Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
  • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
  • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
  • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
  • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
  • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

• the present invention relates to a biocompatible matrix, consisting of at least one polymer of natural origin, highly functionalized, allowing the replacement of biological fluids, the separation of tissues or tissue augmentation.
• the matrix of the present invention is characterized by a long remanence in vivo, obtained by delaying its chemical, biological and mechanical degradation.
• the present invention provides a method and compositions in the form of a complex matrix of at least one polymer of natural origin, for obtaining medical devices (pharmacologically active) intended for augmentation, tissue separation or viscosupplementation. , completely biodegradable but characterized by a long persistence in vivo.
• Tissue augmentation is desired both in the case of therapeutic applications and for cosmetic purposes.
• certain tissues need to be enlarged to ensure their function; this can be the case with the vocal cords, the esophagus, the sphincter of the urethra, other muscles ...
• Patients can resort to cosmetic surgery for filling wrinkles, masking scars, lip augmentation ...
• Particles of silicone, ceramic, carbon, or metal (US-A-5451406, US-A-5792478, US-A- 2002151466), fragments of polytetrafluoroethylene, glass or synthetic polymers (US-A-2002025340) , and collagen beads were also used but the results were disappointing considering the side reactions, the biological degradation and the migration of the residual products.
• particles have at least one of these drawbacks: too large a diameter or an irregular shape which causes the particles to stick to each other, which can make injection difficult through a fine needle, the too fragile particles can break during the injection, the injection of too small particles induces a fast digestion by the macrophages and other components of the lymphatic system, the injected particles can move and do not adhere to the surrounding cells.
• EP-A-0466300 proposes the injection of a viscoelastic gel composed of a matrix dispersed in a liquid phase, the two phases being composed of hylan, high molecular weight hyaluronate of animal origin, crosslinked and extracted. Esters of hyaluronic acid and crosslinked derivatives of hyaluronic acid have been developed with the aim of increasing the absorption times of this glycosaminoglycan and therefore obtaining a longer residence time.
• Restylane® a biphasic gel consisting of a fluid phase (non-crosslinked hyaluronate), and a very crosslinked phase. If inter or intramolecular bridging of polysaccharides or esters of acidic polysaccharides are useful for many applications, for example the prevention of post-surgical adhesions (EP-A-0850074, US-A-4851521, EP-A-0341745) , these products cannot constitute a long-lasting effect taking into account the high level of enzymatic degradation and the short lifespan of the ester bridges which, unlike the ether bonds, are degradable in physiological environments (US-A-4963666).
• EP-A-0 749 982 proposes grafting an antioxidant to a matrix with a low grafting rate.
• the principle of the present invention is based on the occupation of a large number of sites of the polymer chains to retard chemical and enzymatic attacks directly on the main chain of the polymer.
• the grafting of small molecules coupled with crosslinking induces an increase in the density of the matrix, consequently the time necessary for it to be degraded, while limiting its embrittlement induced by too high a degree of crosslinking.
• the coupling of two types of functionalization, crosslinking and grafting also makes it possible to increase the ease of use of a matrix intended to be injected by compared to a matrix which has the same number of sites occupied on the main chain of the polymer but whose degree of crosslinking is greater.
• the effect allowing the long remanence of the composition can be amplified if the grafted molecules have antioxidant properties.
• Antioxidants can also be dispersed in the matrix.
• the use of cellulose derivatives or other polymers naturally absent in humans for the constitution of the product also makes it possible to delay the degradation of the matrix taking into account the lack of specific hydrolases.
• the word site designates all the points of the polymer chain liable to be attacked; they can be pendant functional groups such as hydroxy or carboxy groups or chain chains such as ether bridges.
• the long-lasting effect of the medical device makes it possible to space out medical procedures and therefore improve the quality of life for patients.
• Another object of the present invention is to provide the same composition containing one or more therapeutically active molecules.
• the present invention provides a long-lasting, biocompatible, complex single-phase matrix composed of at least one polymer of highly functional natural origin.
• long remanence is meant a lifetime in vivo greater than that of a product having an identical degree of functionalization but obtained by another process than that of the present invention, most often characterized by a simple crosslinking.
• the substance intended for viscosupplementation or tissue augmentation is composed of at least one polymer with a molecular weight greater than 1 OO'OOO Da, selected from polysaccharides such as hyaluronic acid, chondroitin sulfate, keratane, keratane sulfate , heparin, heparan sulfate, cellulose and its derivatives, xanthans and alginates, proteins, or nucleic acids, this polymer being highly functionalized by the grafting of small chains and a crosslinking allowing the creation of a matrix.
• matrix we therefore mean a three-dimensional network made up of polymers of biological origin doubly functionalized, by crosslinking and grafting.
• the crosslinking agent can be chosen from, in particular, di- or polyfunctional epoxides, for example 1,4-butanediol diglycidyl ether (also called 1,4-bis (2,3-epoxypropoxy) butane), l- (2, 3-epoxypropyl) 2,3-epoxy cyclohexane and 1,2-ethanediol diglycidyl ether, epihalohydrins and divinylsulfone.
• the crosslinking rate defined as the ratio between the number of moles of the crosslinking agent ensuring the bridging of the polymer chains and the number of moles of polymer units, is between 0.5 and 25% in the case of injectable products, 25 to 50% in the case of solids.
• small chains can be grafted by ionic bonds or covalently, preferably by etherification, on the matrix.
• These grafted chains will occupy a large number of matrix sites, which will make it possible to significantly increase the life of the product without modifying the mechanical or rheological character of the polymer constituting the matrix.
• biological and chemical protection made up of "lures".
• the chains grafted onto the functional groups of the hydroxy or carboxy type probably protect on the one hand directly these functional groups which have reacted and on the other hand indirectly the other sensitive sites by steric hindrance.
• the grafted chains can be polymers of natural origin of small size comprising attackable sites more available than the masked sites of the matrix, or polymers not recognized by the enzymes of the organism. In the latter case, they may be cellulose derivatives or derivatives of other biopolymers not naturally present in human beings which will not be degraded by the enzymes of the organism, but which will be susceptible to attack by free radicals and other reactive radicals. It may for example be carboxymethylcellulose.
• the grafted chains can also be non-polymeric chains having antioxidant properties or properties that inhibit degradation reactions of the polymer matrix. It may for example be vitamins, enzymes or cyclic molecules.
• the grafting rate which is defined as the ratio between the number of moles of grafted molecules or the number of moles of units of the grafted polymer and the number of moles of units of the crosslinked polymer (s) is included between 10 and 40%.
• the grafting of small chains that is to say of size less than 50,000 Da, and preferably of the order of 10,000 Da or less, at numerous sites in the polymer matrix, makes it possible to maintain the injectable nature of the final product since the crosslinking rate is not increased, while the presence of these grafted chains prevents the matrix from being attacked by the surrounding medium and ensures a longer remanence after the injection.
• the grafted molecules can be grafted by covalent bond to the main chains, directly for example by esterification or etherification of hydroxy or carboxy groups or by means of a bi or polyfunctional molecule chosen from epoxides, epihalohydrins or divinylsulfone.
• a functionalization process has significant advantages compared to a simple crosslinking.
• the grafting and crosslinking can take place at the same time, or the grafting can precede the crosslinking, or vice versa.
• a molecule with antioxidant properties can also be dispersed in the highly functionalized matrix.
• vitamin C a rare water-soluble molecule with antioxidant properties
• This effect can be particularly advantageous in the case of dermatological and cosmetic applications, in order to improve the elasticity of the skin.
• Vitamin A which has many advantages (antioxidant action, influence on tissue development and participation in skin maintenance) could also be dispersed in this highly modified matrix which, by its density, would allow a gradual release of the pharmacologically active agent.
• Melatonin which would be released at a very low rate, is a powerful antioxidant, skin regenerator and defender of the immune system which could also be dispersed in the matrix.
• FIG. 1 shows the much slower degradation as a function of time of injectable products according to the present invention and of two commercially available products, Juvéderm® and Restylane® (polysaccharide gel composition from US 5827937).
• the invention thus relates to a complex matrix consisting of at least one biocompatible polymer of natural origin, crosslinked and onto which are grafted chains of molecular weight less than 50,000 Da with a grafting rate of 10 to 40%.
• the biocompatible polymer of natural origin constituting the matrix is advantageously chosen from polysaccharides such as hyaluronic acid, chondroitin sulfate, keratan, keratan sulfate, heparin, heparan sulfate, cellulose and its derivatives, xanthans and alginates, proteins, or nucleic acids.
• polysaccharides such as hyaluronic acid, chondroitin sulfate, keratan, keratan sulfate, heparin, heparan sulfate, cellulose and its derivatives, xanthans and alginates, proteins, or nucleic acids.
• the biocompatible polymer of natural origin is a polymer which is not naturally present in humans such as a cellulose derivative, a xanthan or an alginate, which is crosslinked with at least one polymer naturally present in l human being chosen from polysaccharides such as hyaluronic acid, chondroitin sulfate, keratan, keratan sulfate, heparin, heparate sulfate, xanthans and alginates, proteins, or nucleic acids.
• polysaccharides such as hyaluronic acid, chondroitin sulfate, keratan, keratan sulfate, heparin, heparate sulfate, xanthans and alginates, proteins, or nucleic acids.
• the crosslinking rate defined as the ratio between the number of moles of the crosslinking agent ensuring the bridging of the polymer chains and the number of moles of polymer units, is between 0.5 and 50%, in particular between 0, 5 and 25% in the case of injectable products, and between 25 to 50% in the case of solid products.
• the crosslinking agent ensuring the bridging of the chains can come from a bi or poly-functional molecule chosen by the epoxides, the epihalohydrins and the divinylsulfone.
• the matrix may contain antioxidants, vitamins or other dispersed pharmacologically active agents.
• the invention also relates to the use of the matrix defined above to replace, fill, or supplement a biological fluid or tissues.
• the invention also relates to a process for obtaining a slightly biodegradable biocompatible matrix consisting of at least one polymer of natural origin, characterized in that it consists: - on the one hand, of grafting small chains of molecular weight less than 50 000 Da with a grafting rate of 10 to 40%, - on the other hand, to crosslink the main chains of the polymer together, to create a homogeneous matrix.
• BDDE 1,4-butanediol diglycidyl ether
• BDDE 1,4-butanediol diglycidyl ether
• BDDE 1,4-butanediol diglycidyl ether
• the grafting rate calculated assuming that the carboxylic functions are all in the form of the sodium salt and that the carboxymethylcellulose has a substitution rate of 0.9, is 24.6%.
• Rheological studies have shown a slower decrease in these properties for the gel from Example 2 (gel 2) than for that from Example 1 (gel 1) when these gels are stored at 37 ° C.
• degradation of gel 2 is likely to be slower than that gel 1, which itself must be degraded less quickly than a gel synthesized according to the same process but composed exclusively of sodium hyaluronate.
• BDDE 1,4-butanediol diglycidyl ether
• BDDE phosphate buffer solution
• BDDE 1,4-butanediol diglycidyl ether
• BDDE 1,4-butanediol diglycidyl ether
• Rate of grafting (m e h arine P / M arine h e P) / ((m M A / M H A) + (C m C / M CMC)) ⁇ 10,3% with: m: mass in g M: molecular mass of the polymer motif in g / mol HA: hyaluronate CMC: carboxymethylcellulose
• m mass in g M: molecular mass of the polymer motif in g / mol
• HA hyaluronate
• CMC carboxymethylcellulose
• This method is based on the measurement of the force necessary for the ejection of the different gels obtained through a type needle.
• 27G Each gel obtained is placed in a 1 ml syringe, the tip of which is provided with a 27G type needle.
• the syringe is kept vertical thanks to a rack and a mass presses on the syringe plunger, at a constant speed defined by the user.
• a sensor measures the force required to eject the product.
• the ejection speed is 75 mm / min and in the second series of examples, the ejection speed is 15 mm / min.
• Table 1 The values of the ejection force measured for the gels of Examples 1 to 7 are given in Tables 1 and 2 below. Table 1
• the crosslinked and grafted gels according to the invention have a lower ejection force (and therefore better injectability) than that of the crosslinked gels (comparison of Example 2 and Example 3).

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• 2004
  • 2004-07-30 CA CA002534033A patent/CA2534033A1/fr not_active Abandoned
  • 2004-07-30 RU RU2006102198/04A patent/RU2360928C2/ru not_active IP Right Cessation
  • 2004-07-30 JP JP2006521630A patent/JP2007500027A/ja active Pending
  • 2004-07-30 KR KR1020067002010A patent/KR20070012306A/ko not_active Application Discontinuation
  • 2004-07-30 BR BRPI0413086-3A patent/BRPI0413086A/pt not_active IP Right Cessation
  • 2004-07-30 EP EP04786014A patent/EP1648942A2/de not_active Withdrawn
  • 2004-07-30 WO PCT/FR2004/002052 patent/WO2005012364A2/fr active Application Filing
  • 2004-07-30 US US10/565,442 patent/US20060246137A1/en not_active Abandoned
  • 2004-07-30 AU AU2004261752A patent/AU2004261752B2/en not_active Ceased
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