CN1169115A - Liposomes containing a corticosteroid - Google Patents

Liposomes containing a corticosteroid Download PDF

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Publication number
CN1169115A
CN1169115A CN96191591A CN96191591A CN1169115A CN 1169115 A CN1169115 A CN 1169115A CN 96191591 A CN96191591 A CN 96191591A CN 96191591 A CN96191591 A CN 96191591A CN 1169115 A CN1169115 A CN 1169115A
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compositions
liposome
formula
arbitrary
phospholipid
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P·W·泰勒
J·C·马斯
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • 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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition comprising, as active ingredient, a compound of formula I contained in liposomes or dehydrated liposomes.

Description

The liposome that comprises corticosteroid
The present invention relates to pharmaceutical composition, it contains certain specific corticosteroid as active component, is specially adapted to treat asthma by sucking therapy, and relates to the method for preparing this pharmaceutical composition.
The result that environmental pollution increases causes obstructive bronchopneumopathy such as bronchitis and bronchial asthma to spread in a large number.Their pathogenic factor and seriousness have nothing in common with each other.The external source allergic bronchial asthma and the endogenous bronchial asthma that are caused by environmental effect (for example waste gas, weather conversion coating) are feature with various dyspnea serious attacks often.Cough intensity is also different with expectorant.Transitional type and mixed asthma are common and must attach the importance in treatment.
In order to treat this kind intensity disease different, under the situation of not considering combination formulations, can obtain to have and to accept dangerous three groups of active component determining with origin.It is β that this three composition divides 2Agent of-adrenomimetic drug such as epinephrine, bamethan, clenbuterol, fenoterol, Sulbutamol and Te Buta material, xanthine derivative such as theophylline and diprophylline and comprise the anticholinergic of atropine derivant ipratropium bromide and oxitropium bromide.If use preparation for treating to get nowhere, advise so using some corticosteroid as times chlorine half pine (beclomethasone) or budesonide by oral or inhalation based on these three groups of active components.At present only in sucking treatment employed corticosteroid preparation except having the antianaphylaxis that needs, exudation-anti-inflammatory, also have because of absorb that the corticosteroid that sucked causes slightly but system's side effect of not expecting.Usually, necessary with the corticosteroid treatment through a lot of years, thereby obviously increase system's side-effect problem.
Be surprised to find that, in being encapsulated in liposome during administration, 9 α-chloro-6 α-fluoro-11 beta-hydroxies-16 Alpha-Methyls-3-oxo-17 α-propionyloxy androstane-1,4-diene-17 β-carboxylate methyl ester has good especially asthma, and the past attempts suggestion is with the active component of this chemical compound as department of dermatologry ointment, cream, gel and foam.Find that also the whole body of this chemical compound absorbs very low.
Therefore, on the one hand, the invention provides and contain active component formula I chemical compound and it is encapsulated in pharmaceutical composition in liposome or the dehydrated liposomes.
Figure A9619159100061
Described in british patent specification 1578243, but preparation I compound, 9 α-chloro-6 α-fluoro-11 beta-hydroxies-16 Alpha-Methyls-3-oxo-17 α-propionyloxy androstane-1,4-diene-17 β-carboxylate methyl ester.In order to use the suction apparatus administration, liposome can be waterborne suspension or dehydrated form, as dry powder.
Find that in the inductive eosinophilia's of allergy Brown-Norway rat model, the liposome that contains formula I chemical compound is easy to be taken in by pulmonary alveolar macrophage and suppress eosinophilic effectively and replenish.
Suitable liposome generally include those wherein lipid constituent comprise at least-liposome of kind of synthetic phospholipid.The example of synthetic phospholipid is synthetic phosphatidylcholine such as L-Dimyristoylphosphatidylcholine; two palmityl phosphatidylcholines; DSPC; dioleyl phosphatidyl choline; Dlpc lipid; two Laurel acyl phospholipids phatidylcholines; 1-palmityl-2-oleoyl-phosphatidylcholine; 1-myristoyl-2-palmitoylphosphatidyl choline and 1-palmityl-2-myristoyl phosphatidylcholine; synthetic phosphatidyl glycerol is as two lauroyl phosphatidyl glycerols; GLYCEROL,DIMYRISTOYL PHOSPHATIDYL; two palmityl phosphatidyl glycerol and DOPGs; synthetic phosphatidic acid is as two myristoyl phosphatidic acid and two palmityl phosphatidic acid; synthetic PHOSPHATIDYL ETHANOLAMINE as two myristoyl PHOSPHATIDYL ETHANOLAMINE and two palmityl PHOSPHATIDYL ETHANOLAMINE and synthetic Phosphatidylserine as two myristoyl Phosphatidylserine, two palmityl Phosphatidylserine and dioleoyl phospholipid acyl serine.
Preferably, the lipidic component of liposome comprises synthetic phosphatidylcholine, as described above those, not essentially with synthetic Phosphatidylserine or synthetic phosphatidyl glycerol, as described above those, preferably, the weight ratio of phosphatidylcholine and Phosphatidylserine or phosphatidyl glycerol is 60: 40-95: 5, particularly 70: 30-90: 10.
In preferred embodiment, that the lipid constituent of liposome comprises is synthetic, pure formula II phospholipid basically.
Figure A9619159100071
R wherein 1For having the C of even number of carbon atoms 10-C 20Alkanoyl, R 2For having the C of even number of carbon atoms 10-C 20Alkenoyl, R a, R bAnd R cBe hydrogen or C 1-C 4Alkyl, and n is the integer of 2-4.
In formula II phospholipid, as C with even number of carbon atoms 10-C 20The R of alkanoyl 1Be preferably the n-dodecane acyl group, n-tetradecane acyl group, hexadecane acyl group, n-octadecane acyl group or AI3-28404 acyl group.
Preferably, as C with even number of carbon atoms 10-C 20The R of alkenoyl 2Be 9-cis-dodecylene acyl group; 9-cis-tetradecene acyl group; 9-cis-hexadecene acyl group; 6-cis-vaccenic acid acyl group; 6-is trans-the vaccenic acid acyl group; 9-cis-vaccenic acid acyl group, 9-is trans-vaccenic acid acyl group, 11-cis-vaccenic acid acyl group or 9-cis-eicosylene acyl group.In formula II phospholipid, preferably, R a, R bAnd R cBe C 1-C 4Alkyl, particularly methyl.
In formula II, n is the integer of 2-4, preferred 2.Formula-(C n-H 2n)-group be non-branching or sub-branched alkyl, for example, 1,1-ethylidene, 1,1-, 1,2-or trimethylene or 1,2-, 1,3-or tetramethylene.Preferred ethylene (n=2).
In particularly preferred formula II phospholipid, R 1For just-lauroyl, just-tetradecanoyl, just-hexadecanoyl or just-octadecanoyl and R 2Be 9-cis-dodecylene acyl group, 9-cis-tetradecene acyl group, 9-cis-hexadecene acyl group, 9-cis-vaccenic acid acyl group or 9-cis-eicosylene acyl group, R a, R bAnd R cBe methyl, and n is 2.
Particularly preferred formula II phospholipid be synthetic 1-just-16-alkanoyl-2-(9-cis-vaccenic acid acyl group)-3-sn-phosphatidylcholine.
In some particularly preferred liposomees, lipid constituent comprises with synthetic, the bonded formula II phospholipid of pure basically formula III phospholipid
Figure A9619159100081
R wherein 3And R 4Each is the C for having even number of carbon atoms independently 10-C 20Alkenoyl, n are the integer of 1-3, and Y Cation for pharmaceutically acceptable alkali.
In formula III phospholipid, preferably, as C with even number of carbon atoms 10-C 20The R of alkenoyl 3And R 4Be 9-cis-dodecylene acyl group; 9-cis-tetradecene acyl group; 9-cis-hexadecene acyl group; 6-cis-vaccenic acid acyl group; 6-is trans-the vaccenic acid acyl group; 9-cis-vaccenic acid acyl group, 9-is trans-vaccenic acid acyl group, 11-cis-vaccenic acid acyl group or 9-cis-eicosylene acyl group.
The cation Y of pharmaceutically acceptable alkali For, for example, alkali metal ion, lithium for example, sodium or potassium ion, ammonium ion, one, two or three C 1-C 4Alkyl phosphate ion, for example trimethyl-, ethyl-, diethyl-or triethyl ammonium ion, tetramethyl ammonium, 2-ethoxy-three-C 1-C 4-alkyl-ammonium ion, for example choline cation, or 2-hydroxyethyl ammonium ion, or the cation of basic amino acid, for example lysine or arginine.Preferably, Y Be sodium ion.
In particularly preferred formula III phospholipid, R 3And R 4Be identical and be for example 9-cis-dodecylene acyl group, 9-cis-tetradecene acyl group, 9-cis-hexadecene acyl group, 9-cis-vaccenic acid acyl group or 9-cis-eicosylene acyl group, n are 1 and Y Be sodium ion.
Particularly preferred formula III phospholipid is synthetic 1,2-two (9-cis-vaccenic acid acyl group)-3-sn-phosphatidyl S-serine.
In another preferred embodiment, the lipid constituent of liposome comprises two (C 10-C 20The alkane acyl) phosphatidylcholine and two (C 10-C 20The alkane acyl) phosphatidyl glycerol; alkanoyl has even number of carbon atoms and preferred weight ratio as mentioned above; in each phospholipid; two alkanoyls can be identical or different and just be preferably-lauroyl (lauroyl); just-tetradecanoyl (myristoyl); just-hexadecanoyl (palmityl), just-octadecanoyl (stearyl) or just-eicosane acyl group.In particularly preferred example, two (C 10-C 20Alkanoyl) phosphatidylcholine is distearoyl phosphatidylcholine and two (C 10-C 20Alkanoyl) phosphatidyl glycerol is two palmityl phosphatidyl glycerols.
Except that phospholipid, the lipid constituent of liposome can comprise cholesterol, and cholesteric amount is, for example, and the 20-60 of total lipidic component amount, preferred 30-50mol%.In another preferred embodiment, lipidic component comprises synthetic phosphatidylcholine (as indicated above) in the liposome, synthetic Phosphatidylserine or phosphatidyl glycerol (" as indicated above ") and cholesterol, the as indicated above and weight ratio preferred cholesterol and total phospholipids component of the weight ratio of preferred phosphatidylcholine and Phosphatidylserine or phosphatidyl glycerol is 1: 1-1: 5.In particularly preferred example, lipidic component comprises dimyristoyl phosphatidyl choline, cholesterol and dioleoyl phospholipid acyl serine.
Usually require high as far as possible and stable consistent with liposome of the weight ratio of active component and lipid.The maximum of this weight ratio can change according to the character and the composition of lipid constituent, but is typically about 1: 20.Yet, find that weight ratio is 1: 100-1: 50 liposome can obtain the result.
Can utilize the method for known production pastille liposome to prepare the liposome of the present invention that contains reactive compound.For example, in first method, at organic solvent such as alcohol, the solution in ether or halogenated hydrocarbons or its mixture adds gradually with formula I chemical compound and one or more lipids, preferably be added drop-wise in the saline of aqueous medium under stirring such as phosphate-buffered, obtain the waterborne suspension of liposome.In other method, with one or more lipids and formula I compound dissolution at organic solvent such as alcohol, in ether or halogenated hydrocarbons or its mixture, from the solution that obtains, remove solvent by lyophilizing or by rotary evaporation then, and residue is dispersed in aqueous medium, for example in the aqueous solution of lactose, obtain the waterborne suspension of liposome as the saline of phosphate-buffered or sugar.
Can handle the aqueous liposome suspension by known method, remove solvent thus and reduce the size of liposome.For example will be by above-mentioned first method, the not essential ground of aqueous liposome suspension of the mixable organic solvent preparation of water further carries out dialysis after the use medium, and concentrates by the suspension of ultrafiltration with dialysis.Will be by first method, but remove solvent with the aqueous liposome suspension evaporation of water-immiscible organic solvent preparation, pass through ultrafiltration and concentration then.Will be by the preparation of above-mentioned second method, cause aqueous liposome suspension that multilamellar capsule (MLV) forms through having one or more films of selecting the aperture usually, for example the polycarbonate membrane extrusion process reduces the size of liposome.Preferably, the liposome particle size that the present invention uses is less than 1 μ m, and more preferably 20-200nm is in particular 50-100nm.
Preferably,, will contain the liposome dehydration of formula I chemical compound, obtain dry powder, in treatment asthma, be used for by the Diskus administration by lyophilizing (lyophilization).By flowing in patient's air flue, the liposome of dehydration is rehydrated.Usually in the presence of antifreezing agent, carry out the lyophilizing of liposome, wherein, with antifreezing agent incorporate into liposome form in the employed aqueous medium.Preferably, antifreezing agent is a sugar, for example monosaccharide such as glucose, polymerization sugar such as glucosan or preferred disaccharide such as sucrose, lactose, maltose, trehalose.Particularly preferred antifreezing agent is lactose and trehalose.According to the normal freeze-drying technology, preferably carry out elementary lyophilizing under the phase transition temperature for the treatment of freeze dried substance being lower than.
In the presence of antifreezing agent, the liposome dehydration is obtained comprising the dry powder formation of dehydrated liposomes and antifreezing agent mixture.If antifreezing agent is present in the aqueous medium that forms liposome, antifreezing agent is on the inside and outside two sides of liposome particles so.Although can use lower or higher ratio if desired, the weight ratio of antifreezing agent and lipid is 1 in the liposome usually: 1-4: 1.
If desired, will be by containing the liposome dehydration of formula I chemical compound, particularly the product that obtains by the dehydration of lyophilizing in the presence of antifreezing agent grinds, and obtains being applicable to the granularity that sucks treatment, for example uses the dry powder inhaler device administration to suck treatment.Usually suitable granularity is less than 10 μ m, preferred 1-7 μ m.In sucking treatment, if desired, also can be through above-mentioned processing, the particle size reduction of liposome after suitable scope, is used the liposome that contains formula I chemical compound with the form of the suspension in aqueous medium.In order to use with this form, can in sucking treatment, be used as in the aqueous medium of solvent the preparation liposome or can in another kind of medium, prepare and therefrom separate, and randomly dewater as mentioned above before sucking in the aqueous medium that is used as solvent in treating incorporating into.Aqueous medium can be the aqueous medium that is used as solvent usually in sucking treatment; It normally comprises one or more pharmaceutically acceptable excipient such as sodium chloride that are dissolved in wherein, buffer agent, the water of antioxidant and surfactant.Common aqueous medium is the saline of phosphate-buffered, and it can contain antioxidant such as alpha-tocopherol.When in sucking treatment, using, can pass through known nebulizer, for example pneumatic nebulizer come to aqueous liposome suspension of the present invention.
Can be placed on the capsule for example in gelatin or plastic capsule or the bubble that is used for powder inhaler with being encapsulated in the dry powder of the present invention that contains formula I chemical compound in the dehydrated liposomes.Preferably, capsule or bubble comprise the dry powder of dosage unit, and it can comprise, and for example, the formula I chemical compound of the preferred 50-400 μ of 10-1000 μ g g and enough carriers are to obtain the dry powder of the preferred 20-30mg of 4-40mg.Perhaps, dry powder can be placed in the bin of the multiple dose powder inhaler that is suitable for discharging for example each ejection 2mg dry powder that drives.
On the other hand, the invention provides the method for treatment asthma, it comprises that the above-mentioned formula I chemical compound that is included in above-mentioned liposome or the dehydrated liposomes by the suction effective dose comes administration.
Can change dosage every day of formula I chemical compound according to treatment patient's age, body weight and disease seriousness.Usually, every day, dosage can be at 50-2000 μ g, especially in 100-1000 μ g scope.
By the following example the present invention is described, removes explanation in addition, unit is represented by weight.Embodiment 1
Under 40 ℃, with 1-just-hexadecanoyl-2-(9-cis-vaccenic acid acyl group)-3-sn-phosphatidylcholine (700mg) and 1,2-two (9-cis-vaccenic acid acyl)-3-sn-phosphatidyl S-L-Serine sodium (300mg) is dissolved in the tert-butyl alcohol (20ml).With the solution that obtains with by under 40 ℃ with 9 α-chloro-6 α-fluoro-11 beta-hydroxies-16 Alpha-Methyls-3-oxo-17 α-propionyloxy androstane-1,4-diene-17 β-carboxylate methyl ester (Compound I) (10mg) is dissolved in the solution that forms in the tert-butyl alcohol (5ml) to be mixed and makes temperature get back to 40 ℃.At room temperature, the saline solution (PBS) that the drips of solution that obtains is added to pH7.4 and well-beaten phosphate-buffered (200ml) in.Under nitrogen environment, utilize the AMICONYM100 film, with the aqueous liposome suspension dialysis in PBS that obtains, and be concentrated into 20ml.With spissated aqueous liposome suspension is that the filter of 0.8 μ m and 0.2 μ m filters and is assigned in the sterile vials (every bottle 2ml) by the aperture in succession.In inhalation treatment asthma, the suspension that obtains is applicable to by the aerosol apparatus administration.Embodiment 2
Repeat the preparation method of embodiment 1, but liposome form and dialysis in, replace the saline of employed phosphate-buffered among the embodiment 1 with every liter of aqueous solution that contains 94.4g lactose monohydrate and 0.24g sodium chloride, obtain spissated aqueous liposome suspension.Embodiment 3
In Lyovac GT4 lyophil apparatus, with the concentrated aqueous liposome suspension lyophilizing of preparation among the embodiment 2.With Trost air blast aerosol apparatus the cake that obtains is pulverized, obtained having the medium-grained dry powder of 6-7 μ m, it is applicable to by the powder inhaler administration in inhalation treatment asthma.Embodiment 4
With distearoyl phosphatidylcholine (700mg), dipalmitoyl phosphatidyl choline (300mg) and Compound I (20mg) are dissolved among 2: 1 (volume ratio) mixture (20ml) of chloroform and methanol.Remove solvent by rotary evaporation.Residue is dispersed in every liter of 40ml contains in the lactose aqueous solution of 94.4g lactose monohydrate and 0.24g sodium chloride, obtain the waterborne suspension of liposome.With this solution under 70 ℃ and nitrogen environment by 2 200nm polycarbonate membranes extruding twice, reduce the granularity of liposome for ten times by 2 100nm polycarbonate membranes extruding.As embodiment 3,, obtain being applicable to the dry powder that in inhalation treatment asthma, passes through the powder inhaler administration with suspension lyophilizing and the pulverizing that obtains.Embodiment 5
With dimyristoyl phosphatidyl choline (678mg), cholesterol (193mg), dioleoyl phospholipid acyl serine (81mg) and Compound I (20mg) are dissolved in the tert-butyl alcohol (20ml).By lyophilization, the tert-butyl alcohol is removed from the solution that obtains.Residue is dispersed in the embodiment 4 described lactose aqueous solutions and with the liposome that obtains as extruding as described in the embodiment 4, but replace 70 ℃ with 35 ℃, with the particle size reduction of liposome to 100nm.As embodiment 3, the suspension liquid cooling dry doubling that obtains is pulverized, obtain being suitable in inhalation treatment asthma, passing through the dry powder of powder inhaler administration.Embodiment 6
As people such as ElWood at J.Allergy Clin.Immunol 1991,88, described in the 951-60, the effect of inducing the liposome of measuring encapsulated type I chemical compound in eosinophilia's the Brown-Norway rat model that eosinocyte is replenished in allergy.Study with the inbreeding male mouse that four groups of body weight are 180-220g.
Group 1: by peritoneal injection 0.9% (wt/vol) ovalbumin (1mg)/Al (OH) 3(100mg) suspension (1ml) with animal sensitization, after 21 days, exposes 15 minutes in single saline aerosol.
Group 2: as organize shown in 1, with animal sensitization, after 21 days, be exposed in the 1% ovalbumin aerosol 15 minutes with ovalbumin.
Group 3: as organize shown in 1, with animal sensitization, after 19 days, under Patients Under Ketamine Anesthesia, contain embodiment 1 liposome suspension (0.5ml) of 3 μ g Compound I and after 24 hours, inject through trachea again through the trachea injection with ovalbumin.Injected back 24 hours for the second time, animal is exposed in the 1% ovalbumin aerosol 15 minutes.
Group 4: as organize and handle animal shown in 3, but replace containing the liposome of formula I chemical compound, use by the same procedure preparation but do not contain the blank liposome of formula I chemical compound.
With regard to each group rat, be exposed in the aerosol after 24 hours, carry out bronchoalveolar lavage and measure the eosinocyte number.The result shows below:
Organize every several 1 (saline attacks) 0.25 * 10 of rat eosinocyte 52 (ovalbumin attacks) 19.0 * 10 53 (chemical compound 1 liposomees) 10.3 * 10 54 (blank liposomes) 16.9 * 10 5

Claims (29)

1. pharmaceutical composition, it comprises and is encapsulated in liposome or the dehydrated liposomes, as the formula I chemical compound of active component
2. claim 1 compositions, wherein lipid constituent comprises at least a synthetic phospholipid in liposome or the dehydrated liposomes.
3. claim 2 compositions, wherein lipid constituent comprises synthetic phosphatidylcholine, and not essential ground also comprises synthetic Phosphatidylserine or synthetic phosphatidyl glycerol.
4. claim 3 compositions, the weight ratio that wherein has Phosphatidylserine or phosphatidyl glycerol and phosphatidylcholine and Phosphatidylserine or phosphatidyl glycerol is 60: 40-95: 5.
5. claim 4 compositions, wherein said weight ratio is 70: 30-90: 10.
6. the compositions of arbitrary claim 3-5, wherein lipid constituent comprises synthetic formula II phospholipid
Figure A9619159100031
R wherein 1For having the C of even number of carbon atoms 10-C 20Alkanoyl, R 2For having the C of even number of carbon atoms 10-C 20Alkenoyl, R a, R bAnd R cBe hydrogen or C 1-C 4Alkyl, and n is the integer of 2-4.
7. claim 6 compositions, its Chinese style II phospholipid is 1-hexadecane acyl group-2-(9-cis-18 alkanoyl)-3-sn-phosphatidylcholine.
8. the compositions of arbitrary claim 3-7, wherein lipid constituent comprises synthetic formula II phospholipid as claimed in claim 6 and synthetic formula III phospholipid
Figure A9619159100032
R wherein 3And R 4Each is the C for having even number of carbon atoms independently 10-C 20Alkenoyl, n are the integer of 1-3, and Y Cation for pharmaceutically acceptable alkali.
9. claim 8 compositions, wherein formula III phospholipid is 1,2-two (9-cis-vaccenic acid acyl group)-3-sn-phosphatidyl S-L-Serine sodium.
10. the compositions of arbitrary claim 3-5, wherein lipidic component comprises two (C 10-C 20Alkanoyl) phosphatidylcholine and two (C 10-C 20Alkanoyl) phosphatidyl glycerol.
11. claim 10 compositions, wherein phosphatidylcholine is that distearoyl phosphatidylcholine and phosphatidyl glycerol are two palmityl phosphatidyl glycerols.
12. arbitrary one compositions among the claim 2-11, wherein lipid constituent also comprises cholesterol.
13. claim 12 compositions, wherein the amount of fat sterol is the 20-60mol% of total lipid content weight.
14. the compositions of claim 12 or 13, wherein lipid constituent comprises dimyristoyl phosphatidyl choline, cholesterol and dioleoyl phospholipid acyl serine.
15. the compositions of arbitrary claim 1-14, the weight ratio of its Chinese style I chemical compound and lipoid is 1: 100-1: 50.
16. the compositions of arbitrary claim 1-15, wherein the granularity of liposome is less than 1 μ m.
17. the compositions of arbitrary claim 1-16, wherein liposome is a waterborne suspension.
18. the compositions of arbitrary claim 1-16, its form are dry powder, it comprises (a) and contains the dehydrated liposomes of formula I chemical compound and (b) mixture of antifreezing agent.
19. claim 18 compositions, wherein the weight ratio of antifreezing agent and lipid is 1 in the liposome: 1-4: 1.
20. each method for compositions among the preparation claim 1-17, it comprises formula I chemical compound and the solution of one or more lipids in organic solvent is added in the aqueous medium of stirring gradually, obtains the waterborne suspension of liposome.
21. each method for compositions among the preparation claim 1-17, it comprises removes solvent and residue is dispersed in the aqueous medium in the solution organic solvent from one or more lipids and formula I chemical compound, obtains the waterborne suspension of liposome.
22. the method for compositions of preparation claim 1,18 and 19, it comprises containing the liposome dehydration of formula I chemical compound, obtains dry powder.
23. the method for claim 22 is wherein dewatered by lyophilizing.
24. the method for treatment asthma, it comprise by suck effective dose, be encapsulated in liposome or the dehydrated liposomes the described formula I chemical compound of claim 1 and to patient's administration of the described treatment of needs.
25. the application of each compositions in preparation treatment asthmatic medicament among the claim 1-19.
26. claim 1 compositions is basically as described in arbitrary embodiment.
27. the method for claim 20 is basically as described in embodiment 1 or 2.
28. the method for claim 21 is basically as described in embodiment 4 or 5.
29. the method for claim 22 is basically as described in the embodiment 3.
CN96191591A 1995-01-24 1996-01-17 Liposomes containing a corticosteroid Pending CN1169115A (en)

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NO973401D0 (en) 1997-07-23
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WO1996022764A1 (en) 1996-08-01
CA2210482A1 (en) 1996-08-01
CZ234297A3 (en) 1997-10-15
FI973049A0 (en) 1997-07-18
EP0859598A1 (en) 1998-08-26
NO973401L (en) 1997-07-23
JPH10512876A (en) 1998-12-08

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