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WO2008101344A1 - Compositions de composés lipophiles bioactifs solubles - Google Patents

Compositions de composés lipophiles bioactifs solubles Download PDF

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Publication number
WO2008101344A1
WO2008101344A1 PCT/CA2008/000336 CA2008000336W WO2008101344A1 WO 2008101344 A1 WO2008101344 A1 WO 2008101344A1 CA 2008000336 W CA2008000336 W CA 2008000336W WO 2008101344 A1 WO2008101344 A1 WO 2008101344A1
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Prior art keywords
ionic surfactant
mixture
lipophilic
phase solution
bioactive compound
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PCT/CA2008/000336
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English (en)
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Peter Tomlinson
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Peter Tomlinson
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Publication of WO2008101344A1 publication Critical patent/WO2008101344A1/fr

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/60—Fish, e.g. seahorses; Fish eggs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A61K8/355—Quinones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/678—Tocopherol, i.e. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/925—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of animal origin
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/02—Preparations containing skin colorants, e.g. pigments
    • A61Q1/04—Preparations containing skin colorants, e.g. pigments for lips
    • A61Q1/06—Lipsticks
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/02—Preparations containing skin colorants, e.g. pigments
    • A61Q1/08—Preparations containing skin colorants, e.g. pigments for cheeks, e.g. rouge
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/02—Preparations containing skin colorants, e.g. pigments
    • A61Q1/10—Preparations containing skin colorants, e.g. pigments for eyes, e.g. eyeliner, mascara
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/12—Face or body powders for grooming, adorning or absorbing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00—Anti-perspirants or body deodorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A61Q3/02—Nail coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/04—Preparations for permanent waving or straightening the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/06—Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A61Q5/065—Preparations for temporary colouring the hair, e.g. direct dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/10—Preparations for permanently dyeing the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners

Definitions

  • the present invention relates to the solubilization of lipophilic bioactive compounds. More particularly, the invention relates to the solubilization of lipophilic bioactive agents using non-ionic surfactant solubilizers. Even more particularly, the present invention relates to methods for preparing water soluble compositions of lipophilic bioactives.
  • bioactive compounds or bioactives important in the food, pharmaceutical and cosmetic industries are lipophilic and, therefore, insoluble in aqueous solutions. These compounds are used in many different forms for many different purposes. For example, bioactive lipophilic compounds used in the cosmetic industry are often applied to the skin in the form of a cream. Similarly, pharmaceutical uses require dosage forms such as oral, topical or intravenous. Food supplements are usually delivered orally in solid or liquid form. It is recognized, therefore, that there is a pressing need to develop new technologies for improving the bioavailability of these insoluble bioactives. It is also important that any technology for increasing the bioavailability of bioactives produces a composition that is amenable to a broad range of applications. Increasing the bioavailability of these bioactives can be achieved by improving their solubility in aqueous solutions.
  • Coenzyme Qio (“CoQi 0 ”) is one example of a lipophilic bioactive that is of particular interest as it has applications in the food, cosmetic and pharmaceutical fields.
  • CoQio also called ubiquinone, is found naturally in the inner membrane of the mitochondria and is involved in electron transfer in oxidative phosphorylation.
  • US Patent 6,300,377 entitled “Coenzyme Q products exhibiting high dissolution qualities” discloses a liquid dosage form of CoQio for oral, cosmetic, dietary supplement or pharmaceutical dosage form.
  • the formulation is non-aqueous and comprises CoQi 0 , a polysorbate surfactant, a vegetable oil or triglyceride, a glyceryl ester and optionally a phospholipids such as hydroxylated lecithin or tocopherols to solubilize the CoQi 0 .
  • US Patent 6,441,050 entitled “Palatable oral coenzyme Q liquid” discloses a pediatric pharmaceutical liquid dosage form of CoQi 0 that is also pleasant-tasting.
  • the formulation is aqueous based and comprises CoQi 0 , with a polysorbate surfactant, a vegetable oil or triglyceride, a glyceryl ester and optionally a phospholipids such as hydroxylated lecithin to enhance the palatability of CoQi 0 , a sweetener and water.
  • US Patent 6,740,338 entitled “Reduced form of Coenzyme Q in high bioavailability stable oral dosage form” discloses a formulation for the reduced form of CoQi 0 in combination with a lipid soluble reducing agent effective to maintain the CoQi 0 in a reduced state and preferably encapsulated in a soft gelatine capsule.
  • U.S. Patent 6,616,942 entitled “Coenzyme QlO formulation and process methodology for soft gel capsules manufacturing” discloses a method and formulation for improving bioavailability of CoQi 0 by delivering it in a soft get capsules containing CoQi 0 , beta- carotenes, Vitamin E, and medium chain triglycerides in rice bran oil and an optional thickener, such as bee's wax, in a soft gel capsule so that a maximum of the CoQi 0 is absorbed by the human body.
  • U.S. patent 6,623,734 entitled “Super absorption coenzyme QlO” also discloses a soft gel capsule method and formulation for delivery of CoQi o with high bioavailability.
  • Patent 7,094,804 entitled “Water free ubiquinone concentrate” discloses a water soluble, essentially water-free CoQi 0 concentrate comprising CoQio, a light oil containing triglycerides, and an emulsifier such as polysorbate present in at least about 73 weight % of the total weight of the concentrate. A method for preparing the concentrate is also disclosed.
  • U.S. Patent 5,989,583 entitled “Solid lipid compositions of lipophilic compounds for enhanced oral bioavailability” discloses a dry solid lipid composition for use in food additives or dietary supplements that in one form, comprises CoQ 10 , a lipid or mixture of lipids that are solid at room temperature and a phospholipid.
  • Nano-sized self-assembled structured liquids discloses nano-sized self-assembled structured concentrates for use as effective carriers for transferring active components into the human body.
  • the nano-sized self-assembled concentrates are liquid concentrates and comprise an aqueous phase, an oil phase, a surfactant, a co-solvent and co-surfactant.
  • US patents 6,045,826, 6,191,172 and 6,632,443 disclose methods of improving solubility of lipophilic compounds, such as Coenzyme Q 10 , in aqueous media.
  • Non-ionic surfactants such as cremophor have been utilized as excipients for injectable pharmaceuticals with mixed results.
  • Such surfactants have also been utilized in compositions with neutraceutical compounds in the presence of solvents, particularly for anything greater than small amounts of insoluble compounds such as CoQi 0 (see, e.g., U.S. App. #s 2003/147927, 20040167034, 20060198830, 2007/141090 and PCT App. No. WO 2006/080903, WO 2005/079758 and WO 2007/061752).
  • the present invention is a based on the surprising discovery that the solubility and bioavailability of lipophilic bioactive compounds such as CoQi 0 can be greatly improved through the use of non-ionic surfactant solubilizers.
  • non-ionic surfactant solubilizers it has been discovered that water soluble and highly bioavailable compositions of CoQi 0 can be easily prepared using commercially available non-ionic surfactant solubilizers.
  • the present invention provides compositions having enhanced dissolution and bioavailablity of lipophilic bioactive compounds whereby the bioactive compound is combined with a non-ionic surfactant.
  • the present invention provides compositions having enhanced dissolution and bioavailablity of lipophilic bioactive compounds whereby the lipophilic bioactive compound is combined with a non-ionic surfactant having a hydrophilic lipophilic balance of between about 10 and about 20 and wherein the molar ratio of the bioactive lipophilic compound and the non-ionic surfactant is from about 1 :0.5 to about 1 :25.
  • the present invention further provides methods for the preparation of lipophilic bioactive compounds having enhanced dissolution and bioavailability whereby the lipophilic bioactive compound is combined with a non-ionic surfactant.
  • the present invention provides pharmaceutical, food product or cosmetic formulations of CoQio comprising an effective amount of CoQi 0 in the form of a water-soluble composition and a pharmaceutically or food or cosmetically acceptable additive or additives or vehicle(s).
  • the present invention also provides pharmaceutical, food product or cosmetic formulations of lipophilic bioactive compounds comprising an effective amount of the lipophilic bioactive compound in the form of a water-soluble composition and a pharmaceutically or food or cosmetically acceptable additive or additives or vehicles).
  • a method of preparing a stable solution including a lipophilic bioactive compound and water comprising the steps of: providing a non-ionic surfactant; preparing a mixture of the lipophilic bioactive compound and the non-ionic surfactant in a predetermined molar ratio; heating the mixture to a temperature necessary to obtain a clear melt; and adding heated water to the mixture to form the stable solution.
  • a method of preparing a stable solution including a lipophilic bioactive compound and water comprising the steps of: providing a non-ionic surfactant; preparing a mixture of the lipophilic bioactive compound and the non-ionic surfactant in a predetermined molar ratio; heating the mixture to a temperature necessary to obtain a clear melt; and formulating with or without acceptable additives into solid dosage forms.
  • a non- ionic surfactant for preparing a water soluble solution comprising a lipophilic bioactive compound.
  • a water soluble pharmaceutical composition comprising a pharmaceutically effective amount of a lipophilic compound and a non-ionic surfactant.
  • a water soluble cosmetic composition comprising a cosmetically effective amount of an active lipophilic compound and a non-ionic surfactant.
  • a water soluble food composition comprising an effective amount of a bioactive lipophilic compound and a non-ionic surfactant.
  • a water soluble hair care composition comprising an effective amount of a bioactive lipophilic compound and a non-ionic surfactant.
  • a method of the prophylaxis or treatment of a medical disorder associated with oxidative tissue damages or mitochondrial dysfunctions comprising administering to a human or a warm-blooded animal in need of such prophylaxis or treatment a therapeutically effective amount of a water-soluble composition according to the present invention.
  • the lipophilic bioactive compounds of the present invention include all those pharmaceutical and bioactives with bioavailability issues as a result of poor aqueous solubility.
  • pharmaceutical actives include: CoQio, ubiquinones, ubiquinols and sterols for various disorders; amphotericin-B, nystatin, and candicidin antibiotics; anticancer drugs such as taxol and doxorubicin; anesthetics such as propafol; and mixtures thereof.
  • bioactives for cosmetic and food applications include: ubiquinones, ubiquinols, idebenone, phytosterols, sterols, sterol esters; flavonoids, carotenoids, tocopherols and other phytochemicals, fish oil containing polyunsaturated fatty acids, omega 3 fatty acids, EPA, DHA; carotenoids, such as ⁇ -carotene, astaxanthin, canatxanthin, lycopene; squalenes; gamma-tocopherol; curcumin; lignans; lunastatin; leutin; aloe vera; essential oils, such as tea tree, basil, eucalyptus, cedarwood, cypress, lemon, lavender, sage, lemongrass, evening primrose, chamomile, lavender, geranium, rose, neroli, ylang ylang, clary sage, palmarosa, carrot, basil; carrier oils, such as sunflower, walnut, olive
  • the non-ionic surfactant of the present invention is completely miscible with water.
  • the surfactant component has a high affinity for and solubility in water, it is bio-compatible (with little to no side effects) and has a melting point close to or below body temperature (about 37 0 C).
  • Other characteristics of concern preferably include good taste and odor, clarity, low toxicity, and other factors that will be determined by the application of the compound.
  • Various classes of non-ionic surfactants are embraced by the present invention.
  • the non-ionic surfactant contains polyethylene glycol (PEG). More specifically, the most preferred PEG-containing surfactant for use in the preparation of the present invention could be defined in several distinct classes.
  • a first class of PEG has a poly oxy ethylene moiety and a hydrophobic moiety consisting of saturated or unsaturated alkyl or alkylphenyl groups.
  • a second class of PEG-containing surfactants derived from triglyceride oils, which includes polyoxythylated vegetable oils. Other classes of non-ionic surfactants are also within the scope of the present invention.
  • the non-ionic surfactant of the present invention is preferably selected from the group consisting Cremophor RH 40TM (polyoxyl 40 hydrogenated castor oil), Cremophor ELTM (polyoxyl 35 castor oil), Cremophor ELPTM (polyoxyl 35 castor oil), and Solutol HS 15TM (macrogol 15 hydroxystearate), PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-60 castor oil, monostearate (and derivatives thereof), glyceryl laurate, glyceryl stearate, glyceryl oleate, glyceryl monooleate, glyceryl monolaurate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan stearate, nonyl phenols, octyl phenols, caprylocaproyl polyoxyglycerides, lauroyl polyoxyglycerides
  • the non-ionic surfactant is Cremophor RH 40TM (polyoxyl 40 hydrogenated castor oil), Cremophor ELTM (polyoxyl 35 castor oil), Cremophor ELPTM (polyoxyl 35 castor oil), Solutol HS 15TM (macrogol 15 hydroxystearate) or TPGSTM (d- ⁇ -tocopheryl polyethylene glycol succinate).
  • Cremophor RH 40TM polyoxyl 40 hydrogenated castor oil
  • Cremophor ELTM polyoxyl 35 castor oil
  • Cremophor ELPTM polyoxyl 35 castor oil
  • Solutol HS 15TM microgol 15 hydroxystearate
  • TPGSTM d- ⁇ -tocopheryl polyethylene glycol succinate
  • Sustained solubilization ensures that the drug will remain solubilized in the gastrointestinal tract for a significant amount of time and, thus, improve transport across the aqueous boundary layer.
  • compositions having enhanced dissolution and bioavailablity of lipophilic bioactive compounds whereby the lipophilic bioactive compound is combined with a non-ionic surfactant having a hydrophilic lipophilic balance of between about 10 and about 20 and wherein the molar ratio of the bioactive lipophilic compound and the non-ionic surfactant is from about 1.0.5 to about 1 :25.
  • the invention composition comprises the molar ratio of the bioactive lipophilic compound and the non-ionic surfactant of from about 1 : 1 to about 1 : 10; more preferably from about 1 :3 to about 1 :5.
  • the ratio is dependent on the particulate bioactive and is the ratio required to obtain complete solubilization of the bioactive in the non-ionic surfactant as a single- or one-phase solution upon cooling. This ratio results in higher levels of the bioactive compounds in solution than existing technologies, in the range of 10% or greater, more typically 20%, 25%, 33%, 50% or greater of the bioactive compound in relation to the percentage of the surfactant.
  • a method of preparing a stable solution including at least one lipophilic bioactive compound and at least one non-ionic surfactant comprising the steps of: providing a non-ionic surfactant and the lipophilic bioactive compound in a predetermined molar ratio, and heating the non-ionic surfactant and the lipophilic bioactive compound to a temperature necessary to obtain a clear melt.
  • the lipophilic bioactive compound and the non-ionic surfactant compound can be mixed prior to heating to create the clear melt, or heated separately to each (or in groups) create clear melt solutions.
  • the lipophilic bioactive compound(s) and non-ionic compounds can be melted separately, combined in an appropriate ratio and the mixture reheated and mixed until a single phase solution results.
  • the melted formulating can occur with or without acceptable additives into solid dosage forms.
  • the invention also includes compositions produced by this method.
  • the melting point of most compounds are known to those skilled in the art and may depend on factors such as pressure, humidity, and other such factors which trigger melting of compounds.
  • the compounds should be heated to such temperature to obtain a clear melt where the components will appear relatively transparent.
  • preparation can occur at lower temperatures but be stirred or agitated for longer periods of time.
  • the quantity and the preparation temperature the time needed to dissolve the components will vary.
  • it can also be prepared by sonication, microwave, or other mixing method that creates a homogenous liquid or single-phase solution.
  • Suitable manufacturing equipment would include, for example, stainless steel, heating jacketed, pressurized or non-pressurized, lightening mixers.
  • the temperature range for melting the components is preferably from about 20° C and about 120° C, more preferably about 25° C to about95° C, more preferably about 30° C to about 95° C, more preferably about 35° C to about90° C, more preferably about 40° C to about85° C, more preferably about 45° C to about80° C, and most preferably about 50° C to about70°C.
  • a substantially clear or clear emulsion is formed.
  • the emulsion (of individual components or combinations thereof) stays clear on cooling to room temperature.
  • the emulsion does not separate into two layers on cooling to room temperature but remains in a single-phase solution. Sometimes heating to temperatures of 120° C is required (bioactive stability is necessary) but more normally about 50° C to about70° C
  • the mixing or agitation step mixes the components and preferably includes magnetic stirring, sonication, shaking and vortex agitation, and includes agitators such as orbital shakers, sonicators, vibrators, and stirrers.
  • a liquid solubilized, bioavailable form of a lipophilic bioactive agent which for the purposes of the description of the preferred embodiment is CoQ io
  • a suitable non-ionic surfactant as described above
  • a gel forms which is stirred vigorously for about an hour and slowly the CoQi 0 goes into solution to form a bright red/orange clear solution at a concentration of 50mg/g.
  • Such solution is stable and can then be used to manufacture creams, drinks, solid oral dosage forms and IV dosage forms with or without additional materials such as flavours, buffers, preservatives, binders, fillers etc.
  • solubilised, bioavailable CoQio can be prepared by dissolving the bioactive lipophilic compound and the solubilizing agent in a predetermined molar ratio in a water- miscible organic solvent and subsequently diluting the solution with a predetermined amount of water and then removing the organic solvent from the solution and optionally an amount of water necessary to achieve a desired concentration of the water-soluble composition.
  • the solvent and water may be removed by any conventional means known to the person skilled in the art including, for example, evaporation under reduced pressure.
  • a further alternate method of preparing a water soluble composition of a lipophilic bioactive agent such as CoQ 10 involves first dissolving the lipophilic bioactive agent and the non-ionic surfactant in a water miscible solvent. The next step is to dilute the resulting solution with a predetermined amount of water. The following step is the removal from the solution of the organic solvent and optionally an amount of water necessary to achieve a desired concentration of the water soluble composition.
  • the present invention also includes dry formulations of a lipophilic bioactive agent which solubilises in water upon contact.
  • dry formulations are prepared by melting for example CoQi 0 and a suitable non-ionic surfactant together by heating a mixture of the two components to around 65° C in order to form a melt. Water may optionally be added at this point to form a gel which is stirred vigorously for about an hour and slowly the CoQio goes into solution to form a bright red/orange clear solution at a concentration of 50mg/g. The water is then removed by lyophilisation or other methods known in the art. Dry formulations may need additional ingredients such as polyethylene glycol 600, polyethylene glycol 400 or polypropylene glycol to stabilize the complex.
  • the liquid complex may also be lyophilized and filled into capsules or vials or compressed into tablets with or without additional materials.
  • the dry formulation is useful for example in the preparation of oral dosage forms such as tablets and capsules.
  • the lipophilic bioactive agent is solubilized upon ingestion where it is readily absorbed.
  • compositions required in a sterile format can be preferably subjected to heat or filter sterilization.
  • composition of solubilised bioavailable bioactive lipophilic compound of the present invention can be used in the preparation of pharmaceutical dosage forms known in the art including topical, oral, parenteral, suppository and aerosol.
  • Routes of administration include intravenous, oral, topical, rectal, parenteral (injectable), local, inhalant and epidural administration.
  • the compositions of the invention may also be conjugated to transport molecules or included in transport modalities such as vesicles and micelles to facilitate transport of the molecules.
  • the compositions of the invention may also be conjugated to transport molecules, monoclonal antibodies or transport modalities such as vesicles and micelles.
  • Pharmaceutical compositions including the compounds of the present invention can be administered to humans or animals.
  • compositions of the present invention are also used to prepare cosmetic preparations, including hair care products, known in the art including creams, gels or liquid preparations such as aerosols and mists.
  • the cosmetic preparations include foam baths, oil baths, oil moisturizers, sun protection agents, lotions, baby care products, gels or ointments and, oil bodies, emulsifiers, hyperfatting agents, pearl lustre waxes, consistency substances, thickening agents, polymers, silicon compounds, fats, waxes, stabilizing agents, biogenic active substances, deodorants, agents against dandruff, film forming agents, swelling agents, UV light protection factors, antioxidants, inorganic colour pigments, hydrotropes, preservatives, insect repellents, self tanning agents, perfume oils, and colouring agents.
  • cosmetics of the present invention also include: skin-care creams, serums, lotions, powders, perfumes, lipsticks, fingernail polishes, eye and facial makeup, permanent waves, hair colors, hair shampoo, hair conditioners, deodorants, bath oils, bubble baths, and many other types of products.
  • Cosmetic compositions including the compounds of the present invention can be administered to humans or animals.
  • compositions of the present invention are also used to prepare food formulations known in the art including dry solid, wet semi-solid and liquid formulations.
  • Foods of the present invention include liquid and solid dietary supplements, liquid and solid nutritional supplements, functional foods, functional drinks, and many other types of products.
  • Food compositions including the compounds of the present invention can be administered to humans or animals.
  • the composition comprising a non- ionic surfactant and bioactive compound is a nutritional supplement or nutraceutical prepared as a dietary supplement.
  • the composition can be prepared in a hard or soft gelatin capsules by means known in the art.
  • the composition can also be added to drinks or beverages, or in other palatable solution.
  • the non-ionic surfactant will have palatable characteristics or masked with flavoring.
  • an effective amount of the solubilized and bioavailable lipophilic bioactive compound is added to the formulation in a therapeutically effective amount along with any additional acceptable additive or vehicle selected from, for example, solvents, adjuvants, sweeteners, fillers, colourants, flavouring agents, lubricants, binders, moisturizing agents, preservatives and mixtures thereof as the case may be.
  • any additional acceptable additive or vehicle selected from, for example, solvents, adjuvants, sweeteners, fillers, colourants, flavouring agents, lubricants, binders, moisturizing agents, preservatives and mixtures thereof as the case may be.
  • CoQio can be used in the treatment of certain ailments including hypercholesteremia, infectious diseases and cancers.
  • a pharmaceutical preparation for use in the treatment of hypercholesterolemia according to the present invention comprises a therapeutically effective amount of solubilised composition CoQio and a pharmaceutically acceptable carrier.
  • the present invention includes a pharmaceutical composition for the treatment of a fungal infection comprising a therapeutically effective amount of a solubilised composition of CoQio and a macrolide polyene antibiotic as the bioactive lipophilic compound, in conjunction with a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known and understood by person skilled in the art.
  • CoQio and other lipophilic bioactive compounds are also useful ingredients in cosmetics, including hair care products, for alleviating a number of skin conditions.
  • CoQio and other lipophilic bioactive compounds can also be delivered through food compositions for health and therapeutic benefits.
  • the manufacture of the fill formulations of the present invention requires standard mixing and heating equipment known by persons skilled in the art, while conventional emulsion methods require high energy input and shearing during processing.
  • the fill formulations of the present invention are also physically stable without recrystallization during storage. Stable shelf life is critical for commercialization.
  • Solubility and dissolution are the limiting factors in bioavailability of coenzyme Qi 0 . These factors have been successfully overcome by the present invention. Therefore, the bioavailability of the formulations of the present invention is has higher bioavailability than prior art formulations.
  • the principle, methodology and formulations developed in this application are not limited to coenzyme Q 10 . They are also applicable to other poorly water-soluble pharmaceutical active ingredients for improving dissolution and bioavailability.
  • Cremophor RH 40 (10Og) is heated to around 60°C until a clear liquid results.
  • Fish oil (25g) is heated to around 50 0 C until a clear liquid results.
  • Cremophor RH 40 and fish oil are combined in an appropriate ratio and the mixture reheated to around 5O 0 C and mixed until a single phase solution results.
  • 5g of the mixture is added to 50Og of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results.
  • a solution containing Ig of fish oil in 500 ml of spring water results.
  • the fish oil complex can be added to Gatorade, Propel or other sports drink.
  • Cremophor RH 40 (10Og) is heated to around 6O 0 C until a clear liquid results.
  • Oleo resin 25g is heated to around 6O 0 C until a clearer liquid results.
  • Cremophor RH 40 and Oleo resin are combined in an appropriate ratio and the mixture reheated to around 6O 0 C and mixed until a single phase solution results.
  • 2.5g of the mixture is added to 500g of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results.
  • a solution containing 500 mg of Oleo resin in 500 ml of water results.
  • the oleo resin can be added to Gatorade, Propel or other sports drinks.
  • Cremophor RH 40 (10Og) is heated to around 6O 0 C until a clear liquid results.
  • avocado oil 25g is heated to around 60 0 C until a clear liquid results.
  • Cremophor RH 40 and Oleoresin are combined in an appropriate ratio and the mixture reheated 60 0 C and mixed until a single phase solution results.
  • 2.5g of the mixture is added to 500g of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results.
  • a solution containing 500 mg of avocado oil in 500 ml of water results.
  • the avocado oil can be added to Gatorade, Propel or other sports drinks.
  • Cremophor RH 40 (10Og) is heated to around 60 0 C until a clear liquid results.
  • Fish oil 25g is heated to around 5O 0 C until a clear liquid results.
  • Cremophor RH 40 and fish oil are combined in an appropriate ratio and the mixture reheated to 50 0 C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool. A capsule containing 200 mg of water soluble fish oil results.
  • the fish oil complex can be encapsulated in a soft gelatine capsule.
  • CoQi 0 Preparation of a CoQi 0 capsule. Cremophor RH 40 (75g) is heated up to 120 0 C until a clear liquid results. CoQi 0 (25g) is heated to around 60°C until a clear liquid results. Cremophor RH 40 and CoQi 0 are combined in an appropriate ratio and the mixture reheated up to 12O 0 C and mixed until a single phase solution results. The mixture is allowed to cool to room temperature and the cycle repeated until a stable complex is achieved. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool. A capsule containing 300 mg of water soluble CoQio results. Alternatively the CoQi 0 complex can be encapsulated in a soft gelatine capsule.
  • Vitamin E capsule Preparation of a Vitamin E capsule. Cremophor RH 40 (10Og) is heated to around 6O 0 C until a clear liquid results. Vitamin E (25g) is heated to around 60°C until a clear liquid results. Cremophor RH 40 and vitamin E are combined in an appropriate ratio and the mixture reheated to 60 °C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool. A capsule containing 200 mg of water soluble vitamin E results. Alternatively the vitamin E complex can be encapsulated in a soft gelatine capsule.
  • Cremophor RH 40 (10Og) is heated to around 60°C until a clear liquid results.
  • avocado oil 25g is heated to around 60°C until a clear liquid results.
  • Cremophor RH 40 and avocado oil are combined in an appropriate ratio and the mixture reheated to 6O 0 C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool.
  • a capsule containing 200 mg of water soluble avocado oil results.
  • the avocado oil complex can be encapsulated in a soft gelatine capsule.
  • Cremophor RH 40 (4Og) is heated to around 60°C until a clear liquid results.
  • CoQi 0 (5g) and vitamin E (5g) are mixed and heated to around 60°C until a clear liquid results.
  • Cremophor RH 40 and the bioactive mixture are combined in an appropriate ratio and the mixture reheated to around 60 0 C and mixed until a single-phase solution results.
  • 1Og of the mixture is added to 500g of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results.
  • a solution containing Ig of CoQi 0 and 1 g of vitamin E in 500 ml of spring water results.
  • the CoQi 0 /vitamin E complex can be added to Gatorade, Propel or other sports drink.
  • CoQi 0 /avocado oil beverage Preparation of a CoQi 0 /avocado oil beverage. Cremophor RH 40 (4Og) is heated to around 60°C until a clear liquid results. CoQio (5g) and avocado oil (5g) are mixed and heated to around 60 0 C until a clear liquid results. Cremophor RH 40 and the bioactive mixture are combined in an appropriate ratio and the mixture reheated 60 0 C and mixed until a single phase solution results. 1Og of the mixture is added to 500g of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results. A solution containing Ig of CoQi 0 and 1 g of avocado oil in 500 ml of spring water results. Alternatively the CoQi 0 /avocado oil complex can be added to Gatorade, Propel or other sports drink.
  • Cremophor RH 40 and the bioactive mixture are combined in an appropriate ratio and the mixture reheated to around 6O 0 C and mixed until a single phase solution results. 1Og of the mixture is added to 50Og of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results. A solution containing 750 mg of CoQlO,
  • CoQ io /avocado oil complex can be added to Gatorade, Propel or other sports drink.
  • Cremophor EL (6Og) is heated to around 60 0 C until a clear liquid results.
  • CoQio (5g), avocado oil (5g) and vitamin E (5g) are mixed and heated to around 60 0 C until a clear liquid results.
  • Cremophor EL and the bioactive mixture are combined in an appropriate ratio and the mixture reheated to around 60 0 C and mixed until a single phase solution results. 4Og of the mixture is added to 6Og of moisturizing cream to produce a cosmetic cream with 1% of each bioactive.
  • Cremophor EL (4Og) is heated to around 60 0 C until a clear liquid results.
  • CoQio (4g), avocado oil (8g) and vitamin E (6g) are mixed and heated to around 60 0 C until a clear liquid results.
  • Cremophor EL and the bioactive mixture are combined in an appropriate ratio and the mixture reheated to 60 0 C and mixed until a single phase solution results.
  • 2Og of the mixture is added to 500g of spring water and the mixture stirred vigorously until the complex disperses and a clear solution results.
  • the solution containing 0.08% CoQio, 0.16% avocado oil and 0.12% vitamin E is filled into a spray bottle to produce an enriched body spray.
  • Cremophor RH 40 (4Og) is heated to around 60°C until a clear liquid results.
  • CoQi 0 (5g) and vitamin E (5g) are mixed and heated to around 60 0 C until a clear liquid results.
  • Cremophor RH 40 and the bioactive mixture are combined in an appropriate ratio and the mixture reheated 60°C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool.
  • a capsule containing 100 mg of water soluble CoQi 0 and 100 mg of water soluble vitamin E results.
  • the complex can be encapsulated in a soft gelatine capsule.
  • Cremophor RH 40 (4Og) is heated to around 60°C until a clear liquid results.
  • CoQi 0 (5g) and avocado oil (5g) are mixed and heated to around 60 0 C until a clear liquid results.
  • Cremophor RH 40 and the bioactive mixture are combined in an appropriate ratio and the mixture reheated 60 0 C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool.
  • a capsule containing 100 mg of water soluble CoQi 0 and 100 mg of water soluble avocado oil results.
  • the complex can be encapsulated in a soft gelatine capsule.
  • Cremophor RH 40 (6Og) is heated to around 60 0 C until a clear liquid results.
  • CoQi 0 (5g), avocado oil (5g) and vitamin E (5g) are mixed and heated to around 6O 0 C until a clear liquid results.
  • Cremophor EL and the bioactive mixture are combined in an appropriate ratio and the mixture reheated to 6O 0 C and mixed until a single phase solution results. Ig of the mixture while warm is added to a "000" hard gelatine capsule and allowed to cool.
  • a capsule containing 67 mg of water soluble CoQi 0 , 67 mg of water soluble avocado oil amd 67 mg of water soluble vitamin E results.
  • the complex can be encapsulated in a soft gelatine capsule.

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Abstract

L'invention concerne un procédé de préparation d'une solution hydrosoluble stable comprenant un composé bioactif lipophile tel que du CoQ10. Le procédé consiste à : former un tensio-actif non ionique; préparer un mélange du composé bioactif lipophile et du tensio-actif non ionique selon un rapport molaire prédéterminé; chauffer le mélange à la température nécessaire pour obtenir un produit fondu transparent; et ajouter de l'eau chauffée au mélange afin de former la solution stable. L'invention se rapporte à des compositions produites selon ce procédé et à des utilisations desdites compositions, notamment comme compositions pharmaceutiques, alimentaires et cosmétiques.
PCT/CA2008/000336 2007-02-22 2008-02-22 Compositions de composés lipophiles bioactifs solubles WO2008101344A1 (fr)

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CN103462887A (zh) * 2013-08-09 2013-12-25 张蕊 一种维生素k1注射液及其制备方法
US8637569B2 (en) 2009-10-22 2014-01-28 Api Genesis, Llc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compounds
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EP2488022A4 (fr) * 2009-10-16 2014-02-19 Glaxosmithkline Llc Compositions
EP2471545A4 (fr) * 2009-05-11 2014-04-02 Herrero Maria Pilar Mateo Composition microencapsulée à base d'olea europaea saponifiée, son utilisation et son procédé d'obtention
US8795634B2 (en) 2008-09-12 2014-08-05 Critical Pharmaceuticals Limited Absorption of therapeutic agents across mucosal membranes or the skin
JP2016505579A (ja) * 2012-12-19 2016-02-25 アクアノヴァ アクチエンゲゼルシャフト クルクミン可溶化物
WO2016071434A1 (fr) * 2014-11-05 2016-05-12 Abbott Laboratories Gmbh Procédés pour produire des compositions à profil de sécurité d'emploi amélioré comprenant de la pancréatine et des compositions adaptées à un usage pharmaceutique
US9750705B2 (en) 2012-08-31 2017-09-05 The Regents Of The University Of California Agents useful for treating obesity, diabetes and related disorders
US9889098B2 (en) 2009-10-22 2018-02-13 Vizuri Health Sciences Llc Methods of making and using compositions comprising flavonoids
WO2019148282A1 (fr) 2018-02-01 2019-08-08 The Royal Institution For The Advancement Of Learning/Mcgill University Formulations permettant d'améliorer l'administration d'agents hydrophobes
CN110200910A (zh) * 2019-06-17 2019-09-06 宁波海奇合昇环能科技有限公司 一种辅酶q10透明水分散液的制备方法
CN113056260A (zh) * 2018-11-26 2021-06-29 奥尔法尼克斯有限公司 水性儿科视黄醇制剂

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US8795634B2 (en) 2008-09-12 2014-08-05 Critical Pharmaceuticals Limited Absorption of therapeutic agents across mucosal membranes or the skin
US9700509B2 (en) 2008-11-27 2017-07-11 Universität Regensburg Solutions of lipophilic substances, especially medicinal solutions
DE102008059201A1 (de) * 2008-11-27 2010-06-02 GÖPFERICH, Achim, Prof. Dr. In situ präzipitierende Arzneistofflösungen
EP2471545A4 (fr) * 2009-05-11 2014-04-02 Herrero Maria Pilar Mateo Composition microencapsulée à base d'olea europaea saponifiée, son utilisation et son procédé d'obtention
US10668038B2 (en) 2009-10-16 2020-06-02 Mochida Pharmaceutical Co., Ltd. Emulsion and emulsion preconcentrate compositions comprising omega-3 fatty acids and uses thereof are disclosed
US9717703B2 (en) 2009-10-16 2017-08-01 Glaxosmithkline Llc Emulsion and emulsion preconcentrate compositions comprising omega-3 fatty acids and uses thereof are disclosed
EP2488022A4 (fr) * 2009-10-16 2014-02-19 Glaxosmithkline Llc Compositions
US9730953B2 (en) 2009-10-22 2017-08-15 Vizuri Health Sciences Llc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compound
US8637569B2 (en) 2009-10-22 2014-01-28 Api Genesis, Llc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compounds
US11491226B2 (en) 2009-10-22 2022-11-08 Technology Investments Lc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compound
US9889098B2 (en) 2009-10-22 2018-02-13 Vizuri Health Sciences Llc Methods of making and using compositions comprising flavonoids
US11135177B2 (en) 2009-10-22 2021-10-05 Vizuri Health Sciences Consumer Healthcare, Inc. Methods of making and using compositions comprising flavonoids
US9731015B2 (en) 2012-08-04 2017-08-15 Eric Hauser Kuhrts Water-soluble lipophilic natural compound formulations
WO2014025672A1 (fr) * 2012-08-04 2014-02-13 Eric Hauser Kuhrts Formulations de composés naturels lipophiles hydrosolubles
US9750705B2 (en) 2012-08-31 2017-09-05 The Regents Of The University Of California Agents useful for treating obesity, diabetes and related disorders
JP2016505579A (ja) * 2012-12-19 2016-02-25 アクアノヴァ アクチエンゲゼルシャフト クルクミン可溶化物
US11311483B2 (en) 2012-12-19 2022-04-26 Aquanova Ag Curcumin solubilisate
CN103462887A (zh) * 2013-08-09 2013-12-25 张蕊 一种维生素k1注射液及其制备方法
CN107073084A (zh) * 2014-11-05 2017-08-18 雅培制药股份有限公司 用于生产具有改善的安全特性的具有脂肪酶活性的组合物和适用于药物用途的组合物的方法
WO2016071434A1 (fr) * 2014-11-05 2016-05-12 Abbott Laboratories Gmbh Procédés pour produire des compositions à profil de sécurité d'emploi amélioré comprenant de la pancréatine et des compositions adaptées à un usage pharmaceutique
RU2712142C2 (ru) * 2014-11-05 2020-01-24 Эбботт Лабораторис Гмбх Способы получения композиций с улучшенным профилем безопасности, содержащих панкреатин, и композиции, пригодные для фармацевтического применения
WO2019148282A1 (fr) 2018-02-01 2019-08-08 The Royal Institution For The Advancement Of Learning/Mcgill University Formulations permettant d'améliorer l'administration d'agents hydrophobes
US12053441B2 (en) 2018-02-01 2024-08-06 The Royal Institution For The Advancement Of Learning/Mcgill University Formulations for improving the delivery of hydrophobic agents
CN113056260A (zh) * 2018-11-26 2021-06-29 奥尔法尼克斯有限公司 水性儿科视黄醇制剂
CN110200910B (zh) * 2019-06-17 2022-04-19 北京中超海奇科技有限公司 一种辅酶q10透明水分散液的制备方法
CN110200910A (zh) * 2019-06-17 2019-09-06 宁波海奇合昇环能科技有限公司 一种辅酶q10透明水分散液的制备方法

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