EP2504370A1 - Acryl- oder methacrylpolymer mit alpha-tocopherol-pfropfen - Google Patents
Acryl- oder methacrylpolymer mit alpha-tocopherol-pfropfenInfo
- Publication number
- EP2504370A1 EP2504370A1 EP10805323A EP10805323A EP2504370A1 EP 2504370 A1 EP2504370 A1 EP 2504370A1 EP 10805323 A EP10805323 A EP 10805323A EP 10805323 A EP10805323 A EP 10805323A EP 2504370 A1 EP2504370 A1 EP 2504370A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymer
- tocopherol
- alpha
- nanoparticles
- function
- 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- Withdrawn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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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/30—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety
-
- 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/30—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety
- C08F220/302—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety and two or more oxygen atoms in the alcohol moiety
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine
Definitions
- the invention relates to a polymer having a linear backbone of acrylic and / or methacrylic type comprising alpha-tocopherol grafts linked to said backbone.
- These polymers form nanoparticles in water, capable of combining active ingredients of various natures, and are more particularly advantageous for the purpose of increasing the aqueous solubility of active ingredients.
- the active ingredients, PA, class II or class IV of the biopharmaceutical classification essentially have an oral bioavailability limited by their low solubility.
- paclitaxel a natural taxoid, widely used for the treatment of tumors is representative of these poorly water-soluble active ingredients.
- a solubilizing additive should have several essential characteristics.
- the formulation of the active with a solubilizing additive has a low viscosity.
- the viscosity of the suspension containing the active ingredient and the solubilizer must be sufficiently low to allow easy injection through a small diameter needle, for example a gauge needle 27 to 31.
- a low viscosity of the suspension solubilizing the active remains a decisive advantage for the steps of manufacturing microparticles, tablets or any other pharmaceutical form known to those skilled in the art.
- This requirement of low viscosity is particularly restrictive because it limits the acceptable amount of solubilizing additive and excludes the use of high molecular weight polymer type additives that are highly hydrosubstituted but have high viscosities.
- micellar solutions Polymeric micelles formed from amphiphilic copolymers, for example PLGA-PEG diblock copolymers, are thus known. In this form of formulation, the active ingredient is solubilized within the hydrophobic core of PLGA micelles.
- a moderately soluble PA such as, for example, a peptide of medium solubility
- the nanoparticle manufacturing process comprises a step of solubilizing PLGA in a hydrophobic solvent, a step that must be avoided for certain fragile PAs.
- polyglutamic acid-based polymers comprising various hydrophobic grafts. These polymers find applications particularly in the field of controlled release of proteins such as insulin or interferon alpha.
- WO 03/104303 describes more particularly polymers of the polyamino acid type, and in particular polyglutamics, comprising alpha-tocopherol grafts linked by a carboxylate ester function in the gamma position of glutamic acid. These polymers form nanoparticles in water and are able to associate small molecules or proteins. After administration by injection into the subcutaneous tissue, these nanoparticles release proteins over a period that can vary from a few days to two weeks. These polymers are biodegraded by enzymes in vivo.
- amphiphilic polymers having improved resistance to degradation by enzymatic hydrolysis, capable of forming stable nanoparticles in an aqueous medium, and capable of associating with the nanoparticulate state of noncovalently with active ingredients, in particular active agents of low and medium aqueous solubility, and dissociate in vivo.
- the present invention aims precisely to propose a new family of polymers, and new compositions, to satisfy all of the above requirements.
- the present invention relates, in one of its aspects, to a polymer having a linear skeleton of acrylic and / or methacrylic type to which alpha-tocopherol grafts are linked, characterized in that said alpha-tocopherol grafts are linked to said skeleton via a spacer formed in part from at least one hydrolysable function, and in that the distribution of said grafts at said skeleton is random.
- these polymers are biocompatible.
- the polymers according to the invention have a molar grafting level in alpha-tocopherol groups, less than or equal to 30 mol%.
- the polymers of the invention are capable of spontaneously forming, when they are dispersed in an aqueous medium, in particular of pH ranging from 5 to 8, in particular water, nanoparticles.
- the invention relates to a composition, in particular a pharmaceutical, cosmetic, dietetic or phytosanitary composition, comprising at least one polymer as defined above.
- a composition according to the invention may comprise at least one active agent, in particular a low or medium aqueous solubility active agent, said active agent being present in a form non-covalently associated with nanoparticles formed from at least one polymer. as defined above.
- a composition of the invention can be adapted, in particular, to ensure a regulated release profile of the asset as a function of time.
- the invention also relates to the use of nanoparticles of at least one polymer of the invention, non-covalently associated with an active ingredient, in order to convey, solubilize and / or increase the aqueous solubilization of an active agent, in particular an active agent of low or medium aqueous solubility.
- the polymers according to the invention are particularly interesting with regard to their skeleton of acrylic and / or methacrylic type.
- polymers of acrylic or methacrylic type already find many applications in the field of dosage forms for oral administration.
- Commonly used polymers are known by their trade name Carbopol ® or Carbomer ® which are crosslinked polymers most often used as viscosifiers, controlled release matrices or mucoadhesive agents.
- Other families known under the brand names Eudragit ® , Kollicoat ® or Eastacryl ® are for example thickening emulsions or suspensions. These polymers are commonly used as solid matrix, coating materials or thickeners. However, this type of polymer does not provide the properties sought by the applicant.
- Copolymer films obtained from the radical copolymerization of 2-hydroxyethyl methacrylate monomers and tocopherolmethacrylate type monomers. These Copolymers are proposed for tendon healing applications. They form hydrogels hydrated in the presence of water (films) and are not dispersible in the aqueous phase.
- Kim et al. (US 5,869,703) describe nonionic monomers of alpha-tocopherol comprising an acrylate or methacrylate function. Homopolymers derived from these monomers and prepared by radical polymerization in water are able to organize in the form of vesicles from 300 to 1200 nm. These nonionic vesicles are proposed as antioxidants.
- the polymers of the invention make it possible to significantly increase the solubility of poorly soluble or even insoluble active agents in water, and more generally of active agents of any kind, in particular of peptide or protein type.
- the advantageously low viscosity of these polymers makes it possible, by increasing their concentration, to increase the amount of active agents in solution.
- the present invention relates to a method for preparing a polymer as defined above, characterized in that it comprises at least bringing into contact, under conditions conducive to their interaction, at least a (meth) acrylic (co) polymer with at least one alpha-tocopherol derivative functionalized with a spacer having at its free end a function capable of interacting with an acid function of said polymer, said spacer being such that at the end of the reaction with said (co) polymer, it comprises at least one hydrolysable function.
- METH ACRYLIC TYPE POLYMERS
- acrylic and / or methacrylic type polymer polymers whose linear skeleton or the main chain is formed of acrylic acid (s) and / or methacrylic acid (s) and acrylate (s) and / or methacrylate (s) units of methyl, ethyl, propyl or butyl.
- the polymer chain may further comprise acrylate and / or methacrylate units distinct from those derivatized with a tocopherol group.
- acrylate and / or methacrylate units may be derivatized by a polyalkylene glycol unit, as described below, or by a spacer according to the invention but not functionalized at its free end by a tocopherol unit.
- the main chain of the (co) polymers of the acrylic and / or methacrylic type of the invention may comprise acrylic acid and acrylate units or methacrylic acid and methacrylate units, or a combination of the two previous alternatives in the case where the main chain is a copolymer formed by copolymerization of at least two distinct monomers, for example of acrylic and methacrylic type.
- the polymers according to the invention consist of units of acrylic acid and acrylate type, the latter comprising alpha-tocopherol grafts, as specified above.
- the distribution of the acrylate and / or methacrylate type units carrying alpha-tocopherol grafts is, according to the present invention, such that the polymers thus constituted are polymers of the random type.
- random type polymer is intended to mean that the monomer units of the acrylate and / or methacrylate type, bearing alpha-tocopherol grafts, are irregularly distributed within the poly (meth) acrylic chain, regardless of the nature adjacent units.
- the molar grafting level of alpha-tocopherol grafts of the polymer according to the invention is less than or equal to 30 mol%, in particular less than or equal to 20 mol%, in particular greater than or equal to 3%. molar, and preferably between 5 and 10 mol%. In other words, not more than 30% of the acrylic and / or methacrylic units forming the backbone of the (co) polymer according to the invention carry alpha-tocopheryl side segments.
- Alpha-tocopherol can be in its form D-alpha-tocopherol (its natural form) or its form D, L-alpha-tocopherol (racemic and synthetic form).
- alpha-tocopherol according to the invention may be of natural or synthetic origin.
- alpha-tocopherol is of synthetic origin.
- the binding of alpha-tocopherol to the main chain of the polymers according to the invention is established via a spacer.
- a “spacer” according to the invention represents a chemical entity formed in part of at least one hydrolysable function. It is therefore difunctional and different from a simple chemical bond. Similarly, this spacer is different from the reaction unit obtained by direct interaction of an acid function of the polymer backbone with a function carried on the tocopherol backbone.
- This hydrolysable function may be located at the end of said spacer linked to the polymeric backbone, at the end of said spacer linked to the alpha-tocopherol group, or within said spacer.
- this hydrolysable function is derived from the reaction of a function present on the polymer backbone or of a function present on the alpha-tocopherol molecule with a reactive function present on the precursor molecule of the spacer.
- This spacer contains at least one carbon atom.
- linking an alpha-tocopherol unit to a (meth) acrylate unit of (co) polymer advantageously comprises two functions hydrolysable, one establishing a covalent bond with the polymeric backbone and the other with the alpha-tocopherol unit.
- the hydrolysable function (s) present on the spacer is (are) more particularly an ester function (s), amide, carbonate or carbamate.
- the spacer according to the invention is an amino acid residue.
- it is a natural amino acid residue, especially chosen from alanine, glycine, phenylalanine or leucine.
- the spacer is an alanine residue.
- the polymer according to the invention is a polymer of formula (I) below,
- R, R 2 and 5 independently represent H or methyl; -R 3 -A- (R 4 ) P - constitutes the spacer according to the invention;
- ⁇ R 3 is -NH- or -O-;
- ⁇ A represents a linear alkyl to C 2, or a linear or branched C 2 -C 6, or a methylene substituted with a benzyl group;
- ⁇ p is 0 or 1, preferably p is 1;
- ⁇ R 5 is -OH or -OM, where M represents a cation, or R 5 represents a polyalkylene glycol substituent bound to the polymer via an ester function or an amide function;
- ⁇ m and n are positive integers
- ⁇ q is 0 or a positive integer, and q is preferably 0;
- ⁇ (m + n + q) varies from 20 to 300,000;
- n / (m + n + q) is less than or equal to 30% molar
- the polymer according to the invention is a polymer of formula ( ⁇ ) below,
- R 1 to R 5 , m, n and p are as defined above.
- the general formulas (I) and ( ⁇ ) described above should not be interpreted as representing block copolymers (or blocks), involving a specific order between the two or three types of units represented forming the skeleton.
- the order of succession of the two or even three types of pattern is totally random.
- the poly (meth) acrylic polymer contains carboxylic functions which are either neutral (COOH form) or ionized according to the pH and the composition.
- the counter-cation may be an inorganic cation such as sodium, calcium, magnesium or ammonium, or an organic cation such as the protonated form of triethylamine, triethanolamine, tri (hydroxymethyl) amino methane or a tetraalkylammonium (alkyl being methyl, ethyl, propyl or butyl), or the protonated form of an amino acid, especially lysine or arginine.
- an inorganic cation such as sodium, calcium, magnesium or ammonium
- an organic cation such as the protonated form of triethylamine, triethanolamine, tri (hydroxymethyl) amino methane or a tetraalkylammonium (alkyl being methyl, ethyl, propyl or butyl), or the protonated form of an amino acid, especially lysine or arginine.
- linking an alpha-tocopherol unit to a (meth) acrylate type unit of (co) polymer comprises a single hydrolysable function linked to the (meth) acrylate unit, which may be an amide function or an ester function.
- p is 1, the spacer then having two hydrolysable functions.
- the polymer according to the invention is a polymer of formula (I) or (F), preferably of formula (F), in which -R 3 -AR 4 - constitutes an alanine residue .
- the polymer according to the invention has an average molar mass ranging from 2,000 to 1,000,000, and preferably from 5,000 to 50,000.
- the polymer is biocompatible.
- a (co) polymer according to the invention may also carry one or more polyalkylene glycol type grafts, in particular linked to a unit of (meth) acrylate type constituting it.
- the polyalkylene glycol graft is a polyethylene glycol of average molar mass ranging from 1,000 to 5,000 Da, which can be represented diagrammatically according to one of the following structures:
- Such grafts are bound to the polymer via an ester (formula II) or amide (formula III) function.
- the polyalkylene glycol type grafts are implemented with a molar percentage of grafting ranging from 1 to 10%.
- the polymers considered according to the invention are capable of spontaneously forming, when they are dispersed in an aqueous medium of pH ranging from 5 to 7, in particular water, nanoparticles.
- nanoparticles are due to an autoassociation between a multitude of polymer chains with segregation of hydrophobic groups in nanodomains.
- a nanoparticle may contain one or more hydrophobic nanodomains.
- the size of the nanoparticles may vary from 1 to 1,000 nm, in particular from 5 to 500 nm, especially from 10 to 300 nm, and more particularly from 10 to 200 nm, or even from 10 to 100 nm.
- the size of the nanoparticles can be measured by diffraction of light.
- the polymers according to the invention can be obtained according to a process comprising at least bringing into contact, under conditions conducive to their interaction, at least one (meth) acrylic (co) polymer with at least one derivative alpha-tocopherol functionalized with a spacer having at its free end a function capable of interacting with an acid function of said polymer, said spacer being such that after the reaction with said (co) polymer, it comprises at least one hydrolysable function.
- alpha-tocopherol derivative functionalized with a spacer By way of example of an alpha-tocopherol derivative functionalized with a spacer according to the invention, mention may be made of ⁇ -tocopherol leucine, as described for example in document WO 03/104303.
- alpha-tocopherol glycine and alpha-tocopherol gamma-amino butyrate, as described in Takata et al., J. Pharm. Sci., 1995, 84, 96-100.
- the interaction, or else grafting, of said (co) polymer with said alpha-tocopherol derivative leads to the formation of a hydrolysable function at the junction of the two entities.
- Such a method makes it possible in particular to easily control the degree of grafting, and to obtain a polymer of random type.
- the two types of compounds are brought into contact in an adjusted weight or molar ratio so that the grafting is advantageously carried out at less than 30 mol%.
- the establishment of a covalent bond between the two entities can be easily achieved by reaction of the poly (meth) acrylic (co) polymer with the alpha-tocopherol derivative functionalized by the spacer, in the presence of a carbodiimide such as coupling agent and, preferably, a catalyst such as 4-dimethylaminopyridine, and in a suitable solvent such as dimethylformamide (DMF).
- a carbodiimide such as coupling agent and, preferably, a catalyst such as 4-dimethylaminopyridine
- a suitable solvent such as dimethylformamide (DMF).
- the carbodiimide is, for example, diisopropylcarbodiimide.
- the degree of grafting is chemically controlled by the stoichiometry of the constituents and reagents and / or the reaction time.
- the ⁇ -tocopherol derivative is functionalized by a spacer having at its free end a primary amine function, forming after grafting on said (meth) acrylic-type (co) polymer, an amide bond.
- said spacer is an amino acid residue.
- the grafting of the corresponding alpha-tocopherol derivative on the (meth) acrylic (co) polymer is then via the reaction of the free amine function of said spacer with the acid function of the (meth) acrylate unit of said (co) polymer.
- alpha-tocopherol As regards the functionalization of alpha-tocopherol by the spacer according to the invention, it also falls within the competencies of those skilled in the art.
- the second function not dedicated to the reaction with alpha-tocopherol is then generally carried out in a protected form with a protecting group.
- this second function if protected by a protecting group, is deprotected so as to make possible its interaction with an acid function of the (meth) acrylic (co) polymer.
- the functionalization of alpha-tocopherol can be carried out by reacting alpha-tocopherol with a reagent comprising, on the one hand, an amino function or protected alcohol, and on the other hand, a carboxylic function capable of react with alpha-tocopherol in the presence of a coupling agent and a catalyst.
- a reagent comprising, on the one hand, an amino function or protected alcohol, and on the other hand, a carboxylic function capable of react with alpha-tocopherol in the presence of a coupling agent and a catalyst.
- the amine or alcohol function then allows the grafting of the spacer functionalized by alpha-tocopherol on the polymer.
- the spacer is alanine
- the Boc-Alanine derivative is used as reagent to prepare the tocopheryl alanine derivative.
- the nanoparticles formed from at least one polymer as described above can be easily combined non-covalently with active ingredients.
- the present invention advantageously makes it possible to increase the aqueous solubilization of the active principles in general, in particular of active agents of medium or low aqueous solubility.
- the invention thus proves to be particularly advantageous with regard to weakly water-soluble active agents.
- an asset of low aqueous solubility is a compound having a solubility of less than 1 g / l, in particular less than 0.1 g / l, in pure water, measured at ambient temperature, it is ie about 25 ° C.
- a pure water is a water of pH close to neutral (between pH5 and pH8) and devoid of any other solubilizing compound known to those skilled in the art, such as surfactants or polymers ( PVP, PEG).
- the active principles considered according to the invention are advantageously logically active organic compounds which can be administered to an animal or human organism.
- an active agent according to the invention may be any molecule of therapeutic, cosmetic, prophylactic or imaging interest.
- the active agents of low aqueous solubility according to the invention may be chosen especially from anticancer agents, betablockers, antifungal agents, steroids, anti-inflammatory agents, sex hormones, immunosuppressants , antiviral agents, anesthetics, antiemetics and antihistamines.
- taxane derivatives such as paclitaxel, nifedipine, carvedilol, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporin A , PSC 833, amphotericin B, itraconazole, ketoconazole, betamethasone, indomethacin, testosterone, estradiol, dexamethasone, prednisolone, triamcinolone acetonide, nystatin, diazepam, amiodarone, verapamil, simvastatin, rapamycin and etoposide.
- taxane derivatives such as paclitaxel, nifedipine, carvedilol, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, cyclosporin A , PSC 833, amphotericin B, itraconazole, ketoconazole, betamet
- the active agent according to the invention is an asset of therapeutic interest.
- the active agent may be chosen from paclitaxel, carvedilol base, simvastatin, nifedipine and ketoconazole.
- the active agent may be a molecule of average aqueous solubility, the solubility of which may be increased by a composition according to the invention.
- molecule of average aqueous solubility is meant a molecule whose solubility in pure water, measured as indicated above, at ambient temperature is between 1 and 30 g / l, in particular between 2 and 20 g / l of water pure.
- the active agents considered according to the invention are of the peptide or protein type.
- proteins or glycoproteins especially interleukins, erythropoietin or cytokines,
- proteins bound to one or more polyalkylene glycol chains [preferably polyethylene glycol (PEG): “proteins-PEGylated”],
- insulin or analogues insulin or analogues
- GLP-1 derivatives exenatide
- cyclosporine interferons
- interleukins interleukins and growth hormone.
- the active ingredients may associate spontaneously with the polymer as described above.
- association or “associate” used to qualify the relationships between one or more active ingredients and a polymer according to the invention mean that the active principle (s) are (are) associated with the polymer (s) by non-specific physical interactions. covalents, in particular hydrophobic interactions, and / or electrostatic interactions and / or hydrogen bonds and / or steric encapsulation with the polymers of the invention.
- This association is generally the result of hydrophobic and / or electrostatic interactions, carried out by the polymer units, in particular hydrophobic or ionized, capable of generating this type of interaction.
- the combination according to the invention of the active ingredient and the polymer can in particular be carried out according to the following modes.
- the active ingredient is dissolved in an aqueous solution and mixed with an aqueous suspension of the polymer.
- the active ingredient in powder form is dispersed in an aqueous suspension of the polymer and the whole is stirred until a homogeneous clear suspension is obtained.
- the polymer is introduced in powder form into a dispersion or an aqueous solution of the active ingredient.
- the active ingredient and / or the polymer is dissolved in a solution containing a water-miscible organic solvent such as ethanol or isopropanol. Then proceed as in modes 1 to 3 above.
- a water-miscible organic solvent such as ethanol or isopropanol.
- this solvent can be removed by dialysis or any other technique known to those skilled in the art.
- the nanoparticles non-covalently associated with said active principle can be used in a composition according to the invention, in the form of microparticles.
- these microparticles can be obtained by agglomeration of nanoparticles of the invention according to the methods known to those skilled in the art, for example, in an illustrative and nonlimiting manner, by flocculation, atomization, lyophilization or coacervation.
- nanoparticulate or microparticulate forms in neutral or ionized form, are more generally, usable alone or in a liquid, solid or gel composition and in an aqueous or organic medium.
- the microparticulate forms generally have a core containing said nanoparticles, and at least one coating.
- the polymers of the invention may also be used as coating materials alone or in combination with other polymers, especially as described below.
- the microparticles have a core containing said nanoparticles and at least one coating layer conditioning a controlled release profile of said active ingredient as a function of the pH, said coating layer being formed of a material comprising at least one less a water-insoluble polymer A at a pH of less than 5 and soluble in water at pH greater than 7, combined with at least one hydrophobic compound B.
- the controlled release as a function of the pH of the nanoparticles from the microparticles is ensured by the coating surrounding the core of each reservoir particle.
- This coating is designed to release the active ingredient and the (co) polymer (meth) acrylic at specific sites of the gastrointestinal tract corresponding eg to the absorption windows of the active ingredient in the gastrointestinal tract.
- the microparticles considered according to the present invention can thus advantageously have a dual mechanism of release as a function of time and pH.
- solubilization pH value of the polymer A forming the coating of these microparticles release only a very limited amount of nanoparticles. In however, when they are present in the intestine or an assimilable medium, they ensure effective release of the nanoparticles. This release can then be advantageously carried out in less than 24 hours, in particular in less than 12 hours, in particular in less than 6 hours, in particular in less than 2 hours, even in less than 1 hour.
- the release time of the nanoparticles is less than 2 hours and preferably less than 1 hour.
- composition according to the invention is suitable for firstly releasing the active principle associated with the nanoparticles of polymer (s) of the invention and then dissociating in a second time the active principle of said nanoparticles.
- the size of the microparticles considered according to this variant of the invention is advantageously less than 2,000 ⁇ , in particular from 100 to 1,000 ⁇ , in particular from 100 to 800 ⁇ , and in particular from 100 to 500 ⁇ .
- the size of the microparticles can be measured by laser granulometry.
- the coating of the nanoparticles may be formed of a composite material obtained by mixing:
- polymers A that are suitable for the invention, that is to say that are insoluble in water at a pH of less than 5 and which are soluble in water at a pH greater than 7, mention may be made in particular of:
- copolymer (s) of methacrylic acid and of methyl methacrylate the copolymer (s) of methacrylic acid and of ethyl acrylate, cellulose acetate phthalate (CAP),
- cellulose trimellitate acetate CAT
- hydroxypropyl methylcellulose phthalate or hypromellose phthalate
- HPMCAS hydroxypropyl methylcellulose acetate succinate (or hypromellose acetate succinate)
- PVAP polyvinyl acetate phthalate
- this polymer A is chosen from the copolymer (s) of methacrylic acid and of methyl methacrylate, the copolymer (s) of methacrylic acid and of acrylate. ethyl and mixtures thereof.
- the polymers A dissolve in water at a given pH value of between 5 and 7, this value varying according to their intrinsic physicochemical characteristics, such as their chemical nature and their chain length.
- the polymer A may be a polymer whose solubilization pH value is:
- the coating is advantageously composed of 25 to 90%, in particular 30 to 80%, especially 35 to 70%, or even 40 to 60% by weight of polymer (s) A relative to its total weight.
- the polymer A is a copolymer of methacrylic acid and ethyl acrylate 1: 1.
- the compound B can be selected from crystallized products in the solid state and having a melting temperature Ta> 40 ° C., preferably Ta> 50 ° C., and more preferably still 40 ° C. ⁇ Ta ⁇ 90 ° C
- this compound is then chosen from the following group of products:
- hydrogenated vegetable oils taken alone or mixed together; preferably selected from the group consisting of: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil and mixtures thereof;
- the weight ratio B / A may vary between 0.2 and 1.5 and preferably between 0.45 and 1.
- compound B is hydrogenated cottonseed oil.
- Such a coating is described in particular in WO 03/30878.
- the compound B may be a polymer insoluble in water.
- the B polymer, insoluble in water, is more particularly selected from ethylcellulose, e.g. sold under the name Ethocel ®, cellulose acetate butyrate, cellulose acetate, ammonio the (meth) acrylate (copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate), especially those marketed under the denominations Eudragit RL and Eudragit RS, esters of poly (meth) acrylic acids, especially those sold under the name Eudragit ® NE and mixtures thereof.
- Ethocel ® e.g. sold under the name Ethocel ®
- cellulose acetate butyrate cellulose acetate
- ammonio the (meth) acrylate copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate
- esters of poly (meth) acrylic acids especially those sold under the name Eudra
- ethyl cellulose, cellulose acetate butyrate and ammonio (meth) acrylate are particularly suitable for the invention.
- ethyl cellulose, cellulose acetate butyrate and ammonio (meth) acrylate are particularly suitable for the invention.
- Eudragit ® RS and Eudragit ® RL are particularly suitable for the invention.
- the coating of the microparticles may contain from 10% to 75%, preferably from 15% to 60%, more preferably from 20% to 55%, even from 25% to 55% by weight, and more particularly still from 30% to 50% by weight. of polymer (s) B, relative to its total weight.
- the coating may then be formed, according to this embodiment, from a mixture of the two categories of polymers A and B in a weight ratio polymer (s) B / polymer (s) A greater than 0.25 , in particular greater than or equal to 0.3, in particular greater than or equal to 0.4, in particular greater than or equal to 0.5, or even greater than or equal to 0.75.
- the ratio of polymer (s) A / polymer (s) B is also less than 8, in particular less than 4, or even less than 2 and more particularly less than 1.5.
- the coating of the microparticles is formed of at least one mixture comprising, as polymer A, at least ethyl cellulose or cellulose acetate butyrate or the copolymer of ammonio (meth) acrylate or a mixture thereof, with, as polymer B, at least one copolymer of methacrylic acid and ethyl acrylate or a copolymer of methacrylic acid and methyl methacrylate or a mixture thereof.
- the coating of the nanoparticles according to the invention may comprise at least one plasticizer.
- This plasticizing agent may especially be chosen from:
- glycerol and its esters and preferably from acetylated glycerides, glyceryl mono-stearate, glyceryl triacetate, glyceryl tributrate,
- phthalates and preferably from dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, and preferably from acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate,
- sebacates and preferably from diethylsébaçate, dibutylsébaçate,
- fumarates preferably diethylfumarate
- malates preferably diethyl malate
- oxalates preferably diethyloxalate
- succinates preferably dibutylsuccinate
- malonates preferably diethyl malonate
- the coating may comprise less than 30% by weight, preferably from 1% to 25% by weight, and still more preferably from 5% to 20% by weight of plasticizer (s). in relation to its total weight.
- the coating may comprise various other additional adjuvants conventionally used in the field of coating. It can be, for example:
- pigments and dyes such as titanium dioxide, calcium sulphate, precipitated calcium carbonate, iron oxides, natural food dyes such as caramels, carotenoids, carmine, chlorophyllins, Rocou (or annatto) ), xanthophylls, anthocyanins, betanin, aluminum and synthetic food dyes such as yellows # 5 and # 6, reds # 3 and # 40, green # 3 and Emerald green , blues No. 1 and No. 2;
- fillers such as talc, magnesium stearate, magnesium silicate; anti-foam agents, such as simethicone, dimethicone; surfactants, such as phospho lipids, polysorbates, polyoxyethylene stearates, polyoxyethylenated fatty acid and sorbitol esters, polyoxyethylenated hydrogenated castor oils, polyoxyethylenated alkyl ethers, glycerol monooleate,
- the coating can be mono- or multilayer. According to an alternative embodiment, it is composed of a single layer formed from the composite material defined above.
- microparticles according to this variant of the invention can be carried out by any conventional technique conducive to the formation of a reservoir capsule whose core is formed in whole or in part of at least one active ingredient non-covalently associated with polymer nanoparticles, especially as defined above.
- the microparticles are formed by spraying the compounds A and B and if present (s) the other ingredients including the (or) plasticizer (s) in the state of generally solutes.
- This solvent medium generally contains organic solvents mixed or not with water.
- the coating thus formed is homogeneous in terms of composition as opposed to a coating formed from a dispersion of these same polymers in a predominantly aqueous liquid.
- the spray solution contains less than 40% by weight of water, in particular less than 30% by weight of water and more particularly less than 25% by weight of water.
- the nanoparticles non-covalently associated with the active principle may be implemented in a supported form, of microparticle type, in particular on a neutral substrate using one or more binders and with one or more conventional excipients.
- microparticles present in a supported form may be subsequently coated with one or more coating layers, as described above.
- binders are in particular proposed in Khankari R.K. et al., Binders and Solvents in Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh ed., Marcel Dekker Inc., New York, 1997.
- Binder is particularly suitable for the invention: hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), methylcellulose (MC) and hydroxypropylmethylcellulose (HPMC).
- HPC hydroxypropylcellulose
- PVP polyvinylpyrrolidone
- MC methylcellulose
- HPMC hydroxypropylmethylcellulose
- the deposition of the corresponding mixture is then carried out by conventional techniques known to those skilled in the art. It may in particular be a spray of the colloidal suspension of the nanoparticles loaded with active principles, and containing the binder and optionally other compounds, on the support in a fluidized air bed.
- composition according to the invention may for example contain, besides the nanoparticles associated with the active ingredient and the conventional excipients, sucrose and / or dextrose and / or lactose, or else a microparticle of an inert substrate such as cellulose serving as a support for said nanoparticles.
- a composition according to the invention may comprise granules containing a polymer of the invention, the active ingredient, one or more binders ensuring the cohesion of the granule and various excipients known to the invention. skilled in the art.
- a coating may then be deposited on this granule by any technique known to those skilled in the art, and advantageously by spray coating, leading to the formation of microparticles, as described above.
- the weight content of nanoparticles loaded with active principle in the core is between 0.1 and 80%, preferably between 2 and 70%, more preferably between 10 and 60%;
- the weight content of binder in the core is between 0.5 and 40%, preferably between 2 and 25%; the weight content of the coating in the microparticle is between 5 and 50%, preferably between 15 and 35%.
- a composition according to the invention may comprise neutral cores around which a layer has been deposited containing the active principle, the nanoparticles of polymer, a binder ensuring the cohesion of this layer and possibly different excipients known to those skilled in the art, for example sucrose, trehalose and mannitol.
- the neutral core may be a cellulose or sugar particle or any inert organic or saline compound that is suitable for coating.
- the neutral cores thus covered can then be coated with at least one coating layer, to form microparticles, as described above.
- the weight content of nanoparticles loaded with active principle in the core is between 0.1 and 80%, preferably between 2 and 70%, more preferably between 10 and 60%;
- the weight content of the neutral core in the core of the microparticles is between 5 and 50%, preferably between 10 and 30%;
- the binding weight content in the core of the microparticles is between 0.5 and 40%, preferably between 2 and 25%;
- the weight content of the coating in the microparticle is between 5 and 50%, preferably between 15 and 35%.
- the present invention also relates to new pharmaceutical, phytosanitary, food, cosmetic or dietetic preparations prepared from the compositions according to the invention.
- composition according to the invention may thus be in the form of a powder, a solution, a suspension, a tablet or a capsule.
- composition according to the invention may in particular be intended for the preparation of medicaments.
- Polymer 1 polyacrylic acid substituted with about 5 mol% of alpha-tocopherol grafts bound via alanine
- Step 1 Purification of the commercial acrylic polyacid (Degacryl 4779L) 75 g of DEGACRYL solution 4779L (sold by the company Evonik) are diluted with 1425 g of milliQ water and then diafiltered against 8 volumes of water. The solution obtained is then lyophilized. The average molar mass Mn, measured by steric exclusion chromatography, is 33.6 kDa in PMMA (polymethyl methacrylate) equivalent and the polydispersity index is 2.4.
- DEGACRYL solution 4779L sold by the company Evonik
- Step 2 Synthesis of Alanine Ester and ⁇ -Tocopherol Ester (AlaVE) To a solution of 21.1 g of N-Boc alanine, 40 g of ⁇ -tocopherol and 0.567 g of dimethylaminopyridine (DMAP) in 400 ml of dichloromethane are added dropwise 22.08 ml of ⁇ , ⁇ '-Diisopropylcarbodiimide (DIPC). After stirring at 20 ° C. for 22 h, the reaction mixture is successively washed with a solution of 0.1 N HCl, water, a 5% solution of sodium bicarbonate and finally water.
- DMAP dimethylaminopyridine
- the organic phase is evaporated to dryness and the oil obtained is solubilized in 400 ml of a 4M solution of HCl in dioxane. After stirring for 4 hours at room temperature, the reaction mixture is evaporated to dryness and crystallized from ethanol.
- the AlaVE hydrochloride (33.8 g of a white powder) thus prepared is analyzed by proton NMR in CDCl 3 and has a spectrum in accordance with its chemical structure.
- Step 3 Grafting ⁇ AlaVE onto purified acrylic polyacid
- AlaVE 3.74 g of AlaVE are solubilized in 50 ml of DMF and 0.97 ml of triethylamine.
- 10 g of purified Degacryl (step 1) are dissolved in 250 ml of ⁇ , ⁇ -dimethylformamide (DMF) and 0.34 g of 4-dimethylaminopyridine (DMAP). This solution is cooled to 15 ° C., and the suspension is added successively.
- AlaVE / triethylamine then 1.93 g of ⁇ , ⁇ '-Diisopropylcarbodiimide (DIPC). The reaction mixture is stirred overnight at 15 ° C.
- DIPC 4-dimethylaminopyridine
- the percentage of grafted AlaVE, determined by proton NMR in TFA-d, is 5.3%.
- the particle size, measured by light diffraction, is 17 nm.
- the average molar mass is 37 kDa (PMMA equivalents) and the polydispersity index is 2.6.
- polymer 2 poly acrylic acid substituted with about 8 mol% of alpha-tocopherol grafts bound via alanine
- AlaVE (step 2 of Example 1) is solubilized in 10 ml of DMF and 0.31 ml of triethylamine.
- 2 g of purified Degacryl (step 1 of example 1) are solubilized in 50 ml of DMF and 0.14 g of DMAP. This solution is cooled to 15 ° C. and the suspension of AlaVE / triethylamine and then 0.49 g of DIPC are added successively. The reaction mixture is stirred overnight at 15 ° C. After addition of a solution of 35% HCl (0.23 ml) diluted in 2 ml of DMF, the reaction mixture is stirred for 1 h, then 40 ml of ethanol are added.
- This mixture is neutralized with 1N sodium hydroxide in 110 mL of water and the suspension obtained is then successively dialyzed against salt water (0.9% NaCl) and then with water and finally concentrated to 250 mL.
- 110 mL of ethanol is added, and the mixture is heated at 45 ° C for 2 h, then stirred overnight at room temperature.
- the solution obtained is diafiltered against 8 volumes of salt water (0.9%), then 4 volumes of water, and finally concentrated to a volume of about 20 mL.
- the percentage of grafted AlaVE determined by proton NMR in TFA-d is 7.8%.
- the particle size, measured by diffraction of light, is 12 nm.
- the average molar mass is 39 kDa (PMMA equivalents) and the polydispersity index is 2.9.
- Step 1 Purification of Commercial Acrylic Polyacid (Acumer 1100)
- Step 2 Grafting AlaVE onto purified acrylic polyacid
- reaction mixture After addition of a solution of 35% HCl (1.16 mL) diluted in 12 mL of DMF, the reaction mixture is neutralized with 1N sodium hydroxide in 730 mL of water. The resulting solution is purified by diafiltration and concentrated to a volume of about 400 mL.
- the percentage of grafted AlaVE, determined by proton NMR in TFA-d, is 9.9%.
- the size of the particles, measured by diffraction of light, is 10 nm.
- the average molar mass is 15.2 kDa (PMMA equivalents) and the polydispersity index is 1.29.
- reaction mixture After addition of a solution of 35% HCl (1.16 mL) diluted in 12 mL of DMF, the reaction mixture is neutralized with 1N sodium hydroxide in 1040 mL of water. The resulting solution is purified by diafiltration and concentrated to a volume of about 68 mL.
- the percentage of grafted AlaVE, determined by proton NMR in TFA-d, is 18.5%.
- the particle size, measured by light diffraction, is 13 nm.
- the average molar mass is 13.3 kDa (PMMA equivalents) and the polydispersity index is 1.28.
- step 1 of example 1 3 g of purified Degacryl (step 1 of example 1) are solubilized in 75 ml of DMF and 0.10 g of DMAP, cooled to 15 ° C. Then, a suspension of 0.56 g of octadecylamine in 18.5 ml of DMF and 0.58 g of DIPC is successively added. The reaction mixture is stirred for 2 h at 15 ° C and then overnight at 20 ° C. After addition of 35% HCl (0.35 ml) diluted in 2 ml of DMF, the reaction mixture is neutralized with 1N sodium hydroxide in a foot of water of 250 ml.
- the resulting solution is diafiltered against 8 volumes of salt water (0.9%), then 4 volumes of water, and concentrated to a volume of about 100 mL. 20 ml of ethanol are added, and the resulting solution is stirred overnight at room temperature, then diafiltered against 8 volumes of water and concentrated to a concentration of about 25 g / l.
- the percentage of grafted octadecylamine, determined by proton NMR in OMSO-d6, is 5.7%.
- the average molar mass is 38 kDa (PMMA equivalents) and the polydispersity index is 2.5.
- the solubility of paclitaxel which is less than 0.25 ⁇ g / mL in water, can be increased to at least 2.7 mg / mL for a 44 mg / mL polymer solution.
- Example 1 Study of the Association of Polymer 1 (Example 1) with Carvedilol Polymer 1 of Example 1 (10 mg / ml) is dissolved with carvedilol (4 mg, base form) and the mixture is subjected to ultrasound for one hour and then left stirring for one night. The amount of carvedilol in solution after centrifugation is measured by UV spectroscopy. A solubilization of about 3 mg is obtained for 10 mg of polymer in solution, ie a solubilization of 3 g / l. Carvedilol form base is only soluble at 50 mg / L in pure water.
- Polymer 2 of Example 2 (20 mg / g) is dissolved with ketoconazole (1 to 5 mg / g) and the mixtures are sonicated for one hour and then rotated overnight. The transparency of the solution is then visually noted. The compound is completely solubilized when it is transparent and reaches its solubility limit with the appearance of a disorder.
- the low limit of solubility is 3 mg / g, ie about 3 g / L, while the solubility of ketoconazole in pure water is only 10 mg / L.
- aqueous solution containing 10 mg of polymer per milliliter at pH 7.4 and 400 IU insulin (14.8 mg) is prepared.
- the solutions are incubated for 1 h 30 min at 25 ° C. with stirring and the free insulin is separated from the associated insulin by ultrafiltration (100 kDa threshold, 15 minutes at 10,000 g at 18 ° C.).
- the free insulin recovered in the filtrate is then assayed by HPLC (High Performance Liquid Chromatography) and the amount of insulin associated is deduced.
- the associated insulin is equal to 97%.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0958413A FR2952936B1 (fr) | 2009-11-26 | 2009-11-26 | Polymere de type acrylique ou methacrylique comprenant des greffons alpha-tocopherol |
US26509209P | 2009-11-30 | 2009-11-30 | |
PCT/IB2010/055440 WO2011064743A1 (fr) | 2009-11-26 | 2010-11-26 | Polymere de type acrylique ou methacrylique comprenant des greffons alpha-tocopherol |
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EP2504370A1 true EP2504370A1 (de) | 2012-10-03 |
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EP10805323A Withdrawn EP2504370A1 (de) | 2009-11-26 | 2010-11-26 | Acryl- oder methacrylpolymer mit alpha-tocopherol-pfropfen |
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US (1) | US20110129540A1 (de) |
EP (1) | EP2504370A1 (de) |
JP (1) | JP2013512301A (de) |
KR (1) | KR20120099442A (de) |
CN (1) | CN102648221A (de) |
AU (1) | AU2010325556B2 (de) |
CA (1) | CA2781082A1 (de) |
CL (1) | CL2012001358A1 (de) |
FR (1) | FR2952936B1 (de) |
IL (1) | IL219491A0 (de) |
MX (1) | MX2012006042A (de) |
WO (1) | WO2011064743A1 (de) |
ZA (1) | ZA201203225B (de) |
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ES2433248B1 (es) * | 2012-05-07 | 2015-03-10 | Consejo Superior Investigacion | Copolimeros anfifilicos portadores de alfa-tocoferol con propiedades antitumorales |
ES2721675B2 (es) * | 2018-02-02 | 2020-02-06 | Nanomateriales Y Polimeros S L | Procedimiento de obtencion de particulas polimericas funcionalizadas |
ES2735638B2 (es) * | 2018-06-18 | 2021-01-18 | Alodia Farm S L | Copolimeros y terpolimeros acrilicos funcionales autoasociados y su uso como vehiculos de compuestos bioactivos |
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US2680749A (en) * | 1951-12-01 | 1954-06-08 | Eastman Kodak Co | Water-soluble tocopherol derivatives |
US6123928A (en) * | 1992-12-21 | 2000-09-26 | Biophysica, Inc. | Sunblocking polymers and their novel formulations |
KR100195291B1 (ko) | 1997-07-12 | 1999-06-15 | 서경배 | 비이온성 비타민 |
FR2786098B1 (fr) * | 1998-11-20 | 2003-05-30 | Flamel Tech Sa | Particules a base de polyaminoacide(s) et susceptibles d'etre utilisees comme vecteurs de principe(s) actif(s), suspension colloidale les comprenant et leurs procedes de fabrication |
FR2830447B1 (fr) | 2001-10-09 | 2004-04-16 | Flamel Tech Sa | Forme galenique orale microparticulaire pour la liberation retardee et controlee de principes actifs pharmaceutiques |
FR2840614B1 (fr) * | 2002-06-07 | 2004-08-27 | Flamel Tech Sa | Polyaminoacides fonctionnalises par de l'alpha-tocopherol et leurs applications notamment therapeutiques |
WO2006091780A2 (en) * | 2005-02-24 | 2006-08-31 | Elan Pharma International Limited | Nanoparticulate formulations of docetaxel and analogues thereof |
EP2066406A2 (de) * | 2006-09-19 | 2009-06-10 | Basf Se | Kosmetische zubereitungen auf basis molekular geprägter polymere |
US20110150837A1 (en) * | 2009-12-23 | 2011-06-23 | Flamel Technologies | Amphiphilic polymer functionalized by methionine |
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2009
- 2009-11-26 FR FR0958413A patent/FR2952936B1/fr not_active Expired - Fee Related
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2010
- 2010-11-26 AU AU2010325556A patent/AU2010325556B2/en not_active Ceased
- 2010-11-26 EP EP10805323A patent/EP2504370A1/de not_active Withdrawn
- 2010-11-26 CN CN2010800536856A patent/CN102648221A/zh active Pending
- 2010-11-26 JP JP2012540532A patent/JP2013512301A/ja active Pending
- 2010-11-26 KR KR1020127013312A patent/KR20120099442A/ko not_active Application Discontinuation
- 2010-11-26 MX MX2012006042A patent/MX2012006042A/es active IP Right Grant
- 2010-11-26 CA CA2781082A patent/CA2781082A1/fr not_active Abandoned
- 2010-11-26 WO PCT/IB2010/055440 patent/WO2011064743A1/fr active Application Filing
- 2010-11-29 US US12/955,076 patent/US20110129540A1/en not_active Abandoned
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2012
- 2012-04-30 IL IL219491A patent/IL219491A0/en unknown
- 2012-05-04 ZA ZA2012/03225A patent/ZA201203225B/en unknown
- 2012-05-25 CL CL2012001358A patent/CL2012001358A1/es unknown
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Also Published As
Publication number | Publication date |
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CA2781082A1 (fr) | 2011-06-03 |
FR2952936B1 (fr) | 2011-11-25 |
AU2010325556A1 (en) | 2012-05-24 |
IL219491A0 (en) | 2012-06-28 |
MX2012006042A (es) | 2012-10-03 |
CL2012001358A1 (es) | 2012-10-12 |
FR2952936A1 (fr) | 2011-05-27 |
US20110129540A1 (en) | 2011-06-02 |
JP2013512301A (ja) | 2013-04-11 |
WO2011064743A1 (fr) | 2011-06-03 |
AU2010325556B2 (en) | 2013-07-11 |
KR20120099442A (ko) | 2012-09-10 |
ZA201203225B (en) | 2013-01-30 |
CN102648221A (zh) | 2012-08-22 |
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