stability of the liposomes during lyophilization.
  • Components which provides a negative or positive charge may be incorporated in a proportion up to 30 % w/w of the total lipids. They will provide an electrostatic stabilization of the liposome dispersion and may also optimize the uptake of the liposomes in the target cells.
  • negatively charged lipophilic substances are phosphatic acid, dicetyl phosphoric acid, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol and phosphatidyl ethanolamine.
  • positively charged lipophilic substances are stearylamine, stearylamine acetate and cetylpyridinium chloride.
  • the lipid materials are dissolved in an organic solvent and the ß 2 -receptor active substance is dissolved in an aqueous phase.
  • the two solutions are mixed to produce an emulsion of the water-in-oil type.
  • the organic solvent is removed and the resulting gel is suspended in an aqueous solution to give a liposome dispersion.
  • the lipid material is dissolved in a solvent e.g. chloroform or t-butanol, and are evaporated to a thin lipid film (chloroform) or freeze-dried (t-butanol). Distilled water is added and the temperature is raised. The final temperature will be above the phase-transition temperature of the lipid material.
  • the resulting liposome dispersion is mixed with an aqueous solution of a ß 2 -receptor active substance. It is often appropriate to use 0.1 to 10 parts by weight of ß 2 -receptor active substance per part of lipid material. The mixture is freeze-dried, and the dry material is dispersed in a minimal amount of distilled water.
  • the temperature is raised above the phase-transition temperature of the lipid material. After equilibration, the dispersion is diluted with additional aqueous solution. The resulting liposomes will be in a range of sizes (50 nm - 10 ⁇ m ) .
  • Liposomes are formed by adding an aqueous solution of a ß 2 -receptor active substance and raising the temperature above the phase-transition temperature of the lipid material. It is often appropriate to use 0.1 to 10 parts by weight of ß 2 -receptor active substance per part of lipid material. The concentration of ß 2 -receptor active substance during liposome formation should be 1 - 100 mg/ml. The resulting liposomes will be in a range of sizes (50 nm - 10 ⁇ m) .
  • the lipids and the ß 2 -receptor active substance are dissolved in a solvent, e.g. a mixture of t-butanol and water, and freeze-dried. It is often appropriate to use 0.1 to 10 parts by weight of ß 2 -receptor active substance per part of lipid material.
  • the resulting freeze-dried powder is dispersed in a minimal amount of distilled water and the temperature is raised. The final temperature will be above the phase-transition temperature of the lipid material. After equilibration, the dispersion is diluted with additional aqueous solution.
  • the resulting liposomes will be in a range of sizes (50 nm to 10 ⁇ m) .
  • the method used for formation of the liposomes there will be significant amounts of drug not encapsulated into the liposomes but remaining in the continuous aqueous phase. It may be desirable to remove the drug (or a fraction of it) from the continuous phase and this is conveniently done either by dialysing the liposomal formulation against a drug-free aqueous phase, by centrifugation of the liposome dispersion of by chromatography using an ion-exchange resin capable of selectivly binding the non-entrapped ß 2 -receptor active substance.
  • aqueous dispersions of liposomes have a limited stability, it may be favourable to remove the solvent from preparations intended for long-time storage.
  • the dehydration can be performed in a number of different ways, e.g. spray-drying and lyophilization. Lyophilization is particulary preferred.
  • the liposome dispersions described in the present invention are mixed with a cryoprotective agent such as a carbohydrate, e.g. lactose or threhalose at the concentration of 0 to 95 % by weight of the final composition and are rapidly frozen in liquid nitrogen. We find the rapid freezing step important to preserve the liposomal structure.
  • a dry powder suitable for long-time storage is obtained.
  • the liposome dispersion can be reconstituted after addition of an aqueous solution to the said powder.
  • the equilibrated liposome dispersion containing the ß 2 -receptor active substance is, if necessary, diluted with an appropriate aqueous solution (distilled water, saline etc) and centrifuged at 25000 g to 100000 g for 15 ain to 1 hour.
  • an appropriate aqueous solution distilled water, saline etc
  • a 50 ml round bottom flask 60 mg of DPPC and 60 mg of cholesterol are dissolved in 10 g chloroform.
  • 60 mg of terbutaline sulphate is dissolved in 1 g of distilled water.
  • the terbutaline sulphate solution is added to the flask and the two solutions are emulsified with an Ultra-Turrax.
  • the resulting emulsion is evaporated on a Buchi rotary evaporator until a gel is formed.
  • To the gel 3 g of distilled water is added and the sample is mixed until a liposome dispersion forms.
  • the encapsulation of terbutaline sulphate into the liposomes was 38 % according to the method described above.
  • the desired quantities of the appropriate lipids are mixed in a glass tube. All components are dissolved in a small quantity of chloroform and evaporated to dryness to leave a thin lipid film on the inner surface of the glass tube. Distilled water (4 ml) is added to the lipid film and liposomes are formed by sonificating the sample at elevated temperature. Terbutaline sulphate is dissolved in 2 ml distilled water. The liposome dispersion and the drug solution are mixed, frozen and lyophilized. The dry product is dispersed in 100 ⁇ l distilled water per 10 mg phospholipid. Liposomes are formed by heating (60 °C) the sample for 30 minutes. The encapsulation of drug into the liposomes is determined according to the method described above.
  • Liposomes with various ß 2 -receptor active substances are prepared according to the method described in examples 4 -14 and the fraction of the drug encapsulated into the liposomes is determined according to the method described above. Encapsulation efficacy (%)
  • Liposome dispersions are prepared according to the method described in examples 4 - 14. The amount of lipid material was kept constant while the amount of ß 2 -receptor active substance (in this case terbutaline sulphate) was varied. The following liposome compositions were prepared:
  • Liposomes are prepared according to examples 4 - 14.
  • the liposome dispersion (100 ⁇ l) is diluted to 1.5 ml with an aqueous solution of lactose (100 mg/ml).
  • the dispersion is flash-frozen by dripping it into liquid nitrogen and is then lyophilized.
  • the dry powder is dispersed in distilled water and the encapsulation of terbutaline sulphate into the liposomes is calculated according to the method described above. Encapsulation efficacy (%)
  • Liposomes are prepared according to examples 4 - 14.
  • the liposome dispersion (100 ⁇ l ) is diluted to 5 ml with an 0.9 % NaCl solution and centrifuged at 25000 g for 15 min.
  • the pellet is suspended in 1.5 ml of an aqueous solution of lactose (100 mg/ml)
  • the dispersion is flash-frozen by dripping it into liquid nitrogen and is then lyophilized.
  • the dry powder is dispersed in distilled water and the encapsulation of terbutaline sulphate into the liposomes is calculated according to the method described above.
  • Substantially all the non-encapsulated drug is removed from the continuous aqueous phase by centrifugation at 25000 g for 15 minutes and redispersion of the pellet in saline (0.9 % NaCl solution).
  • the liposome dispersion ( 4 ml ) is placed in a dialysis bag (Spectrapor Membran Tubing). The rate of release of ß 2 -receptor active substance from the
  • liposomes is determined by measuring the amount of drug in the liposomes after dialysis at 37 °C against 100 ml of saline. After various times the dialysis is stopped and the amount of ß 2 -receptor active substance in the dialysis bag is measured according to the method described above.
  • TERB-LIP Liposome encapsulated (DPPC, DPPA, cholesterol, 10:1:10 w/w) terbutaline sulphate
  • MAB-LIP Liposome encapsulated (DPPC, DPPA, cholesterol, 10:1:10 w/w) mabuterol
  • DPPC 40 mg
  • DPPA 4 mg
  • cholesterol 40 mg
  • DPPC 40 mg
  • DPPA 4 mg
  • cholesterol 40 mg
  • the components are dissolved in chloroform.
  • the solvent is evaporated by the use of N resulting in a thin film of the lipid components on the inner surface of the glass tube.
  • Distilled water (4 ml) is added to the lipids. Formation of the liposomes is performed by sonication at a temperature above the phase transition temperature.
  • terbutaline sulphate or an other ß 2 -receptor active substance
  • the freeze-dried powder is hydrated in 400 ⁇ l distilled water at 60 °C for 30 minutes and diluted to appropriate concentration with saline. Approximately 40 % of the drug was encapsulated into the liposomes. This formulation was used for determination of anti-edema activity of Sephadex treated rats.
  • the liposome dispersion was centrifuged at 25000 g for
  • Intratracheal instillation of Sephadex beads into rats leads to bronchial and also to alveolar inflammation (Källström, L. et al. Agents and Actions 1985 vol 17, 3/4, 355).
  • This provokes interstitial lung edema, which in creases the lung weight, and the inflammation can be graded as the increase of the lung weight compared to a saline-instilled control group.
  • the lung edema formation can be counteracted by pretreatment with ß 2 -receptor active substances, preferably by local adminstration as intratracheal instillation or by inhalation.
  • an anti-inflammatory action should be obtained only at the site of drug application in the lung, but not in the rest of the body.
  • Spraguo Dawley rats (240 g) were slightly anaesthetized with ether and the ß 2 -receptor active preparation (in liposomes suspended in saline) in a volume of 0.5 ml/kg was instilled into just the left lung lobe.
  • a suspension of Sephadex (5 mg/kg in a volume of 1 ml/kg) was instilled in the trachea well above the bifurcation so that the suspension reached both the left and right lung lobes. 2 hours after Sephadex instillation the test preparation in a volume of 0.5 ml/kg was instilled into the left lung lobe.
  • Control groups got saline instead of the test preparations and saline instead of Sephadex suspension to determine the weight of non-drug treated Sephadex edema and the normal lung weight.
  • TERB-LIP Liposome encapsulated (DPPC, DPPA, cholesterol, 10:1:10 w/w) terbutaline sulphate
  • the liposomal formulation of terbutaline sulphate had a more selective activity for the application site in the lung than free terbutaline sulphate.
  • the two test formulations more or less completely blocked the edema of the left lung lobe but the liposomal formulation was surprisingly coupled to only a moderate protective activity in the other lung lobe wheras free terbutaline sulphate completely blocked the edema of the right lung as well.
  • terbutaline sulphate encapsulated into liposomes shows a surprisingly high absolute potency for the action of the left lung lobe (100 times more potent than free terbutaline sulphate).
  • procaterol, mabuterol and salbutamol encapsulated into liposomes show the same anti-edema profile as terbutaline sulphate encapsulated into liposomes, i.e. a 100-fold potentiation of the anti-edema activity at the site of application compared with free terbutaline sulphate.
  • Inhalation of aerosolized histamine to concious guinea pigs produces a dyspnea.
  • concentration of histamine to be aerosolized can be selected to produce a defined dyspnotic breathing within 2 min of exposure to histamine.
  • Animals pretreated with inhaled bronchospasmolytic drug can be protected from the dyspnotic breathing (animals which withstand the dyspnea for more than 2 min).
  • Guinea pigs were exposed for 15 min to aerosolized terbutaline sulphate or to aerosolized liposome encapsulated terbutaline sulphate generated from a MA2 nebulizer with a terbutaline sulphate concentration of 1 x 10 -3 M of the two formulations.
  • the animals were exposed to the bronchospasmolytic agent 1, 2, 5 and 10 hours before the histamine challenge.
  • Table 3 EFFECT OF FREE AND LIPOSOME ENCAPSULATED TERBUTALINE SULPHATE ON HISTAMINE INDUCED DYSPNEA IN GUINEA PIG.
  • TERB-LIP Liposome encapsulated (DPPC, DPPA, cholesterol, 10:1:10 w/w) terbutaline sulphate
  • Free terbutaline sulphate shows rapid onset of the a protective effect against histamine.
  • a corresponding concentration of liposome-encapsulated terbutaline sulphate appears to have a delay in developing the same protective effect as the free terbutaline sulphate.
  • the two used formulations of terbutaline sulphate have the same effect.
  • there is only a limited protective effect of terbutaline sulphate when adminstered 5 hours before histamine provocation whereas liposome-encapsulated terbutaline sulphate surprisingly shows a maximal protection when the formulation is adminstered at this time. It can be concluded from this study that encapsulation of terbutaline sulphate into liposomes gives a prolonged duration of the bronchospasmolytic activity compared with equal amount of the free drug.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Composition pharmaceutique se composant d'une poudre sèche comprenant des liposomes et une substance active beta2-réceptrice et procédés permettant la préparation de ladite composition. Des effets nouveaux anti-allergiques, bronchodilatateurs est anti-inflammatoires sur les voies respiratoires sont obtenus grâce à l'utilisation desdites compositions.
EP19870902176 1986-04-01 1987-03-23 COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES $g(b) 2?-RECEPTRICES Withdrawn EP0298984A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8601457 1986-04-01
SE8601457A SE8601457D0 (sv) 1986-04-01 1986-04-01 Compositions of liposomes and b?712-receptor active substances for inhalation

Publications (1)

Publication Number Publication Date
EP0298984A1 true EP0298984A1 (fr) 1989-01-18

Family

ID=20364009

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870902176 Withdrawn EP0298984A1 (fr) 1986-04-01 1987-03-23 COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES $g(b) 2?-RECEPTRICES

Country Status (5)

Country Link
EP (1) EP0298984A1 (fr)
JP (1) JPS63502899A (fr)
AU (1) AU7207687A (fr)
SE (1) SE8601457D0 (fr)
WO (1) WO1987005803A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990014105A1 (fr) * 1989-05-15 1990-11-29 The Liposome Company, Inc. Accumulation de medicaments dans des liposomes au moyen d'un gradient protonique
DE3917617A1 (de) * 1989-05-31 1990-12-06 Boehringer Ingelheim Kg Mikronisierte bioabbaubare partikel, verfahren zur ihrer herstellung und ihre verwendung
FR2650181B1 (fr) * 1989-07-27 1993-12-03 Laboratoire Stallergenes Procede pour combiner un melange de substances heterogenes a des liposomes
JPH03178929A (ja) * 1989-09-07 1991-08-02 Glaxo Group Ltd 炎症及びアレルギー治療用化合物
GB9111611D0 (en) * 1991-05-30 1991-07-24 Sandoz Ltd Liposomes
FR2690341A1 (fr) * 1992-04-24 1993-10-29 Patrinove Vecteurs nanoparticulaires contenant un musculotrope ou un neurotrope à effet déclenché par variation du potentiel des membranes des cellules ciblées par l'actif encapsulé.
SA95160463B1 (ar) * 1994-12-22 2005-10-04 استرا أكتيبولاج مساحيق للاستنشاق
ATE226210T1 (de) 1997-08-18 2002-11-15 Max Planck Gesellschaft Phospholipidanaloge verbindungen
GB9912639D0 (en) 1999-05-28 1999-07-28 Britannia Pharmaceuticals Ltd Improvements in and relating to treatment of respiratory conditions
DE10214983A1 (de) * 2002-04-04 2004-04-08 TransMIT Gesellschaft für Technologietransfer mbH Vernebelbare Liposomen und ihre Verwendung zur pulmonalen Applikation von Wirkstoffen
DE102009031274A1 (de) 2009-06-30 2011-01-13 Justus-Liebig-Universität Giessen Liposomen zur pulmonalen Applikation
TW201208716A (en) * 2010-08-05 2012-03-01 Piramal Lifesciences Ltd Microparticle formulation for pulmonary drug delivery of anti-infective molecule for treatment of infectious diseases

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5186117A (en) * 1975-01-27 1976-07-28 Tanabe Seiyaku Co Johoseibiryushiseizainoseiho
GB1575343A (en) * 1977-05-10 1980-09-17 Ici Ltd Method for preparing liposome compositions containing biologically active compounds
CH621479A5 (fr) * 1977-08-05 1981-02-13 Battelle Memorial Institute
EP0152379A3 (fr) * 1984-02-15 1986-10-29 Ciba-Geigy Ag Procédé pour la préparation de compositions pharmaceutiques contenant des liposomes unilamellaires
SE8403905D0 (sv) * 1984-07-30 1984-07-30 Draco Ab Liposomes and steroid esters
GB8423436D0 (en) * 1984-09-17 1984-10-24 Riker Laboratories Inc Preparation of liposomes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8705803A1 *

Also Published As

Publication number Publication date
WO1987005803A1 (fr) 1987-10-08
JPS63502899A (ja) 1988-10-27
SE8601457D0 (sv) 1986-04-01
AU7207687A (en) 1987-10-20

Similar Documents

Publication Publication Date Title
AU603139B2 (en) A new system for administration of liposomes to mammals
RU2162689C2 (ru) Пролипосомные порошки для ингаляции
US4844904A (en) Liposome composition
US4743449A (en) Drug-containing lipid vesicle preparation and method for preparing them
CA1257836A (fr) Methode et systeme d'inhalation
CA1315678C (fr) Vesicules basees sur alpha-tocopherol
CN101366699B (zh) 用于控制释放药物活性成分的新型脂质组合物气雾剂
US4877561A (en) Method of producing liposome
EP1109533A1 (fr) Administration pulmonaire de cannabinoides encapsules dans des liposomes
EP0298984A1 (fr) COMPOSITIONS DE LIPOSOMES ET SUBSTANCES ACTIVES $g(b) 2?-RECEPTRICES
JPH0321525B2 (fr)
JP2002510311A (ja) トコフェロールにより安定化された吸引用プロリポソーム粉末
JPH10512876A (ja) コルチコステロイドを含有するリポソーム
WO1991007973A1 (fr) Emulsion grasse
RU2730488C1 (ru) Фармацевтическая композиция на основе глюкокортикостероида будесонида и фосфатидилхолина для сухой ингаляции
CN100467013C (zh) 一种包覆辛夷挥发油纳米脂质体滴鼻剂
JPH0380773B2 (fr)
MXPA97004406A (en) Proliposomas powders for inhalac
MXPA99011675A (en) Proliposome powders for inhalation stabilised by tocopherol

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19880929

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19890703

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19900116

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BYSTROEM, ULLA, KATARINA

Inventor name: NILSSON, PER-GUNNAR

Inventor name: DAHLBAECK, CARL, MAGNUS, OLOF

Inventor name: TROFAST, JAN, WILLIAM

Inventor name: AXELSSON, BENGT, INGEMAR

Inventor name: KAELLSTROEM, LEIF, ARNE