Classifications

• • 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
  • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • 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
  • A61K9/5123—Organic compounds, e.g. fats, sugars
• • 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
  • 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
  • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• • 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
  • A61K9/5169—Proteins, e.g. albumin, gelatin
• • 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
  • A61K9/5192—Processes
• • 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
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• the present invention aims at providing novel microparticulate oral forms for the modified release of active principle (s), abbreviated as "PA”, in particular of protein or peptide nature. It also relates to applications, particularly therapeutic or cosmetic, of these microparticulate oral forms.
• PA active principle
• the oral route is particularly appreciated, particularly with regard to its comfort for the patient and its compatibility with a wide variety of formulations.
• Multiparticulate oral dosage forms have already been developed to provide satisfaction in this regard. These multiparticulate forms are generally in the form of microparticles or microcapsules whose core, containing the active ingredient or a mixture of active ingredients, is covered with a coating whose composition and / or thickness are precisely adjusted to control the release. of this asset.
• microparticulate systems consisting of a plurality of microcapsules generally less than 2000 ⁇ m in diameter are thus particularly effective in ensuring a delayed and controlled release.
• WO 03/03878 proposes a microparticulate system for the oral administration of at least one active agent and whose release is controlled over time and as a function of the pH via the chemical nature of the envelope encapsulating the heart of the microparticles which contains the active.
• this envelope is formed of a material comprising at least one hydrophilic polymer bearing ionized groups at neutral pH, such as, for example, a copolymer of (meth) acrylic acid and alkyl (meth) acrylate and at least one hydrophobic compound such as vegetable hydrogenated wax.
• a material comprising at least one hydrophilic polymer bearing ionized groups at neutral pH, such as, for example, a copolymer of (meth) acrylic acid and alkyl (meth) acrylate and at least one hydrophobic compound such as vegetable hydrogenated wax.
• microparticulate systems are particularly useful for reliably controlling, on the one hand, the transport of the active ingredient they convey through the gastrointestinal tract and, on the other hand, the release of the latter at the level of the small intestine or, where appropriate, the stomach level for example, are unfortunately not suitable for the transport of assets that have a stability and / or reduced absorption.
• This lack of stability may be the consequence of too rapid degradation due to exposure to an aggressive environment such as gastrointestinal light which has a very acidic pH and / or contains enzymes active on these assets.
• the reduced absorption it can also be the fact of a very low solubility or insufficient permeability of the epithelial membrane vis-à-vis the asset.
• the object of the present invention is, in particular, to propose a novel oral microparticulate system aimed at solving these problems and therefore particularly useful for the vectorization of assets such as proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligo or polynucleotides as well as small molecules, in particular hydrophobes.
• one aspect of the present invention is to provide an oral form consisting mainly of reservoir type microparticles releasably releasing an active principle itself non-covalently associated, at least in part, with nanoparticles of at least one polymer, abbreviated as "POM".
• This system differs from traditional tank-type microparticle systems that release the active ingredient they contain in an unassociated form.
• the present invention relates to a microparticulate oral form, useful for conditioning at least one active principle and the in vivo release of this active ingredient according to a regulated release profile as a function of pH and / or time, comprising at least microparticles having a core containing at least said active principle and coated with at least one coating layer conditioning said release profile of said active ingredient characterized in that the coating layer is formed of a material comprising at least one polymer A having a solubilization pH value in the pH range of 5 to 7 associated with at least one hydrophobic compound B, and
• said active principle present in said core of the microparticles, is at least partly non-covalently associated with nanoparticles formed from at least one POM polymer comprising a hydrophilic hydrocarbon chain carrying one or more hydrophobic groups (G) or a chain amphiphilic hydrocarbon.
• conditioning means the ability of the microparticles according to the invention to contain and convey said active ingredient.
• the invention also relates, according to another of its aspects, to a process for the preparation of microparticles which is useful for conditioning at least one active ingredient and the in vivo release of this active ingredient according to a pH-regulated and / or controlled release profile.
• microparticles having a core containing at least said active ingredient and coated with at least one coating layer conditioning said release profile of said active agent, said method comprising at least the steps of: a) disposing of least one active ingredient non-covalently associated with nanoparticles formed of at least one POM polymer comprising a hydrophilic hydrocarbon chain carrying one or more hydrophobic groups (G) or comprising an amphiphilic hydrocarbon chain, b) forming from the nanoparticles of the step a) a core comprising said nanoparticles and one or more excipients, c) forming, from at least one polymer e A having a solubilization pH value in the pH range of 5 to 7 and at least one hydrophobic compound B, a coating layer disposed around the core formed in step b), and d) recovering the expected microparticles.
• POM polymer comprising a hydrophilic hydrocarbon chain carrying one or more hydrophobic groups (G) or comprising an amphiphilic hydrocarbon chain
• G hydrophobic
• Step b) can be carried out using any conventional granulation technique, such as wet granulation, agglomeration, extrusion / spheronization, compacting, atomization or spray coating.
• any conventional granulation technique such as wet granulation, agglomeration, extrusion / spheronization, compacting, atomization or spray coating.
• step c it is carried out by any conventional coating technique. It can be advantageously carried out by spraying in fluidized air bed on the nanoparticles of step a) at least one polymer A having a pH value solubilizing agent in the pH range of 5 to 7 associated with at least one hydrophobic compound B.
• the present invention results more particularly from the observation by the inventors that an incorporation of an active ingredient in a form associated with nanoparticles of at least one POM polymer according to the invention in a controlled release microparticulate system as defined previously is feasible and that it is possible to release this associated PA / POM form at its absorption site, usually the intestine, with increased bioavailability and / or absorption duration (s) at the of the intestine.
• absorption site usually the intestine
• s absorption duration
• the particulate oral form according to the invention advantageously makes it possible to envisage a release of the active ingredient that it contains in a sequential mode.
• the active ingredient, administered orally is released in a form associated with nanoparticles of a POM polymer, this form having an increased bioavailability and / or absorption time (s) compared to the form free of the same asset.
• the associated fraction of this asset is dissociated from the nanoparticles of POM polymer.
• the use of polymer nanoparticles as considered according to the invention for parenterally administering active agents is known.
• WO 03/04303 More particularly discloses a polyamino acid type polymer comprising aspartic residues and / or glutamic residues, with at least a portion of these residues carrying grafting agents comprising at least one alpha-tocopherol unit, eg polyglutamate or polyaspartate. grafted with alpha tocopherol.
• hydrophobic modified homopolyamino acids spontaneously form in water a colloidal suspension of nanoparticles, which are capable of easily associating in aqueous suspension at pH 7.4, with at least one active protein.
• Application PCT / EP2008 / 055507 proposes, for its part, biodegradable polyamino acids, convertible into colloidal nano- or micro-particles of vectorization able to associate reversibly with active principles. It is more particularly amphiphilic copolyglutamates comprising both positive charges at neutral pH or close to neutrality and pendant hydrophobic groups.
• all these systems do not allow to adjust a release profile as a function of the time and / or pH of the asset they carry, nor to protect this active against gastric juices and therefore does not prove to be suitable for oral administration.
• the microparticles can release the PA / POM nanoparticles for less than 12 hours, preferably less than 6 hours or even less than 2 hours.
• the microparticles release into the intestinal lumen the nanoparticles loaded with active ingredient PA / POM over a short period of time, for example less than 2 hours, or better still less at 1 o'clock.
• This requirement for releasing the nanoparticles over a controlled period of time is particularly difficult to satisfy for nanoparticles formed from a POM polymer and which remain during the gastric retention time in the acid medium of the stomach.
• the nanoparticles are not affected by a prolonged residence time in the acidic medium, and moreover, their individualization is preserved therein, which makes it possible to overcome any risk of subsequent release of these nanoparticles at the same time. state of aggregates.
• the coating layer is precisely for this purpose formed of a material comprising at least one polymer A having a solubilization pH value in the pH range of 5 to 7 associated with at least one hydrophobic compound B and in particular such that defined below. As is apparent from the following, this efficiency is enhanced by adjusting the thickness of the coating layer formed.
• the reservoir type microparticles according to the present invention consist of a core containing the active in a form associated with nanoparticles of at least one POM polymer, and a coating surrounding the core.
• the controlled release 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 POM polymer at specific sites of the gastrointestinal tract corresponding for example to the absorption windows of the active ingredient in the gastrointestinal tract.
• the oral form considered according to the present invention may advantageously have a dual mechanism of release as a function of time and pH.
• the oral form considered according to the invention has the following two specificities. Below the solubilization pH value of the polymer A forming the coating of its microparticles, the oral form according to the invention releases only a very limited amount of nanoparticles. On the other hand, when it is present in the intestine or an assimilable medium, it ensures an 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, especially in less than 6 hours, in particular less than 2 hours or even less than 1 hour.
• the release time of the nanoparticles is less than 2 hours and preferably less than 1 hour.
• the size of the microparticles considered according to the invention is advantageously less than 2000 ⁇ m, in particular ranges from 100 to 1000 ⁇ m, in particular from 100 to 800 ⁇ m and in particular from 100 to 500 ⁇ m.
• the particle size is expressed as the volume average diameter D4 3 measured by laser granulometry using a Mastersizer 2000 device from Malvern Instrument equipped with the Sirocco 2000 dry-mode module.
• the solubilization pH value of the polymer A is a pH value of the physiological medium or the model in vitro medium below which the polymer is in an insoluble state and beyond which this The same polymer A is in a soluble state.
• this pH value is specific to a given polymer and directly related to its intrinsic physicochemical characteristics, such as its chemical nature and its chain length.
• the copolymer (s) of methacrylic acid and of methyl methacrylate the copolymer (s) of acid Methacrylic acid and ethyl acrylate
• cellulose derivatives such as: o cellulose acetate phthalate (CAP), o cellulose acetate succinate (CAS), o acetate trimellitate cellulose (CAT), o the hydroxypropyl methylcellulose phthalate (or hypromellose phthalate) (HPMCP), o acetate hydroxypropyl methylcellulose succinate (or hypromellose acetate succinate) (HPMCAS), shellac gum, polyvinyl acetate phthalate (PVAP), and mixtures thereof.
• CAP cellulose acetate phthalate
• CAS o cellulose acetate succinate
• CAT o acetate trimellitate cellulose
• HPPMCP o the hydroxypropyl methylcellulose phthalate
• HPMCAS o acetate hydroxypropyl
• 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 polymer A considered according to the invention has a different solubility profile depending on whether it is confronted with a pH value higher or lower than its solubilization pH value.
• the polymer A is generally insoluble at a pH value lower than its solubilization pH value and, on the other hand, is soluble at a pH value higher than its solubilization pH value.
• it 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 may be selected from products that are crystalline in the solid state and having a melting temperature T ⁇ 40 0 C, crosslURI T ft> 50 0 C, and still more preferably 40 0 C ⁇ T ft ⁇ 90 0 C
• this compound is then chosen from the following group of products:
• DYNASAN P60 and DYNASAN 116 vegetable waxes taken alone or mixed together, such as those marketed under the trade names DYNASAN P60 and DYNASAN 116; - 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.
• Microparticles formed of such a coating are described in particular in WO 03/30878.
• the compound B may be a polymer insoluble in the liquids of the digestive tract.
• This insoluble polymer in the liquids of the digestive tract or the gastrointestinal fluids is more particularly selected from:
• ethylcellulose and / or derivatives, for example those sold under the name Ethocel ®, cellulose acetate butyrate, cellulose acetate, ammonio the (meth) acrylate , copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate type "A" or type "B", especially those sold under the names Eudragit ® RL and Eudragit ® RS, the acid esters poly (meth) acrylics, especially those marketed under the name Eudragit ® NE and their mixtures.
• Ethocel ® cellulose acetate butyrate
• cellulose acetate ammonio the (meth) acrylate
• copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate type "A" or type "B” especially those sold under the names Eudragit ® RL and Eudragit ® RS
• the coating of the microparticles then contains from 10% to 75%, and can preferably contain from 15% to 60%, more preferably from 20% to 55%, even from 25% to 55% by weight, and more particularly from 30% to 60% by weight. at 50% polymer (s) A 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 polymer mixtures A and B which are particularly suitable for the invention, mention may in particular be made of mixtures of ethylcellulose, cellulose acetate butyrate or ammonio (meth) acrylate copolymer of type A or B with minus a copolymer of methacrylic acid and ethyl acrylate or a copolymer of methacrylic acid and methyl methacrylate or a mixture thereof.
• the coating of the particles according to the invention may comprise at least one plasticizer. Plasticizing agent
• 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, dimethylphthalate, dioctylphthalate, citrates, and preferably from acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate, sebacates, and preferably from diethylsébaçate, dibutylsébaçate, adipates, azelates, benzoates, chlorobutanol, polyethylenes glycols, vegetable oils, fumarates, preferably diethyl fumarate, malates, preferably diethyl malate, oxalates,
• the coating layer has an average thickness greater than or equal to 25 ⁇ m, preferably greater than or equal to 30 ⁇ m, or even greater than or equal to 35 ⁇ m.
• Such a thickness of the coating layer of the microparticulate oral form according to the invention advantageously allows a total release of the active ingredient it contains in a pH medium greater than 5, representative of that of the intestine.
• the coating layer has a thickness of less than 200 ⁇ m, more particularly less than or equal to 100 ⁇ m.
• the coating layer advantageously has a thickness varying from 25 to 50 ⁇ m.
• microparticles according to the invention can be carried out by any conventional technique that is 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.
• POM especially as defined below and supported or not on a neutral substrate, where appropriate with the aid of one or more binders and with one or more conventional excipients.
• the nanoparticles non-covalently associated with the active principle may be present in the microparticles in a supported form.
• the core of the microparticles may for example contain, in addition to the nanoparticles associated with the active ingredient and the conventional excipients, sucrose and / or dextrose and / or lactose, or even a microparticle of a substrate. inert such as cellulose serving as a support for said nanoparticles.
• the core of the microparticles is a granule containing the POM, the active ingredient, one or more binders ensuring the cohesion of the granule and various excipients known to those skilled in the art. .
• a coating is then deposited on this granule by any technique known to those skilled in the art, and advantageously by spray coating.
• 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%.
• the core of the microparticles according to the invention comprises a neutral core around which a layer has been deposited containing the active principle, the nanoparticles POM, a binder ensuring the cohesion of this layer and possibly various excipients known from 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 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
• 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 active principle contained in the core of the microparticles, forming the oral particulate form according to the invention is present in a form at least partly non-covalently associated with nanoparticles of at least a POM polymer.
• association or “associate” used to qualify the relationships between one or more active ingredients and the POM polymer, mean that the active ingredient (s) are associated with the POM polymer (s) in particular by non-covalent physical interactions. , in particular hydrophobic interactions, and / or electrostatic interactions and / or hydrogen bonds and / or via steric encapsulation by POM polymers.
• hydrophobic and / or electrostatic interactions are generally a matter of hydrophobic and / or electrostatic interactions and therefore assumes that the polymer POM incorporates at the level of its structure patterns capable of generating this type of interaction.
• These units in particular hydrophobic or ionized, may be present directly within the hydrocarbon chain forming the backbone of said polymer and / or may be represented by one or more hydrophobic or ionized groups borne by said hydrocarbon chain.
• the term "raised group” means that said group is pendant, that is to say that said group is a side group connected to the main chain of the polymer by one or more covalent bonds.
• said pendant group is a side group with respect to the amino acid residues and can be in particular a substituent of the ⁇ carbonyl function of the amino acid residue which carries it.
• the POM polymers considered according to the invention generally have a degree of polymerization DP of between 10 and 1000, in particular 30 and 500 and more particularly between 50 and 250, or even between 20 and 150.
• the POM polymers considered according to the invention are furthermore capable of spontaneously forming, when they are dispersed in an aqueous medium and in particular water, nanoparticles.
• the nanoparticles can be anionic, cationic or neutral, and preferably are anionic or cationic.
• anionic nanoparticles means nanoparticles of a POM polymer whose overall charge at neutral pH is negative; and "cationic nanoparticles” nanoparticles of a POM polymer whose overall charge at neutral pH is positive.
• the overall charge can be measured by any method known to those skilled in the art, such as measuring the Zeta potential at neutral pH.
• the size of the nanoparticles ranges from 1 to 1000 nm, in particular from 5 to 500 nm, in particular from 10 to 300 nm and more particularly from 10 to 100 nm.
• the size of the nanoparticles of POM is evaluated by the average hydrodynamic diameter of these particles. The measurement is performed by quasi-elastic light scattering with a CGS-3 device from ALV. For this purpose, the POM suspension is concentrated to 0.5 mg / ml in a saline medium such as 0.15 M NaCl after a rest period sufficient to reach equilibrium.
• the POM polymer according to the invention comprises a hydrophilic hydrocarbon chain carrying one or more hydrophobic groups (G) or an amphiphilic hydrocarbon chain.
• it is a polymer comprising a hydrophilic hydrocarbon chain carrying one or more hydrophobic groups (G).
• the hydrocarbon-based chain forming the POM polymer may be chosen from polyamino acids, anionic polysaccharides such as dextran sulfate, carboxymethylcellulose, gum arabic, hyaluronic acid and its derivatives, polygalacturonic compounds, polyglucuronic agents, or cationic polysaccharides such as chitosan, or also collagen and its gelatin derivatives.
• hydrocarbon chain covers hydrocarbon chains that may contain one or more nitrogen atoms.
• hydrocarbon chain and “hydrocarbon chain may contain one or more nitrogen atoms” will be used indifferently.
• the hydrocarbon chain forming the POM polymer is a polyamino acid.
• the POM polymer is biodegradable.
• polyamino acid covers both natural polyamino acids and synthetic polyamino acids, as well as oligoamino acids comprising from 10 to 20 amino acid residues as well as polyamino acids comprising more than 20 amino acid residues.
• Polyamino acids are linear synthetic polymers, advantageously composed of alpha-amino acids bound by peptide bonds. There are numerous synthetic techniques for forming block or random polymers, multi-chain polymers and polymers containing a defined sequence of amino acids (see Encyclopedia of Polymer Science and Engineering, Vol 12, page 786; John Wiley & Sons ).
• this polyamino acid comprises at least one or more hydrophobic neutral amino acids.
• such a POM polymer may be a polyamino acid comprising at least two types of recurring amino acid residues AAN and AAI: the type AAN corresponding to a hydrophobic neutral amino acid, the type AAI corresponding to an amino acid with an ionizable side chain, at least a part of the AAI-type amino acids being in ionized form, the amino acids of each type AAN and AAI being identical to or different from each other, and the weight-average mass of said polyamino acid being greater than or equal to 2500 D, in particular greater than or equal to 4000 D, preferably greater than or equal to 5000 D.
• the AAN (or AAN) is (are) more particularly chosen from the following list: Leu, Ile, Val, AIa, Pro, Phe and their mixtures and AAI (or AAI) is (are) more particularly formed by the Glu and / or the Aps.
• such polyamino acids comprise a single type of AAI monomers corresponding, preferably, to Glu and a single type of AAN monomers corresponding, preferably, to Leu.
• the hydrocarbon chain forming the POM polymer is a hydrophilic polyamino acid.
• the polyamino acids thus forming such POMs are oligomers or homopolymers comprising glutamic or aspartic acid repeating units or copolymers comprising a mixture of these two types of amino acid residues.
• the residues considered in these polymers preferably have the D configuration or
• L or D / L are bound by their alpha or gamma positions for the glutamate or glutamic acid residue and alpha or beta for the aspartic acid or aspartate residue and more preferably have the L configuration and are bound by their alpha position.
• the POM polymer comprises a polyamino acid hydrocarbon chain formed by aspartic acid units and / or glutamic acid units, and at least a portion of these units carries scions comprising at least one hydrophobic group (G).
• the hydrocarbon chain consists of a homopolymer of alpha-L-glutamate or alpha-L-glutamic acid.
• the hydrocarbon chain consists of a homopolymer of alpha-L-aspartate or of alpha-L-aspartic acid.
• the hydrocarbon chain consists of a copolymer of alpha-L-aspartate / alpha-L-glutamate or alpha-L-aspartic acid / alpha-L glutamic acid.
• POM polymers are described in particular in WO 03/104303, WO 96/079614 and PCT / EP / 2008/055507, the contents of which are incorporated by reference.
• These polyamino acids may also be of the type described in PCT patent application WO-A-00/30618.
• polymers can be obtained by methods known to those skilled in the art.
• a number of polymers that can be used according to the invention for example of the poly (alpha-L-glutamic acid), poly (alpha-D-glutamic acid), poly (alpha-D, L-glutamate) and poly (acidic) type can be used.
• gamma-L-glutamic) of variable masses are commercially available.
• the poly (L-glutamic acid) can be further synthesized according to the route described in the patent application FR 2801226.
• the polymer POM is a polyhydroxyalkylglutamine comprising a multiplicity of hydrophobic groups (G) pendant, identical or different and preferably at least 2 hydrophobic groups (G) and optionally one or more cationic groups and / or one or more groups ionizable and / or one or more neutral groups.
• G hydrophobic groups
• cationic group means a group grafted covalently on a glutamic residue, and comprising one or more amino functions or one or more quaternary ammoniums.
• neutral group means a group bearing no charge for any pH of between 3 and 10, for example the groups obtained by condensation on the carboxyl of a glutamic acid residue of ethanolamine (bound by nitrogen), amino-propane diol, an alkylene glycol or a polyoxyalkylene glycol.
• a POM polymer may in fact carry one or more grafts of the polyalkylene glycol type bonded to an amino acid unit constituting it.
• the polyalkylene glycol is a polyethylene glycol and more particularly used with a molar percentage of grafting of polyethylene glycol ranging from 1 to 30%.
• modified polyglutamate of carboxylic residual functions are either neutral (COOH form) or ionized (anion COO "), depending on pH and composition.
• neutral COOH form
• anion COO ionized
• hydrophobic groups G are identical or different from each other and are selected from the group comprising: (i) linear or branched, preferably linear, C 1 -C 20 alkyls, acyls or alkenyls, and more preferably still C2 -C18; (ii) hydrocarbon groups containing one or more heteroatoms, preferably those containing oxygen and / or sulfur and, more preferably, those of the following formula:
• - Réo is a linear or branched, preferably linear C 1 -C 20 and even more preferably C 2 -C 8 alkyl, acyl or alkenyl group;
• hydrophobic derivatives preferably the phosphatidylethanolamino group or the groups chosen from octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy-.
• hydrocarbon groups is meant in the sense of the present invention, groups including in particular hydrogen and carbon atoms.
• the hydrophobic groups are selected from the following group: methyl, ethyl, propyl, docedyl, hexadecyl, octadecyl.
• the hydrophobic groups (G) are chosen from the following group: Linear or branched C 6 to C 30 alkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom,
• C 6 to C 30 alkylaryls or arylalkyls optionally containing at least one unsaturation and / or at least one heteroatom
• C 6 to C 30 cyclic (po Iy) optionally containing at least one unsaturation and / or at least one heteroatom
• At least one of the hydrophobic groups (G) is obtained by grafting, starting from a precursor chosen from the group comprising octanol, dodecanol, tetradecanol, hexadecanol, octadecanol, and the like. oleyl alcohol, tocopherol or cholesterol.
• the hydrophobic groups G considered according to the invention comprise from 8 to 30 carbon atoms.
• At least one and preferably all of the groups G present in a POM polymer include a tocopheryloxy group.
• At least one of the hydrophobic groups G is included in a hydrophobic graft comprising at least one spacer (or "spacer") balloon (or pattern) for connecting the hydrophobic group G to the structure of the POM polymer.
• This patella may comprise, e.g., at least one direct covalent bond and / or at least one amide bond and / or at least one ester bond.
• the patella may be of the type belonging to the group comprising in particular: the amino acid residues different from the monomeric unit constituting the hydrocarbon chain, the aminoalcohol derivatives, the polyamine derivatives (for example the diamines), the derived from polyols (eg diols) and hydroxy acid derivatives.
• the grafting of G on the amino chain can pass through the implementation of precursors of G, able to bind to said chain.
• the precursors of G are, in practice and without being limiting, chosen from the group comprising alcohols and amines, these compounds being able to be easily functionalized by those skilled in the art.
• the patella forming with the G hydrophobic grafts can be di-, tri- or tetra-valent (or even pentavalent and more).
• the graft hydrophobic comprises a single group G
• a trivalent patella gives the hydrophobic graft a bifid character, that is to say that the graft has two substituents G.
• trivalente patella include, among others, amino acid residues, for example glutamic acid or polyol residues, for example glycerol.
• two advantageous but non-limiting examples of hydrophobic grafts comprising G-glycosides are dialkyl glycerol and dialkyl glutamate.
• the coupling of the hydrophobic graft G is within the competence of those skilled in the art and may in particular be carried out according to the protocol described in documents PCT / EP2008 / 055507 and WO 03/104303.
• the polyamino acid according to the invention may also carry cationic groups. These groups are grafted to glutamic residues, preferably via an amide or ester bond.
• the cationic groups may be chosen from those which comprise at least one quaternary ammonium or at least one strong base whose half-neutralization pH is greater than 8.0.
• Such cationic groups can be obtained from the following precursor compounds: a linear diamine of 2 to 6 carbons, preferably putrescine, agmatine, ethanolamine bonded by oxygen, choline bound by oxygen, an ester or amide derivative of an amino acid whose side chain is positively charged at neutral pH, ie lysine, arginine, ornithine, linked by the amine function in the alpha position.
• cationic groups that can be used to functionalize the glutamate residues are identical or different from each other and may correspond to:
• a histidine derivative selected from the group comprising the histidine esters, preferably the methyl ester and the ethyl ester, histidinol, histamine, histidinamide, the JV-monomethyl derivative of the histidinamide and the N, N-dimethyl derivative of histidinamide;
• Y independently H or CH 3
• Z " chloride, sulfate, phosphate or acetate
• L linear (C 2 -C 6 ) alkylene and optionally substituted by a carboxyl or derivative functional group.
• cationic groups that can be used in the present invention are chosen from the following group:
• a group chosen from the following group: -NH- (CH 2 ) 4 -NH-C ( NH) -NH 3 + , Z " , an amino acid residue or an amino acid derivative of formula
• the cationic groups may have the following formulas:
• R 1 represents an alkoxy or alkylamino, preferably -OMe, -OEt, -NH 2 , -NHCH 3 or -N (CH 3 ) 2
• -R 2 represents a hydrogen, CH 2 OH, -CO 2 H or -COO) -R 1 .
• the neutral groups may for their part be chosen from the following group: hydroxyethylamino-, dihydroxypropylamino-, hydroxyalkyloxy- or polyoxyalkylene.
• the coupling of the cationic and optionally neutral groups with an acid function of the polymer is carried out simultaneously in a second step in the presence a chloroformate as a coupling agent and in a suitable solvent such as dimethylformamide, N-methylpyrrolidone (NMP) or dimethylsulfoxide (DMSO).
• a chloroformate as a coupling agent and in a suitable solvent such as dimethylformamide, N-methylpyrrolidone (NMP) or dimethylsulfoxide (DMSO).
• the cationic group contains two chemically undifferentiated amino functions (e.g. linear diamine), it can be introduced in a form in which one of the two functions is protected. A last step of cleavage of the protecting group is then added.
• two chemically undifferentiated amino functions e.g. linear diamine
• the POM polymer is a compound of formula (I) below or a pharmaceutically acceptable salt thereof,
• A represents independently:
• RNH- wherein R is H, a linear C 2 -C 10 branched alkyl C 3 -C 10 or a benzyl, a terminal amino acid residue of the formula:
• -R 7 is -OH, -OR 9 or -NHR 10 , and
• R 8 , R 9 and R 10 independently represent H, linear C 2 -C 10 alkyl, branched C 3 -C 10 alkyl or benzyl;
• B is a direct bond, a divalent, trivalent or tetravalent linking group, preferably chosen from:
• D is H, a linear acyl, C 2 -C 10 acyl branched C 3 -C 10, or a pyroglutamate;
• hydrophobic groups G each independently of one another, are chosen from:
• Linear or branched C 6 to C 30 alkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or
• R 1 is selected from the following group:
• X is an oxygen atom or a -NH-
• R 12 is H, linear C 2 -C 10 alkyl, branched C3 to C10 or benzyl,
• p, q, r and s are positive integers with q, r and s may also be zero;
• (p + q + r + s) which is the degree of polymerization DP varies from 10 to 1000, in particular from 20 to 500, and preferably 30 to 500;
• the molar grafting ratio of the hydrophobic groups G, (p) / (p + q + r + s) varies from 2 to 99 mol%, and preferably from 3 to 50%, provided that each copolymer chain has at least 2 and preferably at least 3 hydrophobic groups;
• the molar grafting ratio of the cationic groups (q) / (p + q + r + s) varies from 0 to 98 mol%;
• the molar grafting rate of the neutral groups (r) / (p + q + r + s) varies from 0 to 98 mol%;
• the molar grafting rate of the anionic groups (s) / (p + q + r + s) varies from 0 to 98 mol%
• the overall loading rate of the chain Q (qs) / (p + q +) r + s) can be positive or negative; the sequence of monomers of said general formula I may be random, block or multiblock.
• pharmaceutically acceptable salts of the polymer according to the invention means all the polymers with the counterions associated with the ionized functions of the polymer. It is also conceivable, for certain structures where there is co-existence of positive and negative charges that there is a total or partial neutralization of charges. A polymer having an equivalent number of positive charges and negative charges (isoelectric point) can exist without the presence of counter-anion or counter-cation.
• the hydrophobic groups G, the anionic groups and the cationic groups are randomly arranged in pendant groups.
• the hydrophobic groups G are selected from the following group: octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy-, B being then a direct bond.
• D represents an H or a pyroglutamate
• the hydrophobic groups G each independently of one another are chosen from: octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy- and "R represents a hydroxyethylamino-, or a dihydroxypropylamino.
• the compounds of general formula I can be distinguished according to the chemical nature of the hydrophobic, cationic and / or anionic groups they carry respectively and also as a function of the molar grafting level in each of these groups. Moreover, with regard to their percentage of grafting in cationic and / or anionic groups, the compounds of general formula I can be anionic, neutral or cationic at neutral pH.
• the compounds are represented by a general formula I or F in which: - (p + q + r + s) varies from 20 to 250, and preferably from 50 to 225;
• (p) / (p + q + r + s) preferably varies between 4 and 30% provided that each copolymer chain has at least 2 hydrophobic groups;" (q) / (p + q + r + s) is greater than or equal to 10%; "(r) / (p + q + r + s) is greater than or equal to 10%;” (s) / (p + q + r + s) is greater than or equal to 10%;
• Q (q-s) / (p + q + r + s) when it is positive, is between + 20% and + 60% and when it is negative is less than -20%.
• the compounds are represented by a general formula I or F in which
• (p + q + r + s) varies from 20 to 250, and preferably from 50 to 225;
• (p + q + r + s) varies from 20 to 250, and preferably from 50 to 225;" (p) / (p + q + r + s) preferably varies between 4 and 30% provided that each copolymer chain has at least 2 hydrophobic groups;
• the compounds are represented by a general formula I or F in which - (p + q + r + s) varies from 20 to 250, and preferably from 50 to 225;
• polymers of the second embodiment variant mentioned above, whose DP is between 70 and 130, the ratio (p) / (p +), are particularly suitable for the invention.
• q + r + s) varies between 7 and 13%
• the ratio (q) / (p + q + r + s) varies between 30 and 50%
• the ratio (r) / (p + q + r + s) varies between 40 and 60%
• the ratio (s) / (p + q + r + s) is less than 1%.
• It may especially be a cationic polyglutamate grafted with 10% vitamin E, 40% arginine and 50% ethanolamine.
• polymers of the fourth embodiment of the invention whose ratio (p) / (p + q + r + s) varies between 15, are particularly suitable for use in the invention. and 25% and the DP is between 150 and 250 or between 70 and 130.
• the active ingredients such as proteins, peptides or small molecules can spontaneously associate with the POM polymer of polyamino acid type.
• small molecule we mean the organic molecules of mass less than 1000 Da.
• this non-specific association is effected by hydrophobic and / or electrostatic interaction, by hydrogen bonding between the polymer and the active ingredient and / or by steric encapsulation of the active ingredient by the polymer. It should be noted that it is not necessary, and often even undesirable, to associate the active principle with the nanoparticles by specific receptors of peptide nature or of antigen / antibody or enzyme / substrate type.
• the combination of the active ingredient and the POM polymer can in particular be carried out according to the following modes.
• a first mode the active ingredient is dissolved in an aqueous solution and mixed with an aqueous suspension of the POM polymer.
• the active ingredient in the form of a powder is dispersed in an aqueous suspension of the POM polymer and the whole is stirred until a homogeneous, clear suspension is obtained.
• the POM polymer is introduced in the form of a powder in 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.
• this solvent can be removed by dialysis or any other technique known to those skilled in the art.
• binders are in particular proposed in Khankari RK et al., Binders and Solvents in Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh ed., Marcel Dekker Inc., New York, 1997.
• 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.
• the weight ratio active ingredient / polymer POM is likely to vary significantly depending on the dose of active ingredient considered.
• this ratio can vary between 0.1 and 300% by weight; between 1 and 100%, by weight or between 5 and 80% by weight.
• the active principles considered according to the invention are advantageously logically active organic compounds which can be administered to an animal or human organism orally.
• active principles that may be associated with the polyamino acids according to the invention, mention may be made, by way of nonlimiting illustration, of: o Proteins such as insulin, interferons, growth hormones, interleukins, erythropoietin or cytokines; o glycoproteins, o proteins bound to one or more polyalkyleneglycol chains [preferably polyethyleneglycol (PEG): "PEGylated proteins”], o peptides, o polysaccharides, o liposaccharides, o oligonucleotides, o polynucleotides and their mixtures.
• PEG polyethyleneglycol
• the particulate oral forms dedicated to active pharmaceutical applications concern both human and veterinary therapeutics.
• the active ingredient is selected from the group consisting of proteins or peptides.
• the active ingredient is insulin.
• the present invention also relates to new pharmaceutical or dietetic preparations prepared from microparticulate oral form according to the invention.
• This particulate form can thus be in the form of a powder, a suspension, a tablet or a capsule.
• an oral form may comprise at least two types of nanoparticles, differing in the nature of the active ingredient and / or the POM associated with said active ingredients.
• an oral form can combine at least two types of microparticles differentiating from each other by the nature of their coating layer and / or the active ingredient. that they incorporate.
• the invention also relates to a method of therapeutic treatment consisting of ingestion in a given posology of a drug comprising the microcapsules as defined above.
• Example 1
• Step 1 Preparation of the carvedilol base combination with the polyglutamate polymer grafted with 20% vitamin E and with a degree of polymerization of about 100 (pGlu-VE 100-20)
• sucrose Teos Compressum PS
• povidone Plasdone K29 / 32 from ISP
• pGlu-VE 100-20 prepared in step 1.
• the solution is sprayed onto 38.0 g of cellulose spheres (Asahi Kasei) in a bed of MiniGlatt fluidized air in a bottom spray configuration (spraying the coating solution via a nozzle located in the lower part of the particle bed). After spraying, the product obtained is screened on a sieve of 630 microns.
• Step 3 Coating phase 45.00 g of granules, as prepared in step 2, are embedded in a MiniGlatt fluidized air bed with 9.00 g of a copolymer of methacrylic acid and ethyl acrylate (Eudragit L100-55 from Evonik) and 6.00 g of hydrogenated cottonseed oil (Lubritab from JRS Pharma) dissolved in 135.3 g of isopropanol at 78 ° C. After spraying, 57.90 g of microparticles are obtained. Their mean diameter in volume, determined by laser diffraction using a Mastersizer 2000 device from Malvern Instrument equipped with the Sirocco 2000 dry modulus module, is 600 ⁇ m.
• the average thickness of the coating deposited on the granule prepared during step 2 calculated from the volume average diameters determined for the granules obtained above in step 2 and the microparticles obtained at step 2.
• step 3 is 32 ⁇ m.
• the dissolution tests are carried out in a pallet apparatus USP type IL
• the rotational speed of the pallets is 100 rpm.
• the amounts present in the dissolving medium of free carvedilol, that is to say not associated with pGlu-VE 100-20, on the one hand, and total carvedilol, that is to say the Free part and the pGlu-VE 100-20 associated part, on the other hand, are followed over time by HPLC liquid chromatography.
• the samples of the dissolution medium are, on the one hand, analyzed directly by HPLC liquid chromatography in order to determine the proportion of total carvedilol, and, on the other hand, treated by ultrafiltration before analysis of the HPLC filtrate to determine the share of carvedilol free base.
• Step 1 Preparation of the insulin combination with the polyglutamate polymer grafted with 20% vitamin E and a degree of polymerization of approximately 100 (pGlu-VE 100-20)
• Step 2 preparation of the granules (coating step)
• sucrose Teos Compressuc PS
• povidone
• the average thickness of the coating deposited on the granule prepared during step 2 calculated from the volume average diameters determined for the granules obtained above in step 2 and the microparticles obtained at step 2.
• step 3 is 44 ⁇ m.
• the dissolution tests are carried out in a pallet apparatus USP type IL
• the rotational speed of the pallets is 100 rpm.
• the amounts present in the free insulin dissolution medium that is to say not associated with the pGlu-VE 100-20 polymer, on the one hand, and total insulin, ie ie, the free part and the part associated with the pGlu-VE 100-20 polymer, on the other hand, are followed over time by HPLC liquid chromatography.
• the samples of the dissolution medium are, on the one hand, analyzed directly by HPLC liquid chromatography in order to determine the proportion of total insulin, and, on the other hand, treated by ultrafiltration before analysis. filtrate by HPLC to determine the free insulin portion.
• the insulin released from Figure 2 and Table II below, in the dissolution medium after adjusting the pH and salinity of the medium is mainly associated with the pGlu-VE 100-20 polymer.
• Step 1 preparation of the insulin combination with the cationic polyglutamate polymer grafted with 10% vitamin E, 40% arginine and 50% ethanolamine
• 0.604 g of insulin (from Biocon) are introduced into a 250 ml glass flask. 133.3 g of aqueous polyglutamate polymer solution grafted with 10% vitamin E, 40% arginine and 50% ethanolamine, at pH 5.9 and concentrated at 79.4 mg / g, are added. The preparation is placed in an ultrasonic bath at room temperature until dissolution complete insulin (ie until no insoluble insulin powder disappears). After dissolving the insulin, a perfectly clear solution is obtained.
• Step 2 preparation of the granules (coating step) 6.0 g of sucrose (Tereos Compressuc PS) and 4.4 g of povidone (Plasdone
• K29 / 32 of ISP are introduced with magnetic stirring into the 250 ml glass flask containing 151.18 g of insulin solution associated with polyglutamate grafted with 10% vitamin E, 40% arginine and 50% ethanolamine, prepared previously .
• the solution is sprayed on 33.0 g of cellulose spheres (Asahi Kasei) in a fluidized MiniGlatt air bed in a bottom spray configuration. coating via a nozzle located in the lower part of the particle bed).
• the product obtained is sieved through a sieve of 710 ⁇ m. 37.4 g of granules, less than 710 ⁇ m, are then recovered.
• Their mean diameter in volume determined in intensity mode by laser diffraction using a Mastersizer 2000 device from Malvern Instrument equipped with the Sirocco 2000 dry modulus module, is 531 ⁇ m.
• Step 3 coating phase
• 30.0 g of granules, as prepared above, are embedded in a MiniGlatt fluidized air bed, with 2.0 g of a copolymer of methacrylic acid and ethyl acrylate (Eudragit L100-55 from Evonik), 4.0 g of a copolymer of methacrylic acid and methyl methacrylate (Eudragit S100 from Evonik) and 4.0 g of hydrogenated cottonseed oil (Lubritab from JRS Pharma), dissolved in 90.47 g of isopropanol at 78 ° C. After spraying, 39.7 g of microparticles are obtained.
• the average thickness of the coating deposited on the granule prepared during step 2 calculated from the volume average diameters determined for the granules obtained above in step 2 and the microparticles obtained at step 2.
• Step 3 is 28.5 ⁇ m.
• the kinetics of in vitro release of the microparticles prepared in Example 5 is followed at 37 ° C. ⁇ 0.5 ° C. in 500 ml of 0.1N HCl medium for 2 hours and then, after adjusting the pH and salinity of the medium by addition of 5N sodium hydroxide and potassium phosphate, in 500 ml of a 0.05M medium at pH 6.8.
• Each sample of the dissolution medium is analyzed directly by HPLC liquid chromatography to determine the proportion of insulin dissolved in the dissolution medium.
• the dissolution tests are carried out in a pallet apparatus USP type IL The rotational speed of the pallets is 100 rpm.
• Step 1 Preparation of the carvedilol base combination with the pGlu-VE polymer grafted with 10% vitamin E
• carvedilol base 1.01 g of carvedilol base are introduced into a 250 ml glass flask. 151.2 g of aqueous polyglutamate polymer solution grafted at 10% vitamin E, at pH 6.9 and concentrated at 52.8 mg / g, are added. The preparation is placed in an ultrasonic bath at room temperature until complete dissolution of the carvedilol base (that is to say until disappearance of carvedilol powder unsolubilized base). After dissolving the carvedilol base, a perfectly clear solution is obtained.
• Step 2 preparation of the granules (coating step)
• sucrose Teos Compressum PS
• povidone Plasdone K29 / 32 from ISP
• sucrose sucrose
• povidone povidone
• the solution is sprayed onto 30.0 g of cellulose spheres (Asahi Kasei) in a fluidized MiniGlatt air bed in a bottom spray configuration (solution spraying). embedding via a nozzle located in the lower part of the particle bed).
• the product obtained is screened on a sieve of 630 microns. 46.0 g of granules, less than 630 ⁇ m, are then recovered. Their mean volume diameter, determined by laser diffraction using a Mastersizer 2000 instrument from Malvern Instrument equipped with the Sirocco 2000 dry modulus module, is 497 ⁇ m.
• 300 mg of granules are introduced into a beaker containing 50 ml of 0.05M phosphate medium at pH 6.8, so as to obtain a concentration of POM polymer in the suspension equal to 1 mg / ml.
• the suspension is stirred with a magnetic bar for 2 hours at room temperature.
• 10 ml of the suspension are then taken and filtered on Acrodisc filters with a pore size of 0.45 ⁇ m.
• the hydrodynamic radius of the nanoparticles then in suspension in the filtrate, determined in the intensity by light scattering at an angle set at 90 ° with a CGS-3 instrument from Malvern Instrument, is 18 nm.
• Step 3 Coating phase 36.00 g of granules, as prepared above, are coated in a MiniGlatt fluidized air bed, with 3.85 g of a copolymer of methacrylic acid and ethyl acrylate (Eudragit L 100-55 of Evonik), 2.17 g of a copolymer of methacrylic acid and methyl methacrylate (Eudragit S100 from Evonik) and 6.00 g of hydrogenated cottonseed oil (Lubritab from JRS Pharma), dissolved in 108.78 g of isopropanol at 78 ° C. After spraying, 44.8 g of microparticles are obtained. Their mean volume diameter, determined by laser diffraction using a Mastersizer 2000 instrument from Malvern Instrument equipped with the Sirocco 2000 dry modulus, is 571 ⁇ m.
• the average thickness of the coating deposited on the granule prepared during step 2 calculated from the volume average diameters determined for the granules obtained above in step 2 and the microparticles obtained at step 2.
• Step 3 is 37 ⁇ m.
• Example 7 The kinetics of in vitro release of the microparticles prepared in Example 7 is followed at 37 ° C., ⁇ 0.5 ° C. by UV spectrometry, in 900 ml of 0.1 N HCl for 3 hours, and then, after adjusting the pH and the salinity of the medium, at pH 6.8 and 0.05M potassium phosphate.
• the dissolution tests are carried out in a pallet apparatus

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