WO2023177313A1 - Composition formant des émulsions monodispersées stables dans l'eau - Google Patents

Composition formant des émulsions monodispersées stables dans l'eau Download PDF

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WO2023177313A1
WO2023177313A1 PCT/PL2023/050015 PL2023050015W WO2023177313A1 WO 2023177313 A1 WO2023177313 A1 WO 2023177313A1 PL 2023050015 W PL2023050015 W PL 2023050015W WO 2023177313 A1 WO2023177313 A1 WO 2023177313A1
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composition
acid
vitamin
active
water
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PCT/PL2023/050015
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Paweł Mituła
Grzegorz Andrzej KIEŁBOWICZ
Tomasz Tronina
Radosław GNIŁKA
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Healthcann Sp. Z O.O.
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Publication of WO2023177313A1 publication Critical patent/WO2023177313A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • 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
    • 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
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol

Definitions

  • composition forming stable monodisperse emulsions in water
  • the subject matter of the invention concerns stable self-emulsifying compositions containing naturally fat-soluble vitamins and provitamin derivatives thereof as well as molecular entities constituting their chemical modifications, including vitamin derivatives non-fat-soluble in their native forms and whose chemical analogs are useful as pharmaceutical and food ingredients, as well as active substances of natural origin with proven biological and/or therapeutic activity being lipophilic and/or hydrophobic compounds, including various extracts of hemp-derived compounds and standardized plant extracts.
  • the present invention concerns novel compositions of single compounds or various combinations thereof which, according to the subject matter of the invention, form aqueous dispersions of substances with low solubility in water, having lipophilic properties in aqueous solutions.
  • the proposed compositions may be readily diluted in aqueous solutions.
  • compositions or foodstuffs which can be easily delivered with simple dosing of adequate amounts of active ingredients.
  • the proposed compositions significantly increase the bioavailability of active substances which show poor gastrointestinal absorption in animals due to their hydrophobic and/or lipophilic properties.
  • the value may be particularly high for products delivered in aqueous systems in a non-modified form, in particular for hydrophobic compounds, wherein the substances precipitate and their bioavailability is low (typically less than 10%) (Rein, M.J., Renouf, M., Cruz-Hernandez, C., Actis-Goretta, L, Thakkar, S.K., da Silva Pinto, M.
  • Bioavailability of bioactive food compounds a challenging journey to bioefficacy, British journal of clinical pharmacology, 75 (3) 588- 602; 2013, Dima, C., Assadpour, E., Dima, S., Jafari, S.M., Bioavailability and bioaccessibility of food bioactive compounds; overview and assessment by in vitro methods, Comprehensive Reviews In Food Science And Food Safety, 19; 2862- 2884; 2020).
  • they lack homogeneity, so that the products do not perform their functions as they fail to deliver the active substance in declared amounts or cause non-uniform delivery.
  • a number of other forms of foodstuffs are water-based or their manufacture and manufacturing processes require water.
  • a system of nanostructural lipid carriers is one of the most interesting colloid systems that provide an extremely attractive strategy to solve the problem of the delivery of active compo unds in liquid formulations for oral intake.
  • active delivery systems micelles, liposomes, lipid micro- and nanoparticles
  • self-emulsifying systems in aqueous solutions have raised great interest.
  • Self-emulsifying systems are lipid compositions made from blends of oils, surface active agents, solvents and co-solvents/surfactants (WO 2015/155703). When blended in adequate proportions, they may be used for designing formulations to improve oral absorption of highly lipophilic active compounds.
  • micelles When being formed, micelles (with typical sizes of up to 250 nm, and frequently below 100 nm) consist of a lipid nucleus (core) principally made of glycerides (essentially triglycerides, di- and monoglycerides) in which the active lipophilic substance is dissolved (molecular dispersion in the lipid core) and a layer of molecules of surfactant(s), which serve as emulsifiers, adsorbed at the oil/water interface and arranged so that the non-polar part of their molecules is immersed in the oil phase and polar parts are in the aqueous phase (WO 2002007712A2).
  • core principally made of glycerides (essentially triglycerides, di- and monoglycerides) in which the active lipophilic substance is dissolved (molecular dispersion in the lipid core) and a layer of molecules of surfactant(s), which serve as emulsifiers, adsorbed at the oil/water interface and arranged so that
  • Vitamins are one of the most important among the multiple chemical compounds necessary for the normal function and course of a number of metabolic processes. Vitamins are low-molecular organic compounds whose presence in low amounts in the body frequently ensures appropriate activity of many enzymes. These are exogenous compounds for a number of organisms, including animals and humans, and they need to be supplied with food (WO 2015/169816). Certain vitamins may be synthesized from precursors known as provitamins, such as vitamin A from carotenoids, vitamin D3 from 7-dehydrocholesterol.
  • Vitamins are classified first of all based on their physical properties, and they are divided into fat-soluble vitamins: vitamin A (retinol and derivatives), vitamin D (cholecalciferol), vitamin E (tocopherol), vitamin K (phylloquinone) and water-soluble vitamins: vitamin C (ascorbic acid), vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin, vitamin H), vitamin B12 (cyanocobalamin) and folic acid.
  • vitamin A retinol and derivatives
  • vitamin D cholesterolcalciferol
  • vitamin E tocopherol
  • vitamin K phytoquinone
  • water-soluble vitamins vitamin C (ascorbic acid), vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin, vitamin
  • the fat-soluble vitamins are non-polar hydrophobic molecules, being isoprene derivatives which should be supplied in everyday diet and theiravailability depends on the adequate absorption of fats.
  • ADEK vitamins are involved in processes, such as regulation of calcium and phosphate metabolism, regulation of blood coagulation processes, act as antioxidants and they are necessary for the normal function of the epithelial tissue and processes of vision (US 6361800 Bl, US 9439913 Bl).
  • vitamin A is retinol and its derivatives.
  • Carotenoids containing at least one P-ionone ring, are direct precursors of vitamin A and they are very common in plants.
  • vitamin A is formed through the enzymatic oxidative breakdown of a provitamin.
  • the vitamin has a prominent role as it is instrumental in healthy vision, adequate skin condition and healthy mucosae.
  • vitamin A is beneficial for immunity.
  • Vitamin D (cholecalciferol and derivatives) is a group of steroid compounds. About 10 provitamins are known from which compounds having vitamin D activity form. In terms of human nutrition, vitamins D2 and D3, known as ergocalciferol and cholecalciferol, respectively, are most important. Vitamin D shows an effect on immunity, healthy structure of the skeletal system as well as on the nervous system, and it even regulates insulin production. Natural vitamin D forms in human skin exposed to sunlight. Unfortunately, irradiation is not sufficient at all latitudes to ensure adequate supply to the body. In addition, due to lifestyle changes, the vitamin is currently commonly supplemented not only in fall and winter but also in spring and summer.
  • Vitamin E is an antioxidant whose function is to protect cells against oxidation and thus death by removing free radicals. What is also important, it has anticoagulant and anticancer properties. In addition, it has an effect on the function of the reproductive system. Vitamin E deficiency may result in keratosis, skin ageing, problems with concentration, loss of vision, anemia or even infertility (EP 0165352).
  • Vitamin K is necessary for normal blood coagulation. In the liver, it is required for the synthesis of prothrombin, a protein from which fibrin (blood clot) forms. It is also involved in bone tissue formation and has antibacterial, antifungal, analgesic and anti-inflammatory properties.
  • vitamin E tocopherol acetate (US 7169943 B2, EP 0882036 Al) is an example of such a compound.
  • derivatives are known which dramatically alter the physicochemical properties of chemical compounds.
  • Aspartic acid palmitate ester CN 102558115 A, CN 102260231 B
  • vitamin C ascorbic acid
  • Ascorbyl palmitate its derivative, yields a fat-soluble form of the vitamin and it is also used as a food-grade antioxidant (E304) in this form, approved in the European Union, the U.S., Australia and New Zealand. Furthermore, ascorbyl stearate is used as a source of vitamin C and as an antioxidative additive to margarine.
  • bioactive lipophilic compounds are known which may be used in foods based on their health-promoting properties, such as carotenoids, omega-3 and omega-6 fatty acids (US 6284268), polyphenols, flavonoids, phytosterols and other standardized plant extracts.
  • carotenoids omega-3 and omega-6 fatty acids (US 6284268)
  • polyphenols polyphenols
  • flavonoids polyphenols
  • phytosterols phytosterols
  • oral de livery of highly hydrophobic compounds in particular in aqueous systems, is a considerable challenge not only due to their low water solubility, rapid oxidation and a low sensory threshold, but also based on their low bioavailability after gastrointestinal digestion.
  • compositions with improved bioavailability useful for compounds of the aforementioned groups, in particular astaxanthin, zeaxanthin, lutein, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA), but also alpha-lipoic acid, naringenin, genistein, silymarin, curcumin, resveratrol, cannabidiol, cannabinoids, ubiquinone (coenzyme Q10) or various plant extracts.
  • astaxanthin zeaxanthin
  • lutein eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • CLA conjugated linoleic acid
  • alpha-lipoic acid alpha-lipoic acid
  • naringenin genistein
  • silymarin silymarin
  • curcumin resveratrol
  • oils from omega-3 fatty acids include for example long-chain polyunsaturated omega-3 fatty acids, such as EPA, DHA, a-linolenic acid (ALA), omega-3 fatty acid glycerol esters, such as mono-, di- and triglycerides; and omega-3 fatty acid esters with primary, secondary and/or tertiary alcohols, such as fatty acid ethyl esters.
  • Omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof of the present disclosure may be used in their pure form and/or as an ingredient of oil, e.g. as marine oil (fish oil, purified fish oil concentrates), algal oils, microbiological oils and other plant oils or mixtures thereof.
  • cannabinoids are an interesting group as natural chemical substances found in hemp (Cannabis sativa L.) - both wild (Cannabis sativa ruderalis J.) and cultivated (Cannabis sativa sativa L.) and Indian (Cannabis sativa indica). Tetrahydrocannabinol (THC) and cannabidiol (CBD) currently attract most attention.
  • cannabinoids are a broad group of compounds which, as single compounds or mixtures in the form of cannabinoid extracts, are insoluble in water. Formulations have been reported, related to a self-dispersing emulsion using cannabinoids as a hydrophobic compound (US 20200037638).
  • compositions that increase the solubility of cannabinoids themselves do not form homogenous systems, and the present application concerns combinations of cannabinoids and/or cannabinoid extracts in self-emulsifying compositions in combination with various active compounds having health-promoting, active or therapeutic properties (US 2020/022386 Al, WO 2019/135224 Al).
  • the problem in this invention is the poor solubility of the active substances having lipophilic and/or hydrophobic properties in aqueous solutions, which results in their low gastrointestinal absorption in animals (low bioavailability).
  • Another problem to be addressed by the present invention is the formation of homogenous suspensions.
  • lipid-based delivery forms for active substances having these parameters are used, no such solutions are available. These are typically so-called “milky” suspensions, unstable over time and showing a tendency of breaking, without proven active substance bioavailability.
  • vigorous stirring or expensive, complex or poorly effective devices, such as ultrasonic or high-pressure homogenizers frequently need to be used to form a homogenous dispersed system in a short time.
  • compositions are not tolerant to dilution, and have low content of substances or inferior stability at low pH values (below 3), applicable to most of the commonly used drinks, which significantly limits the usability of such products.
  • Another but very important factor is the ease of dose dispensing for the active substance, because excessive amounts of active substance (such as ADEK vitamins) are even disadvantageous.
  • the objective of the present invention is to disclose an improved composition with increased bioavailability which contains fat-soluble vitamins, and derivatives thereof and/or active substances of natural origin from groups of carotenoids, fatty acids and their derivatives, polyphenols, flavonoids, phytosterols, standardized plant extracts, etc. being lipophilic and/or hydrophobic active compounds with health-promoting and therapeutic properties, as a result of which a stable self-emulsifying emulsion is obtained which shows high transparency, short time to forming dispersion and yields a homogenous system, easily forming dispersion and providing nanoparticles with small hydrodynamic parameters, monodispersity of the nanosystem and high load (active substance content), wherein the quantity of the active substance may be easily dosed and delivered to the body.
  • the invention provides high stability over time and a wide spectrum of action in terms of tolerance of dilution in aqueous solutions and tolerance of low pH values in the system.
  • Transparency is synonymous to optic transmittance in the context of the invention.
  • a Merck® Pharo 300 spectrometer was used for the measurements described herein.
  • the short time to forming homogenous dispersion of active substances means time less than 60 sec from the addition of the last drop of the blend of ingredients of the composition to water until complete dissolution.
  • Dispersion time may be measured using a spectrometric procedure with any spectrometer in the 520-680 nm range, wherein dispersion time means that a constant transmittance or absorbance value has been achieved which does not change on longer stirring of the dispersion in constant stirring conditions.
  • Dispersion time may also be measured using automated analyzers of stability and ageing of emulsions, dispersions or suspensions, such as Turbiscan instruments.
  • the easy dispersibility means that vigorous stirring is not needed to form dispersion, i.e.
  • nanoparticles with small hydrodynamic d iameter mean nanoparticles with a hydrodynamic diameter of below 220 nm. Values of hydrodynamic diameter are expressed in nanometers (D H , nm), and they may be measured using analyzers for determining particle size distribution based on dynamic light scattering, such as Zetasizer Nano-ZS from Malvern.
  • monodispersity of a nanosystem means a polydispersity value of molecules dispersed in water of below 0.300.
  • Polydispersity of molecules dispersed in water (Polydispersity Index) expressed as a Pdl value may be measured using a Zetasizer Nano-ZS instrument from Malvern.
  • stability of a composition means stability above 12 months.
  • the ease of dose dispensing for the composition and the active substance means that it may be dosed with minimal portioning by the consumer, which means for the composition that commercial pipettes/droppers with a pipette are used, wherein a validated drop weight for the product corresponds to a specific dose of the active substance.
  • the composition may be used for manufacturing products with a different form for easy dosing or as a unit container.
  • the high tolerance of dilution in aqueous solutions means high stability of a nanoemulsion with very high dilution, such as dilutions as high as 10,000x.
  • Nanoemulsion stability with a dilution of 10,000x may be measured using a spectrometric procedure with any spectrometer in the 520-680 nm range, wherein a constant transmittance and/or absorbance value indicates stability during storage.
  • Emulsion stability may also be measured using analyzers of stability and ageing of emulsions, such as Turbiscan.
  • a constant value of hydrodynamic diameter and nanoparticle polydispersity in the system confirms that the emulsion is stable and no aggregation, sedimentation or flocculation occurs.
  • Hydrodynamic diameter and nanoparticle polydispersity may be measured using analyzers for determining particle size distribution based on dynamic light scattering, such as Zetasizer Nano-ZS from Malvern.
  • bioavailability of the active substance contained in a preferred composition is increased by at least 200% compared to a commercially available formulation containing an identical active substance dissolved only in plant oil or a mixture, calculated based on parameters determined from in vivo pharmacokinetic tests.
  • Biological testing is preferably conducted in rats using healthy adult individuals. The testing is preferably conducted using all the required good laboratory practice.
  • the active substance is assayed in blood samples collected over time using UPLC/MS/MS, having first completed full validation of the analytical procedure.
  • the subject matter of the invention is a self-emulsifying composition containing a surfactant, two auxiliary agents constituting distinct lipid fractions and one or more active substances with hydrophobic and/or lipophilic properties from the group of fat-soluble vitamins (A, D, E and K) and derivatives thereof, including provitamins, carotenoids (astaxanthin, zeaxanthin, lutein), fatty acids (such as eicosapentaenoic acid, docosahexaenoic acid, conjugated linoleic acid, alpha-linoleic acid) in the acid form, fatty acid glycerol esters (such as mono-, di- and triglycerides), fatty acid esters with alcohols (primary, secondary and/or tertiary alcohols), derivatives, polyphenols, flavonoids (naringenin, genistein, silymarin, curcumin, resveratrol, alpha-lipoic acid, ubi
  • the composition has very high stability, i.e. more than 12, preferably more than 24 months in standard storage conditions.
  • composition of the invention preferably consists of at least one active compound with hydrophobic and/or lipophilic properties, a surfactant and two distinct lipid fractions and excipients that affect the sensory attributes of the composition.
  • the composition is characterized in that the active substance (or mixtures thereof) with lipophilic and/or hydrophobic properties and health-promoting and therapeutic properties comprises as much as up to 35% by weight of the composition, the surfactant comprises 20-50% by weight of the composition, the first lipophilic fraction comprises 15-35% by weight of the composition and the second lipophilic fraction comprises 15-35% by weight of the composition.
  • the composition may optionally contain additional ingredients that make up the sensory texture (flavoring, aromatic and coloring substances with lipophilic and/or hydrophobic properties) whose content may be as high as up to 2.0% of the total weight.
  • the composition is characterized in that the surfactant is polysorbate 80, the first lipophilic fraction is a C8-C12 medium-chain triacylglyceride and the second lipophilic fraction is a C8-C12 medium-chain mono-diacylglyceride.
  • the composition is characterized in that it forms a clear monodisperse self-emulsifying system in an aqueous solution.
  • the composition enables the active substance to be easily dosed and portioned as a single dose (mg).
  • the composition is characterized in that the monodisperse system forms particles smaller than 220 nm.
  • the composition is characterized in that the polydispersity of particles dispersed in water is lower than 0.300.
  • the composition is characterized in that the monodisperse system forms within less than 60 s and no vigorous stirring is needed.
  • the composition is characterized in that the monodisperse system forms a stable nanoemulsion tolerant to dilution.
  • the composition is characterized in that it may contain flavoring and aromatic additives and colorants.
  • the composition of the invention is useful for manufacturing water-based oral products.
  • the oral product is preferably a pharmaceutical composition or a foodstuff.
  • composition of the invention may be used for manufacturing other products as an intermediate to finally obtain tablets, pills, film-coated tablets, capsules, suppositories, chewing gums, gels, powders, granules, syrups and dispersions, wherein the composition itself aids in the manufacturing process of these products.
  • Another subject matter of the invention is a manufacturing process for a stable monodisperse system characterized in that water or an aqueous solution is mixed with the composition of the invention as illustrated below: mixing is preferably conducted for not less than 120 seconds, preferably for not less than 60 seconds, with mixing speed not greater than 2500 rpm, preferably with mixing speed not greater than 150 rpm.
  • Another subject matter of the invention is a monodisperse system characterized in that it consists of a dispersion medium being water or an aqueous solution and a dispersed phase formed by particles obtained from the composition of the invention as defined above.
  • the monodisperse system of the invention preferably has transparency above 90%, monodispersity below 0.300, and the system maintains nanoemulsion stability when diluted with water or an aqueous solution up to 10,000x and/or maintains nanoemulsion stability with a pH value below 3.
  • the ingredients of the composition of the invention spontaneously form essentially spherical nanoparticles in which the surfactant is the outer layer and the core (inner layer) is a mixture of lipids in which the active substance(s) or derivative(s) is dissolved.
  • the surfactant that forms the outer layer is anchored in the inner core lipid layer with its lipophilic part (a fragment of the surfactant molecule that is the fatty acid residue).
  • lipid 2 which has a key role in the structure of the nanoparticle of the invention, is involved in interactions between its hydrophilic outer layer and the inner hydrophobic core to furnish preferable properties of the nanoparticles illustrated in the application.
  • the ingredients of the composition spontaneously form nanoparticles of the invention whose arrangement changes as follows when going toward the center of the nanoparticle: the environment, that is, the aqueous solution, subsequently the surfactant which dominates in the outer nanoparticle layer, subsequently the mixture of lipids with the active substance (Lipid 1 + Lipid 2 + API), which form the nanoparticle core, wherein the Lipid 2 ingredient highly likely dominates in the outer core layer thus supporting the surfactant.
  • Any possible sensory additives should be fat-soluble and form the nanoparticle core ((Lipid 1 + Lipid 2 + API + OTHER).
  • composition that enables the active substance (or multiple such substances or mixtures thereof) with lipophilic and/or hydrophobic properties and healthpromoting and therapeutic properties to be dissolvedin an aqueous solution is:
  • T80 mixture of polyoxyethylated sorbitan and oleic acid derivatives, polysorbate 80, Tween® 80 surfactant,
  • MCM medium-chain mono-diglycerides, mainly of capric (C8) and caprylic (decanoic, CIO) acids,
  • API active ingredient
  • API means an active pharmaceutical ingredient.
  • the term is very commonly used for active substances of natural origin.
  • it refers to one or more substances representing: fat-soluble vitamins (A, D, E and K) and derivatives thereof, including provitamins, carotenoids (astaxanthin, zeaxanthin, lutein), fatty acids (such as eicosapentaenoic acid, docosahexaenoic acid, conjugated linoleic acid, alpha-linoleic acid) in the acid form, fatty acid glycerol esters (such as mono-, di- and triglycerides), fatty acid esters with alcohols (primary, secondary and/or tertiary alcohols) and their derivatives, polyphenols, flavonoids (naringenin, genistein, silymarin, curcumin, resveratrol, alpha-lipoic acid,
  • All ingredients of the composition are weighed out in a single tank protected from light.
  • the contents of the vessel are stirred for 30 min at room temperature; alternatively, the whole mixture is heated to facilitate dissolution of the ingredients below 60°C and subsequently stirred to homogenize the mixture.
  • composition of the invention contains four principal ingredients and optionally the fifth ingredient.
  • Optimal fractions of the ingredients are listed in Table 1 below, wherein the percentage values mean weight percentage.
  • the surfactant in the composition may be:
  • TweenTM monoacylated polyoxyethylated sorbitol with a trade name of TweenTM
  • Tween 20, 40, 60, 80 and 85 are available depending on the residue and substituent length.
  • TweenTM 80 polyoxyethylene sorbitol monolaurate (Polysorbate 20, Polyoxyethylene 20 sorbitan monolaurate), commercially available and offered by many manufacturers, was also evaluated as Tween 20.
  • ethoxylated oil derivatives a surfactant based on polyoxyethylene(35) castor oil (PEG-35 castor oil, Polyoxyl 35 Castor Oil), as Etocas, commercially available and offered by many manufacturers,
  • acyl polyglyceryl derivatives as Plurol (Polyglyceryl-3 dioleate) , commercially available surfactants offered by many manufacturers.
  • the fraction labelled as Lipid 1 may be medium-chain triacylglycerides with a mixture of C8-C12 fatty acids.
  • the medium-chain triacylglycerides are primarily esters with caprylic (octanoic, C8:0) and capric (decanoic, C10:0) acids.
  • MCT are commercially available and offered by many manufacturers under various trade names, such as: Crodamol GTCC triacylglyceride from CRODA, Labrafac lipophile from GATEFOSSE, Miglyol 808 from IOI OLEOCHEMICAL, Miglyol 812 N from IOI OLEOCHEMICAL, Imwitor® 928 from IOI OLEOCHEMICAL, Captex® 300 from ABITEC or Captex® 355 from ABITEC.
  • the fraction labelled as Lipid 2 may be medium-chain mono-diacylglycerides (MCM) with a mixture of C8- C12 fatty acids.
  • MCM medium-chain mono-diacylglycerides
  • MCM derivatives may be used as Lipid 2 in the composition, that is:
  • GMO glyceryl monooleates
  • GML glyceryl monolinoleate
  • GMR glyceryl monoricinoleate/; trade name: Softigen 701 from 101 OLEOCHEMICAL.
  • APIs may be active substances with lipophilic and/or hydrophobic properties, among which the following are listed:
  • fat-soluble vitamins A, D, E and K
  • derivatives thereof such as K-2
  • provitamins including provitamins
  • carotenoids (astaxanthin, zeaxanthin, lutein),
  • fatty acids such as eicosapentaenoic acid, docosahexaenoic acid, conjugated linoleic acid, alphalinoleic acid
  • fatty acid glycerol esters such as mono-, di- and triglycerides
  • fatty acid esters with alcohols primary, secondary and/or tertiary alcohols
  • polyphenols • polyphenols, flavonoids, cannabinoids, standardized plant extracts and other natural active substances, such as naringenin, genistein, silymarin, curcumin, resveratrol, alpha-lipoic acid or ubiquinone.
  • All the compounds considered OTHER are a group of compounds that affect the sensory texture of the composition and have lipophilic and/or hydrophobic properties. These may be flavonoids (anthocyanins), carotenoids or curcumin, but also ether compounds, that is, natural plant extracts or synthetic products that reproduce aromatic compositions through a mixture of chemical compounds, thus mimicking a profile and chemical fingerprint of natural plant extracts. Testing methodology
  • nanoparticle hydrodynamic diameter was expressed in nanometers (D H , nm) and was measured using a Zetasizer Nano-ZS instrument from Malvern.
  • particle polydispersity when dispersed in water was expressed as a Pdl value and measured using a Zetasizer Nano-ZS instrument from Malvern.
  • the improved bioavailability of the active substance (API) in the composition of the invention was confirmed by in vivo pharmacokinetic tests according to the procedure discussed below.
  • the animal model involved rats (males) divided into three groups: the preferable composition with vitamin D3 was administered to the first group, a commercially available vitamin D3 solution in MCT oil used for vitamin supplementation to the second group and the third control group did not receive the active substance in any form.
  • Each group consisted of 4 adult individuals except for the control of 3 individuals.
  • the animals were maintained in controlled environmental conditions for at least five days before the testing started.
  • Vitamin D3 at a dose of 0.5 mg/kg body weight was administered to the first and second groups. After administration, blood was collected from the rats after 15 min, 30 min, 1, 2, 4, 6, 8, 12, 24 and 48 hours into test tubes with an anticoagulant and centrifuged within 30 minutes; subsequently, plasma was harvested for testing.
  • Plasma samples were stored at -20°C until UPLC/MS/MS analysis. Parameters, such as bioavailability, C max , T max , CL, d, AUC and T1/2, were determined based on vitamin D3 contents in the blood samples. It was found following analysis that the preferred composition significantly improved the bioavailability and peak serum concentration (C max ) of the active substance compared to commercially available products based on plant oils, especially MCT.
  • the preferred composition comprises ingredients:
  • Surfactant means a polyoxyethylated derivative of sorbitan and oleic acid (Polysorbate 80, polyoxyethylated sorbitol monooleate, TweenTM 80), commercially available and offered by many manufacturers. In the experiment, TweenTM 80 from CRODA was used,
  • Lipid 1 means medium-chain triacylglyceride with a mixture of C8-C12 acids, commercially available and offered by many manufacturers.
  • CrodamolTM from GTCC was used
  • Lipid 2 means medium-chain mono-diglycerides, mainly of capric (C8) and caprylic (decanoic, CIO) acids, commercially available and offered by many manufacturers.
  • Imwitor® 988 from 101 OLEOCHEMICAL was used,
  • Vitamin D3 as a typical example of a fat-soluble vitamin and an active substance with lipophilic and/or hydrophobic properties.
  • Vitamin D from Fermenta Biotech Limited wa s used in the application.
  • ether compounds as a typical example of compounds that affect sensory attributes of the composition, with lipophilic and/or hydrophobic properties; ether compounds were used. Terpenes from Eybna Technologies Ltd. were used in the application.
  • the composition was prepared by weighing out 91.84 g surfactant (T80) making up 30.00% by mass of the composition, 212.40 mg of the active substance (vitamin D) making up 0.069% by mass of the composition, 106.43 g Lipid 1 fraction (MCT) making up 34.77% by mass of the composition, 106.64 g Lipid 2 fraction (MCM) making up 34.84% by mass of the composition and 0.99 g OTHER (ether compounds) making up 0.32% by mass of the composition into one vessel. This was stirred for 30 min using a magnetic bar at 300 rpm until homogenous at room temperature.
  • the composition may be used in aqueous systems and other forms with defined unit containers.
  • the composition was tested by precise addition of portions of the composition to aqueous systems.
  • An adequate dosing system ensures precise delivery of the active substance in a specific and constant portion of the composition.
  • Quantitative amounts of the active substance here, vitamin D
  • 1 pg 40 IU
  • a dosing system was tested using pipettes/droppers and appropriate droplets (droplet mass was validated by measuring the mass of ten droplets 100 times and mean droplets mass was determined for which the active substance dose was calculated), wherein one droplet was equivalent to 1000 IU. The results are shown in Table 2.
  • Table 2 Values of nanoemulsion parameters important for the application, obtained from self-emulsifying compositions based on an exemplary composition with vitamin D as the active substance according to the application.
  • compositions with various contents of vitamin D as the active substance were also prepared according to the example above. The results are shown in Table 3.
  • compositions were prepared with other active substances and ingredients of the composition which confirmed the action and unique character of the disclosed compositions. The results are shown in Table 4.
  • composition can be used for preparing mixtures that consist of at least two active substances (APIs) according to the procedure below.
  • APIs active substances
  • composition containing two active substances The composition was prepared by weighing out 612.0 g surfactant (T80) making up 30.0% by mass of the composition, 632.0 mg of the Lipid 1 (MCT) fraction making up 31.0% by mass of the composition, 712.3 g of the Lipid 2 (MCM) fraction making up 34.92% by mass of the composition, 41.9 g vitamin D3 in the form of MCT solution with a concentration of 1 MIU/G making up 2.06% by mass of the composition, 38.5 g of 5% vitamin K2 MK7 solution (all-trans menaquinone-7) in MCT oil making up 1.9% by mass of the composition and OTHER (ether compounds) making up 0.17% by mass of the composition into one vessel. This was stirred for 30 min using a magnetic stirrer at 300 rpm until homogenous at room temperature.
  • the composition was prepared by weighing out 604.7 g surfactant (T80) making up 29.4% by mass of the composition, 284.5 mg of the Lipid 1 (MCT) fraction making up 13.8% by mass of the composition, 716 g of the Lipid 2 (MCM) fraction making up 34.8% by mass of the composition, 50.4 g vitamin D3 in the form of MCT solution with a concentration of 1 MIU/G making up 2.5% by mass of the composition, 46.7 g of 5% vitamin K2 MK7 solution (all-trans menaquinone-7) in MCT oil making up 2.3% by mass of the composition, 47.4 g retinyl palmitate in the form of MCT solution with a concentration of 1 MIU/G making up 2.3% by mass of the composition, 305.6 g a-tocopherol acetate making up 14.9% by mass of the composition into one vessel. This was stirred for 30 min using a magnetic stirrer at 300 rpm until homogenous at room temperature.

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Abstract

L'invention concerne des compositions universelles, facilement émulsifiées dans des solutions aqueuses ayant une large plage de pH qui forment des monodispersions stables pour des composés lipophiles et/ou hydrophobes. Les compositions peuvent améliorer la biodisponibilité de substances actives et peuvent être utilisées pour une administration orale dans des systèmes aqueux et pour fabriquer des produits oraux, en particulier des compositions pharmaceutiques, des dispositifs médicaux et des aliments.
PCT/PL2023/050015 2022-03-15 2023-03-15 Composition formant des émulsions monodispersées stables dans l'eau WO2023177313A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170035691A1 (en) * 2014-04-08 2017-02-09 David J. McClements Food matrices and methods of making and using
US10722465B1 (en) * 2017-12-08 2020-07-28 Quicksilber Scientific, Inc. Transparent colloidal vitamin supplement
US20200246404A1 (en) * 2017-02-15 2020-08-06 Molecular Infusions, Llc Formulations
CA3131799A1 (fr) * 2019-03-04 2020-09-10 Daniel Young Produit et procede destines a une dispersion colloidale hydrosoluble de phytocannabinoide/terpene/flavonoide stable a temperature ambiante, de qualite alimentaire, entierement nat urelle et vegetalienne
US20200306268A1 (en) * 2019-03-25 2020-10-01 Tempus Bio Technologies LLC Vitamin composition
US20200397905A1 (en) * 2018-03-07 2020-12-24 ID CARE UG (haftungsbeschränkt) Krill oil for solubilizing poorly water-soluble dietary supplements and pharmaceutically active agents
US20210015786A1 (en) * 2018-07-19 2021-01-21 Nanogen Lab, Inc. Nanoemulsion hydrophobic substances
US20210186870A1 (en) * 2018-08-27 2021-06-24 Emerald Health Therapeutics Canada Inc. Improved cannabinoid bioavailability

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170035691A1 (en) * 2014-04-08 2017-02-09 David J. McClements Food matrices and methods of making and using
US20200246404A1 (en) * 2017-02-15 2020-08-06 Molecular Infusions, Llc Formulations
US10722465B1 (en) * 2017-12-08 2020-07-28 Quicksilber Scientific, Inc. Transparent colloidal vitamin supplement
US20200397905A1 (en) * 2018-03-07 2020-12-24 ID CARE UG (haftungsbeschränkt) Krill oil for solubilizing poorly water-soluble dietary supplements and pharmaceutically active agents
US20210015786A1 (en) * 2018-07-19 2021-01-21 Nanogen Lab, Inc. Nanoemulsion hydrophobic substances
US20210186870A1 (en) * 2018-08-27 2021-06-24 Emerald Health Therapeutics Canada Inc. Improved cannabinoid bioavailability
CA3131799A1 (fr) * 2019-03-04 2020-09-10 Daniel Young Produit et procede destines a une dispersion colloidale hydrosoluble de phytocannabinoide/terpene/flavonoide stable a temperature ambiante, de qualite alimentaire, entierement nat urelle et vegetalienne
US20200306268A1 (en) * 2019-03-25 2020-10-01 Tempus Bio Technologies LLC Vitamin composition

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