CA2455226C - Compositions comprising an o/w emulsion containing conjugated linoleic acid - Google Patents
Compositions comprising an o/w emulsion containing conjugated linoleic acid Download PDFInfo
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- CA2455226C CA2455226C CA2455226A CA2455226A CA2455226C CA 2455226 C CA2455226 C CA 2455226C CA 2455226 A CA2455226 A CA 2455226A CA 2455226 A CA2455226 A CA 2455226A CA 2455226 C CA2455226 C CA 2455226C
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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Abstract
The present invention provides a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the parenteral administration of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Description
The present invention relates to pharmaceutical compositions comprising aqueous emulsions of conjugated linoleic acid (CLA), in particular compositions comprising a lipophilic drug disposed in the discontinuous oil phase of such emulsions.
Amphotericin B is commonly prescribed as an antifungal agent for intravenous administration to patients with systemic fungal infection, generally patients with reduced immune function such as AIDS
patients and elderly patients. Amphotericin B however is not water-soluble and hence it cannot be administered as an aqueous solution, the preferred administration format for intravenously administered drugs. Liposomal formulations of amphotericin B have been proposed;
however these are expensive and their production is not straightforward. Accordingly, one of the most popular ways for administering amphotericin B is by mixing with a dose of Intralipid and administering the mixture by infusion.
Intralipid is an aqueous emulsion of triglycerides, more specifically soya bean oil, which is normally used for parenteral nutrition for patients unable to take food, or sufficient food, orally. Standard dosages of Intralipid, which are given by intravenous infusion, are of the order of 500 mL of an emulsion containing 200 mg/mL of triglyceride. Such a dose involves the administration into the patient of a large quantity of saturated fat, and for the patients receiving amphotericin B this raises the risk of provoking undesirably high blood cholesterol levels.
CLA, also known as octadecadienoic acid, is a collective name for positional and geometric isomers of linoleic acid with conjugated double bonds at carbon atoms 10 and 12 or 9 and 11 in the various cis-trans configurations, i.e. cis-9, trans-11; cis-9, cis-11;
trans-9, cis-11; trans-9, trans-11; cis-10, trans-12;
cis-10, cis-12; trans-10, cis-12; and trans-10, trans-12. CLA thus differs from ordinary linoleic acid which has double bonds at carbon atoms 9 and 12.
CLA has several unique properties, one of which is the ability to reduce the percentage of fat relative to total body mass when administered orally as a nutritional supplement. CLA is available commercially as a liquid oil from Natural ASA, Oslo, Norway under the trade name Tonalin.
We have f'ound that aqueous suspensions/formulations of CLA can be used as a carrier for intravenously administered lipophilic drugs (such as amphotericin B) thereby avoiding the need for liposomal formulation and avoiding the undesirable exposure to high levels of saturated fatty acid triglycerides which is the consequence of formulation with Intralipid.
Thus viewed from one aspect the present invention provides a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the parenteral administration of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a further aspect the invention provides a pharmaceutical composition comprising an oil-in-water emulsion containing a lipophilic pharmaceutical agent and a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a still further aspect the invention provides the use of a conjugated linoleic acid or a physiologically tolerable derivative thereof for the manufacture of a medicament comprising an oil-in-water emulsion containing a lipophilic pharmaceutical agent and said conjugated linoleic acid or derivative thereof for use in a method of treatment involving administration of said medicament to a human or non-human (e.g. mammalian, reptilian or avian) animal subject.
Viewed from a yet further aspect the invention provides a conjugated linoleic acid or a physiologically tolerable derivative thereof for use in a method of medical treatment involving administration, particularly parenteral administration, of an oil-in-water emulsion containing said conjugated linoleic acid or derivative thereof to a human or non-human (e.g. mammalian, reptilian or avian) animal subject.
Viewed from a yet still further aspect the invention provides the use of an oil-in-water emulsion of a conjugated linoleic acid or a physiologically tolerable derivative thereof in the preparation of a medicament comprising an oil-in-water emulsion containing said conjugated linoleic acid or derivative thereof and a lipophilic pharmaceutical agent.
According to one aspect of the present invention, there is provided use of a conjugated linoleic acid in preparation of a pharmaceutical composition for parenteral administration of a lipophilic pharmaceutical agent in an oil-in-water emulsion to an animal in need thereof, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
According to another aspect of the present invention, there is provided a pharmaceutical composition in the form of a oil-in-water emulsion comprising a lipophilic pharmaceutical agent and a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of - 3a -the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporin.
According to yet another aspect of the present invention, there is provided a kit comprising a first container containing a sterile aqueous medium; a second container containing a limonitic pharmaceutical agent and a conjugated linoleic acid in the form of a oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dilution or emulsification of contents of the second container with contents of the first container.
According to still another aspect of the present invention, there is provided a kit comprising a first container containing a lipophilic pharmaceutical agent; a second container containing an oil-in-water emulsion comprising a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dispersion of contents of the first container in contents of the second container.
According to a further aspect of the present invention, there is provided use of a conjugated linoleic acid in preparation of a pharmaceutical composition for administration into a body cavity of animal in need thereof, wherein the body cavity is externally opening or which has an externally opening duct, of a lipophilic pharmaceutical - 3b -agent in an oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
As used herein the term "lipophilic pharmaceutical agent" means a lipophilic compound or compound mixture which is capable of exerting a medically desired therapeutic, diagnostic or prophylactic effect, especially a therapeutic or prophylactic effect, on administration to a subject.
Generally this will not be a CLA or a CLA derivative;
however the term does cover CLA derivatives which are conjugates of CLA and a drug compound.
While amphotericin B is a preferred pharmaceutical agent for use according to the invention, other lipophilic agents may be used, e.g. taxol, taxoteres, griseofulvin, steroids (e.g. hydrocortisone), cyclosporine, lipid soluble vitamins (e.g. vitamin D3), HIV protease inhibitors, etc.
Indeed, while the emphasis had earlier been on water-soluble drug compounds, lipid-soluble drug compounds are nowadays becoming more attractive to pharmaceutical companies in their current drug discovery procedures.
The CLA used according to the invention may be a single compound or a mixture of two or more of the eight different CLA isomers. Generally it will be preferred to use the cis-9, trans-11 and trans-10, cis-12 isomers, on their own, in admixture or together with minor proportions (i.e., less than 500-k by weight relative to total CLA) of one or more of the other isomers.
Examples of CLA derivatives usable according to the invention include salts, esters (e.g. single, double or multiple esters, in particular di- and triglycerides), amides, etc.
The CLA used is preferably at least 80o wt, more preferably at least 90g wt, cis-9, trans-il and/or trans-10, cis-12, preferably in a weight ratio of 2:98 to 98:2. For elderly patients and reduced immune function patients, the CLA is preferably at least 500 wt, more preferably at least 80% wt cis-9, trans-11.
For diabetic patients or patients who are obese, who have or are at risk of cardiovascular disease or who have elevated blood cholesterol levels, the CLA is preferably at least 50% wt, more preferably at least 800 wt, trans-10, cis-12.
The preparation of CLA is described for example in US-A-6060514 and the references cited therein.
Tne emulsions used according to the invention are referred to as oil-in-water emulsions. By this it is meant that they contain a continuous aqueous phase and a discontinuous lipophilic phase, i.e. a CLA or CLA
derivative phase. The oil droplets are preferably of micrometer size or smaller, e.g. with mode droplet diameters in the range 50 to 100000 nm, preferably 100 to 50000 nm, especially 160 to 6000 nm, more especially 500 to 6000 nm.
The emulsions of the invention are preferably sterile and pyrogen-free. Sterile emulsions may be prepared using sterile components under sterile conditions. Alternatively the oil phase may be prepared, sterilized, then emulsified under sterile conditions with a sterile aqueous phase. As a further alternative, the emulsion may be produced and then sterilized, e.g. by heat treatment (e.g. autoclaving), by irradiation (e.g. Y-irradiation) or, where the oil droplet size is small, by sterile filtration.
The emulsions of the invention may contain further components, e.g. stabilizers, antioxidants, viscosity modifiers, vitamins, minerals, pH adjusting agents, plasma anions (e . g. Na+, Caz+, K+, especially Na+ and Caz+, optionally deriving from their chloride salts), emulsifiers, etc.
The emulsions of the invention can be administered topically and in such cases it is preferable that the emulsion is formulated into a cream for convenient topical administration.
Examples of antioxidants that may be used include EDTA, vitamin C, vitamin E, cyclodextrins and (3- and Y-derivative thereof, and a-tocopherols and derivatives thereof, e.g. salts, esters, etc. Antioxidants are preferably present in the emulsions of the invention, e.g. in amounts of 0.01 to 0.5% wt relative to total emulsion weight. The antioxidants can be added to the oil and/or water phases or to the emulsion. The use of antioxidants extends the shelf life of the emulsion product.
Where the emulsion is to be administered parenterally, it preferably has an aqueous phase which has a tonicity which is within 20% of isotonicity, more preferably within 100 of isotonicity, especially within 2% of isotonicity. Isotonicity in this regard may be taken to be 300 mOsm/kg for human subjects. This may be achieved particularly conveniently by use of physiologically tolerable salts (e.g. chloride salts) of plasma anions such as Na', Ca2 and K. Sodium salts and combinations of sodium and calcium salts are preferred;
however non-ionic agents such as glycerol or sugars may be used to increase tonicity. Formulation in this manner has a cardioprotective effect which is especially important for aged or reduced immune function patients.
Examples of emulsifying agents that may be used in the compositions.of the invention include amphiphilic compounds such as phospholipids (e.g. lecithin), polyoxyethylene sorbates (Tweens), sorbitan carboxylic acid esters (Spans), polyalkyleneoxides (e.g. PEGs and Pluronics).
Such emulsifiers are preferably used in the preparation of the emulsions of the invention and desirably are present in the emulsions in amounts of 0.02 to 10o wt relative to total emulsion weight.
pH modifying agents may be included in the compositions if this does not prejudice the stability of the pharmaceutical agent. Generally the aqueous phase of the emulsions should have a pH in the range 4.5 to 7.5, especially 5.5. to 7Ø
The emulsions of the invention preferably contain 5 to 300 mg/mL of CLA or CLA derivative, e.g. 50 to 250 mg/mL, especially 100 to 200 mg/mL and preferably have viscosities at 20 C of 100 mPas or less. However, the emulsions may be prepared in concentrate, rather than ready-to-use, form and thus may contain for example up to 400 mg/mL CLA or CLA derivative.
The CLA or CLA derivative preferably forms the major proportion, i.e. at least 50% wt, of the oil phase in the emulsions. Particularly preferably it forms at least 70% wt, more especially at least 90% wt of the oil phase. Minor components of the oil phase may include for example the pharmaceutical agent, nutraceuticals, functional foods, antioxidants, vitamins, etc. as well as physiologically tolerable fatty acids (e.g. w-3 acids), and mono-, di- and triglycerides. In general, each such component will generally be present as no more than 30a wt of the oil phase, e.g. 0.05 to 25% wt, preferably 0.1 to 10o wt, and the sum of such components will generally be less than 50% wt, more preferably less than about 30% wt, especially less than 10% wt of the oil phase.
The required dosage of the emulsions of the invention will vary according to the nature and concentration of the pharmaceutical agent; however dosages of between 0.5 mL and 500 mL, particularly 10 and 100 mL per 70 kg bodyweight will generally be used.
As mentioned above, the emulsions of the invention may be produced in concentrate form for dilution at the point of administration. They may also be produced as separate oil and water phases for emulsification at the point of administration. Thus the requisite components may advantageously be provided in kit form. Thus viewed from a further aspect the invention provides a kit comprising: a first container containing a sterile aqueous medium, e.g. an aqueous solution containing an emulsifier, and optionally also tonicity adjusting agents, minerals, vitamins, antioxidants, etc. as described above; a second container containing a lipophilic pharmaceutical agent and a conjugated linoleic acid or derivative thereof, optionally in an oil-in-water emulsion, and optionally containing an emulsifier and one or more other optional components as described above; and optionally instructions for the dilution or emulsification of contents of the second container with contents of the first container.
In a further embodiment, the emulsions may be prepared by admixing the pharmaceutical agent with a CLA
or CLA derivative emulsion. Thus a kit comprising a CLA/CLA derivative emulsion and a separate pharmaceutical agent may be used in this regard and forms a further aspect of this invention. Viewed from this aspect the invention provides a kit comprising: a first container containing a lipophilic pharmaceutical agent, e.g. in powder (e.g. micronized) form or in solution or dispersion (e.g. in CLA or a CLA-miscible physiologically tolerable organic liquid); a second container containing an oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof, and optionally further ingredients such as emulsifiers, etc.
as discussed above; and optionally instructions for the dispersion of contents of the first container in contents of the second container.
The aqueous phase of the emulsions of the invention is preferably"prepared using sterile pyrogen-free water, e.g. water for injections, preferably degassed before use or before admixture with the oil phase. The emulsion, or the contents of a multi-container kit, preferably have an oxygen-free gas (e.g. nitrogen or a noble gas) in the head space above the liquid or solid contents.
The emulsions of the invention may also be used to improve uptake of lipophilic drugs following oral administration or administration into body cavities having external openings or evacuation ducts, and indeed as emulsions they may improve the uptake of the CLA or CLA derivative itself. Thus the methods of treatment according to the invention extend to administration of the emulsions, optionally in packaged (e.g.
encapsulated) form, into the gastrointestinal tract (e.g. oral or rectal administration or administration into the stomach via a tube), the bladder, the vagina, the uterus, the nose, or sub-lingually. Oral administration of the emulsions or of encapsulated emulsions however is preferred.
Thus viewed from a further aspect the invention provides a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the administration into a body cavity of said subject which is externally opening or which has an externally opening duct, of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a further aspect the invention also provides a pharmaceutical composition comprising an encapsulated oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof and, optionally, a lipophilic pharmaceutical agent.
Encapsulation of the emulsion may for example be achieved by conventional means, e.g. using gelatin capsules, optionally internally or externally coated with a delay-release agent, e.g. a material which is insoluble at neutral pH but soluble at the pH of gastric contents, for example Eudragit of Rohm GmbH.
Administration of a CLA or CLA derivative into the gastrointestinal tract as an emulsion may increase uptake from the gut of the CLA itself as well as of any lipophilic material contained therein. Thus besides pharmaceutical agents, the emulsion may be used as a delivery vehicle for other materials which it is desired be delivered to the subject, e.g. nutraceuticals, functional foods, prebiotics, herb or other plant extracts, etc. Examples of materials which can be delivered in this way include flavones (e.g.
ipriflavone), vitamins (e.g. vitamin E, vitamin D (e.g.
D3), vitamin B (e.g. B12)), a-lipoic acid, biotin, minerals (e.g. chromium, zinc, iron, and selenium compounds), indoles (e.g. indole-3-carbinol), glucosamines (e.g. N-acetyl-glucosamine), essential fatty acids (e.g. EPA, DHA and ca-3 acids, e.g. DGLA), 4-hydroxy-androstenedione, amantidine, ribivarine, grape seed extract, betain, niacin, folic acid, herb extracts (e.g. rad. rubine, fructus ameos, vishagal, herb virgaurae, taraxacic, aesin, rad. rubine, and rad.
taraxacic). While lipophilic agents are preferred, water-soluble agents may be included, either in the continuous aqueous phase, as micronized solids in the oil phase, or in an inner discontinuous aqueous phase, i.e. where the emulsion is a water-in-oil-in-water emulsion. Thus viewed from a further aspect the invention provides an oil-in-water emulsion pharmaceutical composition or nutritional supplement containing a conjugated linoleic acid or derivative thereof and, preferably within oil droplets of said emulsion, at least one pharmaceutical agent, nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
Typically in such emulsions the "active" additive (i.e. drug, nutraceutical, etc.) is present at 0.05 to 30o wt relative to the weight of the CLA or CLA
derivative, preferably 0.1 to 10% wt.
Such emulsions will preferably be administered orally or rectally.
Typically in this aspect the emulsions can be used as nutritional supplements and/or food additives and in this way can be administered to both human and non-human animals. A preferred example of the latter is administration as a nutritional supplement to pigs.
Thus, viewed from a further aspect the invention provides a nutritional composition comprising an encapsulated oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof and, optionally, a nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
Also, from a yet further aspect the invention provides a conjugated linoleic acid or a physiologically tolerable derivative thereof for use in a nutritional supplement and/or a food additive for administration to a human or non-human animal subject.
Viewed from a still further aspect the invention provides the use of an oil-in-water emulsion of a conjugated linoleic acid or a physiologically tolerable derivative therof in the preparation of a food additive or a nutritional supplement comprising an oil-in-water emulsion containing said conjugated linoleic acid or derivative therof and a nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
The emulsions may be in ready to use form or alternatively they may be in concentrate form to be diluted before administration. They may also be provided as separate "oil" and "water" compositions for emulsification prior to administration. Kits comprising concentrate or oil phase in one container and aqueous phase in another form a further aspect of the invention.
"Empty" CLA or CLA derivative emulsions, i.e. free of such "active" agents, may be loaded with the active agents after emulsion formation and those empty emulsions form a further aspect of the invention. Such empty emulsions however are preferably sterile and preferably contain an emulsifier and an antioxidant. If for use in parenteral administration, the aqueous phase is preferably produced using sterile pyrogen free water, e.g. water for injections, especially preferably water which has been degassed to reduce the oxygen content to less than 50% of that of water for injections at 1 atmosphere and 21 C, especially preferably to less than 10o and more preferably less than 20 of that oxygen content. The CLA may likewise be degassed and the emulsion is preferably made and stored in an essentially oxygen free atmosphere (e.g. less than 0.02 atmospheres oxygen partial pressure at 21 C).
Emulsification may be achieved by conventional techniques; however the use of intensive mixers, e.g.
rotor-stator or Ultra-Turrax mixers, is preferred.
The invention will now be described further with reference to the following non-limiting Examples:
Amphotericin B is commonly prescribed as an antifungal agent for intravenous administration to patients with systemic fungal infection, generally patients with reduced immune function such as AIDS
patients and elderly patients. Amphotericin B however is not water-soluble and hence it cannot be administered as an aqueous solution, the preferred administration format for intravenously administered drugs. Liposomal formulations of amphotericin B have been proposed;
however these are expensive and their production is not straightforward. Accordingly, one of the most popular ways for administering amphotericin B is by mixing with a dose of Intralipid and administering the mixture by infusion.
Intralipid is an aqueous emulsion of triglycerides, more specifically soya bean oil, which is normally used for parenteral nutrition for patients unable to take food, or sufficient food, orally. Standard dosages of Intralipid, which are given by intravenous infusion, are of the order of 500 mL of an emulsion containing 200 mg/mL of triglyceride. Such a dose involves the administration into the patient of a large quantity of saturated fat, and for the patients receiving amphotericin B this raises the risk of provoking undesirably high blood cholesterol levels.
CLA, also known as octadecadienoic acid, is a collective name for positional and geometric isomers of linoleic acid with conjugated double bonds at carbon atoms 10 and 12 or 9 and 11 in the various cis-trans configurations, i.e. cis-9, trans-11; cis-9, cis-11;
trans-9, cis-11; trans-9, trans-11; cis-10, trans-12;
cis-10, cis-12; trans-10, cis-12; and trans-10, trans-12. CLA thus differs from ordinary linoleic acid which has double bonds at carbon atoms 9 and 12.
CLA has several unique properties, one of which is the ability to reduce the percentage of fat relative to total body mass when administered orally as a nutritional supplement. CLA is available commercially as a liquid oil from Natural ASA, Oslo, Norway under the trade name Tonalin.
We have f'ound that aqueous suspensions/formulations of CLA can be used as a carrier for intravenously administered lipophilic drugs (such as amphotericin B) thereby avoiding the need for liposomal formulation and avoiding the undesirable exposure to high levels of saturated fatty acid triglycerides which is the consequence of formulation with Intralipid.
Thus viewed from one aspect the present invention provides a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the parenteral administration of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a further aspect the invention provides a pharmaceutical composition comprising an oil-in-water emulsion containing a lipophilic pharmaceutical agent and a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a still further aspect the invention provides the use of a conjugated linoleic acid or a physiologically tolerable derivative thereof for the manufacture of a medicament comprising an oil-in-water emulsion containing a lipophilic pharmaceutical agent and said conjugated linoleic acid or derivative thereof for use in a method of treatment involving administration of said medicament to a human or non-human (e.g. mammalian, reptilian or avian) animal subject.
Viewed from a yet further aspect the invention provides a conjugated linoleic acid or a physiologically tolerable derivative thereof for use in a method of medical treatment involving administration, particularly parenteral administration, of an oil-in-water emulsion containing said conjugated linoleic acid or derivative thereof to a human or non-human (e.g. mammalian, reptilian or avian) animal subject.
Viewed from a yet still further aspect the invention provides the use of an oil-in-water emulsion of a conjugated linoleic acid or a physiologically tolerable derivative thereof in the preparation of a medicament comprising an oil-in-water emulsion containing said conjugated linoleic acid or derivative thereof and a lipophilic pharmaceutical agent.
According to one aspect of the present invention, there is provided use of a conjugated linoleic acid in preparation of a pharmaceutical composition for parenteral administration of a lipophilic pharmaceutical agent in an oil-in-water emulsion to an animal in need thereof, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
According to another aspect of the present invention, there is provided a pharmaceutical composition in the form of a oil-in-water emulsion comprising a lipophilic pharmaceutical agent and a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of - 3a -the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporin.
According to yet another aspect of the present invention, there is provided a kit comprising a first container containing a sterile aqueous medium; a second container containing a limonitic pharmaceutical agent and a conjugated linoleic acid in the form of a oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dilution or emulsification of contents of the second container with contents of the first container.
According to still another aspect of the present invention, there is provided a kit comprising a first container containing a lipophilic pharmaceutical agent; a second container containing an oil-in-water emulsion comprising a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dispersion of contents of the first container in contents of the second container.
According to a further aspect of the present invention, there is provided use of a conjugated linoleic acid in preparation of a pharmaceutical composition for administration into a body cavity of animal in need thereof, wherein the body cavity is externally opening or which has an externally opening duct, of a lipophilic pharmaceutical - 3b -agent in an oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
As used herein the term "lipophilic pharmaceutical agent" means a lipophilic compound or compound mixture which is capable of exerting a medically desired therapeutic, diagnostic or prophylactic effect, especially a therapeutic or prophylactic effect, on administration to a subject.
Generally this will not be a CLA or a CLA derivative;
however the term does cover CLA derivatives which are conjugates of CLA and a drug compound.
While amphotericin B is a preferred pharmaceutical agent for use according to the invention, other lipophilic agents may be used, e.g. taxol, taxoteres, griseofulvin, steroids (e.g. hydrocortisone), cyclosporine, lipid soluble vitamins (e.g. vitamin D3), HIV protease inhibitors, etc.
Indeed, while the emphasis had earlier been on water-soluble drug compounds, lipid-soluble drug compounds are nowadays becoming more attractive to pharmaceutical companies in their current drug discovery procedures.
The CLA used according to the invention may be a single compound or a mixture of two or more of the eight different CLA isomers. Generally it will be preferred to use the cis-9, trans-11 and trans-10, cis-12 isomers, on their own, in admixture or together with minor proportions (i.e., less than 500-k by weight relative to total CLA) of one or more of the other isomers.
Examples of CLA derivatives usable according to the invention include salts, esters (e.g. single, double or multiple esters, in particular di- and triglycerides), amides, etc.
The CLA used is preferably at least 80o wt, more preferably at least 90g wt, cis-9, trans-il and/or trans-10, cis-12, preferably in a weight ratio of 2:98 to 98:2. For elderly patients and reduced immune function patients, the CLA is preferably at least 500 wt, more preferably at least 80% wt cis-9, trans-11.
For diabetic patients or patients who are obese, who have or are at risk of cardiovascular disease or who have elevated blood cholesterol levels, the CLA is preferably at least 50% wt, more preferably at least 800 wt, trans-10, cis-12.
The preparation of CLA is described for example in US-A-6060514 and the references cited therein.
Tne emulsions used according to the invention are referred to as oil-in-water emulsions. By this it is meant that they contain a continuous aqueous phase and a discontinuous lipophilic phase, i.e. a CLA or CLA
derivative phase. The oil droplets are preferably of micrometer size or smaller, e.g. with mode droplet diameters in the range 50 to 100000 nm, preferably 100 to 50000 nm, especially 160 to 6000 nm, more especially 500 to 6000 nm.
The emulsions of the invention are preferably sterile and pyrogen-free. Sterile emulsions may be prepared using sterile components under sterile conditions. Alternatively the oil phase may be prepared, sterilized, then emulsified under sterile conditions with a sterile aqueous phase. As a further alternative, the emulsion may be produced and then sterilized, e.g. by heat treatment (e.g. autoclaving), by irradiation (e.g. Y-irradiation) or, where the oil droplet size is small, by sterile filtration.
The emulsions of the invention may contain further components, e.g. stabilizers, antioxidants, viscosity modifiers, vitamins, minerals, pH adjusting agents, plasma anions (e . g. Na+, Caz+, K+, especially Na+ and Caz+, optionally deriving from their chloride salts), emulsifiers, etc.
The emulsions of the invention can be administered topically and in such cases it is preferable that the emulsion is formulated into a cream for convenient topical administration.
Examples of antioxidants that may be used include EDTA, vitamin C, vitamin E, cyclodextrins and (3- and Y-derivative thereof, and a-tocopherols and derivatives thereof, e.g. salts, esters, etc. Antioxidants are preferably present in the emulsions of the invention, e.g. in amounts of 0.01 to 0.5% wt relative to total emulsion weight. The antioxidants can be added to the oil and/or water phases or to the emulsion. The use of antioxidants extends the shelf life of the emulsion product.
Where the emulsion is to be administered parenterally, it preferably has an aqueous phase which has a tonicity which is within 20% of isotonicity, more preferably within 100 of isotonicity, especially within 2% of isotonicity. Isotonicity in this regard may be taken to be 300 mOsm/kg for human subjects. This may be achieved particularly conveniently by use of physiologically tolerable salts (e.g. chloride salts) of plasma anions such as Na', Ca2 and K. Sodium salts and combinations of sodium and calcium salts are preferred;
however non-ionic agents such as glycerol or sugars may be used to increase tonicity. Formulation in this manner has a cardioprotective effect which is especially important for aged or reduced immune function patients.
Examples of emulsifying agents that may be used in the compositions.of the invention include amphiphilic compounds such as phospholipids (e.g. lecithin), polyoxyethylene sorbates (Tweens), sorbitan carboxylic acid esters (Spans), polyalkyleneoxides (e.g. PEGs and Pluronics).
Such emulsifiers are preferably used in the preparation of the emulsions of the invention and desirably are present in the emulsions in amounts of 0.02 to 10o wt relative to total emulsion weight.
pH modifying agents may be included in the compositions if this does not prejudice the stability of the pharmaceutical agent. Generally the aqueous phase of the emulsions should have a pH in the range 4.5 to 7.5, especially 5.5. to 7Ø
The emulsions of the invention preferably contain 5 to 300 mg/mL of CLA or CLA derivative, e.g. 50 to 250 mg/mL, especially 100 to 200 mg/mL and preferably have viscosities at 20 C of 100 mPas or less. However, the emulsions may be prepared in concentrate, rather than ready-to-use, form and thus may contain for example up to 400 mg/mL CLA or CLA derivative.
The CLA or CLA derivative preferably forms the major proportion, i.e. at least 50% wt, of the oil phase in the emulsions. Particularly preferably it forms at least 70% wt, more especially at least 90% wt of the oil phase. Minor components of the oil phase may include for example the pharmaceutical agent, nutraceuticals, functional foods, antioxidants, vitamins, etc. as well as physiologically tolerable fatty acids (e.g. w-3 acids), and mono-, di- and triglycerides. In general, each such component will generally be present as no more than 30a wt of the oil phase, e.g. 0.05 to 25% wt, preferably 0.1 to 10o wt, and the sum of such components will generally be less than 50% wt, more preferably less than about 30% wt, especially less than 10% wt of the oil phase.
The required dosage of the emulsions of the invention will vary according to the nature and concentration of the pharmaceutical agent; however dosages of between 0.5 mL and 500 mL, particularly 10 and 100 mL per 70 kg bodyweight will generally be used.
As mentioned above, the emulsions of the invention may be produced in concentrate form for dilution at the point of administration. They may also be produced as separate oil and water phases for emulsification at the point of administration. Thus the requisite components may advantageously be provided in kit form. Thus viewed from a further aspect the invention provides a kit comprising: a first container containing a sterile aqueous medium, e.g. an aqueous solution containing an emulsifier, and optionally also tonicity adjusting agents, minerals, vitamins, antioxidants, etc. as described above; a second container containing a lipophilic pharmaceutical agent and a conjugated linoleic acid or derivative thereof, optionally in an oil-in-water emulsion, and optionally containing an emulsifier and one or more other optional components as described above; and optionally instructions for the dilution or emulsification of contents of the second container with contents of the first container.
In a further embodiment, the emulsions may be prepared by admixing the pharmaceutical agent with a CLA
or CLA derivative emulsion. Thus a kit comprising a CLA/CLA derivative emulsion and a separate pharmaceutical agent may be used in this regard and forms a further aspect of this invention. Viewed from this aspect the invention provides a kit comprising: a first container containing a lipophilic pharmaceutical agent, e.g. in powder (e.g. micronized) form or in solution or dispersion (e.g. in CLA or a CLA-miscible physiologically tolerable organic liquid); a second container containing an oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof, and optionally further ingredients such as emulsifiers, etc.
as discussed above; and optionally instructions for the dispersion of contents of the first container in contents of the second container.
The aqueous phase of the emulsions of the invention is preferably"prepared using sterile pyrogen-free water, e.g. water for injections, preferably degassed before use or before admixture with the oil phase. The emulsion, or the contents of a multi-container kit, preferably have an oxygen-free gas (e.g. nitrogen or a noble gas) in the head space above the liquid or solid contents.
The emulsions of the invention may also be used to improve uptake of lipophilic drugs following oral administration or administration into body cavities having external openings or evacuation ducts, and indeed as emulsions they may improve the uptake of the CLA or CLA derivative itself. Thus the methods of treatment according to the invention extend to administration of the emulsions, optionally in packaged (e.g.
encapsulated) form, into the gastrointestinal tract (e.g. oral or rectal administration or administration into the stomach via a tube), the bladder, the vagina, the uterus, the nose, or sub-lingually. Oral administration of the emulsions or of encapsulated emulsions however is preferred.
Thus viewed from a further aspect the invention provides a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the administration into a body cavity of said subject which is externally opening or which has an externally opening duct, of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof.
Viewed from a further aspect the invention also provides a pharmaceutical composition comprising an encapsulated oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof and, optionally, a lipophilic pharmaceutical agent.
Encapsulation of the emulsion may for example be achieved by conventional means, e.g. using gelatin capsules, optionally internally or externally coated with a delay-release agent, e.g. a material which is insoluble at neutral pH but soluble at the pH of gastric contents, for example Eudragit of Rohm GmbH.
Administration of a CLA or CLA derivative into the gastrointestinal tract as an emulsion may increase uptake from the gut of the CLA itself as well as of any lipophilic material contained therein. Thus besides pharmaceutical agents, the emulsion may be used as a delivery vehicle for other materials which it is desired be delivered to the subject, e.g. nutraceuticals, functional foods, prebiotics, herb or other plant extracts, etc. Examples of materials which can be delivered in this way include flavones (e.g.
ipriflavone), vitamins (e.g. vitamin E, vitamin D (e.g.
D3), vitamin B (e.g. B12)), a-lipoic acid, biotin, minerals (e.g. chromium, zinc, iron, and selenium compounds), indoles (e.g. indole-3-carbinol), glucosamines (e.g. N-acetyl-glucosamine), essential fatty acids (e.g. EPA, DHA and ca-3 acids, e.g. DGLA), 4-hydroxy-androstenedione, amantidine, ribivarine, grape seed extract, betain, niacin, folic acid, herb extracts (e.g. rad. rubine, fructus ameos, vishagal, herb virgaurae, taraxacic, aesin, rad. rubine, and rad.
taraxacic). While lipophilic agents are preferred, water-soluble agents may be included, either in the continuous aqueous phase, as micronized solids in the oil phase, or in an inner discontinuous aqueous phase, i.e. where the emulsion is a water-in-oil-in-water emulsion. Thus viewed from a further aspect the invention provides an oil-in-water emulsion pharmaceutical composition or nutritional supplement containing a conjugated linoleic acid or derivative thereof and, preferably within oil droplets of said emulsion, at least one pharmaceutical agent, nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
Typically in such emulsions the "active" additive (i.e. drug, nutraceutical, etc.) is present at 0.05 to 30o wt relative to the weight of the CLA or CLA
derivative, preferably 0.1 to 10% wt.
Such emulsions will preferably be administered orally or rectally.
Typically in this aspect the emulsions can be used as nutritional supplements and/or food additives and in this way can be administered to both human and non-human animals. A preferred example of the latter is administration as a nutritional supplement to pigs.
Thus, viewed from a further aspect the invention provides a nutritional composition comprising an encapsulated oil-in-water emulsion containing a conjugated linoleic acid or derivative thereof and, optionally, a nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
Also, from a yet further aspect the invention provides a conjugated linoleic acid or a physiologically tolerable derivative thereof for use in a nutritional supplement and/or a food additive for administration to a human or non-human animal subject.
Viewed from a still further aspect the invention provides the use of an oil-in-water emulsion of a conjugated linoleic acid or a physiologically tolerable derivative therof in the preparation of a food additive or a nutritional supplement comprising an oil-in-water emulsion containing said conjugated linoleic acid or derivative therof and a nutraceutical, prebiotic, functional food or physiologically tolerable plant extract.
The emulsions may be in ready to use form or alternatively they may be in concentrate form to be diluted before administration. They may also be provided as separate "oil" and "water" compositions for emulsification prior to administration. Kits comprising concentrate or oil phase in one container and aqueous phase in another form a further aspect of the invention.
"Empty" CLA or CLA derivative emulsions, i.e. free of such "active" agents, may be loaded with the active agents after emulsion formation and those empty emulsions form a further aspect of the invention. Such empty emulsions however are preferably sterile and preferably contain an emulsifier and an antioxidant. If for use in parenteral administration, the aqueous phase is preferably produced using sterile pyrogen free water, e.g. water for injections, especially preferably water which has been degassed to reduce the oxygen content to less than 50% of that of water for injections at 1 atmosphere and 21 C, especially preferably to less than 10o and more preferably less than 20 of that oxygen content. The CLA may likewise be degassed and the emulsion is preferably made and stored in an essentially oxygen free atmosphere (e.g. less than 0.02 atmospheres oxygen partial pressure at 21 C).
Emulsification may be achieved by conventional techniques; however the use of intensive mixers, e.g.
rotor-stator or Ultra-Turrax mixers, is preferred.
The invention will now be described further with reference to the following non-limiting Examples:
CLA triglyceride emulsion for parenteral administration A mixture of lOg CLA triglyceride (produced by reacting CLA with glycerol), l.Og purified egg phospholipid, 50 mg sodium stearate and 5g alpha-tocopherol is finely dispersed by using an Ultra Turrax.
A mixture of 100 ml water for injection containing 2.5g glycerol and 0.05 mmol NaOH is added to the CLA mixture during stirrin,g at room temperature. The mixture is homogenized in a high pressure homogenator and the final emulsion filled into vials and heat-sterilized according to generally accepted methods.
The final product is a sterile and pyrogen-free emulsion containing 10% CLA triglyceride.
Cyclosporin CLA emulsion for oral delivery Cyclosporin (4g) is mixed with CLA monoglyceride (15g) and oleyl alcohol (5g) and heated to 80 C.
Polysorbate 80 (5g) and water (71g) are mixed and heated to 80 C.
The aqueous phase is added to the drug containing phase and the mixture is stirred vigorously for 5 minutes followed by homogenization using rotor-stator mixer.
The CLA based emulsion contains 4% cyclosporin and is useful for oral delivery.
A mixture of 100 ml water for injection containing 2.5g glycerol and 0.05 mmol NaOH is added to the CLA mixture during stirrin,g at room temperature. The mixture is homogenized in a high pressure homogenator and the final emulsion filled into vials and heat-sterilized according to generally accepted methods.
The final product is a sterile and pyrogen-free emulsion containing 10% CLA triglyceride.
Cyclosporin CLA emulsion for oral delivery Cyclosporin (4g) is mixed with CLA monoglyceride (15g) and oleyl alcohol (5g) and heated to 80 C.
Polysorbate 80 (5g) and water (71g) are mixed and heated to 80 C.
The aqueous phase is added to the drug containing phase and the mixture is stirred vigorously for 5 minutes followed by homogenization using rotor-stator mixer.
The CLA based emulsion contains 4% cyclosporin and is useful for oral delivery.
CLA fat emulsion Galactolipid (1.5g) is dispersed in CLA trigyceride mixture (20g). The mixture is heated to 80 C.
Glycerol (2g) and EDTA as sodium salt (0.1 g) are dissolved in water (76g) and heated to 50 C.
The CLA phase is added to the aqueous phase under high shear mixing followed by homogenization.
The emulsion contains 20% CLA.
Emulsion containing CLA triglyceride y-cyclodextrin complex A stirred mixture of y-cyclodextrin (8g) and CLA
triglyceride (2g) in water (20 ml) is blended for 30 minutes using an Ultra-Turrax dispenser. The mixture is stirred for 24 hours at 40 C.
The mixture is then added to Intralipid 209,5 fat emulsion and the mixture is treated with an Ultra-Turrax dispenser at room temperature for 30 minutes.
Emulsion containing CLA triglyceride CLA triglyceride (cis-9, trans-11 36.0%, trans-10, cis-12 34.7%) was prepared from refined safflower as follows. The conjugation of the acids was carried out as described in US-A-5,504,114 with some modifications. The w/w/w ratios of oil/solvent/catalyst were 2/2/1.
Further, propylene glycol was used instead of ethylene glycol and the temperature used for the conjugation process was 150 C for 3 hours instead of 180 C. The CLA
free fatty acids obtained were then reacted with glycerol using Novozyme 435 as a catalyst to make the triacyl glycerol. Three moles of free fatty acids were added to 1 mole of glycerol and 7% by weight of immobilised lipase. The mixture was stirred under vacuum for 48 hours at 60 C. Oil was then filtered to remove the immobilised enzymes. A mixture of this CLA
trigycleride (1.50g), L-a-phosphatidyl-choline (Egg) (Avanti Polar-Lipids Inc, USA) (120 mg) and water for injection containing 22 mg anhydrous glycerol per ml (to a total of 10 ml) was blended for 10 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The emulsion contained 15% w/v CLA triglyceride.
CLA triglyceride emulation containing amphotericin B
Amphotericin B (USP for use in parenteral products from Dumex Ltd., Denmark) (25 mg) was added to the CLA
triglyceride emulsion from Example 5 (5 ml). The mixture was blended for 15 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A homogenous yellow emulsion containing 5 mg amphotericin B per ml was obtained. The emulsion was filled in a 10 ml vial with rubber stopper.
Glycerol (2g) and EDTA as sodium salt (0.1 g) are dissolved in water (76g) and heated to 50 C.
The CLA phase is added to the aqueous phase under high shear mixing followed by homogenization.
The emulsion contains 20% CLA.
Emulsion containing CLA triglyceride y-cyclodextrin complex A stirred mixture of y-cyclodextrin (8g) and CLA
triglyceride (2g) in water (20 ml) is blended for 30 minutes using an Ultra-Turrax dispenser. The mixture is stirred for 24 hours at 40 C.
The mixture is then added to Intralipid 209,5 fat emulsion and the mixture is treated with an Ultra-Turrax dispenser at room temperature for 30 minutes.
Emulsion containing CLA triglyceride CLA triglyceride (cis-9, trans-11 36.0%, trans-10, cis-12 34.7%) was prepared from refined safflower as follows. The conjugation of the acids was carried out as described in US-A-5,504,114 with some modifications. The w/w/w ratios of oil/solvent/catalyst were 2/2/1.
Further, propylene glycol was used instead of ethylene glycol and the temperature used for the conjugation process was 150 C for 3 hours instead of 180 C. The CLA
free fatty acids obtained were then reacted with glycerol using Novozyme 435 as a catalyst to make the triacyl glycerol. Three moles of free fatty acids were added to 1 mole of glycerol and 7% by weight of immobilised lipase. The mixture was stirred under vacuum for 48 hours at 60 C. Oil was then filtered to remove the immobilised enzymes. A mixture of this CLA
trigycleride (1.50g), L-a-phosphatidyl-choline (Egg) (Avanti Polar-Lipids Inc, USA) (120 mg) and water for injection containing 22 mg anhydrous glycerol per ml (to a total of 10 ml) was blended for 10 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The emulsion contained 15% w/v CLA triglyceride.
CLA triglyceride emulation containing amphotericin B
Amphotericin B (USP for use in parenteral products from Dumex Ltd., Denmark) (25 mg) was added to the CLA
triglyceride emulsion from Example 5 (5 ml). The mixture was blended for 15 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A homogenous yellow emulsion containing 5 mg amphotericin B per ml was obtained. The emulsion was filled in a 10 ml vial with rubber stopper.
CLA triglyceride emulsion containing Vitamin E
Vitamin E(97%, Aldrich) (36 mg) was added to the CLA
triglyceride emulsion from Example 5 (5 ml). The mixture was blended for 5 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
The emulsion was filled in a 10 ml vial with rubber stopper.
Emulsion containing CLA-triglyceride and CLA-ethyl ester Cis-9, trans-10 free fatty acid concentrate and the trans-10, cis-12 fatty acid ethyl ester concentrate were prepared as described in Berdeaux et al., JAOCS, 75 no.12 (1998), the only difference being that ethanol was used instead of methanol in preparing the alkylester of the trans-10, cis-12 concentrate.. A mixture of CLA
triglyceride (same as in Example 5) (740 mg), CLA ethyl ester (cis-9, trans-11 0.20, trans-10, cis-12) (1.04g), L-a-phosphatidylcholine (Egg) (Avanti Polar Lipids Inc., USA) (160 mg) and water for injection containing 22 mg anhydrous glycerol per ml (to a total volume of 20 ml) was blended for 10 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The emulsion contained 37 mg CLA triglyceride and 53 mg CLA ethyl ester per ml.
Vitamin E(97%, Aldrich) (36 mg) was added to the CLA
triglyceride emulsion from Example 5 (5 ml). The mixture was blended for 5 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
The emulsion was filled in a 10 ml vial with rubber stopper.
Emulsion containing CLA-triglyceride and CLA-ethyl ester Cis-9, trans-10 free fatty acid concentrate and the trans-10, cis-12 fatty acid ethyl ester concentrate were prepared as described in Berdeaux et al., JAOCS, 75 no.12 (1998), the only difference being that ethanol was used instead of methanol in preparing the alkylester of the trans-10, cis-12 concentrate.. A mixture of CLA
triglyceride (same as in Example 5) (740 mg), CLA ethyl ester (cis-9, trans-11 0.20, trans-10, cis-12) (1.04g), L-a-phosphatidylcholine (Egg) (Avanti Polar Lipids Inc., USA) (160 mg) and water for injection containing 22 mg anhydrous glycerol per ml (to a total volume of 20 ml) was blended for 10 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The emulsion contained 37 mg CLA triglyceride and 53 mg CLA ethyl ester per ml.
CLA emulsion containing iron (3+) sorbitol citric acid complex and Vitamin E
Jectofer (50 mg iron sorbitol citric acid complex per ml from Astra Zeneca) (2 ml) was added to CLA
triglyceride/ethyl ester emulsion from Example 8 (5 ml).
Vitamin E(970, Aldrich) (30 ml) was added and the mixture was blended from 5 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The brown emulsion contained 30 mg iron sorbitol citric acid complex per ml.
Emulsion containing soya oil, CLA triglyceride and CLA
ethyl ester A mixture of CLA triglyceride (same as in Example 5) (1.0 g), CLA ethyl ester (same as in Example 8) (1.0 g), Vitamin E(970, Aldrich) 81 mg and Intralipid (100 mg/ml from Fresenius Kabi AB, Uppsala, Sweden) to a total volume of 20 ml was blended usirig an Ultra-Turrax dispenser (24000 rpm) for 10 minutes at room temperature.
The emulsion contained 0.1 g CLA triglyceride/ethyl ester per ml.
Jectofer (50 mg iron sorbitol citric acid complex per ml from Astra Zeneca) (2 ml) was added to CLA
triglyceride/ethyl ester emulsion from Example 8 (5 ml).
Vitamin E(970, Aldrich) (30 ml) was added and the mixture was blended from 5 minutes using an Ultra-Turrax dispenser (24000 rpm) at room temperature.
A stable emulsion free from aggregates was formed during the blending.
The brown emulsion contained 30 mg iron sorbitol citric acid complex per ml.
Emulsion containing soya oil, CLA triglyceride and CLA
ethyl ester A mixture of CLA triglyceride (same as in Example 5) (1.0 g), CLA ethyl ester (same as in Example 8) (1.0 g), Vitamin E(970, Aldrich) 81 mg and Intralipid (100 mg/ml from Fresenius Kabi AB, Uppsala, Sweden) to a total volume of 20 ml was blended usirig an Ultra-Turrax dispenser (24000 rpm) for 10 minutes at room temperature.
The emulsion contained 0.1 g CLA triglyceride/ethyl ester per ml.
Emulsion containing CLA trialyceride and cod liver oil for oral administration A mixture of CLA triglyceride (same as in Example 5) (3.85 g), cod liver oil (Moller's Omega-3 tran, from Peter Moller, Oslo, Norway) (6.11 g), L-a-phosphatidylcholine (P-5394, Sigma) (1.3 g) and 25 g water was blended for 30 minutes using an Ultra-Turrax dispenser (24000 rpm). Orange flavour (NO 300004 H from Givaudan Roure BV, The Netherlands) (20 drops) was added and the mixture was blended for another minute.
The product was a cream-white emulsion with no taste of cod liver oil.
The emulsion contained approximately 10% CLA
triglyceride.
Vitamin concentrate in emulsion of soya oil and CLA
triglyceride A complete mixture of fat-soluble and water-soluble vitamins was prepared by dissolving a mixture of water-soluble vitamins (SoluvitO powder for infusion solution prepared by Fresenius Kabi AB) one vial in lipid emulsion containing fat soluble vitamins (Vitalipid Adult for Fresenius Kabi AB) (one vial 10 ml). CLA
triglyceride (same as in Example 5) (1.0 g) and L-a-phosphatidylcholine (P-5394, Sigma) (100 mg) were added and the mixture was blended for 20 minutes using an Ultra-Turrax dispenser at room temperature.
The mixture of vitamins in the fat emulsion can be diluted with fat emulsions before use.
The product was a cream-white emulsion with no taste of cod liver oil.
The emulsion contained approximately 10% CLA
triglyceride.
Vitamin concentrate in emulsion of soya oil and CLA
triglyceride A complete mixture of fat-soluble and water-soluble vitamins was prepared by dissolving a mixture of water-soluble vitamins (SoluvitO powder for infusion solution prepared by Fresenius Kabi AB) one vial in lipid emulsion containing fat soluble vitamins (Vitalipid Adult for Fresenius Kabi AB) (one vial 10 ml). CLA
triglyceride (same as in Example 5) (1.0 g) and L-a-phosphatidylcholine (P-5394, Sigma) (100 mg) were added and the mixture was blended for 20 minutes using an Ultra-Turrax dispenser at room temperature.
The mixture of vitamins in the fat emulsion can be diluted with fat emulsions before use.
Typical fat emulsions for dilution of this vitamin concentrate could be CLA fat emulsions like Example 5 or fat emulsions containing other fat products.
Oral emulsion containing Vitamin C
L(+)Ascorbic acid (990, Aldrich) (1.Og) was added to a CLA-triglyceride/cod liver oil emulsion (from Example 11) (10g). The mixture was blended for 2 minutes using Ultra-Turrax dispenser. The emulsion contained 100mg Vitamin C per"ml. The emulsion tasted of Vitamin C.
Oral emulsion containing L(-)Ascorbic acid 6-palmitate The product was made in a similar fashion to Example 13 using L(-)Ascorbic acid 6-palmitate (95%, Aldrich) (1.Og). The emulsion did not taste of Vitamin C.
Dermal cream containing CLA triglyceride Unguentum M(Hermal, Kurt Herrmann, Reinbek, Germany) (12g) and CLA triglyceride (5.6g) were mixed using mortar and pestle. The cream thus formed can be used as the basis for dermal pharmaceutical products and as the basis for cosmetic products. Such products can be made by mixing pharmaceuticals or other compounds into the cream.
Oral emulsion containing Vitamin C
L(+)Ascorbic acid (990, Aldrich) (1.Og) was added to a CLA-triglyceride/cod liver oil emulsion (from Example 11) (10g). The mixture was blended for 2 minutes using Ultra-Turrax dispenser. The emulsion contained 100mg Vitamin C per"ml. The emulsion tasted of Vitamin C.
Oral emulsion containing L(-)Ascorbic acid 6-palmitate The product was made in a similar fashion to Example 13 using L(-)Ascorbic acid 6-palmitate (95%, Aldrich) (1.Og). The emulsion did not taste of Vitamin C.
Dermal cream containing CLA triglyceride Unguentum M(Hermal, Kurt Herrmann, Reinbek, Germany) (12g) and CLA triglyceride (5.6g) were mixed using mortar and pestle. The cream thus formed can be used as the basis for dermal pharmaceutical products and as the basis for cosmetic products. Such products can be made by mixing pharmaceuticals or other compounds into the cream.
Claims (48)
1. Use of a conjugated linoleic acid in preparation of a pharmaceutical composition for parenteral administration of a lipophilic pharmaceutical agent in an oil-in-water emulsion to an animal in need thereof, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
2. The use of claim 1, wherein the animal is a human.
3. The use of claim 1, wherein the animal is mammalian.
4. The use of claim 1, wherein the animal is avian.
5. The use of claim 1, wherein the animal is reptilian.
6. The use of any one of claims 1 to 5, wherein the conjugated linoleic acid is a single compound.
7. The use of any one of claims 1 to 5, wherein the conjugated linoleic acid is a mixture of two or more conjugated linoleic acid isomers.
8. The use of any one of claims 1 to 5, wherein the conjugated linoleic acid is one or both of cis-9, trans-11 isomer and trans-10, cis-12 isomer.
9. The use of any one of claims 1 to 5, wherein the conjugated linoleic acid comprises at least 80% by weight of one or both of cis-9, trans-11 isomer and trans-10, cis-12 isomer.
10. The use of claim 9 wherein the cis-9, trans-11 isomer and the trans-10, cis-12 isomer are present in a weight ratio of from 2:98 to 98:2.
11. The use of any one of claims 1 to 10, wherein the conjugated linoleic acid forms at least 90% by weight of the oil phase of the oil-in-water emulsion.
12. The use of any one of claims 1 to 11, wherein oil droplets in the oil-in-water emulsion have a mode droplet diameter in the range of 160 to 6,000 nm.
13. The use of any one of claims 1 to 12, wherein the oil-in-water emulsion comprises 5 to 3000 mg/ml of the conjugated linoleic acid.
14. The use of any one of claims 1 to 12, wherein the oil-in-water emulsion comprises 100 to 200 mg/ml of the conjugated linoleic acid.
15. The use of any one of claims 1 to 14, wherein the emulsion has a viscosity at 20°C of 100 mPas or less.
16. The use of any one of claims 1 to 15, wherein the emulsion is in the form of a cream for topical administration.
17. A pharmaceutical composition in the form of a oil-in-water emulsion comprising a lipophilic pharmaceutical agent and a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
18. The pharmaceutical composition of claim 17, wherein the conjugated linoleic acid is a single compound.
19. The pharmaceutical composition of claim 17, wherein the conjugated linoleic acid is a mixture of two or more conjugated linoleic acid isomers.
20. The pharmaceutical composition of claim 17, wherein the conjugated linoleic acid is one or both of the cis-9, trans-11 isomer and the trans-10, cis-12 isomer.
21. The pharmaceutical composition of claim 17, wherein the conjugated linoleic acid comprises at least 80%
by weight of one or both of the cis-9, trans-11 isomer and the trans-10, cis-12 isomer.
by weight of one or both of the cis-9, trans-11 isomer and the trans-10, cis-12 isomer.
22. The pharmaceutical composition of claim 21 wherein the cis-9, trans-11 isomer and the trans-10, cis-12 isomer are present in a weight ratio of from 2:98 to 98:2.
23. The pharmaceutical composition of any one of claims 17 to 22, wherein the conjugated linoleic acid forms at least 90% by weight of the oil phase of the oil-in-water emulsion.
24. The pharmaceutical composition of any one of claims 17 to 23, wherein oil droplets in the oil-in-water emulsion have a mode droplet diameter in the range of 160 to 6,000 nm.
25. The pharmaceutical composition of any one of claims 17 to 24, wherein the oil-in-water emulsion comprises to 3000 mg/ml of the conjugated linoleic acid.
26. The pharmaceutical composition of any one of claims 17 to 24, wherein the oil-in-water emulsion comprises 100 to 200 mg/ml of the conjugated linoleic acid.
27. The pharmaceutical composition of any one of claims 17 to 26, wherein the emulsion has a viscosity at 20°C of 100 mPas or less.
28. The pharmaceutical composition of any one of claims 17 to 27, wherein the emulsion is in the form of a cream for topical administration.
29. The pharmaceutical composition of any one of claims 17 to 27, wherein the oil-in-water emulsion is encapsulated.
30. A kit comprising a first container containing a sterile aqueous medium; a second container containing a limonitic pharmaceutical agent and a conjugated linoleic acid in the form of a oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dilution or emulsification of contents of the second container with contents of the first container.
31. The kit of claim 30, wherein the contents of one or both of the first container and the second container further comprises one or more of a tonicity adjusting agent, a mineral, a vitamin, and an antioxidant.
32. A kit comprising a first container containing a lipophilic pharmaceutical agent; a second container containing an oil-in-water emulsion comprising a conjugated linoleic acid, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine; an emulsifier; and instructions for dispersion of contents of the first container in contents of the second container.
33. Use of a conjugated linoleic acid in preparation of a pharmaceutical composition for administration into a body cavity of animal in need thereof, wherein the body cavity is externally opening or which has an externally opening duct, of a lipophilic pharmaceutical agent in an oil-in-water emulsion, wherein the conjugated linoleic acid forms at least 50% by weight of the oil in the oil-in-water emulsion and wherein the lipophilic pharmaceutical agent is amphotericin B, taxol, a taxotere, griseofulvin, a steroid or cyclosporine.
34. The use of claim 33, wherein the animal is a human.
35. The use of claim 33, wherein the animal is mammalian.
36. The use of claim 33, wherein the animal is avian.
37. The use of claim 33, wherein the animal is reptilian.
38. The use of any one of claims 33 to 37, wherein the conjugated linoleic acid is a single compound.
39. The use of any one of claims 33 to 37, wherein the conjugated linoleic acid is a mixture of two or more conjugated linoleic acid isomers.
40. The use of any one of claims 33 to 37, wherein the conjugated linoleic acid is one or both of cis-9, trans-11 isomer and trans-10, cis-12 isomer.
41. The use of any one of claims 33 to 37, wherein the conjugated linoleic acid comprises at least 80% by weight of one or both of cis-9, trans-11 isomer and trans-10, cis-12 isomer.
42. The use of claim 41 wherein the cis-9, trans-11 isomer and the trans-10, cis-12 isomer are present in a weight ratio of from 2:98 to 98:2.
43. The use of any one of claims 33 to 42, wherein the conjugated linoleic acid forms at least 90% by weight of the oil phase of the oil-in-water emulsion.
44. The use of any one of claims 33 to 43, wherein oil droplets in the oil-in-water emulsion have a mode droplet diameter in the range of 160 to 6,000 nm.
45. The use of any one of claims 33 to 44, wherein the oil-in-water emulsion comprises 5 to 3000 mg/ml of the conjugated linoleic acid.
46. The use of any one of claims 33 to 44, wherein the oil-in-water emulsion comprises 100 to 200 mg/ml of the conjugated linoleic acid.
47. The use of any one of claims 33 to 46, wherein the emulsion has a viscosity at 20°C of 100 mPas or less.
48. The use of any one of claims 33 to 47, wherein the emulsion is in the form of a cream for topical administration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0105622.5 | 2001-03-07 | ||
| GBGB0105622.5A GB0105622D0 (en) | 2001-03-07 | 2001-03-07 | Compositions |
| PCT/GB2002/000996 WO2002070014A1 (en) | 2001-03-07 | 2002-03-07 | Compositions comprising an o/w emulsion containing conjugated linoleic acid |
Publications (2)
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|---|---|
| CA2455226A1 CA2455226A1 (en) | 2002-09-12 |
| CA2455226C true CA2455226C (en) | 2010-05-18 |
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| CA2455226A Expired - Fee Related CA2455226C (en) | 2001-03-07 | 2002-03-07 | Compositions comprising an o/w emulsion containing conjugated linoleic acid |
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| EP (1) | EP1372728B1 (en) |
| AU (1) | AU2002238710B2 (en) |
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| DK (1) | DK1372728T3 (en) |
| ES (1) | ES2404656T3 (en) |
| GB (1) | GB0105622D0 (en) |
| WO (1) | WO2002070014A1 (en) |
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| WO2017056075A1 (en) | 2015-10-01 | 2017-04-06 | Solutex Na, Lcc | Process for the preparation and stabilization of emulsions with omega-3 by means of isometric crystalline networks of cellulose derivatives |
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| NO317310B1 (en) * | 2003-02-28 | 2004-10-04 | Bioli Innovation As | Oil-in-water emulsion concentrate for nutritional formula and its use. |
| WO2005087017A2 (en) * | 2004-03-10 | 2005-09-22 | Natural Asa | Compositions comprising reverse isomers of conjugated linoleic acid |
| US20060051462A1 (en) * | 2004-09-03 | 2006-03-09 | Wang Jimmy X | Self emulsifying compositions for delivering lipophilic coenzyme Q10 and other dietary ingredients |
| DE102004043824A1 (en) | 2004-09-10 | 2006-03-16 | Cognis Ip Management Gmbh | Emulsions with unsaturated fatty acids and their esters |
| ES2335959B1 (en) * | 2008-08-27 | 2011-02-11 | Laboratorios Casen-Fleet, S.L. | FOOD COMPOSITION INCLUDING CONJUGATED LINOLEIC ACID. |
| US8993625B2 (en) | 2009-03-11 | 2015-03-31 | Stable Solutions Llc | Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle |
| US9034389B2 (en) * | 2009-03-11 | 2015-05-19 | Stable Solutions Llc | Omega-3 enriched fish oil-in-water parenteral nutrition emulsions |
| EP2301523A1 (en) | 2009-09-22 | 2011-03-30 | Dr. August Wolff GmbH & Co. KG Arzneimittel | Galenic formulation in colloidal form |
| CN113142585A (en) * | 2021-04-17 | 2021-07-23 | 青岛卓迪生物技术有限公司 | Conjugated linoleic acid nano emulsion and preparation method thereof |
| WO2023076042A1 (en) * | 2021-10-27 | 2023-05-04 | Quicksilver Scientific, Inc. | Transdermal microemulsion delivery systems for alcohol-soluble species including nonderivatized hormones |
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| US3549555A (en) * | 1968-10-08 | 1970-12-22 | Ncr Co | Encapsulation of lipophilic liquid-in-hydrophilic liquid emulsions |
| US3996355A (en) * | 1975-01-02 | 1976-12-07 | American Home Products Corporation | Permanent suspension pharmaceutical dosage form |
| US4292310A (en) * | 1977-05-09 | 1981-09-29 | Gordon Harry W | Method of treating hypercholesterolemia with n-acyl amphotericin B |
| US4663167A (en) * | 1984-04-16 | 1987-05-05 | The Board Of Regents Of The University Of Texas System | Composition and method for treatment of disseminated fungal infections in mammals |
| US5091389A (en) * | 1991-04-23 | 1992-02-25 | Merck & Co., Inc. | Lipophilic macrolide useful as an immunosuppressant |
| US5554646A (en) | 1992-04-29 | 1996-09-10 | Wisconsin Alumni Research Foundation | Method for reducing body fat in animals |
| JP3862295B2 (en) * | 1993-09-30 | 2006-12-27 | 独立行政法人理化学研究所 | Anti-obesity agent |
| US5760082C1 (en) | 1994-08-29 | 2001-03-06 | Wisconsin Alumni Res Found | Dietetic foods containing conjugated linoleic acids |
| US5760083A (en) * | 1996-08-07 | 1998-06-02 | Wisconsin Alumni Research Foundation | Use of CLA to reduce the incidence of valgus and varus leg deforomities in poultry |
| US5837733A (en) * | 1997-02-26 | 1998-11-17 | Wisconsin Alumni Research Foundation | Method for reducing secetion of apolipoprotein B in animals by administering conjugated linoleic acid |
| US5885594A (en) | 1997-03-27 | 1999-03-23 | The Procter & Gamble Company | Oral compositions having enhanced mouth-feel |
| NZ503398A (en) | 1997-08-18 | 2002-06-28 | Univ South Dakota | Dairy products with enhanced conjugated linoleic acid content derived from milk of ruminants fed with fish oil |
| JP4129566B2 (en) | 1997-09-05 | 2008-08-06 | 大塚製薬株式会社 | Liver fat accumulation inhibiting composition and food additive for liver fat accumulation inhibiting |
| US6019990A (en) | 1997-11-21 | 2000-02-01 | Natural Nutrition Ltd. As | Conjugated linoleic acid delivery system in cosmetic preparations |
| MX228618B (en) | 1998-05-04 | 2005-06-21 | Conlinco Inc | Methods of using isomer enriched conjugated linoleic acid compositions. |
| US6060514A (en) | 1998-05-04 | 2000-05-09 | Conlin Co., Inc. | Isomer enriched conjugated linoleic acid compositions |
| WO2000000186A1 (en) | 1998-06-30 | 2000-01-06 | American Medical Research, Inc. | Method of treating topical ailments |
| US6555579B2 (en) | 1998-08-13 | 2003-04-29 | The Wistar Institute | Methods for reducing atherosclerotic plaques |
| FR2784268B1 (en) | 1998-10-12 | 2000-12-29 | Gervais Danone Sa | NEW FOOD COMPOSITION, BASED ON MATERIAL FROM MILK, IN THE FORM OF AN OIL-IN-WATER EMULSION |
| US6642259B1 (en) | 1999-05-07 | 2003-11-04 | Trustees Of Tufts College | Immune stimulating dietary supplement and method of use thereof |
| GB9918025D0 (en) | 1999-07-30 | 1999-09-29 | Unilever Plc | Skin care composition |
| GB9918028D0 (en) | 1999-07-30 | 1999-09-29 | Unilever Plc | Skin care composition |
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- 2001-03-07 GB GBGB0105622.5A patent/GB0105622D0/en not_active Ceased
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2002
- 2002-03-07 WO PCT/GB2002/000996 patent/WO2002070014A1/en not_active Application Discontinuation
- 2002-03-07 EP EP02704908A patent/EP1372728B1/en not_active Expired - Lifetime
- 2002-03-07 US US10/471,049 patent/US8349894B2/en not_active Expired - Fee Related
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017056075A1 (en) | 2015-10-01 | 2017-04-06 | Solutex Na, Lcc | Process for the preparation and stabilization of emulsions with omega-3 by means of isometric crystalline networks of cellulose derivatives |
| US10856564B2 (en) | 2015-10-01 | 2020-12-08 | Solutex Na, Lcc | Process for the preparation and stabilization of emulsions with Omega-3 by means of isometric crystalline networks of cellulose derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2404656T3 (en) | 2013-05-28 |
| WO2002070014A8 (en) | 2003-11-27 |
| EP1372728B1 (en) | 2013-02-20 |
| US8349894B2 (en) | 2013-01-08 |
| US20040077724A1 (en) | 2004-04-22 |
| GB0105622D0 (en) | 2001-04-25 |
| EP1372728A1 (en) | 2004-01-02 |
| AU2002238710B2 (en) | 2007-09-06 |
| WO2002070014A1 (en) | 2002-09-12 |
| DK1372728T3 (en) | 2013-05-13 |
| CA2455226A1 (en) | 2002-09-12 |
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