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WO2020055135A2 - Composition pour le traitement d'une plaie ou d'une cicatrice, comprenant un patch d'hydrogel - Google Patents

Composition pour le traitement d'une plaie ou d'une cicatrice, comprenant un patch d'hydrogel Download PDF

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Publication number
WO2020055135A2
WO2020055135A2 PCT/KR2019/011781 KR2019011781W WO2020055135A2 WO 2020055135 A2 WO2020055135 A2 WO 2020055135A2 KR 2019011781 W KR2019011781 W KR 2019011781W WO 2020055135 A2 WO2020055135 A2 WO 2020055135A2
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WIPO (PCT)
Prior art keywords
wound
composition
hydrogel
fibrin
laminin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/KR2019/011781
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English (en)
Korean (ko)
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WO2020055135A3 (fr
Inventor
김정범
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Supine Therapeutics Co Ltd
UNIST Academy Industry Research Corp
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Supine Therapeutics Co Ltd
UNIST Academy Industry Research Corp
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Publication of WO2020055135A2 publication Critical patent/WO2020055135A2/fr
Publication of WO2020055135A3 publication Critical patent/WO2020055135A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0208—Tissues; Wipes; Patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • composition for treating a wound or scar comprising a hydrogel patch.
  • Skin acts as a protective barrier that protects the body from the outside.
  • blood is filled in the wound site by the natural healing action of the living body, and the granulation of platelets and activation of the hageman factor begin, and the wound healing process proceeds.
  • Coagulation of blood is a temporary protective action, protecting exposed wound tissues and providing a basis for cells to move during the healing process.
  • Wound healing aims to minimize scarring and to heal the wound as early as possible.
  • the mechanism involved in wound healing is different. It is divided into partial skin damage that causes the wound to heal due to the proliferation of epithelial cells, and dermal skin damage that requires the synthesis and decomposition of collagen and the combined action of macrophages. .
  • skin damage occurs, new blood vessels and collagen are formed through an inflammatory reaction process, and then, as the wound is healed, new epithelial cells move and the wound is closed.
  • One aspect is fibrin and / or fibrinogen; Laminin or a peptide or protein derived from laminin; And / or to provide a composition for preventing, improving or treating wounds or scars containing hyaluronic acid or a salt thereof as an active ingredient, for example, a pharmaceutical composition, a composition for external application for skin, or a cosmetic composition.
  • fibrin and / or fibrinogen Laminin or a peptide or protein derived from laminin; And / or a composition for preventing, improving or treating a wound or scar comprising a hydrogel or hydrogel patch containing hyaluronic acid or a salt thereof as an active ingredient, for example, a pharmaceutical composition, a composition for external application for skin, or a cosmetic It is to provide a composition.
  • One aspect is fibrin and / or fibrinogen; Laminin or a peptide or protein derived from laminin; And / or a composition for preventing, improving or treating a wound or scar comprising hyaluronic acid or a salt thereof as an active ingredient, for example, a pharmaceutical composition, a composition for external application for skin, or a cosmetic composition.
  • fibrin and / or fibrinogen Laminin or a peptide or protein derived from laminin; And / or a composition for preventing, improving or treating a wound or scar comprising a hydrogel or hydrogel patch containing hyaluronic acid or a salt thereof as an active ingredient, for example, a pharmaceutical composition, a composition for external application for skin, or a cosmetic Provided is a composition.
  • Another aspect provides a method of preventing, improving or treating a wound or scar comprising administering the hydrogel patch or composition to a subject.
  • Another aspect provides the use of the hydrogel, hydrogel patch or composition for the manufacture of a therapeutic agent for a disease.
  • the hydrogel patch or composition may include fibrin and / or fibrinogen; Laminin or a peptide or protein derived from laminin; And / or hyaluronic acid or salts thereof.
  • the hydrogel patch or composition may include laminin or a laminin-derived peptide or protein; And hyaluronic acid or a salt thereof.
  • the term “treat” may mean that the wound is healed at a shorter time compared to natural healing.
  • the treatment may include improvement and / or alleviation of a wound or scar.
  • the treatment may include both treatment of a wound and / or a wound-related disease.
  • the treatment may refer to the healing and / or regeneration of damaged tissue resulting from a wound.
  • the wound treatment may include the meaning of skin regeneration.
  • the treatment may be to maintain the original composition of the damaged tissue.
  • the treatment may be to promote healing and / or regeneration of the damaged tissue while minimizing scarring and / or complications of a wound-related disease.
  • pharmaceutically effective amount refers to any amount of a composition used in the course of practicing the invention provided herein sufficient to alleviate, inhibit or prevent progression of a disease, disorder or condition, or one or more symptoms thereof. You can.
  • administering is used interchangeably and in a method or route that results in at least partial localization of a patch or composition to a desired site according to one embodiment. It may mean the placement of a patch or composition according to one embodiment into an individual.
  • the term "patch (patch)" has a predetermined shape, may mean a means that can be applied, attached, or contacted to the target site.
  • the hydrogel patch or composition may have a medium property between a solid and a liquid.
  • the hydrogel patch or composition may be amorphous, spherical, hemispherical, discoidal, or cylindrical.
  • the diameter of the hydrogel patch may be 0.05 mm to 10 cm, 0.1 mm to 5 cm, 0.1 mm to 3 cm, or 0.2 mm to 1.5 cm, and may be provided in such a size or shape.
  • the hydrogel patch may be applied to a target site (eg, a tissue damage site), implanted, attached, or contacted to change its shape according to the shape of the damaged site.
  • the hydrogel patch or composition may be solid (including powder), semi-solid, or liquid.
  • the hydrogel patch or composition may undergo a reversible phase transition (eg, depending on temperature change) in a solid (including powder), semi-solid, or liquid state. Since the hydrogel patch may undergo reversible phase transition depending on ambient conditions such as temperature conditions, the hydrogel patch according to one embodiment is produced in solid (including powder) or liquid state, provided, and before administration to the target site, It can be used at the time of administration or after conversion to a hydrogel patch.
  • the hydrogel patch is provided in a sol state containing fibrinogen, laminin, and hyaluronic acid, so that a user can convert fibrinogen to fibrin (for example, thrombin),
  • a hydrogel patch according to one embodiment may be prepared and used.
  • the hydrogel patch according to one embodiment includes fibrin and / or fibrinogen; Laminin; And / or hyaluronic acid, for example, in the form of a prodrug of a solid (powder), liquid (sol), or semi-solid composition.
  • Compositions provided in the form of prodrugs can act in vivo as a hydrogel patch, or modified.
  • the hydrogel patch according to an embodiment may further include thrombin, or thrombin may be provided together as a kit.
  • the hydrogel patch or composition can be porous.
  • the surface of the hydrogel patch may be one having porosity (fine pores).
  • the hydrogel patch according to one embodiment has porosity, thereby enhancing interaction between active materials.
  • the hydrogel patch or composition may include fibrin and / or fibrinogen.
  • the final pharmacological substance acting in vivo includes fibrin, but fibrinogen may be used instead of fibrin as a form of prodrug.
  • the hydrogel patch or composition according to an embodiment may partially include fibrinogen or thrombin.
  • the present specification is fibrinogen; Laminin; And / or hyaluronic acid.
  • the fibrin or fibrinogen is 0.5 to 25 mg / ml, 1 to 25 mg / ml, 1 to 20 mg / ml, 1 to 15 mg / ml, 0.5 to 8 mg / ml, 2 to 8 mg / ml, 3 to 12 mg / ml, 4-12 mg / ml, 8-12 mg / ml or 1-4 mg / ml.
  • the fibrinogen glycoprotein is a hexamer composed of soluble ⁇ , ⁇ , and ⁇ subunits made in liver cells of the liver. Fibrinogen reacts with the thrombin enzyme to phase transition from soluble to insoluble fibrin polymer fibers.
  • the thrombin enzyme is a serine protease and an enzyme that transforms soluble fibrinogen into insoluble fibrin.
  • the thrombin may convert fibrinogen into fibrin, thereby serving to gel the sol-based hydrogel.
  • the term "laminin” is an extracellular matrix protein constituting the basal lamina, and may mean a heterotrimeric protein composed of ⁇ , ⁇ , and ⁇ subunits. Therefore, the laminin may include a laminin-derived peptide or protein as well as a laminin full-length protein.
  • the laminin is laminin-1, laminin-2, laminin-3, laminin-4, laminin-5A, laminin-5B, laminin-6, laminin-7, laminin-8, laminin-9, laminin-10 , Laminin-11, laminin-12, laminin-14, or laminin-15.
  • the laminin-derived peptide may be an ⁇ chain, a ⁇ chain, or a ⁇ chain.
  • the laminin is 1 to 100 ⁇ g / ml, 2 to 80 ⁇ g / ml, 2 to 40 ⁇ g / ml, 5 to 40 ⁇ g / ml, 15 to 25 ⁇ g / ml, 8 to 25 ⁇ g / ml, 15 to 35 ⁇ g / ml, 8 to 30 ⁇ g / ml, or 8 to 40 ⁇ g / ml.
  • the hyaluronic acid (glycosaminoglycan) is D-glucuronic acid and N-acetyl-D-glucosamine have a dividing bond having a change of ⁇ - (1 ⁇ 4) and ⁇ - (1 ⁇ 3) ( It is a polysaccharide of a disaccharide bond composed of glycosidic bonds) and has various molecular weights depending on the length of the disaccharide bond.
  • the molecular weight of hyaluronic acid may be 5,000 to 20,000,000 Da. More specifically, the molecular weight of hyaluronic acid may be 0.5 to 4.0 x 10 6 Da, 1.0 to 2.0 x 10 6 Da, or 1.5 to 1.8 x 10 6 Da.
  • the hyaluronic acid is 10 ⁇ g / ml to 10 mg / ml, 10 ⁇ g / ml to 5 mg / ml, 100 ⁇ g / ml to 3 mg / ml, 500 ⁇ g / ml to 5 mg / ml, 500 ⁇ g / ml to 8 mg / ml, 500 ⁇ g / ml to 4 mg / ml, 500 ⁇ g / ml to 2 mg / ml, 200 ⁇ g / ml to 2 mg / ml, 1 mg / ml to 8 mg / ml, or 1 mg / ml to 5 mg / ml.
  • the hydrogel patch or composition may further include a cell growth factor.
  • the cell growth factor, neuronal growth factor, vascular endothelial cell growth factor, fibroblast growth factor, bone morphogenetic protein, epidermal growth factor, hepatocyte growth factor, transformation growth factor or their It can be a combination.
  • the growth factor is placental growth factor, macrophage colony stimulating factor, granulocyte macrophage colony stimulating factor, neuropilin, fibroblast growth factor (FGF) -1, FGF-2 (bFGF), FGF-3, FGF -4, FGF-5, FGF-6, erythropoietin, BMP-2, BMP-4, BMP-7, TGF-beta, IGF-1, osteopontin, playotropin, activin, endo Choline-1 and combinations thereof.
  • FGF fibroblast growth factor
  • the neuron growth factor is BDNF (Brain-derived neurotropic factor), GDNF (Glial cell derived neurotropic factor), CNTF (Ciliary neurotropic factor), bFGF (basic fibroblast growth factor), cAMP (cyclic adenocyne monophosphate), NT (Neurotropin) , NT3 (Neurotropin-3), NT4 (Neurotropin-4), T3 (Triiodo-L-Thyronine), SHH (Sonic hedgehog), and PDGF (Platelet-derived growth factor) comprising at least one selected from the group consisting of May be
  • the vascular endothelial growth factor may include vascular endothelial growth factor (VEGF) -A, VEGF-A, VEGF-B, VEGF-C, VEGF-D, or VEGF-E.
  • VEGF vascular endothelial growth factor
  • the cell growth factor may have a different concentration included in the hydrogel patch or composition depending on the type of growth factor, but may be generally included at a concentration of 1 ng / ml to 1,000 ng / ml or 0.1 ⁇ M to 100 ⁇ M.
  • the cell growth factor may serve to enhance the tissue damage recovery effect of a hydrogel patch containing fibrin, laminin, and hyaluronic acid, or a composition.
  • the hydrogel patch or composition may or may not contain collagen.
  • the collagen may or may not be substantially included as a component of the composition, but may be more advantageous in some aspects than what is not included.
  • the hydrogel patch or composition may be substantially free of cells.
  • substantially does not comprise means that collagen or cells are included or not included to such an extent that they do not affect the activity or pharmacological activity of the hydrogel patch or composition.
  • the hydrogel patch or composition according to an embodiment does not substantially contain cells, and thus may be distinguished from cell therapy agents used for regeneration of damaged tissue.
  • the hydrogel patch or composition comprises fibrin and / or fibrinogen; Laminin or a peptide derived from laminin; And hyaluronic acid or a salt thereof.
  • the hydrogel patch or composition may include fibrin and / or fibrinogen; Laminin or a peptide derived from laminin; Hyaluronic acid or a salt thereof; Optionally thrombin; Optionally collagen; And optionally a cell growth factor.
  • wound is a disorder in which tissue is cut, torn, broken, burned, or traumatized, or that causes such damage. Or it means an injury to the human body caused by a disease.
  • the wound can be an open wound or a closed wound with no surface open.
  • wound is the epidermis of the skin (epidermis); Dermis; Epidermis and dermis; Or, the epidermis, dermis and subcutaneous layer may be damaged.
  • wounds include cuts, incisions (e.g. surgical incisions), abrasions, lacerations or lacerations, fractures, contusions, burns. , Or amputations.
  • the wound may be selected from the group consisting of chronic wound, acute wound, surgical wound, orthopedic wound, trauma wound, combat wound, and combinations thereof.
  • the wound may be a wound caused by another disease.
  • the wound may be fibrosis, diabetes, diabetic ulcer, autoimmune skin disease, abrasion, laceration, incision, left wound, bruise, puncture, detachment, burn, ulcer, bedsore, or a combination thereof.
  • the diabetes may be type I or type II diabetes. It is known that delays in wound healing are caused by various causes in patients with diabetes or complications thereof, such as diabetic ulcers (Falanga V: Wound healing and its impairment in the diabetic foot.Lancet 366: 1736-43 , 2005).
  • the hydrogel patch or composition promotes the mobility of epithelial cells, induces the migration and proliferation of fibroblasts and keratinocytes to the wound site, thereby inducing premature closing of the wound, or reconstructing the structure of the layer of the skin Induction can be effectively used for diabetic wounds or diabetic ulcers (diabetic skin ulcers or diabetic foot ulcers).
  • scar may mean fibrous tissue that replaces normal tissue destroyed by injury or disease. Damage to the outer layer of the skin is cured by rebuilding the tissue, in which case scarring can be negligible. However, if the thick layer of tissue under the skin is damaged, the reconstruction becomes more complicated. The body accumulates collagen fibers (proteins that are naturally produced by the body), which usually results in pronounced scarring.
  • the scar may be hypertrophic scar, keloid scar, atrophic scar, stretch marks, or a combination thereof.
  • Hyperproliferative scars are raised scars that remain within the boundaries of the original lesion and can generally degenerate naturally after an initial injury. Hyperproliferative scars are hard, raised, red, itchy, tender, and contracted. These typically occur after burn injury to the torso and limbs. Clinically and histologically, hyperproliferative scars and keloid scars are very similar, but unlike keloids, hyperproliferative scars expand by pushing the scar border, while keloids infiltrate surrounding tissue. Hyperproliferative scars mature and flatten over time. Hyperproliferative scars are keloids that represent the same zygotic vitreous bundle of collagen and have more vasculature and cells than typical scars.
  • Keloid scars are benign fiber proliferations of the dermis that occur after skin trauma. It protrudes over the skin surface and extends beyond the boundaries of the original lesion. These scars are permanent and do not degenerate over time. Keloids are often cosmetically unsightly and can be painful.
  • Atrophic scars are flat and pressed under the surrounding skin. It is generally small and often rounded with serrated or inverted centers. Atrophic scarring can be the result of surgery, trauma, acne and chickenpox.
  • Stretch marks are when the fine lines of the surgical scar gradually stretch and widen, which usually occurs within 3 weeks after surgery. This is a flat, faint, soft, asymptomatic scar that is often seen after knee or shoulder surgery.
  • the hydrogel patch or composition according to one embodiment may be one that induces premature closing of the wound by inducing migration and proliferation of fibroblasts and keratinocytes, cells constituting the skin, to the wound site.
  • the hydrogel patch or composition according to one embodiment may be to inhibit the formation of scars by inducing the reconstruction of the structure of the skin layer.
  • the hydrogel patch or composition according to one embodiment may be to induce regeneration of the skin to its original structure by inducing regeneration of blood vessels and hair follicles lost to a wound.
  • the composition may be useful for the treatment of wounds, prevention, improvement or treatment of scars.
  • the dosage of the composition according to one embodiment may be 0.01mg to 10,000mg, 0.1mg to 1000mg, 1mg to 100mg, 0.01mg to 1000mg, 0.01mg to 100mg, 0.01mg to 10mg, or 0.01mg to 1mg.
  • the dosage may be variously prescribed by factors such as the formulation method, the administration method, the patient's age, weight, sex, morbidity, food, administration time, administration route, excretion rate, and response sensitivity, and those skilled in the art Taking these factors into consideration, the dosage can be appropriately adjusted.
  • the number of times of administration may be one or two or more times within the range of clinically acceptable side effects, and the administration site may be administered at one or two or more places.
  • the same dosage as humans per kg is used, or the above dosages are converted, for example, by the volume ratio (eg, average value) of the target animal and human organs (heart, etc.).
  • One amount may be administered.
  • Possible routes of administration include oral, sublingual, parenteral (e.g. subcutaneous, intramuscular, intraarterial, intraperitoneal, intrathecal, or intravenous), rectal, topical (including transdermal), inhalation, and injection, or implantable devices. Or inserting a substance.
  • humans and other target mammals can be exemplified, and specifically, humans, monkeys, mice, rats, rabbits, sheep, cows, dogs, horses, pigs, etc. Is included.
  • the pharmaceutical composition according to one embodiment may include a pharmaceutically acceptable carrier and / or additives.
  • a pharmaceutically acceptable carrier examples include sterile water, physiological saline, conventional buffers (phosphoric acid, citric acid, other organic acids, etc.), stabilizers, salts, antioxidants (ascorbic acid, etc.), surfactants, suspending agents, isotonic agents, or preservatives. can do.
  • it may also include combination with an organic substance such as a biopolymer, an inorganic substance such as hydroxyapatite, specifically a collagen matrix, a polylactic acid polymer or copolymer, a polyethylene glycol polymer or copolymer, and chemical derivatives thereof. You can.
  • the pharmaceutical composition according to one embodiment if necessary depending on the method of administration or formulation, suspending agent, solubilizing agent, stabilizer, isotonic agent, preservative, adsorption inhibitor, surfactant, diluent, excipient, pH adjuster, painless agent, Buffers, reducing agents, antioxidants, and the like.
  • Pharmaceutically acceptable carriers and formulations suitable for the present invention including those exemplified above, are described in detail in Remington's Pharmaceutical Sciences, 19th ed., 1995.
  • the pharmaceutical composition according to an embodiment is a unit dose form by formulating using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. Or by incorporating it into a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in powder, granule, tablet or capsule form.
  • composition can be formulated in oral or parenteral dosage forms.
  • Oral dosage forms can be granules, powders, liquids, tablets, capsules, dry syrups, or combinations thereof.
  • the parenteral dosage form can be an injection or an external preparation for skin.
  • the external skin preparation may be a cream, gel, ointment, skin emulsifier, skin suspension, transdermal delivery patch, drug containing bandage, lotion, or combinations thereof.
  • the external preparation for skin is a component commonly used in external preparations for skin such as cosmetics, pharmaceuticals, and quasi-drugs, for example, aqueous ingredients, oily ingredients, powder ingredients, alcohols, moisturizers, thickeners, ultraviolet absorbers, whitening agents, preservatives, antioxidants, and surfactants. , Fragrance, colorant, various skin nutrients, or a combination of these and may be appropriately blended as needed.
  • the external preparation for skin is a metal blocker such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannins, velapamil, licorice extract, glabridine, and calin Hot water extract of fruits, various herbal medicines, drugs such as tocopherol acetate, glytilitic acid, tranexamic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, Sugars, such as trehalose, can also be mix
  • a metal blocker such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannins, velapamil, licorice extract, glabridine, and calin Hot water
  • the composition may be a quasi-drug composition.
  • quasi-drug is a fiber, rubber product or the like that is used for the purpose of treating, alleviating, treating or preventing a human or animal disease, has a weak effect on the human body or does not act directly on the human body, and is not an instrument or machine.
  • a device that is one of the same as the ones and the agents used for sterilization, pesticide, and similar purposes for the prevention of infection, and devices used for the purpose of diagnosing, treating, reducing, treating or preventing human or animal diseases.
  • the hydrogel, hydrogel patch or composition When the hydrogel, hydrogel patch or composition is added to the quasi-drug composition for the purpose of preventing or improving wounds or scars, the hydrogel, hydrogel patch or composition may be added as it is or used with other quasi-drug components, and is usually used. It can be suitably used depending on the phosphorus method.
  • the mixing amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
  • the quasi-drug composition is not particularly limited to this, and includes personal hygiene products, external preparations for skin, antiseptic cleaners, shower foams, greens, wipes, detergent soaps, hand washes, humidifier fillers, masks, ointments or filter fillers.
  • the external preparation for skin is not particularly limited thereto, but is preferably used in the form of ointment, lotion, spray, patch, cream, powder, suspension, gel, or gel.
  • the personal hygiene product may be soap, wipes, tissues, shampoo, toothpaste, hair care products, air freshener gel or cleaning gel.
  • the composition may be a cosmetic composition for improving or alleviating a wound or scar.
  • the composition of the present invention can be prepared in various forms, for example, emulsions, lotions, creams (oil-in-water, water-in-oil, multi-phase), solutions, suspensions (anhydrous and water-based), anhydrous products (oil And glycol-based), gels, masks, packs, powders, and the like.
  • the cosmetic composition of the present specification may include an acceptable carrier in a cosmetic preparation.
  • the "acceptable carrier in cosmetic preparations" is a compound or composition that is already known and used that may be included in cosmetic preparations, or is a compound or composition to be developed in the future. Say nothing.
  • the carrier may be included in the cosmetic composition of the present specification from about 1% to about 99.99% by weight relative to its total weight, preferably from about 90% to about 99.99% by weight of the weight of the composition.
  • the carrier include alcohols, oils, surfactants, fatty acids, silicone oils, wetting agents, moisturizing agents, viscous modifiers, emulsions, stabilizers, sunscreens, colorants, fragrances, and the like.
  • Another aspect is fibrinogen; Laminin or a peptide derived from laminin; And it provides a method for preparing a hydrogel patch by adding thrombin to a sol composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • the method may also further include the step of combining a cell growth factor with the composition in the sol state.
  • the method may also include the step of gelling by adding thrombin, followed by secondary gelation by adding thrombin again.
  • the gelation may be performed at 10 to 40 ° C. for 5 minutes to 3 hours.
  • the hydrogel patch can be produced in various shapes or sizes depending on the shape of the mold.
  • the method may also include the step of preserving or cryopreserving the hydrogel patch at 4 to -210 ° C in solution.
  • the solution may include DMSO (Dimethyl sulfoxide), but any may be used as long as it does not substantially change the chemical or physical properties of the hydrogel patch.
  • the hydrogel patch does not substantially change its shape or activity even if it is stored at low temperature or frozen.
  • hydrogel patch, fibrin and / or fibrinogen, laminin, hyaluronic acid or cell growth factors are as described above.
  • Another aspect provides a method of preserving or cryopreserving the hydrogel patch at 4 to -210 ° C in a solution (eg, DMSO).
  • a solution eg, DMSO
  • the migration and proliferation of fibroblasts and keratinocytes to the wound site induces premature closing of the wound, and induce structural reconstruction of the skin layer to prevent and improve skin wounds or scars Or there is an effect that can be useful for treatment.
  • 1 is a composition of a hydrogel according to one embodiment (fibrin, hyaluronic acid, and laminin) and the group of the group not treated with it (none) in vitro (in vitro) effect on wound closure (wound closure) of human fibroblasts It is a figure confirmed using an optical microscope; the scale bar represents 500 ⁇ m each.
  • FIG. 2 is a graph showing quantifying the effect of in vitro human fibroblasts on wound repair according to a combination of two components, a hydrogel according to one embodiment, and each component alone; * p ⁇ 0.05, ** p ⁇ 0.005.
  • FIG. 3 is a photograph showing the effect of treating a wound and scar of a hydrogel according to one embodiment.
  • Figure 4 is a graph showing the recovery rate of the wound according to the application of the hydrogel according to one embodiment.
  • Fibrinogen (Sigma, F8630) was dissolved in PBS at 20 mg / ml, hyaluronic acid (Sigma, 53747) was dissolved in PBS at 5 mg / ml, and thrombin 200 U / ml was dissolved in PBS. Dissolved in the state. Subsequently, the sol-form fibrinogen, laminin (Thermofisher, 23017-015), and hyaluronic acid were mixed at 5 mg / ml, 20 ⁇ g / ml, and 1 mg / ml, respectively, to prepare a sol-type hydrogel.
  • a circular shape of 0.3 to 0.8 mm was imprinted on the sterilized parafilm, and 6.7 U / ml of thrombin (Sigma, T4648) in a sol state was dispensed, and 15 ⁇ l of the hydrogel formulated in Example 1-1 was mixed with thrombin. Dispense according to the circle. Subsequently, a hydrogel patch was prepared through sol-gel phase transition by curing at 37 ° C for 30 minutes.
  • human fibroblasts (CRL-2097, ATCC) from 0.1% gelatin (sigma, G1890) coated 12 well culture dishes (corning, 07-200-82) to 100% confluency (CRL-2097, ATCC) 5.0 x 10 Four were cultured. Subsequently, the same wound was made on the human fibroblasts with a 200 ⁇ l filter tip according to an in vitro scratch assay by a known method (Guan J et al. Nat Protoc, 2007).
  • hydrogel (fibrin 5 mg / ml, laminin 20 ⁇ g / ml and hyaluronic acid 1 mg / ml) prepared in the same manner as in the above example was coated and thrombin was added to form a hydrogel.
  • fibrin 15 mg / ml, laminin 60 ⁇ g / ml, and hyaluronic acid 3 mg / ml alone were treated with a combination of fibrin 5 mg / ml and laminin 20 ⁇ g / ml, laminin 20 ⁇ g / ml and hyaluronic acid A combination of 1 mg / ml, and a combination of 5 mg / ml fibrin and 1 mg / ml hyaluronic acid was treated.
  • wound repair was taken using an optical microscope (Leica, DMI3000B) during incubation for 3 hours, 5 hours, 10 hours, and 18 hours and 24 hours, and the results are shown in FIG. 1.
  • image observed with the optical microscope was calculated by using the ImageJ (National Institutes of Health) to calculate the area of the wound, the wound repair rate was calculated, and the results are shown in FIG. 2. All statistical analyzes were performed using unpaired two-tailed Student's t-test, and the significance was * P ⁇ 0.05, or ** P ⁇ 0.005.
  • hydrogel patches were prepared to confirm the effect of wound healing.
  • Example 2 In vivo wound treatment and scar improvement effect check In order to confirm the wound treatment and scar improvement effect of the hydrogel prepared in the above example, it was evaluated whether the skin structure is regenerated in the animal model.
  • Tegaderm (3M, 2-3 / 8 inches X 2-3 / 4 inches) to the wound and wrap it with a compression bandage. gave. Tegaderm was attached to the wound without any treatment in the control group and was wrapped with a compression bandage.
  • the skin tissue in the wound area was extracted 14 days after application of the hydrogel of the above example. Thereafter, the extracted skin tissue is stored in 4% paraformaldehyde for one day, and 50%, 70%, 90%, 100% ethanol, and xylene are sequentially processed, and then preserved in paraffin for one day to block the paraffin block. It was produced. After cutting the paraffin block to 10 um, H & E staining was performed, and the results are shown in FIG. 5.
  • FIG. 3 is a photograph showing the effect of treating a wound and scar of a hydrogel according to one embodiment.
  • Figure 4 is a graph showing the recovery rate of the wound according to the application of the hydrogel according to one embodiment.
  • the hydrogel according to an embodiment induces the movement and proliferation of fibroblasts and keratinocytes, which are cells constituting the skin, to the wound site, thereby inducing premature closing of the wound. there was.
  • the hydrogel according to one embodiment can inhibit the formation of scars by inducing the reconstruction of the skin layer.
  • the hydrogel according to one embodiment induces regeneration of the skin to its original structure by inducing regeneration of blood vessels and hair follicles that have been lost to the wound.

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Abstract

La présente invention concerne une composition pour le traitement d'une plaie ou d'une cicatrice, comprenant un patch d'hydrogel. La composition ou l'hydrogel selon un aspect de l'invention induit le déplacement et la prolifération des fibroblastes et des kératinocytes dans une zone lésée, ce qui induit la fermeture précoce de la plaie, ainsi que la reconstruction structurale des couches cutanées et peut ainsi être utilement utilisé dans la prévention, le soulagement ou le traitement d'une plaie ou d'une cicatrice cutanée.
PCT/KR2019/011781 2018-09-11 2019-09-11 Composition pour le traitement d'une plaie ou d'une cicatrice, comprenant un patch d'hydrogel Ceased WO2020055135A2 (fr)

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CN112587515A (zh) * 2020-12-18 2021-04-02 张青 甘草黄酮类化合物在制备预防和/或治疗瘢痕的药物中的用途

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EP4190317A4 (fr) 2020-09-01 2024-06-26 Cellartgen Inc. Timbre d'hydrogel adhésif à tissu biomimétique porté par une matrice extracellulaire
KR102738375B1 (ko) * 2022-06-23 2024-12-03 성균관대학교산학협력단 신축성이 있는 조직 접착용 패치

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AU2399502A (en) * 2000-11-14 2002-05-27 R Labs Bvi Nv Cross-linked hyaluronic acid-laminin gels and use thereof in cell culture and medical implants
US20070100358A2 (en) * 2002-08-01 2007-05-03 Texas Scottish Rite Hospital For Children A Biomimetic Synthetic Nerve Implant
KR101091028B1 (ko) * 2009-07-02 2011-12-09 아주대학교산학협력단 체내 주입형 하이드로젤 및 이의 생의학적 용도
WO2013116446A1 (fr) * 2012-01-31 2013-08-08 Wake Forest University Health Sciences Structures de muscle lisse biotechnologiques tubulaires

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