Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/55—Protease inhibitors
  • A61K38/57—Protease inhibitors from animals; from humans
  • A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
• • 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
  • A61L31/005—Ingredients of undetermined constitution or reaction products thereof
• • 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
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/81—Protease inhibitors
  • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
  • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
  • C07K14/8114—Kunitz type inhibitors
  • C07K14/8117—Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/81—Protease inhibitors
  • C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
  • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
  • C12N9/6402—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals
• • 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
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
  • A61L2300/254—Enzymes, proenzymes
• • 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
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/30—Compounds of undetermined constitution extracted from natural sources, e.g. Aloe Vera
• • 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
  • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
• • 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
  • A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
• • 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
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
  • A61L2300/626—Liposomes, micelles, vesicles

Definitions

• the invention relates to obtaining biologically active substances with cosmetic or pharmaceutical properties in the form of liposomes.
• these liposomes are natural liposomes extracted from medicinal leeches. These natural liposomes have both anti-coagulant and immunomodulatory properties.
• stents are stents, commonly used in cardiovascular surgery to be implanted in a vascular duct, in particular coronary artery or peripheral artery. It is known to treat vascular atheromatous diseases, which correspond to narrowing of the arteries, by balloon dilation techniques, techniques called angioplasties. The balloon is introduced into the artery, inflated to a pressure such that it crushes the deposit of atheromas.
• a stent more commonly called a stent, typically a metal support acting as a support once it is introduced to inside the artery at the treated area.
• Such stents are for example crimped onto the balloon, in a so-called rest position, prior to the introduction of the balloon into the vascular duct.
• stents for drug delivery is described, for example, in WO 01/01957, US 6,099,561; 6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027 5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172; 5,837,008 5,769,883; 5,735,811; 5,700,286; 5,679,400; 5,649,977; 5,637,113; 5,591,227 5,551,954; 5,545,208; 5,500,013; 5,464,450; 5,419,760; 5,411,550; 5342348 5,286,254; and 5,163,952.
• Methods of dressing stents are described in particular in documents US 6,409,716; 6,464,893; and 5,356,433.
• the prior art does not describe substances capable of forming a covering for stents, which are in the form of a liposome, and which have both anti-coagulant and immunomodulatory properties.
• the patient In the uses of the prior art, the patient must be administered two separate drugs, namely an anti-coagulant substance and an immunomodulatory substance.
• liposomes have the great advantage of serving as vectors for both apolar and polar active pharmaceutical compounds. This liposome form thus makes it possible to administer these two types of compounds on the same site.
• the invention aims to overcome the drawbacks of the prior art, and in particular to obtain a composition having both anti-coagulant and immunomodulatory properties, capable of being combined with equipment such as stents, and presenting in the form of liposomes so as to obtain an appropriate release of the substance.
• the inventors have succeeded in obtaining such a substance from medicinal leeches.
• Prior art is known a method for obtaining a destabilase complex, designated prototype, using a step of affinity chromatography on a support insoluble in water (CNBr activated agarose, for example) carrying immobilized lysine ( REF).
• the extract is conveyed by a buffer with a pH lower than the neutral pH, the pH is neutralized, then dialysis and lyophilization take place.
• the elution of the final product from the immobilized lysine using a buffer with a low pH of less than 9 does not make it possible to obtain a destabilase complex capable of the desired storage and the sufficient enzymatic activity sought .
• the destabilase molecule extracted by this process is in the form of an unstable monomeric enzymatic complex which undergoes a change of conformation, which makes it lose its capacity to form an enzymatic complex in polymeric form.
• the enzymatic complex in the form of a monomer no longer has the capacity to structure itself in a desirable manner into a polymer, a polymer which is organized into a liposome.
• the known complexes (prototypes) produced by medicinal leeches form a complex of hirudin, prostaglandin, destabilase, and kallikrein inhibitors of blood plasma in the ratio 1: 1: 1: 1.
• the abstract XP002237190 of patent application RU 2 129429 C describes a method for isolating prostaglandin complexes from leeches medicinal. The method involves purifying the mixture by affinity chromatography with anti-6-ketoprostaglandin-F1 antibodies immobilized on a water-insoluble support.
• the analysis of the eluate is carried out by electrophoresis.
• the fraction obtained is composed of destabilase monomer aggregate and has the properties of micellar proteins and is represented by a stable lipid-protein complex.
• the destabilase monomers can be in the form of a destabilase complex polymer forming a liposome. Said liposomes have the capacity to rapidly penetrate cell membranes and to have anti-thrombotic activity.
• Patent application WO 92 02206 describes lyophilized native collagen sheets comprising cosmetic forms for the treatment of rosacea.
• the active ingredients in the cosmetic formulation may include hirudin, an anti-coagulant protein from leeches.
• Patent application WO 98 16604 describes cleaning compositions, preferably detergent compositions for detergents, comprising an iso-peptidase type enzyme having the capacity to catalytically cut the bonds between glutamine and lysine.
• Patent application WO 01 47572 describes a method for inhibiting the restenosis of a blood vessel comprising: - the supply of a device comprising an active compound having an anti-thrombotic and anti-inflammatory activity, and
• the inventors have given themselves the goal of obtaining a stable destabilase complex having improved biological activities compared to the compositions of the prior art.
• the inventors have succeeded in obtaining a monomeric destabilase complex which is stable and capable of aggregating into a polymer organizing itself into a liposome.
• the subject of the invention is, according to a first aspect, a stable destabilase complex, in the form of a monomer, capable of aggregating into a polymeric destabilase complex forming a liposome, capable of being obtained from medicinal leeches by a process comprising: - affinity chromatography with said antibodies to 6-ketoprostaglandin immobilized on an appropriate column;
• said complex having an antithrombin activity of at least 700 ATU / mg, a plasma recalcification duration of at least 800 APC / mg, a fibrinolytic activity of at least 40 min 2 / mg, and immunomodulatory activity.
• the purification process is done by chromatography, preferably affinity chromatography. This process includes:
• Said destabilase complex obtained by this process is in the form of a monomer and comprises destabilase and at least one compound from the hirudin group, prostaglandin, kallikrein inhibitor. It is also possible to combine the action of anti-6-keto-PGF1 ⁇ antibodies and of lysine sepharose.
• the destabilase liposome complex has, like the monomeric destabilase complex, very useful pharmaceutical properties, typically an antithrombin activity of at least 500, preferably at least 600 or 700 ATU / mg, a duration of plasma recalcification. at least 800 APC / mg, a fibrinolytic activity of at least 40 mm / mg.
• the antithrombic and thrombolytic action is clearly improved compared to the control and the prototype.
• the invention also relates to a pharmaceutical composition comprising a liposome destabilase complex according to the invention and a pharmaceutically acceptable vehicle.
• pharmaceutically acceptable carrier is used to denote a non-toxic, solid or diluent or encapsulating liquid material, which does not react negatively on the active compound for its effectiveness.
• the invention also relates to a cosmetic composition comprising this liposome destabilase complex according to the invention.
• the invention also relates to the liposome destabilase complex as a medicament, and the use of a liposome monomeric or polymeric destabilase complex for the preparation of a medicament having anti-coagulant and immunomodulatory activity.
• the invention also relates to a device for purifying a destabilase complex from medicinal leeches, comprising an affinity column loaded with anti-6-keto-prostaglandin antibodies.
• the invention also relates to an implantable medical prosthesis, in which at least part of the prosthesis is covered with a covering, said covering comprising a destabilase liposome complex according to the invention.
• the implantable prosthesis is a stent support.
• the method for purifying the stable destabilase complex according to the invention comprises a step of affinity chromatography using antibodies of 6-keto-PGFl ⁇ (6-keto-prostaglandin F l ⁇ ), immobilized on a support insoluble in l 'water.
• the principle of immunoaffinity chromatography is known to those skilled in the art and is based on the specificity of mono or polyclonal antibodies to capture specific protein antigens from complex natural extracts.
• the inventors have succeeded in obtaining, quite surprisingly, a destabilase complex with preserved biological activities which is both anti-coagulant and immunomodulatory, and capable of being structured into liposomes.
• the antibodies are coupled to a solid chromatographic phase, typically of agarose, by covalent bonds (cyanogen bromide, for example CNBR), or other chemical couplings targeting the amino, hydroxyl, carboxyl or sulphidryl groups of the immunoglobulins so as to form a solid matrix.
• a solid chromatographic phase typically of agarose
• covalent bonds cyanogen bromide, for example CNBR
• the solid phase coupled to the antibodies is then placed in an affinity chromatography column.
• the mixture of target antigen and contaminants is diluted in a binding buffer and then applied to the column. Non-adsorbed contaminants are removed by washing with different buffers.
• the elution of the target protein antigen is then obtained using for example extreme pH conditions, changes in ionic strengths.
• Hirudin and kallikrein inhibitors have activity only in the aqueous phase.
• Destabilase has activity only in the nonaqueous phase.
• the stable destabilase complex obtained by the inventors exhibits hydrophobic properties conditioned by the prostaglandin component, and hydrophilic properties by the liposome polypeptides.
• the monomeric form of the destabilase complex has a molecular weight of 25 kDa, is stable, has an aggregation capacity which results in the formation of liposomes. It is obtained from total extracts of leeches, or from a fraction in particular of secretions from the salivary glands or from the blood of the digestive tract of the leech. After purification by affinity chromatography, the destabilase complex obtained comprises the following components: hirudin, prostaglandin (substance similar to prostaciclyne), kallikrein inhibitor, destabilase.
• the destabilase complex has the following properties: antithrombotic activity by hirudin, increased time for recalcification of blood plasma by kallikrein inhibitors, blocking of adhesion and platelet aggregation by prostacyclin-like substances, dissolution of fibrins stabilized by destabilase.
• destabilase complex determines its antithrombotic, thrombolytic (2.5 times greater than those of the prototype), immunomodulatory, and hypotensive activity completely absent in the prototype.
• the following are the methods for measuring the biological activity used for the purified leech extract and in the form of a liposome, then four examples of realization demonstrating both the anti-coagulant and immunomodulatory activity of the destabilase complex according to the invention.
• the antithrombin activity is determined by the lengthening of the duration of fibrinogen precipitation by thrombin.
• the duration of the formation of a precipitate is determined in a system comprising 0.2 ml of a 0.3% fibrinogen solution, and 0.1 ml of the destabilase complex after fixing 0.1 ml of a thrombin solution. comprising a thrombin activity unit.
• Hirudin activity is expressed in international antithrombin units (ATU NIH). 2 /
• the time for recalcification of the blood plasma is determined in a system comprising 0.1 ml of citric blood plasma and 0.1 ml of destabilase complex after fixing 0.1 ml of a 0.025 M solution of CaCl 2 . The increase of this parameter by two corresponds to one APC unit.
• the prostaglandin content is determined using a radio immunoassay for 6-keto-PGFl ⁇ obtained from the "Amersham” Company.
• 4 / The antithrombotic action of the destabilase complex is determined on rats using the thromboformation method of Wessler (5). The level of thromboformation blockage is evaluated in relation to the control. For this, we study the results following a 4-hour separation between the injection of the destabilase complex and an injection of cold-activated human blood serum. This degree of blockage is expressed in% relative to the control (equal volume of normal saline solution).
• hypotensive action is determined following the oral administration of 0.2 ml of a destabilase complex in rats of a SHR line (spontaneously hypertensive).
• the initial pressure level was 165 ⁇ 5 mm.
• the pressure level in the rat is measured in the tail vein.
• the level of hypotensive efficiency is expressed as a percentage relative to the control (equal volume administered with normal saline).
• the protocol is as follows:
• the elution is obtained by a buffer comprising 0.2 M glycine with 0.15 M HC1 and
• the volume of the eluate is 35 ml.
• the final product has fibrinolytic, antithrombin activity, increases recalcification time, contains prostaglandin, and in addition to the high antithrombolytic potential, has a hypotensive action reducing blood pressure by 25% ( bringing it back practically to normal).
• Example 2 5 ml of a secretion from the salivary glands of leeches were introduced into an agarose column with immobilized anti-6-keto-PGF1 ⁇ antibodies. The elution is obtained using a 0.5 M phosphate buffer, pH 6.4. The volume of the eluate is 10 ml.
• the final product has fibrinolytic antithrombin activity, increases recalcification time, contains prostaglandin, and in addition to a high antithrombic and thrombolitic potential, has a hypotensive action, reducing blood pressure by 25 % (bringing it back to practically normal).
• the destabilase complex increases the cytophagous index and the percentage of phagocytosis (Table 1), demonstrating the immunostimulatory action.
• the final product has fibrinolytic antithrombin activity, increases the recalcification time, contains prostaglandin, and in addition to a high antithrombic and thrombolytic potential, has a hypotensive action, reducing blood pressure by 25% (bringing it back to practically normal).
• the destabilase complex increases the cytophagous index and the percentage of phagocytosis (Table 1), demonstrating the immunostimulatory action.
• the protocol is as follows: take twenty medicinal leeches (total 21 g), extract the front part of the animal, homogenize, and collect the aqueous extract. 10 ml of the extract are placed in an L-Lysine-Sepharose column. The elution is obtained with a 1 M KC1 solution. The volume of the eluate is 20 ml.
• the final product has fibrinolytic antithrombin activity, increases recalcification time, contains prostaglandin, and in addition to a high antithrombic and thrombolytic potential, has a hypotensive action, reducing blood pressure by 25 %) (bringing it back to almost normal).
• the destabilase complex increases the cytophagous index and the percentage of phagocytosis (Table 1), demonstrating the immunostimulatory action.
• Table 1 definition activities of leech extracts.
• the support stents of the destabilase complex obtained by the inventors can be of very varied types.
• a stent will have an external polymeric surface on which a gelatinous matrix will be placed, the matrix including the destabilase complex in the form of liposomes.
• the polymer surface will be linked by bonds covalent with the gelatinous matrix.
• the polymer gel can, for example, have a thickness of 10 to 50 ⁇ m in the uncompressed state.
• This gel can be chosen, for example, from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, polyacrylic acid. .

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• 2002
  • 2002-08-07 FR FR0210042A patent/FR2843304B1/fr not_active Expired - Fee Related
• 2003
  • 2003-08-06 AU AU2003282192A patent/AU2003282192A1/en not_active Abandoned
  • 2003-08-06 EP EP03756529A patent/EP1527169A2/de not_active Withdrawn
  • 2003-08-06 WO PCT/FR2003/002473 patent/WO2004015096A2/fr not_active Ceased
  • 2003-08-06 JP JP2004526981A patent/JP2005534331A/ja active Pending
  • 2003-08-06 US US10/523,937 patent/US20060110425A1/en not_active Abandoned

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