CA2731449A1 - Microparticulate oral drug form useful for the modified release of nanoparticles - Google Patents

Abstract

The present invention aims at providing novel microparticulate oral forms for the modified release of active principle (s), in particular of protein or peptide nature. It also relates to the applications, in particular therapeutic or cosmetic applications, of these microparticulate oral forms.

Description

Microparticulate oral form useful for modified release of nanoparticles The present invention aims to propose new oral forms microparticles for the modified release of active principle (s), abridged in PA, particular of protein or peptide nature. It also concerns applications particularly therapeutic or cosmetic, of these oral forms microparticle.

Among all the modes of administration considered for the assets they therapeutic, prophylactic or cosmetic, the oral route is particularly appreciated, especially with regard to his comfort for the patient and his compatibility with wide variety of formulations.
Unfortunately, this mode of administration exposes the ingested its migration through the gastrointestinal tract, under conditions physiological very particular variables depending on the pH can, with respect to certain assets, ask some problems of bioavailability, due for example to the degradation of the principle active in the middle acid. Moreover, it is imperative for certain assets to guarantee a process of specific release depending on the location of their absorption window.
Multiparticulate oral dosage forms have already been developed for give satisfaction in this respect.
These multiparticulate forms are generally in the form of microparticles or microcapsules whose heart, containing the active ingredient or a mix of assets, is covered with a coating whose composition and / or thickness are precisely adjusted to control the release of this asset.
These microparticulate systems consist of a plurality of microcapsules of diameter generally less than 2000 m are thus particularly effective for guarantee a delayed and controlled release.
As an illustration of these forms of controlled release in the state multiparticulate there may be mentioned those described in documents US 2002/0192285, US 6,238,703, US 2002/0192285, US 2005/0118268 and US 5,800,836 and all particularly those described in WO 03/030878. The document WO 03/03878, provides a microparticulate system for oral administration at less an asset and whose release is controlled over time and pH function via the WO 2010/012940

2 PCT / FR2009 / 051495 chemical nature of the envelope encapsulating the heart of the microparticles which contains the asset.
More specifically, this envelope is formed of a material comprising at least a hydrophilic polymer carrying ionized groups at neutral pH, such as by example a copolymer of (meth) acrylic acid and alkyl (meth) acrylate and at least a hydrophobic compound such as vegetable hydrogenated wax.
These microparticulate systems are particularly interesting for controlling of reliable way on the one hand the transport of the asset they convey through the gastrointestinal tract intestinal and on the other hand the release of it at the level of the small intestine or the case in the stomach, for example, unfortunately do not occur appropriate to the transport of assets that exhibit stability and / or absorption scaled down. This defect of stability may be the consequence of too rapid degradation due to exposure to a aggressive environment like gastrointestinal light that has a pH
very acidic and / or contains active enzymes on these assets. As for the absorption reduced, she can also be the fact of a very low solubility or a insufficient permeability of the epithelial membrane vis-à-vis the asset.
The object of the present invention is in particular to propose a new system oral microparticle aimed at solving these problems and therefore particularly useful for vectorization of assets such as proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligo- or poly-nucleotides as well as small molecules, in particular hydrophobic ones.
More specifically, one aspect of the present invention is to provide a form Oral consisting mainly of microparticles of type releasing tank in a way controlled an active ingredient itself associated non-covalently with less in part, nanoparticles of at least one polymer, abbreviated POM. This system distinguished traditional tank-type microparticle systems that release the active ingredient they contain in an unassociated form.
Thus, the present invention relates, according to a first of its aspects, to microparticulate oral form, useful for the conditioning of at least one active ingredient and the in vivo release of this active ingredient according to a release profile regulated according to pH and / or time, comprising at least 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 ingredient characterized in that WO 2010/012940

3 PCT / FR2009 / 051495 the coating layer is formed of a material comprising at least one polymer A having a solubilization pH value within the pH range of 5 to 7 associated with at least one hydrophobic compound B, and said active ingredient, present in said microparticle core, is less part non-covalently associated with nanoparticles formed from minus one POM polymer comprising a hydrophilic hydrocarbon chain bearing one or many hydrophobic groups (G) or an amphiphilic hydrocarbon chain.
For the purposes of the invention, the term "conditioning" means microparticles according to the invention to contain and convey said principle active.
The invention also relates, according to another of its aspects, to a method of microparticle preparation useful for conditioning at least one active ingredient and the in vivo release of this active ingredient according to a release profile regulated according pH and / or time, said microparticles having a core containing at least less said active principle and coated with at least one coating layer conditioning said profile of release of said active agent, said method comprising at least steps consists in :
a) having at least one active ingredient associated non-covalently with nanoparticles formed from at least one POM polymer comprising a chain Hydrophilic hydrocarbon bearing one or more hydrophobic groups (G) or comprising an amphiphilic hydrocarbon chain, b) forming from the nanoparticles of step a) a core comprising said nanoparticles and one or more excipients, c) forming from at least one polymer A having a pH value of solubilization in the pH range of 5 to 7 and at least one compound B
hydrophobic, a coating layer disposed around the core formed in step b), and d) recover the expected microparticles.
Step b) can be carried out using any granulation technique conventional, such as wet granulation, agglomeration, extrusion / spheronisation, compaction, atomization or spray coating.
As for step c), it is carried out by any coating technique conventional. It can be advantageously performed by spraying in bed fluidized air on the nanoparticles of step a) at least one polymer A having a pH value WO 2010/012940

4 PCT / FR2009 / 051495 solubilising agent in the pH range of 5 to 7 associated with at least one compound B
hydrophobic.
The present invention results more particularly from the observation by the inventors that an incorporation of an asset in a form associated with nanoparticles of at least one POM polymer according to the invention in a system microparticulate to controlled release as defined previously is feasible and that it proves possible release this associated form PA / POM at its absorption site, usually intestine, with increased bioavailability and / or absorption duration (s) at the level of the intestine. Without wishing to be bound by the theory, it can be assumed that after their release to from the microparticles, nanoparticles loaded with active ingredient can, because of their submicron size, interact with the mucus of the intestine and improve absorption of active ingredient which is then released gradually.
As can be seen from the examples below, the particulate oral form according to the invention advantageously makes it possible to envisage a liberation of the principle active she contains in a sequential mode. At first, the asset, administered by way oral, is released in a form associated with nanoparticles of a polymer POM, this form having increased bioavailability and / or absorption duration (s) compared to the free form of the same asset. Only in a second time that the associated fraction of this active ingredient is dissociated from the polymer nanoparticles POM.
The use of polymer nanoparticles as considered according to the invention for parenterally administering active agents is known. So the society Flamel Technologies has described a pharmaceutical form in which a protein therapeutic is associated with nanoparticles of a copolyamino acid including hydrophobic groups and hydrophilic groups. (WO 96/29991;
WO 03/04303). WO 03/04303 discloses more particularly a polymer of polyamino acid type comprising aspartic residues and / or residues glutamic, with at least a part of these residues being carrier of grafts comprising at least one alpha-tocopherol unit, eg polyglutamate or polyaspartate grafted with alpha tocopherol.
These hydrophobic modified homopolyamino acids form spontaneously in water a colloidal suspension of nanoparticles, which are capable of associating easily aqueous suspension at pH 7.4, with at least one active protein. Requirement PCT / EP2008 / 055507 offers biodegradable polyamino acids, WO 2010/012940

5 PCT / FR2009 / 051495 convertible into colloidal nano- or micro-particles of suitable vectorization to associate reversibly to active principles. It is more particularly about copolyglutamate amphiphiles comprising both positive charges at neutral pH or near of the neutrality and pendant hydrophobic groups.
However, all these systems do not allow to adjust a profile of release as a function of the time and / or the pH of the asset which they convey, nor to protect this active against gastric juices and as a result does not prove to be appropriate to one oral administration.
The oral particulate forms according to the invention therefore prove to be particularly advantageous in many respects particulate conventional.
They convey the asset effectively to the intended site of absorption. They effectively protect the assets they release at the site absorption against a degradation of hydrolysis type or enzymatic digestion for example and which would be directly detrimental to the manifestation of biological activity searched through oral administration of this asset. Finally, they allow to control effectively the release profile of the asset they contain. So, in the case of a PA with window broad absorption, microparticles can release nanoparticles PA / POM on a duration less than 12 hours, preferably less than 6 hours or less than 2 hours.
Whereas in the case of a PA with a narrow absorption window, it is essential that microparticles release into the intestinal lumen the nanoparticles loaded in principle active PA / POM over a short duration for example less than 2 hours or better again less than 1 hour. This requirement of releasing nanoparticles on a duration controlled is particularly delicate to satisfy for nanoparticles formed from of a POM polymer and that stay during the gastric retention time in the middle acid of the stomach. It is the merit of the Claimant to have identified a family of compositions for coating microparticles that modulate in very wide range the release time of the nanoparticles, after their passage in one acidic medium such as the stomach. Advantageously, the nanoparticles do not turn out affected by prolonged residence time in the acidic environment, and by elsewhere, their individualization is preserved, which makes it possible to get rid of everything risk of liberation resulting from these nanoparticles as aggregates.

WO 2010/012940

6 PCT / FR2009 / 051495 The coating layer is precisely for this purpose formed of a material comprising at least one polymer A having a pH value of solubilization in the pH range of 5 to 7 associated with at least one compound B
hydrophobic and in particular as defined below.
As can be seen from the following, this effectiveness is reinforced by a adjustment the thickness of the coating layer formed.

MICRO
The reservoir type microparticles according to the present invention are consisting of a core containing the active in a form associated with nanoparticles of minus a POM polymer, and a coating surrounding the core.
Controlled release of nanoparticles from 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 sites very specific of the gastrointestinal tract corresponding for example to the windows absorption of active ingredient in the gastrointestinal tract.
Due to the nature of this coating, the oral form considered according to the present The invention may advantageously have a dual mechanism of release in function time and pH.
Under this expression, it is understood that the oral form considered according to the invention has the following two specificities. Below the value of pH of solubilization 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. In however, when it is present in the intestine or an assimilable medium, it ensures a liberation effective nanoparticles. This release can then be realized advantageously in less than 24 hours, especially in less than 12 hours, especially less of 6 hours, especially less than 2 hours or even less than 1 hour.
In the case of active ingredients having a very narrow absorption window, by example limited to duodenum or Peyer's patches, release time of the nanoparticles is less than 2 hours and preferably less than 1 hour.

WO 2010/012940

7 PCT / FR2009 / 051495 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.
For the purposes of the invention, the size of the particles is expressed in diameter way by volume D4,3 measured by laser granulometry using a device Mastersizer 2000 of Malvern Instrument equipped with Sirocco 2000 dry channel module.
As regards their coating, it is formed of a composite material obtained by mixing:
at least one compound A having a solubilization pH value in the pH range of 5 to 7, at least one hydrophobic compound B;
and optionally at least one plasticizer and / or other excipients conventional.

Polymer A
For the purposes of the present invention, the pH value of solubilization of the polymer A is a pH value of the physiological medium or in vitro model medium below the polymer is in an insoluble state and beyond which this same Polymer A is in a soluble state.
For obvious reasons, this pH value is specific to a polymer given and directly related to its physico-chemical characteristics intrinsic, such as its chemical nature and its chain length.
By way of illustration and without limitation, polymers A that are suitable for the invention, we may include:
the copolymer (s) of methacrylic acid and of methyl methacrylate, the copolymer (s) of methacrylic acid and of ethyl acrylate, cellulosic derivatives such as:
o acetate phthalate cellulose (CAP), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), o hydroxypropyl methylcellulose phthalate (or hypromellose) phthalate) (HPMCP), WO 2010/012940

8 PCT / FR2009 / 051495 o acetate hydroxypropyl methylcellulose succinate (or hypromellose acetate succinate) (HPMCAS), - the shellac gum, polyvinyl acetate phthalate (PVAP), - and their mixtures.
According to a preferred embodiment of the invention, this polymer A is chosen from (s) copolymer (s) of methacrylic acid and methyl methacrylate, the copolymer (s) of methacrylic acid and ethyl acrylate and mixtures thereof.
As specified above, 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.
For the purposes of the invention, the polymer A is generally insoluble at a value pH lower than its solubilization pH value and on the other hand soluble to a value of pH above its solubilization pH value.
For example, it may be a polymer whose pH value solubilization is of :
- 5.0 in the image for example of hydroxypropylmethylcellulose phthalate and especially that sold under the name HP-50 by Shin-Etsu, - 5.5 for example, hydroxypropylmethylcellulose phthalate and especially the one sold under the name HP-55 by Shin-Etsu or copolymer of methacrylic acid and ethyl acrylate 1: 1 and in particular the one marketed under the name Eudragit L100-55 of Evonik, For example, 6.0 for a copolymer of methacrylic acid and methyl methacrylate 1: 1 and especially that marketed under the denomination Eudragit L100 from Evonik, - 7.0, for example a copolymer of methacrylic acid and methyl methacrylate 1: 2 and in particular that marketed under the denomination Eudragit SI 00 from Evonik.
All of these polymers are soluble at a pH value higher than their solubilization pH.

WO 2010/012940

9 PCT / FR2009 / 051495 The coating is advantageously composed of 25 to 90%, in particular of 30 to 80%, especially 35 to 70%, or even 40 to 60% by weight of polymer (s) A by report to its total weight.
More preferably, the polymer A is an acid copolymer methacrylic acid and ethyl acrylate 1: 1.

Hydrophobic compound B
According to a first variant, compound B can be selected from among products crystallized in the solid state and having a melting temperature Tt,>
40 C, of Tt,> 50 C, and more preferably 40 C <Tth <90 C
More preferably, this compound is then chosen from the group of following products:
- vegetable waxes taken alone or mixed together, such as those marketed under the DYNASAN P60 and DYNASAN 116 brands, - hydrogenated vegetable oils taken alone or as a mixture they;
preferably selected from the group consisting of: hydrogenated cottonseed oil, oil of hydrogenated soybean, hydrogenated palm oil and mixtures thereof, mono and / or di and / or tri esters of glycerol and of at least one fatty acid, preferably behenic acid, taken alone or in mixture with each other;
- and their mixtures.
According to this embodiment, the weight ratio B / A can vary between 0.2 and 1.5 and preferably between 0.45 and 1.
More preferably, compound B is hydrogenated cottonseed oil.
Microparticles formed of such a coating are described in particular in the WO 03/30878.

According to a second variant, compound B may be an insoluble polymer in the liquids of the digestive tract.
This insoluble polymer in the liquids of the digestive tract or the fluids gastrointestinal is more particularly selected from:
the non-water-soluble derivatives of cellulose, non-water-soluble derivatives of (meth) acrylic (co) polymers, WO 2010/012940

10 PCT / FR2009 / 051495 - and their mixtures.
More preferentially, it may be chosen from ethylcellulose, and / or derivatives, for example those marketed under the name Ethocel, acetate cellulose butyrate, cellulose acetate, ammonio copolymers (meth) acrylate, copolymer of ethyl acrylate, methyl methacrylate and methacrylate of trimethylammonioethyl type A or type B especially those marketed under the names Eudragit RL and Eudragit RS, the acid esters poly (meth) acrylics, in particular those marketed under the name Eudragit NE and mixtures thereof.
Ethylcellulose and acetate are particularly suitable for the invention.
cellulose butyrate and ammonio (meth) acrylate copolymers in particular those marketed under the name Eudragit RS and Eudragit RL.
The coating of the microparticles then contains from 10% to 75%, and may contain preferably from 15% to 60%, more preferably from 20% to 55%, or even from 25 to 55%
by weight, and more particularly still from 30 to 50% of polymer (s) A per report to his total weight.
Advantageously, the coating can then be formed, according to this mode of realization, from a mixture of the two categories of polymers A and B
in a report polymer weight (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 greater than or equal to 0.75.
According to another variant embodiment, the ratio of polymer (s) A / polymer (s) B
is also less than 8, especially less than 4, or even less than 2 and more especially less than 1.5.
As representative of the polymer blends A and B, which are all suitable particularly to the invention, may especially be mentioned mixtures ethyl cellulose, cellulose acetate butyrate or ammonio (meth) acrylate copolymer type A or B
with at least one copolymer of methacrylic acid and ethyl acrylate or a copolymer of methacrylic acid and methyl methacrylate or one of their mixtures.
In addition to the two types of compounds A and B mentioned above, the coating of the particles according to the invention may comprise at least one plasticizer.

WO 2010/012940

11 PCT / FR2009 / 051495 Plasticizing agent This plasticizing agent may especially be chosen from:
glycerol and its esters, and preferably from acetylated glycerides, glycerol mono-stearate, glycerol triacetate, glyceryl tributrate, phthalates, and preferably from dibutyl phthalate, diethyl phthalate, dimethylphthalate, dioctylphthalate, citrates, and preferably from acetyl tributyl citrates, acetyltriethylcitrate, tributylcitrate, triethylcitrate, sebacates, and preferably from diethylsébaçate, dibutylsébaçate, - adipates, azelates - benzoates, chlorobutanol, polyethylene glycols, - vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates; preferably the dibutylsuccinate, - butyrates, esters of cetyl alcohol, malonates, preferably diethyl malonate, - Castor oil, - and their mixtures.
In particular, the coating may comprise less than 30% by weight, of preferably 1% to 25% by weight, and still more preferably 5%
at 20% in weight of plasticizing agent (s) relative to its total weight.
According to a particularly advantageous embodiment, the layer coating 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.

WO 2010/012940

12 PCT / FR2009 / 051495 Such a thickness of the coating layer of the oral form microparticle according to the invention advantageously allows a total release of the principle active she contains in a pH medium greater than 5, representative of that of the intestine.
According to another particular embodiment, the coating layer exhibits a thickness of less than 200 m, more particularly less than or equal to 100 m.
In particular, for particles of size ranging from 500 to 700 m, the layer coating material advantageously has a thickness varying from 25 to 50 m.
The formation of the microparticles according to the invention can be carried out by all conventional technique conducive to the formation of a reservoir capsule of which the heart is formed in whole or in part of at least one non-associated active ingredient covalent to POM polymer nanoparticles, especially as defined below and supported or not on a neutral substrate, where appropriate with one or more binders and with one or several conventional excipients.
Thus, according to an alternative embodiment, the nanoparticles associated with way non-covalent to the active ingredient may be present in the microparticles under a supported form.
Without this being limiting, the core of the microparticles may for example contain, in addition to the nanoparticles associated with the active ingredient and excipients conventional products, sucrose and / or dextrose and / or lactose, or a microparticle of an inert substrate such as cellulose serving as a support for said nanoparticles.
Thus, in a first preferred embodiment of the invention, the heart of the microparticles is a granulate containing the POM, the active ingredient, one or several binders ensuring the cohesion of the granulate and various excipients known to the man of art. A
coating is then deposited on this granulate by any known technique of the skilled person, and advantageously by spray coating.
The weight composition of a microparticle conforming to this mode of production is the following :
the weight content of nanoparticles loaded with active principle in the heart is between 0.1 and 80%, preferably between 2 and 70%, preferably between 10 and 60%, WO 2010/012940

13 PCT / FR2009 / 051495 the weight content of binder in the core is between 0.5 and 40%, of preferably between 2 and 25%, the weight content of the coating in the microparticle is between 5 and 50%, preferably between 15 and 35%.
In a second preferred embodiment, 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 optionally different excipients known to those skilled in the art, for example sucrose, the trehalose and mannitol. The neutral heart can be a particle of cellulose or sugar or any inert organic or saline compound that is suitable for coating.
The weight composition of a particle according to this embodiment is then next :
the weight content of nanoparticles loaded with active principle in the heart is between 0.1 and 80%, preferably between 2 and 70%, preferably between 10 and 60%;
the weight content of neutral heart in the heart of the microparticles is range between 5 and 50%, preferably between 10 and 30%, the weight content of the binder in the core of the microparticles is included enter 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%.
Preferably, the microparticles are formed by spraying compounds A and B and if present (s) the other ingredients of which the plasticizer (s) to the condition usually solutes. This solvent medium generally contains solvents organic mixed or not with water. The coating thus formed proves to be homogeneous terms of composition as opposed to a coating formed from a dispersion of these same polymers, in a predominantly aqueous liquid.
According to a preferred embodiment variant, the spray solution contains less 40% by weight of water, in particular less than 30% by weight of water and more especially less than 25% by weight of water.

WO 2010/012940

14 PCT / FR2009 / 051495 Nanoparticles As can be seen from the above, the active substance contained in the heart of the microparticles, forming the oral particulate form according to the invention, is present under a shape at least partly non-covalently associated with nanoparticles of less a POM polymer.
The terms association or associate used to qualify the relationship between one or more active ingredients and the POM polymer, mean that the or the principles active ingredients are associated with the POM polymer (s) in particular through interactions physical non covalents, in particular hydrophobic interactions, and / or interactions electrostatic and / or hydrogen bonds and / or via encapsulation steric by the POM polymers.
This association is generally associated with hydrophobic interactions and / or electrostatic and therefore assumes that the polymer POM integrates at its level structure patterns capable of generating this type of interaction.
These patterns, in particular hydrophobic or ionized, may be present directly within the hydrocarbon chain forming the skeleton of the polymer and / or may be represented by one or more hydrophobic or ionized groups worn by said hydrocarbon chain.
The term "grouping" means that said group is pendant, that is to say that said group is a lateral group connected to the chain main polymer by one or more covalent bonds. For example, when the polymer is a polyamino acid comprising amino acid residues, said group being is a lateral group with respect to the amino acid residues and may be in particular a substituent of the carbonyl function in y of the amino acid residue which carries it.

The POM polymers considered according to the invention generally have a degree of polymerization DP between 10 and 1000, in particular 30 and 500 and more especially between 50 and 250, or even between 20 and 150.
The POM polymers considered according to the invention are furthermore capable of forming spontaneously, when they are dispersed in an aqueous medium and especially water, nanoparticles.
The nanoparticles can be anionic, cationic or neutral, and preferably are anionic or cationic.

WO 2010/012940

15 PCT / FR2009 / 051495 For the purposes of the present invention, the term anionic nanoparticles nanoparticles of a POM polymer whose overall charge at neutral pH is negative; and cationic nanoparticles of the nanoparticles of a POM polymer whose load overall at neutral pH is positive.
The overall load can be measured by any method known to man art, such as measuring the Zeta potential at neutral pH.
In general, the size of the nanoparticles varies from 1 to 1000 nm, in particularly 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 diameter hydrodynamic medium of these particles. The measurement is carried out by quasi-elastic diffusion light with a CGS-3 device from ALV. To this end, the suspension of POM is concentrated at 0.5 mg / ml in a saline medium such as NaCl 0.15 M after a rest period sufficient for to achieve balance.

Hydrocarbon chain As stated above, the POM polymer according to the invention comprises a hydrophilic hydrocarbon chain carrying one or more groups hydrophobic (G) or an amphiphilic hydrocarbon chain.
According to a particular embodiment, it is a polymer comprising a hydrophilic hydrocarbon chain carrying one or more groups hydrophobic (BOY WUT).
The hydrocarbon 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, polyglucuronic, or cationic polysaccharides such as chitosan, or also collagen and its gelatin derivatives.
In view of the foregoing, it is understood that for the purposes of the invention, the term hydrocarbon chain covers hydrocarbon chains may contain one or more nitrogen atoms.
In what follows, the expressions hydrocarbon chain and chain hydrocarbon which may contain one or more nitrogen atoms will be used of indifferent way.

WO 2010/012940

16 PCT / FR2009 / 051495 Advantageously, the hydrocarbon chain forming the POM polymer, is a polyamino acid. According to one aspect of the invention, the POM polymer is biodegradable.
For the purposes of the invention, the term polyamino acid covers both natural polyamino acids than synthetic polyamino acids, as well as oligoamino acids comprising from 10 to 20 amino acid residues in the same way as the polyamino acids comprising more than 20 amino acid residues.
Polyamino acids are linear synthetic polymers, composed of advantageously alpha-amino acids bound by peptide bonds.
There are many synthetic techniques for forming polymers to blocks or statistics, multi-chain polymers and polymers containing a defined sequence of amino acids (see Encyclopedia of Polymer Science and Engineering, Vol. 12, p. 786; John Wiley & Sons).
The skilled person is able by his knowledge to implement these techniques for accessing polymers suitable for the invention. In particular, he will be able to also refer to teaching documents WO 96/29991, WO 03/104303, WO 96/079614 and PCT / EP / 2008/055507. In the variant of the invention, where the chain hydrocarbon-forming POM polymer is of an amphiphilic nature, this polyamino comprises at least one or more hydrophobic neutral amino acids.
More particularly, 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 AAI type corresponding to an amino acid with an ionizable side chain, with less a part of the amino acids of type AAI being in ionized form, the amino acids of each type AAN and AAI being identical or different enter them, and the molar mass by weight of said polyamino acid being greater or equal to 2500 D, in particular greater than or equal to 4000 D, preferably greater than or equal to 5000 D.
Such polyamino acids are described in particular in the document WO 96/29991 whose content is incorporated by reference.
In this embodiment variant of POM according to the invention, the AAN (or the NAAs) is (are) more particularly chosen from the following list:
Leu, Ile, Val, WO 2010/012940

17 PCT / FR2009 / 051495 Ala, Pro, Phe and their mixtures and the AAI (or AAI) is (are) more particularly formed by Glu and / or Asp.
More preferably still, such polyamino acids comprise a single type of AAI monomers corresponding, preferably, to Glu and a single type of monomers AAN corresponding, preferably, to Leu.

According to another variant embodiment, the hydrocarbon chain forming the POM polymer is a hydrophilic polyamino acid.
More particularly, the polyamino acids thus forming such POMs are oligomers or homopolymers comprising acid repeating units glutamic or aspartic acid or copolymers comprising a mixture of these two types of acid residues amine. The residues considered in these polymers preferably have the configuration D or L or D / L and are bound by their alpha or gamma positions for the residue glutamate or glutamic acid and alpha or beta for the aspartic acid or aspartate residue and more preferentially have the configuration L and are bound by their position alpha.
Preferably, the polymer POM comprises a hydrocarbon chain polyamino acid formed by aspartic acid units and / or acid units glutamic, and at least a part of these units carries grafts comprising at least minus one hydrophobic group (G).
According to an alternative embodiment, the hydrocarbon chain consists of a homopolymer of alpha-L-glutamate or alpha-L-glutamic acid.
According to another variant embodiment, the hydrocarbon chain is incorporated a homopolymer of alpha-L-aspartate or alpha-L-aspartic acid.
According to another particularly preferred embodiment, the chain hydrocarbon is a copolymer of alpha-L-aspartate / alpha-L-glutamate or of alpha-L-aspartic acid / glutamic alpha-L.
Such POM polymers are described in particular in the documents WO 03/104303, WO 96/079614 and PCT / EP / 2008/055507 whose content is incorporated by reference. These polyamino acids may also be of the type described in the PCT Patent Application WO-A-00/30618.
These polymers can be obtained by methods known to the human art.

WO 2010/012940

18 PCT / FR2009 / 051495 A number of polymers that can be used according to the invention, for example, type poly (alpha-L-glutamic acid), poly (alpha-D-glutamic acid), poly (alpha-D, L-glutamate) and poly (gamma-L-glutamic acid) of variable masses are available commercially.
Poly (L-glutamic acid) can be further synthesized according to the described in the patent application FR 2 801226.
The polymerization chemistry and the coupling reactions of the groups are conventional and well known to those skilled in the art (see for example patents or requests applicant's patent cited above).
More particularly, the POM polymer is a polyhydroxyalkylglutamine comprising a multiplicity of pendant hydrophobic groups (G), identical or different and preferably at least 2 hydrophobic groups (G) and the case appropriate a or more cationic groups and / or one or more groups ionizable and / or one or more neutral groups.
In the present description, cationic group is understood to mean a group covalently grafted onto a glutamic residue, and comprising one or several amine functions or one or more quaternary ammoniums. In the case of a amine function, the grouping will be mainly ionized at any pH below of his pKa, in the case of a quaternary ammonium, the group will be ionized at all pH.
In the present description, the term "neutral group" means group carrying no charge for any pH between 3 and 10, by example groups obtained by carboxyl condensation of an acidic residue glutamic ethanolamine (nitrogen bonded), amino-propane diol, alkylene glycol or a polyoxyalkylene glycol.
A POM polymer may indeed carry one or more grafts of the type polyalkylene glycol bound to an amino acid unit constituting it. Of preferably, the polyalkylene glycol is a polyethylene glycol and more particularly work with a molar percentage of grafting polyethylene glycol ranging from 1 to 30%.
It should also be noted that the residual carboxylic functions of the modified polyglutamate are either neutral (COOH form) or ionized (COO-anion ), according to pH and composition. We will therefore speak indifferently i) of glutamate residue or glutamic acid residue, ii) polyglutamate or polyglutamic acid.

WO 2010/012940

19 PCT / FR2009 / 051495 Hydrophobic group More particularly, the hydrophobic groups G are identical or different from each other and are selected from the group consisting of:
(i) alkyls, acyls or linear or branched alkenyls of preference C1-C20 linear and more preferably still C2-C8, (ii) hydrocarbon groups containing one or more heteroatoms, preferably those containing oxygen and / or sulfur and, more preferably again, those of the following formula:
HH
Ç-CH2O to C-CH2OR62 in which:
R 60 is a linear or branched alkyl, acyl or alkenyl group of C1-C20 linear preference and, more preferably still, C2-C18, R61 and R62 are identical or different from each other and correspond to hydrogen or a linear alkyl, acyl or alkenyl group or branched, preferably linear C1-C20 and, more preferably still in C2-Cig, -q = 1à100;
(iii) aryls, aralkyls or alkylaryls, preferably aryls;
(iv) the hydrophobic derivatives, preferably the grouping phosphatidylethanolamino- or the groups chosen from octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy-.
By hydrocarbon groups is meant for the purposes of the present invention, groups including in particular hydrogen and carbon atoms.
Preferably, in this variant, the hydrophobic groups are selected from the following group: methyl, ethyl, propyl, docedyl, hexadecyl, octadecyl.
In a particularly preferred manner, the hydrophobic groups (G) are chosen from the following group:

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20 PCT / FR2009 / 051495 linear or branched C8 to C30 alkyls which may comprise optionally at least one unsaturation and / or at least one heteroatom, C8 to C30 alkylaryls or arylalkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom, = and the (poly) cyclic C8 to C30 may optionally include less unsaturation and / or at least one heteroatom.
More specifically, at least one of the hydrophobic groups (G) is obtained by grafting, starting from a precursor chosen from the group comprising octanol, the dodecanol, tetradecanol, hexadecanol, octadecanol, oleyl alcohol, tocopherol or cholesterol.
Advantageously, the hydrophobic groups G considered according to the invention comprise from 8 to 30 carbon atoms.
According to a particular embodiment at least one and preferably all of the groups G present in a POM polymer are group tocophéryloxy-.
Advantageously, at least one of the hydrophobic groups G is included in a hydrophobic graft comprising at least one patella (or pattern) spacer (spacer) for connecting the hydrophobic group G to the structure of the polymer POM.
This patella may comprise, eg at least one direct covalent bond and or at least one amide bond and / or at least one ester bond. For example, the patella can be of the type belonging to the group including: residues acids different amines from the constituent monomeric unit of the chain hydrocarbon, derivatives of aminoalcohols, derivatives of polyamines (for example diamines), the derivatives of polyols (for example diols) and derivatives of hydroxy acids.
The grafting of the G on the amine chain can go through the implementation of precursors of G, able to bind to said chain.
The precursors of G are, in practice and without being restrictive, choose in the group comprising alcohols and amines, these compounds being easily functionalized by those skilled in the art.
The patella forming with the G hydrophobic grafts, can be di-, tri-or tetravalent (or even pentavalent and more). In the case of a kneecap divalent, the graft WO 2010/012940

21 PCT / FR2009 / 051495 hydrophobe has a single group G, while a trivalent patella confers on the hydrophobic graft a bifid character, that is to say that the present graft two G. As an example of a trivalent patella, mention may be made of others, residues amino acid, for example glutamic acid or polyol residues, for example glycerol.
Thus, two advantageous but non-limiting examples of hydrophobic grafts comprising G-glycids are dialkyl glycerol and dialkyl glutamate. The graft coupling hydrophobic G is within the competence of those skilled in the art and may especially be realized according to the protocol described in PCT / EP2008 / 055507 and WO
03/104303.

Cationic or neutral group The polyamino acid according to the invention may also carry cationic groups. These groups are grafted to glutamic residues, of preferably via an amide or ester bond.
According to another variant of the invention, the cationic groups can be selected from those comprising at least one quaternary ammonium or at least less a strong base whose half-neutralization pH is greater than 8.0.
Such cationic groups can be obtained from the compounds following precursors:
a linear diamine of 2 to 6 carbons, preferably putrescine, agmatine, ethanolamine bound 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, bound over there amine function in alpha position.
Thus, the cationic groups that can be used to functionalize the residues glutamates are the same or different from each other and may correspond to:

= a histidine derivative selected from the group consisting of esters histidine, preferably the methyl ester and the ethyl ester, histidinol, histamine, histidinamide, the N-monomethyl derivative of histidinamide and the N, N'-derivative dimethyl of histidinamide, = the following general formula:

WO 2010/012940

22 PCT / FR2009 / 051495 The X / NY3 +, Z
in which :
X = O, NH, Y = independently an H or a CH3, Z = chloride, sulphate, phosphate or acetate, L = a linear alkylene (C2 to C6) and optionally substituted by a group functional carboxyl or derivative type.
More specifically, the cationic groups that can be used in the present invention are selected from the following group:

NH 3 (CH 2) w NH 3 +, Z- with w ranging from 2 to 6, and preferably w is equal to 4, -O- (CH 2) 2 -NH 3 +, Z, -O- (CH 2) 2 -N + (CH 3) 3, Z-, = a grouping chosen from the following group:
-NH- (CH2) 4-NH-C (= NH) -NH3 +, Z-, an amino acid residue or an amino acid derivative of formula:

H

in which :
R 'is alkoxy, preferably -OMe or -OEt, or -R' is -NH2, alkylamino, preferably -NH-CH3 or -N (CH3) 2 R13 is - (CH2) 4 -NH3 +, Z-, - (CH2) 3-NH-C (= NH) -NH3 +, Z-, - (CH2) 3 -NH3 +, Z
where Z- is chloride, sulfate, phosphate or acetate, preferably a chloride.

WO 2010/012940

23 PCT / FR2009 / 051495 For example, the cationic groups may have the formulas following HN HN HN

RZ
~ '3 N H', Cr NH3 ', Cr NMe3', Cl Ethanolamine Choline NH3 +, CI-NH N
H
HN derivatives Putrescine of hiistidine NH3 ', CI
agmatine HN HN HN
COR, COR, COR1 NH3 ', CI- NH

Cr, 'HN Ornithine HN
3 ester or amide Lysine NH3, C [
ester or am ide Arg'rnine ester or am ide in which -Ri represents an alkoxy or alkylamino, preferably -OMe, -Et2, -NH2, -NHCH3 or -N (CH3) 2, and -R2 represents hydrogen, -CH2OH, -CO2H
or -C (= O) -Ri.

Neutral groupings can be selected from the group hydroxyethylamino-, dihydroxypropylamino-, hydroxyalkyloxy- or polyoxyalkylene.

The coupling of the cationic and possibly neutral groups with a acid function of the polymer is carried out simultaneously in a second step in the presence WO 2010/012940

24 PCT / FR2009 / 051495 of a chloroformate as a coupling agent and in a suitable solvent such that the dimethylformamide, N-methylpyrrolidone (NMP) or dimethylsulfoxide (DMSO).
In the case where the cationic group contains two non-amine functional groups chemically differentiated (eg linear diamine), it can be introduced in a form in which one of the two functions is protected. A last step of cleavage protective group is then added.
The polymerization chemistry and the coupling reactions of the groups are conventional and well known to those skilled in the art (see for example patents or requests Applicant's patent cited above).
POM Polymer of General Formula I
According to a preferred variant of the invention, the POM polymer is a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, AN R 'O OH
OO
NOT
ND
H
L-JOO
pqrs s BOY WUT
(I) in which :
^ A represents independently:
- RNH- in which R represents an H, a linear C2-CIO alkyl, branched C 3 to C 10 alkyl or benzyl, a terminal amino acid residue of formula:
H

WO 2010/012940

25 PCT / FR2009 / 051495 in which -R7 is -OH, -OR9 or -NHR10, and R8, R9 and R10 independently represent H, linear alkyl in C2 to C10, branched C3 to C10 alkyl or benzyl;
B is a direct bond, a divalent, trivalent, or tetravalent, preferably selected from:

-O-, -NH-, -N (C 1.5 alkyl) -, an amino acid residue (preferably natural), diol, triol, diamine, triamine, aminoalcohol or hydroxy acid having 1 to 6 carbon atoms;
D is H, C 2 -C 10 linear acyl, C 3 -C 10 branched acyl, or pyroglutamate;
the hydrophobic groups G, each independently of one another are chosen from:

linear or branched C8 to C30 alkyls which may comprise optionally at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or = C8 to C30 alkylaryls or arylalkyls which may comprise optionally at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or = the (poly) cyclic C8 to C30 may include possibly minus one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S);
^ Ri is chosen from the following group:

-NH- (CH2) W NH3 +, Z- with w ranging from 2 to 6, and preferably w is equal to 4, -NH- (CH2) 4-NH-C (= NH) -NH3 +, Z-, -O- (CH 2) 2 -NH 3 +, Z, -O- (CH 2) 2 -N + (CH 3) 3, Z-, an amino acid residue or an amino acid derivative of formula:

WO 2010/012940

26 PCT / FR2009 / 051495 H

in which :
X is an oxygen atom or a -NH-, R 1 2 is H, C 2 to C 10 linear alkyl, C 3 to C 10 branched alkyl or benzyl, -R13 is - (CH2) 4 -NH3 +, Z-, - (CH2) 3 -NH-C (= NH) -NH3 +, Z, - (CH2) 3-NH3 +, Z;
with the counteranion Z- being a chloride, a sulphate, a phosphate or a acetate, preferably chloride;
R 3 represents a hydroxyethylamino-, a dihydroxypropylamino, a alkylene glycol residue, a polyoxyalkylene glycol or a group of formula :

NNH
HH
-NC

where -R10 is -H, -CO2H, an alkyl ester (preferably -COOMe or -COOEt), -CH2OH, -C (= O) -NH2, -C (= O) -NH-CH3 or -C (= O) -N (CH3) 2;
^ p, q, r and s are positive integers with q, r and s can also be void;
^ (p + q + r + s) which is the degree of polymerization DP varies from 10 to 1000, in in particular from 20 to 500, and preferably from 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 between 3 and 50% under condition that each copolymer chain has at least 2 and preferably at least minus 3 hydrophobic groups;
the molar grafting rate of the cationic groups (q) / (p + q + r + s) varies from 0 to 98 mol%;

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27 PCT / FR2009 / 051495 the molar grafting rate of the neutral groups (r) / (p + q + r + s) varies from 0à98 mol%;
the molar grafting rate of the anionic groups / (p + q + r + s) varies from 0 to 98 mol%;
^ the overall load rate of the chain Q = (qs) / (p + q + r + s) can be positive or negative;
the sequence of the monomers of said general formula I which can be random, block type, or multiblock.
Such polymers are particularly detailed in the document PCT / EP2008 / 055507 whose contents are incorporated by reference. For more details about their synthesis we will usefully refer to the documents FR 02 07008 and FR 03 50190.

The general formula (I) described above should not be interpreted as representing only block copolymers (or blocks), but also of the random copolymers or multiblock copolymers.
The term pharmaceutically acceptable salts of the polymer according to the invention all the polymers with the counterions associated with ionized functions of the polymer. It is also possible for some structures where there is co-existence of positive and negative charges that there is a total neutralization or partial charges.
A polymer having an equivalent number of positive charges and charges negative (isoelectric point) can exist without presence or counter-anion or against-cation.
Preferably, the hydrophobic groups G, the anionic groups and the cationic groups are randomly arranged in groups counterparts.
Preferably, the hydrophobic groups G are chosen from the group octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy-, B being then a bond direct.
In particular, the compounds of formula general corresponding to the general formula I in which ^ A represents -NH2 ^ B is a direct link, D is H or pyroglutamate;

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28 PCT / FR2009 / 051495 the hydrophobic groups G each independently of one another are chosen from: octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy-, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy- and R3 is hydroxyethylamino- or dihydroxypropylamino.
The compounds of general formula I can be distinguished according to the nature chemical groups of hydrophobic, cationic and / or anionic carry respectively and also according to the molar grafting rate in each of these groups.
Moreover, with regard to their percentage of grafting in groups cationic and / or anionic compounds, the compounds of general formula I can be anionic, neutral or cationic at neutral pH.
Thus, according to a first variant embodiment, the compounds are represented by a general formula I or 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 = (qs) / (p + q + r + s) when positive, is between + 20% and + 60 %
and when negative is less than - 20%.

According to a second variant embodiment, the compounds are represented by a general formula I or the one 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 between 10 and 80%, and preferably between 10 and 60 %
((r) / (p + q + r + s) is greater than or equal to 10%;
^ (s) / (p + q + r + s) is less than 15%.

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29 PCT / FR2009 / 051495 According to a third variant embodiment, the compounds are represented by a general formula I or the one 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 less than 5%;
((s) / (p + q + r + s) is greater than 10%;
^ Q = (qs) / (p + q + r + s) is when it is positive between + 20% and + 60%
;
and when negative, less than - 20%.

According to a fourth variant embodiment, the compounds are represented by a general formula I or the one 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 less than 1%;
((r) / (p + q + r + s) is less than 1%.
According to a particular embodiment, they are particularly suitable for the invention, as polymer POM polymers according to the second variant of mentioned above, and whose DP is between 70 and 130, the report (P) / (p + q + r + s) varies between 7 and 13%, the ratio (q) / (p + q + r + s) varies between 30 and 50%, the report (r) / (p + q + r + s) varies between 40 and 60%, and the ratio (s) / (p + q + r + s) is less than 1%.
It may especially be a cationic polyglutamate grafted with 10% of vitamin E, 40% arginine and 50% ethanolamine.
According to another particular embodiment, all particularly to the invention, as polymer POM polymers according to the fourth embodiment of the above-mentioned embodiment and whose ratio (p) / (p + q + r + s) varies between 15 and 25% and the DP is between 150 and 250 or between 70 and 130.
It may especially be a polyglutamate grafted with 20% vitamin E.

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30 PCT / FR2009 / 051495 Association of POM to an asset Techniques for associating one or more active ingredients with polymer POM according to the invention and more particularly modified polyamino acids according to the invention are similar to those described in particular in the US patent 6630171.
Active ingredients such as proteins, peptides or small molecules, can spontaneously associate with the POM polymer type polyamino.
By small molecule, we mean the organic molecules of mass lower than 1000 Da.
This association is purely physical and does not involve the creation of covalent bond between the active ingredient and the polymer.
Without being bound by the theory, we can suppose that this association specificity is achieved by hydrophobic and / or electrostatic interaction, by bond hydrogen between the polymer and the active ingredient and / or by encapsulation steric active ingredient by the polymer. It should be noted that it is not necessary, and often not even desirable, to associate the active ingredient with nanoparticles by specific receptors of peptide nature or of antigen / antibody or enzyme / substrate type.
No chemical crosslinking step is provided for the particles obtained.
The absence of chemical crosslinking makes it possible to avoid the chemical degradation of the principle active during the step of crosslinking the particles containing the principle active. Such a chemical crosslinking is indeed usually driven by activation entity polymerizable and involves potentially denaturing agents such as the UV radiation, or glutaraldehyde.
The combination of the active ingredient and the POM polymer can in particular be carried out according to the following modes.
In a first mode, the active ingredient is dissolved in an aqueous solution and mixed with an aqueous suspension of the POM polymer.
In a second mode, the active ingredient in powder form is dispersed in an aqueous suspension of the POM polymer and the whole is stirred until getting a clear, homogeneous suspension.
In a third mode, the POM polymer is introduced in powder form in an aqueous solution of the active ingredient.

WO 2010/012940

31 PCT / FR2009 / 051495 In a fourth mode, the active ingredient and / or the polymer is dissolved in a solution containing an organic solvent miscible with water such as ethanol or isopropanol.
Then proceed as in modes 1 to 3 above. Possibly, this solvent can be eliminated by dialysis or any other technique known to those skilled in the art.
For all these modes, it may be advantageous to facilitate the interaction between the active ingredient and the POM polymer using ultrasound or elevation of temperature.
In the case where it is desired to deposit the PA / POM mixture on a neutral substrate of type neutral sphere, we can proceed as follows:
To the homogeneous mixture of active ingredient and POM a binder is added conventional for ensuring the cohesion of the layer deposited on the core neutral.
Such binders are in particular proposed in Khankari RK et al., Binders and Solvents in Pharmaceutical Granulation Technology Handbook, Dilip M. Parikh ed., Marcel Dekker Inc., New York, 1997.
Particularly suitable for the invention as a binder hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC).
The deposit of the corresponding mixture is then carried out by the techniques conventional known to those skilled in the art. It may in particular be a spray of suspension colloidal nanoparticles loaded with active ingredients, and containing the binding and optionally other compounds, on the support in a fluidized air bed.
For obvious reasons, the weight ratio active principle / polymer POM
is likely to vary significantly depending on the dose in principle considered asset.
More particularly, this ratio can vary between 0.1 and 300% by weight;
between 1 and 100%, by weight or between 5 and 80% by weight.

Active ingredient The active principles considered according to the invention are advantageously biologically active compounds that can be administered to an organism animal or human oral.
Examples of active ingredients that may be associated with polyamino acids according to the invention, may be mentioned by way of illustration and not Restrictions:

WO 2010/012940

32 PCT / FR2009 / 051495 o Proteins such as insulin, interferons, growth, interleukins, erythropoietin or cytokines;
o glycoproteins, o proteins bound to one or more polyalkylene glycol chains [of preferably polyethylene glycol (PEG): proteins-PEGylated], o the peptides, o polysaccharides, o liposaccharides, o oligonucleotides, polynucleotides o and their mixtures.
In general, it can be any therapeutic asset or cosmetic, and therefore assets other than those mentioned above. Within the meaning of the invention particulate oral forms dedicated to pharmaceutical applications active concern both human and veterinary therapeutics.
Preferably, the active ingredient is selected from the group consisting of proteins or peptides.
According to a particularly preferred embodiment, the active ingredient is insulin.
The present invention furthermore relates to novel preparations Pharmaceuticals or dietetics made from oral form microparticulate the invention.
This particulate form can thus be in the form of a powder, a suspension, a tablet or a capsule.
According to an alternative embodiment, an oral form may comprise at least two types of nanoparticles, differentiated by the nature of the active ingredient and / or POM
associated with said active ingredients.
According to yet another variant, which can be combined with the variant previous, an oral form can combine at least two types of microparticles himself differentiating one from the other by the nature of their coating layer and / or the principle asset they incorporate.

WO 2010/012940

33 PCT / FR2009 / 051495 Finally, the invention also provides a method of therapeutic treatment consisting of ingestion in a specific posology of a medicinal product comprising microcapsules as defined above.
The invention will be better explained by the examples given below, given only for illustration.

FIG. 1 represents the in vitro release profiles of carvedilol of microparticles of Example 1, on the one hand, of free carvedilol not associated with polymer POM (+) and, on the other hand, total carvedilol (=), ie carvedilol free and carvedilol associated with POM, in 0.1 N HCl medium for 3 h and then after pH adjustment and the salinity of the medium by adding 5N sodium hydroxide and phosphate potassium, in the middle 0.05 M at pH = 7.0 as a function of time T in hours;

FIG. 2 represents the in vitro release profiles of the insulin of the microparticles of Example 3, on the one hand, of the non-associated free insulin at the POM (+) and, on the other hand, total insulin (=), that is to say free and associated with POM, in the middle HC10.1 N for 3 h and then, after adjusting the pH and salinity of the medium by adding 5N sodium hydroxide and potassium phosphate, in 0.05M medium at pH = 7.0 time function T in hours.
FIG. 3 represents the in vitro release profile of the insulin of the microparticles of Example 5, in HC1,1N medium for 2 h and then after adjustment of pH and salinity of the medium by adding 5 N sodium hydroxide and phosphate potassium, in 0.05 M medium at pH = 6.8 as a function of time T in hours.
FIG. 4 represents the in vitro release profiles of carvedilol of microparticles of Example 7, in an HCl medium of 10 N for 3 h and then after adjustment of pH and salinity of the medium by adding 5 N sodium hydroxide and phosphate potassium, in 0.05 M medium at pH = 6.8 as a function of time T in hours.

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34 PCT / FR2009 / 051495 Example 1 Preparation and formulation of microparticles of carvedilol base associated with a polyglutamate grafted with 20% vitamin E and degree of polymerisation about 100 Step 1: Preparation of the combination of carvedilol base with the polymer polyglutamate grafted with 20% vitamin E and with a degree of polymerization about 100 (pGlu-VE 100-20) Referring to formula I, this POM polymer is characterized by: p + q + r + s =
100, p = 20, q = 0, r = 0, and s = 80.
1.21 g of carvedilol base are introduced into a 250 ml glass flask.
133.29 g of pGlu-VE 100-20 aqueous solution, at pH = 7.0 and concentrated at 90.degree.
mg / g, are added. The preparation is placed in a temperature ultrasonic bath ambient up complete dissolution of the carvedilol base (that is, until the disappearance of powder carvedilol unsolubilized base). After dissolution of the carvedilol base, a solution perfectly clear is obtained.
Step 2: preparation of the granules (coating step) 12.5 g of sucrose (Tereos Compressuc PS) and 6.3 g of povidone (Plasdone K29 / 32 from ISP) are introduced with magnetic stirring into the bottle.
250 ml glass containing 134.5 g of carvedilol base solution combined with pGlu-VE 100-20 prepared for step 1. Once the sucrose crystals and the dissolved povidone powder, the solution is sprayed on 38.0 g of cellulose spheres (Asahi Kasei) in an air bed fluidized MiniGlatt in a bottom spray configuration (spraying the solution embedding via a nozzle located in the lower part of the particle bed). After spraying, the product obtained is screened on a sieve of 630 m. 70.5 g of granules, size less than 630 m, are then recovered.
Their mean diameter by volume, determined by laser diffraction using a Mastersizer 2000 instrument from Malvern Instrument equipped with dry path module Sirocco 2000, is 536 m.
580 mg of granules are introduced into a beaker containing 100 ml of medium 0.05 M potassium phosphate at pH = 7.0, so as to obtain a concentration in POM polymer in the suspension equal to 1 mg / ml. The suspension is agitated by a bar magnet for 2 hours at room temperature. 10 ml of the suspension are then taken and filtered on 0.45 pore size Acrodisc filters m. The diameter WO 2010/012940

35 PCT / FR2009 / 051495 hydrodynamics of the nanoparticles then in suspension in the filtrate, determined in mode intensity by scattering light at an angle set at 90 using a CGS-3 device from ALV, is 14 nm.
Step 3: coating phase 45.00 g of granules, as prepared in step 2, are embedded in a bed of air fluidized MiniGlatt with 9.00 g of a methacrylic acid copolymer and acrylate of ethyl (Eudragit L100-55 from Evonik) and 6.00 g of cottonseed oil hydrogenated (Lubritab from JRS Pharma) dissolved in 135.3 g of isopropanol at 78 C. After spraying, 57.90 g of microparticles are obtained. Their average diameter in volume, determined by laser diffraction using a Mastersizer 2000 device from Malvern Instrument equipped with Sirocco 2000 dry track module, is 600 m.
Thus, 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 in step 3, is 32 m.
Example 2 In vitro dissolution tests The kinetics of in vitro release of the microparticles prepared in The example 1 is evaluated at 37 C 0.5 C in 900 ml of 0.1 N HCl medium for 3 h then after adjusting the pH and salinity of the medium by adding 5 N sodium hydroxide and phosphate potassium, in 900 ml of a 0.05 M medium at pH = 7.0. Dissolution tests are performed in a USP type II pallet apparatus. The speed of rotation of pallets is from 100 rpm.
More precisely, the quantities present in the dissolution medium of carvedilol free, ie not associated with pGlu-VE 100-20, on the one hand, and of carvedilol total, that is, the free part and the pGlu-VE 100-20 associated part, on the other hand, are followed over time by HPLC liquid chromatography. For that, to every time samples, the samples of the dissolution medium are, on the one hand, analyzes directly by HPLC liquid chromatography to determine the proportion of carvedilol and, on the other hand, treated by ultrafiltration before analysis filtrate by HPLC
to determine the share of carvedilol free base.
The results are illustrated in Figure 1.

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36 PCT / FR2009 / 051495 It is noted from Figure 1 and Table I below that carvedilol released in the dissolution medium after adjusting the pH and salinity of the middle east Mostly associated with pGlu-VE 100-20.
TABLE I
Hours Carvedilol total (%) Carvedilol free (%) 24,100 16 Example 3 Preparation and formulation of insulin microparticles associated with a pGlu-VE polymer Step 1: Preparation of the insulin combination with the polymer polyglutamate grafted with 20% vitamin E and degree of polymerization about 100 (pGlu-VE 100-20) 2.40 g of insulin (Biocon) are introduced into a 250 ml glass flask.
133.7 g of pGlu-VE 100-20 aqueous solution, concentrated at 90 mg / g, are added. The preparation is placed in an ultrasonic bath at room temperature until dissolution complete insulin. After dissolving the insulin, a solution perfectly clear is obtained.
Step 2: preparation of the granules (coating step) 12.00 g of sucrose (Tereos Compressuc PS) and 6.60 g of povidone (Plasdone K29 / 32 from ISP) are introduced with magnetic stirring in the glass bottle 250 ml containing 136.1 g of insulin solution associated with pGlu-VE 100-20, prepared previously. Once sucrose crystals and povidone powder dissolved, the The solution is sprayed onto 38.00 g of cellulose spheres (Asahi Kasei) in an air bed fluidized MiniGlatt in a bottom spray configuration (spraying the solution coating via a nozzle located in the lower part of the bed of particles). After spraying, the product obtained is sieved on a sieve of 630 m. 66.2 g of granules, size less than 630 m, are then recovered.

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37 PCT / FR2009 / 051495 Their mean diameter by volume, determined by laser diffraction using a Mastersizer 2000 instrument from Malvern Instrument equipped with dry path module Sirocco 2000, is 535 m.
580 mg of granules are introduced into a beaker containing 100 ml of medium 0.05 M potassium phosphate at pH = 7.0, so as to obtain a concentration in POM polymer in the suspension equal to 1 mg / ml. The suspension is agitated by a bar magnet for 2 hours at room temperature. 10 ml of the suspension are then taken and filtered on 0.45 pore size Acrodisc filters m. The diameter hydrodynamics of nanoparticles, determined in diffusion intensity mode of the light at an angle set at 90 with a CGS-3 from Malvern Instrument, is from 12 nm.

Step 3: coating phase 36.06 g of granules, as prepared above, are embedded in a bed of air fluidized MiniGlatt, with 7.20 g of a copolymer of methacrylic acid and acrylate of ethyl (Eudragit L100-55 from Evonik) and 4.80 g of cottonseed oil hydrogenated (Lubritab from JRS Pharma), dissolved in 108.34 g of isopropanol at 78 C. After spraying, 46.30 g of microparticles are obtained. Their average diameter in volume, determined by laser diffraction using a Mastersizer 2000 device from Malvern Instrument equipped with Sirocco 2000 dry track module, is 623 m.
Thus, 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 in step 3, is 44 m.

Example 4 In vitro dissolution tests The kinetics of in vitro release of the microparticles prepared in The example 3 is monitored at 37 ° C. for 0.5 min in 900 ml of 0.1 N HCl medium for 3 hours.
then after adjusting the pH and salinity of the medium by adding 5 N sodium hydroxide and phosphate potassium, in 900 ml of a 0.05 M medium at pH = 7.0. Dissolution tests are performed in a USP type II pallet apparatus. The speed of rotation of pallets is from 100 rpm.

WO 2010/012940

38 PCT / FR2009 / 051495 More precisely, the quantities present in the dissolution medium of free insulin, that is to say not associated with the pGlu-VE 100-20 polymer, of a part, and total insulin, that is, the free part and the part associated with polymer pGlu-VE 100-20, on the other hand, are followed over time by liquid chromatography HPLC. For this, at each sampling time, the samples of the dissolution medium are, of a analyzed directly by HPLC liquid chromatography to determine the proportion of total insulin, and, on the other hand, treated by ultrafiltration before analysis of the filtrate by HPLC to determine the free insulin portion.

The results are illustrated in Figure 2.
It is noted that the insulin released, according to Figure 2 and Table II below.
below, in the dissolution medium after adjusting the pH and salinity of the middle east predominantly associated with the pGlu-VE 100-20 polymer.
TABLE II
Hours Total insulin (%) Free insulin (%) 4,103 8 24 103 '10 * In accordance with acceptable experimental error limits Example 5 Preparation of insulin microparticles associated with a cationic polymer pGlu- VE-Arg-EA
Step 1: Preparation of the insulin combination with the polymer polyglutamate cationic grafted with 10% vitamin E, 40% arginine and 50% ethanolamine With reference to formula I, this POM polymer is characterized by:
p + q + r + s = 100, p = 10, q = 40, r = 50, and s = 0.
0.604 g of insulin (from Biocon) are introduced into a glass bottle of 250 ml.
133.3 g of polyglutamate polymer aqueous solution grafted to 10% of vitamin E, 40%
in 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 WO 2010/012940

39 PCT / FR2009 / 051495 complete insulin (ie until the insulin powder disappears no solubilized). After dissolution of insulin, a solution perfectly limpid 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 from ISP) are introduced with magnetic stirring into the bottle.
250 ml glass containing 151.18 g of insulin solution combined with polyglutamate grafted to 10% in vitamin E, 40% arginine and 50% ethanolamine, prepared previously. A
times dissolved sucrose crystals and povidone powder, the solution is sprayed on 33.0 g of cellulose spheres (from Asahi Kasei) in a fluidized air bed MiniGlatt in bottom spray configuration (spraying the coating solution via a nozzle located in the lower part of the particle bed). After spraying, product obtained is sieved on a sieve of 710 m. 37.4 g of granules, less than 710 m, are so recovered. Their average diameter by volume, determined in intensity mode by diffraction laser using a Mastersizer 2000 instrument from Malvern Instrument equipped with module Dry Sirocco 2000, is 531 m.
95.8 mg of granules are introduced into a beaker containing 20 ml of medium 0.05M phosphate at pH 6.8, so as to obtain a concentration of POM polymer in the suspension equal to 1 mg / ml. The suspension is agitated by a bar magnetized for 2 hours at room temperature. The suspension are then taken and filtered on Acrodisc filters with a pore size of 0.45 m. The Ray hydrodynamics of nanoparticles then suspended in the filtrate, determined in intensity by diffusion light at an angle set at 90 with a CGS-3 from Malvern Instrument, is of 6 nm.
Note the hydrodynamic radius of polyglutamate nanoparticles grafted to 10% vitamin E, 40% arginine and 50% ethanolamine, before association with insulin and determined by light scattering at an angle set at 90 to using a CGS-3 instrument from Malvern Instrument, is 7 nm. The concentration of solution has been adjusted to 1 mg / ml POM polymer before measurement.

WO 2010/012940

40 PCT / FR2009 / 051495 Step 3: coating phase 30.0 g of granules, as prepared above, are embedded in a bed of air fluidized MiniGlatt, with 2.0 g of a methacrylic acid copolymer and ethyl acrylate (Eudragit L100-55 from Evonik), 4.0 g of a methacrylic acid copolymer and methyl methacrylate (Eudragit S100 from Evonik) and 4.0 g of cotton hydrogenated (Lubritab from JRS Pharma), dissolved in 90.47 g of isopropanol C. After spraying, 39.7 g of microparticles are obtained. Their average diameter in volume, determined by laser diffraction using a Mastersizer 2000 device from Malvern Instrument equipped with Scirocco 2000 dry track module, is 588 m.
Thus, 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 in step 3, is 28.5 m.
Example 6 In vitro dissolution tests The kinetics of in vitro release of the microparticles prepared in example 5 is monitored at 37 ° C., 0.5 ° C. in 500 ml of a HCl medium for 1 hour then after adjusting the pH and salinity of the medium by adding 5N sodium hydroxide and phosphate potassium, in 500 ml of a 0.05M medium at pH 6.8. Each of the samples from middle of dissolution are analyzed directly by HPLC liquid chromatography to of determine the proportion of insulin dissolved in the dissolution medium.
The tests of dissolution are carried out in a pallet USP type II. Speed rotation of pallets is 100 rpm.

The results are illustrated in Figure 3.
It is noted that the entire dose of insulin is released into the dissolution medium after adjustment of pH and salinity of the medium.

WO 2010/012940

41 PCT / FR2009 / 051495 Example 7 Preparation of microparticles of carvedilol base associated with a polymer pGlu-VE
Step 1: Preparation of the combination of carvedilol base with the polymer pGlu VE grafted with 10% vitamin E
With reference to formula I, this POM polymer is characterized by:
p + q + r + s = 100, p = 10, q = 0, r = 0, and s = 90.
1.01 g of carvedilol base are introduced into a 250 ml glass flask.
151.2 g of aqueous solution of polyglutamate polymer grafted with 10% vitamin E, pH 6.9 and concentrated at 52.8 mg / g, are added. The preparation is placed in a bath ultrasound to ambient temperature until complete dissolution of carvedilol base (ie to say up disappearance of carvedilol powder unsolubilized base). After dissolution Carvedilol base, a perfectly clear solution is obtained.

Step 2: preparation of the granules (coating step) 4.00 g of sucrose (Tereos Compressum PS) and 3.03 g of povidone (Plasdone K29 / 32 from ISP) are introduced with magnetic stirring into the bottle.
250 ml glass containing 152.2 g of carvedilol base solution combined with polyglutamate grafted to 10% of vitamin E, prepared previously. Once the sucrose crystals and the powder povidone dissolved, the solution is sprayed onto 30.0 g of spheres of cellulose (from Asahi Kasei) in a fluidized MiniGlatt air bed in a bottom configuration spray (spraying the coating solution via a nozzle located in the part lower bed of particles). After spraying, the product obtained is sieved on a sieve from 630 m.
46.0 g of granules, less than 630 m, are then recovered. Their diameter medium in volume, determined by laser diffraction using a Mastersizer device 2000 from Malvern Instrument equipped with Sirocco 2000 dry track module, is 497 m.
300 mg of granules are introduced into a beaker containing 50 ml of medium 0.05M phosphate at pH 6.8, so as to obtain a concentration of POM polymer in the suspension equal to 1 mg / ml. The suspension is agitated by a bar magnetized for 2 hours at room temperature. 10 ml of the suspension are then collected and filtered on Acrodisc filters with a pore size of 0.45 m. The Ray hydrodynamics of the nanoparticles then in suspension in the filtrate, determined in mode WO 2010/012940

42 PCT / FR2009 / 051495 intensity by scattering light at an angle set at 90 using a CGS-3 device from Malvern Instrument, is 18 nm.

Step 3: coating phase 36.00 g of granules, as prepared above, are embedded in a bed of air fluidized MiniGlatt, with 3.85 g of a methacrylic acid copolymer and ethyl acrylate (Eudragit L100-55 from Evonik), 2.17 g of a methacrylic acid copolymer and of methyl methacrylate (Eudragit S 100 from Evonik) and 6.00 g of seed oil of cotton hydrogenated (Lubritab from JRS Pharma), dissolved in 108.78 g of isopropanol vs.
After spraying, 44.8 g of microparticles are obtained. Their diameter medium in volume, determined by laser diffraction using a Mastersizer device 2000 from Malvern Instrument equipped with Sirocco 2000 dry track module, is 571 m.
Thus, 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 in step 3, is 37 m.
Example 8 In vitro dissolution tests The kinetics of in vitro release of the microparticles prepared in example 7 is monitored at 37 ° C., 0.5 ° C. by UV spectrometry, in 900 ml of 0.1 N HCl.
during 3 hours and then, after adjusting the pH and the salinity of the medium, to pH 6.8 and 0.05M from potassium phosphate. The dissolution tests are carried out in a pallet machine USP type II. The rotation speed of the pallets is 100 rpm.
The profiles obtained are shown in FIG.
It is noted that carvedilol base is released entirely in the medium of dissolution after adjusting the pH and salinity of the medium.

Claims (44)

1. Microparticulate oral form, useful for conditioning at least an active principle and the in vivo release of this active ingredient according to a release profile pH and / or time-dependent regulation, comprising at least microparticles having a heart containing at least said active ingredient and coated with at least a diaper coating method conditioning said release profile of said active ingredient characterized in that than :
the coating layer is formed of a material comprising at least one polymer A having a solubilization pH value within 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 less part non-covalently associated with nanoparticles formed from minus one POM polymer, said polymer comprising a hydrophilic hydrocarbon chain wearing one or more hydrophobic groups (G) or a hydrocarbon chain amphiphilic. An oral form according to claim 1, wherein said POM polymer is able to form spontaneously when it is dispersed in a medium aqueous and especially water, nanoparticles. 3. Oral form according to claim 1 or 2, wherein the nanoparticles non-covalently associated with said active ingredient are implemented under a supported form. 4. Oral form according to any one of the preceding claims, in the size of the microparticles is less than 2000 μm, in particular ranges from 100 to 1000 μm, in particular from 100 to 800 μm and in particular from 100 to 500 μm. 5. Oral form according to any one of the preceding claims, in which the size of the nanoparticles varies 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. Oral form according to any one of the preceding claims, in which which the coating layer has a greater average thickness or equal to 25 μm, preferably greater than or equal to 30 μm, or even greater or equal to 35 μm. 7. Oral form according to any one of the preceding claims, when present in the intestine or an assimilable medium, to be released in less than 24 hours, especially in less than 12 hours, especially in less than 6 hours in especially less than 2 hours or even less than 1 hour nanoparticles that it contains. 8. Oral form according to any one of the preceding claims, in which the hydrocarbon chain is selected from the group consisting of polyamino acids, anionic polysaccharides such as dextran sulfate, carboxymethylcellulose, gum arabic, hyaluronic acid and its derivatives, polygalacturonic, polyglucuronic, or cationic polysaccharides such as chitosan, or also collagen and its gelatin derivatives. 9. Oral form according to any one of the preceding claims, in which the hydrocarbon chain is represented by a polyamino acid, linear to chained .alpha.-peptide. 10. Oral form according to any one of the preceding claims in wherein the POM polymer is a polyamino acid comprising at least two types of recurring amino acids AAN and AAI:
the type AAN corresponding to a hydrophobic neutral amino acid, the AAI type corresponding to an amino acid with an ionizable side chain, with less a part of the AAI-type recurring amino acids being in ionized form, the recurring amino acids of each type AAN and AAI being identical or different from each other, and the molar mass by weight of said polyamino acid being greater than or equal to at 2500 D, in particular greater than or equal to 4000 D, preferably greater than or equal to 5000 D. 11. Oral form according to any one of claims 1 to 9 wherein the POM polymer is a polyamino acid formed of aspartic acid units and / or acid glutamic, at least a part of these units being graft carriers with minus one hydrophobic group (G). 12. Oral form according to any one of claims 1 to 9 and 11, in which hydrocarbon chain consists of a homopolymer of alpha-L-glutamate or alpha-L-glutamic acid. 13. Oral form according to any one of claims 1 to 9 and 11, in which hydrocarbon chain consists of a homopolymer of alpha-L-aspartate or of alpha-L-aspartic acid. 14. Oral form according to any one of claims 1 to 9 and 11, in which the hydrocarbon chain consists of a copolymer alpha-L-aspartate / alpha-L-glutamate or alpha-L-aspartic acid / alpha-L
glutamic. 15. Oral form according to any one of claims 1 to 9 and 11 or 12, wherein the POM polymer is a polyhydroxyalkylglutamine comprising at least less a multiplicity of pendant hydrophobic groups (G), which are identical or different. 16. Oral form according to any one of claims 1 to 9 and 11, 12 or 13, characterized in that it comprises as POM polymer at least one composed of following formula (I) or a pharmaceutically acceptable salt thereof, in which :
~ A represents independently:
- RNH- in which R represents an H, a linear C2-C10 alkyl, branched C 3 -C 10 alkyl or benzyl, a terminal amino acid residue of formula:

in which -R7 is -OH, -OR9 or -NHR10, and R8, R9 and R10 independently represent H, linear alkyl in C2 to C10, branched C3 to C10 alkyl or benzyl;

~ B is a direct bond, a divalent, trivalent or tetravalent, preferably selected from:

-O-, -NH-, -N (C1-5 alkyl) -, an amino acid residue, diol, triol, diamine, triamine, aminoalcohol or hydroxy acid having from 1 to 6 carbon atoms;
D is H, linear C 2 -C 10 acyl, branched C 3 acyl C10, or pyroglutamate;
the hydrophobic groups G each independently of one another are chosen from:

.cndot. linear or branched C8 to C30 alkyls which may comprise optionally at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or .cndot. C8 to C30 alkylaryls or arylalkyls which may comprise optionally at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or .cndot. the (poly) cyclic C8 to C30 may optionally include minus one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S);
and preferably one are selected from the following group: octyloxy-, dodecyloxy-, tetradecyloxy-, hexadecyloxy-, octadecyloxy, 9-octadecenyloxy-, tocopheryloxy- or cholesteryloxy-, B being then a direct connection;
~ R1 is selected from the following group:

-NH- (CH 2) w -NH 3 +, Z- with w between 2 and 6, and preferably w is equal to 4, -NH- (CH2) 4-NH-C (= NH) -NH3 +, Z-, -O- (CH 2) 2 -NH 3 +, Z, -O- (CH 2) 2 -N + (CH 3) 3, Z-, an amino acid residue or an amino acid derivative of formula:

in which :

X is an oxygen atom or a -NH-, R12 is H, C2 to C10 linear alkyl, C3 to C10 branched alkyl or benzyl, -R13 is - (CH2) 4-NH3 +, Z-, - (CH2) 3 -NH-C (= NH) -NH3 +, Z-, - (CH2) 3-NH3 +, Z-;
in which the counteranion Z- is a chloride, a sulfate, a phosphate or an acetate, preferably a chloride;

~ R3 represents a hydroxyethylamino-, a dihydroxypropylamino, a alkylene glycol residue, a polyoxyalkylene glycol or a group of formula :

where -R10 is -H, -CO2H, an alkyl ester (preferably -COOMe or -COOEt), -CH2OH, -C (= O) -NH2, -C (= O) -NH-CH3 or -C (= O) -N (CH3) 2;
~ p, q, r and s are positive integers with q, r and s can be furthermore void;
~ (p + q + r + s) varies from 10 to 1000, in particular from 20 to 500, and preferably from 30 to 500;
~ the molar grafting rate of the hydrophobic groups G, (p) / (p + q + r + s) varies from 2 to 99 mol%, and preferably between 3 and 50% under condition that each copolymer chain has at least 2 and preferably at least minus 3 hydrophobic groups;

~ the molar grafting rate 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 load rate of the chain Q = (qs) / (p + q + r + s) can be positive or negative;
the sequence of the monomers of said general formula I which can be random, type monobloc, or multiblock. 17. Oral form according to the preceding claim wherein ~ A represents -NH2 ~ B is a direct link, 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 R3 represents hydroxyethylamino- or dihydroxypropylamino. 18. Oral form according to claim 16 or 17 wherein:
~ (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 = (qs) / (p + q + r + s) when it is positive, is between + 20% and + 60 %
and when negative is less than - 20%. 19. Oral form according to claim 16 or 17 wherein ~ (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 between 10 and 80%, and preferably between 10 and 60 %
~ (r) / (p + q + r + s) is greater than or equal to 10%;
~ (s) / (p + q + r + s) is less than 15%; 20. Oral form according to claim 16 or 17 wherein ~ (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 less than 5%;
~ (s) / (p + q + r + s) is greater than 10%;
Q = (qs) / (p + q + r + s) is when it is positive between + 20% and + 60 %;
and when negative is less than - 20%. 21. Oral form according to claim 16 or 17 wherein ~ (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 less than 1 and ~ (r) / (p + q + r + s) is less than 1%. 22. Oral form according to claim 16 or 17 or 21, wherein the ratio (p) / (p + q + r + s) varies between 15 and 25%;
~ (q) / (p + q + r + s) is less than 1 and ~ (r) / (p + q + r + s) is less than 1%
~ and the degree of polymerization is between 150 and 250 or 70 and 130. 23. Oral form according to any one of claims 1 to 9 and 11 to 22 in which at least one and preferably all the groups G
include a tocopheryloxy group. 24. Oral form according to any one of the preceding claims, characterized in that the POM polymer has a degree of polymerization DP
understood between 10 and 1000, 30 and 500 and more particularly between 50 and 250. 25. Oral form according to any one of the preceding claims, characterized in that the POM carries at least one graft of the type polyalkylene glycol bound to a glutamate and / or aspartate unit. 26. Oral form according to the preceding claim, wherein the polyalkylene glycol is a polyethylene glycol and more particularly work with a molar percentage of grafting polyethylene glycol ranging from 1 to 30%. 27. Oral form according to any one of the preceding claims, in wherein the polymer A is selected from the acid copolymer (s) methacrylic and methyl methacrylate, the copolymer (s) of methacrylic acid and of ethyl acrylate, cellulose derivatives such as acetate phthalate cellulose, acetate succinate cellulose, cellulose trimellilate acetate, phthalate hydroxypropylmethylcellulose, hydroxypropyl methylcellulose acetate succinate, shellac gum, phthalate acetate polyvinyl and mixtures thereof. 28. Oral form according to any one of the preceding claims, in which the coating of the microparticles contains from 25 to 90% by weight, including 30% to 80% by weight, in particular 35% to 70% by weight, or even 40 to 60% by weight % of polymer (s) A with respect to its total weight. 29. Oral form according to any one of the preceding claims, in which the hydrophobic compound B is selected from the products crystallized in the state solid, and having a melting temperature Tfb> = 40 ° C, of preferably Tfb> = 50 ° C, and more preferably still 40 ° C> = Tfb> = 90 ° C. 30. Oral form according to the preceding claim, wherein the compound B
is chosen from among:

- vegetable waxes;

- hydrogenated vegetable oils taken alone or as a mixture between they, of preferably selected from the group consisting of: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil;

mono and / or di and / or tri esters of glycerol and of at least one fatty acid, preference Behenic acid, taken alone;

- and their mixtures. 31. Oral form according to any one of claims 1 to 28, in which compound B is a polymer insoluble in gastric fluids Intestinal. 32. Oral form according to the preceding claim wherein said polymer B is selected from:

non-water-soluble derivatives of cellulose and more particularly cellulose acetate butyrate, cellulose acetate, - non-water-soluble derivatives of (meth) acrylic (co) polymers and more especially the (co) polymer of ethyl acrylate, methacrylate methyl and Trimethylammonioethyl methacrylate type A or type B, and esters poly (meth) acrylic acids. 33. Oral form according to any one of the preceding claims, in which the active ingredient is a molecule of therapeutic interest or cosmetic. 34. Oral form according to any one of the preceding claims, in which the active ingredient is a protein, a glycoprotein, a polysaccharide, a liposaccharide, an oligonucleotide, a polynucleotide or a peptide. 35. Oral form according to any one of the preceding claims, in which active ingredient is insulin. 36. Oral form according to any one of the preceding claims comprising at least two types of nanoparticles, said nanoparticles differentiating by the nature of the active ingredient and / or the POM associated with said active ingredients. 37. Oral form according to any one of the preceding claims combining at least two types of microparticles differing from each other the other from the nature of their coating layer and / or the active ingredient they incorporate. 38. Oral form according to any one of the preceding claims formulated as a powder, a suspension, or in the form of a tablet or of a capsule. 39. Oral form according to any one of the preceding claims, characterized in that it is intended for the preparation of medicaments, and / or of products cosmetics. 40. Oral form according to any one of the preceding claims, to release initially the active ingredient associated with the (x) nanoparticles polymer (s) POM then to dissociate in a second time the active ingredient said nanoparticles. 41. Process for the preparation of microparticles useful for conditioning of at least one active principle and the in vivo release of this active ingredient according to a profile of regulated release according to pH and / or time, said microparticles possessing a heart containing at least said active ingredient and coated with at least one layer coating conditioning said release profile of said asset, said method comprising at least steps of:

a) having at least one active ingredient associated non-covalently with of the nanoparticles formed of at least one POM polymer comprising a chain Hydrophilic hydrocarbon bearing one or more hydrophobic groups (G) or comprising an amphiphilic hydrocarbon chain, b) forming from the nanoparticles of step a) a core comprising said nanoparticles and one or more excipients, c) forming from at least one polymer A having a pH value of solubilization in the pH range of 5 to 7 and at least one compound B
hydrophobic, a coating layer disposed around the core formed in step b), and d) recover the expected microparticles. 42. The method according to the preceding claim wherein step c) is carried out by fluidised air bed spraying on the nanoparticles of step b) at least a polymer A having a pH value of solubilization included in the pH range from 5 to 7 combined with at least one hydrophobic compound B. The method of claim 41 or 42, wherein the particles of step a) are as defined in claims 2 to 26. 44. The method of any one of claims 40 to 43 wherein the Polymer A and Compound B are as defined in Claims 27 to 32.