CA1185185A - STABLE INJECTABLE .beta.-CAROTENE MICELLAR SOLUTIONS AND THEIR PREPARATION - Google Patents
STABLE INJECTABLE .beta.-CAROTENE MICELLAR SOLUTIONS AND THEIR PREPARATIONInfo
- Publication number
- CA1185185A CA1185185A CA000391630A CA391630A CA1185185A CA 1185185 A CA1185185 A CA 1185185A CA 000391630 A CA000391630 A CA 000391630A CA 391630 A CA391630 A CA 391630A CA 1185185 A CA1185185 A CA 1185185A
- Authority
- CA
- Canada
- Prior art keywords
- carotene
- beta
- weight
- ionic emulsifier
- preparation
- 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.)
- Expired
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
Abstract
Abstract of the Disclosure: A process for the preparation of .beta.-carotene micellar solutions, wherein a non-ionic emul-sifier which is suitable for the preparation of micellar solutions is heated at from 160 to 180°C and a total of from 20 to 30% by weight, based on the emulsifier, of .beta.-carotene is introduced in the presence of a conventional anti-oxidant, the hot homogeneous mixture is cooled rapidly to below 100°C by adding water, and the formulation is brought to the desired concentration of from 3 to 6% by weight by adding further water, and the .beta.-carotene micellar solutions obtained by this process. The non-ionic emulsifiers used in this process have an HLB value of from 12 to 16, and are in particular oxyethylated triglycerides of fatty acids of 12 to 18 carbon atoms con-taining 20 - 60 oxyethylene units. Parenteral adminis-tration of the stable .beta.-carotene micellar solutions according to the invention to cattle relieves the disturbed estrus cycle and impaired fertility caused by .beta.-carotene deficiency.
Description
-- 1 -- O . Z ~ 0050/034833 Stable injectable ~carotene micellar solutions and their preparation The present invention relates to stable injectable micellar solutions of ~-carotene and a process for their preparation.
~ -Carotene has the chemical -~ormula:
~CH=CH-C-CH ~ C~~CX ~ C~=C~CH-CH ~
Studies by Lotthammer (cf. Dtsch. Tier~rtz].
Wschr. 82 (1975), 444-49; 83 (1976), 353-58; 84 (1977), 220-26 and 307-310; and 85, (1978~, 7-12) have shown that ~-carotene deficiency in cattle causes a disturbed estrus cycle and poor fertility. A lo~ ~carotene blood level characterizes thedeficiency.
~-Carotene deficiency has hitherto been treated by feeding animals with carotene-rich straight fodder, such as lucerne green meal, grass green meal or carrots, and/or dry synthetic ~-carotene powder. However, oral adminis-tration of ~-carotene has little effect on its leveL in blood, because absorption of ~carotene from the in-tes-tinal tract is poor.
In contrast, the blood level can be increased rapidly and over a relatively long period by paren-teral administration of ~-carotene.
For such administration, the formulations to be injected should have a relatively hig`n content of~-carotene in extremely finely divided form, so that the ~olume -to ~ 2 - O.Z. 0050/03~i833 be injected is kept to a minimum.
In the case of animals which have a relatively low level of ~-carotene in the blood plasma, it is not possible to increase this level rapidly (within two days) and economically by a gastroenteral route, so that -the carotene must be administered parenterally.
However9 conventional solutions of ~carotene in vegetable oils contain not more than 0.3 - 0.5% (UllmannS
Enzyklop~die der technischen Chemie, Volume 11 (1976), page 106)~ and such concentrations are -too low if the required dose of 500 mg of 3-carotene is to be administered in the usual injection volume of 10-20 ml.
Japanese Preliminary Published Application 38,556/1970 discloses that carotenoid compounds can be - converted into wa-ter-soluble carotenoid preparations by dissolving them together with aliphatic esters of sugars, heating the solution and removing the solvent. How-ever, the solutions of ~-carotene which can be prepared in this manner are of only about 0. 2% strength.
5erman Published Application DAS 1,210,127 dis-closes carotene emulsions containing polyoxyethylated castor oil or polyoxyethylerle sorbitan fatty acid es-ters as emulsifiers,together with ionic wetting agents. However, these emulsions are not stable for a prolonged period, since the carotene crystallizes out.
German Laid-Open Application DOS 2, 236, 899 there-~ore proposes the preparation of more highly concentrated emulsions using special soaps, namely soaps of tris-(hydroxymethyl)-aminomethane and saturated or unsaturated fatty acids of 9 -to 20 carbon atoms. However, the method proposed in that Application is not sa-tisEactory, since, on the one hand the procedure presents difficulties in practice, and on -the o-ther hand only water-miscible carotenoid emulsions containing not more -than ~% of ~-carotene can be prepared.
It is an ob~ect of the present invention to prepare rela-tively highly concentrated clear stable emulsions or micel]ar solutions of ~-carotene We have found that this object is achieved by a process for the preparation o ~-caro-tene micellar solutions wherein a non-ionic emulsifier which is suitable for the preparation of micellar solutions and has an HLB
value of Erom 12 to 16, is heated at Erom 160 -to 180C and a total of from 20 to 30% by weight, based on the emulsifier, of ~-carotene is introduced in the presence of a conventional antioxidant, the hot homogeneous mix-ture is cooled rapidly to below 100C by adding water, and -the formulation is brought to the desired concentra-tion oE from 3 to 6~ by weight by adding further water, and by the stable injectable 3-carotene micellar solutions ob-tainable by this process.
It is surprising that not just a milky -turbid ~-carotene emulsion but a transparent ~-caro-tene micellar solution containing up to 6% by weight of ~-carotene can be obtained in the manner described.
Non-ionic emulsifiers which are suitable for the preparation of micellar solutions are -those having an HLB
value (cf. H.P. Fiedler, Lexikon der Pharmazie, Kosmetik und angrenzenden Gebiete, 1971, pages 263-270, especially ., ~ ~s~
- ~ - O.Z. 0050/034833 pages 267-69) of from 12 to 16, especially oxyethylated triglycerides of fatty acids of 12 to 18 carbon a-toms con taining 20 - 60 oxyethylene units, oxyethylated sorbitan fatty acid esters having about 20 oxyethylene units, or oxyethylated monohydroxy-fatty acids having from 14 to 17 oxyethylene units 9 such as are disclosed in German Laid-Open Application DOS 2,911,241. Such emulsifiers are also called solubiliz~rs, because they are soluble in water and thereby act as solubilizing agents for lipophilic substances by keeping these in micellar solution.
Micellar solutions are transparent and clear.
Examples of particularly suitable non-ionic emul-sifiers are: glycerol polyoxyethylene glycol ricinoleate, glycerol polyoxyethylene glycol hydroxystearate, polyoxy-ethylene-20 sorbitan monooleate, polyoxyethylene-20 sorbitan monostearate and the adduct monohydroxystearic acid with 15 units of ethylene oxide.
Specifically, the micellar solutions are prepared by adding from 20 to 30% by weight, based on the emulsifier, of ~-carotene a little at a time to the emulsifier, which is heated at from 160 to 180C and contains conventional antioxidants, whereupon the ~carotene melts and dissolves virtually immediately. The mixture is rapidly brough-t to below 100C by adding water, and the formulation is then brought to the desired concentration by adding further water. After filtration and cooling to room tempera-ture, a stable 4-6% preferably about 5%, strength by weight transparent micellar solution is obtained, which is still stable after 12 months.
- 5 - O.Z. 0050/034833 Examples of conventional antioxidants which can be used in the process according to the invention are butylhydroxytoluene, butylhydroxyanisole and d,1-a -tocopherol. The antioxidants are generally used in amounts of from 10 ko 20% by weight, based on the ~carotene employed.
According to the examples in German Laid-Open Application DOS 2,236,899, temperatures above 110C are to be avoided when the ~-carotene is introduced into the emulsifier. This requirement is understandable to those skilled in the art, since at higher temperatures isomerization of ~-carotene is to be feared.
It is therefore surprising that the procedure according to the invention gives a micellar solution which is sufficiently concentrated for injection purposes and which displays its full action in animals even though some o~
the ~-carotene has probably been isomerized.
EXAMPLE
300 g of Chromophor EL ~ (glycerol polyoxyethylene glycol ricinoleate) and 6 g of butylhydroxytoluene are introduced into a 2 1 4-necked round-bottomed flaslc f:i-tted with a stirrer, nitrogen inlet and reflux condenser. The mix--ture is heated to an internal temperature of 160C, whilst being s-tirred and gassed wi-th nitrogen. 66 g of ~carotene are added in the course of about 5 minutesO The heating bath is removed and water is added dropwise until the internal temperature of the mixture has ~allen to 100C.
The mixture is brought to 60 - 80C by rapid addition of the remainder of the water (total amount: 828 g) and - 6 - O.Z. 0050/034833 by using the heating bath. The still warm micellar solution is filtered through a glass filter frit to give an abou-t 5% strength -transparent ~-carotene solution which can be used as an injection solution.
ANIMAL EXPERIMENTS
3 experimental groups (Friesian heifers) were com-pared. They were treated as follows:
Group 1 received 10 ml of an aqueous ~-carotene micellar solution according to the invention, containing ~50 mg of ~-carotene, intramuscularly.
Group 2 received an intr~nuscular injection of an oily carotene solution containing 450 mg of ~caroteneO
Group 3 received no ~-carotene injection.
The average plasma levels of ~-caro-tene (~g/100 ml) in the test animals were measured before the treatment and 1, 2, 4 and 32 days after the treatment~
Group Average plasma ~-carotene level (~g/100 ml) _ ~ ~ay 0 Day 1 Day 2 Day 4 Day 32 1 230 1,5471 9 705 1,214 369
~ -Carotene has the chemical -~ormula:
~CH=CH-C-CH ~ C~~CX ~ C~=C~CH-CH ~
Studies by Lotthammer (cf. Dtsch. Tier~rtz].
Wschr. 82 (1975), 444-49; 83 (1976), 353-58; 84 (1977), 220-26 and 307-310; and 85, (1978~, 7-12) have shown that ~-carotene deficiency in cattle causes a disturbed estrus cycle and poor fertility. A lo~ ~carotene blood level characterizes thedeficiency.
~-Carotene deficiency has hitherto been treated by feeding animals with carotene-rich straight fodder, such as lucerne green meal, grass green meal or carrots, and/or dry synthetic ~-carotene powder. However, oral adminis-tration of ~-carotene has little effect on its leveL in blood, because absorption of ~carotene from the in-tes-tinal tract is poor.
In contrast, the blood level can be increased rapidly and over a relatively long period by paren-teral administration of ~-carotene.
For such administration, the formulations to be injected should have a relatively hig`n content of~-carotene in extremely finely divided form, so that the ~olume -to ~ 2 - O.Z. 0050/03~i833 be injected is kept to a minimum.
In the case of animals which have a relatively low level of ~-carotene in the blood plasma, it is not possible to increase this level rapidly (within two days) and economically by a gastroenteral route, so that -the carotene must be administered parenterally.
However9 conventional solutions of ~carotene in vegetable oils contain not more than 0.3 - 0.5% (UllmannS
Enzyklop~die der technischen Chemie, Volume 11 (1976), page 106)~ and such concentrations are -too low if the required dose of 500 mg of 3-carotene is to be administered in the usual injection volume of 10-20 ml.
Japanese Preliminary Published Application 38,556/1970 discloses that carotenoid compounds can be - converted into wa-ter-soluble carotenoid preparations by dissolving them together with aliphatic esters of sugars, heating the solution and removing the solvent. How-ever, the solutions of ~-carotene which can be prepared in this manner are of only about 0. 2% strength.
5erman Published Application DAS 1,210,127 dis-closes carotene emulsions containing polyoxyethylated castor oil or polyoxyethylerle sorbitan fatty acid es-ters as emulsifiers,together with ionic wetting agents. However, these emulsions are not stable for a prolonged period, since the carotene crystallizes out.
German Laid-Open Application DOS 2, 236, 899 there-~ore proposes the preparation of more highly concentrated emulsions using special soaps, namely soaps of tris-(hydroxymethyl)-aminomethane and saturated or unsaturated fatty acids of 9 -to 20 carbon atoms. However, the method proposed in that Application is not sa-tisEactory, since, on the one hand the procedure presents difficulties in practice, and on -the o-ther hand only water-miscible carotenoid emulsions containing not more -than ~% of ~-carotene can be prepared.
It is an ob~ect of the present invention to prepare rela-tively highly concentrated clear stable emulsions or micel]ar solutions of ~-carotene We have found that this object is achieved by a process for the preparation o ~-caro-tene micellar solutions wherein a non-ionic emulsifier which is suitable for the preparation of micellar solutions and has an HLB
value of Erom 12 to 16, is heated at Erom 160 -to 180C and a total of from 20 to 30% by weight, based on the emulsifier, of ~-carotene is introduced in the presence of a conventional antioxidant, the hot homogeneous mix-ture is cooled rapidly to below 100C by adding water, and -the formulation is brought to the desired concentra-tion oE from 3 to 6~ by weight by adding further water, and by the stable injectable 3-carotene micellar solutions ob-tainable by this process.
It is surprising that not just a milky -turbid ~-carotene emulsion but a transparent ~-caro-tene micellar solution containing up to 6% by weight of ~-carotene can be obtained in the manner described.
Non-ionic emulsifiers which are suitable for the preparation of micellar solutions are -those having an HLB
value (cf. H.P. Fiedler, Lexikon der Pharmazie, Kosmetik und angrenzenden Gebiete, 1971, pages 263-270, especially ., ~ ~s~
- ~ - O.Z. 0050/034833 pages 267-69) of from 12 to 16, especially oxyethylated triglycerides of fatty acids of 12 to 18 carbon a-toms con taining 20 - 60 oxyethylene units, oxyethylated sorbitan fatty acid esters having about 20 oxyethylene units, or oxyethylated monohydroxy-fatty acids having from 14 to 17 oxyethylene units 9 such as are disclosed in German Laid-Open Application DOS 2,911,241. Such emulsifiers are also called solubiliz~rs, because they are soluble in water and thereby act as solubilizing agents for lipophilic substances by keeping these in micellar solution.
Micellar solutions are transparent and clear.
Examples of particularly suitable non-ionic emul-sifiers are: glycerol polyoxyethylene glycol ricinoleate, glycerol polyoxyethylene glycol hydroxystearate, polyoxy-ethylene-20 sorbitan monooleate, polyoxyethylene-20 sorbitan monostearate and the adduct monohydroxystearic acid with 15 units of ethylene oxide.
Specifically, the micellar solutions are prepared by adding from 20 to 30% by weight, based on the emulsifier, of ~-carotene a little at a time to the emulsifier, which is heated at from 160 to 180C and contains conventional antioxidants, whereupon the ~carotene melts and dissolves virtually immediately. The mixture is rapidly brough-t to below 100C by adding water, and the formulation is then brought to the desired concentration by adding further water. After filtration and cooling to room tempera-ture, a stable 4-6% preferably about 5%, strength by weight transparent micellar solution is obtained, which is still stable after 12 months.
- 5 - O.Z. 0050/034833 Examples of conventional antioxidants which can be used in the process according to the invention are butylhydroxytoluene, butylhydroxyanisole and d,1-a -tocopherol. The antioxidants are generally used in amounts of from 10 ko 20% by weight, based on the ~carotene employed.
According to the examples in German Laid-Open Application DOS 2,236,899, temperatures above 110C are to be avoided when the ~-carotene is introduced into the emulsifier. This requirement is understandable to those skilled in the art, since at higher temperatures isomerization of ~-carotene is to be feared.
It is therefore surprising that the procedure according to the invention gives a micellar solution which is sufficiently concentrated for injection purposes and which displays its full action in animals even though some o~
the ~-carotene has probably been isomerized.
EXAMPLE
300 g of Chromophor EL ~ (glycerol polyoxyethylene glycol ricinoleate) and 6 g of butylhydroxytoluene are introduced into a 2 1 4-necked round-bottomed flaslc f:i-tted with a stirrer, nitrogen inlet and reflux condenser. The mix--ture is heated to an internal temperature of 160C, whilst being s-tirred and gassed wi-th nitrogen. 66 g of ~carotene are added in the course of about 5 minutesO The heating bath is removed and water is added dropwise until the internal temperature of the mixture has ~allen to 100C.
The mixture is brought to 60 - 80C by rapid addition of the remainder of the water (total amount: 828 g) and - 6 - O.Z. 0050/034833 by using the heating bath. The still warm micellar solution is filtered through a glass filter frit to give an abou-t 5% strength -transparent ~-carotene solution which can be used as an injection solution.
ANIMAL EXPERIMENTS
3 experimental groups (Friesian heifers) were com-pared. They were treated as follows:
Group 1 received 10 ml of an aqueous ~-carotene micellar solution according to the invention, containing ~50 mg of ~-carotene, intramuscularly.
Group 2 received an intr~nuscular injection of an oily carotene solution containing 450 mg of ~caroteneO
Group 3 received no ~-carotene injection.
The average plasma levels of ~-caro-tene (~g/100 ml) in the test animals were measured before the treatment and 1, 2, 4 and 32 days after the treatment~
Group Average plasma ~-carotene level (~g/100 ml) _ ~ ~ay 0 Day 1 Day 2 Day 4 Day 32 1 230 1,5471 9 705 1,214 369
2 221 288 371 355 232
3 182 183 191 204 207 As can be seen from the experiment, when the aqueous ~-carotene injection preparation was administered, the blood level was at all times signi ican-tly higher -than when the comparative product was administered. It is thus possible to eliminate ~ carotene deficiency for more than 1 month with a single injection and to ensure a physiological estrus cycle.
Claims (10)
1. A process for the preparation of .beta.-carotene micellar solution, wherein a non-ionic emulsifier which is suitable for the preparation of micellar solutions and has an HLB value of from 12 to 16 is heated at from 160 to 180°C
and a total of from 20 to 30% by weight, based on the emulsifier, of .beta.-carotene is introduced in the presence of a conventional antioxidant, the hot homogeneous mixture is cooled rapidly to below 100°C by adding water, and the formulation is brought to the desired concentration of from 3 to 6% by weight by adding further water.
and a total of from 20 to 30% by weight, based on the emulsifier, of .beta.-carotene is introduced in the presence of a conventional antioxidant, the hot homogeneous mixture is cooled rapidly to below 100°C by adding water, and the formulation is brought to the desired concentration of from 3 to 6% by weight by adding further water.
2. A process as claimed in claim 1, wherein an oxy-ethylated triglyceride of a fatty acid of 12 to 18 carbon atoms containing 20 - 60 oxyethylene units is used as the non-ionic emulsifier.
3. A process as claimed in claim 1, wherein glycerol polyoxyethylene glycol ricinoleate is used as the non-ionic emulsifier.
4. A process as claimed in claim 1, wherein glycerol polyoxyethylene glycol hydroxystearate is used as the non-ionic emulsifier.
5. A process as claimed in claim 1, wherein a poly-oxyethylated sorbitan fatty acid ester is used as the non-ionic emulsifier.
6. A process as claimed in claim 1, wherein poly-oxyethylene-20 sorbitan monooleate is used as the non-ionic emulsifier.
7. A process as claimed in claim 1, wherein poly-oxyethylene-20 sorbitan monostearate is used as the non-ionic emulsifier.
8. A process as claimed in claim 1, wherein the adduct of monohydroxystearic acid with 15 units of ethylene oxide is used as the non-ionic emulsifier.
9. A process as claimed in claim 1, wherein from 10 to 20% by weight, based on the .beta.-carotene, of butylhydroxy-toluene, butylhydroxyanisole or d,l-.alpha.-tocopherol is used as the antioxidant.
10. A stable aqueous injection solution which contains from 3 to 6% by weight of .beta.-carotene and can be obtained by introducing into a non-ionic emulsifier having an HLB value of from 12 to 16, which is suitable for the preparation of a micellar solution and is heated at from 160 to 180°C a total of from 20 to 30% by weight, based on the emulsifier, of .beta.-carotene, rapidly cooling the resulting hot homogeneous mixture to below 100°C by adding water and bringing the formula-tion to the desired final concentration of from 3 to 6% by weight by adding further water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3048000.3 | 1980-12-19 | ||
| DE19803048000 DE3048000A1 (en) | 1980-12-19 | 1980-12-19 | STABLE INJECTABLE (BETA) CAROTINE SOLUBILISATES AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1185185A true CA1185185A (en) | 1985-04-09 |
Family
ID=6119676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000391630A Expired CA1185185A (en) | 1980-12-19 | 1981-12-07 | STABLE INJECTABLE .beta.-CAROTENE MICELLAR SOLUTIONS AND THEIR PREPARATION |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4435427A (en) |
| EP (1) | EP0055817B1 (en) |
| CA (1) | CA1185185A (en) |
| CS (1) | CS228528B2 (en) |
| DE (2) | DE3048000A1 (en) |
| ES (1) | ES8300472A1 (en) |
| HU (1) | HU185159B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3048000A1 (en) * | 1980-12-19 | 1982-07-15 | Basf Ag | STABLE INJECTABLE (BETA) CAROTINE SOLUBILISATES AND METHOD FOR THE PRODUCTION THEREOF |
| US4680314A (en) * | 1985-08-30 | 1987-07-14 | Microbio Resources, Inc. | Process for producing a naturally-derived carotene/oil composition by direct extraction from algae |
| DE4031094A1 (en) * | 1990-10-02 | 1992-04-09 | Basf Ag | METHOD FOR PRODUCING STABLE INJECTABLE (BETA) CAROTINE SOLUBILISATES |
| GB9219524D0 (en) * | 1992-09-15 | 1992-10-28 | Smithkline Beecham Plc | Novel composition |
| US5260340A (en) * | 1992-11-19 | 1993-11-09 | Baranowitz Steven A | Prevention and amelioration of acetaminophen toxicity with beta-carotene |
| DE19609538A1 (en) * | 1996-03-11 | 1997-09-18 | Basf Ag | Finely divided carotenoid and retinoid suspensions and process for their preparation |
| US5686488A (en) * | 1995-08-25 | 1997-11-11 | Alcon Laboratories, Inc. | Polyethoxylated castor oil products as anti-inflammatory agents |
| DE19609477A1 (en) * | 1996-03-11 | 1997-09-18 | Basf Ag | Stable aqueous solubilisates of carotenoids and vitamins |
| DE19609476A1 (en) * | 1996-03-11 | 1997-09-18 | Basf Ag | Stable parenteral administration suitable carotenoid emulsions |
| ATE262316T1 (en) * | 1996-05-14 | 2004-04-15 | Dsm Ip Assets Bv | PRODUCTION PROCESS FOR CAROTENOID COMPOSITIONS |
| DE19653410A1 (en) | 1996-12-20 | 1998-06-25 | Basf Ag | Use of carotenoid solubilisates for coloring food and pharmaceutical preparations |
| US6007856A (en) * | 1997-08-08 | 1999-12-28 | The Procter & Gamble Company | Oil-in-water dispersions of β-carotene and other carotenoids stable against oxidation prepared from water-dispersible beadlets having high concentrations of carotenoid |
| DE19831865A1 (en) | 1998-07-16 | 2000-01-20 | Basf Ag | Use of organic sulfur compounds as a means for bathochromic shifting of the UV / Vis absorption band of carotenoids |
| DE19838636A1 (en) | 1998-08-26 | 2000-03-02 | Basf Ag | Carotenoid formulations containing a mixture of beta-carotene, lycopene and lutein |
| AT408186B (en) * | 1998-12-15 | 2001-09-25 | Sanochemia Pharmazeutika Ag | AQUEOUS PREPARATION OF BETA CAROTINE |
| WO2002085328A2 (en) * | 2001-02-11 | 2002-10-31 | Aquanova German Solubilisate Technologies (Agt) Gmbh | Method for producing an active ingredient concentrate, and an active ingredient concentrate |
| US20050059635A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling C-reactive protein levels |
| US7375133B2 (en) * | 2002-07-29 | 2008-05-20 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
| US7521584B2 (en) * | 2002-07-29 | 2009-04-21 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of disease |
| US20050148517A1 (en) * | 2002-07-29 | 2005-07-07 | Lockwood Samuel F. | Carotenoid ether analogs or derivatives for controlling connexin 43 expression |
| US20050026874A1 (en) * | 2002-07-29 | 2005-02-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for the inhibition and amelioration of liver disease |
| US7145025B2 (en) * | 2002-07-29 | 2006-12-05 | Hawaii Biotech, Inc. | Structural carotenoid analogs for the inhibition and amelioration of disease |
| US7723327B2 (en) * | 2002-07-29 | 2010-05-25 | Cardax Pharmaceuticals, Inc. | Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease |
| US20050004235A1 (en) * | 2002-07-29 | 2005-01-06 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for the inhibition and amelioration of liver disease |
| US20050009788A1 (en) * | 2002-07-29 | 2005-01-13 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling connexin 43 expression |
| US7763649B2 (en) * | 2002-07-29 | 2010-07-27 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for controlling connexin 43 expression |
| US20050143475A1 (en) * | 2002-07-29 | 2005-06-30 | Lockwood Samuel F. | Carotenoid analogs or derivatives for the inhibition and amelioration of ischemic reperfusion injury |
| US20050049248A1 (en) * | 2002-07-29 | 2005-03-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for controlling C-reactive protein levels |
| US7345091B2 (en) * | 2002-07-29 | 2008-03-18 | Cardax Pharmaceuticals, Inc. | Carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
| US20050059659A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for controlling C-reactive protein levels |
| US7320997B2 (en) * | 2002-07-29 | 2008-01-22 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ester analogs or derivatives for the inhibition and amelioration of disease |
| US20060058269A1 (en) * | 2004-04-14 | 2006-03-16 | Lockwood Samuel F | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
| EP1750723A1 (en) * | 2004-04-14 | 2007-02-14 | Hawaii Biotech, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
| US20060183185A1 (en) * | 2004-10-01 | 2006-08-17 | Lockwood Samuel F | Method for the synthesis of astaxanthin |
| DE102005032352A1 (en) * | 2005-07-08 | 2007-01-11 | Aquanova German Solubilisate Technologies (Agt) Gmbh | Solubilizer for an active ingredient concentrate in the food industry comprises a St. John's wort extract, a roseda extract or a tarragon extract, a polysorbate emulsifier and water |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2417299A (en) * | 1943-08-06 | 1947-03-11 | Us Vitamin Corp | Fat-soluble vitamin solutions |
| US2518230A (en) * | 1947-11-15 | 1950-08-08 | Us Vitamin Corp | Aqueous solutions of lipoid-soluble vitamins |
| US2524247A (en) * | 1948-07-10 | 1950-10-03 | Hoffmann La Roche | Aqueous solutions of lipoid-soluble vitamins |
| DE970772C (en) * | 1951-06-05 | 1958-10-30 | Wander Ag Dr A | Process for the production of aqueous, in particular concentrated aqueous solutions of vitamins D and / or D. |
| CH437995A (en) * | 1963-11-01 | 1967-06-15 | Hoffmann La Roche | Process for the production of preparations containing lipophilic substances |
| DE2236899A1 (en) * | 1972-07-27 | 1974-02-07 | Philips Patentverwaltung | Water-miscible carotenoid emulsions - contg tris(hydroxymethyl) amino methane soaps as emulsifiers |
| US3998753A (en) | 1974-08-13 | 1976-12-21 | Hoffmann-La Roche Inc. | Water dispersible carotenoid preparations and processes thereof |
| DE2526938C2 (en) * | 1975-02-14 | 1982-04-22 | F. Hoffmann-La Roche & Co. AG, 4002 Basel | Vitamin preparations |
| DE3048000A1 (en) * | 1980-12-19 | 1982-07-15 | Basf Ag | STABLE INJECTABLE (BETA) CAROTINE SOLUBILISATES AND METHOD FOR THE PRODUCTION THEREOF |
-
1980
- 1980-12-19 DE DE19803048000 patent/DE3048000A1/en not_active Withdrawn
-
1981
- 1981-10-29 EP EP81109220A patent/EP0055817B1/en not_active Expired
- 1981-10-29 DE DE8181109220T patent/DE3175119D1/en not_active Expired
- 1981-12-07 CA CA000391630A patent/CA1185185A/en not_active Expired
- 1981-12-09 US US06/329,124 patent/US4435427A/en not_active Expired - Lifetime
- 1981-12-18 CS CS819510A patent/CS228528B2/en unknown
- 1981-12-18 ES ES508145A patent/ES8300472A1/en not_active Expired
- 1981-12-18 HU HU813873A patent/HU185159B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0055817A3 (en) | 1983-03-30 |
| ES508145A0 (en) | 1982-11-01 |
| DE3175119D1 (en) | 1986-09-18 |
| DE3048000A1 (en) | 1982-07-15 |
| HU185159B (en) | 1984-12-28 |
| US4435427A (en) | 1984-03-06 |
| EP0055817B1 (en) | 1986-08-13 |
| CS228528B2 (en) | 1984-05-14 |
| ES8300472A1 (en) | 1982-11-01 |
| EP0055817A2 (en) | 1982-07-14 |
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