Classifications

• • 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
  • A61K38/22—Hormones
  • A61K38/2292—Thymosin; Related peptides
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• Corneal damage prevention or treatment composition comprising thymosin beta 4 and citric acid as an active ingredient
• the present invention relates to a composition for preventing or treating corneal damage comprising thymosin ⁇ 4 and citric acid as an active ingredient.
• the cornea is a transparent, bloodless tissue on the anterior surface of the eye, often called the black jerky.
• the cornea is a transparent tissue that not only protects the eyes from the outside but also allows the light to pass through and be refracted, making it possible for the refraction and transmission of light.
• the cornea consists of five layers: corneal epithelium, Bowman's cornea, corneal parenchyma, posterior border plate (Desme's membrane) and corneal endothelium.
• the corneal surface is directly exposed to the outside, making it vulnerable to trauma and scratches.
• corneal damage frequently occurs in patients suffering from diseases such as dry eye syndrome, which is caused by a significant decrease in eye protection due to tears.
• irritation symptoms such as irritation, foreign body or dryness, as well as keratitis may develop if the damage is severe. Therefore, in order to maintain eye health and preserve vision, it is essential to prevent corneal damage, to prevent minor corneal damage, or to treat damaged corneas.
• thymosin ⁇ 4 is a protein first discovered in the thymus in 1981, and consists of 41 to 43 amino acids, isoelectric point (isoelectric point) is in the 5.1 protein eu actin in an animal cell or the like 1991 Riva-isolated molecule Thymosin ⁇ 4, which has been identified as an ac tin-sequestering molecule, was later found to be involved in immune regulation and neuroendocrine.
• Korean Unexamined Patent Publication No. 10-2008-33939 discloses an eye drop composition comprising thymosin ⁇ 4 and an amino acid stabilizer, and discloses an eye drop composition further comprising a bulking agent, a laxative agent, and a ⁇ regulator.
• Republic of Korea publication does not disclose the combination and content of ingredients that can optimize or enhance the efficacy of thymosin 4.
• the inventors have combined the components to optimize the efficacy of thymosin ⁇ 4, and each component. While trying to find the content, it was confirmed that a specific organic acid may affect the activity of thymosin 4, and completed the present invention by confirming that the composition containing this specific organic acid can be used for the treatment of corneal damage. .
• the present invention provides a composition for preventing or treating corneal damage comprising thymosin ⁇ 4, and citric acid or salts thereof as an active ingredient.
• the present invention also provides an ophthalmic preparation comprising the composition.
• the present invention provides a method for treating corneal injury comprising administering the composition to a subject.
• the present invention provides the use of the composition for use in the manufacture of a medicament for preventing or treating corneal damage.
• the composition of the present invention includes thymosin ⁇ 4 and citric acid or salts thereof as active ingredients, thereby promoting corneal epithelial cell migration and proliferation and inhibiting the penetration of ⁇ ⁇ in the damaged cornea than when thymosin ⁇ 4 is used alone. This can help to repair corneal damage.
• thymosin ⁇ 4 citric acid and acetic acid at the same time, showing excellent cell migration and proliferative efficiency compared to thymosin 4 and at the same time lowering the infiltration effect compared to each of them, thymosin ⁇ It can be utilized as a composition for preventing or treating corneal damage by increasing the utility of 4.
• 1 to 3 shows the cell migration after treatment with the composition combining thymosin ⁇ 4 and an organic acid.
• Figure 4 shows the degree of cell proliferation according to the composition in which thymosin ⁇ 4 and the organic acid is mixed.
• FIG. 5 illustrates the effect of inhibiting the infiltration of the cyanide of the composition in which the thymosin ⁇ 4 and the organic acid were mixed.
• the present invention provides a composition for preventing or treating corneal damage comprising thymosin ⁇ 4 and citric acid or salts thereof as an active ingredient.
• ⁇ thymosin ⁇ 4 '' as used herein is a protein, also referred to as Thymosin bet a-4 or ⁇ 4, isolated from the initial thymus and composed of 43 amino acids of 4.9 kDa identified in various tissues.
• the protein is a protein that is upregulated during endothelial cell migration and differentiation in vitro, and many thymosin ⁇ 4 iso forms have been identified.
• the thymosin ⁇ 4 of the present invention may have a homology of about or about 75%, or about 80% or more with the known amino acid sequence of thymosin ⁇ 4.
• the thymosin ⁇ 4 of the present invention can be applied to the N-terminal variant of wild type thymosin ⁇ 4, and the C-terminal variant of thymosin 4.
• the thymosin ⁇ 4 may be a protein having an amino acid sequence set forth in SEQ ID NO: 1.
• Citric acid used in the present invention also called citric acid, is a compound having a chemical formula of C 6 3 ⁇ 40 7 .
• citric acid used in the present invention may be used in the form of citrate.
• the citrate is a derivative of citric acid, in one embodiment may be sodium citrate or trisodium citrate.
• the citric acid or salts thereof are generally used as a laxative to alleviate the change in pH, but the citric acid or salts thereof used in the present invention should be used in a larger amount than the amount commonly used.
• the citric acid or a salt thereof may include 1% (w / v) to 15% (w / v) in the total composition.
• the citric acid or salt thereof may include 5% (w / v) to 12% (w / v), or 10% (w / v) in the total composition.
• the composition may include 10 to 120 parts by weight and citric acid or a salt thereof based on 1 part by weight of thymosin ⁇ 4. Specifically, the composition may include 10 to 100 parts by weight of citric acid or a salt thereof based on 1 part by weight of thymosin ⁇ 4. More specifically, the composition may include 15 to 100 parts by weight of citric acid or a salt thereof based on 1 part by weight of thymosin ⁇ 4. More specifically, the composition may include 50 to 100 parts by weight of citric acid or a salt thereof based on 1 part by weight of thymosin J34.
• the term "corneal injury" refers to the cornea that is the surface of the eyeball.
• wound means a wound and can be created by factors not only in external stratification but also in the body.
• wounds include wounds that may occur in any one of corneal epithelium, Bowman's membrane, corneal parenchyma, posterior border plate or corneal endothelium.
• weight / volume percent or “% (w / v)” as used herein refer to the percent by mass of solute in solution, calculated as the mass of solute to the volume of the solution, for example (w / v ) Solution means that 1 g of solute is dissolved in 100 i solution.
• the composition may further comprise at least one organic acid selected from the group consisting of acetic acid, ascorbic acid, or salts thereof.
• Acetic acid used in the present invention is a weak acid having the chemical formula CH 3 C00H, also referred to as acetic acid.
• the acetic acid used in the present invention may be used in the form of an acetate salt.
• One embodiment of the acetate salt may be sodium acetate.
• Ascorbic acid used in the present invention is a weak acid having the chemical formula C 6 3 ⁇ 40 6 , also referred to as vitamin C.
• ascorbic acid used in the present invention may be used in the form of a salt.
• Ascorbate may be sodium ascorbate.
• the organic acid may be generally used as a laxative or an antioxidant to alleviate the pH change, but the organic acid should be used in an amount larger than the amount commonly used.
• the organic acid may be included in an amount of 0.5% (w / v) to 8 (w / v), or 1.0% (w / v) to 5% (w / v) in the total composition.
• the organic acid may be included in the total composition in an amount of 1.5% (w / v) to 5% (w / v).
• the organic acid may be included in an amount of 15 to 400 parts by weight based on 100 parts by weight of citric acid or salts thereof. Specifically, the organic acid may be included in an amount of 15 to 350 parts by weight, 15 to 100 parts by weight, 15 to 70 parts by weight, or 30 to 100 parts by weight based on 100 parts by weight of citric acid or salts thereof. More specifically, the organic acid may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of citric acid or a salt thereof.
• the present invention provides an ophthalmic formulation comprising the composition.
• the formulation may be in the form of a solution, lotion, plaster, gel, cream, paste, spray, suspension, dispersion, hydrogel, ointment, oil or blowing agent.
• the composition may be formulated by mixing with a pharmaceutically acceptable, in particular non-toxic excipient or carrier which is acceptable for ophthalmic use.
• a pharmaceutically acceptable in particular non-toxic excipient or carrier which is acceptable for ophthalmic use.
• carriers such as those of the types mentioned below, in particular carriers, stabilizers, solubilizers, lamellar substrates, preservatives, thickeners, tonics and other excipients can be used.
• each agent can be used to adjust to the desired pH.
• Carriers that can be used according to the invention are typically suitable for topical or general purpose administration, for example a mixture of water, water and water-miscible solvents
• the water-miscible solvent is for example d to C 7 alkanes, vegetable oils or mineral oils (e.g. 0.5 to 5% by weight of hydroxyethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinyl-pyridone, etc.), acrylates (e.g. Salts of polyacrylic acid or ethyl acrylate), methacrylates, polyacrylamides, natural products (e.g.
• gelatin alginates, pectins, tragacanth, karaya gum, xanthan gum, catheters
• cellulose-induced alkali metal salts of methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl hydroxypropyl cellulose and hydroxypropyl cellulose
• synthetic products e.g.
• the carrier may be water, a cellulose derivative, (eg, methyl cellulose, alkali metal salts of carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl hydroxypropyl cellulose, and hydroxy).
• Propylcelose Propylcelose
• neutral carbopol or a combination thereof.
• the stabilizer examples include tyloxapol, fatty acid glycerol, poly-lower alkylene glycol esters, fatty acid poly-lower alkylene glycol esters, polyethylene glycols, glycerol ethers, and combinations thereof.
• the addition amount of the additive stabilizer may be an amount sufficient to dissolve the composition as the active ingredient.
• the loosening agent may be selected from the group consisting of borate-based, hydrogen carbonate / carbonate-based, gluconate-based, phosphate-based, propionate-based and tromethamine (TRIS) -based buffers.
• the release agent may be a tromethamine-based release agent or a borate-based release agent.
• the amount of laxative substrate can be, for example / the amount necessary to ensure and maintain a physiologically acceptable pH range.
• the physiologically acceptable pH range may be pH 5 to 9, specifically 6 to 8.2, more specifically, 6.8 to 8.1.
• the preservatives may be quaternary ammonium salts (e.g. cetrimide, benzalkonium chloride or benzoxium chloride), alkyl-mercury salts of thiosalicylic acid (e.g. thimerosal, phenylmercuric acid nitrate, phenylmercuric acid acetate or phenyl Mercuric acid borate), parabens (e.g. phenylparaben or propylparaben), alcohols (e.g. chlorobutane, benzyl alcohol or phenyl ethanol), guanidine derivatives (e.g. chloronucidine or polynuclear methylene biguani De) or sorbic acid.
• the preservative may be a quaternary ammonium salt or parabens.
• the content of the preservative is not particularly limited as long as it is an amount capable of preventing secondary contamination caused by use by bacteria and fungi.
• the tonicity agent is used to control the target formulation physiological tonicity (eg 0.9% saline).
• the amount of tonicity may vary depending on the specific agent to be added.
• the compositions of the present invention may be added with a tonic agent to make the final composition osmotic to 150-450 mOsm, more specifically 250-350 mOsm.
• the tonicity agent may be a sodium salt or a potassium salt. More specifically, the tonicity agent may be sodium chloride or potassium chloride.
• the tonicity agent may be selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, dextrose and mannelite. More specifically, the tonicity agent may be sodium chloride.
• formulations may be used to maintain the appropriate viscosity in ophthalmic formulations: (a) monomeric poly (s) (eg tyloxapol, glycerol, propylene glycol, ethylene glycol); (b) polymeric polyethers (e.g., polyethylene glycol (e.g. PEG 300, PEG 400)); (c) cellulose derivatives (cells of the cellulose family) (e.g.
• hydroxyethyl cellulose Hypromellose , Hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxyl propyl cellulose); (d) textrans (eg dextran 70); (e) water soluble proteins (eg gelatin); (f) vinyl polymers (for example, polyvinyl alcohol, polyvinyl pyrrolidine); (g) other polyols (eg, polysorbate 80, povidone); (h) carbomers (eg, carbomer 934P, carbomer 941, carbomer 940, carbomer 974P); And 0 polysaccharides / glycosaminoglycans (eg, hyaluronan (hyaluroranic acid / hyaluronate), chondroitin sulfate).
• textrans eg dextran 70
• e water soluble proteins
• vinyl polymers for example, polyvinyl alcohol, polyvinyl pyrrolidine
• the amount and type of excipient added may vary depending on the specific requirements, but can be used in the range of 0.0001 to 90 weight 3 ⁇ 4 with respect to the total weight of the ophthalmic formulation, and can be used within the range normally used by those skilled in the ophthalmic arts.
• the pH range of the ophthalmic preparation may be 3.5 to 9, specifically, 4.5 to 8, more specifically, 5.5 to 7.8, more specifically, about 7.0.
• a method for preventing or treating corneal damage comprising administering to a subject a composition as described above.
• the present invention can provide a method for treating corneal damage comprising contacting an eye tissue with an effective amount of a composition containing thymosin ⁇ 4 and citric acid as an active ingredient.
• a composition containing thymosin ⁇ 4 and citric acid as an active ingredient.
• examples of such administration are tissues, for example, by direct application with solutions, lotions, plasters, 3 ⁇ 4, creams, pastes, sprays, suspensions, dispersions, hydrogels, ointments, oils or blowing agents comprising a composition as disclosed herein. And contacting it.
• thymosin ⁇ 4 and citric acid or salts thereof may be administered in combination or sequentially, and may be administered in appropriate amounts divided into several times daily.
• the most preferred form of administration is the simultaneous administration of thymosin 4 and citric acid or salts thereof.
• the additive composition comprises 0.05 to 0.5% (w / v) thymosin ⁇ 4 based on the total composition and may be dosed at a total dose of 0.08 to 2.0 per day. That is, thymosin ⁇ 4 may be administered at a dose of 0.04 to 10 mg per day.
• the composition may include 0.1 to 0.4% (w / v) of thymosin 4 based on the total composition.
• the composition containing the thymosin ⁇ 4 divided once or several times a day It may be administered, specifically, it may be administered twice to five times a day.
• the composition comprises 1.0 to 10% (w / v) citric acid or a salt thereof, based on the total composition, and may be administered in a total dose of 0.1 to 4.0 per day. That is, citric acid or a salt thereof may be administered at a dose of 1 to 400 mg per day.
• the composition containing the citric acid or a salt thereof may be administered once or divided into several times daily, specifically, may be administered twice to five times daily.
• acetic acid, ascorbic acid, or salts thereof may be administered in combination or sequentially with thymosin ⁇ 4 and citric acid or salts thereof. Specifically, acetic acid, ascorbic acid, or salts thereof may be administered simultaneously with thymosin 4 and citric acid or salts thereof.
• the composition comprises 0.5 to 8 (w / v), or 1.0 to 5 3 ⁇ 4> (w / v) acetic acid, ascorbic acid, or a salt thereof, based on the total composition, in a total dose of 0.1 to 4.0 i per day Can be administered. That is, acetic acid, ascorbic acid, or salts thereof may be administered at a dose of 1 to 400 mg per day.
• the composition containing the acetic acid, ascorbic acid, or salts thereof may be administered once or divided into several times daily, specifically, may be administered twice to five times daily.
• Examples of routes of administration of the compositions for preventing or treating corneal injury of the present invention are preferably transdermal (such as topical) dosage forms, including but not limited to parenteral, intranasal (such as inhalation), administration via mucous membranes. It doesn't work.
• the treatment method may be a subject in need of preventing or treating corneal damage, for example, a mammalian animal, and more specifically, a human.
• the present invention also provides the use of a composition comprising thymosin ⁇ 4, and citric acid or a salt thereof for use in the manufacture of a medicament for preventing or treating corneal damage.
• the composition may further comprise citric acid, acetic acid and salts thereof.
• Example 1 Preparation of a composition comprising thymosin ⁇ 4
• sodium citrate was quantified to 1.5% (w / v) based on the total composition, mixed until the reagents were dissolved, and then mixed
• the drug thymosin ⁇ 4 was added by 0.01% (w / v) and mixed until dissolved.
• composition of the composition shown in Table 2 was prepared in the same manner as in Example 1.
• the unit of the numerical value is not indicated. % (W / v), which is a reference concentration.
• HCEO CATCC Primary human corneal epithelial cells
• 96 well plates (Thermo, Ltd) were inoculated with 3 ⁇ 10 3 cells within 100 ⁇ per well, followed by thymosin ⁇ 4 prepared in the control group, Example 1, Example 3, Example 4, and Comparative Example 3. A composition to add was added.
• the supernatant 0.1 was mixed with 0.19 mg / l o_ dianisidine hydrochloric acid and 2.9 50 mM complete phosphate solution (pH 6.0) containing 0.0005% hydrogen peroxide. Absorbance change at 460 nm was measured using a UV spectrometer at 25 ° C. for 5 minutes. 1 uni t of MP0 activity was defined as degrading 1 ⁇ peroxide at 25 ° C. per minute.
• composition including a composition containing a ⁇ 4 with citric acid thymosin T, citric acid and acetic acid compared to the composition comprising normal saline or thymosin ⁇ 4 manyi was confirmed that inhibiting ⁇ penetration (see FIG. "5).

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• 2015
  • 2015-09-03 US US14/844,421 patent/US9867868B2/en active Active
• 2016
  • 2016-08-12 EP EP16837270.4A patent/EP3338792B1/en active Active
  • 2016-08-12 KR KR1020160103066A patent/KR20170021745A/ko not_active Withdrawn
  • 2016-08-12 WO PCT/KR2016/008924 patent/WO2017030328A1/ko not_active Ceased
  • 2016-08-12 ES ES16837270T patent/ES2895923T3/es active Active
  • 2016-08-12 JP JP2018503784A patent/JP6910072B2/ja active Active

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