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WO2008037262A1 - Composition pharmaceutique et SON utilisations - Google Patents

Composition pharmaceutique et SON utilisations Download PDF

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Publication number
WO2008037262A1
WO2008037262A1 PCT/DK2007/050133 DK2007050133W WO2008037262A1 WO 2008037262 A1 WO2008037262 A1 WO 2008037262A1 DK 2007050133 W DK2007050133 W DK 2007050133W WO 2008037262 A1 WO2008037262 A1 WO 2008037262A1
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WO
WIPO (PCT)
Prior art keywords
iron
copper
composition
phosphate
wound
Prior art date
Application number
PCT/DK2007/050133
Other languages
English (en)
Inventor
Niels Erik Van Wyhe
Original Assignee
Stormøllen A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Stormøllen A/S filed Critical Stormøllen A/S
Publication of WO2008037262A1 publication Critical patent/WO2008037262A1/fr

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Classifications

    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; 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
    • A61K33/34—Copper; 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
    • A61K33/42—Phosphorus; Compounds 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/18—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0004—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing inorganic materials
    • 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

Definitions

  • the present invention relates to a wound healing composition and uses thereof in the treatment of wounds in an individual such as the human or animal body.
  • the compositions according to the present invention are used in the treatment of bedsores in sows.
  • Tissue damage is not restricted to the initial area of injury, it may increase over the next several hours or days as a result of the release of lysomal enzymes from the injured cells or as a consequence of swelling and infection.
  • Coagulation the first phase of the healing process, bridges the gap between the injury and the inflammatory response, the second phase of wound healing. It stops the loss of blood and restores some of the mechanical and physical integrity to the damaged tissue.
  • the proteins of the coagulation cascade are normally confined to the intravascular space but are released into the tissues after blood vessel disruption. Coagulation is initiated by either the intrinsic or extrinsic pathway, both of which must be activated for maximum fibrin formation. The result of the activation of either of the two coagulation pathways is the generation of thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin monomer. Fibrin monomer spontaneously polymerizes to form the clot.
  • Fibrin stabilizing factor which is generated from its proenzyme by thrombin, covalently cross-links the fibrin fibrils by catalyzing a transamination reaction between glutamine and lysine residues in adjacent fibers.
  • the cross-linking of fibers greatly increases the mechanical strength of the clot. Platelets, along with other blood cells, are trapped in the fibrin mesh as the clot forms by fibronectin. The platelet surfaces are heavily coated, and each looks like a nexus with the fibrin fibers radiating out from it.
  • the second phase of wound repair is the inflammatory response, which is necessary for subsequent phases of healing. It is initiated by the release of histamine and serotonin from platelets and mast cells and by kinins. Histamine and kinins act to increase capillary dilation, opening previously closed capillaries in the area of injury. The increased blood flow through the capillary beds produces two of the characteristics of the inflammatory response: redness and heat. Prostaglandin release within a few hours of injury results in the full development of the inflammatory response, which may last from 3 to 5 days depending on the extent of the injury. The extreme vasodilation produced by the factors just discussed causes a widening of the endothelial cell junctions lining the capillaries.
  • PMN's polymorphonuclear leukocytes
  • the PMN's subsequently pass through the endothelial junctions of the capillary wall into the site of the injury. If bacteria are present in the wound, they may release soluble chemotactic factors and/or activate complement with the subsequent generation of chemotactic fragments.
  • PMN's at the site of an infection or injury release substance that affect the PMNs' mobility, keeping them at the site. Fibronectin facilitates the attachment of the bacterium to the membrane of the phagocyte.
  • Macrophages are primarily responsible for the clearance of wound debris.
  • Wound macrophages like wound PMN's, are actively phagocytic. They migrate into the wound using the fibers of the fibrin clot as a scaffold to move within the clot, attaching to the fibers through fibronectin. The macrophages encounter, engulf, and destroy the dead cells trapped in the clot matrix, as well as the damaged cells from the wound margin.
  • the fibrin clot itself is resolved primarily by the activation of the plasminogen that was incorporated into the fibers during their formation.
  • Some of the fibrin fragments are engulfed by macrophages in the area. Since most of the clot fragments are released away from the area of the most intense macrophage activity, many of the fragments are removed by lymphatic drainage and thus enter the circulation. These soluble complexes are removed by the sessile cells of the RES, primarily those of the spleen and liver. Also, PMN's trapped in the clot die as a result of anoxia, releasing their lysosomal contents. These enzymes attack the surrounding clot and dissolve it. Although the release of lysosomal enzymes by PMN's may be considered beneficial to the host in most cases, they may also increase tissue destruction and delay healing.
  • fibroblasts including those at some distance from the wound margins, begin to move toward the area of injury and to proliferate. This response is apparently due to factors released by the injured tissue and platelets and possibly to factors released by the kinin, complement or coagulation cascades.
  • the proliferating fibroblasts derive part of their nutrients from the components of tissue debris and cells released by macrophages.
  • the fibroblast phase may last 2 to 4 weeks in a skin wound, whereas it may persist several months in an injury to the stomach or intestines.
  • Angiogenesis begins with the growth of capillary beds into the area directly behind the fibroblasts.
  • the capillaries are much more numerous than in normal tissue, which probably reflects the high oxygen and nutrient requirements of the rapidly regenerating tissue.
  • the capillaries are very leaky, which facilitates the movement of cells and macromolecules into the wound site.
  • the capillaries originating from one side of the wound grow into contact with capillaries originating from the other sides and fuse, reestablishing complete circulation within the wound.
  • fibroblasts begin laying down large quantities of collagen.
  • the collagen molecule is synthesized on the membrane of the endoplastic reticulum. It then undergoes extensive postranslational modification, hydroxylation, glycosylation, and further steps to form the procollagen molecule.
  • the procollagen molecule is then secreted and is further modified to tropocollagen by specific serum peptidases. These activated tropocollagen molecules quickly polymerize to form increasingly large collagen fibers. Thereafter, crosslinking among the collagen fibers occurs.
  • the collagen network in effect replaces the fibrin clot as the major structural element of the wound. This becomes particularly important during the remodeling phase of wound healing.
  • Reepithelialization begins to occur within a few hours of injury as the attachment of the epithelial cells to the dermis loosened near the margin of the wound, and the cells begin to migrate over the defect, always maintaining contact with the mesenchymal tissue. By 48 hours after the injury, the cells are also beginning to proliferate to replace the lost cells. The epithelial cells continue to divide after the bridge is complete to form a thicker epithelium. Wound contracture aids reepithelialization insofar as it reduces the size of the defect to be reepithelialized by as much as 50%. Contracture is believed to occur as a result of the cellular element of the granulation tissue in the wound ⁇ the fibroblasts and myofibroblasts.
  • Remodeling is the last step of wound healing. Scar tissue continues to gain tensile strength for several months after collagen content stabilizes. This gain in strength comes from the rearrangement of the collagen in the wound and perhaps from increased crosslinking of the collagen. Collagen accumulation is the sum of synthesis and destruction, and both occur simultaneously during the wound healing process. After about 14 days, a balance between collagen synthesis and degradation is reached. The collagenase involved in the remodeling comes from epithelial cells, from fibroblasts encountering new epithelium, and from macrophages that contain collagenase in their lysosomes.
  • Typical wound healing takes anywhere from 5 to 21 days. This time period is of course longer for the immune compromised patient because such patients are frequently unable to sufficiently stabilize the wound and ward off infection which prevents the proper adherence of fibrin, fibronectin or collagen at an acceptable rate at the locus of the wound.
  • those with vasculitis or other rheumatic or diabetic diseases frequently experience wound healing times far in excess of several weeks. Diabetics frequently develop lesions that take weeks to heal.
  • compositions according to the present invention are capable of treating and/or stimulating and/or accelerating wound healing in an individual.
  • the compositions have great value in medical and veterinary practice and can be used to improve or speed up the healing of many types of wounds or lesions, including fx. bedsores in animals, such as pigs, in particular sows, cuts in fingers or the forearm resulting from unintentional handling of e.g. kitchen knives, severe sunburns, wounds resulting from burns or cuts with sharp objects in the workplace, surgical incisions, burns induced by heat, chemicals, or irradiation, as well as abrasions, lacerations and amputations.
  • the pharmaceutically active composition can also be used when wound healing of an individual is impaired, such as in diabetic patients, or in individuals undergoing cancer chemotherapy (e.g. with adriamycin or cyclophosphamide) or corticosteroid treatment, or in patients after therapeutic or accidental exposure to ionizing radiation.
  • cancer chemotherapy e.g. with adriamycin or cyclophosphamide
  • corticosteroid treatment e.g. with adriamycin or cyclophosphamide
  • the wound healing agents of the pharmaceutically active composition are preferably non-antigenic and preferably they do not carry genetic information.
  • the effective wound healing agents of the pharmaceutically active compositions according to the present invention are inexpensive, uniform and stable.
  • the wound healing agents of the pharmaceutically active composition can be effectively administered locally.
  • the wound healing agents have no undesirable toxic effects and they can be administered to animals and humans to effectively promote healing of wounds, ulcers, burns, and other types of lesions.
  • the effective wound healing agents are preferably applied locally and/or topically in a variety of delivery vehicles, such as gels and ointments.
  • the present invention in one aspect is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one iron compound, at least one copper compound and at least one phosphor compound, in combination with a physiologically acceptable carrier adapted for local and/or topical administration, wherein said compounds are each present in a concentration so that the composition is capable of promoting wound healing in an individual.
  • compositions for wound healing or for accelerating wound healing comprising
  • Wound The term refers to cuts, incisions, abrasions, lacerations, amputations, burns induced by heat, ionizing radiation, ultraviolet radiation including sunlight, electricity, or chemical substances as well as to other forms of lesions such as ulcers, pressure sores and bedsores.
  • the term refers to vertebrates, particular members of the mammalian species, and includes, but is not limited to domestic animals, such as cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs, camels, and primates, including humans.
  • composition Any composition according to the invention comprising pharmaceutically active compounds, including at least one iron compound, at least one copper compound and at least one phosphor compound in combination with a physiologically acceptable carrier adapted for local and/or topical administration, said composition exerting a physiological effect when administered to an individual.
  • the pharmaceutically active composition can be formulated e.g. as a an ointment or a salve or a creme or a lotion or a gel, in which case the pharmaceutically active composition is mixed with e.g. one or more of an emulsifying agent, a stabilizing agent, a dispersing agent, a suspending agent, a thickening agent and a colouring agent.
  • Figure legends Figure 1 Graphic illustration on the grade of shoulder ulcers at the inclusion of the sows and in the end at the weaned/exclusion time for control and Stalosan Salve.
  • Control Weaned/excluded versus start, t 7,8 * 10 '5 ;
  • Stalosan Salve Weaned/excluded versus start, t 0,03;
  • Start Stalosan Salve versus control, t 0,05;
  • One strategy for the administration of the pharmaceutically active compounds according to the present invention is to administer the pharmaceutically active composition according to the invention locally and/or topically e.g. in gels, ointments, solutions, impregnated bandages, liposomes, biodegradable microcapsules comprising the pharmaceutically active compounds according to the present invention.
  • compositions or dosage forms for topical application may include solutions, lotions, ointments, cremes, gels, suppositories, sprays, aerosols, suspensions, dusting powder, impregnated bandages and dressings, liposomes and biodegradable polymers.
  • a semi-solid pharmaceutical composition for wound healing or for accelerating wound healing comprising
  • the iron ions are preferably provided by one or more of iron chloride, iron fluoride, iron nitrate, iron oxide and/or iron sulphate.
  • the copper ions are preferably provided by one or more of copper acetate, copper bromide, copper carbonate, copper chloride, copper fluoborate, copper gluconate, copper nitrate, copper oxide and/or copper sulphate.
  • the phosphate ions are preferably provided by one or more of calcium diphosphate, calcium phosphate, monoammonium phosphate and/or diammonium phosphate .
  • the above-mentioned pharmaceutical composition comprises phosphate ions, iron ions and copper ions, wherein the relative amounts (w/w) of phospor (P) and iron (Fe), P : Fe, in said composition are given by the ratio 100 : 20 to 50; such as 100 : 25 to 50; for example 100 : 30 to 50; such as 100 : 35 to 50; for example 100 : 40 to 50; such as 100 : 45 to 50; for example 100 : 15 to 45; such as 100 : 15 to 40; for example 100 : 15 to 35; such as 100 : 15 to 30; for example 100 : 15 to 25; such as 100 : 15 to 20; for example 100 : 20 to 25; such as 100 : 25 to 30; for example 100 : 30 to 35; such as 100 : 35 to 40; for example 100 : 40 to 45.
  • the relative amounts (w/w) of phospor (P) and copper (Cu), P : Cu, in said composition are given by the ratio 100 : 6 to 15; such as 100 : 7 to 15; for example 100 : 8 to 15; such as 100 : 9 to 15; for example 100 : 10 to 15; such as 100 : 1 1 to 15; for example 100 : 12 to 15; such as 100 : 13 to 15; for example 100 : 14 to 15; such as 100 : 5 to 14; for example 100 : 5 to 13; such as 100 : 5 to 12; for example 100 : 5 to 1 1 ; such as 100 : 5 to 10; for example 100 : 5 to 9; such as 100 : 5 to 8; for example 100 : 5 to 7; such as 100 : 5 to 6; for example 100 : 6 to 7; such as 100 : 7 to 8; for example 100 : 8 to 9; such as 100 : 9 to 10; for example 100 : 10 to
  • the pharmaceutical composition comprises phosphate ions, iron ions and copper ions, wherein the relative amounts A : B : C (w/w of anhydrous compounds) of
  • A calcium diphosphate and calcium phosphate
  • B iron sulphate and/or iron oxide
  • C copper sulphate; are given by the ratios 100 : 1.5 to 10 : 0.5 to 5.0.
  • the above-mentioned pharmaceutical composition comprises phosphate ions, iron ions and copper ions, wherein the relative amounts of A : B (w/w of anhydrous compounds) are given by the ratio 100 : 2.0 to 10; such as 100 : 2.5 to 10; for example 100 : 3.0 : 10; such as 100 : 3.5 to 10; for example 100 : 4.0 to 10; such as 100 : 4.5 to 10; for example 100 : 5.0 to 10; such as 100 : 5.5 to 10; for example 100 : 6.0 to 10; such as 100 : 6.5 to 10; for example 100 : 7.0 to 10; such as 100 : 7.5 to 10; for example 100 : 8.0 to 10; such as 100 : 8.5 to 10; for example 100 : 9.0 to 10; such as 100 : 9.5 to 10; for example 100 : 1 .5 to 9.5; such as 100 : 1 .5 to 9.0; for example 100 : 1.5 to 8.5; such as 100 : 1.5
  • the relative amounts of A : C are given by the ratio 100 : 1.0 to 5.0; such as 100 : 1.5 to 5.0; for example 100 : 2.0 to 5.0; such as 100 : 2.5 to 5.0; for example 100 : 3.0 to 5.0; such as 100 : 3.5 to 5.0; for example 100 : 4.0 to 5.0; such as 100 : 4.5 to 5.0; for example 100 : 0.5 to 4.5; such as 100 : 0.5 to 4.0; for example 100 : 0.5 to 3.5; such as 100 : 0.5 to 3.0; for example 100 : 0.5 to 2.5; such as 100 : 0.5 to 2.0; for example 100 : 0.5 to 1 .5; such as 100 : 0.5 to 1.0; for example 100 : 1 .0 to 1.5; such as 100 : 1 .5 to 2.0; for example 100 : 2.0 to 2.5; such as 100 : 2.5 to 3.0; for example 100
  • the concentration of the above-mentioned active compounds in pharmaceutically acceptable carriers can range e.g. from 0.1 to 45%, such as 0.1 to 40%, for example 0.1 to 30%, such as 0.1 to 10%, for example 0.1 to 5%.
  • the dose used in a particular formulation or application will be determined by the requirements of the particular type of tissue lesion and the constraints imposed by the characteristics and capacities of the carrier materials.
  • the pharmaceutical composition comprises phosphate ions, iron ions and copper ions, wherein the absolute amount of iron ions in said composition is in the range of from 0.25 % to 4.0 % (w/w).
  • the pharmaceutical composition according to the invention comprises phosphate ions, iron ions and copper ions, wherein the absolute amount of iron ions in said composition is in the range of from 0.50 % to 4.0 % (w/w), such as from 1.0 % to 4.0 %, for example from 1.5 % to 4.0 %, such as from 2.0 % to 4.0 %, for example from 2.5 % to 4.0 %, such as from 3.0 % to 4.0 %, for example from 3.5 % to 4.0 %, such as from 0.25 % to 3.5 %, for example from 0.25 % to 3.0 %, such as from 0.25 % to 2.5 %, for example from 0.25 % to 2.0 %, such as from 0.25 % to 1.5 %, for example from 0.25 % to 1 .0 %, such as from 0.25 % to 0.50 %, for example from 0.50 % to 1.0 %, such as from 1.0 % to 1.5 %, for example from 1.5 % to
  • composition according to the invention comprises phosphate ions, iron ions and copper ions, wherein the absolute amount of copper ions in said composition is in the range of from 0.05 % to 1 .8 % (w/w).
  • the pharmaceutical composition according to the invention comprises phosphate ions, iron ions and copper ions, wherein the absolute amount of copper ions in said composition is in the range of from 0.1 % to 1.8 %, for example from 0.1 % to 1.5 %; such as from 0.25 % to 1 .5 %, for example from 0.50 % to 1.5 %; such as from 0.75 % to 1.5 %, for example from 1.0 % to 1.5 %; such as from 1.25 % to 1.5 %, for example from 0.05 % to 1.25 %; such as from 0.05 % to 1 .0 %, for example from 0.05 % to 0.75 %; such as from 0.05 % to 0.50 %, for example from 0.05 % to 0.25 %; such as from 0.05 % to 0.1 %; for example from 0.1 % to 0.2 %; such as from 0.2 % to 0.4 %; for example from 0.4 % to 0.6 %; such as from 0.6 %
  • the active compounds described herein may be combined or used together or in coordination with e.g. an antibiotic, antifungal, or antiviral substance or substances to accelerate the healing of sores or other infection-damaged tissue simultaneously or sequentially with the treatment of the underlying infection.
  • the active compounds according to the invention can be combined with or used simultaneously or sequentially with other tissue healing promoters, such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor alpha, transforming growth factor beta, and insulin-like growth factor 1 (Brunt, J. V., and Tilansner, A., Biotechnology 6:25-30 (1988)) to promote a more rapid healing of damaged tissue.
  • compositions according to the present invention are particularly useful in conditions in which normal wound healing is impaired.
  • types of wounds that heal poorly or slowly include venous stasis ulcers, decubitus ulcers, and cutaneous and alimentary tract wounds, or ulcers in patients with diabetes, and in patients subjected to irradiation, cancer chemotherapy (e.g. with adriamycin or cyclophosphamide), and topical or systemic anti-inflammatory glucocorticosteriods.
  • the following supplementary compounds can be administered simultaneously or sequentially in any order with the pharmaceutically active compositions according to the invention in a method for the treatment of wounds. These supplementary compounds can be used in parallel or in series with the pharmaceutically active composition according to the invention.
  • the supplementary compounds include, but are not limited to: allantoin, retinoic acid, aloe vera, glycine, vitamin A, the B vitamins, especially nicotinamide, vitamins C and E, antibacterial agents (e.g., quaternary ammonium compounds, bacitracin, neomycin and polymyxin), comfrey root preparations, platelets and/or platelet extracts, ribonucleosides, collagen, proline, lysine, elastin, fibronectin, glycosaminoglycans, spermidine (and other polyamines), angiogenic factors, zinc, sucrose, and various peptide growth factors such as the somatomedins, lamin, EGF,
  • the pharmaceutically active composition according to the present invention can be incorporated into any suitable ointment, solution, or insert for the treatment of lesions or ulcers resulting e.g. from chemical damage, surgery, injury, burns, or infection.
  • the pharmaceutical compositions can be used to accelerate the healing of mechanical wounds or abrasions of the skin or other tissues which are exposed by mechanical injury to the skin or gastrointestinal mucosa of the body.
  • the invention can also be used to accelerate the healing of burns inflicted upon the skin, and any underlying tissues which may be exposed by such injury.
  • the burns may be those caused by heat, ionizing radiation, ultraviolet radiation including sunlight, electricity, or chemical substances.
  • the pharmaceutical compositions are used for treating bedsores in sows.
  • the pharmaceutical compositions are applied to the area of the wound. This has two effects. Firstly, the pharmaceutical composition is brought into contact with the wounded area, thereby promoting wound healing. Secondly, the application of the pharmaceutical composition to the wounded area prevents or reduces dirt and bacteria from getting acces to the actual wound.
  • compositions may be used to accelerate the healing of surgical incisions in any part of the body, external or internal, into which a solution or other carrier composition containing the active compounds of the invention may be introduced.
  • the compositions can also be used to accelerate the healing of ischemic ulcers, pressure sores, bed sores, or ulcers caused by diabetes or other disease processes.
  • the active compounds according to the present invention In promoting the healing of skin wounds, including bedsores and surgical incisions, it is best to apply the active compounds according to the present invention locally, either in an ointment or in a wound dressing.
  • a topical antibiotic or antiviral agent might be co- administered.
  • the molar equivalent of about 0.1 to 200 mg of a mixture of active compound(s) according to the present invention can be applied per square cm of wound area, or 0.1 to 100 mg per cm of linear incision.
  • compositions of the pharmaceutically active composition are preferably formulated e.g. as an ointment or a salve or a creme or a lotion or a gel.
  • the aforementioned terms will all form a semi-solid composition capable of being applied to a skin area for topical adiministration of the active compounds according to the invention.
  • Regions for topical administration include the skin surface and also mucous membrane tissues of e.g. the rectum, the nose, the mouth, and the throat.
  • Compositions for topical administration via the skin and mucous membranes should not give rise to signs of irritation, such as swelling or redness.
  • the topical compositions according to the invention may include a pharmaceutically acceptable carrier adapted for topical administration.
  • the composition may take the form of an ointment or a salve or a creme or a lotion or a gel.
  • the composition according to the invention may - for example - be in the form of a suspension, a solution, a foam, an aerosol, a spray, a suppository, a syrup or a balm. Methods for preparing such compositions are well known in the pharmaceutical industry.
  • composition according to the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Cremes, ointments or pastes according to the present invention are semi-solid compositions of the bioactive compounds according to the invention for external application. They may be made by mixing the pharmaceutically active compounds in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap
  • a mucilage an oil of natural origin such as almond, corn, arachis, castor or olive oil
  • wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the pharmaceutically active composition may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Lotions according to the present invention include those suitable for application to the skin.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • the pharmaceutical compositions according to the invention can also include non-toxic, pharmaceutically acceptable carriers, diluents and excipients, suitable for topical application, as are well known, see for example Merck Index, Merck & Co., Rahway, NJ. ; and Gilman et al., (eds) (1996) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8 th Ed., Pergamon Press.
  • non-toxic, pharmaceutically acceptable carriers, diluents and excipients suitable for topical application, as are well known, see for example Merck Index, Merck & Co., Rahway, NJ. ; and Gilman et al., (eds) (1996) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8 th Ed., Pergamon Press.
  • For standard dosages of conventional pharmacological agents see, e.g., Physicians Desk Reference (1997 Edition); and U.S. Pharmacopeia National Formulary (1995) United
  • Typical pharmaceutically acceptable carriers which make up the for going compositions include alginates, carboxymethylcellulose, methylcellulose, agarose, pectins, gelatins, collagen, vegetable oils, mineral oils, stearic acid, stearyl alcohol, petrolatum, polyethylene glycol, polysorbate, polylactate, polyglycolate, polyanhydrides, phospholipids, polyvinylpyrrolidone, and the like.
  • Dosage forms for the topical administration of an active composition according to the invention include various mixtures and combinations that can be applied topically and will permit even spreading and absorption into the cutaneous surfaces.
  • Non-limiting examples include sprays, mists, aerosols, lotions, creams, solutions, gels, ointments, pastes, emulsions, foams and suspensions.
  • the active compounds or a composition thereof can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives or buffers which may be required.
  • Topical preparations can be prepared by combining the pharmaceutically active composition with conventional pharmaceutically acceptable carriers commonly used in topical dry, liquid and creme formulations.
  • Ointment and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • An exemplary base is water.
  • Thickening agents can be used according to the nature of the base.
  • Lotions can be formulated with an aqueous base and will, in general, also include one or more of the following: stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like.
  • Powders can be formed with the aid of any suitable powder base, e.g., talc, lactose starch and the like.
  • Drops can be formulated with an aqueous base or non-aqueous base, and can also include one or more dispersing agents, suspending agents, solubilizing agents, surface active agents and the like.
  • Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, silicones, bentonites, silicie acid, and talc, or mixtures thereof.
  • Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, and calcium silicates, or mixtures of these substances.
  • Solutions of the pharmaceutically active composition can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals.
  • such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice.
  • Sprays can additionally contain customary propellants, such inert gases such as nitrogen, carbon dioxide, argon or neon.
  • inactive ingredients are generally incorporated in topical formulations to improve cosmetic acceptability, and are optional ingredients in the formulations. Such ingredients are included only in therapeutically acceptable forms and amounts. Examples of such ingredients are emulsifiers, emollients, thickening agents, solvents, hydrating or swelling agents, flavours, sweetening agents, surface active agents, colouring agents, anti-foaming agents, preservatives, fragrances, and fillers may also be added, as is well known in the art; for example, preservatives such as methyl paraben and propyl paraben, texturizing agents, thickeners, anticoagulants such as heparin, ⁇ -glucan, hormones, hyaluronic acid, immune potentiating agents such as adjuvants and cytokines such as epidermal growth factor, platelet derived growth factor, transforming growth factor and interleukins, and bone morphogenetic proteins, and the like.
  • preservatives such as methyl paraben and propyl paraben
  • Polyvinyl alcohol is a particularly preferred gelling polymer and also acts as a texturizing agent, methyl or propyl parabens are particularly preferred preservatives. These other agents may be included in amounts in the range of 0.1 to 5 wt %.
  • Surface active agents or foaming agents may be added to the formulations and are particularly advantageous for addition to liquid formulations for use as skin cleansers or for aerosol or foam applications.
  • Surface active agents selected for use should not substantially interfere with the antimicrobial or anti-inflammatory effects of the pharmaceutically active composition.
  • All agents must be non-toxic and physiologically acceptable for the intended purpose, and must not substantially interfere with the activity of the pharmaceutically active composition so as to deleteriously affect the antimicrobial and anti-inflammatory effect. Ingredients are thus only included in therapeutically acceptable amounts. Ingredients to be generally avoided or limited in the formulations of the present invention, at least in amounts greater than 0.01 wt %, are glycerin, glycerols, chloride salts, aldehydes, ketones, long chain alcohols, and triethanolamine.
  • the dosage of the pharmaceutically active composition depends upon many factors that are well known to those skilled in the art, for example, the particular form of the active ingredient, the condition being treated, the age, weight, and clinical condition of the recipient patient, and the experience and judgement of the clinician or practitioner administering the therapy.
  • a therapeutically effective amount of the pharmaceutically active composition provides either subjective relief of symptoms, or an objectively identifiable improvement, as noted by the clinician or other qualified observer.
  • the dosing range varies with the pharmaceutically active compositions used, its form, the route of administration and the potency of the particular active compound(s).
  • the dressing When the formulation is in the form of a dressing, the dressing can be placed on the affected area of the skin and, depending on the degree of moisture at the membrane, may be further moistened with drops of sterile water, tap water, body fluids such as exudate, or, for example 70% ethanol. The dressing may be then secured in place with an occlusive or semi-occlusive layer, such as an adhesive tape or polyurethane film, which keeps the dressing in a moist environment.
  • an occlusive or semi-occlusive layer such as an adhesive tape or polyurethane film
  • formulations such as gels, pastes, ointments, cremes, emulsions, foams, and liquids can be prepared in stable forms, or prepared fresh from one or more phases, for instance in multicomponent kit form, so as to avoid aging and to maximize the therapeutic effectiveness of the pharmaceutically active composition.
  • Formulations are best used within about 30 days after combining the phases.
  • kits or containers are well known for maintaining the phases of formulations separate until the time of use.
  • the pharmaceutically active composition may be packaged separately from therapeutically acceptable carriers, and possibly other ingredients for mixing at the time of use.
  • the pharmaceutically active composition may be in dressing or patch form for direct application, or may take other suitable forms to generate liquid formulations and the like, such as a coating on the inside surface of a vial or container, a mesh, or a film.
  • a kit containing e.g. one or more phases, for instance, the pharmaceutically active composition may be packaged separately from therapeutically acceptable carriers, and possibly other ingredients for mixing at the time of use, can further provide a sterile carrier such as water (and other ingredients) in a separate container in dosage specific amounts.
  • the pharmaceutically active composition is Stalosan F (commercially available from Storm ⁇ llen A/S Denmark). Stalosan F can be provided in powdered form and mixed with pharmaceutically acceptable carriers to generate a semi-solid pharmaceutical composition as disclosed herein. Reference is made to Example 1 , panel b).
  • the term "kit” refers to packaged formulations, whether the ingredients are in separate phases or mixed, and thus for example, may include a gel in a tube with all ingredients in admixture, or any formulation wherein the ingredients are separated from each other.
  • Administration as aerosols produces droplets preferably less than 10 ⁇ m in size, more preferably less than 5 ⁇ m in size, most preferably 1 -3 ⁇ m in size.
  • Control of the droplet size is important both to control the dosage delivered and to enhance delivery to the target tissue; thus, depending on the dosage required and the target tissue, it may be important to regulate the droplet size of the aerosol.
  • droplet size can be regulated, to at least some extent, by the mechanical mister which is used to produce the aerosol.
  • the aerosol's droplet size can be adjusted, to at least some extent, by modifying the surface tension of the solution.
  • the pharmaceutically active composition to be administered in aerosol form typically has water as its solvent, and water has a relatively high surface tension, so it is relatively straightforward to create an aerosol having relatively small droplet size.
  • Surface active agents can be added to the solution so as to reduce the surface tension of the solution, whereby to create an aerosol having a relatively large droplet size.
  • surfactants may comprise sodium alkyl sulfates, sodium laryl sulfate, sodium lauroyl sarconsinate, phospholipids, e.g., lecithin, sphingomyelin, etc.
  • solutions generated from powders of the pharmaceutically active composition should avoid inclusion of particulates larger than 2 ⁇ m, and more preferably no larger than 1 ⁇ m (i.e., submicron) to avoid deleterious immune responses or toxic effects.
  • Larger particulates may be removed by, for example filtration.
  • Particulates may be formed in the liquid and can be removed, for example by filtration.
  • the aerosol may be created by passing a liquid solution of the active compounds through a mechanical mister (e.g., a nebulizer) and may be applied directly with a pressurized pack (e.g., via a hand inhaler with a propellant such as carbon dioxide or other gas, with a valve metered dosage) or through some other delivery system (e.g., an oxygen tent, etc.).
  • a mechanical mister e.g., a nebulizer
  • a pressurized pack e.g., via a hand inhaler with a propellant such as carbon dioxide or other gas, with a valve metered dosage
  • some other delivery system e.g., an oxygen tent, etc.
  • the invention provides a method for manufacturing the pharmaceutical composition according to the invention, said method comprising the steps of
  • a second composition comprising an aqueous or oily base and optionally a thickening and/or a gelling agent,
  • the first composition comprises phosphate, iron and copper, wherein the relative amounts A : B : C (w/w of anhydrous compounds) of
  • A phosphate
  • B iron
  • C copper
  • the first composition comprises phosphate , iron and copper, wherein the relative amounts of A : B (w/w of anhydrous compounds) are given by the ratio 100 : 20 to 50; such as 100 : 25 to 50; for example 100 : 30 to 50; such as 100 : 35 to 50; for example 100 : 40 to 50; such as 100 : 45 to 50; for example 100 : 15 to 45; such as 100 : 15 to 40; for example 100 : 15 to 35; such as 100 : 15 to 30; for example 100 : 15 to 25; such as 100 : 15 to 20; for example 100 : 20 to 25; such as 100 : 25 to 30; for example 100 : 30 to 35; such as 100 : 35 to 40; for example 100 : 40 to 45.
  • a : B w/w of anhydrous compounds
  • the first composition comprises phosphate, iron and copper, wherein the relative amounts of A : C (w/w of anhydrous compounds) are given by the ratio 100 : 6 to 15; such as 100 : 7 to 15; for example 100 : 8 to 15; such as 100 : 9 to 15; for example 100 : 10 to 15; such as 100 : 1 1 to 15; for example 100 : 12 to 15; such as 100 : 13 to 15; for example 100 : 14 to 15; such as 100 : 5 to 14; for example 100 : 5 to 13; such as 100 : 5 to 12; for example 100 : 5 to 1 1 ; such as 100 : 5 to 10; for example 100 : 5 to 9; such as 100 : 5 to 8; for example 100 : 5 to 7; such as 100 : 5 to 6; for example 100 : 6 to 7; such as 100 : 7 to 8; for example 100 : 8 to 9; such as 100 : 9 to 10; for example 100 : 10 to 1 1 ; such as 100 : 100
  • the first composition comprises phosphate in the form of a phosphate complex or a phosphate compound, iron in the form of inorganic iron and copper in the form of inorganic copper, wherein the absolute amount of phosphate complex and/or phosphate compound is from 80 % to 90 % (w/w), such as 85 % or about 85%.
  • the phosphate complex comprises 5 % to 25 % (w/w) of phosphor, such as 5 % to 20%, for example from 5 % to 15 %, such as from 5 % to 10 %, for example from 7 % to 10 %, such as from 8 % to 10 %, for example from 10 % to 25 %, such as from 15 % to 20 %, for example 20 % to 25 %.
  • the phosphate compound of the first composition is selected from the group consisting of, but not limited to, calcium diphosphate, calcium phosphate, diammonium phosphate, mono-ammonium phosphate, disodium phosphate, monosodium phosphate, potassium phosphate, rock phosphate, sodium tripolyphosphate, potassium tripolyphosphate, sodium pyrophosphate and/or potassium pyrophosphate.
  • the phosphate complex is selected from the group consisting of, but not limited to, superphosphate and/or triple superphosphate.
  • the iron is preferably in the form of iron chloride, iron fluoride, iron nitrate, iron oxide and/or iron sulphate.
  • the copper is preferably in the form of copper acetate, copper bromide, copper carbonate, copper chloride, copper fluoborate, copper gluconate, copper nitrate, copper oxide and/or copper sulphate.
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of phosphate in said composition is in the range of from 5.0 % to 9.0 % (w/w).
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of phosphate in said composition is in the range of from 5.0 % to 9.0 % (w/w), such as from 5.5 % to 9.0 %, for example from 6.0 % to 9.0 %, such as from 6.5 % to 9.0 %, for example from 7.0 % to 9.0 %, such as from 7.5 % to 9.0 %, for example from 5.0 % to 8.5 %, such as from 5.0 % to 8.0 %, for example from 5.0 % to 7.5 %, such as from 5.0 % to 7.0 %, for example from 6.5 % to 7.5 %, such as from 7.0 % to 6.0 %, for example from 7.2 % of phosphate.
  • the phosphate is in the form of a phosphate complex.
  • the phosphate complex comprises calcium diphosphate and/or calcium phosphate.
  • the phosphate complex is super
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of iron in said composition is in the range of from 1.2 % to 9.0 % (w/w).
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of iron in said composition is in the range of from 1.2 % to 9.0 % (w/w), such as from 1 .5 % to 9.0 %, for example from 2.0 % to 9.0 %, such as from 2.5 % to 9.0 %, for example from 3.0 % to 9.0 %, such as from 3.5 % to 9.0 %, for example from 1.2 % to 8.5 %, such as from 1.2 % to 8.0 %, for example from 1 .2 % to 7.5 %, such as from 1 .2 % to 7.0 %, for example from 1.2 % to 6.5 %, such as from 1.2 % to 6.0 %, for example from 1.2 % to 5.5 %, such as from 1.2 % to 5.0 %, for example from 1.2 % to 4.5 %, for example from 1 .5 % to 4.0 %, such as from 2.0
  • the iron is in the form of inorganic iron.
  • the iron is iron sulphate and/or iron oxide.
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of copper in said composition is in the range of from 0.4 % to 4.5 % (w/w).
  • the first composition comprises phosphate, iron and copper, wherein the absolute amount of copper in said composition is in the range of from 0.4 % to 4.5 %, for example from 0.4 % to 4.0 %; such as from 0.4 % to 3.5 %, for example from 0.4 % to 3.0 %; such as from 0.4 % to 2.5 %, for example from 0.4 % to 2.0 %; such as from 0.5 % to 1.5 %, for example from 0.5 % to 1.0 %, such as 0.7 % copper.
  • the copper is in the form of inorganic copper.
  • the copper is copper sulphate.
  • the first composition is Stalosan F (commercially available from Storm ⁇ llen A/S, Denmark).
  • first and/or second compositions are further mixed with a thickening agent.
  • first and/or second compositions are further mixed with one or more of a stabilizing agent, an emulsifying agent, a dispersing agent, a suspending agent, a coloring agent and a perfume.
  • first and/or second compositions are further mixed with one or more of a starch, a tragacanth, a cellulose derivative, a silicone, a bentonite, a silicic acid, and talc, or mixtures thereof.
  • first and/or second compositions are further mixed with one or more of a lactose, talc, aluminum hydroxide, and calcium silicates, or mixtures of these thereof.
  • the present invention also provides methods of treatment by administering a therapeutically effective amount of the pharmaceutically active composition, or a solution derived from a nanocrystalline powder of the pharmaceutically active composition, as either a topical formulation, or as a coating on medical dressing, applied to the locally affected area of the skin.
  • the invention relates to a method for healing a wound and/or accelerating wound healing in an individual, said method comprising the steps of contacting the composition according to the invention to said wound, and healing said wound and/or accelerating wound healing as a result of said contacting.
  • the individual is preferably a mammal. More preferably the individual is a human and/or a domestic animal, such as an animal selected from the group consisting of but not limited to cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs, camels, and primates.
  • a domestic animal such as an animal selected from the group consisting of but not limited to cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs, camels, and primates.
  • the animal is a pig and the wound is a bedsore.
  • a therapeutically effective amount can be determined by testing formulations containing the pharmaceutically active compositions by in vitro or in vivo testing.
  • Formulations may be applied one or more times a day.
  • Dressings coated with the pharmaceutically active composition may be changed daily, or even less frequently, and should be kept in a moist condition with the addition of saline, alcohols, or more preferably sterile water, in order to release the pharmaceutically active composition on a sustained basis.
  • the invention further relates to the use of pharmaceutically active compounds or compositions according to the invention in the manufacture of a medicament for treating a wound or burn in an individual.
  • the composition is Stalosan F (Storm ⁇ llen A/S, Denmark).
  • the invention also relates to the use of pharmaceutically active compounds or compositions according to the invention in the manufacture of a medicament for accelerating wound healing in an individual.
  • the composition is Stalosan F (Storm ⁇ llen A/S, Denmark).
  • the invention relates to the use of a pharmaceutically active composition according to the invention comprising phosphate ions, iron ions, and copper ions, wherein the relative amounts (w/w) of phospor (P), iron (Fe) and copper (Cu), P : Fe : Cu, in said composition are given by the ratios 100 : 15 to 50 : 5 to 15, in the manufacture of a medicament for treating a wound or burn in an individual.
  • the invention relates to the use of a pharmaceutically active compound according to the invention comprising phosphate ions, iron ions, and copper ions, wherein the relative amounts (w/w) of phospor (P), iron (Fe) and copper (Cu), P : Fe : Cu, in said composition are given by the ratios 100 : 15 to 50 : 5 to 15, in the manufacture of a medicament for accelerating wound healing in an individual.
  • the individual receiving treatment with the medicament is preferably a mammal, more preferably the individual is a human and/or a domestic animal, such as an animal selected from the group consisting of but not limited to cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs, camels, and primates.
  • a domestic animal such as an animal selected from the group consisting of but not limited to cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs, camels, and primates.
  • the animal is a pig and the wound is a bedsore.
  • the absolute amount of phosphor, iron and copper can be measured with Inductive Coupled Plasma Atomic Emission Spectrometry (ICO-AES) according to AOAC method 984.27 (Official Methods of Analysis of AOAC INTERNATIONAL (OMA), 18th Edition, William Horwitz; 2005 ).
  • OMA Inductive Coupled Plasma Atomic Emission Spectrometry
  • OMA Inductive Coupled Plasma Atomic Emission Spectrometry
  • the precipitation usually used to identify phosphate is the formation of yellow ammonium molybdophosphate from ammonium molybdate in acidic solution.
  • the lesion is limited to the epidermis, eventually with a moderate crust. 2
  • the lesion involves the dermis, eventually with extensive crusting. There is little fibrosis and/or granulation tissue.
  • Table 2-16 is the raw data collected from the observations made by veterinarian Gitte
  • Table 2-7 is control sows that received no treatment and table 8-16 represent sows that received treatment with "Stalosan Salve" twice a day.
  • Table 2 Control group including sow 1717-3 and 944-3.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 3 Control group including sow 1934 and 1651-1.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Control group including sow 2194 and 485.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Control group including sow 1322-1 and 558.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Control group including sow 1028-3 and 806.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 7 Control group including sow 1355 and 1684.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Sow 1355 leaves the study before time, since the shoulder ulcer is above the legal accepted limit (Grade 2).
  • Table 8 Stalosan Salve group including sow 898 and 1393-3.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 9 Stalosan Salve group including sow 2230-3 and 1402-3.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 10 Stalosan Salve group including sow 804-1 and 1636.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 11 Stalosan Salve group including sow 826 and 1366.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 12 Stalosan Salve group including sow 1660 and 1339.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 13 Stalosan Salve group including sow 673 and 803-6.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 14 Stalosan Salve group including sow 845 and 998.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 15 Stalosan Salve group including sow 951-3 and 1384-3.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • Table 16 Stalosan Salve group including sow 961-3.
  • Figures are expressed in cm 2 . If the ulcer grade is 0 or 1 , it will be expressed in the column of inflammation and if the ulcer grade is 2 or above, it will be expressed in the column of ulcer.
  • the mean grade of shoulder ulcer seen with the included sows is illustrated for the control and Stalosan Salve groups (figure 1 ). It can be calculated that the grade of shoulder wound for the Stalosan Salve group is significantly more decreased compared to control (dark grey columns). Also, it can be calculated that the level of shoulder ulcer is significantly lower after treating with Stalosan Salve at the weaning point compared to before treatment at the start (Stalosan salve columns dark grey and light grey). This is completely opposite in the control group, where the weaning point shows a significantly higher shoulder ulcer grade compared to the start (Control columns dark grey and light grey).
  • Stalosan Salve has proven a significantly increased healing of shoulder ulcers on sows compared to control/no treatment (see figure 1 ).

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Abstract

La présente invention concerne une composition pharmaceutique permettant la cicatrisation des plaies ou accélérant la cicatrisation des plaies, ladite composition comprenant des ions phosphate, des ions fer, 5 et des ions cuivre. Les teneurs relatives (poids/poids) de phosphore (P), de fer (Fe) et de cuivre (Cu), P : Fe : Cu, dans ladite composition, sont données par les rapports suivants : 100 : 15 à 50 : 5 à 15. L'invention concerne, en outre, des procédés de fabrication et d'utilisation de la composition. 10 15
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US11193184B2 (en) 2019-02-22 2021-12-07 Cda Research Group, Inc. System for use in producing a metal ion suspension and process of using same
US11318089B2 (en) 2013-03-15 2022-05-03 Cda Research Group, Inc. Topical copper ion treatments and methods of making topical copper ion treatments for use in various anatomical areas of the body
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