Classifications

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  • 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
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
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  • A61K31/16—Amides, e.g. hydroxamic acids
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  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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  • 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
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
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  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/24—Phosphorous; Compounds thereof
• • A—HUMAN NECESSITIES
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  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
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  • 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
  • A61L27/02—Inorganic materials
  • A61L27/12—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
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  • 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
  • A61L27/20—Polysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
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  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
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  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/524—Preservatives
• • A—HUMAN NECESSITIES
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  • A61K2800/74—Biological properties of particular ingredients
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• • A—HUMAN NECESSITIES
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  • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
  • A61K2800/91—Injection
• • A—HUMAN NECESSITIES
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  • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
• • 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
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/06—Flowable or injectable implant compositions

Definitions

• the present invention relates to the field of sterile and injectable compositions comprising hyaluronic acid or a salt thereof, and especially soft tissue filler compositions, for in particular the augmentation and/or repair of soft tissue, including periodontal tissue, and especially for treatment of defects and imperfections of keratin materials, like the skin.
• the invention is also directed to related methods. DESCRIPTION OF RELATED ART
• compositions useful to correct defects in skin such as scars and wrinkles or to augment the tissue of a subject in order to improve the appearance of the skin, particularly facial skin.
• the principal method employed to correct such defects involves injecting a filler composition into the dermal layer of the skin proximate to the effect or desired tissue augmentation.
• the hyaluronic acid is the major component of the extracellular matrix (ECM). It is thus found in large quantities mainly in the skin. It is also the major physiological component of the articular cartilage matrix and is particularly abundant in synovial fluid.
• the hyaluronic acid in its acid or salt form, is a biomaterial largely used as injectable filler material for tissue engineering application and especially for augmentation of dermal tissue or other soft tissue like gingival tissue.
• Hyaluronic acid is a linear non-sulfated glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine (Tammi R., Agren UM., Tuhkanen AL., Tammi M. Hyaluronan metabolism in skin. Progress in Histochemistry & Cytochemistry 29 (2): 1. -81, 1994).
• hyaluronic acid is primarily synthesized by dermal fibroblasts and epidermal keratinocytes (Tammi R., cited above). Through its residues bearing a negative charge, hyaluronic acid acts as a water pump for maintaining the elasticity of the skin.
• the ECM is a dynamic structure with a structural and regulatory role for the tissues.
• the ECM is composed of collagen and elastin and also fundamental substance, mainly water, minerals and proteoglycans. This matrix gives to the skin its turgor and mechanical properties of firmness, elasticity and tone. Regarding the skin, it is noticed that, with age, the amount of hyaluronic acid and its degree of polymerization decreases, resulting in a decrease in the amount of water retained in the connective tissue.
• ECM components are degraded, mainly by endopeptidase type enzymes called matrix metalloproteinases or MMPs.
• the skin is then subjected to an aging process leading to the appearance of defects and blemishes of keratinous substances, in particular of the skin.
• gels consisting mainly of hyaluronic acid, the case arising chemically crosslinked, are injected intradermally to fill the depression dug by the ride.
• the crosslinking can increase the persistence of the product within the dermis.
• Such gels based on hyaluronic acid if necessary crosslinked, allow a reduction of wrinkles by the mechanical effect of the filler resulting from the vacuum skin wrinkle.
• lidocaine may display the disadvantage, regarding its vasodilatory properties, to imply a too rapid absorption by the patient's body and sometimes an exacerbated occurrence of hematoma which are, for obvious aesthetic reasons, to be avoided as much as possible.
• a solution to overcome the above- mentioned problems may consist to implement the lidocaine in association with a vasoconstrictor, in particular epinephrine (J. Endod. 2013 May; 39(5):597-9).
• a vasoconstrictor like epinephrine may require adding a preservative which isn't always inert with respect to the patient and may conduct to allergies.
• the invention relates to a method comprising at least the administering by injection to a patient in need thereof of:
• the method of the invention is intended to soft tissue augmentation.
• the target tissue may be skin but also gingival tissue.
• the present method may be efficiently used (i) for preventing and/or treating the surface appearance of the skin.
• the present method may thus advantageously be used (ii) to prevent and/or treat cutaneous signs of chronological aging and/or induced by external factors such as stress, air pollution, tobacco or prolonged exposure to ultraviolet (UV) exposure, (iii) to prevent and/or treat impaired surface appearance of the skin, (iv) to prevent and/or treat impaired viscoelastic or biomechanical properties of the skin and/or (v) for the long- lasting filling of volume defects of the skin, and in particular the filling of wrinkles.
• UV ultraviolet
• the method of the invention may be advantageously also used for treating sites of deficiencies and defects in gingival architecture and contour and bony tissue such as occur with teeth loss, increase in age, periodontal disease and disorders, periodontal trauma and after tooth implants, for the enhancement of fit and function of dental prosthetics including but not limited to implants, crown, bridges....
• the method of the invention is also useful for cartilage regeneration.
• the method of the invention may be used as a treatment for arthritis
• the hyaluronic acid is a thick transparent liquid similar to the natural fluid located in eyes. Accordingly, it is already proposed for maintaining eyes fluid volume during surgery.
• the method of the invention is also useful in most ophthalmic intraocular surgeries, including cataract extraction, Intraocular Lens (IOL) insertion and removal, corneal surgery, glaucoma surgery, trauma surgery, ocular plastic surgery and muscle surgery.
• IOL Intraocular Lens
• the invention relates to a sterile and injectable composition, more particularly a soft tissue filler composition, comprising an effective amount of at least hyaluronic acid or a salt thereof and including an effective amount of at least mepivacaine or a salt thereof as anesthetic agent.
• the invention relates to a method of preparing a sterile and injectable composition, more particularly a soft tissue filler composition, the method comprising at least the steps of:
• the invention relates to a method comprising at least the administering by injection to a patient in need thereof of:
• a method according to the invention may constitute a viable alternative to current methods for in particular preventing and/or treating the surface appearance of the skin which consider the implementation of hyaluronic acid with lidocaine but also (i) for treating sites of deficiencies and defects in gingival architecture and contour and bony tissue, (ii) for ophthalmic intraocular surgeries, (ii) for the regeneration of the cartilage and (iv) in the treatment of arthritis.
• mepivacaine do not displays significant vasodilatory properties than lidocaine.
• mepivacaine has a pKa of 7,6 whereas lidocaine has a pKa of 7,9. Therefore, mepivacaine having a pKa lower than lidocaine, it displays a better lipid solubility which improves its diffusion through lipid barriers. Therefore, due to the fact that mepivacaine may be absorbed more rapidly than lidocaine, mepivacaine is therefore appropriate to better prevent a painful sensation during the injection.
• a filler compositions according to the invention i.e including mepivacaine as anesthetic agent
• the gels of hyaluronic acid are particularly sensible to the heat treatment like required for their sterilization and that this low stability may be increased by the presence of further materials like the anesthetic agent.
• this indesirable phenomenon is significantly lowered with mepicavaine comparatively to lidocaine, as shown in the following examples 1 and 2.
• the inventors have shown that a composition according to the invention further complies with the requirements in terms of stability in time, as hereinafter shown in example 3.
• the hyaluronic acid or a salt thereof is administered concurrently with the mepivacaine or a salt thereof.
• the administering by injection is an intraepidermal and/or intradermal and/or subcutaneous injection.
• it may be also administered by a gingival, articular and intraocular road.
• hyaluronic acid also called hyaluronan or hyaluronate
• hyaluronan is a linear non-sulfated glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine (Tammi R., Agren UM., Tuhkanen AL., Tammi M. Hyaluronan metabolism in skin. Progress in Histochemistry & Cytochemistry 29 (2): 1. -81, 1994).
• hyaluronic acid is primarily synthesized by dermal fibroblasts and epidermal keratinocytes (Tammi R., cited above). Through its residues bearing a negative charge, hyaluronic acid acts as a water pump for maintaining the elasticity of the skin.
• the present invention considers the implementation of hyaluronic acid as such but also a salt thereof.
• the hyaluronic acid in accordance with the invention may be more particularly chosen from physiologically acceptable salts such as the sodium salt, the potassium salt, the zinc salt, the silver salt and mixtures thereof, preferably the sodium salt.
• the hyaluronic acid according to the invention has a high average molecular weight, preferably ranging from 50 000 to 10 000 000 Dal tons, preferably from 500 000 to 4 000 000 daltons.
• One particularly preferred salt of hyaluronic acid is sodium hyaluronate (NaHA).
• hyaluronic acid is administered by injection in an effective amount.
• an "effective amount" of hyaluronic acid is an appropriate amount to obtain the desired technical effect, notably to have a visible result on the surface appearance of the skin.
• an effective amount of hyaluronic acid is an appropriate amount of hyaluronic acid for a good filling of volume defects of the skin, and in particular the filling of wrinkles.
• the hyaluronic acid or a salt thereof in a method according to the invention is present in a solution.
• an effective amount of hyaluronic acid may range from 0.1 to 5% by weight, preferably from 1 to 3% by weight, relative to the total weight of said solution comprising the hyaluronic acid or a salt thereof.
• the hyaluronic acid may be present under an uncrosslinked form.
• the term "uncrosslinked” or “non-crosslinked” is understood in the context of the present invention to mean a gel of hyaluronic acid which is not crosslinked or slightly crosslinked, that is to say a gel having a phase-shift angle ⁇ , measured under dynamic rheology conditions at 1 Hz, that is greater than 40° when subjected to a stress above 1 Pa.
• the hyaluronic acid may be present under a crosslinked form.
• the hyaluronic acid may be present under crosslinked and non-crosslinked forms.
• the weight ratio "crosslinked hyaluronic acid/non-crosslinked hyaluronic acid” is preferably greater than 1.
• the solution comprising the hyaluronic acid and being intended to be administered may comprise:
• the ratio between the weight of the crosslinked hyaluronic acid gel and the weight of the free hyaluronic acid being between 1 : 1 and 1 :0.02.
• said crosslinked hyaluronic acid has preferably a degree of modification ranging from 0.1 to 20%, preferably from 0.4 to 10%.
• degree of modification is meant, in the sense of the present invention, the ratio between the number of moles of crosslinking agent attached to the hyaluronic acid and the number of moles of hyaluronic acid forming said crosslinked hyaluronic acid gel. This value may be measured by a NMR analysis ID 1H of the crosslinked gel.
• number of moles of hyaluronic acid is meant the number of moles of repeating disaccharide units of the hyaluronic acid, a disaccharide unit being composed of D- glucuronic acid and D-N-acetylglucosamine linked together by alternated beta- 1,4 and beta-1,3 glycosidic bonds.
• the characterizing of the degree of modification of the hyaluronic acid is carried out by spectroscopy by NMR (spectrometer Bruker Avance 1 operating at 400 MHz (3 ⁇ 4)).
• the degree of modification is obtained by integrating the signal of 3 ⁇ 4 NMR N-acetyl group ( ⁇ ⁇ 2 ppm) present in the hyaluronic acid and a signal present in the crosslinking agent (two -CH2- groups, ⁇ ⁇ 1.6 ppm).
• the ratio of integrals of these two signals (crosslinking agent/NaHA) relates to the degree of modification, after correcting the number of protons attached to each signal. :
• crosslinking agent is understood to mean any compound capable of inducing a crosslinking between the various chains of the hyaluronic acid.
• a crosslinking agent in accordance with the invention may be chosen from difunctional or multifunctional epoxy crosslinking agents but also polyamines like for example hexamethylenediamine (HMD A) or endogeneous polyamines.
• HMD A hexamethylenediamine
• endogenous polyamine within the meaning of the present invention is meant a polyamine naturally present in living organisms and particularly the human body.
• endogenous polyamines may be especially mentioned those cited in eukaryotes animals, such as the putrescine (or 1,4-diaminobutane), the spermidine (or l,8-diamino-5-azaoctane) and the spermine (l, 12-diamino-5,9-diazadodecane), preferably the spermine.
• a crosslinking agent according to the present invention may be preferably selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), l,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, l,2-bis(2,3- epoxypropoxy)ethylene and l-(2,3-epoxypropyl)-2,3-epoxycyclohexane, an endogenous polyamine, and mixtures thereof.
• BDDE 1,4-butanediol diglycidyl ether
• l,4-bis(2,3-epoxypropoxy)butane 1,4-bisglycidyloxybutane
• l,2-bis(2,3- epoxypropoxy)ethylene l-(2,3-epoxypropyl)-2,3-epoxycyclohexane
• an endogenous polyamine and mixtures thereof.
• a crosslinking agent according to the invention is 1,4-butanediol diglycidyl ether (BDDE).
• BDDE 1,4-butanediol diglycidyl ether
• the coupling reaction with the hyaluronic acid may be carried out in the presence of at least one activator, and the case arising associated with at least one auxiliary coupling.
• the activator may be selected from water-soluble carbodiimides such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), l-ethyl-3-(3-25 trimethylaminopropyl)carbodiimide hydrochloride (ETC), l-cyclohexyl-3-(2- mo hilinoethyl)carbodiimide (CMC) and a salt thereof, and mixtures thereof, preferably is represented by the EDC.
• EDC water-soluble carbodiimides
• ETC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
• ETC l-ethyl-3-(3-25 trimethylaminopropyl)carbodiimide hydrochloride
• CMC l-cyclohexyl-3-(2- mo hilinoethyl)carbodiimide
• the coupling auxiliary when it is present, it may be selected from N-hydroxy succinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo- 1,2,3-benzotriazole (HOOBt), l-hydroxy-7-7azabenzotriazole (HAt) and N- hydroxysylfosuccinimide (sulfo NHS), and mixtures thereof, preferably is represented by the HOBt.
• NHS N-hydroxy succinimide
• HOBt N-hydroxybenzotriazole
• HOBt 3,4-dihydro-3-hydroxy-4-oxo- 1,2,3-benzotriazole
• HAt l-hydroxy-7-7azabenzotriazole
• NHS N- hydroxysylfosuccinimide
• the crosslinking agent is implemented in an effective amount.
• an "effective amount" of crosslinking agent is an appropriate amount to obtain an appropriate degree of crosslinking of hyaluronic acid.
• an effective amount of crosslinking agent may range from 0.05 to 15% by weight relative to the total weight of the hyaluronic acid or a salt thereof.
• the amount in mole ratio of nBDDE/n hyaluronic acid may range between 0.01 and 0.5, preferably between 0.04 and 0.25.
• An anesthetic agent according to the present invention has the particular advantage to reduce or eliminate the pain sensation experienced by the patient during and/or following the injection.
• an anesthetic agent according to the present invention is chosen among compounds which do not raise risk of incompatibility with other compounds used in a composition according to the invention, especially with hyaluronic acid.
• an anesthetic agent according to the present invention is mepivacaine, or a salt thereof.
• the mepivacaine is a local anesthetic of the amino-amids family of the formula (I):
• the mepivacaine is notably sold under the name Carbocaine ® by the company Cook- Waite.
• the mepivacaine is a molecule having a good stability. Its main degradation product is 2,6-dimethylaniline. Mepivacaine is a molecule containing a chiral center (asymmetric carbon). Thus, there are the R and S enantiomers. In the following examples, it is considered the racemic mixture of the two forms of mepivacaine.
• the mepivacaine is under a salt form, and more particularly the salt of mepivacaine is chlorhydrate mepivacaine.
• the mepivacaine or a salt thereof is administered by injection in an effective amount.
• an "effective amount" of mepivacaine or a salt thereof is an appropriate amount to effectively reduce or eliminate the pain sensation experienced by the patient during and/or following the injection.
• the mepivacaine or a salt thereof in a method according to the invention is present in a solution.
• an effective amount of the mepivacaine or a salt thereof may range from 0.05 to 3 % by weight relative to the weight of the solution comprising said mepivacaine or a salt thereof
• the method may further comprises the administration, the case arising joint to the mepivacaine, of at least one additional anesthetic agent or a salt thereof different from the mepivacaine,
• This further anesthetic agent may be in particular selected from ambuca ' ine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxyca ' ine, cartica ' ine, chloroprocaine, cocaethylene, cocaine, cyclomethyca ' ine, dibucaine, dimethysoquine, dimethocaine, diperodone, dycyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocine fenalcomine, formoca ' ine, hexylcaine, hydroxytetraca ' ine, isobutyl p- aminobenzoate, leucinoca ' ine mesylate, levoxadrol, lidoca
• this additional anesthetic agent is lidocaine or a salt thereof.
• the additional anesthetic agent is administered alone, previous to the hyaluronic acid and the mepivacaine or a salt thereof.
• the additional anesthetic agent is administered together with the mepivacaine or a salt thereof, previous to the hyaluronic acid or a salt thereof.
• the additional anesthetic agent is administered together with the mepivacaine or a salt thereof and the hyaluronic acid or a salt thereof.
• both anesthetic agents may be present therein in a ratio "mepivacaine/lidocaine" 1 : 1, preferably a ratio 1 :0.1.
• Balanced salt solution
• the method according to the invention may further comprise at least a step of administering by injection to said patient of (c) at least a balanced salt solution, concurrently with said hyaluronic acid and/or mepivacaine, preferably with mepivacaine.
• said balanced salt solution is a phosphate buffered saline, and more particularly is a phosphate buffered saline and particularly a KH2PO4/K2HPO4 saline buffer.
• said balanced salt solution may further comprise at least one compound selected from the group consisting of an alpha-lipoic acid; N- Acetyl-L-cysteine; reduced glutathion; amino acid such as L-Arginine, L-Isoleucine, L- Leucine, monohydrated L-Lysine, Glycine, L-Valine, L-Threonine, L-Proline; pyridoxine Hydrochloride; dehydrated zinc acetate; pentahydrates copper sulphate, and mixture thereof .
• amino acid such as L-Arginine, L-Isoleucine, L- Leucine, monohydrated L-Lysine, Glycine, L-Valine, L-Threonine, L-Proline; pyridoxine Hydrochloride; dehydrated zinc acetate; pentahydrates copper sulphate, and mixture thereof .
• the present invention also relates to a sterile and injectable composition, in particular a soft filler composition, comprising an effective amount of at least hyaluronic acid or a salt thereof and including an effective amount of at least mepivacaine or a salt thereof as anesthetic agent.
• sterile in the sense of the present invention, is meant an environment capable of guaranteeing to the considered compounds in a composition according to the invention safety requirements for the administration routes such as above-mentioned, notably into or through the skin. Indeed, for obvious reasons, it is essential that a composition according to the invention be devoid of any contaminant body capable of initiating an undesirable side reaction at the host organism.
• the hyaluronic acid, the crosslinking agent, and the anesthetic agent(s) are such as above-mentioned.
• a composition according to the invention may comprise from 0.1 to 5% by weight, preferably from 1 to 3 % by weight of hyaluronic acid, relative to the total weight of said composition.
• the hyaluronic acid may be present in crosslinked and non-crosslinked forms.
• the ratio "crosslinked hyaluronic acid/non-crosslinked hyaluronic acid” is preferably greater than 1.
• composition according to the invention may comprise:
• the ratio between the weight of the crosslinked hyaluronic acid gel and the weight of the non-crosslinked hyaluronic acid being between 1 : 1 and 1 :0.02.
• a composition according to the invention may comprise from 0.01% to 5 % by weight, preferably from 0.05% to 3 % by weight of anesthetic agent(s), based on the total weight of said composition.
• composition according to the invention necessarily comprises a physiologically acceptable medium.
• a “physiologically acceptable medium” means a medium devoid of toxicity and compatible with the injection and/or the application of the composition such as considered in the present invention.
• the composition may comprise a solvent or a mixture of physiologically acceptable solvents.
• composition may comprise a physiologically acceptable aqueous medium.
• aqueous medium suitable for the invention may be for example mentioned water.
• isotonic agents suitable for the preparation of a composition according to the invention it may be mentioned sugars and sodium chloride.
• a composition according to the invention may further comprise at least a balanced salt solution such as above-mentioned.
• a composition according to the invention may further comprise at least one compound selected from the group consisting of an alpha- lipoic acid; N-Acetyl-L-cysteine; reduced glutathion; amino acid such as L-Arginine, L- Isoleucine, L-Leucine, monohydrated L-Lysine, Glycine, L- Valine, L-Threonine, L- Proline; pyridoxine Hydrochloride; dehydrated zinc acetate; pentahydrates copper sulphate, and mixture thereof.
• amino acid such as L-Arginine, L- Isoleucine, L-Leucine, monohydrated L-Lysine, Glycine, L- Valine, L-Threonine, L- Proline; pyridoxine Hydrochloride; dehydrated zinc acetate; pentahydrates copper sulphate, and mixture thereof.
• a composition according to the invention may comprise, in addition to the above- mentioned compounds, at least one additional compound compatible with use in the field of soft tissue filler composition compositions.
• additional compounds which may be implemented in a composition according to the invention may be chosen from copper salt, alpha-lipoic acid, acetylated derivative of cysteine or mixture thereof.
• a composition further comprising at least one copper salt may preferably comprises said copper salt in an amount ranging from 0.1 a 50 ppm based on the total weight of said composition.
• a composition further comprising at least one alpha-lipoic acid preferably comprises said alpha-lipoic acid in an amount ranging from 0.5 to 10 000 ppm, preferably from 5 to 100 ppm of alpha-lipoic acid, based on the total weight of said composition.
• a composition further comprising at least one acetylated derivative of cysteine preferably comprises said acetylated derivative of cysteine in an amount ranging from 0.5 to 10 000 ppm based on the total weight of said composition.
• antioxidants may be mentioned antioxidants, amino acids, vitamins, minerals, nucleic acids, co- enzymes, adrenal derivatives, and mixtures thereof, said additional compounds being distinct from those indicated above.
• antioxidant it may be mentioned glutathione, ellagic acid, spermine, resveratrol, retinol, L-carnitine, polyols, polyphenols, flavonols, theaflavins, catechins, caffeine, ubiquinol, ubiquinone, and mixture thereof.
• amino acid there may be mentioned arginine, isoleucine, leucine, lysine, glycine, valine, threonine, proline, methionine, histidine, phenylalanine, tryptophan, and mixture thereof.
• vitamins and their derivatives may be mentioned vitamins E, A, C, B, especially vitamins B6, B8, B4, B5, B9, B7, B12, and pyridoxine better.
• nucleic acids may be mentioned in particular the derivatives of adenosine, cytidine, guanosine, thymidine, the cytodine and mixture thereof.
• co-enzymes may be cited coenzyme Q10, CoA, NAD, NADP, and mixtures thereof.
• an adrenaline derivatives may be mentioned adrenaline, noradrenaline.
• composition according to the invention may further comprise any excipient commonly used in the technical field, such as for example mono-and/or di- hydrated dihydrogenophosphate sodium and sodium chloride, in physiological concentrations.
• a composition according to the invention may have a complex viscosity ⁇ * of between about 5 Pa*s and about 450 Pa*s when measured at about lHz.
• a composition according to the invention made up of crosslinked hyaluronic acid may have a viscosity between 200 and 2000 Pa.s, preferably between 1000 and 1800 Pa.s.
• the viscoelastic properties of a composition according to the invention may be measured using a rheometer (notably Haake RS6000) with a cone/plate geometry (l°cone angle/35 mm diameter plate).
• a strain scan is carried out and the elastic modulus G' (in Pa) and the phase-shift angle ⁇ (in °) are measured for a stress of 5 Pa.
• the present invention also relates to a method of preparing a sterile and injectable composition, more particularly a soft tissue filler composition, the method comprising at least the steps of:
• the mepivacaine or a salt thereof is added to an injectable form of hyaluronic acid.
• the gel of hyaluronic acid considered in step a) already exhibits a concentration in hyaluronic acid, in crosslinking agent residues if presents, and physiological and/or pH conditions which are compatible with an injectable use, in particular in the fields of the applications considered above.
• the mixture advantageously undergoes only one sterilization step.
• This step is preferably carried out on the mixture already packaged in its delivery device, usually a syringe, as herein after defined.
• the sterilization step can be performed by thermal means.
• the sterilization is carried out at a temperature ranging from 120 to 140°C.
• the sterilization step can be performed in an autoclave (moist heat) T°C > 121 ° C, to obtain a F0> 15 (sterilizing value).
• a composition according to the invention is particularly advantageous in that it displays a very interesting high resistance to this sterilization step.
• the loss of G' generated by sterilization for a composition according to the invention is less than for a composition comprising lidocaine instead of mepivacaine.
• the method for preparing a gel of hyaluronic acid according to the invention may further comprise a step d) consisting of adding an additional anesthetic agent or a salt thereof, different from the mepivacaine or a salt thereof, such as above-mentioned, preferably lidocaine or a salt thereof, said step d) being carried out before, simultaneously and/or after the step b).
• a step d) consisting of adding an additional anesthetic agent or a salt thereof, different from the mepivacaine or a salt thereof, such as above-mentioned, preferably lidocaine or a salt thereof, said step d) being carried out before, simultaneously and/or after the step b).
• the gel considered in step a) comprises a crosslinked hyaluronic acid form, this last may be obtained beforehand from an uncrosslinked form of hyaluronic acid.
• the reticulation may be performed by a conventional way with at least one crosslinking agent, such above-mentioned.
• the aqueous mixture comprising the crosslinking agent and the hyaluronic acid to crosslink is advantageously homogenized before performing the crosslinking.
• the purpose of this operation is more particularly for the hyaluronic acid or a salt thereof in the aqueous medium to be hydrated and homogenized perfectly and thus to help to optimize the properties of the gel of hyaluronic acid expected.
• This step of homogenization is more important when the hyaluronic acid has a high molecular weight, because the hydration of such a compound tends to result in the formation of a high- viscosity solution within which the appearance of agglomerates is commonly observed.
• This operation is also intended to homogenize perfectly the crosslinking agent within the mixture so as to subsequently assure a homogeneous crosslinking reaction.
• the homogenization is considered to be satisfactory when the solution obtained is uniformly coloured, with no agglomerates, and has a uniform viscosity.
• the homogenization may advantageously be carried out under mild operating conditions so as to prevent degradation of the hyaluronic acid chains.
• the duration of this homogenization step depends on the nature of the hyaluronic acid or a salt thereof, and more particularly the molecular weight and the concentration thereof, on the operation conditions within the aqueous medium and on the homogenizing device used, generally a device which allows a soft mechanical agitation.
• a homogenization step may take place over a time of less than 200 minutes, preferably less than 150 minutes, or even between 15 and 100 minutes.
• the purpose of the crosslinking reaction is to create bridges between the hyaluronic acid chains making it possible to obtain a dense solid three-dimensional network from a viscous solution.
• the particular conditions to be adopted in order to stimulate the crosslinking reaction may depend on the molecular weight of the hyaluronic acid, on the aqueous medium and on the nature of the crosslinking agent. In general, this reticulation may be achieved by bringing the mixture comprising the non crosslinked hyaluronic acid and at least one crosslinking agent as above-mentioned, into contact with a triggering element, or stimulant, such as, for example by heating or exposure to UV, or even by bringing said mixture into contact with a material of the catalyst type.
• this triggering element is advantageously represented by an increase in temperature imposed on the mixture "non-crosslinked hyaluronic acid/aqueous medium/crosslinking agent".
• a particularly suitable temperature for the crosslinking reaction is between 35°C and 60°C, preferably between 45 and 55°C, and better still between 48 and 52°C.
• the degree of crosslinking also depends on the crosslinking time and of the temperature imposed on the mixture "non-crosslinked hyaluronic acid/aqueous medium/crosslinking agent". The longer the time is, the higher the degree of crosslinking will be, with however an optimum not to be exceeded without running the risk of degrading the hyaluronic acid.
• the crosslinking reaction may be carried out over a time ranging from 30 to 300 minutes, preferably 100 to 200 minutes, and better still 150 to 190 minutes.
• the crosslinking conditions are adjusted to obtain a degree of crosslinking such that the gel of crosslinked hyaluronic acid formed is a viscous, viscoelastic gel, or even a solid gel.
• Stopping the crosslinking reaction requires exposing the crosslinked gel or, during crosslinking, even the receptacle containing it, to conditions propitious for stopping the crosslinking or else to conditions capable of stopping the formation of bonds between the various hyaluronic acid chains.
• the crosslinking may be stopped:
• the homogenization and crosslinking may be carried out within a hermetic cavity delimited at least partially by a deformable wall, preferably made within a deformable pouch, which may be deformed at least manually by palpation, such as described notably in WO 2010/131175.
• the gel obtained at the end of the crosslinking step cannot in general be injected directly, in particular because of its high hyaluronic acid concentration and/or of the possible presence of crosslinking agent residues or else because of its physiological and/or pH conditions incompatible with use in the fields of applications considered above.
• some gels may especially have too high a stiffness to be injected as such into a patient. Therefore, several additional steps, known to those skilled in the art, can be carried out to obtain an injectable hydrogel. More particularly, a step of neutralizing and expanding this gel is required in order to give it its implant qualities. The chains of the hyaluronic acid network are then stretched and hydrated, while the pH is brought to that of the dermis.
• a step of protecting and redensifying the gel can also be carried out for further improving the qualities of the implant, according to the know-how of a person skilled in the art.
• the gel must be physiologically formulated by virtue of the presence of salts in equivalent amounts to those of the medium injected.
• an additional purification step may also be carried out.
• the mepivacaine or salt thereof and, the case arising, additional anesthetic agent(s), is/are added at the end of this protocol of preparation of an injectable form of hyaluronic acid, just before the step of sterilization, such as above- defined.
• the hydrogel added of mepicacaine and optionally of additional anesthetic agent(s), may be used to fill syringes under controlled atmosphere conditions, said syringes then possibly undergoing a sterilization step, preferably a thermal sterilization step such as above- defined.
• a composition according to the invention can be injected using any of the known methods in the art.
• composition of the invention may be administered by means of an injection device suitable for intraepidermal and/or intradermally and/or subcutaneously.
• a composition of the invention may also be administered by means of an injection device suitable for gingival, articular and/or intraocular regions.
• the injection device notably when a composition of the invention is administered by means of an injection device suitable for intraepidermal and/or intradermally and/or subcutaneously, may be selected from a syringe, a set of microsyringes, a laser device, a hydraulic device, an injection gun, a needleless injection device, a rolling with microneedles.
• the injection device may be selected from a syringe or a set of microsyringe.
• the injection device can be adapted to the technique of mesotherapy.
• Mesotherapy is a treatment technique by intraepidermal and/or intradermally and/or subcutaneously active(s) product(s).
• the administration intraepidermal and/or intradermally and/or subcutaneously according to the invention is to inject a composition of the invention in an epidermal region, dermo-epidermal and/or dermal.
• the injection device may comprise any conventionally used injection such as hypodermic needle or cannula.
• a needle or a cannula according to the invention can have a diameter ranging between 18 and 34 G, preferably 25 to 32 G, and a length varying from 4 to 70 mm, preferably 4 to 25 mm.
• the needle or cannula is preferably disposable.
• the needle or cannula is associated with a syringe or other device capable of delivering through the needle or cannula said injectable composition.
• a catheter may be inserted between the needle/cannula and syringe.
• the syringe can be operated manually by the practitioner or by a syringe holder as guns.
• the viscoelastic properties of a composition are measured using a rheometer (Haake RS6000) with a cone/plate geometry (l°cone angle/35 mm diameter plate). A strain scan is carried out and the elastic modulus G' (in Pa) and the phase-shift angle ⁇ (in °) are measured for a stress of 5 Pa.
• Example 1 protocol of preparing a composition according to the invention implementing a non crosslinked hyaluronic acid and analysis regarding its stability to the sterilization
• the protocol of preparing is as follows:
• fraction Al 2. separating the obtained non-crosslinked gel into 2 equivalent fractions (called hereinafter fractions Al and A2); 3. regarding fraction Al, adding to gel 1% by weight of a solution of mepivacaine (30% by weight in phosphate buffer medium) and 0.4% by weight of a solution of NaOH 1% ; or
• fraction A2 adding to gel 1% by weight of a solution of lidocaine (30% by weight in phosphate buffer medium) and 0.4% by weight of a solution of NaOH 1%;
• Example 2 protocol of preparing a composition according to the invention implementing crosslinked and non crosslinked hyaluronic acid and analysis regarding its stability to the sterilization
• the protocol of preparing is as follows:
• the loss in sterilization is calculated as displayed in example 1.
• Example 3 protocol of preparing a composition according to the invention implementing crosslinked and non crosslinked hyaluronic acid and analysis regarding its stability in time
• the preparation procedure is as follows:

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