Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/145—Hydrogels or hydrocolloids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/26—Mixtures of macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/52—Hydrogels or hydrocolloids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/04—Macromolecular materials
  • A61L31/041—Mixtures of macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/30—Joints
  • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
  • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
  • A61F2002/3006—Properties of materials and coating materials
  • A61F2002/30107—Properties of materials and coating materials using materials or accessories for preventing galvanic or electrolytic corrosion
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
  • A61F2210/0009—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using materials or accessories for preventing galvanic or electrolytic corrosion

Definitions

• Biphasic injectable compositions in particular useful in reconstructive and cosmetic surgeries
• the main object of the present invention is injectable biphasic compositions, in particular useful in reconstructive and cosmetic surgeries. More specifically, its purpose is:
• compositions comprising a dispersed phase suspended in a continuous phase
• the present invention provides in particular a satisfactory solution to the technical problem of lasting filling of skin volume defects, such as wrinkles or scars, in particular on the face.
• EP-A-0 406 375 an alloplastic implant, based on a histocompatible solid; said solid, pulverulent, consisting of solid particles with a diameter on average of between 10 ⁇ m and 200 ⁇ m, and which have a smooth surface, free of angles and edges.
• Said product commercialized under the trademark Artecoll ®, consists of microspheres polymethacrylate (PMMA), suspended in a collagen solution;
• EP-A-0 466 300 a viscoelastic gel comprising a gelatinous phase (having undergone crosslinking at a low rate) dispersed in a liquid phase (not having undergone crosslinking); said two phases having advantageously been prepared from Hylan fibers (natural hyaluronic acid chemically modified in situ in order to facilitate its extraction from the tissues);
• a product, of the biphasic composition type, would also be under evaluation in the United States. It mainly consists of silicone beads, dispersed in a solution of polyvinylpyrrolidone. It is incidentally noted here that the documents EP-A-826,381,
• FR-A-2 568 127, US-A-4 657 553 and US-A-4 563 490 do not describe biphasic compositions.
• the Applicants propose a new type of biphasic composition, which is particularly effective.
• the biocompatible two-phase composition of the type of the invention therefore comprises a dispersed phase suspended in a continuous phase and, typically, said dispersed phase consists of particles of at least one hydrogel of a (co) polymer obtained by polymerization and crosslinking acrylic acid and / or methacrylic acid and / or at least one derivative of said acids.
• the biphasic compositions of the invention are injectable compositions. They were formulated with this in mind. It is in particular for this purpose that they contain a continuous phase; said phase serving as an injection vehicle for the particles of the dispersed phase.
• the qualifier injectable used in the present text, means manually injectable by means of syringes fitted with conventional needles.
• the biphasic compositions of the invention are particularly advantageous in that they can be formulated to be injectable by means of very fine needles (with a diameter of between 0.3 and 0.5 mm).
• the determining parameter is that of the largest dimension of the particles in suspension.
• the biphasic injectable compositions of the invention are very particularly intended for a dermal injection (surface, medium or deep) for implantation in the dermis.
• they are advantageously buffered at a pH of between 6.5 and 7.5, preferably between 7 and 7 , 4, even more preferably between 7.2 and 7.3.
• the two continuous and dispersed phases of said two-phase compositions are advantageously buffered at this pH.
• a phosphate buffer is generally used.
• compositions of the invention therefore comprise an original dispersed phase, as specified above, suspended in an adequate continuous phase.
• Said continuous phase must, in fact, be able to perform several functions, and in particular: a) it must maintain the dispersed phase in suspension, in a stable manner; b) it must constitute an efficient injection vehicle; c) after injection and implantation of the biphasic composition, it must advantageously protect said dispersed phase (in particular preventing it from migrating and promoting the formation of fibroblasts around its particles, which slows down its degradation).
• Said continuous phase must be sufficiently fluid to be able to be easily injected and sufficiently viscous to avoid settling of the dispersed phase.
• the compromise mentioned above can be obtained with different types of continuous phase. In the context of the invention, certain types, specified below, are widely preferred.
• an aqueous solution of at least one polymer chosen from proteins, polysaccharides and their derivatives is advantageously used, crosslinked or not.
• Said polymer depending on its nature, to perform the functions mentioned above is capable of intervening, not crosslinked, weakly crosslinked or highly crosslinked.
• polysaccharide or derivative of polysaccharide hyaluronic acid, its salts, chondroitin, keratan sulfates, heparin, l alginic acid, starch, carboxymethylcellulose, chitosan.
• hyaluronic acid its salts
• chondroitin keratan sulfates
• heparin l alginic acid
• starch carboxymethylcellulose
• an aqueous solution of a polymer chosen from hyaluronic acid, its salts and mixtures of its salts; said polymer being advantageously crosslinked.
• said continuous phase of the biphasic compositions of the invention is a hydrogel of a crosslinked polymer chosen from hyaluronic acid, its salts and mixtures of its salts; said crosslinked polymer advantageously consisting of a sodium hyaluronate.
• hyaluronic acid is used in the remainder of this text as a generic name to designate both hyaluronic acid per se and its salts or mixtures of salts, and in particular the hyaluronate salts.
• the biphasic compositions of the invention advantageously contain, in their continuous phase, as polymer chosen from hyaluronic acid, its salts and mixtures of its salts, sodium hyaluronate. It is already specified that said intervening sodium hyaluronate is advantageously of bacterial origin.
• Said hyaluronic acid (or at least one of its salts) has been more particularly chosen in view of its advantageous properties. It can in particular be obtained by the bacterial route, by the cellular route (therefore free of any contaminant of the virus or prion type). It presents at the same time a strong gelatinous character, an appreciable lubricating power, a good biocompatibility and a good behavior in the organism. It is also easily crosslinkable.
• Crosslinked it is capable of exhibiting the viscosity required in the context of the invention and, in any event, it is more resistant to degradation and to heat (the latter point is not negligible insofar as the compositions of the invention are generally sterilized in an autoclave).
• the continuous phase of the compositions of the invention is advantageously based on crosslinked hyaluronic acid. It is no longer really an aqueous solution but a hydrogel. Said hyaluronic acid has been crosslinked, conventionally, using at least one crosslinking agent.
• hyaluronic acid whose molecular mass is greater than or equal to 1 million Daltons. According to an advantageous variant, it is recommended to use a hyaluronic acid whose molecular mass is between 2 and 4 million Daltons.
• crosslinking via the hydroxy functions of hyaluronic acid, by means of a crosslinking agent (at least one), under conditions which lead to a crosslinking rate of said hyaluronic acid (material of departure) characterized by the ratio: total number of reactive functions of said crosslinking agent / total number of disaccharide units of the hyaluronic acid molecules present between 0.25 and 0.50.
• the hydrogel network which thus constitutes the continuous phase of the two-phase compositions of the invention, is based on molecules of hyaluronic acid linked by bridges of molecules of crosslinking agent; each of the disaccharide units of said hyaluronic acid molecules advantageously having between 0.25 and 0.50 of its hydroxy functions engaged in such bridges.
• crosslinking agent any agent known for crosslinking hyaluronic acid can be used through its hydroxy functions - crosslinking agent at least bifunctional - and in particular a polyepoxide or its derivatives.
• BDDE 1,4-butanediol diglycidyl ether
• the hydrogel constituting the continuous phase of the biphasic compositions of the invention, based on crosslinked hyaluronic acid, advantageously contains said crosslinked hyaluronic acid at a concentration comprised between 10 and 25 mg / g, advantageously between 15 and 25 mg / g.
• said hydrogel generally contains in fact more than 95% by weight of water ...
• hyaluronic acid from which the hydrogel constituting the continuous phase of the biphasic compositions of the invention is preferably produced, is advantageously obtained by bacterial route (rather than by extraction from tissues of animals, rooster crests and umbilical cords in particular ...) and that the intervention of a sodium hyaluronate is particularly recommended.
• the intervention of sodium hyaluronate fibers obtained by the bacterial route.
• the dispersed phase consists of particles of at least one hydrogel of a (co) polymer obtained by polymerization and crosslinking of acrylic acid and / or methacrylic acid and / or at least one derivative of said acids.
• Said particles conventionally have their more or less defined size, insofar as:
• hypodermic needles such as 30 G Vi needles which have an internal diameter of 160 ⁇ m
• they could not not suitable for filling small wrinkles ...
• hypodermic needles such as 30 G Vi needles which have an internal diameter of 160 ⁇ m
• said particles have their largest dimension between 10 and 120 ⁇ m, advantageously between 20 and 80 ⁇ m.
• the largest dimension of said particles ie their equivalent diameter
• fragments of hydrogel generally obtained by grinding a mass of hydrogel.
• the fragments constituting the dispersed phase of the compositions of the invention may in fact have completely random shapes and in particular oval, rounded, triangular, square geometries ... or even a form of rods ...
• Said particles are hydrogel particles . In this, they are in particular less traumatic than particles, PMMA type, of the prior art.
• said particles have, at equilibrium, a water content of between 10 and 40% by weight, advantageously close to 25% by weight.
• Said hydrogel is a hydrogel of a methacrylic and / or acrylic crosslinked hydrophilic polymer or copolymer. It is obtained by polymerization and crosslinking of at least one monomer chosen from acrylic acid, methacrylic acid and their derivatives.
• EMA acrylic acid methacrylic acid ethyl
• (co) (meth) acrylic polymer must be hydrophilic (to constitute said hydrogel), it is excluded that it is a polymethyl methacrylate (PMMA).
• PMMA polymethyl methacrylate
• hydrophilic (meth) acrylic (co) polymer constituting the particles of the dispersed phase of the biphasic compositions of the invention, advantageously consists of crosslinked hydroxyethyl polymethacrylate (PHEMA) or, even more advantageously, of a crosslinked copolymer:
• HEMA hydroxyethyl methacrylate
• EMA ethyl methacrylate
• said copolymer is advantageously obtained by copolymerization, per 100 parts by weight of monomers: HEMA + EMA, from 77.5 to 87.5 parts by weight (advantageously, from 80 to 85 parts by weight) of HEMA and from 12.5 to 22.5 parts by weight (advantageously from 15 to 20 parts by weight) of EMA.
• Said poly [HEMA / EMA] copolymer is. as specified above, crosslinked. Such crosslinking is essential to ensure the cohesion of the material and its stability.
• One (at least one) cross-linking agent - bifunctional - must therefore intervene, in an effective amount, during the copolymerization of the HEMA and EMA monomers.
• This effective amount - generally, at most a few parts by weight: in principle between 0.5 and 5 parts by weight, advantageously between 0.5 and 2 parts by weight, per 100 parts by weight of monomers: HEMA + EMA - must obviously remain reasonable. It is not a question of the intervening crosslinking agent constituting a comonomer and consequently modifying the properties, in particular mechanical, of the poly (HEMA / EMA) copolymer.
• crosslinking agent In any event, those skilled in the art are aware that the increase in the level of crosslinking agent involved decreases the water content of the hydrogels and increases their glass transition temperature. It is indicated here that said crosslinking agent intervenes in the structure of the copolymer, generally in an amount such that the ratio:
• crosslinking agent As regards the reactive functions of said crosslinking agent. they are advantageously acrylate and / or methacrylate functions.
• a person skilled in the art knows numerous crosslinking agents which carry such functions, and in particular: butanediol dimethacrylate and diacrylate, hexanediol dimethacrylate and diacrylate, decanediol dimethacrylate and diacrylate, ethylene glycol dimethacrylate (EDMA) ), tetraethylene glycol dimethacrylate.
• EDMA ethylene glycol dimethacrylate
• the intervention of the crosslinking agents listed above, and in particular that of EDMA is recommended in a nonlimiting manner.
• the poly (HEMA / EMA) copolymer constituting the particles of the dispersed phase of the biphasic compositions of the invention, is it crosslinked by crosslinking agents of this type (or of an equivalent type) which are obviously found trace in its skeleton.
• Said poly (HEMA / EMA) copolymer is prepared, in a manner known per se, by copolymerization of a mixture of HEMA and EMA monomers in the presence of effective amounts of at least one polymerization initiator and at least one crosslinking agent .
• crosslinking agent there is an effective amount (generally from 0.5 to 5 parts by weight and advantageously from 0.5 to 2 parts by weight, per 100 parts by weight of monomers: HEMA + EMA), of a crosslinking agent, such as EDMA.
• EDMA can in particular intervene at a rate of 0.8 parts by weight.
• Other crosslinking agents can intervene in place of said EDMA.
• initiator of the radical HEMA -EMA copolymerization it is possible in particular to use:
• an azo compound such as razobisisobutyronitrile (AIBN) or (2,2'-azobis (2,4-dimethyl valeronitrile) (AIVN), in particular sold by the company WAKO under the reference V65, the formulas of which are reproduced below developed:
• AIBN razobisisobutyronitrile
• AIVN (2,2'-azobis (2,4-dimethyl valeronitrile)
• a person skilled in the art knows how to control the amount of intervention of said radical polymerization initiator (generally less than 1 part by weight, per 100 parts by weight of monomers: HEMA + EMA) and in general the kinetics of polymerization of the reaction mixture. He knows in particular that, the oxygen neutralizing the action of said polymerization initiator, it is highly preferable to eliminate it from the reaction mixture before the temperature rise. Bubbling of inert gas of said reaction mixture is strongly recommended. Regarding the heating program, its optimization is within the reach of the skilled person.
• HEMA + EMA poly crosslinked copolymer
• the particles of the dispersed phase generally intervene at a rate of 10 to 30% by mass, advantageously at a rate of 15 to 25% by mass.
• the continuous phase is considered hydrated, while the dispersed phase can be considered dry or in equilibrium.
• the dry mass of the dispersed phase is considered, ie the dry mass of the particles. It is specified here that there generally occurs within the dispersed phase a single type of particles. It is however in no way excluded from the scope of the invention to involve jointly particles of different shape and / or nature ...
• Said preparation which constitutes the second object of the present invention, comprises:
• the preparation of the dispersed phase particles of at least one hydrogel of a (co) polymer obtained by polymerization and crosslinking of acrylic acid and / or methacrylic acid and / or of at least one derivative said acids); - Incorporation and mixing in said continuous phase of said dispersed phase.
• the particles of the dispersed phase can be obtained by any method known per se. Particles with symmetry of revolution, with a smooth surface, and in particular microspheres, can be obtained by emulsification. We have seen that it was recommended to prepare fragments with a rough surface; said fragments being advantageously obtained by mechanical grinding of a suitable hydrogel mass.
• the biphasic composition prepared is advantageously sterilized for storage. It is recommended to condition it, before sterilization and storage.
• the invention therefore relates to a filling material, useful in restorative surgery and in cosmetic surgery, based on biphasic compositions as described above.
• Said material is particularly efficient, particularly in terms of stability and non-traumatic nature, by the nature and consistency of its continuous (advantageously crosslinked HA) and dispersed (hydrogel) phases.
• a biphasic composition of the invention was prepared from fibers of sodium hyaluronate (NaHa) for the continuous phase and fragments of a poly hydrogel [HEMA / EMA] for the dispersed phase.
• NaHa sodium hyaluronate
• HEMA / EMA poly hydrogel
• Said continuous phase is prepared with sodium hyaluronate fibers (molecular weight: M w ⁇ 2.9 10 6 Da), of bacterial origin. An 11.5% by mass solution of said fibers in 0.25 M sodium hydroxide is first prepared. • To said homogenized solution, 60 ⁇ l of 1,4-butanediol diglycidyl ether (BDDE) are added. The mixture obtained, homogenized, is placed in a water bath, at 50 ° C., for 2 hours.
• BDDE 1,4-butanediol diglycidyl ether
• the resulting gel is then neutralized by adding 1M hydrochloric acid, then diluted with phosphate buffer at pH 7.2, until a concentration of 20 mg / g of NaHa is obtained.
• This gel is then purified by dialysis in a phosphate buffer bath in order to remove from its structure both the crosslinking agent (BDDE) and the polymer which have not reacted.
• BDDE crosslinking agent
• the ratio: total number of reactive functions of said crosslinking agent / total number of disaccharide units of the polymer molecules present is 0.27.
• Palets or sticks of an acrylic hydrogel were first prepared as follows. 82.5 g of hydroxyethyl methacrylate (HEMA), 17.5 g of ethyl methacrylate (EMA), 1 g of 4-methacryloxy-2-hydroxybenzophenone (MOBP) were poured into a beaker. g of ethylene glycol dimethacrylate (EDMA) and 0.2 g of benzoyl peroxide. The reaction mixture was homogenized and then bubbled with argon for 2 min. The solution thus deoxygenated was then distributed in molds; said molds being then placed:
• HEMA hydroxyethyl methacrylate
• EMA ethyl methacrylate
• MOBP 4-methacryloxy-2-hydroxybenzophenone
• the material obtained after cooling, was removed from the mold. • The demoulded pucks or sticks were then mechanically ground. The powder thus obtained was successively sieved through 100, 40 and 25 ⁇ m mesh sieves. Only the fragments recovered on the 25 ⁇ m sieve were kept. These were then purified in an alcohol / water bubbling bath, left to settle for the elimination of small fragments which would have remained on the 25 ⁇ m sieve, and finally rinsed in two successive baths of deionized water. After drying, under flow (class 100), of the fragments thus obtained, these were again sieved over 25 ⁇ m, before being used for the final product.
• Samples of said biphasic composition obtained were notably subjected to extrudability tests. in order to characterize the force necessary for its injection.
• the said tests were carried out using a VERSATEST traction device (MECMESIN).
• a needle is 25 to 30 N,
• the dispersion or suspension obtained is put into syringes which are sterilized in an autoclave. Said dispersion is injectable, in particular through needles of 25 G to 30 G Vz.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Chemical & Material Sciences (AREA)
• Surgery (AREA)
• Medicinal Chemistry (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Vascular Medicine (AREA)
• Heart & Thoracic Surgery (AREA)
• Transplantation (AREA)
• Dermatology (AREA)
• Dispersion Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Materials For Medical Uses (AREA)
• Cosmetics (AREA)
• Compositions Of Macromolecular Compounds (AREA)

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• 1998
  • 1998-07-01 FR FR9808386A patent/FR2780730B1/fr not_active Expired - Fee Related
• 1999
  • 1999-06-30 US US09/720,936 patent/US6685963B1/en not_active Expired - Fee Related
  • 1999-06-30 JP JP2000557874A patent/JP4577987B2/ja not_active Expired - Fee Related
  • 1999-06-30 CA CA002335928A patent/CA2335928C/en not_active Expired - Fee Related
  • 1999-06-30 DE DE69902913T patent/DE69902913T2/de not_active Expired - Lifetime
  • 1999-06-30 BR BRPI9911998-6B8A patent/BR9911998B8/pt not_active IP Right Cessation
  • 1999-06-30 EP EP99926570A patent/EP1091775B1/fr not_active Expired - Lifetime
  • 1999-06-30 ES ES99926570T patent/ES2184462T3/es not_active Expired - Lifetime
  • 1999-06-30 WO PCT/FR1999/001568 patent/WO2000001428A1/fr not_active Ceased

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