IE65555B1 - Process for the preparation of aqueous mixed micelle solutions - Google Patents
Process for the preparation of aqueous mixed micelle solutionsInfo
- Publication number
- IE65555B1 IE65555B1 IE36690A IE36690A IE65555B1 IE 65555 B1 IE65555 B1 IE 65555B1 IE 36690 A IE36690 A IE 36690A IE 36690 A IE36690 A IE 36690A IE 65555 B1 IE65555 B1 IE 65555B1
- Authority
- IE
- Ireland
- Prior art keywords
- mixed micelle
- aqueous mixed
- micelle solutions
- active ingredients
- preparation
- Prior art date
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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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Biophysics (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Detergent Compositions (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Mushroom Cultivation (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Colloid Chemistry (AREA)
Abstract
A process for producing aqueous mixed micelle solutions containing mixed micelles formed from lipoids and salts of bile acids, in which, if desired, active substances hardly soluble or insoluble in water are solubilized, is characterized in that the free bile acids are suspended in an aqueous solution possibly containing isotonizing additives and/or water-soluble active substances at a temperature of 40C to 100C, the lipoids are dispersed in this suspension at a temperature of 40C to 100C and the dispersion obtained is neutralized with bases at a temperature of 0C to 100C, provided that, if necessary, the active substances which are hardly soluble or insoluble in water are dispersed together with the lipoids or solubilized in the mixed micelle solution which does not contain these active substances.
Description
The invention relates to a process for the preparation of clear aqueous mixed micelle solutions containing mixed micelles formed from lipids and salts of bile acids» in which, if desired, active ingredients that are insoluble or sparingly soluble in water are solubilised.
Processes for the preparation of such mixed micelle solutions are knownt for example, from German Patent Specification No. 27 30 570.
In the known processes the mixed micelle solutions are prepared by dissolving the lipids, the salts of bile acids, and optionally the active ingredients that are insoluble or sparingly soluble in water, in an organic solvent (for example ethanol), and concentrating the solutions, so that a lipid film is formed at the vessel walls that is released by means of aqueous solutions (Biochemistry 19, 1980, 602 ff and 615 ff; Naturforsch. 32c. 1977, 748 ff).
That process is, however, very complex and its application on a commercial scale is possible only with considerable expenditure on apparatus.
Apart from that preferred process, a process is known, for example, from Example 3 of the patent specification 27 30 570 already mentioned and from European Patent Application 0 280 887 in which such mixed micelle solutions are prepared by mixing the components and stirring the mixture.
That process, however, not only has the disadvantage that it takes several days, but it can be seen in the working up of that Example - without active ingredient - that there are obtained using that process only markedly turbid solutions that contain mixed micelles having a mean diameter of approximately 340 nm.
Clear solutions having mixed micelles with a mean diameter of approximately 10 nm cannot be obtained by that process.
It has now been found that such clear aqueous solutions of mixed micelles can be prepared simply and quickly by means of a process that is characterised in that the free bile acids are suspended at a temperature of from 40°C to 100 C in an aqueous solution optionally containing isotonising additives and/or water-soluble active ingredients, the lipids are dispersed in that suspension at a temperature of from 40 C to 100 "C and the resulting dispersion is neutralised with bases at a temperature of from o‘C to 100c, with the proviso that, where appropriate, the active ingredients that are insoluble or sparingly soluble in water are dispersed together with the lipids or are solubilised in the mixed micelle solution not containing those active ingredients.
The process according to the invention may be carried out using the same bile acids as those in the known processes. Suitable bile acids are 5S-cholanic-24 acid wherein Ry and R2 and also R3 and R4 together represent an oxo group, two hydrogen atoms, or a hydrogen atom and a hydroxy group, and X represents a hydroxy group or a grouping of the formula ~MH-CH2~CO2H or ~NH-(CH2)2-SO3K.
Th© following may be mentioned by way of example as suitable bile acids : cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid.
Preferably from 1 to 30 g, and especially from 2 g to 15 g, of bile acid per 100 g of the aqueous solution optionally containing isotonising additives and watersoluble active ingredients are used to prepare the aqueous mixed micelle solution.
The same lipids as those used in the known processes may be used in the process according to the invention for the preparation of aqueous mixed micelle solutions.
Suitable lipids are, for example, monoglycerides, sulphatides, and especially phospholipids, such as sphingomyelins, plasmalogens, phosphatidyl cholines, phosphatidyl ethanolamines, phosphatidyl serines, phosphatidyl inositols and cardiolipins, and also mixtures of those lipids (Dr. Otto-Albert Neumuller; Rompps CheraieLexikon; Franck'sche Verlagshandlung (Franck's publishing company), Stuttgart (DE) 2665, 3159, 3920 and 4045).
Preferably from 3 to 40 %, and especially from 5 to 20 %, of lipid per 100 g of the aqueous solution optionally containing isotonising additives and/or water-soluble active ingredients are used to prepare the aqueous mixed micelle solutions. The ratio by weight of lipid to bile acid is preferably from 0.1:1 to 2:1 and especially from 0.8:1 to 2:1.
Suitable bases for the preparation of the aqueous mixed micelle solutions by the process according to the invention are on the one hand alkali hydroxides, such as lithium hydroxide, potassium hydroxide and especially also sodium hydroxide, and on the other hand organic nitrogen bases, provided they form physiologically tolerable salts. Such nitrogen bases are, for example, ammonia, primary, secondary or tertiary amines, ethanolamine, diethanolamine, piperazine, morpholine, lysine, ornithine, arginine, N,Ν-dimethylglucamine, choline and, especially, M-methylglucamine and trishydroxymethylaminomethane.
Suitable active ingredients that are insoluble or sparingly soluble in water are preferably those with a solubility in water at room temperature that does not exceed 2 %. Such active ingredients are, for example, plant protective agents, such as sparingly soluble insecticides or herbicides, and especially sparingly soluble pharmaceutical active ingredients.
Pharmaceutical active ingredients that are insoluble or sparingly soluble in water and that belong to the following groups of active ingredient are, for example, suitable for the preparation of the medicaments according to the invention: Gestagenically active steroid hormones, such as, for example, 13-ethyl-17B-hvdroxy~l8,19-dinor-17a-pregn~4-en20-yl-3-=one (=levonorgestrel) , 13-ethyl-l7B-hydroxy18,19-dinor-17a-pregna-4,15-dien-20-vn-3-one (= gestodene) or 13-ethyl-17B-hydroxy-ii-methylene-l8,19-dinor17c-pregn-4-en-20-yne (desorgestrel), oestrogenically active steroid hormones, such as 3-hvdroxy-l,3,5(10)oestratrien-17-one (=oestrone) or 1,9-nor-17a-pregna1,3„5(10)trien-20-yne-3,176~diol (ethynvioestradiol).
Androgenically active steroid hormones, such as Ι7βhydroxy-4-androsten-3-one (=testosterone) and its esters or 17S-hydroxy-lG--methyl-Sc-androsten-3-ona (=mesterolone).
Antiandrogenically active steroid hormones, such as 17aacetoxy-o-chloro-lS,2B-dih,ydro-3H-cyclopropa[1„2]pregna1,4,6-triene-3,20-dione (cypoterone acetate), Corticoids, such as llB,17a,21-trihydroxy-4-pregnene3,20-dione (^hydrocortisone), llB,17c,21-trihydroxy~i,4~ pregnadiena-3,20-dione (=prednisolone), 11B,I7g,2Itrihydroxy-6a-methyl-l, 4-pregnatriene-3,20-dione (=methylprednisolone) and Sa-fluoro-IlB,21-dihydroxyloe-raethyl-l,4-pregnadiene-3,20-dione (=difluocortolone).
Ergolines, such as 3-( 9,10-dihydro-6-niethyl~8G"ergolinyl)-1,1-diethylurea (=ergoline), 3-(2~bromo-9,10dihydro-6-methyl"8cergolinyl)-1,1-diethylurea (=bromoergoline) or 3-(6-methyl-8c~ergolinyl)-1,1-diethylurea (=terguride).
Antihypertensives, such as 7c-acetylthiOl7G-hydroxy~3oxo-4-pregnene-21-carboxylic acid (7-lactone ^spironolactone) or 7G"acetylthio-15B,16B~methylene-3-oxo-i7ttpregna-1„4-diene~21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5-[hexahydro-5-hvdroxy-4-(3hydroxy-4-methyl"l-octen-6-ynyl )-2(1H)-pentalenylidene)]pentanoic acid (=iloprost).
Psychopharmacological agents, such as 4-(3-cyclopentyl6 oxy-4-methoxypheny1-2-pyrrolidone (-rolipram) and 7chloro-1,3-dihydro-l-methyl-5-phenyl~2H-l,4-benzodiazepin-2-one (=diazepam).
Carotinoids, such as c-carotene and B-carotene.
Fat-soluble vitamins, such as vitamins from the vitamin A, vitamin D, vitamin E and vitamin K groups.
An especially preferred group is β -carbolines, as described, for example, in European Patent Applications 234 173 and 239 357 The following B-carbolines may be mentioned by way of example : 5-benzoyloxy-4-raethoxy" methyl-B-carboline-3-carboxylic acid isopropyl ester (=becarnil), 5-(4-chlorophenoxv)-4-methoxymethyl-Bcarboline-3-carboxylic acid isopropyl ester (=C1-PHOCIP), 5-isopropoxy-4-methyl-S-carboline-3"Carboxylic acid ethyl ester (=IPMCE) and 5-(4-chlorophenoxy)-3~(3-ethyl-l,2,4oxadiazol"5"yl)-4"methoxymefchyl-B-carboline (=phoco). The optimum concentration of active ingredient in the mixed micelle solutions naturally depends on the structure of the active ingredient and has to be ascertained by means of common preliminary tests. Usually, the concentration of B-carbolines is from 1 μς to 40 mg, preferably from 100 p,q to 10 mg, of active ingredient per ml of mixed micelle solution., For the preparation of the mixed micelles themselves, glycocholic acid and phospholipids are preferably used.
The aqueous mixed micelle solutions prepared by the process according to the invention may, if desired, contain isotonic additives for the purpose of increasing their osmotic pressure. Suitable additives are, for example, inorganic or organic salts or buffer substances, such as sodium chloride, phosphate buffers, citrate buffers, glycine buffers, citrate/phosphate Ί buffers, malate buffers, etc., mono- or di-saccharides, such as glucose, lactose» saccharose, sugar alcohols, such as mannitol, sorbitol» xvlitol or glycerol, or water-soluble polymers, such as dextran or polyethylene glycol.
Those isotonising substances are usually added in such concentrations that the resulting aqueous mixed micelle solution has an osmotic pressure of from 5 to 1000 mosm, and in the case of injection solutions optimally 300 mosm.
Furthermore, the aqueous mixed micelle solutions may also contain additional water-soluble active ingredients for the production of combination preparations. Examples of such combination preparations are mixtures of watersoluble and fat-soluble vitamins or preparations that contain water-soluble antibiotics in addition to corticoids.
In addition to the conditions listed in patent claim 1, the preparation of the water-soluble mixed micelle solutions is carried out by means of conventional methods in which the mixtures are heated, with vigorous stirring, to the temperatures specified in patent claim 1.
Since the lipids and also some active ingredients are sensitive to oxidation, the process is advantageously carried out under an inert gas atmosphere, such as under nitrogen or argon, and the resulting aqueous mixed micelle solutions are stabilised by the addition of antioxidants, such as sodium ascorbate, tocopherol or sodium hydrogen sulphite.
The process according to the invention can normally be carried out in a few minutes and has the advantage that mixed micelle solutions that are free of organic solvent ' residues are obtained. Furthermore, the process according to the invention can be carried out using conventional v 5 mixing and dispersion techniques (for example according to the rotor/stator principle), such as are customary in pharmaceutical technology (see The Theory and Practice of Industrial Pharmacy, L Lachman, H.A. Lieberman, J.L. Kanig, Philadelphia (1970), p. 481 or Pharmazeutische TechnoXogie, K.H. Bauer, K-H. Froraming and C. Fuhrer, Stuttgart/New York (1986) p. 103), thereby providing a good prerequisite for a reproducible process protocol, especially under GMP conditions (Good Manufacturing Practices).
When the preparation is complete, the resulting aqueous mixed micelle solution can be sterile-filtered and/or can be heat-sterilised at from 100C to l40c.
The following example embodiments serve to illustrate the process according to the invention in detail. 2o Example 1 700 ml of 0.0 2W acetate buffer, pH 6.0, are heated to 80*C in a heatable stirring and homogenising apparatus with the introduction of argon. 54.2 g of glycocholic acid are then added, with stirring, and stirring is continued until a homogeneous suspension is obtained (approximately 5 minutes). 90 g of phosphatidyl choline (soya lecithin) and 10 g of becarnil = 6-benzoyloxy-4methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester are then added to the suspension, and the whole is stirred at 80°C until the dispersion is homogeneous (approximately 10 minutes). Subsequently, 20 % aqueous sodium hydroxide solution is added until a pH of 6.0 is reached, and a clear solution is immediately obtained which, after cooling, is made up with water to a final volume of 1000 ml. The aqueous mixed micelle solution so obtained is sterile-filtered.
Example 2. 700 ml of 0.015H phosphate buffer, pH 7.0, are heated to 80 'C in a heatable stirring and homogenising apparatus with the introduction of argon. 47.6 g of cholic acid are then added, with stirring, and stirring is continued until a homogeneous suspension is obtained (approximately 5 minutes). 90 g of phosphatidyl choline (soya lecithin) are then added to the suspension and the whole is stirred at 80 C until the dispersion is homogeneous (approximately 10 minutes). Subseguently, 20 % aqueous sodium hydroxide solution is added until a pH of 7.0 is reached, and a clear solution is immediately obtained. 10 g of Becarnil =S-ben2oyIoxy-4-methoxyraefchyl-B-carboline-3carboxylic acid isopropyl ester are stirred into that solution and dissolve rapidly therein. After cooling, the resulting solution is made up with water to a final volume of 1000 ml. The nixed micelle solution so obtained is sterilised at 121°C.
Example 3 700 ml of 0.02N acetate buffer, pH 6.0, are heated to 80*C in a heatable stirring and homogenising apparatus with the introduction of argon. 54.2 g of glycocholic acid are then added, with stirring, and stirring is continued until a homogeneous suspension is obtained (approximately 5 minutes). 90 g of phosphatidyl choline (Phospholipon 100 L, Nattermann) and 1.1 g of Cl-Phocip =6-benzoyloxy-4-methoxymethyl-B-carbol ine-3-carboxy lie acid isopropyl ester are then added to the suspension and the whole is stirred at that temperature until the dispersion is homogeneous. After cooling to 40 to 50’C, the dispersion is neutralised with 20 % aqueous sodium hydroxide solution, resulting in a clear solution having a pH of 5,0. After making up to a final volume of 1000 ral, the aqueous mixed micelle solution is sterilefiltered and can optionally be sterilised at 121°C.
Example 4 700 ml of water for injection purposes are heated to 80 °C in a heatable stirring and homogenising apparatus with the introduction of argon. 54.2 g of glycocholic acid are then added, with stirring, and stirring is continued until a homogeneous suspension is obtained (approximately 5 minutes). 90 g of phosphatidyl choline and 2 g of IPMCE =5-isopropoxy-4~methyl-S-carboline-3-carboxy 1 ic acid ethyl ester are then added to the suspension and the whole is stirred at that temperature until the dispersion is homogeneous (approximately 10 to 15 minutes). Subsequently, 20 % aqueous sodium hydroxide solution is added until a pH of 6.0-6.5 is reached, and a clear solution is obtained which, after cooling, is made up with water to 1000 ml. The aqueous mixed micelle solution so obtained is sterile-filtered.
Example 5 700 ml of water for injection purposes are heated to 80°C in a heatable stirring and homogenising apparatus with the introduction of argon. 54.2 g of glycocholic acid are then added, with stirring, and stirring is continued until a homogeneous suspension is obtained (approximately 5 minutes). 90 g of phosphatidyl choline and 1 g of Phoco =5- ( 4-chlorophenoxv) -3- ( 3-ethyl-l, 2,4-oxadiazol-5-yl-4methoxymethyl-B-carboline are then added to the suspension and the whole is stirred at that temperature until the dispersion is homogeneous (approximately 10 to 15 minutes). Subsequently, 20 % aqueous sodium hydroxide solution is added until a pH of 6.0-6.5 is reached, and a clear solution is obtained which, after cooling, is made up with water to 1000 ml. The aqueous mixed micelle solution so obtained is sterile-filtered.
Claims (13)
1. Process for the preparation of clear aqueous mixed micelle solutions, containing mixed micelles formed from lipids and salts of bile acids, in which, if desired, 5 active ingredients-that are insoluble or sparingly soluble in water are solubilised, characterised in that the free bile acids are suspended at a temperature of from 40C to IGO’C in an aqueous solution optionally containing isotonising additives and/or water-soluble 10 active ingredients, the lipids are dispersed in that suspension at a temperature of from 40*C to 100*C and the resulting solution is neutralised with bases at a temperature of from QC to 100“C, with the proviso that, where appropriate, the active ingredients insoluble or 15 sparingly soluble in water are dispersed together with the lipids or solubilised in the mixed micelle solution not containing those active ingredients.
2. Process for the preparation of clear aqueous mixed micelle solutions according to patent claim 1, charac20 terised in that there is used as bile acid a 58-cholanic- wherein R 3 and R 2 and also R 3 and R^ together represent an oxo group, two hydrogen atoms, or a hydrogen atom and a hydroxy group, and X represents a hydroxy group or a grouping of the formula -NH“CH 2 ~CO 2 H or -NH“(CH 2 ) 2 -SO 3 H.
3. Process for the preparation of clear aqueous mixed micelle solutions according to patent claim 1 and 2, characterised in that the lipids used are phospholipids.
4. Process for the preparation of clear aqueous mixed micelle solutions according to any one of patent claims 1 to 3, characterised in that pharmaceutically active ingredients are used as active ingredients that are insoluble or sparingly soluble in water.
5. Process for the preparation of clear, aqueous mixed micelle solutions according to patent claim 4, characterised in that B-carbolines are used as pharmaceutically active ingredients.
6. Use of clear aqueous mixed micelle solutions prepared in accordance with patent claim 4 and 5 for the preparation of injection solutions.
7. Clear aqueous mixed micelle solutions containing βcarbolines.
8. Clear aqueous mixed micelle solutions containing 6benzoyloxy-4-methoxymethyl-B-carboline-3-carboxy 1 ic acid isopropyl ester.
9. Clear aqueous mixed micelle solutions containing 5(4-chlorophenoxy)“4-methoxymethyl-e-3-carboxylic acid isopropyl ester.
10. Clear aqueous mixed micelle solutions containing 5- 14 isopropoxy~4~methyΙ-β-carboline-3-carboxy1ic acid ethyl ester.
11. Clear aqueous mixed micelle solutions containing 5(4—chlorophenoxy) - 3-( 3-ethyl-1,2 , 4-oxadiazol-5-yl )-4methoxymethy1-5-carboline.
12. A process substantially as hereinbefore described with reference to the Examples.
13. A solution substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3903753A DE3903753A1 (en) | 1989-02-06 | 1989-02-06 | METHOD FOR PRODUCING AQUEOUS MIXED MICRO SOLUTIONS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE900366L IE900366L (en) | 1990-08-06 |
| IE65555B1 true IE65555B1 (en) | 1995-11-01 |
Family
ID=6373663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE36690A IE65555B1 (en) | 1989-02-06 | 1990-02-01 | Process for the preparation of aqueous mixed micelle solutions |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0409936B1 (en) |
| JP (1) | JPH03503899A (en) |
| AT (1) | ATE103803T1 (en) |
| AU (1) | AU636327B2 (en) |
| CA (1) | CA2009307A1 (en) |
| DD (1) | DD291696A5 (en) |
| DE (2) | DE3903753A1 (en) |
| DK (1) | DK0409936T3 (en) |
| ES (1) | ES2052246T3 (en) |
| FI (1) | FI904892A0 (en) |
| GR (1) | GR900100034A (en) |
| HU (1) | HU206260B (en) |
| IE (1) | IE65555B1 (en) |
| PT (1) | PT93055B (en) |
| WO (1) | WO1990008534A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2033725C (en) * | 1990-01-24 | 2001-05-29 | Folker Pittrof | Pharmaceutical and cosmetic compositions containing a salt of cholanic acid |
| EP0471309A1 (en) * | 1990-08-17 | 1992-02-19 | F. Hoffmann-La Roche Ag | Use of mixed micelles |
| DE4120109A1 (en) * | 1991-06-15 | 1992-12-17 | Schering Ag | 3-ARYL OR 3-HETARYL (BETA) CARBOLINES, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| JP2740153B2 (en) * | 1995-03-07 | 1998-04-15 | エフ・ホフマン−ラ ロシユ アーゲー | Mixed micelle |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1202370B (en) * | 1976-07-12 | 1989-02-09 | Hoffmann La Roche | INJECTABLE SOLUTIONS IN WHICH THE EMOLITHIC LIFE OF NATURAL MICELLES TRAINING AGENTS IS AVOIDED BY THE ADDITION OF LIPOIDS AND RELATED PRODUCTS |
| CA1319886C (en) * | 1987-02-03 | 1993-07-06 | Alberto Ferro | Mixed micelle solutions |
-
1989
- 1989-02-06 DE DE3903753A patent/DE3903753A1/en not_active Withdrawn
-
1990
- 1990-01-16 HU HU901153A patent/HU206260B/en not_active IP Right Cessation
- 1990-01-16 EP EP90901552A patent/EP0409936B1/en not_active Expired - Lifetime
- 1990-01-16 AT AT90901552T patent/ATE103803T1/en not_active IP Right Cessation
- 1990-01-16 ES ES90901552T patent/ES2052246T3/en not_active Expired - Lifetime
- 1990-01-16 JP JP2502164A patent/JPH03503899A/en active Pending
- 1990-01-16 DE DE90901552T patent/DE59005243D1/en not_active Expired - Fee Related
- 1990-01-16 DK DK90901552.1T patent/DK0409936T3/en active
- 1990-01-16 WO PCT/DE1990/000028 patent/WO1990008534A1/en active IP Right Grant
- 1990-01-19 GR GR900100034A patent/GR900100034A/en not_active IP Right Cessation
- 1990-02-01 IE IE36690A patent/IE65555B1/en not_active IP Right Cessation
- 1990-02-02 DD DD90337551A patent/DD291696A5/en unknown
- 1990-02-05 PT PT93055A patent/PT93055B/en not_active IP Right Cessation
- 1990-02-05 CA CA002009307A patent/CA2009307A1/en not_active Abandoned
- 1990-02-06 AU AU49186/90A patent/AU636327B2/en not_active Ceased
- 1990-10-04 FI FI904892A patent/FI904892A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990008534A1 (en) | 1990-08-09 |
| PT93055B (en) | 1995-12-29 |
| DD291696A5 (en) | 1991-07-11 |
| AU636327B2 (en) | 1993-04-29 |
| DK0409936T3 (en) | 1994-07-18 |
| HU901153D0 (en) | 1991-03-28 |
| ATE103803T1 (en) | 1994-04-15 |
| EP0409936B1 (en) | 1994-04-06 |
| HUT55219A (en) | 1991-05-28 |
| FI904892A0 (en) | 1990-10-04 |
| DE3903753A1 (en) | 1990-08-23 |
| HU206260B (en) | 1992-10-28 |
| PT93055A (en) | 1990-08-31 |
| EP0409936A1 (en) | 1991-01-30 |
| AU4918690A (en) | 1990-08-09 |
| IE900366L (en) | 1990-08-06 |
| DE59005243D1 (en) | 1994-05-11 |
| GR900100034A (en) | 1991-06-28 |
| CA2009307A1 (en) | 1990-08-06 |
| JPH03503899A (en) | 1991-08-29 |
| ES2052246T3 (en) | 1994-07-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |