GB2184355A - Ubiquinone pharmaceutical compositions - Google Patents
Ubiquinone pharmaceutical compositions Download PDFInfo
- Publication number
- GB2184355A GB2184355A GB08630158A GB8630158A GB2184355A GB 2184355 A GB2184355 A GB 2184355A GB 08630158 A GB08630158 A GB 08630158A GB 8630158 A GB8630158 A GB 8630158A GB 2184355 A GB2184355 A GB 2184355A
- Authority
- GB
- United Kingdom
- Prior art keywords
- composition according
- coenzyme
- active principle
- ubiquinone
- dimethylacetamide
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K31/12—Ketones
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Pharmaceutical compositions containing, as active principle, ubiquinone, comprise at least one non- ionic emulsifier, a hydroxylated solvent, at least one anti-oxidizing agent and, optionally, dimethylacetamide. The emulsifier is preferably a condensate of ethylene oxide and a fatty acid oil, the solvent may be an alcohol, glycol, polyglycol, glycerine, glycofurol, sorbitol or water and the anti-oxidant may be vitamin E, ascorbic acid or pyrogallol.
Description
SPECIFICATION
Ubiquinone pharmaceutical compositions
The present invention refers to hydrosoluble pharmaceutical formulations containing ubiquinone as the active principle.
The ubiquinones, and in particular Coenzyme Q10, exhibit a series of biological activities making then useful in different therapeutic fields.
For instance, Coenzyme Q1O plays an important role in electron transport and in oxygen utilization at the cellular mitochondrial level (De Pierre V.C. and coll.-Ann. Rev. Biochem, 46-201-1977; Nakamura T. et al. Chem Pharm. Bull. 27-1101-1979).
Its activity is necessary for ATP formation and for the various cellular and tissular energetic functions. A lack thereof has been demonstrated in many pathologic conditions such as in myocardial insufficiencies, hypertension, post-infarctual states and myastenia (Folkers K. et al. J.
Vit. Nutr. Res. 40-380-1970; Sugijama S. Experientia 36-1002-1980).
In said pathological conditions, the hexogenous administration of Coenzyme 0,, leads to noticeable improvements and to important therapeutic results (Yamasawa G.-Biomedical and
Clinical Aspects of Coenzyme Q-Elsevier-North Holland-Ed. Vol. Ii, pag. 333-1980).
However, oral absorption of Coenzyme Q10, administered with the usual excipients, is very low and particular techniques are necessary to increase absorption. Moreover, in many of the above cited diseases, it is necessary that Coenzyme Q10 rapidly achieves high ematic and tissular concentrations.
For these reasons, the possibility of administering Coenzyme Q1O in the form of easily absorbable solutions and allowing parenteral administration both by the venous and intramuscular or subcutaneous route, alone or combined with other aqueous preparations, appears to be very desirable.
Japanese patent application No. 58-113127 discloses Ubidecarenone aqueous formulations containing, as stabilizing and solubilizing agents, variable amounts of hydrogenated lecithins.
It has now been found that it is possible to obtain ubiquinone formulations which can be administered by the oral, parenteral and topical routes, hydrosoluble and stable, i.e. without the occurrence of precipitation phenomena of the active principle also following dilution with large amounts of water. The compositions to which the invention relates are also endowed with improved bioavailability (better absorption of the active principle) involving increased therapeutic effectiveness.
The ubiquinone formulations of the invention comprise a non-ionic emulsifying agent for example of the kind obtainable by the condensation of ethylene oxide and a non-hydrogenated fatty acid oil, together with a hydroxylated solvent, one or more anti-oxidizing agents and, optionally, dimethylacetamide as coadjuvant. It is particularly preferred to use the non-ionic surfactant emulsifier known under the trade mark Cremophor EL8 sold by BASF, whereas glycols, glyceral, polyglycols, alcohols, glycofural, sorbitol, water and the like may be conveniently used as polyhydroxylated solvents. Suitable anti-oxidizing agents include Vitamin E, pyrogallol, ascorbic acid or other known anti-oxidizing agents.
The non-ionic emulsifier, e.g. Cremophor EL, is preferably present in the compositions of the invention in amounts ranging from 4 to 10 times the weight of the active principle whereas the polyhydroxylated solvent is present in amounts of from 10 to 25 times the weight of the active principle.
The anti-oxidizing agents are preferably added in amounts ranging from 0.5 to 2 mg per 100 mg of active principle, whereas the dimethylacetamide (if present), whose function is that of allowing a reduction of the amounts of the Cremophor EL and polyhydroxylated solvents, is preferably present in amounts ranging from 0.5 to 5 ml per 100 mg of active principle. Finally, the active principle, for instance Coenzyme Q1O, will be usually present in the formulations of the invention in amounts ranging from 50 to 500 mg.
The compositions of the invention, which may obviously contain other excipients such as flavouring, sterilizing and buffering agents according to the needs and techniques of the art, may be diluted at the moment of use even with saline, glucosate, or vitamin solutions and the like, without the occurrence of any precipitation or incompatibility problem.
The following non-limitative examples further illustrate the invention.
EXAMPLE 1
100 mg of Coenzyme Q1O were dissolved at 60"C in 800 mg of Cremophor EL. Keeping the temperature at 600C, 0.4 ml of 70% sorbitol, pre-heated at 60"C, were added with stirring.
Thereafter 1.6 ml of H20 heated at 60"C and containing 0.2 ml of dimethylacetamide and the anti-oxidizing agents (chosen from pyrogallol 0.5 mg; Vit. E 0.5 mg; Vit. C 1 mg) were added.
Working in a similar way, the following compositions have been prepared.
EXAMPLE 2 -Coenzyme Q10 100 mg -Cremophor EL 400 mg -Dimethylacetamide 2.30 ml -Glycofurol 1.15 ml -Pyrogallol 11 mg.
EXAMPLE 3 -Coenzyme Q1O 100 mg -Cremophor EL 1000 mg -Dimethylacetamide 0.5 ml -Glycofurol 1.0 ml - Pyrogallol 1 mg
EXAMPLE 4 -Coenzyme Q10 100 mg -Cremophor EL 780 mg -Glycofurol 600 mg - H20 220 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 5 -Coenzyme Q1O 100 mg -Cremophor EL 500 mg -Glycofurol 700 mg -H20 200 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 6 -Coenzyme Oio 100 mg -Cremophor EL 600 mg - Polyglycol 200-400 400 mg -H20 100 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 7 -Coenzyme Q1O 100 mg -Cremophor EL 600 mg - Glycerine 400 mg - H20 100 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 8 -Coenzyme Q1O 100 mg -Cremophor EL 600 mg -70% Sorbitol 400 mg -H20 100 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 9 -Coenzyme Q1O 100 mg -Cremophor EL 600 mg -95% Ethanol 400 mg -H20 100 mg -Dimethylacetamide 0.5 ml.
EXAMPLE 10 -Coenzyme 0,, 100 mg - Cremophor EL 500 mg -Glycofurol 700 mg -Dimethylacetamide 0.5 ml -Vitamin E 0.5 mg -Vitamin C 1.0 mg - H20 100 mg.
EXAMPLE 11 -Coenzyme Q1O 100 mg -Cremophor EL 500 mg -Glycofurol 500 mg -Dimethylacetamide 0.5 ml -Vitamin E 0.5 mg -H20 100 mg.
EXAMPLE 12 -Coenzyme Q1O 100 mg -Cremophor EL 600 mg - Polyglycol 200-400 400 mg -Dimethylacetamide 0.5 ml -Vitamin E 0.5 mg -H20 100 ml.
EXAMPLE 13 -Coenzyme Q1o 100 mg -Cremophor EL 1000 mg -Dimethylacetamide 0.5 ml -Glycofurol 0.5 ml - Pyrogailol 0.1 mg -Vitamin E 0.1 mg.
Toxicological tests
The different toxicological tests carried out in the experimental animals (both in the rats and in the guinea-pig and rabbit) have shown that the results obtainable by Coenzyme Q1O administration of the solution according to the invention are comparable to those for the use of Coenzyme 0,, adminstered with other excipients exhibiting the same characteristics of low toxicity and good tolerability.
Pharmacological tests
The Coenzyme Q1O solution prepared according to the formulation disclosed in the present invention shows absorption and pharmacokinetic characteristics by far better, for therapeutic purposes, than thiose obtainable by oral Coenzyme Q1O administration or by parenteral Coenzyme Q1O administration after dissolution in other fatty or aqueous vehicles.
The comparative examination of the plasmatic, hepatic and cardiac Coenzyme Q1O concentrations, administered to male, Sprague-Dawley rats by the venous route in the form of an aqueous formulation prepared according to the present invention (I) (Example 10) or in glycofurol (Il) or in a soy-lecithin preparation (Ill) or administered by the oral route in soy oil, has shown that the preparation of the invention gives a faster absorption and higher tissular concentrations, as is shown by the values reported in Table 1. Similar favourable results have also been obtained using other kinds of solutions disclosed in the invention, such as those of Exampies 1, 2, 5, 6, 7 and 12.
The method used for the Coenzyme 0,, assay in the plasma and in the tissues of the animals injected with the different Coenzyme Q1O preparations was that of high performance liquid chromatography (HPLC) (Ikenoya at al.-Chem. Pharm. Bull. 29-158-1981; Takada M; et al.-
Methods in Enzimology 105-147-1984).
2 ml of distilled M20, 4ml of ethanol and 10 ml of n-hexane were added to 1 ml of plasma coming from treated rats. The solution was placed in test-tubes, stirred and centrifuged at 2000 g for 10'. The volumes of n-hexane, collected by three extractions, were collected and evaporated under N2 flow. The dry residue was dissolved in 100 mcl of dioxane and 10 mcl were injected in HPLC. The same extractive process was used for the tissue homogenate obtained by 100 mg of tissue in 2 ml of distilled water.
The venous administration of Coenzyme Q1O prepared according to the invention caused rapidly, and for a prolonged period of time, high hematic and tissular Coenzyme Q1O concentrations, which are up to about 100 times higher with respect to oral administration and more than twice in comparison with conventional parenteral administration.
This represents an evident therapeutic advantage in the clinical use of Coenzyme Q1O. Also, oral Coenzyme Q1O administration by the formulations of the invention shows more advantageous absorption properties than when using the conventional formulations.
TABLE 1 - Plasma (mcg/ml) and tissular (mcg/g) Coenzyme Q10 concentrations after intravenous treatment (5 mg/kg) of the preparations (I = Example 10); (TI = only glycofurol); (III = only soy lecithin) and oral (100 mg/kg) of the preparation (IV = soy bean oil) in the rat.
Concentrations Preparations Time after administration (hours) present in: 0 0.5 1 3 6 12 Plasma I i.v. - 70.10 50.70 25.40 18.60 5.50 II it " - 50.40 25.50 18.70 12.40 3.15 II III " ~ 45.10 18.30 10.15 7.30 1.20 Iv , it Os - 0.25 0.95 2.25 1.95 0.20 Liver I i.v. 11.50 45.20 75.40 70.50 60.70 55.30 .. II " 12.20 36.80 40,60 38.30 32.30 45.60 III 11.80 25.50 26.20 22.80 20,50 18.10 IV it os 12.10 14.30 15.50 20.80 30.50 38.10 9art I i.v. 12.30 26.10 30.30 24.50 22.10 18.30 II " 11.50 10.10 21.70 18.10 15.30 12.40 III 12.50 15.70 18.20 14.20 13.30 10.70 IV it os 12.35 15.30 22.10 16.70 20.10 12.10
Claims (9)
1. A liquid pharmaceutical composition containing as the active principle an ubiquinone suited for oral, parenteral, rectal or topical administration, the composition comprising one or more nonionic emulsifiers, a hydroxylated solvent, one or more anti-oxidizing agents and, optionally, dimethylacetamide.
2. A composition according to claim 1, wherein the non-ionic emulsifier is a polymer derived from the condensation of ethylene oxide and a non-hydrogenated fatty acids oil.
3. A composition according to claim 1 or 2, wherein the hydroxylated solvent is selected from an alcohol, glycol, polyglycol, glycerine, glycofurol, sorbitol, water and mixtures thereof.
4. A composition according to claim 1, 2 or 3, wherein the anti-oxidizing agent is selected from Vitamin E, ascorbic acid and pyrogallol.
5. A composition according to any one of the preceding claims, wherein the non-ionic surfactant is CREMOPHOR EL.
6. A composition according to any one of the preceding claims, wherein the non-ionic emulsifier is present in an amount of from 4 to 10 times the weight of the active principle.
7. A composition according to any one of the preceding claims, wherein the hydroxylated solvent is present in an amount of from 10 to 25 times the weight of the active principle.
8. A composition according to any one of the preceding claims, wherein the active principle is ubiquinone Q10.
9. A pharmaceutical composition substantially as described herein with reference to any one of Examples 1 to 13.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH5525/85A CH667387A5 (en) | 1985-12-24 | 1985-12-24 | UBICHINONE AQUEOUS PHARMACEUTICAL FORMULATIONS. |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8630158D0 GB8630158D0 (en) | 1987-01-28 |
GB2184355A true GB2184355A (en) | 1987-06-24 |
GB2184355B GB2184355B (en) | 1990-03-28 |
Family
ID=4295081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8630158A Expired - Fee Related GB2184355B (en) | 1985-12-24 | 1986-12-17 | Ubiquinone pharmaceutical compositions |
Country Status (7)
Country | Link |
---|---|
JP (1) | JPS62158209A (en) |
BE (1) | BE906034A (en) |
CH (1) | CH667387A5 (en) |
DE (1) | DE3643330A1 (en) |
FR (1) | FR2598320B1 (en) |
GB (1) | GB2184355B (en) |
IT (1) | IT1198247B (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0522433A1 (en) * | 1991-07-11 | 1993-01-13 | Inverni Della Beffa S.P.A. | Oral aqueous solutions containing ubidecarenone |
GR1001364B (en) * | 1992-10-16 | 1993-10-29 | Inverni Della Beffa Farma | Ubidecarenone oral formulations in the form of aqueous solutions. |
ES2051643A1 (en) * | 1992-10-13 | 1994-06-16 | Idb Holding Spa | Oral ubidecarenone formulations in the form of aqueous solutions |
WO1998035658A2 (en) * | 1997-02-12 | 1998-08-20 | Mse Pharmazeutika Gmbh | The use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
EP0888774A2 (en) * | 1997-06-30 | 1999-01-07 | Soft Gel Technologies, Inc. | Soft gel Coenzyme Q10 formulation |
EP1084701A1 (en) * | 1999-09-15 | 2001-03-21 | Beiersdorf Aktiengesellschaft | O/W-emulsion comprising one or several bioquinones and an elevated amount of glycerine |
EP1135100A1 (en) * | 1998-12-11 | 2001-09-26 | Q-Pharma, Inc. | Oral care compositions comprising coenzyme q 10? |
WO2002090304A1 (en) * | 2001-05-09 | 2002-11-14 | Kaneka Corporation | Stable solution of reduced coenzyme q |
EP1398026A2 (en) * | 1997-02-12 | 2004-03-17 | MSE Pharmazeutika GmbH | The use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
US8961958B2 (en) | 2004-11-16 | 2015-02-24 | Bioavailability, Inc | High concentration self-microemulsifying coenzyme Q10 preparations for nutritional use |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5925335A (en) * | 1997-06-12 | 1999-07-20 | C.S. Bioscience Inc. | Dental formulation |
JP2004532831A (en) * | 2001-03-27 | 2004-10-28 | シー.エス. バイオサイエンス、 インコーポレイテッド | Dental preparation |
WO2005035477A1 (en) * | 2003-10-08 | 2005-04-21 | Kaneka Corporation | Method of stabilizing compound having quinone skeleton and stabilized composition |
JP5999765B2 (en) * | 2012-12-07 | 2016-09-28 | バイオアバイラビリティ,インク. | High concentration self-microemulsifying coenzyme Q10 preparation for nutritional use |
JP5722299B2 (en) * | 2012-12-07 | 2015-05-20 | バイオアバイラビリティ,インク. | High concentration self-microemulsifying coenzyme Q10 preparation for nutritional use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1317865A (en) * | 1971-11-15 | 1973-05-23 | Jujo Paper Co Ltd | Biologically active composition |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL275602A (en) * | 1961-03-06 | |||
FR1334961A (en) * | 1961-03-06 | 1963-08-16 | Merck & Co Inc | Stable aqueous solutions based on substituted benzoquinone |
JPS498246B1 (en) * | 1965-07-15 | 1974-02-25 | ||
GB1225979A (en) * | 1967-03-23 | 1971-03-24 | ||
JPS5218811A (en) * | 1975-08-01 | 1977-02-12 | Eisai Co Ltd | Preparation of aqueous solution of fat- soluble substances |
JPS58113127A (en) * | 1981-12-28 | 1983-07-05 | Ajinomoto Co Inc | Aqueous solution containing ubidecarenone |
JPS6025918A (en) * | 1983-07-25 | 1985-02-08 | Ajinomoto Co Inc | Aqueous solution containing fat-soluble drug |
-
1985
- 1985-12-24 CH CH5525/85A patent/CH667387A5/en not_active IP Right Cessation
-
1986
- 1986-12-17 GB GB8630158A patent/GB2184355B/en not_active Expired - Fee Related
- 1986-12-18 DE DE19863643330 patent/DE3643330A1/en not_active Ceased
- 1986-12-23 JP JP61307593A patent/JPS62158209A/en active Granted
- 1986-12-23 FR FR868618075A patent/FR2598320B1/en not_active Expired - Fee Related
- 1986-12-23 BE BE0/217600A patent/BE906034A/en not_active IP Right Cessation
- 1986-12-23 IT IT22844/86A patent/IT1198247B/en active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1317865A (en) * | 1971-11-15 | 1973-05-23 | Jujo Paper Co Ltd | Biologically active composition |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0522433A1 (en) * | 1991-07-11 | 1993-01-13 | Inverni Della Beffa S.P.A. | Oral aqueous solutions containing ubidecarenone |
FR2678836A1 (en) * | 1991-07-11 | 1993-01-15 | Idb Holding Spa | ORAL FORMULATIONS OF UBIDECARENONE IN THE FORM OF AQUEOUS SOLUTIONS. |
ES2051643A1 (en) * | 1992-10-13 | 1994-06-16 | Idb Holding Spa | Oral ubidecarenone formulations in the form of aqueous solutions |
GR1001364B (en) * | 1992-10-16 | 1993-10-29 | Inverni Della Beffa Farma | Ubidecarenone oral formulations in the form of aqueous solutions. |
WO1998035658A3 (en) * | 1997-02-12 | 1999-01-21 | Mse Pharmazeutika Gmbh | The use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
EP1398026A2 (en) * | 1997-02-12 | 2004-03-17 | MSE Pharmazeutika GmbH | The use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
WO1998035658A2 (en) * | 1997-02-12 | 1998-08-20 | Mse Pharmazeutika Gmbh | The use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
US6228891B1 (en) | 1997-02-12 | 2001-05-08 | Mse Pharmazeutika Gmbh | Use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
EP1398026A3 (en) * | 1997-02-12 | 2004-06-02 | MSE Pharmazeutika GmbH | the use of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone |
EP0888774A2 (en) * | 1997-06-30 | 1999-01-07 | Soft Gel Technologies, Inc. | Soft gel Coenzyme Q10 formulation |
EP0888774A3 (en) * | 1997-06-30 | 1999-11-10 | Soft Gel Technologies, Inc. | Soft gel Coenzyme Q10 formulation |
EP1135100A1 (en) * | 1998-12-11 | 2001-09-26 | Q-Pharma, Inc. | Oral care compositions comprising coenzyme q 10? |
EP1135100A4 (en) * | 1998-12-11 | 2002-07-17 | Pharma Inc Q | Oral care compositions comprising coenzyme q 10? |
EP1084701A1 (en) * | 1999-09-15 | 2001-03-21 | Beiersdorf Aktiengesellschaft | O/W-emulsion comprising one or several bioquinones and an elevated amount of glycerine |
WO2002090304A1 (en) * | 2001-05-09 | 2002-11-14 | Kaneka Corporation | Stable solution of reduced coenzyme q |
US8961958B2 (en) | 2004-11-16 | 2015-02-24 | Bioavailability, Inc | High concentration self-microemulsifying coenzyme Q10 preparations for nutritional use |
Also Published As
Publication number | Publication date |
---|---|
IT8622844A1 (en) | 1988-06-23 |
JPS62158209A (en) | 1987-07-14 |
CH667387A5 (en) | 1988-10-14 |
GB8630158D0 (en) | 1987-01-28 |
FR2598320B1 (en) | 1990-11-02 |
GB2184355B (en) | 1990-03-28 |
BE906034A (en) | 1987-04-16 |
FR2598320A1 (en) | 1987-11-13 |
JPH0455404B2 (en) | 1992-09-03 |
DE3643330A1 (en) | 1987-06-25 |
IT8622844A0 (en) | 1986-12-23 |
IT1198247B (en) | 1988-12-21 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19931217 |