Pharmaceutical composition for treating wounds and scars

Abstract

A pharmaceutical composition for treating wounds and scars is disclosed. A pharmaceutical composition for treating wounds and scars, according to one embodiment, may comprise: octenidine or a pharmaceutically acceptable salt thereof; heparin or a pharmaceutically acceptable salt thereof; and melatonin.

Description

Pharmaceutical composition for the treatment of wounds and scars

[0001] The present disclosure relates to a pharmaceutical composition for treating wounds and scars.

[0002] Generally, a wound refers to a condition in which the continuity and integrity of skin tissue are lost due to external factors, and skin appendages are damaged. Wound healing proceeds through a complex process, roughly tracing the stages of hemostasis, inflammation, epithelialization, proliferation, and maturation.

[0003] During the hemostasis stage, blood vessels around the wound constrict to stop bleeding, and platelets in the blood begin to function. During the inflammatory stage, cells in the damaged blood vessels around the wound (e.g., platelets, leukocytes, macrophages, etc.) are activated to remove bacteria, foreign substances, and necrotic tissue. These cells secrete various active substances that stimulate skin cells around the wound. During the epithelialization stage, epithelial cells on the wound surface differentiate and migrate through cell division, filling the entire wound area with epithelial cells. During the proliferation stage, cytoplasm and extracellular matrix proliferate, primarily to synthesize collagen. During the maturation stage, collagen production and degradation occur appropriately within the scar tissue formed through the epithelialization and proliferation stages.

[0004] Common types of wounds include abrasions, contusions, incisions, fissures, puncture wounds, acne, bedsores, burns, and ulcers. Abrasions are scratches that cause damage of varying depth and loss of epidermis. Abrasions can cause inflammation and are prone to bacterial infection. Contusions are caused by external impact and appear as a bruise on the skin's surface. Incisions are cuts from knives, glass fragments, or surgical procedures that result in significant bleeding. Dehiscence wounds are caused by pressure or friction, causing skin contraction or expansion. They are highly contagious and prone to inflammation. Puncture wounds are caused by nails, needles, or knives and are difficult to disinfect, making them highly susceptible to bacterial infection. Acne is a wound where the skin is torn by a blunt external force. Bedsores are a secondary condition caused by insufficient blood flow to a specific area under weight-bearing pressure. A burn is a condition in which the skin is damaged by direct flame or high heat, and depending on the depth of damage, it is classified as a first-degree burn (superficial burn: only the epidermis layer is damaged), a second-degree burn (partial-thickness burn: the entire epidermis and a significant portion of the dermis are damaged), and a third-degree burn (full-thickness burn: the entire dermis and subcutaneous tissue are damaged). An ulcer is a condition in which the skin or mucous membrane is damaged and torn, making it prone to bleeding. In the skin, an ulcer is mainly a condition in which the epidermis is missing, and granulation is created in the ulcerated area to repair it, and if the body's regenerative ability becomes dominant, the damaged area can be completely repaired. Although an ulcer may initially be just a perforation of the mucous membrane, it is characterized by the defect gradually growing larger and deeper under the influence of various material tissues and bacteria in the lumen.

[0005] The most fundamental goals of wound healing are to prevent secondary infection and minimize scarring. Staphylococcus aureus and Pseudomonas aeruginosa are the most common pathogens in wounds. Scar treatment drugs are medications that help remove abnormal scars formed during the wound healing process. They lighten scar color and reduce their size by inhibiting collagen proliferation in skin tissue. While scarring is unlikely if a wound heals rapidly without an inflammatory response, repeated inflammatory reactions increase the likelihood of scarring. Furthermore, a moist environment promotes the movement of cells and substances that promote inflammatory responses and wound healing, facilitating scar healing.

[0006] Hypertrophic scars and keloids occur when collagen in the dermis overgrows, pushing through thinned skin even after the wound has healed. Hypertrophic scars do not increase in size over time, but keloids grow in size over time as the scar invades normal skin. Furthermore, the cytokines responsible for scar formation during the inflammatory response are interleukin-6 (IL-6) and IL-8. The more inflammatory cytokines secreted, the more likely a scar is to form.

[0007] Therefore, there is an urgent need to develop a treatment that can simultaneously increase the efficiency of wound healing and scar removal by preventing infection and shortening the speed of the inflammatory response after stopping the bleeding in the wound.

[0008] The present inventors have made diligent efforts to develop a pharmaceutical composition for treating wounds and scars that sterilizes bacteria in inflamed areas more effectively than existing drugs that have low sterilizing power against infectious bacteria in wounds, improves the stability of pharmaceutical preparations used for treating wounds and scars, and further enhances the suppression power against inflammatory cytokines that can cause scars, and as a result, have completed the present invention.

[0009] [Prior Art Literature]

[0010] [Non-patent literature]

[0011] Kim Seong-cheol, "A Rational Approach to Skin Wound Treatment," Pharmaceutical Information Center, 2017

[0012] The technical idea of ​​the present disclosure is to solve the above-described problems, and provides a technology for a pharmaceutical composition having an excellent therapeutic effect on wounds and scars.

[0013] In addition, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition having an excellent effect of sterilizing bacteria causing infection of a wound.

[0014] In addition, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition capable of suppressing cytokines that induce an inflammatory response of a wound.

[0015] Additionally, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition with improved storage stability.

[0016] And, the technical idea of ​​the present disclosure provides a pharmaceutical composition for wound treatment.

[0017] In addition, the technical idea of ​​the present disclosure provides a pharmaceutical composition for treating scars.

[0018] Additionally, the technical idea of ​​the present disclosure provides uses for treating wounds and scars.

[0019] And, the technical idea of ​​the present disclosure provides a method for treating a wound by applying a pharmaceutical composition to the wound.

[0020] Additionally, the technical idea of ​​the present disclosure provides a method for treating a scar by applying a pharmaceutical composition to the affected area.

[0021] The problems to be solved by the present invention are not limited to the problems described above, and other technical problems not mentioned will be clearly understood by those skilled in the art to which the present invention pertains from the contents described below.

[0022] In order to achieve this purpose, as one embodiment of the present invention, a pharmaceutical composition for treating wounds and scars may include octenidine or a pharmaceutically acceptable salt thereof; heparin or a pharmaceutically acceptable salt thereof; and melatonin.

[0023] And, the content of octenidine or a pharmaceutically acceptable salt thereof may be 0.01 to 5 wt% based on the total weight of the composition.

[0024] Additionally, the content of heparin or a pharmaceutically acceptable salt thereof may be 0.05 to 1 wt% based on the total weight of the composition.

[0025] Additionally, the content of melatonin may be 0.05 to 1 wt% based on the total weight of the composition.

[0026] And, the pharmaceutically acceptable salt of octenidine may include at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of the octenidine.

[0027] Additionally, the pharmaceutically acceptable salt of heparin may include at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of the heparin.

[0028] Additionally, the pharmaceutical composition for treating wounds and scars may further comprise at least one of eufolin, acetylcarnosine, centella asiatica extract, coriander extract, bakuchiol, warfarin sodium, bisabolol, and bromelain.

[0029] And, the wound may include at least one of abrasions, contusions, lacerations, lacerations, puncture wounds, boils, bedsores, burns and ulcers.

[0030] Additionally, the pharmaceutical composition for treating wounds and scars may further comprise an additive comprising at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH adjusting agent and a viscosity adjusting agent.

[0031] Additionally, the pH of the pharmaceutical composition for treating wounds and scars may be 2 to 10.

[0032] And, the density of the pharmaceutical composition for treating wounds and scars may be 0.1 to 2 g / cm3.

[0033] Additionally, the surface tension of the pharmaceutical composition for treating wounds and scars may be 1 to 75 dyn / cm.

[0034] Additionally, the moisture content of the pharmaceutical composition for treating wounds and scars may be 0.1 to 95 wt%.

[0035] And, the pharmaceutical composition for treating wounds and scars may have any one formulation selected from among solutions, ointments, lotions, creams, gels, emulsions, suspensions, sticks, plasters, patches, compresses, microcapsules, detergents, liposomes, and sprays.

[0036] In another embodiment of the present invention, the wound dressing may comprise the pharmaceutical composition for treating wounds and scars as described above.

[0037] As another embodiment of the present invention, the pharmaceutical composition described above can be used for the manufacture of a medicament for treating wounds and scars.

[0038] The solutions to the above-described problems are merely exemplary and should not be construed as limiting the scope of the present invention. In addition to the exemplary embodiments described above, additional embodiments may exist, as described in the drawings and detailed description of the invention.

[0039] As described above, the various embodiments of the present invention not only exhibit excellent wound and scar treatment effects, but also exhibit high medication compliance due to their outstanding antibiotic effects. Specifically, the various embodiments of the present invention exhibit superior inhibitory effects against inflammatory cytokines compared to heparin monocomponent formulations, exhibit superior scar treatment effects, and exhibit superior pharmaceutical composition stability.

[0040] Furthermore, according to various embodiments of the present invention, the compositions of the present invention exhibit significantly superior bactericidal effects compared to single-component heparin preparations. That is, the pharmaceutical compositions according to various embodiments of the present invention have excellent bactericidal effects against Staphylococcus aureus, Pseudomonas aeruginosa, and the like.

[0041] Furthermore, according to various embodiments of the present invention, the formulation is preserved in good condition, exhibits excellent sterilizing effects on inflamed areas, and shows enhanced inhibitory effects against inflammatory cytokines. That is, the pharmaceutical composition according to various embodiments of the present invention has improved sterilizing effects and superior inhibitory effects against inflammatory cytokines compared to heparin single-component formulations, and thus has a superior therapeutic effect on wounds and scars, and can significantly improve the storage stability of the formulation compared to single formulations containing only heparin components.

[0042] In addition, according to various embodiments of the present invention, the storage stability of the pharmaceutical composition is excellent even when stored at 45°C for 4 weeks.

[0043] The effects according to various embodiments of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description of the claims.

[0044] Figure 1 is a graph showing the results of an antibacterial activity test according to Control Example 1 and Manufacturing Example 2.

[0045] Figure 2 is a graph showing the results of an inhibitory effect experiment on IL-6 and IL-8 according to Control Example 1 and Manufacturing Example 2.

[0046] Figure 3 is a graph showing the results of the scar elevation index (SEI) experiment according to control examples 1 to 3 and manufacturing examples 1 to 12.

[0047] A preferred embodiment of the present invention will be described in more detail with reference to the attached drawings, but technical parts already known will be omitted or compressed for the sake of brevity.

[0048] It should be noted that references in this specification to “one” or “an” embodiment of the invention are not necessarily to the same embodiment, but rather mean at least one.

[0049] In the examples below, singular expressions include plural expressions unless the context clearly indicates a different meaning.

[0050] In the examples below, terms such as “include” or “have” mean that a feature or component described in the specification is present, and do not preclude the possibility that one or more other features or components may be added.

[0051] As used herein, the term “treatment” means any action by which the symptoms of a disease are improved or beneficially changed by administration of a pharmaceutical composition according to various embodiments of the present invention.

[0052] As used herein, the term “administration” means providing an active ingredient to a subject by any suitable method.

[0053] The term "subject" as used herein includes, but is not limited to, mammals including humans, guinea pigs, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats or rabbits, and preferably may be humans.

[0054] As used herein, the term "pharmaceutically acceptable" means physiologically acceptable and does not typically cause allergic reactions such as urticaria, gastrointestinal upset, dizziness or similar reactions when administered to humans.

[0055] As used herein, the term "salt" means an acid addition salt formed by a pharmaceutically acceptable free acid. Accordingly, a pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, an inorganic ionic salt prepared with calcium, potassium, sodium or magnesium, etc.; an inorganic acid salt prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; an organic acid salt prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc. Sulfonate salts made with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid; amino acid salts made with glycine, arginine or lysine; or amine salts made with trimethylamine, triethylamine, ammonia, pyridine or picoline; etc.; However, the types of salts meant in this specification are not limited by these listed salts.

[0056] In this specification, the term "density" refers to a value indicating mass per unit volume, generally expressed in units of g / cm3. The density described in this specification It can be measured by a surface tension meter (Easy Dyne surface tension meter model K20) sold by the company.

[0057] As used herein, the term "moisture content" refers to the moisture content contained in a pharmaceutical composition, expressed as a percentage. The moisture content described herein is measured by the Karl Fischer titration method, and a Metrohm 901 KF Titrando moisture meter can be used for the measurement.

[0058] As used herein, the term "surface tension", generally expressed in units of dyn / cm, means the force required to increase the unit area of ​​a liquid surface or the unit area of ​​an interface between two liquids or between a liquid and a gas. The surface tension described herein is De Nuy ring surface tension method (Du) using a surface tensiometer (Easy Dyne surface tensiometer model K20) sold by It is measured by the Ring Method.

[0059] In this specification, the term "d(0.9) of melatonin" refers to the particle size when the cumulative weight reaches 90 wt% starting from the smallest melatonin particle. The d(0.9) of melatonin described in this specification is measured in accordance with ISO 13320:2020, and a particle size analyzer (Mastersizer 3000) from Malvern Instruments can be used for the measurement.

[0060] In one embodiment, the structural formula of octenidine (CAS registration number: 71251-02-0) can be represented by the following chemical formula 1. The molecular formula of octenidine is C 36 H 62 It is N4 and has a molecular weight of 550.9. Octenidine has antibacterial activity and is effective in killing bacteria and fungi.

[0061] [Chemical Formula 1]

[0062]

[0063] In one embodiment, the octenidine salt is a pharmaceutically acceptable salt of octenidine, which may include at least one selected from an inorganic ionic salt of octenidine, an inorganic acid salt of octenidine, an organic acid salt of octenidine, a sulfonate salt of octenidine, an amino acid salt of octenidine, and an amine salt of octenidine.

[0064] For example, pharmaceutically acceptable salts of octenidine include inorganic ionic salts prepared with calcium, potassium, sodium or magnesium, etc.; inorganic salts prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; organic salts prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc.; sulfonic salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc.; amino acid salts prepared with glycine, arginine or lysine, etc.; Or amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine or picoline; etc.; but the types of octenidine salts are not limited by these listed salts.

[0065] As a specific example, a pharmaceutically acceptable salt of octenidine may be octenidine dihydrochloride. Octenidine dihydrochloride (CAS registration number: 70775-75-6) is a white or light yellow powder and is a pyridine compound.

[0066] The chemical name of octenidine dihydrochloride is N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride. The molecular formula of octenidine dihydrochloride is C36 H 64 Cl2N4 (molecular weight: 623.84, melting point: 215∼217℃). The structural formula of octenidine dihydrochloride can be expressed by the following chemical formula 2.

[0067] [Chemical Formula 2]

[0068]

[0069] In one specific example, octenidine dihydrochloride exhibits excellent bactericidal effects by strongly adsorbing to the cell surface of anionic bacteria, binding to phospholipids and anionic polysaccharides in the cell membrane, and impairing cell function, causing plasma membrane leakage and inhibiting mitochondrial function. Furthermore, octenidine dihydrochloride exhibits excellent anti-inflammatory properties by inhibiting Langerhans gland cell activation and suppressing the secretion of inflammatory cytokines.

[0070] Molecular biological mediators that induce inflammatory responses associated with wounds and scars include inflammatory cytokines such as Tumor Necrosis Factor-Alpha (TNF-α), IL-1β, IL-6, and IL-8, with IL-6 and IL-8 having the greatest impact. Bacteria that cause wound-related infections include Staphylococcus aureus and Pseudomonas aeruginosa.

[0071] In one embodiment, octenidine and octenidine salts may be used as at least one of an antifungal agent and an antibacterial agent. For example, octenidine and octenidine salts may exhibit bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa.

[0072] In one embodiment, the content of octenidine or a pharmaceutically acceptable salt thereof may be from about 0.01 wt % to about 5 wt % based on the total weight of the composition. As a specific example, the content of octenidine or octenidine salt is 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 %, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt% or 5 wt%. In addition, the content of octenidine or an octenidine salt can be in a range of one or more of the above values ​​and one or less of the above values.

[0073] For example, the content range of octenidine or octenidine salt can be set to be 0.01 wt% to 1 wt%, 1 wt% to 5 wt%, 2 wt% to 5 wt%, 3 wt% to 5 wt%, 4 wt% to 5 wt%, 0.01 wt% to 5 wt%, 0.1 wt% to 4 wt%, 1 wt% to 4 wt%, 3 wt% to 4 wt%, or 1 wt% to 3 wt%.

[0074] Additionally, the content of octenidine or octenidine salt may be applied at more than one of the above values, or may be applied at less than one of the above values. For example, the content of octenidine or octenidine salt is applied as 0.01 wt% or more, 0.02 wt% or more, 0.03 wt% or more, 0.04 wt% or more, 0.05 wt% or more, 0.06 wt% or more, 0.07 wt% or more, 0.08 wt% or more, 0.09 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more or 4 wt% or more, or 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, 0.1 wt% or less or It can be applied at 0.05% by weight or less. In one embodiment, the content of octenidine or octenidine salt is not limited to the above examples, and can be applied in an amount effective for the treatment of wounds and scars. For example, the level of the amount effective for the treatment of wounds and scars can be determined based on the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration, the excretion rate, the duration of treatment, concomitant drugs, and other factors well known in the medical field. It is important to take all of the above factors into consideration and administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art.

[0075] In one embodiment, the content of heparin or a pharmaceutically acceptable salt thereof may be from about 0.05 wt% to about 1 wt% based on the total weight of the composition. As specific examples, the content of heparin or a pharmaceutically acceptable salt thereof may be 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1 wt%. In addition, the content of heparin or a heparin salt may be in a range of one or more of the above values ​​and one or less of the above values.

[0076] For example, the content range of heparin or heparin salt can be set to be 0.05 wt% to 1 wt%, 0.06 wt% to 1 wt%, 0.07 wt% to 1 wt%, 0.08 wt% to 1 wt%, 0.09 wt% to 1 wt%, 0.1 wt% to 1 wt%, 0.2 wt% to 1 wt%, 0.3 wt% to 1 wt%, 0.4 wt% to 1 wt%, or 0.5 wt% to 1 wt%.

[0077] In addition, the content of heparin or a heparin salt may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the content of heparin or a heparin salt may be applied as 0.05 wt% or more, 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more, or 0.6 wt% or more, or 1 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, 0.1 wt% or less, 0.09 wt% or less, 0.08 wt% or less, 0.07 wt% or less, or 0.06 wt% or less. In one embodiment, the content of heparin or a heparin salt is not limited to the above-described examples, and can be applied in an amount effective for the treatment of wounds and scars by a person skilled in the art.

[0078] In one embodiment, the heparin salt is a pharmaceutically acceptable salt of heparin, which may include at least one selected from an inorganic ionic salt of heparin, an inorganic acid salt of heparin, an organic acid salt of heparin, a sulfonate salt of heparin, an amino acid salt of heparin, and an amine salt of heparin.

[0079] For example, pharmaceutically acceptable salts of heparin include inorganic ionic salts made with calcium, potassium, sodium or magnesium, etc.; inorganic salts made with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; organic salts made with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc.; sulfonic acid salts made with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc.; amino acid salts made with glycine, arginine or lysine, etc.; Or amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine or picoline; etc.; but the types of heparin salts are not limited by these listed salts.

[0080] As a specific example, a pharmaceutically acceptable salt of heparin can be applied as heparin sodium. The molecular formula of heparin sodium (CAS registration number: 9041-08-1) is C 26 H 42 N2NaO 37 S5 (molecular weight: 1157.92 g / mol) is a white or gray powder. Heparin sodium is a highly sulfated glycosaminoglycan, a heparin polymer that activates antithrombin to produce an anticoagulant effect, and can prevent thrombosis.

[0081] The structural formula of heparin sodium can be represented by the following chemical formula 3.

[0082] [Chemical Formula 3]

[0083]

[0084] In one embodiment, the structural formula of melatonin (Melatonin; CAS registration number 73-31-4) can be represented by the following chemical formula 4. The molecular formula of melatonin is C13 H 16 N2O2 (molecular weight 232.2 g / mol), melting point 117℃, biological half-life 30 to 50 minutes. Its appearance is a white or yellow crystalline powder.

[0085] [Chemical Formula 4]

[0086]

[0087] In one embodiment, melatonin may help skin regeneration by creating new blood vessels at the site of the injury and may activate collagen production to help prevent scarring at the site of the injury.

[0088] In one embodiment, the particle size of the melatonin may be from about 40 μm to about 70 μm. As a specific example, the particle size of the melatonin may be 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59 μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69 μm, or 70 μm.

[0089] Additionally, the particle size of melatonin may be in a range of one or more of the above values ​​and one or less of the above values. For example, the particle size of melatonin may be in a range of 40 μm to 70 μm, 50 μm to 70 μm, 60 μm to 70 μm, 40 μm to 60 μm, 50 μm to 70 μm, or 40 μm to 50 μm.

[0090] In addition, the particle size of melatonin may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the particle size of melatonin may be applied as 40㎛ or more, 50㎛ or more, or 60㎛ or more, or 70㎛ or less, 60㎛ or less, or 50㎛ or less.

[0091] According to one specific example, in order to adjust the particle size of melatonin to about 40㎛ or more and about 70㎛ or less, large-particle melatonin may be first crushed using equipment such as a hammer mill, ball mill, pin mill, or roll mill, and then secondarily crushed using a jet mill.

[0092] In one embodiment, when the particle size of melatonin is less than 40㎛, the melatonin powder must be pulverized multiple times, making it difficult to manufacture and potentially reducing economic feasibility. In addition, when the particle size of melatonin exceeds 70㎛, the solubility of melatonin at room temperature (e.g., 20-25℃) may decrease or storage stability may be negatively affected.

[0093] In one embodiment, the d(0.9) of melatonin can be applied as 40 µm, 41 µm, 42 µm, 43 µm, 44 µm, 45 µm, 46 µm, 47 µm, 48 µm, 49 µm, 50 µm, 51 µm, 52 µm, 53 µm, 54 µm, 55 µm, 56 µm, 57 µm, 58 µm, 59 µm, 60 µm, 61 µm, 62 µm, 63 µm, 64 µm, 65 µm, 66 µm, 67 µm, 68 µm, 69 µm or 70 µm.

[0094] In one embodiment, the content of melatonin may be from about 0.05 wt% to about 1 wt% based on the total weight of the composition. As specific examples, the content of melatonin may be 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1 wt%. In addition, the content of melatonin may be in a range of one or more of the above values ​​and one or less of the above values.

[0095] For example, the content range of melatonin can be set to be 0.05 wt% to 1 wt%, 0.06 wt% to 1 wt%, 0.07 wt% to 1 wt%, 0.08 wt% to 1 wt%, 0.09 wt% to 1 wt%, 0.1 wt% to 1 wt%, 0.2 wt% to 1 wt%, 0.3 wt% to 1 wt%, 0.4 wt% to 1 wt%, or 0.5 wt% to 1 wt%.

[0096] In addition, the content of melatonin may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the content of melatonin may be applied as 0.05 wt% or more, 0.1 wt% or more, 0.2 wt% or more, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more, or 0.6 wt% or more, or 1 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, 0.1 wt% or less, 0.09 wt% or less, 0.08 wt% or less, 0.07 wt% or less, or 0.06 wt% or less.

[0097] In one embodiment, if the melatonin content is less than 0.05 wt%, it is difficult to expect the wound and scar healing effect due to the addition of melatonin, and if the melatonin content exceeds 1 wt%, the storage stability of the pharmaceutical composition may be reduced. For example, if the melatonin content exceeds 1 wt%, the storage stability of the pharmaceutical composition may be reduced, and crystals may precipitate or sediment may occur during storage of the composition, and there is a concern that this may negatively affect the physical properties of the composition.

[0098] In one embodiment, a pharmaceutical composition for treating wounds and scars may further comprise at least one of Eufolin, N-Acetyl carnosine, Centella Asiatica Extract, Coriandrum Sativum Extract, Bakuchiol, Warfarin Sodium, Bisabolol, and Bromelain. In one embodiment, Eufolin is an extract extracted from the leaves of Chromolaena odorata, and may be used for treating wounds or skin infections.

[0099] In one embodiment, the wound may include at least one of an abrasion, a contusion, an incision, a laceration, a puncture wound, a boil, a bedsore, a burn, and an ulcer, and the pharmaceutical composition may be used for the treatment of such a wound.

[0100] In one embodiment, the pharmaceutical composition for treating wounds and scars may further comprise an additive. In one embodiment, the additive may comprise at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH adjusting agent, and a viscosity adjusting agent.

[0101] In one embodiment, the solvent may include at least one of an organic solvent, water for injection (WFI), purified water, and saline. The organic solvent may include at least one selected from the group consisting of alkanes, alkenes, alcohols, esters, ketones, and ether solvents. For example, the solvent may include at least one of ethanol, isopropyl alcohol, dimethyl sulfoxide, benzyl alcohol, triacetin, propyl carbonate, water for injection, purified water, and saline.

[0102] In one embodiment, the solvent content may be from about 1 wt % to about 70 wt % (e.g., 1 wt %, 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, 60 wt %, 65 wt %, or 70 wt %) based on the total weight of the composition.

[0103] In one embodiment, a moisturizer is an additive that provides moisture to the stratum corneum of the skin or prevents excessive skin dryness. In one embodiment, the moisturizer may include at least one selected from the group consisting of Propylene glycol, 1,3-Butylene glycol, 1,3-Propanediol, Glycerin, Isopentyldiol, 1,2-Pentanediol, Polyethylene glycol 400, Sorbitol, Sodium hyaluronate, Isoamyl laurate, Coconut oil, Dexpanthenol, Dimethicone, Lecithin, Xylitol, Niacinamide, Urea, and mixtures thereof.

[0104] In one embodiment, the content of the moisturizer may be from about 1 wt % to about 60 wt % (e.g., 1 wt %, 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, or 60 wt %) based on the total weight of the composition.

[0105] In one embodiment, the penetrant is a substance added to increase the penetration ability of a drug into the skin and thereby improve the therapeutic effect. According to one embodiment, the penetrant may include at least one selected from the group consisting of acetyl cysteine, oleic acid, oleyl oleate, capric / caprylic triglyceride, 2-Methyl-1,3-propanediol, hexylene glycol, diethylene glycol monoether (e.g., diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, etc.), and mixtures thereof.

[0106] In one embodiment, the amount of penetrant can be from about 1 wt % to about 80 wt % (e.g., 1 wt %, 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, 60 wt %, 65 wt %, 70 wt %, 75 wt %, or 80 wt %) based on the total weight of the composition.

[0107] In one embodiment, the surfactant may include at least one selected from the group consisting of Poloxamer 407, Poloxamer 188, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan trioleate, Polyglycerol-10-laurate, Polysorbate 80, Polysorbate 60, Polysorbate 40, Polysorbate 20, Glyceryl monostearate, Docusate sodium, Cocamidopropyl betaine, and mixtures thereof.

[0108] In one embodiment, the content of the surfactant may be from about 1 wt % to about 30 wt % (e.g., 1 wt %, 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, or 30 wt %) relative to the total weight of the composition.

[0109] In one embodiment, the antioxidant may include at least one selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, tocopherol acetate, sodium sulfite, methionine, and mixtures thereof.

[0110] In one embodiment, the amount of antioxidant may be from about 0.001 wt % to about 3 wt % (e.g., 0.001 wt %, 0.005 wt %, 0.01 wt %, 0.05 wt %, 0.1 wt %, 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 2.5 wt % or 3 wt %) based on the total weight of the composition.

[0111] In one embodiment, the chelating agent is a metal ion sequestering agent that binds to and inactivates oxygen, nitrogen, or various metal ions. In one embodiment, the chelating agent may include at least one selected from the group consisting of pentasodium pentetate, glutamic acid, methylglycine, sodium pyrophosphate, disodium EDTA, tetrasodium EDTA, oxyquinoline sulfate, and mixtures thereof.

[0112] In one embodiment, the amount of chelating agent may be from about 0.001 wt % to about 3 wt % (e.g., 0.001 wt %, 0.005 wt %, 0.01 wt %, 0.05 wt %, 0.1 wt %, 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 2.5 wt % or 3 wt %) based on the total weight of the composition.

[0113] In one embodiment, the pH adjusting agent may include at least one selected from the group consisting of hydrochloric acid, phosphoric acid, pentetic acid, acetic acid, citric acid, tartaric acid, succinic acid, lactic acid, malic acid, triethanolamine, sodium hydroxide, sodium citrate, calcium citrate, diisopropylamine, lysine, arginine, and mixtures thereof.

[0114] In one embodiment, a pH adjuster may be used to adjust the pH range of the composition to a range of about 2 or more and about 10 or less (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0115] In one embodiment, the amount of pH adjuster can be from about 0.01 wt % to about 5 wt % (e.g., 0.01 wt %, 0.05 wt %, 0.1 wt %, 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 2.5 wt %, 3 wt %, 3.5 wt %, 4 wt %, 4.5 wt % or 5 wt %) based on the total weight of the composition.

[0116] In one embodiment, the viscosity modifier may include at least one selected from the group consisting of sodium alginate, carboxymethylcellulose, ethyl cellulose, methyl cellulose, sodium polyacrylate, pectin, gelatin, dextrin, hydroxypropylmethyl cellulose, povidone, and mixtures thereof. Preferably, carboxymethyl cellulose, sodium polyacrylate, hydroxypropylmethyl cellulose, povidone, or the like may be used as the viscosity modifier. However, depending on the viscosity of the pharmaceutical composition, the viscosity modifier may or may not be added to the composition.

[0117] The excipients of the pharmaceutical composition according to one embodiment may be ingredients commonly used in the art, and examples thereof are included in the literature (Raymond C. Rowe. Handbook of Pharmaceutical Excipients 7th edition). In addition, the aforementioned types of additives, such as solvents, moisturizers, penetrants, surfactants, antioxidants, chelating agents, pH regulators, and viscosity regulators, may be manufactured by adding them in various compositions depending on the intended use and conditions, and, if necessary, the use of at least some of the types of additives may be omitted, or other types of known ingredients may be additionally used.

[0118] In one embodiment, a pharmaceutical composition for treating wounds and scars may be implemented in the form of a solution comprising 0.05 to 1 wt% of heparin sodium, 0.01 to 5 wt% of octenidine dihydrochloride, 0.05 to 1 wt% of melatonin, 1 to 70 wt% of solvent, 1 to 60 wt% of moisturizer, 1 to 80 wt% of penetrant, 1 to 30% of surfactant, 0.001 to 3 wt% of antioxidant, 0.001 to 3 wt% of chelating agent, and 0.01 to 5 wt% of pH adjusting agent (e.g., citric acid).

[0119] In another embodiment, the pharmaceutical composition for treating wounds and scars may be implemented in the form of a solution comprising 0.05 to 1 wt% of heparin sodium, 0.01 to 5 wt% of octenidine dihydrochloride, 0.05 to 1 wt% of melatonin, 1 to 70 wt% of solvent, 1 to 60 wt% of moisturizer, 1 to 80 wt% of penetrant, 1 to 30% of surfactant, 0.001 to 3 wt% of antioxidant, 0.001 to 3 wt% of chelating agent, and 0.01 to 5 wt% of pH adjusting agent (e.g., tartaric acid).

[0120] In another embodiment, a pharmaceutical composition for treating wounds and scars may be implemented in the form of a solution comprising 0.05 to 1 wt% of heparin sodium, 0.01 to 5 wt% of octenidine dihydrochloride, 0.05 to 1 wt% of melatonin, 1 to 70 wt% of solvent, 1 to 60 wt% of moisturizer, 1 to 80 wt% of penetrant, 1 to 30% of surfactant, 0.001 to 3 wt% of antioxidant, 0.001 to 3 wt% of chelating agent, and 0.01 to 5 wt% of pH adjusting agent (e.g., succinic acid).

[0121] Meanwhile, the pH of the pharmaceutical composition for treating wounds and scars according to one embodiment may be about 2 or more and about 10 or less. As a specific example, the pH of the pharmaceutical composition for treating wounds and scars may be prepared as 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. In addition, the pH of the pharmaceutical composition for treating wounds and scars according to one embodiment may be in a range of one or more of the above values ​​and one or less of the above values. For example, the pH range of the pharmaceutical composition may be prepared in a range of 2 to 10, 3 to 9, 4 to 8, 5 to 7, 4 to 9, 4 to 10, 5 to 9.5, 6 to 8, or 7 to 8.

[0122] The density of the pharmaceutical composition for treating wounds and scars according to one embodiment may be from about 0.1 g / cm3 or more to about 2 g / cm3 or less. As a specific example, the density of the pharmaceutical composition for treating wounds and scars may be applied as 0.1 g / cm3, 0.2 g / cm3, 0.3 g / cm3, 0.4 g / cm3, 0.5 g / cm3, 0.6 g / cm3, 0.7 g / cm3, 0.8 g / cm3, 0.9 g / cm3, 1 g / cm3, 1.1 g / cm3, 1.2 g / cm3, 1.3 g / cm3, 1.4 g / cm3, 1.5 g / cm3, 1.6 g / cm3, 1.7 g / cm3, 1.8 g / cm3, 1.9 g / cm3 or 2 g / cm3.

[0123] Additionally, in one embodiment, the density of the pharmaceutical composition for treating wounds and scars can range from one or more of the above values ​​to one or less of the above values. For example, the density range of the pharmaceutical composition can be set to be in the range of 0.1 g / cm3 to 2 g / cm3, 0.4 g / cm3 to 1 g / cm3, 0.8 g / cm3 to 1.5 g / cm3, 1.2 g / cm3 to 1.7 g / cm3, 1 g / cm3 to 2 g / cm3, 1.5 g / cm3 to 2 g / cm3, 0.5 g / cm3 to 2 g / cm3, 0.8 g / cm3 to 2 g / cm3, 1.2 g / cm3 to 1.8 g / cm3, 1.5 g / cm3 to 1.7 g / cm3 or 1.5 g / cm3 to 2 g / cm3.

[0124] In one embodiment, the surface tension of the pharmaceutical composition for treating wounds and scars may be from 1 to 75 dyn / cm. As a specific example, the surface tension of the pharmaceutical composition for treating wounds and scars is 1 dyn / cm, 2 dyn / cm, 3 dyn / cm, 4 dyn / cm, 5 dyn / cm, 6 dyn / cm, 7 dyn / cm, 8 dyn / cm, 9 dyn / cm, 10 dyn / cm, 11 dyn / cm, 12 dyn / cm, 13 dyn / cm, 14 dyn / cm, 15 dyn / cm, 16 dyn / cm, 17 dyn / cm, 18 dyn / cm, 19 dyn / cm, 20 dyn / cm, 21 dyn / cm, 22 dyn / cm, 23 dyn / cm, 24 dyn / cm, 25 dyn / cm, 26 dyn / cm, 27 dyn / cm, 28 dyn / cm, at 25°C. 29dyn / cm, 30dyn / cm, 31dyn / cm, 32dyn / cm, 33dyn / cm, 34dyn / cm, 35dyn / cm, 36dyn / cm, 37dyn / cm, 38dyn / cm, 39dyn / cm, 40dyn / cm, 41dyn / cm, 42dyn / cm, 43dyn / cm, 44dyn / cm, 45dyn / cm, 46dyn / cm, 47dyn / cm, 48dyn / cm, 49dyn / cm, 50dyn / cm, 51dyn / cm, 52dyn / cm, 53dyn / cm, 54dyn / cm, 55dyn / cm, 56dyn / cm, 57dyn / cm, 58dyn / cm, It can be applied as 59dyn / cm, 60dyn / cm, 61dyn / cm, 62dyn / cm, 63dyn / cm, 64dyn / cm, 65dyn / cm, 66dyn / cm, 67dyn / cm, 68dyn / cm, 69dyn / cm, 70dyn / cm, 71dyn / cm, 72dyn / cm, 73dyn / cm, 74dyn / cm or 75dyn / cm.

[0125] Additionally, the surface tension of the pharmaceutical composition according to one embodiment may be in a range of one or more of the above values ​​and one or less of the above values. For example, the surface tension range of the pharmaceutical composition may be 1 dyn / cm to 75 dyn / cm, 5 dyn / cm to 60 dyn / cm, 10 dyn / cm to 50 dyn / cm, 15 dyn / cm to 65 dyn / cm, 20 dyn / cm to 60 dyn / cm, 10 dyn / cm to 40 dyn / cm, 15 dyn / cm to 30 dyn / cm, 25 dyn / cm to 55 dyn / cm, 30 dyn / cm to 50 dyn / cm, 41 dyn / cm to 50 dyn / cm, 42 dyn / cm to 50 dyn / cm, 43 dyn / cm to 50 dyn / cm, 44 dyn / cm to 50 dyn / cm, 45 dyn / cm to 50 dyn / cm, 41 dyn / cm to It can be provided in the range of 45 dyn / cm, 41 dyn / cm to 44 dyn / cm, 41 dyn / cm to 43 dyn / cm or 50 dyn / cm to 75 dyn / cm.

[0126] In one embodiment, the moisture content of the pharmaceutical composition for treating wounds and scars is measured by the Karl Fischer method, and the moisture content of the composition measured by the Karl Fischer method may be from about 0.1 wt% or more to about 95 wt% or less. As a specific example, the moisture content of the pharmaceutical composition for treating wounds and scars is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, It can be applied at 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%.

[0127] Additionally, in one embodiment, the moisture content of the pharmaceutical composition for treating wounds and scars can be in a range of one or more of the values ​​and one or less of the values. For example, the moisture content of the pharmaceutical composition can be in a range of 0.1% to 95%, 0.5% to 90%, 0.1% to 80%, 1% to 70%, 2% to 5%, 3% to 5%, 5% to 85%, 7% to 60%, 8% to 55%, 9% to 50%, 10% to 45%, 10% to 20%, 10% to 15%, 10% to 13%, 15% to 40%, or 20% to 95%.

[0128] According to one embodiment, a pharmaceutical composition for treating wounds and scars may be prepared in any one formulation selected from among a solution, an ointment, a lotion, a cream, a gel, an emulsion, a suspension, a stick, a plaster, a patch, a cataplasa, a microcapsule, a cleaning agent, a liposomal drug, and a spray.

[0129] Meanwhile, a wound dressing according to one embodiment may include the aforementioned pharmaceutical composition for treating wounds and scars. For example, the wound dressing may be manufactured using the aforementioned pharmaceutical composition for treating wounds and scars.

[0130] Pharmaceutical compositions according to various embodiments of the present invention can be manufactured by mixing the above-described ingredients according to a conventional method, and since they do not undergo heating and cooling processes, the convenience and economy of process control can be improved.

[0131] The present invention is described in more detail below through specific manufacturing examples. The following manufacturing examples are merely examples intended to aid understanding of the present invention and are not intended to limit or restrict the scope of the present invention.

[0132] Preparation of solutions according to Control Examples 1 to 3 and Manufacturing Examples 1 to 12

[0133] Pharmaceutical compositions were prepared according to the ingredients and compositions listed in Tables 1, 2, and 3 below. The unit of content of each ingredient listed in Tables 1 to 3 is gram. 1,3-propanediol was added to each preparation container at room temperature (25°C), and heparin sodium (200 IU / mg) was added and dissolved. Then, octenidine dihydrochloride, polyethylene glycol 400, glycerin, cocoamidopropyl betaine, urea, melatonin {50 μm, d(0.9)}, butylhydroxytoluene, disodium ethylenediamine tetraacetic acid, and citric acid (or tartaric acid or succinic acid) were added in sequence, and purified water was added so that the total weight of the solution became 100, and then filtered through a 0.45 μm filter to prepare a transparent solution. As a result of measuring the pH, density, surface tension and moisture content of the manufactured solution, the pH was within the range of 3 to 7, the density was within the range of 0.6 to 1 g / cm3, the surface tension (25°C) was within the range of 40 to 60 dyn / cm, and the moisture content was within the range of 51 to 60 wt%.

[0134] Ingredients Manufacturing Example Comparison Example 1 Manufacturing Example 1 Manufacturing Example 2 Manufacturing Example 3 Manufacturing Example 4 Octenidine dihydrochloride-0.100.500.015.00 Heparin sodium 0.500.500.501.000.05 1,3-propanediol 10.0010.0010.0010.0010.0010.00 Polyethylene glycol 400 10.0010.0010.0010.0010.00 Glycerin 10.0010.0010.0010.0010.00 Cocoamido Propyl Betaine 10.0010.0010.0010.0010.00 Urea 3.003.003.003.003.00 Melatonin 0.500.500.500.500.50 Butyl Hydroxytoluene 0.010.010.010.010.01 Disodium Ethylenediaminetetraacetic Acid 0.010.010.010.010.01 Citric Acid 0.100.100.100.100.10 Purified Water 55.8855.7855.3855.3751.33 Total 100.00100.00100.00100.00100.00

[0135] Ingredients Manufacturing Example Comparison Example 2 Manufacturing Example 5 Manufacturing Example 6 Manufacturing Example 7 Manufacturing Example 8 Octenidine dihydrochloride-0.100.500.015.00 Heparin sodium 0.500.500.501.000.05 1,3-propanediol 10.0010.0010.0010.0010.0010.00 Polyethylene glycol 400 10.0010.0010.0010.0010.00 Glycerin 10.0010.0010.0010.0010.00 Cocoamido Propyl Betaine 10.0010.0010.0010.0010.00 Urea 3.003.003.003.003.00 Melatonin 0.500.500.500.500.50 Butyl Hydroxytoluene 0.010.010.010.010.01 Disodium Ethylenediaminetetraacetic Acid 0.010.010.010.010.01 Tartaric Acid 0.100.100.100.100.10 Purified Water 55.8855.7855.3855.3751.33 Total 100.00100.00100.00100.00100.00

[0136] Ingredients Manufacturing Example Comparison Example 3 Manufacturing Example 9 Manufacturing Example 10 Manufacturing Example 11 Manufacturing Example 12 Octenidine dihydrochloride-0.100.500.015.00 Heparin sodium 0.500.500.501.000.05 1,3-propanediol 10.0010.0010.0010.0010.0010.00 Polyethylene glycol 400 10.0010.0010.0010.0010.00 Glycerin 10.0010.0010.0010.0010.00 Cocoamido Propyl Betaine 10.0010.0010.0010.0010.00 Urea 3.003.003.003.003.00 Melatonin 0.500.500.500.500.50 Butyl Hydroxytoluene 0.010.010.010.010.01 Disodium Ethylenediaminetetraacetic Acid 0.010.010.010.010.01 Succinic Acid 0.100.100.100.100.10 Purified Water 55.8855.7855.3855.3751.33 Total 100.00100.00100.00100.00100.00

[0137] Test Example 1. Susceptibility Test for Antibacterial Activity Evaluation

[0138] Typically, clinical treatment outcomes can be predicted through antimicrobial susceptibility testing. The test strains used for the antimicrobial susceptibility test are Staphylococcus aureus and Pseudomonas aeruginosa, which are bacteria that cause wound infections. To evaluate the antimicrobial activity against the two microorganisms mentioned above, this experiment was conducted using the tube dilution technique. The antimicrobial activity was evaluated by determining the minimum growth inhibitory concentration (MIC) for each microorganism. 90 : The results of comparing Control Examples 1 to 3 and Manufacturing Examples 1 to 12 as Minimum Inhibitory Concentration (MIC) are as shown in Tables 4, 5, and 6 below. The MIC test was conducted according to the CLSI (Clinical and Laboratory Standards Institute) standards, and the test was performed on Staphylococcus aureus and Pseudomonas aeruginosa as follows.

[0139] 1) Pre-culture of test bacteria

[0140] Staphylococcus aureus and Pseudomonas aeruginosa were each inoculated onto Tryptic Soy Agar (TSA) medium and cultured at 35±2℃ for 16 to 24 hours.

[0141] 2) Preparation of test bacteria solution

[0142] Staphylococcus aureus and Pseudomonas aeruginosa 1×10 6 Each was diluted in Cation-Adjusted Muller-Hinton Broth (CAMHB) medium to CFU / ml and used as a test bacterial solution.

[0143] 3) Inoculation of test bacteria solution

[0144] Each tube containing the test solution for each concentration was inoculated with 1 ml of each test bacterial solution for Staphylococcus aureus and Pseudomonas aeruginosa. Each tube containing 2 ml of the solution (Control Examples 1 to 3, Preparation Examples 1 to 12) on CAMHB medium was used as a negative control group, and each tube containing 1 ml of the solution (Control Examples 1 to 3, Preparation Examples 1 to 12) and 1 ml of the test bacterial solution on CAMHB medium was used as a positive control group. The tubes that had been treated with the test bacterial solution were cultured at 35±2°C for 16 to 24 hours.

[0145] 4) Judging the results

[0146] After incubation, the minimum concentration at which no bacterial growth occurred was considered the minimum growth inhibitory concentration. After incubation, no bacterial growth should be observed in the negative control group, and bacterial growth should be observed in the positive control group. The results obtained using the above antibacterial activity test method are presented in Tables 4, 5, and 6.

[0147] Minimum growth inhibitory concentration (MIC) of the strain 90 , mg / ml)Control Example 1 Manufacturing Example 1 Manufacturing Example 2 Manufacturing Example 3 Manufacturing Example 4 Staphylococcus aureus (S. aureus) ATCC 653854.715.612.219.510.5 Pseudomonas aeruginosa (P. aeruginosa) ATCC 902765.417.216.420.514.6

[0148] Minimum growth inhibitory concentration (MIC) of the strain 90 , mg / ml)Control Example 2 Manufacturing Example 5 Manufacturing Example 6 Manufacturing Example 7 Manufacturing Example 8 Staphylococcus aureus (S. aureus) ATCC 653859.119.216.223.312.4 Pseudomonas aeruginosa (P. aeruginosa) ATCC 902768.218.716.122.613.7

[0149] Minimum growth inhibitory concentration (MIC) of the strain 90 , mg / ml)Control Example 3Manufacturing Example 9Manufacturing Example 10Manufacturing Example 11Manufacturing Example 12Staphylococcus aureus (S. aureus) ATCC 653862.318.117.322.714.3Pseudomonas aeruginosa (P. aeruginosa) ATCC 902772.521.419.825.917.3

[0150] As can be seen from the results in Tables 4, 5, and 6 above, the compositions of Preparation Examples 1 to 12 showed significantly increased antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. The antibacterial activity of Preparation Examples 1 to 4 was 2.8 to 5.2 times higher than that of Control Example 1 against Staphylococcus aureus, and 3.2 to 4.5 times higher than that of Control Example 1 against Pseudomonas aeruginosa. The antibacterial activity of Preparation Examples 5 to 8 was 2.5 to 4.8 times higher than that of Control Example 2 against Staphylococcus aureus, and 3 to 5 times higher than that of Control Example 2 against Pseudomonas aeruginosa.

[0151] The antibacterial activity of Preparation Examples 9 to 12 was 2.7 to 4.4 times higher than that of Control Example 3 against Staphylococcus aureus, and 2.8 to 4.2 times higher than that of Control Example 3 against Pseudomonas aeruginosa. Therefore, the pharmaceutical compositions of Preparation Examples 1 to 12 showed good susceptibility test results against infectious bacteria in wounds, and thus can be expected to show excellent clinical treatment results.

[0152] Figure 1 is a graph showing the results of antibacterial activity experiments according to Control Example 1 and Manufacturing Example 2. Referring to Figure 1, it can be seen that the composition according to Manufacturing Example 2 has superior antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa compared to Control Example 1.

[0153] Test Example 2. Storage Stability Evaluation

[0154] Each sample from Control Examples 1 to 3 and Manufacturing Examples 1 to 12 was taken in an amount of 10 ml and placed in a 20 ml vial, sealed hermetically, and stored at 45°C for 4 weeks. The UV-visible absorption spectra of the samples at the beginning and after 4 weeks at 45°C were measured. That is, the absorbance was measured at 500 nm using a spectrophotometer (Mega-800, Scinco, Korea), and the results are shown in Table 7 below.

[0155] [Absorbance at 500 nm] After the initial 4 weeks of the sample Control Example 10.117 ± 0.000 20.124 ± 0.000 3 Manufactured Example 10.121 ± 0.000 30.123 ± 0.000 2 Manufactured Example 20.142 ± 0.000 20.144 ± 0.000 3 Manufactured Example 30.137 ± 0.000 20.140 ± 0.000 1 Manufactured Example 40.172 ± 0.000 30.175 ± 0.000 4 Control Example 20.131 ± 0.000 10.139 ± 0.000 2 Manufactured Example 50.147 ± 0.000 20.149 ± 0.000 3 Manufactured Example 60.169 ± 0.00020.172 ± 0.0003Manufacturing example 70.154 ± 0.00040.157 ± 0.0002Manufacturing example 80.182 ± 0.00030.185 ± 0.0001Control example 30.125 ± 0.00030.132 ± 0.0002Manufacturing example 90.138 ± 0.00040.140 ± 0.0003Manufacturing example 100.153 ± 0.00020.156 ± 0.0001Manufacturing example 110.142 ± 0.00010.145 ± 0.0002Manufacturing example 120.176 ± 0.00020.179 ± 0.0003

[0156] As described in Table 7, the solutions of Preparation Examples 1 to 12 showed improved stability compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. In the 500 nm absorbance measured after 4 weeks, Control Example 1 showed an absorbance increase of about 6%, whereas Preparation Examples 1 to 4 showed an increase of about 1 to 2%, Control Example 2 showed an absorbance increase of about 6%, whereas Preparation Examples 5 to 8 showed an increase of about 1 to 2%, and Control Example 3 showed an absorbance increase of about 6%, whereas Preparation Examples 9 to 12 showed an increase of about 1 to 2%. Therefore, it can be seen that the compositions of Preparation Examples 1 to 12 showed superior stability compared to Control Examples 1 to 3 even after 4 weeks at 45°C.

[0157] Test Example 3. Evaluation of the ability to suppress inflammatory cytokines

[0158] The ability to suppress inflammatory cytokines was evaluated for Control Examples 1 to 3 and Manufacturing Examples 1 to 12 using the method described below.

[0159] (1) Ability to suppress cytotoxicity and inflammatory cytokines in mast cells

[0160] Mast cells (HMC-1: Human Mast Cell-1) were purchased from the Korea Cell Line Bank (Seoul, Korea). Mast cells were cultured in IMDM (Iscove's Modified Dulbecco's Medium, Gibco BRL, USA) containing 10% heat-inactivated fetal bovine serum (HIFBS; Gibco BRL, USA) and 1% penicillin / streptomycin (penicillin 100 IU / ml, streptomycin 100 μg / ml; Thermo Fisher Scientific) at 37°C in a 5% CO2 incubator for 24 h.

[0161] ① Cytotoxicity assessment (MTT Assay)

[0162] Cultured mast cells were 1×10 6100 μl was dispensed into a 96-well plate at cells / ml and cultured for 24 hours under 37°C, 5% CO₂ conditions. The medium was removed, and 100 μl of DMEM medium and 100 μl of sample (control examples 1-3, preparation examples 1-12) were added to each well and cultured for 24 hours. After 24 hours, 100 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) solution (0.5 mg / ml, Sigma Aldrich, St. Louis, MO, USA) was added to each well and cultured for 4 more hours to reduce MTT, and the supernatant was removed. Afterwards, 100 μl of dimethyl sulfoxide (DMSO) was dispensed into each well and mixed for 1 hour, and then the absorbance was measured at 540 nm using an ELISA microplate reader (Bio-Rad model 680, Bio-Rad Laboratories INC., Tokyo, Japan). Cell viability was calculated as the percentage of the absorbance of the sample-added group compared to the absorbance of the sample-free group, and the results are shown in Table 8.

[0163] * Cell viability (%) = (absorbance of sample added group / absorbance of sample-free group) × 100

[0164] ② Ability to suppress inflammatory cytokines

[0165] Mast cells were seeded at 5×10 per well in a 96-well plate. 5After seeding with a cell line and culturing for 24 hours, 20 nM of PMA (Phorbol 12-myristate 13 acetate) and 1 μM of calcium ionophore (Calcium ionophore A23187) were added to each well, and simultaneously, Control Examples 1 to 3 and Manufacturing Examples 1 to 12 were treated at a concentration of 100 μg / ml each, and then cultured in an incubator at 37°C and 5% CO2 for 8 hours. After the culture was completed, the culture solution was centrifuged (2,000 rpm, 5 minutes) and the supernatant was collected. To confirm the concentration of each cytokine (IL-6, IL-8) contained in the supernatant using an ELISA kit (LEGEND MAX; BioLegend, USA), the absorbance was measured at 450 nm using an ELISA microplate reader (Bio-Rad model 680, Bio-Rad Laboratories INC., Tokyo, Japan), and the inhibitory concentration of each cytokine is shown in Table 8.

[0166] Sample cytotoxicity (cell viability%)Cytokine inhibitory power (ng / ml)IL-6IL-8Control Example 110063.272.4Manufactured Example 110118.620.7Manufactured Example 210015.218.5Manufactured Example 310020.425.8Manufactured Example 49912.215.4Control Example 210171.385.7Manufactured Example 510020.124.7Manufactured Example 610018.222.4Manufactured Example 710026.427.7Manufactured Example 810014.619.1Control Example 310178.783.5Manufactured Example 910122.823.4Manufactured Example 1010019.218.2Manufactured Example Manufacturing example 1110028.126.1 1210016.715.8

[0167] As can be seen from the results in Table 8, the compositions of Preparation Examples 1 to 12 showed significantly increased inhibitory effects on IL-6 and IL-8 compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. The inhibitory effects of Preparation Examples 1 to 4 were 3.1 to 5.2 times higher for IL-6 and 2.8 to 4.7 times higher for IL-8 than Control Example 1. The inhibitory effects of Preparation Examples 5 to 8 were 2.7 to 4.9 times higher for IL-6 and 3.1 to 4.5 times higher for IL-8 than Control Example 2. The inhibitory effects of Preparation Examples 9 to 12 were 2.8 to 4.7 times higher for IL-6 and 3.2 to 5.3 times higher for IL-8 than Control Example 3. Therefore, the pharmaceutical compositions of Manufacturing Examples 1 to 12 exhibit good inhibitory effects on major cytokines (IL-6, IL-8) that cause wounds and scars, and thus can be expected to show excellent clinical treatment results. Fig. 2 is a graph showing the results of the IL-6 and IL-8 inhibitory effects experiment according to Control Example 1 and Manufacturing Example 2. Referring to Fig. 2, it can be seen that the composition according to Manufacturing Example 2 exhibits better inhibitory effects on IL-6 and IL-8 than Control Example 1.

[0168] Test Example 4. Scar Elevation Index (SEI) Evaluation

[0169] The back area of ​​rats was shaved, and wounds were created by excising the entire epithelium and dermis with a diameter of 10 mm at two points (left and right) per rat. Four weeks after the creation of the wounds, when epithelialization was completed, the compositions of Control Examples 1 to 3 and Manufacturing Examples 1 to 12 were applied to the wounded areas of each rat for four weeks. Thereafter, the scar elevation index (SEI) was measured through histological evaluation, and the results are shown in Fig. 3. The method for measuring the scar elevation index is a well-known method as described in a known literature (The Anti-Scar Effects of Basic Fibroblast Growth Factor on the Wound Repair In Vitro and In Vivo, PLoS One. 2013; 8(4): e59966.), so a detailed description thereof will be omitted.

[0170] As shown in Figure 3, the compositions according to Manufacturing Examples 1 to 12 had a relatively lower scar thickening index than those of Control Examples 1 to 3, confirming that they had a scar improvement effect.

[0171] Test Example 5. Evaluation of the ability to suppress crystal precipitation during low-temperature storage

[0172] In order to evaluate the ability to inhibit crystal precipitation during low-temperature storage, pharmaceutical compositions were prepared according to the ingredients and compositions in Table 9. The unit of content of each ingredient listed in Table 9 is gram. 1,3-propanediol was added to each preparation container at room temperature (25℃), and heparin sodium (200 IU / mg) was added and dissolved. Then, octenidine dihydrochloride, polyethylene glycol 400, glycerin, cocoamidopropyl betaine, urea, melatonin {50㎛, d(0.9)}, butylhydroxytoluene, disodium ethylenediamine tetraacetic acid, and citric acid were added in sequence, and purified water was added so that the total weight of the solution became 100, and then filtered through a 0.45μm filter to prepare a transparent solution. Each of the above manufactured samples was added at 10 ml per 20 ml vial and stored in a low-temperature freezer at -15°C for 2 weeks. The crystal and precipitate formation status of each sample was observed with the naked eye at room temperature (25°C), and the results are shown in Table 10.

[0173] Ingredients Manufacturing Examples Manufacturing Example 13 Manufacturing Example 14 Manufacturing Example 15 Manufacturing Example 16 Octenidine dihydrochloride 0.100.100.100.10 Heparin sodium 0.500.500.500.501,3-propanediol 10.0010.0010.0010.00 Polyethylene glycol 400 10.0010.0010.0010.00 Glycerin 10.0010.0010.0010.00 Cocoamido Propyl Betaine 10.0010.0010.0010.00 Urea 3.003.003.003.00 Melatonin 0.050.501.001.50 Butyl Hydroxytoluene 0.010.010.010.01 Disodium Ethylenediaminetetraacetic Acid 0.010.010.010.01 Citric Acid 0.100.100.100.10 Purified Water 56.2355.7855.2854.78 Total 100.00100.00100.00100.00

[0174] Manufacturing Example 13 Manufacturing Example 14 Manufacturing Example 15 Manufacturing Example 16 Crystal / precipitate → None Crystal / precipitate → None Crystal / precipitate → None Crystal / precipitate → Yes

[0175] Referring to the results in Table 10, in Manufacturing Examples 13, 14, and 15, in which the melatonin content was 1 wt% or less with respect to the total weight of the composition, the storage stability was good (no crystal precipitation or precipitation occurred) under low-temperature conditions (-15°C for 2 weeks), but in Manufacturing Example 16, in which the melatonin content exceeded 1 wt% with respect to the total weight of the composition, the storage stability was poor (no crystal precipitation or precipitation occurred). As described above, according to various embodiments of the present invention, not only is the wound and scar treatment effect excellent, but also has high medication compliance due to the excellent antibiotic effect.

[0176] Furthermore, according to various embodiments of the present invention, the composition of the present invention exhibits a significantly superior bactericidal effect compared to single-component preparations of heparin sodium. That is, the pharmaceutical composition of the present invention has an excellent bactericidal effect against Staphylococcus aureus and Pseudomonas aeruginosa. The bacteria causing the infection may include at least one of Staphylococcus aureus and Pseudomonas aeruginosa, and the pharmaceutical composition of the present invention has an excellent antibacterial effect against these causative bacteria.

[0177] And, according to various embodiments of the present invention, the preparation is preserved in a good state, has an excellent sterilizing effect on the wound site, shows an improved inhibitory effect on inflammatory cytokines, and has an excellent scar treatment effect.

[0178] In addition, according to various embodiments of the present invention, the storage stability of the pharmaceutical composition is excellent even when stored at 45°C for 4 weeks.

[0179] As described above, the present invention has been specifically described by way of examples. However, since the above-described examples are merely preferred examples of the present invention, the present invention should not be understood as being limited to the above-described examples, and the scope of the present invention should be understood by the claims described below and their equivalents.

Claims

1. Octenidine or a pharmaceutically acceptable salt thereof; Heparin or a pharmaceutically acceptable salt thereof; and characterized by containing melatonin; Pharmaceutical composition for the treatment of wounds and scars.

2. In paragraph 1, The content of the octenidine or a pharmaceutically acceptable salt thereof is characterized in that it is 0.01 to 5 wt% based on the total weight of the composition. Pharmaceutical composition for the treatment of wounds and scars.

3. In paragraph 1, The content of the heparin or pharmaceutically acceptable salt thereof is characterized in that it is 0.05 to 1 wt% based on the total weight of the composition. Pharmaceutical composition for the treatment of wounds and scars.

4. In paragraph 1, The content of the above melatonin is characterized by being 0.05 to 1 wt% with respect to the total weight of the composition. Pharmaceutical composition for the treatment of wounds and scars.

5. In paragraph 1, The pharmaceutically acceptable salt of the above octenidine is characterized in that it comprises at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt and an amine salt of the above octenidine. Pharmaceutical composition for the treatment of wounds and scars.

6. In paragraph 1, The pharmaceutically acceptable salt of the above heparin is characterized in that it includes at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt and an amine salt of the above heparin. Pharmaceutical composition for the treatment of wounds and scars.

7. In paragraph 1, The pharmaceutical composition for treating wounds and scars is characterized in that it further comprises at least one of eufolin, acetylcarnosine, centella asiatica extract, coriander extract, bakuchiol, warfarin sodium, bisabolol and bromelain. Pharmaceutical composition for the treatment of wounds and scars.

8. In paragraph 1, The above wound is characterized by including at least one of abrasions, contusions, incisions, lacerations, puncture wounds, boils, bedsores, burns and ulcers. Pharmaceutical composition for the treatment of wounds and scars.

9. In paragraph 1, The above pharmaceutical composition for treating wounds and scars characterized in that it further comprises an additive including at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH regulator and a viscosity regulator; Pharmaceutical composition for the treatment of wounds and scars.

10. In paragraph 1, The pH of the pharmaceutical composition for treating wounds and scars is characterized by being 2 to 10. Pharmaceutical composition for the treatment of wounds and scars.

11. In paragraph 1, The density of the pharmaceutical composition for treating wounds and scars is characterized by being 0.1 to 2 g / cm3. Pharmaceutical composition for the treatment of wounds and scars.

12. In paragraph 1, The surface tension of the pharmaceutical composition for treating wounds and scars is characterized by being 1 to 75 dyn / cm. Pharmaceutical composition for the treatment of wounds and scars.

13. In paragraph 1, The moisture content of the pharmaceutical composition for treating wounds and scars is characterized by being 0.1 to 95 wt%. Pharmaceutical composition for the treatment of wounds and scars.

14. In paragraph 1, The above-mentioned pharmaceutical composition for treating wounds and scars is characterized in that it has a formulation selected from among a solution, an ointment, a lotion, a cream, a gel, an emulsion, a suspension, a stick, a plaster, a patch, a wet compress, a microcapsule, a detergent, a liposome, and a spray. Pharmaceutical composition for the treatment of wounds and scars.

15. A wound dressing comprising a composition according to any one of claims 1 to 14.

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