WO2012038333A2 - Composition to act in prevention and to take care of diabetic foot - Google Patents
Composition to act in prevention and to take care of diabetic foot Download PDFInfo
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- WO2012038333A2 WO2012038333A2 PCT/EP2011/066079 EP2011066079W WO2012038333A2 WO 2012038333 A2 WO2012038333 A2 WO 2012038333A2 EP 2011066079 W EP2011066079 W EP 2011066079W WO 2012038333 A2 WO2012038333 A2 WO 2012038333A2
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- ions
- antimicrobic
- bentonite
- silver
- composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- 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
- A61K31/16—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
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Definitions
- the invention concerns medicine and can be used to manufacture liquid compositions for external application, possessing antimicrobic properties and intended for preventive maintenance and treatment of diseases of integuments of people, for treatment of wounds and ulcers for stimulation of regeneration and healing of wound surfaces specifically related to the syndrome of diabetic foot.
- compositions including film-forming solutions of polymeric compounds, medicinal substances and antimicrobic agents are used in modern therapeutic practice and dermatology for preventive protection and treatments of defeats of integuments of various etiologies; at treatment of a wound, a thin protective polymeric film containing medicinal and antimicrobic substances forms on the wound surface, after evaporation of solvent.
- the syndrome of diabetic foot combines pathological changes of peripheral nervous system, of arterial and micro-circulating channels, representing threat of development of wound, ulcerous-necrotic processes and occurrence of a gangrene of foot.
- the course of the wound process in patients with diabetes has the following features:
- Efficiency of wound-healing compositions is determined by various functional properties [see, for example, M.I.Shtilman, Polymers for medical and biologic purposes, M., "Akademkniga", 2006, p. 182] including the following: - ability to protect a wound from mechanical influence, pollution and penetration of pathogenic microorganisms;
- compositions including film-forming solutions of polymeric compounds (as a basis), medicinal substances and antimicrobic agents are known. They are widely used in medicine for local prevention and treatment of wounds.
- compositions containing active components such as for example : nitrofurans, hydroxymethylhinoxilindioxide, trimecaine, yodovidon, miramistin (dymetyl benzyl [3- (miristoilamino) propyl] ammoniumchloride), aminitrozol, chloramphenicol, methyluracil, hydrocortisone acetate, neomycin sulfate, heliomitsin, are commercially available.
- active components such as for example : nitrofurans, hydroxymethylhinoxilindioxide, trimecaine, yodovidon, miramistin (dymetyl benzyl [3- (miristoilamino) propyl] ammoniumchloride), aminitrozol, chloramphenicol, methyluracil, hydrocortisone acetate, neomycin sulfate, heliomitsin, are commercially available.
- a composition for treatment and preventive protection of a wound surface containing water solution of sodium alginate, enzyme terrilitin and calcium gluconate, is described in the specification of the Russian patent RU No. 2028158.
- a composition for treatment of wounds containing as the basis polyethylenoxides, water and additionally lanolin and active substances such as acetyl aminocaproic acid and sodium hydrocarbonate, is described in the specification of the Russian patent RU No. 2123843.
- a composition containing a methacrylic copolymer (chosen from EUDRAGIT RL and EUDRAGIT RS or their mix) and a therapeutic agent is described in the specification of the Russian patent RU No. 2301056.
- This composition provides transfer of the therapeutic agent into tissues of the organism, mechanical protection of wounds and a barrier to bacteria.
- Binding components of the composition can be liquid polyols, a polymeric binding agent, silicon dioxide, pitch or their combination.
- the composition includes an active component chosen from salts containing cations of metals (lithium, sodium or potassium) and oxide of halogens forming anions.
- This composition contains mixes of various polyethyleneoxides and propylene glycol as a hydrophilic basis and trimekain, antiseptic miramistin, D-Panthenol and-or calcium pentetonate as the active ingredients.
- a composition containing a film-forming substance, an antiseptic preparation in polar solvent and a locally anesthetic substance is described in the specification of the Russian patent RU No. 2312658.
- This composition is intended for processing wounds and possesses protective, anesthetizing and disinfectant properties. It can be used in the syndrome of diabetic foot.
- the composition contains a film-forming component as a polysiloxane-polycarbonate block-copolymer, an antiseptic preparation in a polar solvent, anesthetizing substance and solvent of the block-copolymer as chloroform. Brilliant green, blue, yodopiron and some other iodine-containing compounds are used as the antiseptic ingredient.
- Chloroform trichloromethane
- the antiseptic preparation as brilliant green does not possess a wide spectrum of action and the necessary level of antimicrobic activity; it is active only in relation to gram-positive bacteria and causes irritation of integuments.
- the antiseptic preparation yodopiron (povidone-iodine and potassium iodide) causes dryness of the skin, skin itch, allergic reactions (dermahemia, nettle rash); it does not possess the necessary selective action and it is contra-indicated to application in cease of hyperthyroidism, adenoma of thyroid gland, heart and chronic renal failure.
- antibiotics including those mentioned above
- compositions on the basis of biologically active metals asilver, copper, zinc, ferrum, gold, tin, etc.
- biologically active metals silver, copper, zinc, ferrum, gold, tin, etc.
- compositions containing silver sulfadiazin and sodium piperacillin (USA patent US No. 4535078, published in 1985) or wound-healing materials containing tissues of animals impregnated with silver salt of sulfadiazine (Patent US No. 4599226, published in 1987).
- a preparation for treatment of wounds and burns consisting of a water solution containing basic copper acetate, sodium acetate, an acetic acid and water is described in the specification of the Russian patent RU No. 2155047.
- the therapeutic effect results in analgesic, anti-inflammatory and bactericidal action.
- a water-soluble silver-containing bactericidal composition for therapy of pyo- septic complications of wounds and burns, containing the superdispersed metal silver stabilized with poly-N-vinylpirrolidone, is described in the technical decision according to the Russian patent RU No. 2128047.
- a biologically active bactericidal preparation for treatment of wounds, burns, umours is described in the specification of the Russian patent RU No. 2379042.
- the preparation is a suspension of particles of powders of copper, ferrum and zinc with dispersiveness of particles 180-220 nm.
- a perfluorocarbon emulsion with colloidal silver for medical, biologic and cosmetic purposes is described in the specification of the patent application for invention RU No. 2009104356. It is also described as antimicrobic means for drawing, irrigation, wetting of long scars and ulcers.
- powders of metals and solutions are not technologically acceptable forms for maintenance of effective regulation of penetration of ions of metals to wound surfaces from the carrier (film-forming substance);
- Antiseptic agents produced on the basis of natural inorganic components are also known (see Russian patent RU No. 2330673).
- an antiseptic agent consisting of a nanostructured powder of bentonite intercalated by ions of silver (Ag + ).
- Said agent is obtained by modifying a bentonite with a solution of silver nitrate, after a preliminary enrichment with cations of sodium (Na + ) through processing with a water solution of NaCl and subsequent cleaning from anions of chlorine.
- bentonite is cleaned from salt of sodium by grinding up to a size of the particles of the powder of no more than 150 nm.
- the antiseptic agent consisting of a powder of bentonite intercalated by ions of Ag + , is obtained from the mineral components which are biologically compatible with tissues of live organisms and can be used as additives in various compositions and preparations for preventive protection, treatment and antimicrobic processing of the injured zones of integuments.
- the problem of medical processing wounds, ulcers, pustular diseases of a skin of patients with the syndrome of diabetic foot is not solved in the Russian patent RU No. 2330673.
- the problem of the present invention consisted in the creation of an effective composition, having preventive action, for treatment of diabetic foot, on the basis of components possessing biological compatibility and providing antimicrobic action, acceleration of regeneration and healing of integuments.
- the present invention describes compositions for preventive protection and care of diabetic foot, containing a film-forming substance, an antimicrobic agent in polar solvent and a locally anesthetic substance, able to solve the put technical problem.
- an alcohol solution of a block-copolymer of polydimethylsiloxane and polyurethane, with viscosity from 10000 up to 45000 Pa-s at 110°C is used as a film- forming substance.
- the composition additionally contains a second antimicrobic agent on the basis of a mix of nano structured powders of bentonite intercalated by ions of silver (Ag + ) and ions of cerium (Ce 3+ ).
- a second antimicrobic agent on the basis of a mix of nano structured powders of bentonite intercalated by ions of silver (Ag + ) and ions of cerium (Ce 3+ ).
- the composition has the following contents of components, in % b.w.:
- a mix of a nanostructured powder of bentonite intercalated by ions of silver (Ag + ) and a nanostructured powder of bentonite intercalated by ions of cerium (Ce 3+ ) is used at the ratio of 1 : (0.1-0.5) parts by weight of the two components.
- the nanostructured powder of bentonite intercalated by ions of silver (Ag + ) has the size of particles of no more than 150 nm.
- a nanostructured powder of bentonite intercalated by ions of cerium (Ce 3+ ) is obtained at modification of a semifinished product of bentonite with a 0,3-2,0 % water solution of nitrate salt of cerium Ce(N0 3 ) 3 -6H 2 0.
- Bentonite is preliminary enriched with cations of sodium (Na + ) by processing with a 3-10% water solution of sodium chloride and subsequently is cleaned from anions of chlorine.
- bentonite is cleaned from salts of sodium with grinding up to a size of the particles of no more than 150 nm.
- the locally anesthetic substance is selected out of the pharmacological group of local anesthetics; 2-diethylamino-2',6'-acetoxylidide hydrochloride is preferably used.
- aqueous-alcohol solution is used as polar solvent.
- the microbic infection in wounds is suppressed, regeneration and healing of integuments in patients with the syndrome of diabetic foot is accelerated due to the following elements:
- compositions of antimicrobic agents on the basis of a water solution of polyhexanide hydrochloride and of nanostructured powder of bentonite intercalated by ions of silver (Ag + ), possessing activity against many kinds of microorganisms (including aerobic, anaerobic bacteria, funguses);
- compositions due to presence of ions of silver.
- Biologically active ions of silver are released out owing to an ionic exchange between particles of the intercalated bentonite and the contacted biological environment created by wound surfaces, tissues and liquids;
- compositions of a film-forming substance forming a polymeric film as the carrier of the antimicrobic agents, possessing good gas permeability, elasticity and adhesion to a surface protecting an integument from action of external factors (mechanical influences, infections).
- the present declared invention can be industrially realized by using known technological processes, equipment and materials intended for manufacturing preparations for medical purposes.
- Active substance and polymeric components known in the pharmaceutical industry and medicine and intended for manufacturing various compounds are used for realization of the invention.
- the antimicrobic agent is a water solution of polyhexanide hydrochloride with polyethylene glycol 4000, at the ratio polyhexanide hydrochloride : polyethylene glycol : water as 1: 0.05 : (3 ⁇ 4) weight parts.
- the given preparation has the trade mark "Lavasept” and pertains to the pharmacological group of antiseptics and disinfectants.
- the preparation is intended for antiseptic processing of infected wounds and superficial injures of soft tissues including processing of integuments with the syndrome of diabetic foot.
- the quantitative content of the antimicrobic agent in the composition specified in the present invention is the optimum and corresponds to the requirements for application in external antiseptic processing of infected wounds. Decrease in the quantitative content of antimicrobic preparation in the composition worsens its antimicrobic and fungicidal properties. Increase in the quantitative contents leads to increase in costs and raises the risk of allergic reactions on the skin.
- Locally anesthetic substance 2-diethylamino-2',6'-acetoxylidide hydrochloride.
- the given compound has the trade mark "Lidocaine Hydrochloride” and pertains to the pharmacological group of local anesthetics and anti-arhythmic means. It stabilizes cellular membranes, blocks sodium channels, increases permeability of membranes to ions of potassium. Locally anesthetic action is caused by blockage of the voltage-dependent sodium channels that impedes generation of impulses in sensitive teleneurons and carrying out of impulses in nervous fibres.
- the film- forming substance is 0.5-2.0% alcoholic solution of a block-copolymer of polydimethylsiloxane and polyurethane.
- the trade name of block-copolymer of polydimethylsiloxane and polyurethane is «Penta-1009». It has a viscosity from 10000 up to 45000 Pa » s at 110°C. It is used in manufacture of elastomeric products and transparent films; it is applied as a gas-permeable textile coating (for textile fibres).
- the antimicrobic agent is a nano structured powder of bentonite intercalated by ions of silver (Ag + ).
- the given antimicrobic agent is obtained according to the known technology described in the Russian patent RU No. 2330673.
- a natural mineral montmorillonite (bentonite in Na-form) is used for obtaining the antimicrobic agent.
- Bentonite is processed with 3-10% water solution of sodium chloride, with subsequent washing and filtering of the obtained semifinished product for removal of chlorine.
- the semifinished product of bentonite is modified by 10-20% solution of silver nitrate, with retention interval of modified bentonite in the specified salt solution.
- the obtained product is cleaned from salts of sodium; then it is nanostructured to obtain a powder of bentonite.
- the size of the particles of the powder of bentonite is no more than 150 nm. Processing of the mineral with the named solutions of salts is carried out at the ratio, in parts by weight, bentonite : solution as 1 : (10-40).
- the powder of bentonite intercalated by ions of silver contains from 2 up to 8% b.w. of silver, depending on the amount of activating and modifying agents.
- the specified amount of the named metal in the bentonite powder is the optimum. Increase in amount of metals leads to increase in costs for obtaining the antimicrobic agent and decrease leads to worsening of antimicrobic activity.
- the quantitative contents of a nanostructured powder of bentonite intercalated by ions of silver specified in the present invention are the optimum.
- Antimicrobic properties of the composition worsen at decrease in the content of the given antimicrobic agent in said composition.
- Increase in the quantitative content of the given antimicrobic agent in the compositions increases expenses for its manufacturing.
- the given product is obtained at modification of a semifinished product of bentonite by 0.3-2.0% water solution of nitrate salt of cerium Ce(N0 3 )3-6H 2 C).
- Bentonite is obtained after its enrichment with cations of Na + by processing with 3-10% water solution of sodium chloride and subsequent cleaning from anions of chlorine.
- bentonite is cleaned from salts of sodium and nanostructured up to a size of the particles of no more than 150 nm.
- a 0,5% water solution of cerium nitrate Ce(N0 3 )3-6H 2 C) was used for realizing the present invention, in the process of intercalation of the semifinished product of bentonite obtained after its enrichment with cations of Na + .
- the powder of bentonite obtained after intercalation, cleaning and nanostructuring contains cerium in amount of no more than 0.5% b.w..
- cerium metal of variable valency
- Ce0 2 cerium dioxide
- Inactivating and blocking influence on formation of peroxides and hydroperoxide radicals generated at oxidizing processes is peculiar to it.
- the given metal is a recognised biologically compatible material and is used in medicine, for example, in prosthetics, stomatology.
- the quantitative contents of a nanostructured powder of bentonite intercalated by ions of cerium (Ce 3+ ) specified in the present invention are the optimum for blocking free radicals and peroxides formed at oxidizing processes in wounds integuments of patients. Efficiency of influence of ions of cerium on free radicals and peroxides worsens at decrease in the contents of the given component in the composition. Increase of the quantitative contents of the given component in the composition increases costs for its manufacturing.
- Nano structured powders of bentonite with a size of the particles of no more than 150 nm are obtained.
- a method of microscopy was used for estimation of the size of the particles of bentonite.
- composition according to the invention is obtained as follows.
- Film-forming substance i.e. an alcoholic solution of a block-copolymer of polydimethylsiloxane and polyurethane was mixed with a polar solvent at a temperature of + 20° / + 30°C. Then other components specified in the invention, i.e. antimicrobic agents and a locally anesthetic substance are added in the obtained solution. Mixing of the composition according to the invention is carried out preferably with use of the ultrasonic equipment, providing effective dispersion of intercalated nano structured powders of bentonite in the solution.
- a composition for processing integuments in a case of syndrome of diabetic foot, according to the present invention was obtained with the following examples where all amounts are expressed in % by weight (b.w.)
- compositions obtained according to Examples 1-3 have a liquid homogeneous structure.
- the composition according to the invention is placed on an integument or a wound surface with the help of a spray bottle, from distance of 10-20 cm, providing formation of a uniform coating with thickness 5-15 microns.
- the formed polymeric film possesses good gas permeability, elasticity and adhesion to a surface; it also protects an integument from action of external factors (mechanical influences, infections).
- the composition is intended for application in I and III phases of wound process of a syndrome of diabetic foot.
- the composition In the 1st phase (inflammation and infection, vascular reactions, hypostasis, infiltration of tissues) the composition is used for suppression of infections and of the microbic environment in the wound, for decreasing inflammation of the tissues, for inhibiting oxidizing processes and action of free radicals; as an interim sparing medical coating (bandage).
- the composition In the Illrd phase (reorganization of a scar epithelization) the composition is used for stimulation of reparative processes in wounds, epithelization and formation of a film possessing protective action from mechanical damages and drying, in respect of regenerable tissues and neo epithelium.
- White rats weighting 180-210 g were used for carrying out the estimation laboratory tests of the compositions according to the Examples 1-3. They were divided into three groups each comprising 7 individuals. A wound was made by mechanical way (scalpel) on a shaved integument of each rat. Depth of the wound was 0.8 - 1.0 mm, the area was 150 mm . To perform the tests, wound areas of rats (from each group) were treated with compositions according to Examples 1-3. The treatment was repeated 2 times a day (daily, in the morning and in the evening) up to full healing of wounds.
- the size of wound areas at rats were estimated and terms of resorption of infiltration, occurrences of granulation, epithelization of wounds were determined during the tests.
Abstract
The invention concerns medicine and can be used to manufacture liquid compositions for external application, possessing antimicrobic properties and intended for preventive maintenance and treatment of diseases of integuments of people, for treatment of wounds and ulcers and for stimulation of regeneration and healing of wound surfaces in the syndrome of diabetic foot. The composition for preventive maintenance and care of diabetic foot comprises a film-forming substance, an antimicrobic agent in polar solvent and a locally anesthetic substance. The new compositions additionally contain a second antimicrobic agent on the basis of a mix of nano structured powders of bentonite intercalated by ions of silver (Ag+) and ions of cerium (Ce3+). The use of the new compositions according to the present invention, in preventive maintenance and treatment of the effects of the syndrome of diabetic foot, has promoted suppression of the microbic infection in wounds, acceleration of regeneration and healing of integuments of patients.
Description
COMPOSITION TO ACT IN PREVENTION AND TO TAKE CARE OF DIABETIC FOOT
Field of the invention
The invention concerns medicine and can be used to manufacture liquid compositions for external application, possessing antimicrobic properties and intended for preventive maintenance and treatment of diseases of integuments of people, for treatment of wounds and ulcers for stimulation of regeneration and healing of wound surfaces specifically related to the syndrome of diabetic foot.
Compositions including film-forming solutions of polymeric compounds, medicinal substances and antimicrobic agents are used in modern therapeutic practice and dermatology for preventive protection and treatments of defeats of integuments of various etiologies; at treatment of a wound, a thin protective polymeric film containing medicinal and antimicrobic substances forms on the wound surface, after evaporation of solvent.
Prior art
Appearing of the syndrome of diabetic foot is one of the hard complications of diabetes. The syndrome of diabetic foot combines pathological changes of peripheral nervous system, of arterial and micro-circulating channels, representing threat of development of wound, ulcerous-necrotic processes and occurrence of a gangrene of foot.
The course of the wound process in patients with diabetes, has the following features:
- low speed epithelization of the ulcer surface owing to more intensive processes of peroxide oxidations of lipids. What leads to formation of free radicals and peroxides, considerably slowing down processes of healing;
- complex pathogenesis of the wound process, accompanying both anaerobic microflora and hypoxia, causing destructive changes of tissues owing to lacking of a selective filtration of biological liquids and exchange diffusion. That interferes with removal of metabolic products and maintenance of tissues with nutrients and oxygen.
Efficiency of wound-healing compositions, including compositions for preventive maintenance and treatment of diabetic foot, is determined by various functional properties [see, for example, M.I.Shtilman, Polymers for medical and biologic purposes, M., "Akademkniga", 2006, p. 182] including the following:
- ability to protect a wound from mechanical influence, pollution and penetration of pathogenic microorganisms;
- adhesion to tissues of a wound;
- ability to release and transport a medicinal and antimicrobic substances into tissues of an organism;
- sufficient gas permeability for maintenance of the regenerative processes demanding presence of oxygen;
- presence of biologically active action;
- possibility of application by patients and medical staff due to ease of treatment and absence of pain for removal of the structure.
Compositions including film-forming solutions of polymeric compounds (as a basis), medicinal substances and antimicrobic agents are known. They are widely used in medicine for local prevention and treatment of wounds.
Compositions containing active components such as for example : nitrofurans, hydroxymethylhinoxilindioxide, trimecaine, yodovidon, miramistin (dymetyl benzyl [3- (miristoilamino) propyl] ammoniumchloride), aminitrozol, chloramphenicol, methyluracil, hydrocortisone acetate, neomycin sulfate, heliomitsin, are commercially available.
A composition for treatment and preventive protection of a wound surface, containing water solution of sodium alginate, enzyme terrilitin and calcium gluconate, is described in the specification of the Russian patent RU No. 2028158.
A composition for treatment of wounds, containing as the basis polyethylenoxides, water and additionally lanolin and active substances such as acetyl aminocaproic acid and sodium hydrocarbonate, is described in the specification of the Russian patent RU No. 2123843.
A composition containing a methacrylic copolymer (chosen from EUDRAGIT RL and EUDRAGIT RS or their mix) and a therapeutic agent is described in the specification of the Russian patent RU No. 2301056. This composition provides transfer of the therapeutic agent into tissues of the organism, mechanical protection of wounds and a barrier to bacteria.
A composition for obtaining a medical product for treatment of open wounds and burns is described in the specification of the patent application for invention RU No. 2007116956. Binding components of the composition can be liquid polyols, a polymeric
binding agent, silicon dioxide, pitch or their combination. The composition includes an active component chosen from salts containing cations of metals (lithium, sodium or potassium) and oxide of halogens forming anions.
A composition with antiseptic, reparative and pain-relieving properties is described in the specification of the Russian patent RU No. 2177314.
This composition contains mixes of various polyethyleneoxides and propylene glycol as a hydrophilic basis and trimekain, antiseptic miramistin, D-Panthenol and-or calcium pentetonate as the active ingredients.
A composition containing a film-forming substance, an antiseptic preparation in polar solvent and a locally anesthetic substance is described in the specification of the Russian patent RU No. 2312658. This composition is intended for processing wounds and possesses protective, anesthetizing and disinfectant properties. It can be used in the syndrome of diabetic foot. The composition contains a film-forming component as a polysiloxane-polycarbonate block-copolymer, an antiseptic preparation in a polar solvent, anesthetizing substance and solvent of the block-copolymer as chloroform. Brilliant green, blue, yodopiron and some other iodine-containing compounds are used as the antiseptic ingredient.
However, the components of the given composition can show negative effects. Chloroform (trichloromethane) possesses irritating and allergic action, has hepatic toxic influence on the organism of a person (damaging of functions of liver and kidneys is possible), and has a slow elimination from the organism. The antiseptic preparation as brilliant green (synthetic dye of triphenylmethane kind) does not possess a wide spectrum of action and the necessary level of antimicrobic activity; it is active only in relation to gram-positive bacteria and causes irritation of integuments. The antiseptic preparation yodopiron (povidone-iodine and potassium iodide) causes dryness of the skin, skin itch, allergic reactions (dermahemia, nettle rash); it does not possess the necessary selective action and it is contra-indicated to application in cease of hyperthyroidism, adenoma of thyroid gland, heart and chronic renal failure.
It is necessary to note that the above mentioned medicinal forms and the compositions and preparations for preventive maintenance and treatments of wounds, ulcers, burns, inflammatory processes in the considered patents for inventions, can possess a number of short-comings. It is possible to mention the following:
- occurrence of allergic and toxic reactions in patients with individual intolerance to medical and to antimicrobic components, in particular to antibiotics;
- occurrence of reinfection of wounds owing to a narrow spectrum of antimicrobic action of the components, insufficient efficiency in the treatment of inflammations of tissues and wounds infected with pathogenic funguses;
- insufficient efficiency of release and transfer of medicinal and antimicrobic substances into tissues of an organism from formed medical coatings.
In medical practice, alongside with antimicrobic components of a natural and synthetic origin, antibiotics (including those mentioned above) compositions on the basis of biologically active metals (silver, copper, zinc, ferrum, gold, tin, etc.) are used in composition of antiseptic, wound-healing and anti-inflammatory preparations. They have a wide spectrum of antimicrobic and fungicidal actions, (see for example, the following documents:
- H.E. Morton, Pseudomonas in Disinfection, Sterilisation and Preservation, ed. S.S. Block, Lea and Febider 1977 and N. Grier, Silver and Its Compounds in Disinfection,
Sterilisation and Preservation, ed. S.S. Block, Lea and Febiger, 1977).
- Compositions containing silver sulfadiazin and sodium piperacillin (USA patent US No. 4535078, published in 1985) or wound-healing materials containing tissues of animals impregnated with silver salt of sulfadiazine (Patent US No. 4599226, published in 1987).
- A preparation for treatment of wounds and burns, consisting of a water solution containing basic copper acetate, sodium acetate, an acetic acid and water is described in the specification of the Russian patent RU No. 2155047. The therapeutic effect results in analgesic, anti-inflammatory and bactericidal action.
- A water-soluble silver-containing bactericidal composition, for therapy of pyo- septic complications of wounds and burns, containing the superdispersed metal silver stabilized with poly-N-vinylpirrolidone, is described in the technical decision according to the Russian patent RU No. 2128047.
- A biologically active bactericidal preparation for treatment of wounds, burns, umours is described in the specification of the Russian patent RU No. 2379042. The preparation is a suspension of particles of powders of copper, ferrum and zinc with dispersiveness of particles 180-220 nm.
- A perfluorocarbon emulsion with colloidal silver for medical, biologic and cosmetic purposes is described in the specification of the patent application for invention RU No. 2009104356. It is also described as antimicrobic means for drawing, irrigation, wetting of long scars and ulcers.
All above mentioned patents or patent applications using salts and complex compounds of metals, dispersed metal powders and colloidal solutions of metals as antimicrobic components in anti-inflammatory and wound-healing compositions possess a number of short-comings:
- salts and complex compounds of metals exert allergic and toxicological influence on human organisms;
- in colloidal solutions of metals biological action of ions of metals (for example silver) can be inactivated owing to formation of colloidal particles or complexes with the impurity dissolved in water;
- the given compounds, powders of metals and solutions are not technologically acceptable forms for maintenance of effective regulation of penetration of ions of metals to wound surfaces from the carrier (film-forming substance);
- salts and complex compounds of metals and powders of metals do not show the necessary biological compatibility with the tissues of integuments.
Antiseptic agents produced on the basis of natural inorganic components are also known (see Russian patent RU No. 2330673).
In said patent an antiseptic agent is described consisting of a nanostructured powder of bentonite intercalated by ions of silver (Ag+). Said agent is obtained by modifying a bentonite with a solution of silver nitrate, after a preliminary enrichment with cations of sodium (Na+) through processing with a water solution of NaCl and subsequent cleaning from anions of chlorine. After intercalation bentonite is cleaned from salt of sodium by grinding up to a size of the particles of the powder of no more than 150 nm.
The antiseptic agent consisting of a powder of bentonite intercalated by ions of Ag+, is obtained from the mineral components which are biologically compatible with tissues of live organisms and can be used as additives in various compositions and preparations for preventive protection, treatment and antimicrobic processing of the injured zones of integuments.
However, the problem of medical processing wounds, ulcers, pustular diseases of a skin of patients with the syndrome of diabetic foot is not solved in the Russian patent RU No. 2330673.
After analysis of all available art, the Russian patent RU No. 2312658 is chosen as the nearest analogue of the present invention.
Disclosure of the invention
The problem of the present invention consisted in the creation of an effective composition, having preventive action, for treatment of diabetic foot, on the basis of components possessing biological compatibility and providing antimicrobic action, acceleration of regeneration and healing of integuments.
The present invention describes compositions for preventive protection and care of diabetic foot, containing a film-forming substance, an antimicrobic agent in polar solvent and a locally anesthetic substance, able to solve the put technical problem. According to the invention an alcohol solution of a block-copolymer of polydimethylsiloxane and polyurethane, with viscosity from 10000 up to 45000 Pa-s at 110°C, is used as a film- forming substance. A water solution of polyhexanide hydrochloride with polyethylene glycol 4000 at the ratio polyhexanide hydrochloride: polyethylene glycol : water, of 1:0,05: (3÷4) parts by weight (b.w.), is used as the antimicrobic agent. The composition additionally contains a second antimicrobic agent on the basis of a mix of nano structured powders of bentonite intercalated by ions of silver (Ag+) and ions of cerium (Ce3+). Thus the composition has the following contents of components, in % b.w.:
film- forming substance - 1.0 - 10.0 nano structured powder of bentonite
intercalated by ions of silver (Ag+) - 0.1-0. 5 nano structured powder of bentonite
intercalated by ions of cerium (Ce3+) - 0.01-0.05 water solution of polyhexanide
with polyethylene glycol 4000 - 0.1 -0.2 locally anesthetic substance - 0.1-1.0 polar solvent - the rest.
According to the invention a 0.5-2.0% alcohol solution of the named block- copolymer of polydimethylsiloxane and polyurethane is used as the film-forming substance.
According to the invention a mix of a nanostructured powder of bentonite intercalated by ions of silver (Ag+) and a nanostructured powder of bentonite intercalated by ions of cerium (Ce3+) is used at the ratio of 1 : (0.1-0.5) parts by weight of the two components.
According to the invention the nanostructured powder of bentonite intercalated by ions of silver (Ag+) has the size of particles of no more than 150 nm.
According to the invention a nanostructured powder of bentonite intercalated by ions of cerium (Ce3+) is obtained at modification of a semifinished product of bentonite with a 0,3-2,0 % water solution of nitrate salt of cerium Ce(N03)3-6H20. Bentonite is preliminary enriched with cations of sodium (Na+) by processing with a 3-10% water solution of sodium chloride and subsequently is cleaned from anions of chlorine. After intercalation, bentonite is cleaned from salts of sodium with grinding up to a size of the particles of no more than 150 nm.
According to the invention the locally anesthetic substance is selected out of the pharmacological group of local anesthetics; 2-diethylamino-2',6'-acetoxylidide hydrochloride is preferably used.
According to the invention 30-50% aqueous-alcohol solution is used as polar solvent.
At realization of the present invention the microbic infection in wounds is suppressed, regeneration and healing of integuments in patients with the syndrome of diabetic foot is accelerated due to the following elements:
- use in the composition of antimicrobic agents on the basis of a water solution of polyhexanide hydrochloride and of nanostructured powder of bentonite intercalated by ions of silver (Ag+), possessing activity against many kinds of microorganisms (including aerobic, anaerobic bacteria, funguses);
- activity of the composition also at the presence of blood and purulent exudates (due to polyhexanide);
- prolonged antimicrobic and fungicidal action of the compositions (due to presence of ions of silver). Biologically active ions of silver are released out owing to an ionic
exchange between particles of the intercalated bentonite and the contacted biological environment created by wound surfaces, tissues and liquids;
- use in the composition of a nanostructured powder of bentonite intercalated by ions of cerium (Ce3+), possessing antimicrobic activity and high potential of inhibition of oxidizing processes and giving also protection against free radicals and peroxides formed in the inflamed areas, wounds and ulcers of integuments of patients with the syndrome of diabetic foot;
- use in the composition of a film-forming substance forming a polymeric film as the carrier of the antimicrobic agents, possessing good gas permeability, elasticity and adhesion to a surface protecting an integument from action of external factors (mechanical influences, infections).
Analysis of the available art did not reveal patents with a set of characteristics corresponding to those of the present patent application and providing the results described above.
Analysis of the available art testifies the conformity of the present declared invention to the criteria of "novelty" and "degree of inventiveness".
The present declared invention can be industrially realized by using known technological processes, equipment and materials intended for manufacturing preparations for medical purposes.
Detailed description of the invention
The essence of the invention is explained by a choice of raw components for realization of the invention, examples of its realization and results of tests.
Active substance and polymeric components, known in the pharmaceutical industry and medicine and intended for manufacturing various compounds are used for realization of the invention.
1. The antimicrobic agent is a water solution of polyhexanide hydrochloride with polyethylene glycol 4000, at the ratio polyhexanide hydrochloride : polyethylene glycol : water as 1: 0.05 : (3÷ 4) weight parts.
The given preparation has the trade mark "Lavasept" and pertains to the pharmacological group of antiseptics and disinfectants. The preparation is intended for antiseptic processing of infected wounds and superficial injures of soft tissues including processing of integuments with the syndrome of diabetic foot.
The quantitative content of the antimicrobic agent in the composition specified in the present invention is the optimum and corresponds to the requirements for application in external antiseptic processing of infected wounds. Decrease in the quantitative content of antimicrobic preparation in the composition worsens its antimicrobic and fungicidal properties. Increase in the quantitative contents leads to increase in costs and raises the risk of allergic reactions on the skin.
2. Locally anesthetic substance 2-diethylamino-2',6'-acetoxylidide hydrochloride. The given compound has the trade mark "Lidocaine Hydrochloride" and pertains to the pharmacological group of local anesthetics and anti-arhythmic means. It stabilizes cellular membranes, blocks sodium channels, increases permeability of membranes to ions of potassium. Locally anesthetic action is caused by blockage of the voltage-dependent sodium channels that impedes generation of impulses in sensitive teleneurons and carrying out of impulses in nervous fibres.
3. The film- forming substance is 0.5-2.0% alcoholic solution of a block-copolymer of polydimethylsiloxane and polyurethane. The trade name of block-copolymer of polydimethylsiloxane and polyurethane is «Penta-1009». It has a viscosity from 10000 up to 45000 Pa»s at 110°C. It is used in manufacture of elastomeric products and transparent films; it is applied as a gas-permeable textile coating (for textile fibres).
4. The antimicrobic agent is a nano structured powder of bentonite intercalated by ions of silver (Ag+).
The given antimicrobic agent is obtained according to the known technology described in the Russian patent RU No. 2330673.
A natural mineral montmorillonite (bentonite in Na-form) is used for obtaining the antimicrobic agent. Bentonite is processed with 3-10% water solution of sodium chloride, with subsequent washing and filtering of the obtained semifinished product for removal of chlorine. Then the semifinished product of bentonite is modified by 10-20% solution of silver nitrate, with retention interval of modified bentonite in the specified salt solution.
After intercalation, the obtained product is cleaned from salts of sodium; then it is nanostructured to obtain a powder of bentonite. The size of the particles of the powder of bentonite is no more than 150 nm. Processing of the mineral with the named solutions of salts is carried out at the ratio, in parts by weight, bentonite : solution as 1 : (10-40). The
powder of bentonite intercalated by ions of silver contains from 2 up to 8% b.w. of silver, depending on the amount of activating and modifying agents.
The specified amount of the named metal in the bentonite powder is the optimum. Increase in amount of metals leads to increase in costs for obtaining the antimicrobic agent and decrease leads to worsening of antimicrobic activity.
The quantitative contents of a nanostructured powder of bentonite intercalated by ions of silver specified in the present invention are the optimum. Antimicrobic properties of the composition worsen at decrease in the content of the given antimicrobic agent in said composition. Increase in the quantitative content of the given antimicrobic agent in the compositions increases expenses for its manufacturing.
5. Nanostructured powder of bentonite intercalated by ions of cerium (Ce3+) used in the antimicrobic agent.
The given product is obtained at modification of a semifinished product of bentonite by 0.3-2.0% water solution of nitrate salt of cerium Ce(N03)3-6H2C). Bentonite is obtained after its enrichment with cations of Na+ by processing with 3-10% water solution of sodium chloride and subsequent cleaning from anions of chlorine. After intercalation bentonite is cleaned from salts of sodium and nanostructured up to a size of the particles of no more than 150 nm.
A 0,5% water solution of cerium nitrate Ce(N03)3-6H2C) was used for realizing the present invention, in the process of intercalation of the semifinished product of bentonite obtained after its enrichment with cations of Na+.
The powder of bentonite obtained after intercalation, cleaning and nanostructuring contains cerium in amount of no more than 0.5% b.w..
It was recognized that cerium (metal of variable valency) actively interacts with oxygen with formation of cerium dioxide (Ce02), which is an antioxidant. Inactivating and blocking influence on formation of peroxides and hydroperoxide radicals generated at oxidizing processes is peculiar to it. The given metal is a recognised biologically compatible material and is used in medicine, for example, in prosthetics, stomatology.
The quantitative contents of a nanostructured powder of bentonite intercalated by ions of cerium (Ce3+) specified in the present invention are the optimum for blocking free radicals and peroxides formed at oxidizing processes in wounds integuments of patients.
Efficiency of influence of ions of cerium on free radicals and peroxides worsens at decrease in the contents of the given component in the composition. Increase of the quantitative contents of the given component in the composition increases costs for its manufacturing.
5% water solution of sodium chloride was used at the stage of obtaining of the semifinished product of bentonite enriched with cations of sodium and the ultrasonic dispersant Sonopuls HD-2070, company Bandelin, with power 35-75 W/cm and frequency 20-50 kHz, was used at the stage of nanostructuring bentonite intercalated by ions of silver (Ag+) or ions of cerium (Ce3+).
Nano structured powders of bentonite with a size of the particles of no more than 150 nm are obtained. A method of microscopy was used for estimation of the size of the particles of bentonite.
The composition according to the invention is obtained as follows.
Film-forming substance, i.e. an alcoholic solution of a block-copolymer of polydimethylsiloxane and polyurethane was mixed with a polar solvent at a temperature of + 20° / + 30°C. Then other components specified in the invention, i.e. antimicrobic agents and a locally anesthetic substance are added in the obtained solution. Mixing of the composition according to the invention is carried out preferably with use of the ultrasonic equipment, providing effective dispersion of intercalated nano structured powders of bentonite in the solution.
A composition for processing integuments in a case of syndrome of diabetic foot, according to the present invention, was obtained with the following examples where all amounts are expressed in % by weight (b.w.)
Example 1:
film-forming substance 5.0 nano structured powder of bentonite
intercalated by ions of silver (Ag+) . 0.1 nano structured powder of bentonite
intercalated by ions of cerium (Ce ) 0.01 water solution of polyhexanide hydrocloride
with polyethylene glycol 4000
(preparation Lavasept) 0.15
locally anesthetic substance - 0.5 polar solvent - the rest.
Example 2:
film- forming substance - 5.0 nano structured powder of bentonite
intercalated by ions of silver (Ag+) - 0.3 nano structured powder of bentonite
intercalated by ions of cerium (Ce3+) - 0.03 water solution of polyhexanide hydrochloride
with polyethylene glycol 4000
(preparation Lavasept) - 0.15 locally anesthetic substance - 0.5 polar solvent - the rest
Example 3 (control):
film- forming substance - 5.0 water solution of polyhexanide hydrochloride
with polyethylene glycol 4000
(preparation Lavasept) - 0.15 locally anesthetic substance - 0.5 polar solvent - the rest
The compositions obtained according to Examples 1-3 have a liquid homogeneous structure.
For preventive treatment and care of patients, the composition according to the invention is placed on an integument or a wound surface with the help of a spray bottle, from distance of 10-20 cm, providing formation of a uniform coating with thickness 5-15 microns. The formed polymeric film possesses good gas permeability, elasticity and adhesion to a surface; it also protects an integument from action of external factors (mechanical influences, infections).
The composition is intended for application in I and III phases of wound process of a syndrome of diabetic foot. In the 1st phase (inflammation and infection, vascular reactions, hypostasis, infiltration of tissues) the composition is used for suppression of infections and of the microbic environment in the wound, for decreasing inflammation of
the tissues, for inhibiting oxidizing processes and action of free radicals; as an interim sparing medical coating (bandage). In the Illrd phase (reorganization of a scar epithelization) the composition is used for stimulation of reparative processes in wounds, epithelization and formation of a film possessing protective action from mechanical damages and drying, in respect of regenerable tissues and neo epithelium.
Efficiency of the compositions according to the examples 1-3, was estimated basing on their influence on processes of epithelization and healing of wound surfaces, which processes describe regenerative properties of the composition.
White rats weighting 180-210 g were used for carrying out the estimation laboratory tests of the compositions according to the Examples 1-3. They were divided into three groups each comprising 7 individuals. A wound was made by mechanical way (scalpel) on a shaved integument of each rat. Depth of the wound was 0.8 - 1.0 mm, the area was 150 mm . To perform the tests, wound areas of rats (from each group) were treated with compositions according to Examples 1-3. The treatment was repeated 2 times a day (daily, in the morning and in the evening) up to full healing of wounds.
The size of wound areas at rats were estimated and terms of resorption of infiltration, occurrences of granulation, epithelization of wounds were determined during the tests.
Formations of scabs began in 1-2 days of their application, for rats from 1st and 2nd group with use of the compositions according to Examples 1 and 2.
Lips of wounds were tightened together and combined with gentle granulation tissue in 5-6 days. Full epithelization of wounds of rats took place in 7-8 days. Full epithelization of wounds at rats of the 3 group took place in 10-1 ldays by application of a composition according to the Example 3.
The results of the tests testify that the compositions manufactured according to the invention, possess antimicrobic properties and promote acceleration of regeneration and healing of integuments. What testifies the efficiency of the compositions according to the invention.
Claims
Compositions suitable for preventive maintenance and for treatment of diabetic foot, comprising a film-forming substance, a first antimicrobic agent in polar solvent, a local anesthetic and a second antimicrobic agent consisting of a mixture of nano structured powders of bentonite intercalated by ions of silver (Ag+) and by ions of cerium (Ce3+).
Compositions according to claim 1, wherein the film-forming substance is a block-copolymer of polydimethylsiloxane and a polyurethane, dissolved in a suitable alcohol, forming a solution having a viscosity from 10000 up to 45000 Pa-s at 110°C.
Compositions according to claim 1, wherein the first antimicrobic agent consists of a water solution of polyethylene glycol 4000 and polyhexanide hydrochloride in a ratio polyhexanide hydrochloride : polyethylene glycol : water of 1 : 0.005 : (3-4) expressed in parts by weight.
Compositions according to claim 1, wherein the second antimicrobic agent, consists of a mixture of nanostructured powders of bentonite intercalated by ions of silver (Ag+) and by ions of cerium (Ce3+) in a ratio 1 : (0.1-0.5) parts by weight.
Compositions according to claim 4, wherein the nanostructured powders of bentonite intercalated with ions of silver (Ag+) or with ions of cerium (Ce3+) have a size of the particles of no more then 150 nm.
Compositions according to claim 1, wherein the local anhesteic is 2- diethylamino-2' ,6' -acetoxylidide hydrochloride.
Compositions according to claim 1, having a content of the essential components as follows, expressed in parts by weight:
- film-forming substance 1.0 - 10.0
- nanostructured powder of bentonite intercalated
by ions of silver (Ag+) 0.1 - 0.5
- nanostructured powder of bentonite intercalated by ions of (Ce3+) 0.01 - 0.05
- first antimicrobic agent 0.1 - 0.2
- local anesthetic 0.1 - 1.0
- polar solvent the rest
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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RU2010138449/15A RU2427379C1 (en) | 2010-09-20 | 2010-09-20 | Diabetic foot prevention and care composition |
RU2010138449 | 2010-09-20 |
Publications (2)
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WO2012038333A2 true WO2012038333A2 (en) | 2012-03-29 |
WO2012038333A3 WO2012038333A3 (en) | 2012-05-24 |
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PCT/EP2011/066079 WO2012038333A2 (en) | 2010-09-20 | 2011-09-16 | Composition to act in prevention and to take care of diabetic foot |
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RU (1) | RU2427379C1 (en) |
WO (1) | WO2012038333A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102014100274A1 (en) * | 2013-11-21 | 2015-05-21 | Farco-Pharma Gmbh | Composition, in particular in the form of a gel, and its use |
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Also Published As
Publication number | Publication date |
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RU2427379C1 (en) | 2011-08-27 |
WO2012038333A3 (en) | 2012-05-24 |
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