Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5089—Processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
  • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the present invention relates mainly to particles coated at least partially on the surface with hyaluronan or derivative and the use of these particles with title of biological vectors for active ingredients.
• Vectorization is an operation aimed at modulating and if possible completely controlling the distribution of a substance, by associating it with an appropriate system called a vector.
• the in vivo fate of the vector is conditioned by its size, its physicochemical characteristics and, in particular, its surface properties which, on the one hand play a determining role with the components of the biological medium and, on the other share can induce targeted behavior towards a specific site to be treated.
• Biological vectors more particularly concerned in the context of the present invention, belong to the field of particles, in particular nano- and microparticles.
• PLA poly (lactic acid)
• biodegradable polyester whose degradation products are natural metabolites of a human organism
• the hydrophobic nature of the surface of these particles as well as the presence of carboxylate groups (ends of the PLA chains) cause adsorption of plasma proteins, the opsonins, responsible in particular for the capture of the particles by the cells of the Phagocyte System. Mononuclear (SPM). This results in a rapid disappearance of particles from the circulating volume at the same time as an accumulation in the organs of PMS (liver, spleen, kidneys).
• SPM Mononuclear
• the object of the present invention is in particular to propose new particles having an extended lifespan and which are particularly advantageous for conveying biological or synthetic active materials which are advantageous in the field of rheumatology.
• the practitioner is often confronted with inflammatory and / or degenerative pathologies which generate, in the more or less long term, sometimes irreversible degradations of the cartilage.
• corticosteroids can be used, among others.
• the high doses of corticosteroids used in this scenario can, however, induce significant side effects.
• the present invention aims in particular to propose a particle type vector which, on the one hand is biodegradable and suitable for the controlled release of an active material and, on the other hand is capable of effectively targeting the release of this active ingredient at the level of tissue cells and more particularly cells possessing specific receptors for hyaluronans, also called CD44.
• Chondrocytes are cells involved in the synthesis of the cartilage matrix. They also manage the maintenance of cartilage homeostasis.
• Synoviocytes which are cells located in the synovial membrane, are involved in the synthesis of hyaluronan in synovial fluid.
• a first aspect of the invention therefore relates to particles the core of which is based on at least one biodegradable organosoluble polymer, characterized in that they are coated, at least partially on the surface, with at least one hyaluronan or one of its derivatives.
• Hyaluronic acid is a natural polysaccharide constituted by a succession of disaccharide units N-acetylglucosamine / glucuronic acid and whose aqueous solutions have a high viscosity. It is present in particular in the umbilical cord, in the vitreous humor and in the synovial fluid. It is also produced by certain bacteria, in particular by hemolytic streptococci from groups A and C.
• the molar mass of hyaluronic acid can vary from 10,000 to 10,000,000 g approximately, depending on the origin.
• Hyaluronic acid is sold in particular in the form of its sodium salt (also called hyaluronate).
• hyaluronan is used to denote hyaluronic acid and hyaluronates without distinction, in particular in the form of inorganic or organic salts and in particular the alkaline and / or alkaline earth salts.
• this hyaluronan is used in the form of an amphiphilic, water-soluble hyaluronan, the carboxylic functions of which are partly transformed so as to represent hydrophobic groups.
• the fixing of these hydrophobic groups can in particular be established by reaction of these with the carboxylic functions of the hyaluronate according to an esterification or amidation reaction. This transformation is carried out at a rate sufficient to confer amphiphilic behavior on said hyaluronan.
• the hydrophobic groups can in particular derive from the esterification of the carboxylic functions by at least one group chosen from: alkyl chains, linear or branched, saturated or unsaturated, which can be interrupted by one or more heteroatoms such as the atoms of S, O and N , and where appropriate, substituted by at least one aromatic ring, and oligomers such as those derived from ⁇ -hydroxy acids.
• the alkyl chains can have a number of carbon atoms greater than 5 and in particular greater than 10. However, in the particular case where such a chain is substituted by an aromatic ring, its number of carbon atoms can be reduced.
• the transformation rate is generally adjusted so as to preserve sufficient water-solubility for the amphiphilic hyaluronan derivative thus obtained.
• the longer the chain the lower the rate of fixation in the hyaluronan skeleton.
• the rate of attachment may be higher. It is clear that this adjustment between the rate of attachment and the length of the alkyl chains falls within the competence of a person skilled in the art.
• the rate of esterification can be at most 15%, or even less than 10% and, in particular less than 7% and in particular between 0.05 and 5%.
• this esterification rate can be greater than or equal to 25% and for an alkyl chain of 6 carbon atoms, it can be around 50%.
• This transformation rate is generally adjusted so as to allow the hyaluronan derivative to be fixed on the surface of the particles thanks to the interaction of its hydrophobic groups with the hydrophobic polymer matrix constituting the particles.
• the alkyl chains are anchored in the hydrophobic matrix during the formation of the particles.
• the functionalization at the surface of the particles by hyaluronan does not involve a covalent or ionic bond between these two entities.
• the binding of the hyaluronan derivative essentially comes from hydrophobic and Nan der Waals interactions.
• the transformation rate is also adjusted so as not to affect the natural affinity of hyaluronan for CD44 receptors.
• hyaluronan on the surface of particles is particularly advantageous for directing them selectively towards the CD44 receptors present in particular on the cells of the articular sphere.
• the particles according to the invention used as a biological vector for a biological or synthetic active material advantageously make it possible to effectively target the release of this active material at the level of cells with CD44 receptors, for example chondrocytes and / or synoviocytes. This results in a controlled and prolonged action of this active material at the level of the target lesion.
• This last aspect is particularly interesting for the well-being of the patient, insofar as it gives access to better availability of the drug and therefore makes it possible to reduce the quantities administered and their frequency of administration.
• the biodegradability of the claimed particles is also ensured thanks to the nature of the polymers which constitute them.
• biodegradable is intended to denote any polymer which dissolves or degrades in a period acceptable for the application for which it is intended, usually in in vivo therapy. Generally, this period must be less than 5 years and more preferably one year when a corresponding physiological solution is exposed to a pH of 6 to 8 and at a temperature between 25 ° C and 37 ° C.
• biodegradable polymers according to the invention are or are derived from synthetic or natural biodegradable polymers.
• organosoluble biodegradable polymers which can be used to constitute the core of the particles, they can in particular be chosen from polyesters such as poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly ( ⁇ -caprolactone) (PCL) , polyanhydrides, poly (alkylcyanoacrylates), polyorthoesters, poly (alkylene tartrate), polyphosphazenes, polyamino acids, polyamidoamines, polycarbonates, polymethylidenemalonate, polysiloxane, polyhydroxybutyrate or ⁇ oly (malic acid), as well as their copolymers and derivatives.
• polyesters such as poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly ( ⁇ -caprolactone) (PCL) , polyanhydrides, poly (alkylcyanoacrylates), polyorthoesters, poly (alkylene tartrate), polyphosphazenes, polyamino acids, polyamidoamine
• the claimed particles have a polymer matrix incorporating at least one polymer different from hyaluronan. More preferably, this matrix consists of one or more polymers other than hyaluronan.
• Polyesters such as poly (lactic acid), poly (glycolic acid), poly ( ⁇ -caprolactone), and their copolymers, such as poly (lactic acid-co- glycolic acid) (PLGA).
• the particles are mainly composed, that is to say more than 50% by weight, in particular more than 75% by weight, or even entirely, of poly (lactic acid).
• the particles according to the invention preferably comprise at least one biological or synthetic active material of the drug type in a form encapsulated in the polymer core.
• biological active materials mention may more particularly be made of peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides or their mixtures. It can also be synthetic organic or inorganic molecules, which, administered in vivo to an animal or to a patient, are capable of inducing a biological effect and / or manifesting therapeutic activity. It can thus be antigens, enzymes, hormones, receptors, vitamins and / or minerals.
• anti-inflammatory compounds include anesthetics, chemotherapeutic agents, immunotoxins, immunosuppressive agents, steroids, antibiotics, antivirals, antifungals, antiparasitics, vaccinating substances, immunomodulators and analgesics.
• the particles according to the invention are advantageously targeted towards cells with a tissue structure such as, for example, chondrocytes and synoviocytes
• the following compounds may be used as active materials: anti-inflammatories, matrix components like for example glycosaminoglycans and biological factors involved in the process of regeneration and / or protection of cartilage.
• anti-inflammatories matrix components like for example glycosaminoglycans and biological factors involved in the process of regeneration and / or protection of cartilage.
• Particular advantages of particles are that they effectively protect this type of active material which is particularly sensitive to the phenomenon of biodegradation.
• They may also be biological compounds which are more particularly active with regard to osteoarthritis, such as, for example, the glucosamine of glycosaminoglycans, hyaluronic acid, chondroitin sulfate and their mixtures.
• the particles in accordance with the invention can comprise up to 95% by weight of an active material.
• the active ingredient can thus be present in an amount varying from 0.001 to
• the particles according to the invention can have a size varying from 50 nm to 600 ⁇ m and in particular from 80 nm to 250 ⁇ m.
• the particles according to the invention having a size between 1 and 1000 nm are called nanoparticles.
• Particles ranging in size from 1 to several thousand microns refer to microparticles.
• the particles are generally in spherical form, but can also occur in other forms.
• the claimed nanoparticles or microparticles can be prepared according to methods already described in the literature, and more particularly can be obtained by the solvent emulsion / evaporation technique and in particular that described by R. Gurny et al. "Development of biodegradable and injectable latices for controlled release ofpotent drugs” Drug Dev. Ind. Pharm., Vol. 7, p. 1-25 1981.
• amphiphilic hyaluronans could advantageously be used in place of conventional surfactants for the preparation of particles according to the emulsion / solvent evaporation technique.
• two variants of this technique are considered according to the hydrophobic or hydrophilic nature of the active material to be encapsulated.
• a simple emulsion is prepared.
• the selected biodegradable polymer is dissolved in the organic phase, in particular a solvent poorly soluble in water such as, for example, methylene chloride or ethyl acetate, with the active material to be encapsulated.
• the amphiphilic hyaluronan for its part, is dissolved in the aqueous phase which serves as a dispersing medium for the organic phase.
• the hyaluronan derivative After mixing these two phases, the hyaluronan derivative is localized at the water / organic phase interface thanks to its amphiphilic properties and thus stabilizes the emulsion.
• the amphiphilic derivatives of hyaluronan advantageously remain attached to the surface of the particles thus formed, the hydrophobic groups being anchored more or less deeply in the core of organosoluble polymer forming the particles and the hydrophilic part, corresponding mainly to the hyaluronan skeleton, being exposed on the surface.
• particles conforming to the invention At the end of the evaporation of the solvent, particles conforming to the invention which are then washed with water, centrifuged or lyophilized.
• a first oil-in-water type emulsion is prepared, composed of an organic phase containing the biodegradable organosoluble polymer and of a first phase aqueous containing the active ingredient.
• This so-called inverted emulsion is then placed in the presence of a second aqueous phase containing the amphiphilic hyaluronan derivative so as to obtain a double water / oil / water emulsion vis-à-vis which the amphiphilic hyaluronan plays the role of stabilizer.
• particles are recovered in accordance with the present invention which are treated as above.
• the conditions used during the preparation of the emulsions generally determine the size of the particles and their adjustment is within the competence of a person skilled in the art.
• the use of a hyaluronan derivative as a stabilizing agent in this type of process for preparing particles is therefore particularly advantageous in at least two respects: it makes it possible to dispense with the presence of surfactants systematically used in the processes conventional. In this case, the latter are not always biocompatible and sometimes difficult to eliminate at the end of the synthesis; at the end of the synthesis of the particles, it leads to a vector manifesting a selective affinity for cells of tissue structure and more particularly for cells of the articular sphere and in particular for chondrocytes and synoviocytes.
• the concentration of hyaluronan in the particle synthesis medium determines the recovery rate of the particles, that is to say the amount of hyaluronan deposited on their surface.
• the hyaluronan derivative is generally distributed homogeneously on the surface of the particles with a surface density which can vary significantly. It is also possible to incorporate into the particles, compounds for diagnostic purposes. It can thus be substances detectable by X-rays, fluorescence, ultrasound, nuclear magnetic resonance or radioactivity. Particles can thus include magnetic particles, radio-opaque materials, such as barium or fluorescent compounds. Alternatively, gamma emitters (for example Indium or Technetium) can be incorporated.
• the active ingredient is preferably incorporated into these particles during their formation process. However, when this proves possible, it can also be charged at the level of the particles once these are obtained.
• the particles according to the invention can be administered in different ways, for example by oral or parenteral route and in particular by intra-articular, ocular, pulmonary, nasal, vaginal, cutaneous and / or buccal routes.
• marker type molecules and compounds capable of potentiating the targeting function provided by hyaluronan such as for example RGD peptides (arginine glycine - aspartic acid) which promote adhesion between cells and their extracellular matrices.
• a second aspect of the invention relates to a biological vector in particular for one or more active (s) biological (s) or synthetic (s) material comprising at least particles according to the invention.
• the invention also relates to the use of this vector, or of the particles claimed for encapsulating at least one active, biological or synthetic material.
• compositions comprising at least one vector and in particular particles according to the invention, if appropriate associated (s) with at least one pharmaceutically acceptable and compatible vehicle.
• the particles claimed are particularly advantageous from the pharmaceutical or diagnostic point of view. They provide satisfactory protection of the encapsulated active material. They limit the diffusion of this active ingredient in the body thanks to the steric effect of the particles per se and to the natural affinity of hyaluronan for CD44 receptors. They allow a gradual release of this active substance near the lesion and / or the targeted cells, thus allowing a prolonged action. Finally, they slowly degrade into products that are well tolerated by the body.
• Another aspect of the present invention relates to the use of particles as defined above see of a biological vector by incorporating for the preparation of a pharmaceutical composition intended for the treatment of osteoarthritis.
• the particles can also be incorporated into capsules, or incorporated into implants, gels or tablets. They can also be formulated directly in an oil-type fluid for example and be injected directly at the biological site to be treated.
• Another aspect of the invention relates to the use of hyaluronan or amphiphilic derivative as defined above as targeting agent on the surface of particles, in particular consisting of at least one biodegradable polymer or capsules, in particular hollow.
• particles or capsules can in particular be nano- or micro-spheres or nano- or micro-particles.
• FIGURES are a diagrammatic representation of FIGURES.
• Figure 1 Representation of cell proliferation of rat chondrocytes cultured in a monolayer system after 48 h of treatment in the presence of nanoparticles based on PLA (control) and PLA coated with amphiphilic hyaluronan.
• Figure 2 Representation of cell proliferation and proteoglycan synthesis activity, of chondrocytes cultured on alginate beads (three-dimensional culture) after 48 hours of treatment in the presence of nanoparticles based on PLA (control) and PLA coated with amphiphilic hyaluronan .
• a derivative of sodium hyaluronate is thus obtained, of which approximately 4% of the carboxylic functions are esterified by chains with 18 carbons.
• the protocol for the synthesis of particles covered with amphiphilic hyaluronate HA-C 18 -1.3% that is to say a polymer containing 1.3 alkyl chains with 18 carbons, is given below. for 100 glucose reasons.
• the aqueous suspension of particles thus obtained is washed with water by 3 successive centrifugations of 10 min at 12,000 rpm.
• the particles obtained under these conditions have an average diameter of 450 nm
• Chondrocytes (cartilage cells) of rats obtained after digestion of cartilage fragments by pronase and by collagenase, are cultured in DMEM (Gibco BRL, RU) in the presence of particles obtained according to example 1. Two systems are used:
• the chondrocytes are distributed in 24-well culture plates at the rate of approximately 100,000 chondrocytes per well.
• a suspension of nanoparticles covered with amphiphilic HA and synthesized according to Example 1, is prepared in the DMEM culture medium so as to have on average approximately 10 7 particles per ml. 1 ml of this suspension is brought into contact with the chondrocytes in the culture wells, which gives an average ratio of approximately 100 particles per chondrocyte. Contact is maintained for 48 h.
• FIG. 1 shows that after this 48 h contact with particles covered with amphiphilic HA substituted at different rates by chains with 18 or 12 carbon atoms, the viability and proliferation of the chondrocytes are similar to those obtained with the control.
• Figure 2 shows that contact with nanospheres covered with amphiphilic HA substituted at different rates by chains with 18 or 12 carbon atoms, does not significantly disturb the proliferation and metabolic activity of chondrocytes in this environment.

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