WO2015059193A1 - Formulation d'organogel et ses utilisations - Google Patents

Formulation d'organogel et ses utilisations Download PDF

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Publication number
WO2015059193A1
WO2015059193A1 PCT/EP2014/072657 EP2014072657W WO2015059193A1 WO 2015059193 A1 WO2015059193 A1 WO 2015059193A1 EP 2014072657 W EP2014072657 W EP 2014072657W WO 2015059193 A1 WO2015059193 A1 WO 2015059193A1
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Prior art keywords
organogel
formulation
lecithin
organogel formulation
formulation according
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PCT/EP2014/072657
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English (en)
Inventor
Abdelkader MOURI
Caroline BAUER
Elsa COMPTE
Lorraine BENIGNO
Patrick Maurel
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Medesis Pharma
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Publication of WO2015059193A1 publication Critical patent/WO2015059193A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention deals with a new organogel formulation, comprising lecithin, water, ethanol and at least one acylglycerol.
  • Said organogel formulation can be used for therapeutical purposes, both per se and as matrix for a pharmaceutically or veterinary active agent.
  • Said organogel formulation can also be used in the treatment of dermatological affections or as a matrix for cosmetic or personal care substances
  • Topical administration of drugs in order to achieve optimal cutaneous and percutaneous drug delivery, is a favorite subject to study nowadays because of various advantages such as ease of administration and delivery benefits.
  • Formulations in gel form are particularly appropriate for topical administration route.
  • Lecithin organogels have been for instance studied as vehicles for topical drug delivery (see for instance, Kumar et al. AAPS PharmSciTech 2005, 6(2), E298-E310). Said organogels are formed by gelation of a binary system comprising lecithin and an apolar solvent, for instance oil, when said system is contacted with traces of a polar solvent, for instance water. According to the physical interpretation presented in publications, the obtained organogel is a jelly-like structure that consists of three-dimensional networks of entangled reverse cylindrical micelles, which immobilize the continuous phase and thus convert from liquid to viscous gel.
  • organogels can only be obtained when the lecithin contains more than 95% phosphatidylcholine and is free from fat as well as moisture (for instance Kumar et al., see above, or Raut et al. Acta Pharmaceutica Sinica B 2012, 2(1), 8-15).
  • the organogels comprise a substantial amount of lecithin (the molar ratio of water to lecithin in organogels is typically 2: 10)
  • the need of highly pure lecithin can be an issue, in particular regarding the industrial development of lecithin organogels, because it is expensive and difficult to obtain in large quantities.
  • Lecithin plays the role of gelator molecules in said ternary systems.
  • organogels when such organogels are used as a vehicle for the delivery of hydrophilic active agents, the amount of active agent that can be incorporated is limited by the amount of water comprised in the system. Actually, when the water amount is increased in said organogels, the 3-dimensional network collapses over a certain n ratio, wherein n ratio is the molar ratio of water to lecithin.
  • n ratio is the molar ratio of water to lecithin.
  • organogels can be formed with the combination of lecithin, water, ethanol and at least one acylglycerol.
  • the acylglycerol preferably acts as a gel-forming agent, like lecithin.
  • organogels according to the invention may comprise relatively high amounts of water, thus affording the possibility to incorporate higher amounts of hydrophilic compounds, such as hydrophilic active agents.
  • a first object of the invention is an organogel formulation, wherein said organogel comprises lecithin, water, ethanol and a mixture of acylglycerols of formula (I) as defined below.
  • Another object of the present invention is an organogel formulation comprising:
  • Another object of the invention is an organogel formulation comprising lecithin, water, ethanol and at least one acylglycerol, for use as a medicament.
  • Another object of the invention is an organogel formulation comprising lecithin, water, ethanol and at least one acylglycerol, and further comprising at least one active agent.
  • Figure 1 Photograph of an organogel sample and a liquid sample
  • FIG. 1 Polarized microscopy micrographs of samples 1 (a), 2 (b), 3 (c), 4 (d), 5
  • Figure 4 SAXS characterization of samples 2 ( ⁇ ), 3 ( B ) and 4 (A) (a), and of samples 5 ( ⁇ ) and 7 ( ⁇ ) (b).
  • a first object of the invention is an organogel formulation, wherein said organogel comprises lecithin, water, ethanol and a mixture of acylglycerols.
  • organogel or “organogel formulation” represent a semi-solid, jelly-like material (gel), for instance with a viscoelastic behavior.
  • the organogel according to the invention presents rheological characteristics different from those of a Newtonian liquid.
  • the yield stress of an organogel formulation according to the invention is strictly superior to the yield stress of a Newtonian liquid (that is 0 Pa under conditions as described below).
  • the yield stress is the stress level at which the gel ceases to behave elastically.
  • the rheological characterization of the organogels according to the invention is preferably performed using TA instrument Rheometer (AR 2000 EX).
  • a cone plate with a diameter of 4cm and 6cm and an angle of 2° and 1.1° respectively is used.
  • Temperature is preferably between around 20 and around 25 °C.
  • organogel formulations according to the invention can be prepared by classical formulation methods used for preparing organogels.
  • One of ordinary skill in the art is able to determine the appropriate experimental conditions (such as stirring rate and/or temperature for instance) for forming the organogel by mixing the different components.
  • Acylglycerols are amphiphilic compounds and can thus cooperate with lecithin to form stable structures in the organogel. Said cooperation favors the gelation of the composition comprising lecithin, water, ethanol and a mixture of acylglycerols according to the invention.
  • acylglycerols are gel-forming agents. They can consequently be implied in favoring gelation of the composition and/or stabilizing said organogel.
  • the organogel formulation according to the invention does not comprise, as compulsory components for obtaining the organogel, any apolar solvent like alkanes, alkenes or mixtures thereof.
  • the organogel formulation according to the invention does not comprise any polymer, such as poloxamers.
  • the organogel formulation according to the invention comprises:
  • compositions of the organogel formulation > Acylglycerols
  • Acylglycerols used in the organogel formulation according to the invention can be isolated from the majority of animals, and more preferably plants.
  • Acylglycerols used in the organogel formulation according to the invention include mono-, di- and/or tri-acylglycerols of the following formula (I): in which:
  • - Ri is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms;
  • R 2 is an acyl residue of a linear or branched unsaturated fatty acid having between 2 and 18 carbon atoms, or a hydrogen atom;
  • R 3 is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms, or a hydrogen atom.
  • Ri or R 3 preferably only one of Ri and R 3 , in particular only Ri, represents an acyl residue of oleic acid (CI 8: l[cis]-9).
  • R 2 is an acyl residue of a linear or branched unsaturated fatty acid having between 2 and 18 carbon atoms, and preferably has 18 carbon atoms, preferably R 2 is an oleic acid residue (oleoyl group), one of its positional isomers with respect to the double bond (cis-6,7,9,11 and 13) or one of its iso-branched isomers.
  • Ri represents an oleoyl group.
  • R 3 is a hydrogen atom.
  • oil containing a high concentration of oleic acid will be chosen as a useful source of acylglycerols according to the invention.
  • Such oil usually contains a high proportion of acylglycerols useful according to the invention.
  • the preferred acylglycerols are glycerol 1 -monooleate and glycerol 1,2 -dioleate.
  • glycerol monooleate 40 contains about 32 to 52% of monoacylglycerol, 30 to 50% of diacylglycerol, 5 to 20% of triacylglycerol and is pharmaceutically accepted ⁇ European Pharmacopeia (8 th Edition), USP 25/NF20, and Japanese Standard of food Additives).
  • Such product is for instance commercially available by Gattefosse Company under the name Peceol ® .
  • Peceol ® may comprise around 45.3 wt% of monoacyl glycerol, around 44.5 wt% of diacylglycerol and around 8,6 wt% of triacyl glycerol (the acyl fraction of Peceol ® is mainly made of oleoyl - usually around 80% of the acyl residue is oleoyl fraction).
  • the acylglycerol comprised in the composition of the invention is a mixture of acylglycerols, of formula (I) as defined above, and more specifically said mixture comprises monoacylglycerol and diacylglycerol, of formula (I), and optionally triacylglycerol of formula (I), as defined above.
  • the mixture comprises more than 25% of monoacylglycerol, based on the total weight of said mixture.
  • said mixture comprises 32 to 52% of monoacylglycerol, 30 to 50% of diacylglycerol, and 5 to 20% of triacylglycerol, based on the total weight of said mixture.
  • the acylglycerols are preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 23 g to 49 g, more preferably from 30 g to 46 g, with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • the weight of acylgylycerol corresponds to the total weight of the mixture usually containing acylglycerols, or a mixture of acylglycerols, with glycerol and fatty acids derived from said acylglycerol(s), such as Peceol ® described above.
  • Acylglycerols preferably act as gel-forming agents in the organogel formulations according to the invention.
  • Acylglycerols are natural compounds, and may be extracted and/or derived from vegetable sources. Their use is thus favoured in terms of biocompatibility and environmental concerns when compared to synthetic compounds. > Lecithin
  • lecithin designates phosphatidylcholine.
  • Phosphatidylcholine is also known as l,2-diacyl-glycero-3-phosphocholine or PtdCho.
  • Phosphatidylcholine is formed from a choline, a phosphate group, a glycerol and two fatty acids. It is actually a group of molecules, wherein the fatty acid compositions varies from one molecule to another.
  • Phosphatidylcholine may be obtained from commercial lecithin that contains phosphatidylcholine in weight concentrations of 20 to 98%.
  • the lecithin preferably used in the organogel formulations according to the invention is Epikuron 200 ® and contains phosphatidylcholine at a concentration of more than 90%.
  • the lecithin used in the organogel formulations according to the invention comprises more than 93% phosphatidylcholine.
  • the weight ratio lecithin/acylglycerol in organogel formulations according to the invention is preferably from 0.51 to 2.20, preferably 0.51 to 1.64.
  • the lecithin is preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 15 g to 50 g, preferably from 25 to 50 g, with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • the water useful for the preparation of the organogel formulation according to the invention is preferably purified water.
  • the weight ratio lecithin/water in organogel formulations according to the invention is preferably from 1.0 to 10.0.
  • Water is preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 5 g to 50 g, preferably from 5 to 23 g with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • One of ordinary skill in the art will adapt the amount of lecithin, ethanol and/or acylglycerol in the organogel formulations to the desired properties for said organogel.
  • the amount of lecithin and/or acylglycerol will be adapted to the desired amount of water in the organogel.
  • the molar ratio water/(surface active agents), wherein the surface active agents are lecithin, diacylglycerols and monoacylglycerols, is at least equal to
  • Ethanol is preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 0.01 to 9.5 g, preferably from 6 to 9 g with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • ethanol is useful to make the organogel formulation more spreadable. It is also useful as permeation enhancer, for instance when the organogel formulation comprising an active agent is applied topically. > Other components
  • the organogel formulation according to the invention may comprise additional components.
  • additional components one can cite sterols and alcohols different from ethanol.
  • the organogel formulation does not comprise liposomes.
  • the organogel formulation according to the invention may comprise at least one sterol, preferably natural sterol, such as cholesterol or phytosterol (vegetable sterols).
  • Sitosterol and cholesterol are the preferred sterols that can be present in an organogel formulation according to the invention.
  • the organogel comprises sitosterol.
  • Sitosterol and cholesterol are commercially available. More particularly, commercial sitosterol which is extracted from soya can be used. In such a product, the sitosterol generally represents from 50 to 80 % by weight of the product and is generally found in a mixture with campesterol and sitostanol in respective proportions in the order of 15% each.
  • Commercial sitosterol which is extracted from a variety of pine called tall oil can also be used.
  • the sterol is preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 0.825 g to 4.5 g, preferably from 2 g to 3 g, in particular around 2.5 g, with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • the organogel formulation according to the invention may comprise at least one alcohol in addition to ethanol as defined above.
  • the alcohols that may be used according to the invention are preferably linear or branched mono-alcohols from C2 to C3. Examples of alcohols are 1-propanol, 2-propanol, 2-methyl-l-propanol, isopropanol, and any mixture thereof.
  • Polyols that may be used according to the invention are preferably glycerol and propylene glycol.
  • an alcohol is present in the organogel formulation in addition to ethanol, it is preferably incorporated or comprised in the organogel formulation in an amount by weight ranging from 0.01 g to 10 g, preferably from 2 g to 9 g, in particular around 9 g, with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • the total amount of the alcohols comprised in the organogel formulation, including ethanol is comprised between 6 g and 9 g, in particular around 9 g, with respect to 100 g of the total weight of the organogel formulation according to the invention.
  • the amounts of the components of the gel are defined with respect to the total weight of the organogel, in absence of active agent incorporated therein. If a great amount of an active agent is added to the gel, modifying substantially the total weight of the gel, the amounts of the components (apart from the active agent) may be out of the ranges defined above. Consequently, the amounts specified in the present description are the amounts (or %) of the components of the organogel formulation without any active agent, unless otherwise specified.
  • An organogel formulation according to the invention may be used for therapeutical, more specifically dermatological, and/or cosmetic purposes.
  • An organogel formulation according to the invention may be used for human and/or animal, preferably mammal, subjects.
  • an object of the present invention is an organogel formulation according to the invention, for use as a medicament.
  • the organogel formulation is used per se (i.e. without incorporation of any active agent, specifically pharmaceutically active agent) for a therapeutical purpose.
  • the invention relates to a pharmaceutical composition comprising the organogel formulation as defined above, and optionally a pharmaceutically acceptable support.
  • the organogel formulation according to the invention or the composition comprising the same is used in the field of cicatrisation and/or healing, more specifically skin cicatrisation and/or healing.
  • the organogel formulation or the composition comprising the same may be used for improving and/or accelerating cicatrisation of a wound, a burn, an inflammation and/or a bedsore.
  • the organogel formulation or the composition comprising the same according to the invention reduces the cicatrisation time of a wound, a burn, an inflammation and/or a bedsore, preferably a non infected wound, burn, inflammation and/or bedsore.
  • the organogel formulation or the composition comprising the same used for cicatrisation does not comprise any pharmaceutically active agent.
  • the organogel formulation according to the invention further comprises at least one active agent, preferably at least one pharmaceutically or veterinary active agent.
  • the invention relates to a pharmaceutical composition comprising the organogel formulation as defined above, at least one active agent, preferably at least one pharmaceutically or veterinary active agent, and optionally a pharmaceutically acceptable support.
  • Another object of the invention is thus an organogel formulation according to the invention or a composition comprising the same, further comprising at least one active agent, preferably pharmaceutically or veterinary active agent.
  • pharmaceutically or veterinary active agent refers in the present invention to any compound susceptible to have a prophylactic and/or therapeutical action, preferably in the course of the treatment of a pathology.
  • the pharmaceutically active agent is more specifically hydrophilic.
  • pharmaceutically active agents that can be added to an organogel formulation according to the invention can be cited for instance metals, such as selenium, silver, copper, vanadium, manganese or zinc, or any pharmaceutically acceptable salt thereof, antalgics, analgesics, anesthetics, such as lidocaine chloride, alkaloids such as caffeine, anti-inflammatory compounds, anti-microbial compounds such as antibiotics, antivirals and antifungals, antiseptics, immunosuppressants, antihistamines, cytostatics, retinoids, antioxidants, peptides, polypeptides, proteins, neurotoxins such as botulinum toxin, polysaccharides, nucleic acids for gene therapy [DNA or RNA (more particularly RNAi)
  • Another object of the invention is an organogel formulation according to the invention or a cosmetic composition comprising the same, further comprising at least one cosmetic or personal care substance.
  • the organogel that comprises at least one cosmetic or personal care substance does not comprise any pharmaceutically and/or veterinary active agent.
  • cosmetic or personal care substance refers for instance to components useful for shampoo, conditioner, hair gel, toothpaste, soap, skin treatments, shaving treatments, lotions, and may be for instance fragrances, skin-care additives, botanicals, astringents, moisturizers, emollients, make-up items, anti-cellulite agents, UV protectors, active agents against skin aging, or skin coloring substances.
  • organogel formulation as matrix for at least one active agent or cosmetic or personal care substance affords several advantages.
  • the organogel formulation affords the possibility of sustained release of the active agent or cosmetic or personal care substance. It also allows the simultaneous delivery of several active ingredients and/or cosmetic or personal care substances over a prolonged period of time.
  • the use of said organogel formulation may improve the stability of the at least one active agent or cosmetic or personal care substance, preferably its in vivo stability.
  • the use of the present organogel formulation as a matrix may limit the enzymatic degradation of the at least one active agent or cosmetic or personal care substance.
  • the organogel formulation according to the invention per se or as a matrix for at least one active agent or cosmetic or personal care substance, can be administered by any appropriate route.
  • the organogel formulation or composition comprising the same is administered by the topical, transdermal or transmucosal route.
  • the organogel formulation or composition comprising the same is administered topically onto the skin.
  • organogel formulation according to the invention or the composition comprising the same is advantageously dermo and/or muco-adhesive.
  • the organogel formulation according to the invention or the composition thereof provides a comfortable feel when applied onto the skin.
  • the organogel formulation according to the invention is preferably highly biocompatible, in particular at the cellular level.
  • the organogel formulation according to the invention presents improved properties for the restructuration and/or regeneration of biological materials such as skin or cellular membranes.
  • the use of the organogel formulation according to the invention for the delivery of a pharmaceutically active agent increases the ability of said agent to cross the skin and/or the cellular membranes.
  • the organogel formulation according to the invention may be used in the treatment of any pathological condition and/or disease for which at least one of the active agents that can be incorporated in the organogel formulation has a beneficial effect. This effect can be for instance a prophylactic and/or therapeutic treatment, a slow-down of the progression of the disease, or the reduction of at least one symptom of the disease.
  • the organogel formulation according to the invention may be used in the treatment of dermatological affections, for instance acne, eczema, fungal, viral or bacterial affections, psoriasis or pruritus.
  • the organogel formulation according to the invention may be used for cosmetics and/or personal care.
  • the term "comprise(s)” or “comprising” can be generally interpreted such that all of the specifically mentioned features and any optional, additional and unspecified features are included; it can also be interpreted more specifically as the expression “consisting of where only the specified features are included, unless otherwise specified.
  • the present invention includes the specific embodiments as described above and any combination thereof.
  • the percentage values are weight percentage values, unless otherwise indicated.
  • lecithin containing 94.5% of phosphatidylcholine
  • Phystosterol containing 78.6% of beta-sitosterol
  • Peceol ® was added thereto and magnetic stirring was carried out at 700 r/min at 37°C to form an oil mixture.
  • the lipid mixture was ready for use immediately and contacted to purified water at room temperature and stirred at 700 r/min. If necessary, bubbles could be removed by heating samples at 50°C.
  • the samples were then stored at least over night at room temperature before further characterization in order to determine visually texture and phase boundary.
  • Table 1 shows the quantities (g) and the % of individual components in the different samples.
  • Table 2 below presents the water/lecithin molar ratio, and the water/(surface active agents) molar ratio for each sample of table 1.
  • the surface active agents are lecithin, and glycerol monooleate and glycerol dioleate comprised in Peceol ® .
  • the mean molecular weight of glycerol monooleate and glycerol dioleate is used for calculating said ratio.
  • Figure 1 presents comparative sample 1 (right side) and sample 2. It is clear that sample 2 is an organogel, when sample 1 is a liquid.
  • Example 2 Characterization of the samples
  • Polarizing light microscopy can be used to differentiate microemulsion (isotropic liquid) to liquid crystalline phases (LC). LC is easily distinguished by the birefringence displayed with the polarized light. Samples were analyzed under a polarized light microscope (Axiolab, Zeiss) at lOx magnification, the microscope is attached to a canon A620 camera, slides were examined at ambient temperature (25°C). A drop of sample was placed between a coverslip and a glass slide and then examined under cross- polarized light. Results:
  • Sample 1 is not birefringent under polarized light, which is characteristic of an isotropic medium, in the present case an isotropic liquid.
  • samples 2, 3, 4, 5, 6 and 7 are highly birefringent under polarized light, which is characteristic of an anisotropic medium, in the present case liquid crystalline phases.
  • Rheology measurements were performed using TA instrument Rheometer (AR 2000 EX). A cone plate with a diameter of 4cm and 6cm and an angle of 2° and 1.1° respectively was used. Temperature was maintained at 25 + 0.1 °C. Shear rate measurements were performed between 0.01 and 1000 s "1 . A sample volume of 1 ml was used.
  • Figure 3 presents the shear stress in function of the shear rate for samples 1, 2, 3, 4, 5, 6 and 7.
  • Sample 1 exhibits a linear dependence of the shear stress as a function of shear rate, which is characteristic of a Newtonian liquid.
  • Samples 2, 3, 4, 5, 6 and 7 exhibit a non-linear dependence of the shear stress as a function of shear rate, which is characteristic of a viscoelastic medium. This viscoelastic behavior with such yield stress values indicates higher order of structure of the system (i.e. liquid crystalline phase).
  • Table 3 below presents the viscosity (Pa.s) and yield stress (Pa) values for samples 2, 3, 4, 5, 6 and 7.
  • organogel samples 2 to 7 present a viscoelastic behavior.
  • Figure 4 presents the SAXS spectra obtained for samples 2, 3 and 4 on one hand, and 5 and 7 on the other hand. Several sharp diffraction peaks are evidenced in the low angle X-ray region for all samples. These peaks are characteristic of liquid crystalline structure of the samples.
  • Example 3 Organogels comprising active agents
  • Organogels could be successfully obtained when adding caffeine, silver, copper, zinc, manganese or niflumic acid to formulations comprising lecithin, Peceol ® , water, ethanol and beta- sitosterol.
  • formulations comprising lecithin, Peceol ® , water, ethanol and beta- sitosterol.
  • Samples were then stored at least over night at room temperature before further characterization in order to determine visually texture and phase boundary.
  • Table 4 shows % of individual components in the different samples. > Silver
  • the samples were then stored at least over night at room temperature before further characterization in order to determine visually texture and phase boundary.
  • Samples were then stored at least over night at room temperature before further characterization in order to determine visually texture and phase boundary.
  • Table 4 shows % of individual components in the different samples.
  • Samples were then stored at least over night at room temperature before further characterization in order to determine visually texture and phase boundary.
  • Table 4 shows % of individual components in the different samples.

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Abstract

La présente invention concerne une nouvelle formulation d'organogel comprenant de la lécithine, de l'eau, de l'éthanol et des acylglycérols. Ladite formulation d'organogel peut être utilisée à des fins thérapeutiques, à la fois à elle seule et comme matrice pour un agent actif sur le plan pharmaceutique ou vétérinaire. Ladite formulation d'organogel peut également être utilisée dans le traitement d'affections dermatologiques ou comme matrice pour des substances cosmétiques ou de soins personnels.
PCT/EP2014/072657 2013-10-22 2014-10-22 Formulation d'organogel et ses utilisations WO2015059193A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006075123A1 (fr) * 2005-01-14 2006-07-20 Camurus Ab Formulations bioadhesives topiques
WO2011075623A1 (fr) * 2009-12-18 2011-06-23 Latitude Pharmaceuticals, Inc. Composition de gel à une phase comprenant des phospholipides
WO2011117333A2 (fr) * 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des ions métalliques et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006075123A1 (fr) * 2005-01-14 2006-07-20 Camurus Ab Formulations bioadhesives topiques
WO2011075623A1 (fr) * 2009-12-18 2011-06-23 Latitude Pharmaceuticals, Inc. Composition de gel à une phase comprenant des phospholipides
WO2011117333A2 (fr) * 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des ions métalliques et son utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LI-JUAN HAN ET AL: "Rheological properties of organogels developed by sitosterol and lecithin", FOOD RESEARCH INTERNATIONAL, vol. 53, no. 1, 1 August 2013 (2013-08-01), pages 42 - 48, XP055101374, ISSN: 0963-9969, DOI: 10.1016/j.foodres.2013.03.039 *
MURDAN SUDAXSHINA: "ORGANOGELS IN DRUG DELIVERY", EXPERT OPINION ON DRUG DELIVERY, INFORMA HEALTHCARE, GB, vol. 2, no. 3, 1 January 2005 (2005-01-01), pages 489 - 505, XP008071792, ISSN: 1742-5247, DOI: 10.1517/17425247.2.3.489 *
RAJIV KUMAR ET AL: "Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: A review", AAPS PHARMSCITECH, vol. 6, no. 2, 1 June 2005 (2005-06-01), pages E298 - E310, XP055099144, DOI: 10.1208/pt060240 *

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