WO2006094064A2 - Methode de diminution de cicatrices a l'aide de vitamine d - Google Patents

Methode de diminution de cicatrices a l'aide de vitamine d Download PDF

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Publication number
WO2006094064A2
WO2006094064A2 PCT/US2006/007286 US2006007286W WO2006094064A2 WO 2006094064 A2 WO2006094064 A2 WO 2006094064A2 US 2006007286 W US2006007286 W US 2006007286W WO 2006094064 A2 WO2006094064 A2 WO 2006094064A2
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vitamin
hydrogel
agent
gel
scar
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PCT/US2006/007286
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English (en)
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WO2006094064A3 (fr
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Anita Mehta
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Avocet Polymer Technologies, Inc.
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Publication of WO2006094064A3 publication Critical patent/WO2006094064A3/fr

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    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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 present invention relates to in general to wound healing and, in particular to a process for improving the size and appearance of scar tissue.
  • the ability to heal by forming scars is essential for mammalian systems to survive wounding after injury.
  • a hypertrophic scar is an excessive wound scar which is thick and raised, having grown in size beyond that required for normal wound healing.
  • a hypertrophic scar stays essentially within the boundaries of the original injury.
  • a keloid is a raised scar that exceeds the boundaries of the initial injury, and which is rarely corrected by surgical intervention.
  • the changing patterns of the connective tissue matrix during repair following injury require a delicate balance between synthesis and degradation of collagen and proteoglycans. Under normal circumstances this balance is maintained, while in many diseased states it is altered, leading to an excessive deposition of collagen, to a loss of functional tissue, or to disfigurement. With hypertrophic scars and keloids, the biosynthetic phase continues longer than necessary to repair the wound. In order to maintain nutrient supply in hypertrophic scars and keloids scars, vascular in-growth occurs, resulting in a large, highly vascularized scar which are unsightly and can be disabling.
  • Vitamin D is a name applied to two related fat soluble substances, cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), that have in common the ability to prevent or cure rickets (Reference - text book Godman & Gilman's -The pharmacological basis of Therapeutics, Ninth Edition , p 1529). These compounds require metabolic activation. The history of metabolic activation is primarily attributable to studies conducted in the labs of DeLuka in the USA and Kodiceck in England
  • Vitamin D as used herein, the term "activated vitamin D” or “active vitamin D” in reference to a compound is intended to include any biologically active vitamin D compound, including a pro-drug (or pro-hormone), a precursor, a metabolite or an analog, in any stage of its metabolism. It is contemplated that any of the biologically active forms of vitamin D can be used in the formulations in accordance with the present invention. Generally, an active vitamin D compound or analog is hydroxylated in at least the C-I, C-24 or C-25 position of the molecule, and either the compound itself or its metabolite binds to the vitamin D receptor (VDR).
  • VDR vitamin D receptor
  • Pro-drugs include vitamin D3 compounds that are, e.g., hydroxylated in the C-I. Such compounds undergo further hydroxylation in vivo, and their metabolites bind the VDR.
  • Precursors include pre-vitamins such as Ia-, 25-hydroxyprevitamin D3 and Ia-, 25-dihydroxyprevitamin D3, which are thermal isomeric forms of the vitamins.
  • Metabolites generally include compounds or analogs that have undergone further metabolic processing, e.g., hydroxylation.
  • Factors affecting the production of vitamin D3 synthesis are aging, sunscreens, latitude, time of day and season, and skin pigmentation.
  • the amount of skin pigmentation has been directly correlated to vitamin D3 synthesis suggesting melanin competes with vitamin D for photons from the sun. It has been well established that the levels of provitamin D are similar in all ethnic populations but variations came when the skin was photolyzed.
  • the amount of vitamin D3 produced was the function of the skin type (Matsuka L Y, Arch Dermatol., 1991; 127: 536-538). Clemens et al. (Lancet, 1982, 8263 (1), 74-76) published their results to show that increased skin pigmentation reduces the capacity of skin to synthesize Vitamin D3.
  • Vitamin D3 has been shown to act as an anti-inflammatory agent (Harant H, FEBS Lett. 1998; 436: 329-334; Arroyo CM et al., Pharmacol Toxicol. 2003; 92: 204-213; Inoue M et al., Eur J Dermatol. 1998; 8(1): 16-20). In dark skin individuals the amount of vitamin D3 production is lower thus increasing the susceptibility to inflammatory diseases. Elevated interleukin -6 expressions were exhibited in keloid fibroblasts (Xue H et al., J Surg Res. 2000; 89: 74-77). Vitamin D2 and vitamin D3 are generally considered equivalent in humans. Nevertheless, some differences between the two forms have been reported in the literature (Journal of Clinical Endocrinology and Metabolism, Vol. 89, no. 11, 5387-5391).
  • Hypertrophic scar are the major limiting consequence of injury from wound caused by laceration; a wound caused by avulsion; a wound caused by burn; a wound caused by radiation; a wound caused by chemical facial peel; and a wound caused by accident.
  • a safe and a cost effective therapy to reduce scarring conditions.
  • One way to increase safety is to use an agent which is inexpensive and effective.
  • One of them is vitamin D and its derivatives, analogues and active metabolites.
  • vitamin D derivatives are unstable under heat and light and are toxic on long term use such as is desired here. They are chemically unstable to heat, light and oxygen and means such as refrigeration, light shading or replacement with an inert gas are required for storage of these vitamin D themselves.
  • the object of the invention is to provide methods and compositions for improving the size or appearance of a closed wound comprising administering to the healed wound, orally administering, externally administering, administering by injection or some combination thereof, a therapeutically effective amount of a composition comprising Vitamin D or active Vitamin D analogues including a pro-drug (or pro-hormone), a precursor, a metabolite. Also provided are novel hydrogels as thermal insulating material useful for treatment of excess scarring conditions.
  • Hydrogels and gels are preferred formulations for example due to their applicability in external as well as internal scarring conditions. Even though there are several hydrogels available, there is a need for a scar reducing hydrogel that incorporates the desired properties specifically tailored for this application.
  • One criterion for commercial success of such a gel will be its ability to withstand washing with either water or water and mild soap.
  • the scar reducing hydrogels needs to be applied for a long time (scar remodeling can last more than one year) thus safety requirements are high. Reusability is highly desirable especially in external applications.
  • a self-adhering gel able to withstand microbial infiltration is highly desirable.
  • the present invention provides a method for improving the size or appearance of a closed wound on a patient's skin comprising administering to the closed wound a gel or hydrogel and a therapeutically effective amount of a Vitamin D agent.
  • the present invention also provides a method for improving the size or appearance of a closed wound on a patient's skin comprising administering to the closed wound a gel or hydrogel containing a Vitamin D agent.
  • the present invention also provides a method for improving the size or appearance of a closed wound on a patient's skin comprising administering to the closed wound a gel or hydrogel and a composition containing a therapeutically effective amount of a Vitamin D agent.
  • the wound healing process may be divided into three phases.
  • the first phase is an intensely degradative phase called the inflammatory stage. It occurs immediately after injury and provides a means to remove the damaged tissues and foreign matter from the wound as well as regain immunological control over invading skin surface microbes. This phase lasts approximately one week when the wound is immediately closed, for example in a surgical incision. However, the level of the inflammatory response continues at elevated levels in open wounds until the wound surface is closed by regrowth of the epithelial barrier. If wound inflammation is prolonged or more intense, excessive scarring, called hypertrophic scars, usually appear.
  • Inflammation is the net result of interconnected physiological events, including increased vascular permeability, fluid accumulation, and the migration of a changing population of inflammatory cells into an inflamed area.
  • the clinical manifestations of inflammation include swelling, increased local temperature, erythema, and pain.
  • the inflammatory response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, and the like.
  • the inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive resulting in functional impairment.
  • the second stage of wound healing typically occurs 2-3 days later and typically lasts about 3 weeks.
  • This stage may be referred to as the proliferation and matrix synthesis stage.
  • fibroblasts from the surrounding tissue invade the wound and proliferate.
  • the fibroblasts in the wound proliferate and actively produce macromolecules, such as collagen and proteoglycans, which are secreted into the extracellular matrix.
  • Fibroblast activity is driven by the chemical signals produced by inflammation.
  • the newly-synthesized collagen fibrils are cross-linked by lysyl oxidase and provide structural integrity to the wound.
  • fibroblasts also contract the intact collagen in order to reduce the surface area of the wound.
  • the remodeling stage the previously constructed and randomly organized matrix is remodeled into an organized structure which is highly cross-linked and aligned to maximize mechanical strength. Natural skin wrinkles (relaxed skin tension lines) which align themselves in the direction of mechanical tension and become permanent on the face over time are a common manifestation of this control process.
  • This step can last for more than one year.
  • the end result of mammalian wound healing is scar formation. Scars are not an exact replacement for undamaged tissue. Skin scars are generally less elastic, creating contour irregularities; color changes and maybe painful if they entrap nerves. Control of dermal scarring is one of the most important objectives in the management of trauma particularly burn trauma. Minimizing dermal scarring and may lead to optimum post-traumatic functional and aesthetic recovery.
  • hypertrophic scar includes a scar characterized by thick, raised scar tissue that stays essentially within the boundaries of the original injury. Hypertrophic scars contain characteristic nodules, and result from a full-thickness injury, such as a surgical incision on skin. These scars can cause problems such as aesthetic deformity and severe limitation of motion. For example, an excessive postoperative scar can develop as a result of "over-healing" or hypertrophic healing of a post-operative site.
  • Hypertrophic scars generally result from an over-production of cells, collagen and proteoglycan (Linares, H. A. et al., Plast. Reconst. Surg., 62:589 (1978); Linares, H. A., Plast. Reconstr. Surg., 818-820 (1983)). These scars more frequently occur among children and adolescents, suggesting that growth factors may influence the development of this type of scar.
  • Hypertrophic scars are especially common in patients who have burns or wounds that are allowed to remain open for more than a few weeks. These scars, by definition, exceed normal wound healing, causing problems that range from aesthetic deformity to severe limitation of motion. In these scars, the overproduction and compaction of collagen and proteoglycans exceeds the proliferation of cells. These histological observations suggest that the lesions result from loss of the normal control mechanisms which regulate the synthesis of extracellular matrix during wound healing.
  • Hypertrophic scars are more common on the anterior surfaces of the neck, the shoulder, the chest wall and, in general, the flexor surfaces of the extremities. While some hypertrophic scars will spontaneously resolve within a few years, in many instances, especially in the locations mentioned above, they persist indefinitely. Because these scars are so common, particularly in burns or wounds that heal by secondary intention, their management represents a major unsolved clinical problem. Another type of scar in which there is an excess deposition of scar tissue is called a "reactive scar.” As the term is used herein, a reactive scar is a normal, healed scar which, through mechanical disruption such as scratching or other irritation, is actively producing a hypertrophic tissue response.
  • a fibrotic scar is an accumulation of irritated fibrotic tissue at the site of a healed injury which may or may not have involved an observable wound.
  • keloid includes a scar characterized by thick, raised scar tissue that exceeds the initial boundaries of the trauma and that lacks nodules.
  • keloids proliferate beyond the wound edges, can result from superficial injuries, and are rarely treated successfully by surgery. Keloids frequently develop after burns, particularly where the skin is under tension, such as on the breastbone.
  • keloids may occur with only minor insults to the skin.
  • hypertrophic scars are usually the result of injury to the deep dermis. They also tend to be more pronounced in wounds with a prolonged inflammatory phase and may develop in areas with increased mechanical tension. Both types of scars may produce considerable cosmetic disfigurement and prompt many patients affected to seek treatment.
  • keloids can be successfully treated in a single application, patients may require multiple modes of therapy (Shaffer JJ et al., J. Am. Acad. Dermatol. 2002; 46: 63-67).
  • the present invention is based, in part, on the discovery that the size and appearance of a healed wound can be improved, and the discomfort, itching, pain, and/or other symptoms caused by excessive tissue growth in a healed wound can be alleviated (partially or completely) by solving the problem of administering externally, orally or by injection or some combination thereof, a therapeutically effective amount of a composition comprising Vitamin D or active Vitamin D analogues including a pro-drug (or pro-hormone), a precursor, a metabolite or an analog.
  • the present invention relates to methods and compositions for improving the appearance and/or reducing the size of a closed wound, which may be a scar.
  • a closed wound may be a hypertrophic scar, keloid, Dupuytren's contracture, f ⁇ brotic scar, or a reactive scar.
  • the present invention relates to methods that comprise administering to an individual having a closed wound or scar a therapeutically effective amount of a composition comprising Vitamin D or active Vitamin D analogues including a pro-drug (or pro-hormone), a precursor, a metabolite or an analogue.
  • the terms "closed wound” or “scar” refer to a wound or a wound surface that is closed by regrowth of an epithelial barrier. A wound is “closed” after an open wound has been re-epithelialized. A wound is typically closed within 48-72 hours after injury. Closed wounds can result in the formation of a scar, which is never an exact replacement of the original tissue. Scar tissue is less elastic than the undamaged tissue and has surface and contour irregularities. As used herein, the term “affected area of skin” may also be used to refer to either a "closed wound” or a "scar.”
  • a closed wound is an area of skin that has pain, tingling, burning, and/or itching.
  • a closed wound is a scar.
  • a scar is an area of skin that has pain, tingling, burning, itching, discoloration, surface irregularities, and/or an erratic accumulation of fibrous tissue.
  • a closed wound may result from any of a number of types of skin traumas such as laceration, avulsion, burn, surgery, infection, chemical facial peel, and accident.
  • An open wound closes by regrowth of an epithelial barrier, the regrowth replacing some of the normal tissue which had been destroyed by trauma.
  • excessive and disfiguring deposits of fibrous tissue having an erratic accumulation of collagen occur.
  • wound healing is a continuous process extending over a one-to- two-year period.
  • vitamin D and active vitamin D compounds are formulated in gels or hydrogels to produce a stable and safe preparation with improved drug performance which is applied to inflamed scar tissue to relieve the inflamed condition and improve scar size and appearance.
  • the method includes contacting a closed wound with a thermal insulating material that elevates the surface temperature of the closed wound, and that includes an effective amount of at least vitamin D or active vitamin D compound.
  • the thermal insulating material may also include a deodorant agent to reduce surface bacteria and odor formation. The thermal insulating material is allowed to remain in contact with the closed wound for a period of time sufficient to allow a noticeable improvement in its size and appearance.
  • Keloids and hypertrophic scars can thus be treated by the present invention.
  • Another type of scar tissue that may be treated by embodiments of the method and compositions of the present invention is Dupuytren's contracture.
  • Dupuytren's contracture arises from unknown causes and is a progressive, scar-like shrinkage and thickening of the flexion contracture of the cusp-like extended palmar aponeurosis in the palm of the hand, whereby, as the curvature of the fingers increases, especially that of the fourth and fifth fingers, stretching of the fingers becomes ever more restricted.
  • the related diseases treated by this invention are for example Peyronnie's Disease, a reactive scar, an excessive post-operative scar or a fibrotic scar.
  • the present invention also relates to pharmaceutical compositions which include a suitable pharmaceutical carrier containing Vitamin D or active Vitamin D analogues and a deodorant agent, aluminum hydroxide, and an anti-microbial substance such as sodium salicylate, parabens, aluminum zirconium trichlorohydrex, or other metallic anti-microbial.
  • a suitable pharmaceutical carrier containing Vitamin D or active Vitamin D analogues and a deodorant agent, aluminum hydroxide, and an anti-microbial substance such as sodium salicylate, parabens, aluminum zirconium trichlorohydrex, or other metallic anti-microbial.
  • suitable pharmaceutical carrier and “pharmaceutically acceptable” refer to non-toxic materials that do not interfere with the effectiveness of the biological activity of active ingredients, and represent that the materials are capable of administration to or upon a vertebrate with a minimum of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
  • the characteristics of the carrier will depend on the route of administration.
  • compositions and methods according to embodiments of the invention can be used on any vertebrate with skin.
  • vertebrates include mammals (for example, human, bovine, porcine, canine, feline) and avian.
  • Hydrogels could be a good medium for reducing scars. They have been shown to be useful for the treatment of scarring conditions (for example US 5552162) and several types of hydrogels have been disclosed. It has been found by us that gels with water and without water are preferred formulations for example due to their applicability in external as well as internal scarring conditions. Even though there are several hydrogels available/ theoretically possible, there is a need for a scar reducing hydrogel that incorporates the desired properties specifically tailored for this application. One criterion for the suitability of the gel will be washing the gel in water and cleaning with mild soap. The scar reducing hydrogels needs to be applied for a long time (scar remodeling can last more than one year) thus safety requirements are high. Reusability is highly desirable especially in external applications. Self Adhering nature of the gel along with ability to stand microbial infiltration is equally important.
  • the thermal insulating material when used to cover the affected area, causes an elevation in the surface temperature of the healed wound or scar of from about 0.5 0 C to about 5 0 C. In another embodiment, the thermal insulating material, when used to cover the affected area, causes an elevation in the surface temperature of the healed wound or scar of from about 1 °C to about 4 0 C. In a preferred embodiment, the thermal insulating material, when used to cover the affected area, causes an elevation in the surface temperature of the healed wound or scar of from about 2 0 C to about 3 0 C.
  • the thermal insulating material may be a sponge.
  • sponge materials suitable for use as a thermal insulating material in the present invention include collagen and cross-linked collagen.
  • cross-linked refers to covalent bonds formed among polymeric chains and to an interconnected structure wherein cross-links are formed between hydrophobic molecules, between hydrophilic molecules and between hydrophobic molecules and hydrophilic molecules.
  • the thermal insulating material may be a gel, a hydrogel, or a biodegradable hydrogel.
  • Gels and hydrogels generally contain a very high concentration of water, e.g., about 60% to about 98% water and are held together by a variety of cellular groups.
  • the water may be bound in the form of various hydrates, or unbound, entrapped in cellular pockets formed by the polymer network groups.
  • hydrogel is used herein to mean a polymeric material which can include a cross-linked macromolecular network, which exhibits the ability to swell in water and to retain a significant portion of water within its structure without dissolving.
  • a “biodegradable hydrogel,” as the term is used herein, is a hydrogel formed from a hydrogel-forming system containing at least one biodegradable component, i.e., a component which is degraded by water and/or by enzymes found in nature. These hydrogels are particularly useful in preventing restenosis by coating implantation devices such as stents for implantation in human vessels for creating and sustaining openings and for preventing re-occlusion thereof after implantation.
  • Hydrogels could be a good medium for reducing scars. They have been shown to be useful for the treatment of scarring conditions (for example US 5552162) and several types of hydrogels have been disclosed. Even though there are several hydrogels available/ theoretically possible, there is a need for a scar reducing hydrogel that incorporates the desired properties specifically tailored for this application. For example it is not advisable to use the hydrogel patch on the skin as this may promote unwanted growth of bacteria.
  • One criterion for the suitability of the gel will be the ability to with stand washing of the gel in water and cleaning with mild soap.
  • the scar reducing hydrogels needs to be applied for a long time (scar remodeling can last more than one year) thus safety requirements are high. Reusability is highly desirable especially in external applications. Self Adhering nature of the gel along with ability to stand microbial infiltration is equally important.
  • a typical wound dressing hydrogel is applied on an open wound and should not stick to the open wound and absorb wound exudates and does not require repeated applications.
  • a typical scar reducing gel/ hydrogel is applied on the closed wound and does not have to absorb the exudates.
  • the gel should actually stick to the skin without the aid of tapes and bandages and should have the ability to resist 'dry out' and retain its adhesion after repeated applications.
  • the gel should have a soft feel and gentle release from the skin as well as high safety index.
  • polyacrylate polymer hydrogel containing from about 20 to 90 percent, and preferably from about 30 to 50 percent, by weight of a polymer prepared by the co polymerization of formula I (for example sodium 2-acrylamido-2-methylpropane sulphonate) or formula II (for example 2-acryloamino propyl trimethyl ammonium chloride compounds) with one or more monomers selected from monomers or the derivative of the monomers such as acrylic acid, water soluble acrylic functional monomers such as acrylamide, methacrylamide/N-vinyl2-pyrollidone, acrylic acidmethaacrylic acid, vinyl acetate, vinyl chloride, maleic anhydride.
  • formula I for example sodium 2-acrylamido-2-methylpropane sulphonate
  • formula II for example 2-acryloamino propyl trimethyl ammonium chloride compounds
  • hydrogels typically have a glycol component (can be selected from the group consisting of the formula OH- (C 2 H 4 O)-H, OH-(C 3 H 6 O) n -H wherein n is in the range of about 1- 16).
  • the balance can be water and or a pharmaceutical carrier.
  • R is selected from the group consisting of hydrogen or alkyl radicals containing from 1 to 6 carbon atoms
  • R 1 , R 2 and R 3 are independently alkyl C 1 - C 8
  • R 4 is selected from the group consisting of alkylene radicals containing from 1 to 6 carbon atoms or an arylene radical containing from 6 to 10 carbon atoms
  • M is selected from the group consisting of hydrogen, ammonium, potassium, or sodium, of which 2-acrylamido-2-methylpropane sulphonic acid or sodium 2- acrylamido-2-methylpropane sulphonate are the preferred examples of formula I.
  • 2-Acrylamidopropyl trimethyl ammonium chloride is a preferred formula II.
  • the monofunctional monomer component is predominantly acrylamidopropyl trimethyl ammonium chloride , 2-acryloamido-2-methyl propane sulphonic acid or a soluble salt.
  • the gels containing glycerol along with water have exceedingly better applicability in reducing the scar.
  • the glycerol content in the gel is preferred to be between 20- 60%.
  • the glycerol content in the gel is preferred to be between 20-60%.
  • Glycerol and glycerine are two words for the same substance
  • Hydrogels materials based on polymerized 2- acryloamido- 2 methyl propane sulphonic acid are known from US pat numbers 4,391,278 an 4,768,523 for wound dressing.
  • the polymerization of any of the above-described monomers and their resulting polymers are well known to those skilled in the art.
  • vitamin D and active forms of vitamin D are chemically unstable to heat, light and oxygen and means such as refrigeration, light shading or replacement with an inert gas are required for storage of these vitamin D themselves. If a method to deliver vitamin D vitamin D and active forms of vitamin D can be produced. It will be practical to apply a hydrogel patch to cover the ointment which has been applied on the scar to help further in the treatment of the scarring conditions by further assisting the degradation of the scar.
  • breathable top layer on the gel that control loss of moisture.
  • Breathable film for example be of polyethylene or polyurethane.
  • Our results showed that the gel's top layer has a great influence on gel's suitability for scar reduction.
  • MVTR moisture vapor transmission rates
  • the thickness of the gel required for a particular gel is dependent on the hydrogel used.
  • an electrical conductivity enhancer such as potassium chloride
  • salt solutions of sodium or potassium chloride at lower concentrations, may be present as polymerization enhancers in the formation of the hydrogels but are preferably restricted to 0.0% to 0.9%.
  • the new hydrogel should be preserved and capable of use for intended wear period of 30 days without microbial growth.
  • One way to ensure the sterility is to use antimicrobial gel or gamma irradiates the hydrogel.
  • the process of sterilization also changes the mechanical properties of the gel and may destroy integrity of vitamin D and active analogues.
  • Several attempts to find a gel which would meet our product criteria were made but it was not possible to find a gel which after irradiation will retain desired mechanical properties. This resulted in a loss of lots of time.
  • hydrogels are known in the literature for wound dressing hydrogels but no hydrogel for suitability for our application has been disclosed in the prior art.
  • Methyl parabens and propyl parabens are most commonly used preservatives and are generally considered to be good preservatives. In the new hydrogel they provide good protection against fungal and bacterial infections.
  • parabens are not the perfect preservatives; several attempts have been made to combine parabens with other anti-microbial agents to overcome the shortcoming of parabens.
  • Cocktails of preservatives have been prepared which contain additional anti-microbial agents. Any anti-microbial agent or combination of agents can be used. Preferably, a cocktail combination of 0.5% sodium salicylate, 0.2% methyl parabens and 0.1% propyl parabens is used.
  • Sodium salicylate is considered very safe and is commonly used as preservative (Cosmetic Ingredient Review committee refers to a review in International Journal of Toxicology; 2003 Supplement 3, Vol. 22 Issue s3, pl-108, 108p). It has been concluded in the review that 0.09 % to 2% of sodium salicylate is a safe widely used preservative.
  • Biofilm production is an important virulence attribute in the pathogenesis of device-related infections. If biofilm builds up on our hydrogel that needs to be worn for extended time, it can become a source of irritation for the patient's scars. Therefore, elimination of any possibility of formation of biofilms is highly desirable.
  • Sodium salicylate has been demonstrated to have remarkable antibacterial activity, including the ability to enhance the activities of certain antibiotics. This drug inhibits adherence (55%), growth, and biofilm production of S. epidermidis (Farber, B. F. and A. G. Wolff, J. Infect. Dis., 1998, 166:861-865 (Medline); Muller, E., J. et al., J. Infect. Dis. (1998) 117:501-503).
  • the method of the present invention also may include the simultaneous administration of a substance such as an anti microbial agent or and anti-irritant, for example, diphenhydramine, to reduce skin irritation, and/or the simultaneous administration of an ointment and/ or a gel/ hydrogel patch.
  • a substance such as an anti microbial agent or and anti-irritant, for example, diphenhydramine
  • Vitamin D a Vitamin D analogue, a Vitamin D precursor, a Vitamin D pro-drug or a Vitamin D metabolite or a combination thereof may be included in the present hydrogel either before or after the preparation of polymeric hydrogels.
  • the appropriateness of the method is generally dependent on the stability of a particular Vitamin D, a Vitamin D analogue, a Vitamin D precursor, a Vitamin D pro-drug or a Vitamin D metabolite or a combination thereof.
  • PEGs can be considered Newtonian fluids since their viscosities are nearly independent of shear. Kinematic viscosity measurements, therefore, are the most practical way of characterizing PEG viscosity. Viscosities of PEG materials decrease as temperature increases.
  • Polyethylene glycols may be liquids or solids at room temperature, depending on the average molecular weight of the PEG. Higher molecular weight PEGs form more rigid solids, while lower molecular weight PEGS tend to be viscous liquids at room temperature.
  • PEGs having average molecular weights from 200-600 are typically clear, viscous liquids at room temperature; PEGs having average molecular weights from 900-1500 are typically soft, opaque white solids at room temperatures; and PEGs having average molecular weights from 3350-8000 typically are hard, opaque white solids at room temperature.
  • Increased molecular weight results in decreased solubility in water and other solvents, decreased hygroscopicity and vapor pressure, and increased melting/freezing range and viscosity.
  • Intermediate physical properties can be achieved by blending PEGs of differing molecular weights. It has been found by us that for example, blending two PEGs, for example a 400 MW PEG and a 3350 MW PEG can lead to a composition with the consistency of an ointment or salve, or a composition having a gel tendency.
  • Polyethylene glycols make excellent water-soluble ointment bases; they spread easily and evenly over the skin, even if the skin is moist.
  • the good water solubility of PEGs makes it easy to incorporate aqueous ingredients in the formulation, and they do not become rancid or support microbial growth.
  • the vitamin D level in skin can be controlled over a wide range, from low to high levels, by incorporation of vitamin D by varying relative percentages of mixed polyethylene glycols.
  • the PEG material creates a waxy gel on the surface of the closed wound or scar that can decrease UV light penetration and buffers superoxide radicals.
  • PEG materials preferably limit the area of treatment to an appropriate level of moisture.
  • the structure of the PEG material provides a mechanical barrier for decreased penetration of bacteria and foreign materials.
  • the PEG material also creates an evaporative barrier which augments transdermal delivery of the drugs into the closed wound or scar area.
  • the PEG material comprises an acidic composition, which is favorable for the skin and for longevity of the PEG material.
  • one or more therapeutically effective substances may be applied to one surface of a thermal insulating material.
  • the thermal insulating material is then applied to the closed wound in a manner such that the therapeutically effective substance is placed in contact with the closed wound.
  • the therapeutically effective substance is dispersed within a hydrogel, a water-insoluble gel, a sponge or a PEG material.
  • the hydrogel, water-insoluble gel, sponge or PEG material, within which the therapeutically effective substance is dispersed is then placed in contact with the affected surface of the skin, and allowed to remain in place for a period of time sufficient to bring about an improvement in the size and appearance of the closed wound.
  • the term "dispersed” includes ionic, covalent, hydrophilic, or hydrophobic interactions between the therapeutically effective substance and the hydrogel, water-insoluble gel, sponge, or PEG material.
  • a therapeutically effective substance containing a cationic moiety can be immobilized on a hydrogel polymer chain.
  • this cationic site may serve as a non-covalent, ionic binding site for anionic substances.
  • a hydrogel or sponge can be chosen which covalently bonds to the therapeutic substance used according to one embodiment.
  • any water soluble drug will dissolve in the hydrogel.
  • a hydrophobic interaction between a non-water soluble therapeutic substance and a hydrogel can occur when the hydrogel selected includes a hydrophobic entity which is receptive to further interaction with a therapeutic substance having a hydrophobic moiety.
  • hydrogels or PEG materials are suitable for dispersing a particular therapeutic substance.
  • a therapeutic substance which covalently bonds to the hydrogel, sponge or PEG material can form a drug delivery substance with controlled or sustained release. If a biodegradable hydrogel or sponge is used, delivery of the therapeutic substance to the closed wound or scar is also related to the rate of degradation of the hydrogel or sponge.
  • the degradation rate of the hydrogel or sponge is usually slower than the diffusion rate of the therapeutic substance. It is well-known to those of skill in the art that the rate of delivery of the therapeutic substance can be controlled by choosing a particular concentration of each therapeutic substance used in a particular embodiment, and a particular hydrogel or sponge, one can control the rate of degradation or the rate of diffusion, and thus,.
  • the hydrogel, other thermal insulating material, or PEG material containing the therapeutically effective substance can remain in contact with the surface of the affected area of skin for about between 0.5 to about one hour per day, from about one hour to about 8 hours per day, from about 12 hours to about 15 hours per day, from about 12 hours to about 18 hours per day, from about 18 hours to about 24 hours per day, or over a number of days, for a sufficient number of days to bring about an improvement in the size and appearance of the closed wound or scar.
  • the hydrogel, other thermal insulating material, or PEG material can be removed periodically in order to cleanse the scar surface and to apply a fresh sample of therapeutically effective substance and hydrogel, other thermal insulating material, or PEG material.
  • At least one cyclooxygenase inhibitor, and/or at least one NF-kB inhibitor, or combinations thereof, are administered topically with a suitable pharmaceutical carrier, including one or more substances that relieve skin irritation.
  • a suitable pharmaceutical carrier including one or more substances that relieve skin irritation.
  • the substance that relieves skin irritation includes at least one of the following substances: glyceryl monooleate, diphenhydramine, calamine, and a C3-C4 diol.
  • a closed wound such as a scar
  • a hydrogel or PEG material comprising at least one Vitamin D or vitamin D derivative/ analogue or combinations thereof, and a deodorant agent to reduce surface bacteria and odor formation.
  • a closed wound is treated by contacting the closed wound with a hydrogel or a PEG material comprising an effective amount of vitamin D and other Vitamin D active analogues or derivatives thereof in a pharmaceutically acceptable carrier.
  • the hydrogel preferably elevates the surface temperature of the affected area of skin.
  • the hydrogel or PEG material is allowed to remain in contact with the affected area of skin for a period of time sufficient to result in an improvement in the closed wound.
  • suitable patterns of use according to an embodiment of the invention include, among others: use of various hydrogel or PEG material combinations in sequence; use of various hydrogel or PEG material combinations simultaneously; use of various hydrogel or PEG material combinations in systemic-topical co-administration, such as oral administration simultaneously with topical administration; use of combinations of active ingredients mixed by a pharmacist according to a prescription; and use of combinations of separate active ingredients available in kit form, mixed by the patient and self-administered according to physician instructions or directions provided with the kit.
  • hydrogel or PEG combinations i.e., hydrogel or PEG material combined with one or more active ingredients
  • Hydrogel may apply an active ingredient with one or more of the following advantageous properties: efficacy, sustained delivery, consistency in, dosage, enhanced delivery, dosage control, efficiency, stability and bioavailability for scar reducing.
  • vitamin D any of the biologically active forms of vitamin D can be used in the formulations in accordance with the present invention.
  • an active vitamin D compound or analog is hydroxylated in at least the C-I, C-24 or C-25 position of the molecule, and either the compound itself or its metabolite binds to the vitamin D receptor (VDR).
  • Pro-drugs include vitamin D compounds that are, e.g., hydroxylated in the C-I. Such compounds undergo further hydroxylation in vivo, and their metabolites bind the VDR.
  • Precursors include pre vitamins, such as Ia-, 25-dihydroxyprevitamin D3, which are thermal isomeric forms of the vitamin forms.
  • Metabolites generally include compounds or analogs that have undergone further metabolic processing, e.g., hydroxylation.
  • Examples of compounds suitable for formulations of the present invention include all biologically active forms of Vitamin D, without limitation vitamin D2,Viatmin D3, calcipotriene (a synthetic vitamin D3 derivative) l ⁇ ,25- dihydroxyvitamin D3 (calcitriol), l ⁇ -hydroxyvitamin D3 ( ⁇ -calcidol), seocalcitol (EB- 1089), calcipotriol, 22-oxacalcitriol (maxacalcitol), fluorinated compounds such as falecalcitriol derivatives , and 19-nor compounds such as paricalcitol derivatives.
  • Vitamin D without limitation vitamin D2,Viatmin D3, calcipotriene (a synthetic vitamin D3 derivative) l ⁇ ,25- dihydroxyvitamin D3 (calcitriol), l ⁇ -hydroxyvitamin D3 ( ⁇ -calcidol), seocalcitol (EB- 1089), calcipotriol, 22-oxacalcitriol (maxacalcitol), fluorinated compounds such as fal
  • Vitamin D2 and derivatives can also be used for the purpose of the invention (Armas LA et al., J Clin Endocrinol Metab. 2004 Nov; 89(11):5387-91)
  • One object of the invention was to produce a pharmaceutical preparation which is microbe free. Ideally, the preparation should be preserved and capable of use for long duration (long shelf life). Either raw materials are obtained in sterile conditions or / and formulations are produced aseptically.
  • the invention includes an anti-irritant, an anti-microbial agent, an anti- prurient agent, a deodorant agent and combinations thereof.
  • Amount of sodium salicylate (or related compounds) may be used in a range of 1-5 %, methyl- paraben in a range of 0.1-0.5%, and propyl-paraben in a range of 0.1-0.5% within a soluble PEG material.
  • Vitamin E aloe vera
  • amount of salicylic acid in a range of 1-5%
  • aloe in a range of 0.2-2%
  • Vitamin E in a range of 0.2-2%
  • methyl-paraben in a range of 0.1-0.5%
  • propyl-paraben in a range of 0.1-0.5% within a soluble PEG material that contained vitamin D3.
  • compositions suitable for topical or transdermal administration to the affected area of skin may be those suitable for oral or parenteral (including intramuscular, sub-cutaneous and intravenous) administration, or those in a form suitable for administration by inhalation.
  • the therapeutically effective substance of the invention together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; or in the form of sterile injectable solutions for parenteral (including sub-cutaneous) use.
  • aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Solid form preparations include, among others, powders, tablets, pills, capsules, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa buffer, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • lozenges are included. Tablets, powders, capsules, pills and lozenges can be used as solid forms suitable for oral administration.
  • liquid preparations include solutions, suspensions, and emulsions, for example, sterile water or water- propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated with PEG in aqueous solution.
  • suitable pharmaceutical carriers for parenteral administration include, for example, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • An embodiment of a therapeutically effective substance according to the present invention may thus be formulated for parenteral administration (by injection, for example, by bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • administration may also be made to the respiratory tract by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dosage of the therapeutic substance may be controlled by provision of a metered valve.
  • compounds used in an embodiment will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known
  • the terms “therapeutically effective amount” and “therapeutically effective dose” refer to the amount of an active agent, for example, a therapeutically effective substance, such as a, vitamin D and active vitamin D compounds or an anti-irritant, required to be administered in order to induce a desired result in the patient. That result may be alleviation or amelioration (complete or partial) of the symptoms or condition of irritation, pain, tingling, redness or other discoloration of a closed wound, an improvement in the appearance or reduction in the size of the closed wound, or any other desired improvement in the affected area of skin.
  • a therapeutically effective substance such as a, vitamin D and active vitamin D compounds or an anti-irritant
  • the term "therapeutically effective amount” may also refer to the quantity of active agent or therapeutically effective substance, the administration of which results in improvement in the size, appearance, or condition of a closed wound, where little or no improvement would occur in the absence of the active agent.
  • the active agent is administered for a sufficient period of time to achieve the desired therapeutic effect.
  • Therapeutic efficacy may be determined as described herein and by using standard pharmacological procedures in experimental animals.
  • the active ingredient of an embodiment of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use, or in the form of aerosol formulations for inhalation therapy.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Merck Publishing Co., Easton, Pa.).
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the dose administered is adjusted to the size and severity of the closed wound or affected area of skin, the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired.
  • the exact dosage should of course be determined by the practitioner.
  • the active ingredient can be administered in one or several doses per day.
  • at least one composition of the present invention such as vitamin D and active vitamin D compounds and antimicrobial agent, can be administered in an amount comprising from about 0.1 microgram to about 3000 micrograms, from about 10 micrograms to about 2000 micrograms, from about 20 micrograms to about 1000 micrograms, or from about 40 micrograms to about 400 micrograms per square centimeter of treated tissue.
  • At least one vitamin D and active vitamin D compounds is administered in an amount comprising from about less than 0.1 microgram to about 2000 micrograms, from about 10 micrograms to about 1000 micrograms, or from about 40 micrograms to about 400 micrograms per square centimeter of treated tissue.
  • the amount of composition of the present invention can be administered by any suitable method of administration, including, but not limited to, topical application, subcutaneous or parenteral administration, oral administration, administration by inhalation, and by combinations of these methods.
  • the PEG material of the present invention may be prepared by combining approximately 63% PEG 400 (e.g. Carbowax® available from The Dow Chemical Company® ) with approximately 37 % of PEG 3350 (e.g. Carbowax® available from The Dow Chemical Company®) in a reaction vessel made with glass.
  • PEG 400 e.g. Carbowax® available from The Dow Chemical Company®
  • PEG 3350 e.g. Carbowax® available from The Dow Chemical Company®
  • the liquid PEG is maintained at 65 0 C and methyl parabenzene, propyl parabenzene and BHT are added. Then the mixture is cooled. Vitamin D is dissolved in ethanol and added. PEG materials were formed into a shape for use in the present invention.
  • Ointment Formulation Ointment Formulation:
  • the PEG material of the present invention may be prepared by combining approximately 63% ( w/w) PEG 400 (e.g. Carbowax® available from The Dow Chemical Company® ) with approximately 37% ( w/w) of PEG 3350 (e.g. Carbowax® available from The Dow Chemical Company®) in a reaction vessel made with glass.
  • PEG 400 e.g. Carbowax® available from The Dow Chemical Company®
  • PEG 3350 e.g. Carbowax® available from The Dow Chemical Company®
  • the liquid PEG is maintained at 65 0 C and methyl parabenzene, propyl parabenzene and BHT are added. Then the mixture is cooled. Vitamin D is dissolved in ethanol and added during stirring. PEG materials were formed into a shape for use in the present invention.
  • the PEG material of the present invention may be prepared by first dissolving 0.05 gm BHT by stirring in 16 gm PEG 400 (e.g. Carbowax® available from The Dow Chemical Company® ) with approximately 9 gm of PEG 3350 (e.g. Carbowax® available from The Dow Chemical Company®) in a reaction vessel made with glass.
  • PEG 400 e.g. Carbowax® available from The Dow Chemical Company®
  • PEG 3350 e.g. Carbowax® available from The Dow Chemical Company®
  • the liquid PEG is maintained at 65°C and methyl parabenzene and propyl parabenzene are added. Then the mixture is cooled. Vitamin D3 is dissolved in minimum amount of ethanol and added. PEG materials were formed into a shape for use in the present invention.
  • Aerobic count CFU/g for hydrogel was less than 10. Both mold and yeast counts were also less than 10.
  • This formulation passed ISO skin irritation study. Under the conditions of this study, no erythmia and no edema were observed on the skin of the rabbits.
  • the primary irritation index for the test was calculated to be 0.0.
  • Aerobic count CFU/g was less than 10. Both mold and yeast counts were also less than 10.

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Abstract

La présente invention concerne une méthode permettant d'améliorer la taille ou l'apparence d'une plaie fermée sur la peau d'un patient, cette méthode consistant à administrer à ladite plaie fermée un gel ou un hydrogel et une quantité efficace thérapeutiquement d'un agent de la vitamine D.
PCT/US2006/007286 2005-02-28 2006-02-28 Methode de diminution de cicatrices a l'aide de vitamine d WO2006094064A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009014510A1 (fr) * 2007-07-20 2009-01-29 Alcon, Inc. Formulation pharmaceutique d'administration, dans l'oeil, de composés inhibiteurs des récepteurs tyrosine kinases
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
WO2016115448A1 (fr) * 2015-01-15 2016-07-21 Marshall University Research Corporation Couvertures de plaie comprenant de la vitamine d et procédés associés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5185150A (en) * 1990-08-24 1993-02-09 Wisconsin Alumni Research Fdn. Cosmetic compositions containing 19-nor-vitamin D compounds
US5459136A (en) * 1990-08-24 1995-10-17 Wisconsin Alumni Research Foundation Methods using vitamin D compounds for improvement of skin conditions
US6075015A (en) * 1993-06-04 2000-06-13 Duphar International Research B.V. Vitamin D compounds and method of preparing these compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5185150A (en) * 1990-08-24 1993-02-09 Wisconsin Alumni Research Fdn. Cosmetic compositions containing 19-nor-vitamin D compounds
US5459136A (en) * 1990-08-24 1995-10-17 Wisconsin Alumni Research Foundation Methods using vitamin D compounds for improvement of skin conditions
US6075015A (en) * 1993-06-04 2000-06-13 Duphar International Research B.V. Vitamin D compounds and method of preparing these compounds

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
US8629128B2 (en) 2005-06-01 2014-01-14 Stiefel West Coast, Llc Vitamin formulation
WO2009014510A1 (fr) * 2007-07-20 2009-01-29 Alcon, Inc. Formulation pharmaceutique d'administration, dans l'oeil, de composés inhibiteurs des récepteurs tyrosine kinases
WO2016115448A1 (fr) * 2015-01-15 2016-07-21 Marshall University Research Corporation Couvertures de plaie comprenant de la vitamine d et procédés associés
US10806819B2 (en) 2015-01-15 2020-10-20 Marshall University Research Corporation Wound coverings comprising vitamin d and related methods

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