EP3004182A1 - Self-associating microparticles and nanoparticles consisting of proteins - Google Patents
Self-associating microparticles and nanoparticles consisting of proteinsInfo
- Publication number
- EP3004182A1 EP3004182A1 EP14727610.9A EP14727610A EP3004182A1 EP 3004182 A1 EP3004182 A1 EP 3004182A1 EP 14727610 A EP14727610 A EP 14727610A EP 3004182 A1 EP3004182 A1 EP 3004182A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- groups
- cyclodextrin
- inclusion complex
- proteins
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
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- A—HUMAN NECESSITIES
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- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
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- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/645—Proteins of vegetable origin; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
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- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
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- 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/738—Cyclodextrins
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61K9/5052—Proteins, e.g. albumin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
- A61K9/5057—Gelatin
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61Q15/00—Anti-perspirants or body deodorants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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- A61Q19/008—Preparations for oily skin
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- 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
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- A—HUMAN NECESSITIES
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- A61Q19/00—Preparations for care of the skin
- A61Q19/06—Preparations for care of the skin for countering cellulitis
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- A61Q19/08—Anti-ageing preparations
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- 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
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
Definitions
- the invention relates to microparticles and nanoparticles composed of proteins.
- the invention also relates to their use as an encapsulation system and their method of preparation.
- microparticles capable of encapsulating an active ingredient of interest or an active substance of interest are the subject of active research.
- the microparticles and nanoparticles can be obtained by three major classes of processes: (i) physicochemical processes based on variations in the solubility of the materials used for encapsulation and temperature or pH / z3 ⁇ 4 variations ) mechanical processes such as hot-melt extrusion or gelation; and (iii) chemical processes in which the polymer synthesis and the encapsulation of the active molecules take place simultaneously.
- the particles must be capable of trapping an active substance of interest, transporting it in the body to the target cell or tissue, and then releasing it without altering its structure. It is therefore important that these particles are not toxic.
- the processes for preparing said particles very often use organic solvents in order to dissolve the proteins. These methods also have other disadvantages. Indeed, these often require, during at least one step, the use of surfactants, the use of reagents, or even an extreme variation in pH. In some cases, it is also necessary to use heating or a strong agitation which is at the origin of a loss of energy and which increases the time and the cost of the production.
- the active substance of interest can thus undergo a degradation because of the solvents, the surfactants, the reagents used, the agitation or the heating necessary for the manufacture of the particles. These conditions could also be at the origin of a therapeutic inefficiency of the particles obtained.
- Proteins are widely used in the pharmaceutical or cosmetic field, in particular for the encapsulation of active substances of interest.
- gliadin and gelatin are advantageous because of their muco-adhesive properties.
- Gliadin is a protein derived from wheat composed of a polypeptide chain of variable molecular weight between 25 and 100 kDacharacterized by the presence of disulfide bridges. Gliadin can interact with keratin at the level of the epidermis (Teglia, A. and Secchi, G., Int J. Costa, Sci.16 (1994) 235 246). This protein has, for example, been used for the oral administration of active molecules, such as clarithromycin, omeprazole (Ramteke & Jain, Journal of Drug Targeting, 2008, 16 (1), 65-72), and ⁇ tocopherol (Duclairor et al, Journal of Microencapsulation, 2002, 19 (1), 53-60).
- active molecules such as clarithromycin, omeprazole (Ramteke & Jain, Journal of Drug Targeting, 2008, 16 (1), 65-72), and ⁇ tocopherol (Duclairor et al, Journal of Microencapsulation, 2002, 19 (1),
- the gelatins have a number average molecular weight (Mn) of between 50 Da and 100 kDa, and a weight average molecular weight (Mw) of between 100 Da and 1000 kDa, with a polydispersity index Ip (Mw). / Mn) often greater than 2, due to the very heterogeneity of gelatin (Wiley, Gelatin Handbook).
- Gelatin is obtained by partial hydrolysis of collagen (Harding, JJ (1965), The Unusual Links and Cross-links of Collagen, Advances in Protein Chemistry, 20, 109-190, Veis, A. (1964) .
- Collagen is extracted from the skin, for example proc skin, bones, cartilage.
- Elastin is also a protein that is often used, particularly in the cosmetics field. It has a very dense structure that makes it insoluble in water. Studies have nevertheless been made to show that there is the possibility of modifying elastin to make it more soluble in water (US 4,363,760).
- US Pat. No. 4,659,740 describes the use in the field of cosmetics of elastin derivatives grafted with fatty acids (such as lauric acid, palmitic acid or oleic acid) by forming amide bonds, by conversion of the acid to anhydride capable of reacting with the amino groups of elastin.
- fatty acids such as lauric acid, palmitic acid or oleic acid
- This formulation has allowed for better penetration of elastin through the skin, including better absorption in the stratum corneum.
- alpha-elastin derivatives capable of self-association in an aqueous medium has also been described.
- the resulting particles were cross-linked by gamma radiation to solidify them (Fujimoto et al., Radiation Physics and Chemistry, 2009, 78, 1046-1048). Nanoparticles with a size of 150 nm and 300 nm have been obtained (Fujimoto et al., Polymer Bulletin, 2010, 64, 707-716).
- One of the aims of the invention is therefore to provide inclusion complexes between a hydrophobized protein and a cyclodextrin.
- Another object of the invention is to provide a process for the simple preparation of said particles without systematic use of solvents, surfactants or reagents.
- Another object of the invention is to provide a process for preparing said particles that does not require a sharp increase in temperature or a strong agitation of the preparation.
- the invention also relates to the use of said particles, as well as compositions containing said particles.
- the invention also relates to an encapsulation system containing said particles, and to a process for preparing said encapsulation system.
- the invention thus relates to an inclusion complex formed by the interaction between
- ⁇ at least one protein comprising hydrophobic groups covalently bonded to said protein, and ⁇ at least one ⁇ -cyclodextrin (CD) as a monomer, the protein and the cyclodextrin being linked noncovalently.
- CD ⁇ -cyclodextrin
- inclusion complex refers to a system consisting of a host molecule capable of accommodating a chemical species.
- protein refers to a biological macromolecule composed of one or more amino acid chains linked together by peptide bonds.
- Amino acids are a class of chemical compounds of the formula H 2 N-CHR-COOH. Each amino acid therefore has an amino group -NH 2 , a carboxyl group -COOH, and a group R which represents the side chain which identifies the amino acid, (for example CH 2 -SH for cysteine, CH 2 -OH for serine, H for glycine ).
- protein comprising hydrophobic groups means that the protein has been hydrophobized by grafting, on the amino groups and / or the carboxyl groups and / or the hydroxyl groups and / or the thiol groups, alkyl chains which are by nature hydrophobic because of their apolar nature.
- Proteins grafted by hydrophobic chains are amphiphilic systems capable of self-associating spontaneously in aqueous medium in the form of heart-crown type micelles that can host an active ingredient.
- the proteins are in particular grafted with lipid groups. These systems have shown great stability over time. The solubility of said proteins in aqueous medium decreases, however, because of the presence of hydrophobic grafted chains.
- Cyclodextrin is a cyclic oligosaccharide of ⁇ -D-glucopyranose linked by ⁇ (1-4) linkages. It is a cage molecule of natural origin that can encapsulate various molecules, including molecules of therapeutic interest. There are different sizes ( ⁇ , ⁇ , ⁇ ), each having the shape of a "lampshade”. It carries hydrophilic -OH groups located outside, the assembly delimiting a relatively hydrophobic cavity. This amphiphilic character allows the cyclodextrin to include hydrophobic molecules in its cavity to form inclusion complexes which are soluble in water. Its biodegradable nature predisposes it to important applications in the agro-food and pharmaceutical fields. Encapsulation in cyclodextrins makes it possible to protect fragile molecules or to ensure their slow and controlled release.
- cyclodextrin refers to only ⁇ -cyclodextrin.
- cyclodextrin means that only one unit of cyclodextrin is present.
- Using alpha-cyclodextrin as a monomer instead of a Cyclodextrin polymer represents a clear advantage from an economic and regulatory point of view because this cyclodextrin is commercially available and is recognized as being a pharmaceutical excipient accepted by the majority of pharmacopoeias.
- the protein and the cyclodextrin being non-covalently bound means that the interactions between these molecules are of the Van der Waals and / or hydrogen type and / or of the hydrophobic and / or electrostatic type, and not covalent bonds.
- inclusion complexes according to the invention are thus exclusively formed by non-covalent bonds by simple mixture of ⁇ -cyclodextrin and of protein grafted with hydrophobic groups. By using the same procedure and varying the type of these non-covalent interactions, it is then possible to form particles of various sizes and structures.
- the protein has a molar mass ranging from 100 Da to 1 000 000 kDa, and in particular from 10 to 100 kDa.
- the ratio between the concentration of the cyclodextrin in g / L and that of the protein is from 10 -6 to 900,000.
- the ratio between the concentration of the cyclodextrin in g / L and that of the protein is from 0.01 to 1500, in particular from 4 to 15. and in particular equal to 10.
- the invention relates to an inclusion complex formed by the interaction between
- CD ⁇ -cyclodextrin
- protein association means that at least two different proteins are present in the inclusion complex, for example gelatin and gliadin.
- the invention particularly relates to an inclusion complexin which the protein is selected from elastin, collagen, gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibrinonectin, a hormone, an enzyme, a coagulation factor, transferrin, fibrillin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived from seeds or nuts, a protein outcome algae, a silk protein, an egg protein, a potato protein, and derivatives of said proteins, and is especially gliadin or gelatin.
- the protein is selected from elastin, collagen, gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibrinonectin, a hormone, an enzyme, a coagulation factor, transferrin, fibrillin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived
- the degree of substitution of the protein by the hydrophobic groups is between 0.001 and 100%.
- the degree of substitution of the protein by the hydrophobic groups is comprised of 0.005 to 50%.
- the degree of substitution is also a parameter for modulating the average size of the particles formed from the inclusion complexes.
- the degree of grafting of the protein by the hydrophobic groups can be calculated using different analytical methods such as elemental analysis and proton NMR proton spectroscopy of the grafted protein.
- the invention relates to an inclusion complex formed by the interaction between
- ⁇ at least one ⁇ -cyclodextrin (CD) as a monomer, the protein and the cyclodextrin are linked non-covalently,
- the protein is selected from elastin, collagen, gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibrinonectin, a hormone, an enzyme, a coagulation factor, transferrin, fibrin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived from seeds or nuts, a protein derived from seaweed, a silk protein , an egg protein, a potato protein, and derivatives of said proteins, and is especially gliadin or gelatin,
- the hydrophobic groups are alkyl groups, linear or branched, in particular linear, containing from 6 to 100 carbon atoms, or linear or branched alkenyl groups, especially linear, containing from 6 to 100 carbon atoms.
- Palmitic acid, oleic acid, lauric acid, stearic acid and / or linoleic acid are in particular used for the grafting of hydrophobic chains on the protein, but this list is by no means exhaustive and limiting.
- the hydrophobic groups are covalently attached to the protein by the amine function and / or the carboxylic function and / or the hydroxyl function and / or the thiol function.
- Said hydrophobic groups are thus fixed by reaction of N-acylation and / or O-acylation and / or S-acylation with a fatty acid or a fatty acid derivative such as a fatty acid chloride (the chloride of palmitic acid or oleic acid chloride for example).
- a fatty acid chloride the chloride of palmitic acid or oleic acid chloride for example.
- the hydrophobization of the proteins can be carried out by dissolving the protein and then heating the mixture at 90 ° C. with continuous magnetic stirring.
- the fatty acid chloride for example palmitoyl chloride is then added.
- the mixture is left at 90 ° C for a few hours, then left at room temperature.
- the acylated protein is then precipitated, collected, washed and dried.
- Said hydrophobization can be done in a solvent if the protein is soluble in the latter and if it is desired to graft the protein with an acid chloride (the acid chloride is hydrolysed in the presence of water). It is also not possible to use a solvent, and to carry out hydrophobization only in the presence of water provided that the protein is soluble in it and provided that other grafting methods, such as those with the acid anhydride, are used. (see US Patent 4,659,740 for example).
- solvent thus denotes any solvent with the exception of water or an aqueous medium.
- the cyclodextrin (CD) has the formula
- ⁇ p is an integer equal to 6
- ⁇ RI, R2, R3, identical or different, in particular identical are hydrogen atoms, alkyl groups having 1 to 3 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, amino -NH 2 groups, ammonium groups -NH 3 + , or sulfate groups - SO 4 2- , and are especially hydrogen atoms or methyl groups,
- said CD being in monomeric form
- cyclodextrin is functionalized with a ligand selected from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- the -OH groups may be substituted, in particular with methyl, hydroxypropyl or sulfobutyl groups.
- the substitutions may increase the solubility of the cyclodextrin.
- ⁇ -cyclodextrin is its small size which allows it to interact with the hydrophobic chains bound to the protein.
- the cyclodextrin is functionalized with a ligand chosen from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- ligand refers to a molecule capable of binding covalently to cyclodextrin.
- the ligand is chosen from protein compounds involved in particular in the recognition and / or neutralization of pathogens (anti-bodies or fragments, receptors, lectins), involved in the metabolism of fatty acids (biotin and derivatives).
- the cyclodextrin is charged or uncharged.
- the cyclodextrin is substituted or unsubstituted.
- substituted cyclodextrin is meant, for example, an alkyl substituted cyclodextrin, for example a methylated cyclodextrin, a hydroxyalkyl group, a maltosyl group, a galactosyl group, or any other molecule.
- the invention relates to an inclusion complex, wherein the protein is functionalized with a ligand selected from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- the invention relates to an inclusion complex, in which the protein is gliadin bearing hydrophobic groups attached by the amine function and / or the carboxylic function and / or the hydroxyl function and / or the thiol function. , and representing groups of formula:
- R represents the hydrophobic group and is chosen from:
- a linear or branched alkyl group containing from 1 to 1000 carbon atoms in particular the groups - (CH 2 ) 14 -CH 3 or - (CH 2 ) 16 -CH 3 ,
- the invention relates to an inclusion complex, in which the protein is gelatin bearing hydrophobic groups fixed by the amine function. and / or the carboxylic function and / or the hydroxyl function and / or the thiol function, and representing groups of formula:
- R represents the hydrophobic group and is chosen from:
- a linear or branched alkyl group containing from 1 to 1000 carbon atoms in particular the groups - (CH 2 ) 14 -CH 3 or - (CH 2 ) 16 -CH 3 ,
- inclusion complexes according to the present invention, it is possible to form particles. Said particles indeed contain an association of several inclusion complexes.
- Another aspect of the invention thus relates to a particle of size ranging from 1 nm to 100,000 nm, in particular 200 nm to 8000 nm, containing inclusion complexes between
- ⁇ at least one protein comprising hydrophobic groups covalently bonded to said protein, and ⁇ at least one ⁇ -cyclodextrin (CD) as a monomer.
- the invention thus relates to nanometric particles, ranging in size from 1 nm to 1000 nm, and micrometric particles, ranging in size from 1000 nm to 100,000 nm.
- the size of the particles formed was evaluated by quasi-elastic light scattering (DQEL) on the one hand and by transmission electron microscopy (TEM) on the other hand.
- DQEL quasi-elastic light scattering
- TEM transmission electron microscopy
- Size plays a very important role concerning the amount of encapsulated active ingredient and the applications envisaged, and the route of administration of the active ingredient.
- the invention relates to a particle in which the protein has a molar mass of from 100 Da to 1 000 000 kDa, and in particular from 10 to 100 kDa, said protein being chosen in particular from elastin, collagen gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibronectin, a hormone, an enzyme, a clotting factor, transferrin, fibrinin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived from seeds or nuts, a protein derived from seaweed, a silk protein, an egg protein, a potato protein, and derivatives of said proteins, and is especially gliadin or gelatin.
- the invention relates to a particle wherein said protein and / or said ⁇ -cyclodextrin (CD) are functionalized with a ligand selected from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- a ligand selected from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- the invention relates to a particuleparticularlyt inclusion complexes in which the ratio between the concentration of cyclodextrin in g / L and that of the protein, especially gliadin or gelatin, is from 10 "6 to 900,000.
- the invention relates to a particuleparticularlyt inclusion complexes in which the ratio between the cyclodextrin concentration in g / L and that of the protein, especially gliadin or gelatin, is from 0.01 to 1500, in particular from 4 to 15 and especially equal to 10.
- the ratio between the concentration of cyclodextrin in g / L and that of the protein is a very important parameter because it makes it possible to modulate the size of the particles obtained from the above inclusion complexes, by modifying the concentration ratio between the cyclodextrin and the protein.
- the invention relates to a particuleparticularlyt inclusion complexes wherein the degree of substitution of the protein by hydrophobic groups is from 0.001 to 100%, including from 0.005 to 50%.
- lipidic hydrophobic groups in particular palmitic acid, oleic acid, lauric acid, stearic acid and / or linoleic acid.
- the invention relates to a particulecontaining inclusion complexes in which the hydrophobic groups are covalently attached to the protein by the amine function and / or the carboxylic function and / or the hydroxyl function and / or the thiol function.
- the invention relates to a particle containing inclusion complexes formed by the interaction of a combination of proteins and at least one ⁇ -cyclodextrin (CD).
- CD ⁇ -cyclodextrin
- the proteins contained in the inclusion complexes according to the invention can also be used to encapsulate active substances of interest.
- the invention thus relates to an encapsulation system containing one or more of the above-mentioned particles, and one or more active substance (s) of interest used for its properties in the pharmaceutical, medical and pharmaceutical fields.
- active substance (s) of interest used for its properties in the pharmaceutical, medical and pharmaceutical fields.
- an inclusion complex-forming protein according to the present invention may itself be the host of one or more active substance (s) of interest.
- the active substance of interest has pharmaceutical properties and is chosen from inorganic compounds and organic, synthetic or natural compounds.
- the previously defined encapsulation system can be used to prepare appropriate compositions in the pharmaceutical, medical, paramedical, medical device, cosmetic, veterinary, food, animal feed, agrochemical, pesticide, cosmeto-textile, and perfume industries. , environmental, or in the paint, building and / or automobile industry.
- the active substance of interest encapsulated may possess pharmaceutical properties and be an active ingredient for therapeutic use. It may belong to the following list, the latter being in no way limiting, to the group of compounds with vitamin properties, in particular vitamin A, vitamin E, vitamin C, vitamin K, vitamin B, vitamin D , anti-tumors, including paclitaxel, docetaxel, tamoxifen, doxorubicin, painkillers, especially paracetamol, anti-inflammatories, including diclofenac, ibuprofen, ketoprofen, antibiotics, including penicillins, tetracyclines, antifungals, in particular ketoconazole, clotrimazole, nystatin, chlorhexidine and its derivatives, antiparasitic agents, in particular albendazole, metronidazole, enzymatic agents, in particular alkaline phosphatase, acetylcholinesterase, alcohol dehydrogenase, hormonal agents, in particular testosterone, levonorgestrel
- the active substance of interest encapsulated may also have cosmetic properties and belong to the group of compounds with anti-inflammatory, anti-aging, anti-ultraviolet (anti-UV), depigmenting, healing, moisturizing, fragrant, deodorant, antibacterial, antiperspirants, cleansers, colorants, preservatives.
- anti-UV anti-ultraviolet
- the active substance of interest has food properties and belongs to the group of compounds with vitamin, enzymatic, sweetening properties. It can also be an essential oil, a dye, a preservative, an antioxidant, a probiotic.
- Some molecules or families of molecules that can be encapsulated as active substances of interest are: molsidomine, ketoconazole, gliclazide, diclofenac, levonorgestrel, paclitaxel, docetaxel, tamoxifen, hydrocortisone, pancratistatin, ketoprofen, diazepam, ibuprofen, nifedipine, testosterone, tamoxifen, furosemide, tolbutamide, chloramphenicol, benzodiazepines, naproxen, dexamethasone, diflunisal, anadamide, pilocarpine, daunorubicin, doxorubicin , essential oils, terpenes, terpenoids.
- a solvent or a mixture of solvents in particular: alkyl acetate (ethyl acetate, butyl acetate, methyl acetate), acetone, acetonitrile, acetic acid, acid methanoic acid, ammonia, acetic anhydride, aniline, anisole, benzene, butanol, butanone, chlorobenzene, chloroform, cyclohexane, cyclopentane, dichloroethane, dichloromethane, diisopropyl ether, dimethylformamide, dimethylsulfoxide, dioxane, ethanol, glycol ether, diethyl ether, ethylene glycol, heptane, hexamethylphosphoramide, hexane, methanol, methyl ethyl ketone, nitrobenzene, pentane, percgloroethylene, propanol
- alkyl acetate ethyl acetate
- Said solvent or solvent mixture is added before adding the cyclodextrin and the hydrophobized protein.
- the invention relates to a pharmaceutical composition containing as active substance of interest a substance encapsulated in inclusion complexes as mentioned above or in the aforementioned particles, in solid form, in the form of a solution or as a suspension in an aqueous medium such that pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), especially sucrose or glucose, a solution or an injectable suspension or a solution of physiological saline solution optionally enriched with glucose, an emulsion, a gel, a cream, or any other pharmaceutically acceptable excipient.
- a pharmaceutical composition containing as active substance of interest a substance encapsulated in inclusion complexes as mentioned above or in the aforementioned particles, in solid form, in the form of a solution or as a suspension in an aqueous medium such that pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), especially sucrose
- the invention relates to a pharmaceutical composition, said composition being usable for the routes:
- parenteral intravenous, oral, buccal, sublingual, cutaneous, subcutaneous, nasal, rectal, vaginal, pulmonary, or ocular and for any administration at the level of a mucosa, or at a specific site (tumor, some blood vessels),
- compositions in the pharmaceutical field are tablets, soft capsules, hard capsules (capsules), powders, granules, patches, implants, suppositories, solutions, suspensions, syrups, pastes, creams, gels, emulsions, sprays, lotions, ointments, varnishes and lacquers.
- Advantageous forms in the paramedical field are dressings, catheters, compress, gauze, hydrophilic cotton, physiological saline, spray, etc.
- Implants in the field of medical devices are implants, prostheses, instrument washer-disinfectors, compresses, dressings (especially healing), sprays, gauzes, hydrophilic cotton, etc.
- oral forms tablettes, powders, soft capsules, hard capsules (capsules), granules, pastes, solutions, suspensions), injectables (solutions, suspensions, emulsions) and topicals whose action can be local or systemic (spray, necklaces, ear loops, powders, lotions, ointments, shampoos, patch, emulsions, milk, gel, cream, varnish, lacquers).
- the invention relates to a cosmetic composition containing, as active substance of interest, a substance encapsulated in inclusion complexes as mentioned above or in the aforementioned particles, in solid form, in the form of a solution or in the form of a solution.
- aqueous medium such as pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or polymer (s), and / or surfactants, in particular polysorbate 80 or lauryl sulfate.
- aqueous medium such as pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or polymer (s), and / or surfactants, in particular polysorbate 80 or lauryl sulfate. sodium, an emulsion, a gel, a cream, or any other cosmetically acceptable excipient.
- the invention relates to a cosmetics composition, said composition being usable for the oral, the cutaneous, at the level of the nails, at the capillary level,
- the invention also relates to a process for preparing an inclusion complex as defined above comprising a mixing step of at least
- the invention relates to a process for preparing an inclusion complex as defined above comprising a mixing step of at least
- the use of several proteins may have the advantage of modulating the properties of the particles by modifying the ratio between the proteins. Thus, it is expected that the size, overall charge and target applications of these particles may be modulated.
- the invention relates to a preparation process comprising a mixing step of at least a protein selected from elastin, collagen, gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibronectin, a hormone, an enzyme, a coagulation factor, transferrin, fibrinin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived from seeds or nuts, a protein derived from seaweed, a silk protein, a protein from egg, a potato protein, and derivatives of said proteins, and is especially gliadin or gelatin, said protein comprising hydrophobic groups of formula
- R represents the hydrophobic group and is chosen from:
- ⁇ p is an integer equal to 6
- ⁇ RI, R2, R3, identical or different, in particular identical are hydrogen atoms, alkyl groups having 1 to 3 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, amino group - NH 2, of ammonium groups -NH 3 + , or sulfate groups -SO 4 2 " , and are in particular hydrogen atoms or methyl groups, said CD being in the form of a monomer,
- said protein and ⁇ -cyclodextrin (CD) are functionalized with a ligand selected from antibodies, antibody fragments, receptors, lectins, biotin or its derivatives.
- the invention relates to a method of preparation wherein the mixing step is carried out at room temperature.
- the protein may be in solution in an aqueous medium or as a suspension in an aqueous medium.
- the cyclodextrin may be in solution in an aqueous medium or as a suspension in an aqueous medium.
- aqueous medium is meant especially in the sense of the present invention pure water, an aqueous solution comprising one or more solutes, including one or more salt (s) and / or sugar (s), especially sucrose or glucose, an injectable solution or suspension or a saline solution optionally enriched with glucose, an emulsion, a gel, a cream, or any other pharmaceutically acceptable excipient.
- the invention relates to a preparation process, in which
- said protein is in the form of suspension in an aqueous medium
- ⁇ said ⁇ -cyclodextrin (CD) is preferably dissolved in aqueous unmilieu,
- said aqueous medium being selected from pure water, an aqueous solution of pH of 1 to 14, in particular 5 to 8, comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, an injectable solution or suspension, a physiological saline solution, optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use.
- injectable solution is meant especially in the sense of the present invention water for injections, sodium chloride solution, or a sodium-based solution.
- the invention relates to a method of preparation, in which
- ⁇ said ⁇ -cyclodextrin (CD) is preferably dissolved in aqueous unmilieu,
- said aqueous medium being selected from pure water, an aqueous solution of pH of 1 to 14, in particular 5 to 8, comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, an injectable solution or suspension, or a physiological saline solution, optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use.
- the invention relates to a method of preparation, in which
- ⁇ said ⁇ -cyclodextrin (CD) is in the form of aqueous suspension in unmilieu,
- said aqueous medium being selected from pure water, an aqueous solution of pH of 1 to 14, in particular 5 to 8, comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, a solution or suspension injectable, a physiological saline solution, optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use.
- the invention relates to a method of preparation, in which
- said protein is in the form of suspension in an aqueous medium
- ⁇ said ⁇ -cyclodextrin (CD) is in the form of aqueous suspension in unmilieu,
- said aqueous medium being selected from pure water, an aqueous solution of pH of 1 to 14, in particular 5 to 8, comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, an injectable solution or suspension, a physiological saline solution, optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use.
- the invention relates to a method of preparation, said method comprising, prior to the mixing step, a step of preparation of a protein carrying hydrophobic groups, by reaction of N-acylation and / or O-acylation and / or S-acylation between said protein and 0.1 to 100 equivalents per unit protein, fatty acid chloride of formula
- R represents a hydrophobic group and is chosen from:
- the invention relates to a preparation process comprising a mixing step between
- ⁇ a protein especially gliadin, or gelatin having hydrophobic groups covalently bonded to said protein, and ⁇ an ⁇ -cyclodextrin (CD) as monomer,
- R represents the hydrophobic group and is chosen from:
- a linear or branched alkyl group containing from 1 to 1000 carbon atoms in particular the groups - (CH 2 ) 14 -CH 3 or - (CH 2 ) 16 -CH 3 ,
- ⁇ p is an integer equal to 6
- ⁇ RI, R2, R3, identical or different, in particular identical are hydrogen atoms, alkyl groups having 1 to 3 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, amino -NH 2 groups, ammonium groups -NH 3 + , or sulfate groups - SO 4 2 " , and are especially hydrogen atoms or methyl groups,
- aqueous medium at a concentration of from 0.01 to 9000 g / L of aqueous medium, in particular of from 1 to 300 g / l, and in particular of approximately 200 g / l of aqueous medium,
- said protein in particular gliadin or gelatin, being
- an aqueous medium chosen from pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, a solution or an injectable suspension or a physiological saline solution, optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use,
- the weight percentage of said protein, in particular gliadin or gelatin being from 0.01% to 99.9%, especially from 0.5% to 70%,
- the weight percentage of the cyclodextrin being from 0.01% to 99.9%, in particular from 0.5% to 70%
- the weight percentage of the water or of the aqueous medium being from 0.01% to 99.9%, especially from 70% to 99%, said mixing being carried out with stirring, at a temperature of 0 to 100 ° C, in particular at a temperature of 10 to 40 ° C, and in particular at a temperature of about 20 ° C.
- the invention relates to a method of preparation, said method being devoid of use of solvent and / or surfactant and / or reagent.
- the invention relates to a method of preparation, said method possibly containing a purification step.
- the invention relates to a method of preparation, said process being devoid of a purification step.
- the invention also relates to a gliadin bearing hydrophobic groups having the formula:
- R represents the hydrophobic group and is chosen from:
- a linear or branched alkyl group containing from 1 to 1000 carbon atoms in particular the groups - (CH 2 ) 14 -CH 3 or - (CH 2 ) 16 -CH 3
- the invention also relates to particles comprising an inclusion complex as defined above, for their use as medicaments, in particular medicaments having at least one antitumor activity, painkiller, anti-inflammatory, antibiotic, antifungal, antiparasitic, enzymatic, hormonal, anxiolytic, antidiabetic, antihypertensive, vaccinal, antiviral, analgesic, antiepileptic, local and general anesthetic, hypnotic, sedative, antipsychotic, neuroleptic, antidepressant, anticholinergic, cholino mimetic, antimuscarinic, muscarinic, antiadrenergic, antiarrhythmic, antiarthritic, antiasthmatic, anticonvulsant, antihistamine, anti-emetic, antineoplastic, antipyretic, antipruritic, antispasmodic, vasodilator, central nervous system stimulant, decongestant, bone growth stimulant, bone resorption inhibitor, immunosuppressant, muscle
- the invention also relates to particles, comprising an inclusion complex as defined above, for their use in the preparation of medicaments having at least one anti-tumor, pain-relieving, anti-inflammatory, antibiotic, antifungal, antiparasitic, enzymatic activity, hormonal, anxiolytic, antidiabetic, antihypertensive, vaccinal, antiviral, analgesic, antiepileptic, local and general anesthetic, hypnotic, sedative, antipsychotic, neuroleptic, antidepressant, anticholinergic, cholino mimetic, antimuscarinic, muscarinic, antiadrenergic, antiarrhythmic, antiarthritic, antiasthmatic, anticonvulsant, antihistamine, anti-emetic, antineoplastic, antipyretic, antipruritic, antispasmodic, vasodilator, central nervous system stimulant, decongestant, bone growth stimulant, bone resorption inhibitor, immunosuppressant
- the invention also relates to particles, comprising an inclusion complex as defined above, for their use as veterinary medicaments, especially veterinary anti-tumor, anti-pain, anti-inflammatory, antibiotic, antifungal, antiparasitic, enzymatic, hormonal, anxiolytic medicaments.
- antidiabetic agents antihypertensives, vaccines, antivirals, analgesics, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anticholinergics, cholinomimetics, antimuscarinics, muscarinics, antiadrenergics, antiarrhythmics, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, anti-emetic, antineoplastic, antipyretic, antipruritic, antispasmodic, vasodilators, central nervous system stimulants, decongestants, bone growth stimulants, bone resorption inhibitors, immunosuppressants, r muscle stimulants, psychostimulants, tranquilizers, or especially medicaments containing proteins, peptides or fragments thereof, said proteins, peptides or fragments being natural, recombinant or produced by the chemical
- the invention also relates to the use of particles comprising an inclusion complex as defined above as a cosmetic agent, especially as an anti-aging agent, depigmenting, brightening, depigmenting, concealer, anti-puffiness, soothing, exfoliating, exfoliating, nourishing, mattifying, sebum secretion regulator, astringent, purifying, regenerating, restructuring, retexturizing, dermoprotective, anti-cellulite, firming, slimming, tensing, toning, immediate tightening, immediate toning, anti-dandruff, antiseborrhoeic, anti-hair loss , detangling, looping, capillary fortifying, restructuring, sun protection factor, self tanning, tanning accelerator, tanning extension, healing, anti-stretch marks, anti-redness, cell renewal activator, moisturizer, fragrance, deodorant, antiperspirant, cleaner, dye, preservative.
- a cosmetic agent especially as an anti-aging agent, depigmenting,
- the invention also relates to the use of these particles in makeup.
- the invention also relates to the use of particles, comprising an inclusion complex as defined above for the implementation of a method for preparing devices, in particular healing dressings, said devices comprising said particles, and being capable of releasing said particles or one or more active substance (s) of interest contained in said particles.
- the invention also relates to a method for preparing an encapsulation system comprising a step of mixing particles containing inclusion complexes according to the invention, with an active substance of interest used for its properties in the pharmaceutical fields, medical, paramedical, medical devices, cosmetic, veterinary, agri-food, animal feed, agrochemical, pesticides, cosmeto-textiles, perfume, environmental, or in the paint, building and / or automotive industry ,
- an active substance of interest being previously dissolved in an aqueous medium such as pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, an injectable solution or suspension or a solution of physiological saline optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use,
- an aqueous medium such as pure water, an aqueous solution comprising one or more solutes, in particular one or more salt (s) and / or sugar (s), in particular sucrose or glucose, an injectable solution or suspension or a solution of physiological saline optionally enriched with glucose, an emulsion, a gel, a cream, or any other excipient for pharmaceutical, cosmetic, agri-food or veterinary use,
- said aqueous medium optionally containing a solvent chosen in particular from ethanol or acetone, or a surfactant chosen from polysorbate derivatives, especially Tween 80 or Tween 40, to obtain particles containing inclusion complexes containing said active substance of interest.
- the process for preparing an encapsulation system according to the invention comprises a mixing step:
- a protein comprising hydrophobic groups covalently linked to the protein by the amine function and / or the carboxylic function and / or the hydroxyl function and / or the thiol function,
- said protein being selected from elastin, collagen, gliadin, gelatin, keratin, albumin, legumin, vicilin, casein, fibrinogen, insulin, fibrinonectin, a hormone, an enzyme, a coagulation factor, transferrin, fibrin, an immunoglobulin, a cereal protein (wheat, rice, ...), a protein derived from seeds or nuts, a protein derived from seaweed, a silk protein, a protein of egg, a potato protein, and the derivatives of said proteins, and is especially gliadin or gelatin,
- an active substance of interest used for its properties in the fields of pharmaceutical, medical, paramedical, devices medical, cosmetic, veterinary, agri-food, animal feed, agrochemical, pesticides, cosmeto-textiles, perfume, environmental, or in the paint, building and / or automobile industry,
- the weight percentage of said protein, in particular gliadin or gelatin being from 0.01% to 99.9%, especially from 0.5% to 70%,
- the weight percentage of the cyclodextrin being from 0.01% to 99.9%, in particular from 0.5% to 70%
- the mass percentage of the aqueous medium being from 0.01% to 99.9%, especially from 70% to 99%,
- the mass percentage of the solvent being from 0% to 99.9%, especially 10% to
- the step of mixing the process for preparing an encapsulation system comprises a step of dissolving the active substance of interest in an aqueous medium, followed by the addition in the medium of the protein and ⁇ -cyclodextrin.
- the mixture is placed under magnetic stirring for 3 days. But in a practical way, it is possible to mix all the components at the same time.
- the particles can be isolated:
- Figure 1 shows the characteristic IR spectrum of N-acylated gelatin by palmitic acid compared to that of native gelatin.
- Figure 2 shows the characteristic IR spectrum of N-acylated gliadin by palmitic acid in comparison with that of native gliadin.
- Figure 3 shows the size of particles formed from ⁇ -cyclodextrin and palmitic acid grafted gliadin (API) with a degree of substitution (DS) of 0.22%.
- API ⁇ -cyclodextrin and palmitic acid grafted gliadin
- Figure 4 shows the size of the particles formed from ⁇ -cyclodextrin and gliadin grafted with palmitic acid (AP2) with a degree of substitution (DS) of 0.69%.
- FIG. 5 represents the particles obtained in solution with palmitic acid grafted gelatin (API) with a degree of substitution (DS) of 0.19%.
- Figure 6 shows the size of the particles formed from ⁇ -cyclodextrin and palmitic acid (AP1) grafted gelatin with a degree of substitution (DS) of 0.19%.
- FIG. 7 represents the particles obtained in solution with the gelatine grafted with palmitic acid (AP2) with a degree of substitution (DS) of 0.59%.
- Figure 8 shows the size of the particles formed from ⁇ -cyclodextrin and palmitic acid (AP2) grafted gelatin with a degree of substitution (DS) of 0.59%.
- FIG. 9 represents images of gelatin particles observed by electron transmission microscopy (Gelatine AP2DS 0.59 1/10% w / w).
- Figure 10 represents ⁇ -cyclodextrin. In the figure, the dimensions are given in Angstroms.
- IR spectra (ATR-FTIR, FT / IR-4100 spectrometer, JASCO): the principle consists in putting a crystal (diamond) in contact with the sample to be analyzed, before being crossed by the infrared beam.
- Particle size measurements The particle sizes were evaluated by the hydrodynamic diameter. Measurements of the average hydrodynamic diameters of the nanoparticles were carried out with a Nano-ZS90 nanoseries Zetasizer from Malvern Instruments SA (Orsay, France) by quasi-elastic light scattering. The hydrodynamic diameters of the microparticles were measured by a laser granulometer (MasterSizer 2000) from Malvern Instruments SA (Orsay, France).
- TEM Transmission electron microscopy
- Alpha-cyclodextrin is from Cyclolab (Budabest, Hungary). Hydroxypropyl- ⁇ -cyclodextrin ( ⁇ - ⁇ -CD) was provided by Sigma-Aldrich Chemical Co, Saint Quentin Fallavier, France. Gamma-cyclodextrin ( ⁇ -CD) was obtained from Wacker-Chemie (Germany). Synthesis of proteins bearing hydrophobic groups:
- Gelatin (1 g) was dissolved in 11 ml of formamide. The mixture is heated to 90 ° C with continuous magnetic stirring. Subsequently, 3 mL of anhydrous pyridine and 1.2 mL of formamide containing palmitoyl chloride were added to the solution. The amount of palmitoyl chloride was varied to obtain different degrees of substitution (1 g (DS 0.19), 3 g (DS 0.56) and 5 g (DS 1.70)).
- the gelatins obtained respectively carry the codes: gelatin-AP1, gelatin-AP2 and gelatin-AP3. After 3 hours at 90 ° C. and 10 minutes at room temperature, the mixture is poured into 100 ml of ethanol. The precipitate was collected and washed with 200 mL of ethanol and then with 150 mL of diethylether using Buchner type filtration. The solid is lyophilized for 24 hours.
- Gliadin (1 g) is dissolved in 11 mL of 70% ethanol solution.
- the mixture is heated to 60 ° C under continuous magnetic stirring.
- 3 mL of pyridine and 1.2 mL of 70% ethanol solution containing palmitoyl chloride are added to the previous solution.
- the amount of palmitoyl chloride is varied from 1 g to 5 g to obtain different degrees of substitution.
- the gliadins obtained bear the codes gliadin-API and gliadin-AP2 respectively.
- the mixture is poured into 100 ml of ethanol previously cooled.
- the precipitate is collected and washed with 100 ml of ethanol and then with 100 ml of diethyl ether using the Buchner type filter.
- the harvested solid is lyophilized for 24 hours.
- microparticles and nanoparticles were formed from ⁇ -cyclodextrin and palmitic acid grafted protein.
- the protocol consists of weighing ⁇ -cyclodextrin and the acylated protein in a small vial. Subsequently, the distilled water is added to the mixture. The same result is obtained regardless of the order of addition of the ingredients. Magnetic or orbital agitation for a maximum of 3 days is at the origin of the formation of the particles.
- Example 4 Formation of Microparticles and Nanoparticles from Cyclodextrin and Acylated Gelatin
- the microparticles and nanoparticles were formed from ⁇ -cyclodextrin and palmitic acid grafted protein.
- the protocol consists of weighing ⁇ -cyclodextrin and the acylated protein in a small vial. Subsequently, the distilled water is added to the mixture. The same result is obtained regardless of the order of addition of the ingredients. Magnetic or orbital agitation for a maximum of 3 days is at the origin of the formation of the particles.
Abstract
Description
Claims
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CN114478800B (en) * | 2021-02-05 | 2022-10-11 | 华南理工大学 | Fusion protein based on serum albumin, nano assembly, preparation method and application thereof |
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US5679657A (en) | 1994-08-11 | 1997-10-21 | Shiseido Co., Ltd. | Low molecular weight acetylhyaluronate, skin-softening composition, method of manufacturing the same, and method of purifying the same |
FR2739860B1 (en) * | 1995-10-17 | 1998-01-02 | Coletica | AMPHIPHILIC COMPLEXES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THE SAME |
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JP3908969B2 (en) | 2002-03-18 | 2007-04-25 | ピアス株式会社 | Cosmetics |
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RU2524663C1 (en) | 2013-04-26 | 2014-07-27 | Общество с ограниченной ответственностью "ДЖИ-Групп" | Complex cosmetic agent |
KR20150015209A (en) | 2013-07-31 | 2015-02-10 | 주식회사 피코테라 | A manufacturing method of low molecular weight and acetylation hyaluronic acid and use thereof |
-
2013
- 2013-05-31 FR FR1355003A patent/FR3006315B1/en not_active Expired - Fee Related
-
2014
- 2014-05-02 US US14/894,708 patent/US10111961B2/en not_active Expired - Fee Related
- 2014-05-02 EP EP14727610.9A patent/EP3004182A1/en not_active Withdrawn
- 2014-05-02 WO PCT/FR2014/051052 patent/WO2014191645A1/en active Application Filing
Non-Patent Citations (2)
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None * |
See also references of WO2014191645A1 * |
Also Published As
Publication number | Publication date |
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WO2014191645A1 (en) | 2014-12-04 |
US10111961B2 (en) | 2018-10-30 |
FR3006315B1 (en) | 2015-10-02 |
US20160120991A1 (en) | 2016-05-05 |
FR3006315A1 (en) | 2014-12-05 |
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