WO2020027571A1 - Préparation pharmaceutique de cicatrisation de plaies - Google Patents

Préparation pharmaceutique de cicatrisation de plaies Download PDF

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Publication number
WO2020027571A1
WO2020027571A1 PCT/KR2019/009531 KR2019009531W WO2020027571A1 WO 2020027571 A1 WO2020027571 A1 WO 2020027571A1 KR 2019009531 W KR2019009531 W KR 2019009531W WO 2020027571 A1 WO2020027571 A1 WO 2020027571A1
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Prior art keywords
silica particles
porous silica
hours
particles
pores
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PCT/KR2019/009531
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English (en)
Korean (ko)
Inventor
원철희
민달희
Original Assignee
주식회사 레모넥스
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Application filed by 주식회사 레모넥스 filed Critical 주식회사 레모넥스
Priority to EP19845244.3A priority Critical patent/EP3845218A4/fr
Priority to CN201980050585.9A priority patent/CN112533590A/zh
Priority to JP2021504531A priority patent/JP7140431B2/ja
Priority claimed from KR1020190092942A external-priority patent/KR102316726B1/ko
Publication of WO2020027571A1 publication Critical patent/WO2020027571A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to a pharmaceutical composition having an excellent wound healing effect.
  • Drug delivery system refers to a medical technology that can efficiently deliver the required amount of drugs, such as proteins, nucleic acids, or other small molecules by minimizing the side effects and maximizing the efficacy and effects of existing drugs.
  • This technology which saves the cost and time required for the development of new drugs, has recently become one of the cutting-edge technologies that create new added value in the pharmaceutical industry, in combination with nanotechnology.
  • the company has been focusing on the development of drug delivery systems along with the development of new drugs, especially companies and companies.
  • Efficient delivery systems are needed for the study of the function of bioactive substances in cells or for intracellular delivery.
  • a universal delivery system capable of delivering a wide range of bioactive substances, a system capable of accommodating and delivering a large amount of drugs, and a system for releasing drugs in a sustained manner is still in shortage.
  • An object of the present invention is to provide a pharmaceutical composition having an excellent wound healing effect.
  • composition for wound treatment wherein the porous silica particles have a t of 24 or more so that the ratio of the absorbance of the following formula (1) is 1/2:
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles in a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • the pH of the suspension is 7.4,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • the average diameter of the porous silica particles is 150 nm to 1000 nm
  • the BET surface area is 200m 2 / g to 700m 2 / g
  • the volume per g of pores is 0.7ml to 2.2ml
  • wound Therapeutic pharmaceutical composition wound Therapeutic pharmaceutical composition.
  • polypeptide is lactoferrin, epidermal growth factor, hepatocyte growth factor or vascular endothelial growth factor.
  • composition of claim 4 wherein the epidermal growth factor is SEQ ID NO: 2, the hepatocyte growth factor is SEQ ID NO: 3, and the vascular endothelial growth factor is SEQ ID NO: 4.
  • composition for wound treatment according to 1 above, wherein the substance is a plasmid carrying a gene encoding the sequence of SEQ ID NO: 1.
  • the porous silica particles are carried a polypeptide having an epithelial or endothelial cell growth promoting capacity, the particles are negatively charged at the neutral pH of the outer surface or the pores for wound treatment Pharmaceutical composition.
  • the porous silica particles carry a plasmid carrying a gene encoding a polypeptide having epidermal or endothelial cell growth promoting capacity
  • the particles are positively charged at the neutral pH of the outer surface or inside the pore Pharmaceutical composition for the treatment of wounds.
  • compositions of the present invention include a polypeptide having epithelial or endothelial cell growth promoting ability; Alternatively, a substance that increases its activity or expression can be delivered in a sustained manner with high efficiency to treat the wound with excellent efficiency.
  • compositions of the present invention include a polypeptide having epithelial or endothelial cell growth promoting ability; Or a polypeptide having a sustained release of a substance that increases its activity or expression, thereby promoting epithelial or endothelial cell growth in the body; Alternatively, the substance that increases its activity or expression can be maintained for a long time, and thus can exhibit excellent efficacy.
  • FIG. 1 is a micrograph of porous silica particles according to an embodiment of the present invention.
  • FIG. 2 is a micrograph of porous silica particles according to one embodiment of the present invention.
  • Figure 3 is a micrograph of the small pore particles during the manufacturing process of the porous silica particles according to an embodiment of the present invention.
  • Figure 4 is a micrograph of the small pore particles according to an embodiment of the present invention.
  • Figure 5 is a micrograph of the pore diameter of the porous silica particles according to an embodiment of the present invention.
  • DDV Delivery Vehicle
  • the particle of the embodiment the number in parenthesis means the diameter of the particle, the number of subscripts means the pore diameter.
  • DDV 200 10 refers to a particle of an embodiment having a particle diameter of 200 nm and a pore diameter of 10 nm.
  • Figure 6 is a micrograph to confirm the biodegradability of the porous silica particles according to an embodiment of the present invention.
  • FIG. 7 is a tube having a cylindrical permeable membrane according to one example.
  • Figure 11 is a result of reducing the absorbance for each pH of the environment over time of the porous silica particles according to an embodiment of the present invention.
  • FIG. 13 is a result of increasing VEGF expression of a porous silica particle carrying lactoferrin protein or a gene encoding the same according to an embodiment of the present invention.
  • FIG. 14 shows the results of cell proliferation of porous silica particles carrying lactoferrin protein or a gene encoding the same according to an embodiment of the present invention.
  • 16 to 19 are wound healing results of porous silica particles carrying lactoferrin protein or gene encoding the same according to one embodiment of the present invention.
  • the pharmaceutical composition for treating wounds of the present invention may include a polypeptide having epidermal or endothelial cell growth promoting ability; Or porous silica particles carrying a substance that increases its activity or expression.
  • the polypeptide having epithelial or endothelial cell growth promoting ability may be used without limitation as long as it has epithelial cell or endothelial cell growth promoting ability, for example, may be lactoferrin, cell growth factor, and the like, and the cell growth factor may specifically be epithelial cell growth.
  • Factor, hepatocyte growth factor, or vascular endothelial growth factor but is not limited thereto.
  • Polypeptides having epithelial or endothelial cell growth-promoting ability may be derived from the same species as the subject to be administered, but are not limited thereto, and may be used as long as they are able to function in the same / similar function depending on the similarity between sequences even from other species. Do.
  • the administration target is a human, it may include the amino acid sequence of SEQ ID NO: 1 derived from a human, and specifically, may be composed of the sequence of SEQ ID NO: 1.
  • the epidermal growth factor may include the amino acid sequence of SEQ ID NO: 2
  • the hepatocyte growth factor may include the amino acid sequence of SEQ ID NO: 3
  • the vascular endothelial growth factor may include the amino acid sequence of SEQ ID NO: 4 Specifically, it may be composed of the above sequence.
  • a substance that increases the activity or expression of a polypeptide having epidermal or endothelial cell growth promoting ability is not limited as long as it can increase its activity or expression, for example, a poly having epidermal or endothelial cell growth promoting ability. It may be a plasmid carrying a gene encoding a peptide.
  • the plasmid carrying the lactoferrin gene is the nucleotide sequence of SEQ ID NO: 5
  • the plasmid carrying the epidermal growth factor is the nucleotide sequence of SEQ ID NO: 6
  • the plasmid carrying the hepatocyte growth factor is the nucleotide sequence of SEQ ID NO: 7
  • the plasmid carrying the vascular endothelial growth factor may comprise the nucleotide sequence of SEQ ID NO: 8, specifically, may be composed of the above sequence.
  • the subject to be administered may be an entire mammal including a human, and in particular, may be human, but is not limited thereto.
  • wound means that the tissue is cut, torn, broken, burned, or traumatized, or such. Damage to a human body arising from a disorder or disease causing injury.
  • the wound may be an open wound with an open surface, or a closed wound with no open surface.
  • One example of such a wound may be an open wound in the skin.
  • the wound may include lesions, sores, necrosis, and ulcers.
  • the necrosis may be related to dead tissue resulting from infection, injury or infarction.
  • the ulcer may be a local defect or dent in the surface of an organ or tissue, produced by stripping of necrotic tissue.
  • wounds are the epidermis of the skin; Dermis; Epidermis and dermis; Or wounds with damaged epidermis, dermis and subcutaneous fat layer.
  • wounds include wounds, hypertrophic scars, keloids, cuts, incisions (eg surgical incisions), abrasions, lacerations or lacerations, fractures, bruises ( contusions, burns, or amputations.
  • the wound treatment means inhibiting the development of skin damage, reducing skin damage, or eliminating damage to the skin, and the wound specifically includes burns, ulcers, traumas, post-surgical, childbirth, and chronic wounds. damage due to wound or dermatitis.
  • the porous silica particles according to the present invention are particles of silica (SiO 2 ) material and have a particle size of nano size.
  • Porous silica nanoparticles of the present invention is a porous particle, a polypeptide having a nano-sized pores, and having an ability to promote epithelial or endothelial cell growth on the surface and / or pores; Or a substance that increases its activity or expression.
  • Porous silica particles of the present invention is a biodegradable particle, a polypeptide having an epithelial or endothelial cell growth promoting ability; Or a polypeptide having an ability to promote epithelial or endothelial cell growth while biodegrading in the body when administered to the body by carrying a substance which increases its activity or expression; Or may release a substance that increases its activity or expression, wherein the porous silica particles of the present invention are polypeptides having an ability to promote epithelial or endothelial cell growth that is slowly degraded and supported in the body; Or a substance that increases its activity or expression can be released in a sustained manner.
  • t which is the ratio of the absorbance of the following formula 1 to 1/2, is 24 or more:
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles in a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • the pH of the suspension is 7.4,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • Equation 1 means that the rate at which the porous silica particles are degraded in an environment similar to the body.
  • Absorbance A 0 , A t in Equation 1 may be measured by putting porous silica particles and a suspension in a cylindrical permeable membrane and putting the same suspension outside the permeable membrane, as illustrated in FIG. 7.
  • the porous silica particles of the present invention are biodegradable, and can be slowly decomposed in suspension, 50 kDa in diameter corresponds to about 5 nm, and biodegradable porous silica particles can pass through a permeable membrane of 50 kDa in diameter, and a cylindrical permeable membrane is 60 rpm horizontal. Under stirring, the suspension can be mixed evenly and the degraded porous silica particles can come out of the permeable membrane.
  • the absorbance in Equation 1 may be measured, for example, under an environment in which the suspension outside the permeable membrane is replaced with a new suspension.
  • the suspension can be one that is constantly replaced, one that can be replaced every period, and the period can be periodic or irregular. For example, within the range of 1 hour to 1 week, 1 hour interval, 2 hours interval, 3 hours interval, 6 hours interval, 12 hours interval, 24 hours interval, 2 days interval, 3 days interval, 4 days interval, 7 It may be replaced at day intervals, but is not limited thereto.
  • the ratio of the absorbance to 1/2 means that the absorbance is half of the initial absorbance after t hours, which means that approximately half of the porous silica particles are decomposed.
  • the suspension may be a buffer solution, for example, at least one selected from the group consisting of phosphate buffered saline (PBS) and simulated body fluid (SBF), and more specifically, PBS.
  • PBS phosphate buffered saline
  • SBF simulated body fluid
  • T of the absorbance ratio of Equation 1 of the present invention is 1/2 or more, for example, t may be 24 to 120, for example, 24 to 96, 24 to 72, 30 within the above range To 70, 40 to 70, 50 to 65 and the like, but is not limited thereto.
  • t for example, the absorbance ratio of Equation 1 is 1/5 may be, for example, 70 to 140, for example, 80 to 140, 80 to 120, and 80 to 110 within the above range. , 70 to 140, 70 to 120, 70 to 110, and the like, but is not limited thereto.
  • t may be 130 to 220, for example, wherein the ratio of absorbance of Equation 1 is 1/20, for example, 130 to 200, 140 to 200, 140 to 180 within the above range. , 150 to 180, and the like, but is not limited thereto.
  • the porous silica particles of the present invention may have a measured absorbance of 0.01 or less, for example, 250 or more, for example, 300 or more, 350 or more, 400 or more, 500 or more, 1000 or more, and the upper limit thereof is 2000 days. May be, but is not limited thereto.
  • the ratio of the absorbance of Formula 1 and t have a high positive correlation.
  • the Pearson correlation coefficient may be 0.8 or more, for example, 0.9 or more and 0.95 or more. .
  • T in Equation 1 means how fast the porous silica particles decompose in an environment similar to the body, for example, the surface area, particle diameter, pore diameter, surface and / or inside the pores of the porous silica particles. It can be controlled by controlling the substituent, the degree of compactness of the surface, and the like.
  • the surface area of the particles can be increased to reduce t, or the surface area can be reduced to increase t.
  • the surface area can be adjusted by adjusting the diameter of the particles and the diameter of the pores.
  • substituents on the surface and / or within the pores it is possible to increase t by reducing the direct exposure of porous silica particles to the environment (such as solvents).
  • a polypeptide having epithelial or endothelial cell growth promoting ability in the porous silica particles Or a polypeptide that carries a substance that increases its activity or expression and has an epithelial or endothelial cell growth promoting ability; Or by increasing the affinity between the porous silica particles and the substance that increases their activity or expression, thereby increasing t by reducing the direct exposure of the porous silica silica particles to the environment.
  • the surface may be made more densely at the time of preparation of the particles to increase t.
  • Porous silica particles of the present invention may be, for example, spherical particles, but is not limited thereto.
  • the porous silica particles of the present invention may have an average diameter of, for example, 150 nm to 1000 nm, for example, within the above range, for example, 150 nm to 800 nm, 150 nm to 500 nm, 150 nm to 400 nm, 150 nm to 300 nm, and 150 nm to 200 nm. May be, but is not limited thereto.
  • the porous silica particles of the present invention may have an average pore diameter of, for example, 1 nm to 100 nm, for example, within the above range, for example, 5 nm to 100 nm, 7 nm to 100 nm, 7 nm to 50 nm, 10 nm to 50 nm, 10 nm to 30 nm. , 7 nm to 30 nm, but is not limited thereto.
  • the porous silica particles of the present invention may have a BET surface area of, for example, 200 m 2 / g to 700 m 2 / g.
  • a BET surface area of, for example, 200 m 2 / g to 700 m 2 / g, 200 m 2 / g to 650 m 2 / g, 250 m 2 / g to 650 m 2 / g, 300 m 2 / g to 700 m 2 / g, 300 m 2 / g to 650m 2 / g, 300m 2 / g to 600m 2 / g, 300m 2 / g to 550m 2 / g, 300m 2 / g to 500m 2 / g, 300m 2 / g to 450m 2 / g, etc. It is not limited to this.
  • the porous silica nanoparticles of the present invention may have a volume per gram of pores, for example, 0.7 ml to 2.2 ml.
  • a volume per gram of pores for example, 0.7 ml to 2.2 ml.
  • within the above range may be 0.7ml to 2.0ml, 0.8ml to 2.2ml, 0,8ml to 2.0ml, 0.9ml to 2.0ml, 1.0ml to 2.0ml and the like, but is not limited thereto. If the volume per gram is too small, the rate of decomposition may be too high, and excessively large particles may be difficult to manufacture or may not have an intact shape.
  • the porous silica particles of the present invention may have hydrophilic substituents and / or hydrophobic substituents on the outer surface and / or inside the pores.
  • hydrophilic substituents may exist on both the surface and inside of the pores, or only hydrophobic substituents may exist, hydrophilic substituents may exist on the surface or inside of the pores, hydrophobic substituents may exist on the surface, hydrophilic substituents on the surface, and hydrophobic substituents inside the pores. It may be present and vice versa.
  • polypeptides having poorly soluble (hydrophobic) epithelial or endothelial cell growth promoting ability may be present in the pores to enhance binding to substances that increase their activity or expression, and the surface of the particles may have hydrophilic substituents in view of ease of use and formulation. .
  • Hydrophilic substituents are, for example, hydroxyl groups, carboxy groups, amino groups, carbonyl groups, sulfhydryl groups, phosphate groups, thiol groups, ammonium groups, ester groups, imide groups, thiimide groups, keto groups, ether groups, indene groups, sulfonyl groups, polyethylene Glycol groups and the like
  • the hydrophobic substituent is, for example, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted Or an unsubstituted C2 to C30 heteroaryl group, a halogen group, a C1 to C30 ester group, a halogen-containing group, and the like.
  • the porous silica particles of the present invention may be one in which the outer surface and / or the inside of the pores are positively and / or negatively charged.
  • both the surface and the inside of the pore may be positively charged, or may be negatively charged, only the surface or the inside of the pore may be positively charged, or may be negatively charged, the surface may be positively charged, and the interior of the pore may be negatively charged.
  • the porous silica particles carry the polypeptide
  • the outer surface and / or the inside of the pore may be negatively charged
  • the cathode may be positively charged. Can be.
  • the charging may be, for example, by the presence of a cationic substituent or an anionic substituent.
  • the cationic substituent may be, for example, an amino group, other nitrogen-containing groups, etc. as the basic group, and the anionic substituent may be, for example, a carboxy group (-COOH), a sulfonic acid group (-SO 3 H), a thiol group as an acidic group, and the like. (-SH), etc., but is not limited thereto.
  • the polypeptide having the ability to promote epithelial or endothelial cell growth by regulation of the substituent by the charging Or a polypeptide having an ability to promote epithelial or endothelial cell growth by controlling interaction of porous silica particles with a release environment of a substance that increases its activity or expression, thereby controlling the rate of degradation of the nanoparticles themselves; Or a polypeptide having a release rate of a substance that increases its activity or expression, and which has epithelial or endothelial cell growth promoting ability;
  • the substance that increases its activity or expression may be released from the nanoparticles by diffusion, polypeptides having the ability to promote epithelial or endothelial cell growth under the control of the substituents; Or polypeptides having a binding ability to a nanoparticle of a substance that increases its activity or expression, thereby promoting epithelial or endothelial cell growth; Or release of a substance that increases its activity or expression.
  • the porous silica particles of the present invention may include a polypeptide having an ability to promote epithelial or endothelial cell growth in addition to the above on the surface and / or the pores; Or a polypeptide having an ability to support, epithelial or endothelial cell growth of a substance that increases its activity or expression; Or a substituent for transfer of a substance that increases its activity or expression to a target cell, support of a substance for other purposes, or binding of another additional substituent, and the like, and an antibody, ligand, cell permeable peptide, or the like bound thereto Eptamers and the like may be further included.
  • Substituents, charges, binders and the like within the aforementioned surfaces and / or pores may be added, for example, by surface modification.
  • Surface modification can be carried out, for example, by reacting a compound having a substituent to be introduced with the particles, which may be, for example, an alkoxysilane having a C1 to C10 alkoxy group, but is not limited thereto.
  • the alkoxysilane has one or more alkoxy groups, and may have, for example, 1 to 3, and there may be a substituent to be introduced into a site where the alkoxy group is not bonded or a substituent substituted therewith.
  • the porous silica particles of the present invention may be manufactured through a small pore particle preparation and a pore expansion process, and may be manufactured through a calcination process, a surface modification process, and the like, as necessary. If both the calcination and the surface modification process has gone through may be surface modified after calcination.
  • the small pore particles may be, for example, particles having an average pore diameter of 1 nm to 5 nm.
  • the small pore particles can be obtained by adding a surfactant and a silica precursor in a solvent, stirring and homogenizing.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachlor
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • the ratio may be, for example, water and the organic solvent in a volume ratio of 1: 0.7 to 1.5, for example, 1: 1: 0.8 to 1.3, but is not limited thereto.
  • the surfactant may be, for example, cetyltrimethylammonium bromide (CTAB), hexadecyltrimethylammonium bromide (TMABr), hexadecyltrimethylpyridinium chloride (TMPrCl), tetramethylammonium chloride (TMACl), and the like, and specifically, CTAB may be used.
  • CTAB cetyltrimethylammonium bromide
  • TMABr hexadecyltrimethylammonium bromide
  • TMPrCl hexadecyltrimethylpyridinium chloride
  • TMACl tetramethylammonium chloride
  • the surfactant may be added, for example, in an amount of 1 g to 10 g, for example, 1 g to 8 g, 2 g to 8 g, 3 g to 8 g, etc., per liter of solvent, but is not limited thereto.
  • the silica precursor may be added after stirring with the addition of a surfactant to the solvent.
  • the silica precursor may be, for example, tetramethyl orthosilicate (TMOS), but is not limited thereto.
  • the stirring may be performed, for example, for 10 minutes to 30 minutes, but is not limited thereto.
  • the silica precursor may be added, for example, 0.5 ml to 5 ml per liter of solvent, for example, 0.5 ml to 4 ml, 0.5 ml to 3 ml, 0.5 ml to 2 ml, 1 ml to 2 ml, etc. within the above range, but is not limited thereto. It doesn't happen.
  • sodium hydroxide may further be used as a catalyst, which may be added with stirring after adding the surfactant to the solvent and before adding the silica precursor.
  • the sodium hydroxide is, for example, 0.5ml to 8ml per liter of solvent on the basis of 1M aqueous sodium hydroxide solution, for example 0.5ml to 5ml, 0.5ml to 4ml, 1ml to 4ml, 1ml to 3ml, 2ml to 3ml, etc. within the above range. May be, but is not limited thereto.
  • the solution can be reacted with stirring.
  • the stirring may be performed for example, for 2 hours to 15 hours, for example, within the above range, for example, 3 hours to 15 hours, 4 hours to 15 hours, 4 hours to 13 hours, 5 hours to 12 hours, 6 hours to 12 hours. , 6 hours to 10 hours, and the like, but is not limited thereto. If the stirring time (reaction time) is too short, nucleation may be insufficient.
  • the solution may be aged. Aging may be performed for example, from 8 hours to 24 hours, for example, within the range of 8 hours to 20 hours, 8 hours to 18 hours, 8 hours to 16 hours, 8 hours to 14 hours, 10 hours to 16 hours. , 10 hours to 14 hours, and the like, but is not limited thereto.
  • reaction product may be washed and dried to obtain porous silica particles, and if necessary, separation of unreacted material may be preceded before washing.
  • Separation of the unreacted material may be carried out by separating the supernatant, for example by centrifugation, centrifugation may be carried out, for example at 6,000 to 10,000 rpm, the time is for example 3 minutes to 60 minutes, For example, it may be performed within 3 minutes to 30 minutes, 3 minutes to 30 minutes, 5 minutes to 30 minutes, and the like, but is not limited thereto.
  • the washing may be performed with water and / or an organic solvent, and in particular, since a substance that can be dissolved in each solvent may be different, water and an organic solvent may be used once or several times, or once or even with water or an organic solvent alone. Can be washed several times.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichlor
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • the washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 within the above range. It may be performed in minutes to 30 minutes, 5 minutes to 30 minutes and the like, but is not limited thereto.
  • the washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. Filtering the reaction liquid with such a filter leaves only particles on the filter, which can be washed by pouring water and / or an organic solvent on the filter.
  • water and an organic solvent may be used alternately once or several times, and may be washed once or several times even with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the drying may be performed at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • the pores of the obtained porous silica particles are expanded, and the pore expansion may be performed using a pore swelling agent.
  • the pore swelling agent may be trimethylbenzene, triethylbenzene, tripropylbenzene, tributylbenzene, tripentylbenzene, trihexylbenzene, toluene, benzene, and the like, and specifically, trimethylbenzene may be used. It is not limited.
  • the pore swelling agent may use, for example, N, N-dimethylhexadecylamine (N, N-dimethylhexadecylamine, DMHA), but is not limited thereto.
  • the pore expansion can be carried out, for example, by mixing porous silica particles in a solvent with a pore swelling agent and heating to react.
  • the solvent may be, for example, water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; And the like
  • the porous silica particles are, for example, 10 g to 200 g per liter of solvent, for example, 10 g to 150 g, 10 g to 100 g, 30 g to 100 g, 40 g to 100 g, 50 g to 100 g, 50 g to 80 g, 60 g to 80 g, etc., within the above range. It may be added in a ratio of, but is not limited thereto.
  • the porous silica particles may be evenly dispersed in a solvent, for example, the porous silica particles may be added to the solvent and ultrasonically dispersed.
  • the second solvent may be added after the porous silica particles are dispersed in the first solvent.
  • the pore swelling agent is for example 10 to 200 parts by volume, 100 to 150 parts by volume, 10 to 100 parts by volume, 10 to 80 parts by volume, 30 to 80 parts by volume, 30 to 80 parts by volume based on 100 parts by volume of solvent. 70 parts by volume may be added, but is not limited thereto.
  • the reaction can be carried out, for example, at 120 ° C to 190 ° C.
  • 120 ° C to 190 ° C For example, within the range of 120 °C to 190 °C, 120 °C to 180 °C, 120 °C to 170 °C, 130 °C to 170 °C, 130 °C to 160 °C, 130 °C to 150 °C, 130 °C to 140 °C It may be performed, but is not limited thereto.
  • the reaction may be performed, for example, for 6 hours to 96 hours.
  • 6 hours to 96 hours within the range of 30 hours to 96 hours, 30 hours to 96 hours, 30 hours to 80 hours, 30 hours to 72 hours, 24 hours to 80 hours, 24 hours to 72 hours, 36 hours to 96 hours, 36 36 hours to 80 hours, 36 hours to 72 hours, 36 hours to 66 hours, 36 hours to 60 hours, 48 hours to 96 hours, 48 hours to 88 hours, 48 hours to 80 hours, 48 hours to 72 hours, 6 hours to 96 hours, 7 hours to 96 hours, 8 hours to 80 hours, 9 hours to 72 hours, 9 hours to 80 hours, 6 hours to 72 hours, 9 hours to 96 hours, 10 hours to 80 hours, 10 hours to 72 hours , 12 hours to 66 hours, 13 hours to 60 hours, 14 hours to 96 hours, 15 hours to 88 hours, 16 hours to 80 hours, 17 hours to 72 hours, and the like, but is not limited thereto.
  • the time and temperature can be adjusted within the ranges exemplified above so that the reaction can be carried out sufficiently without excess. For example, when the reaction temperature is lowered, the reaction time may be increased, or when the reaction temperature is lowered, the reaction time may be shortened. If the reaction is not sufficient, the expansion of the pores may not be sufficient, and if the reaction proceeds excessively, the particles may collapse due to the expansion of the pores.
  • the reaction can be carried out, for example, by gradually raising the temperature. Specifically, it may be carried out by gradually raising the temperature at a rate of 0.5 °C / min to 15 °C / min from the room temperature to the above temperature, for example, 1 °C / min to 15 °C / min, 3 °C / min within the above range To 15 ° C./minute, 3 ° C./minute to 12 ° C./minute, 3 ° C./minute to 10 ° C./minute, and the like, but are not limited thereto.
  • the reaction can be carried out under stirring. For example, it may be stirred at a speed of 100 rpm or more, and specifically, may be performed at a speed of 100 rpm to 1000 rpm, but is not limited thereto.
  • the reaction solution can be cooled slowly, for example, it can be cooled by gradually reducing the temperature. Specifically, it may be carried out by gradually decreasing the temperature at a rate of 0.5 °C / min to 20 °C / min from the temperature to room temperature, for example, 1 °C / min to 20 °C / min, 3 °C / min to within the above range 20 ° C./minute, 3 ° C./minute to 12 ° C./minute, 3 ° C./minute to 10 ° C./minute, and the like, but is not limited thereto.
  • reaction product After cooling, the reaction product may be washed and dried to obtain porous silica particles having expanded pores, and if necessary, separation of unreacted material may be preceded before washing.
  • Separation of the unreacted material may be carried out by separating the supernatant, for example by centrifugation, centrifugation may be carried out, for example at 6,000 to 10,000 rpm, the time is for example 3 minutes to 60 minutes, For example, it may be performed within 3 minutes to 30 minutes, 3 minutes to 30 minutes, 5 minutes to 30 minutes, and the like, but is not limited thereto.
  • the washing may be performed with water and / or an organic solvent, and in particular, since a material that can be dissolved in each solvent may be different, water and an organic solvent may be used once or several times, or once or even with water or an organic solvent alone. Can be washed several times.
  • the number of times may be, for example, two or more times, ten times or less, for example, three times, four times, five times, six times, seven times, eight times, and the like.
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; And the like, and specifically, alcohol, more specifically ethanol can be used, but is not limited
  • the washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 within the above range. It may be performed in minutes to 30 minutes, 5 minutes to 30 minutes and the like, but is not limited thereto.
  • the washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. Filtering the reaction liquid with such a filter leaves only particles on the filter, which can be washed by pouring water and / or an organic solvent on the filter.
  • water and an organic solvent may be used alternately once or several times, and may be washed once or several times even with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the drying may be performed at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • the obtained particles may be calcined, which is a process of heating the particles to remove silanol groups on the surface and inside thereof to lower the reactivity of the particles, to have a more compact structure, and to remove organic substances filling the pores.
  • it may be heated to a temperature of 400 °C or more.
  • the upper limit thereof is not particularly limited, and may be, for example, 1000 ° C, 900 ° C, 800 ° C, 700 ° C, or the like.
  • the heating can be carried out for example for 3 hours or more, for 4 hours or more.
  • the upper limit is not particularly limited and may be, for example, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 5 hours, or the like. More specifically, it may be performed for 3 hours to 8 hours at 400 ° C to 700 ° C, specifically 4 hours to 5 hours at 500 ° C to 600 ° C, but is not limited thereto.
  • the porous silica particles obtained can then be surface modified, and the surface modification can be carried out on the surface and / or inside the pores.
  • the particle surface and the inside of the pore may be surface modified identically, or may be surface modified differently.
  • the surface modification can cause the particles to charge or to have hydrophilic and / or hydrophobic properties.
  • polypeptides having epithelial or endothelial cell growth promoting ability Or at least one substituent selected from the group consisting of an amino group, an aminoalkyl group, an alkylamino group, a heterocyclic aromatic compound group containing a nitrogen atom, a cyan group and a guanidine group for effective loading of a substance that increases the activity or expression thereof.
  • substituents selected from the group consisting of an amino group, an aminoalkyl group, an alkylamino group, a heterocyclic aromatic compound group containing a nitrogen atom, a cyan group and a guanidine group for effective loading of a substance that increases the activity or expression thereof.
  • Surface modification of the porous silica particles can be carried out.
  • Surface modification can be carried out, for example, by reacting a compound having substituents such as hydrophilic, hydrophobic, cationic, anionic and the like to be introduced with the particles, and the compound can be, for example, an alkoxysilane having a C1 to C10 alkoxy group. However, it is not limited thereto.
  • the alkoxysilane has one or more alkoxy groups, and may have, for example, 1 to 3, and there may be a substituent to be introduced into a site where the alkoxy group is not bonded or a substituent substituted therewith.
  • the alkoxysilane reacts with the porous silicon particles, a covalent bond is formed between the silicon atom and the oxygen atom so that the alkoxysilane may be bonded to the surface and / or the inside of the pores of the porous silicon particle, and the alkoxysilane has a substituent to be introduced.
  • the corresponding substituents may be introduced into the surface of the porous silicon particles and / or within the pores.
  • the reaction may be carried out by reacting porous silica particles dispersed in a solvent with an alkoxysilane.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachlor
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • the charge to the positive charge can be carried out by reacting with an alkoxysilane having a basic group such as a nitrogen-containing group such as an amino group, an aminoalkyl group, for example.
  • an alkoxysilane having a basic group such as a nitrogen-containing group such as an amino group, an aminoalkyl group, for example.
  • the charge to the negative charge can be carried out by reacting with an alkoxysilane having an acidic group such as, for example, a carboxyl group, a sulfonic acid group, a thiol group, a methylphosphonate group, a phosphonate group, and the like.
  • an alkoxysilane having an acidic group such as, for example, a carboxyl group, a sulfonic acid group, a thiol group, a methylphosphonate group, a phosphonate group, and the like.
  • 3-Mercaptopropyl) trimethoxysilane may be used, but is not limited thereto.
  • the hydrophilic property is a hydrophilic group such as hydroxy group, carboxy group, amino group, carbonyl group, sulfhydryl group, phosphate group, thiol group, ammonium group, ester group, imide group, thiimide group, keto group, ether group, indene group, sulfo It may be made to react with the alkoxysilane which has a silyl group, a polyethyleneglycol group, etc.
  • the hydrophobic nature may include hydrophobic substituents such as substituted or unsubstituted C1 to C30 alkyl groups, substituted or unsubstituted C3 to C30 cycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted It can be made to react with the alkoxysilane which has a C2-C30 heteroaryl group, a halogen group, C1-C30 ester group, a halogen containing group, etc.
  • Trimethoxy (octadecyl) silane, Trimethoxy-n-octylsilane, Trimethoxy (propyl) silane, Isobutyl (trimethoxy) silane, Trimethoxy (7-octen-1-yl) silane, Trimethoxy (3,3,3-trifluoropropyl) Silane, Trimethoxy (2-phenylethyl) silane, Vinyltrimethoxysilane, Cyanomethyl, 3- (trimethoxysilyl) propyl] trithiocarbonate, (3-Bromopropyl) trimethoxysilane, etc. may be used, but is not limited thereto.
  • hydrophobic substituents are present in the pores in order to enhance binding to substances that increase their activity or expression, and in view of ease of use and formulation, the surface of the particles may be treated with hydrophilic substituents.
  • the surface modification may be carried out in combination.
  • two or more surface modifications may be performed on the outer surface or inside the pores.
  • a compound including a carboxyl group may be bonded to silica particles into which amino groups are introduced by amide bonds to change the positively charged particles to have different surface properties, but is not limited thereto.
  • the reaction of the porous silica particles with the alkoxysilane can be carried out, for example, under heating, and the heating is for example from 80 ° C. to 180 ° C., for example from 80 ° C. to 160 ° C., from 80 ° C. to 150 ° C. within the above range. , 100 ° C. to 160 ° C., 100 ° C. to 150 ° C., 110 ° C. to 150 ° C., etc., but is not limited thereto.
  • the reaction of the porous silica particles with the alkoxysilane is, for example, 4 hours to 20 hours, for example, 4 hours to 18 hours, 4 hours to 16 hours, 6 hours to 18 hours, 6 hours to 16 hours within the above range. , 8 hours to 18 hours, 8 hours to 16 hours, 8 hours to 14 hours, 10 hours to 14 hours, etc., but is not limited thereto.
  • the reaction temperature, time, and the amount of the compound used for surface modification may be selected according to the extent to which the surface is to be modified, a polypeptide having epithelial or endothelial cell growth promoting ability; Or a polypeptide having epithelial or endothelial cell growth promoting ability by controlling the hydrophilicity, hydrophobicity, and charge of the porous silica particles by varying the reaction conditions depending on the hydrophilicity, hydrophobicity, and degree of charge of the substance that increases its activity or expression; Or release rate of a substance that increases its activity or expression.
  • polypeptides having epithelial or endothelial cell growth promoting ability may be increased or the reaction time may be increased to increase the throughput of the compound, so that the porous silica particles have a strong positive charge. May be, but is not limited thereto.
  • porous silica particles of the present invention may be produced through, for example, the preparation of small pores, pore expansion, surface modification, and internal pore modification.
  • the small pore particle production and pore expansion process may be based on the above-described process, and the washing and drying process may be performed after the small pore particle production and after the pore expansion process.
  • separation of the unreacted material may be preceded before washing, and separation of the unreacted material may be performed by separating the supernatant, for example, by centrifugation.
  • the centrifugation may be performed, for example, at 6,000 to 10,000 rpm, and the time may be, for example, 3 to 60 minutes, specifically, 3 to 30 minutes, 3 to 30 minutes, and 5 minutes within the above range. To 30 minutes, etc., but is not limited thereto.
  • the washing after the preparation of the particles of the small pores may be performed by a method / condition within the above-described range, but is not limited thereto.
  • the washing after the pore expansion may be performed under more relaxed conditions than the above example.
  • washing may be performed within three times, but is not limited thereto.
  • the surface modification and internal pore modification may be by the processes described above, respectively, the process may be performed in the order of surface modification and internal pore modification, and the washing process of the particles may be further performed between the two processes. Can be.
  • the reaction solution such as a surfactant used for particle production and pore expansion is filled in the pores so that the inside of the pores is not modified during surface modification. Only the surface can be modified. Then, washing the particles may remove the reaction solution in the pores.
  • Particle washing between the surface modification and the internal pore reforming process may be water and / or an organic solvent, and in particular, water and an organic solvent may be alternately used once or several times because different materials may be dissolved for each solvent.
  • Water or organic solvents alone may be washed once or several times. The number of times may be, for example, two or more, ten or less, specifically, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, specifically 3 to 30 minutes, 3 within the above range. It may be performed in minutes to 30 minutes, 5 minutes to 30 minutes and the like, but is not limited thereto.
  • the washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. Filtering the reaction liquid with such a filter leaves only particles on the filter, which can be washed by pouring water and / or an organic solvent on the filter.
  • water and an organic solvent may be used alternately once or several times, and may be washed once or several times even with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, specifically, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the drying may be performed at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • Polypeptides having epithelial or endothelial cell growth promoting ability may be carried on the surface and / or inside the pores of the porous silica particles, and the supported may include, for example, a polypeptide having epithelial or endothelial cell growth promoting ability with the porous silica particles in a solvent; Or by mixing substances which increase the activity or expression thereof.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Etc. can be used.
  • PBS phosphate buffered saline solution
  • SBF Simulated Body Fluid
  • Borate-buffered saline Borate-buffered saline
  • Tris-buffered saline may be used as the solvent.
  • porous silica particles according to the present invention are polypeptides having a slow decomposition and supported epithelial or endothelial cell growth promoting ability; Or a substance that increases its activity or expression can be released in a sustained manner. This may be controlled by, for example, adjusting the surface area, particle diameter, pore diameter, substituents on the surface and / or pores, degree of compactness of the porous silica particles, and the like, but are not limited thereto.
  • a polypeptide having an epithelial or endothelial cell growth promoting ability supported on the porous silica particles; Or a substance that increases its activity or expression can be released while being diffused from the porous silica particles, which includes: a polypeptide having epithelial or endothelial cell growth promoting ability with the porous silica particles; Or a polypeptide having a substance, epithelial or endothelial cell growth-promoting ability that increases its activity or expression; Or a polypeptide having an ability to promote epithelial or endothelial cell growth by controlling the relationship with a release environment of a substance that increases its activity or expression; Or release of a substance that increases its activity or expression.
  • Polypeptides having the ability to promote epithelial or endothelial cell growth of porous silica particles for example by surface modification; Or by enhancing or weakening binding to a substance that increases its activity or expression.
  • polypeptides having an ability to promote supported epithelial or endothelial cell growth include polypeptides having an ability to promote supported epithelial or endothelial cell growth; Or a polypeptide having an ability to promote epithelial or endothelial cell growth with porous silica particles having a hydrophobic substituent on the surface and / or the pore inside of the particle when the substance which increases its activity or expression is poorly soluble (hydrophobic); Or a polypeptide having increased binding ability with a substance that increases its activity or expression, whereby a polypeptide having epithelial or endothelial cell growth promoting ability; Or substances which increase their activity or expression may be released in a sustained manner.
  • This may be, for example, the surface-modified porous silica particles with an alkoxysilane having a hydrophobic substituent.
  • “poorly soluble” means to be insoluble (practically insoluble) or only slightly soluble (with respect to water), which means “Pharmaceutical Science” 18 th Edition ( USP, Remington, Mack Publishing Company).
  • the poorly water-soluble material may be, for example, water solubility of less than 10 g / L, specifically less than 5 g / L, more specifically less than 1 g / L at 1 atmosphere and 25 ° C., but is not limited thereto.
  • Polypeptides having an ability to promote supported epithelial or endothelial cell growth Or a polypeptide having an ability to promote epithelial or endothelial cell growth with porous silica particles when the substance that increases its activity or expression is water soluble (hydrophilic) and has a hydrophilic substituent on the surface and / or inside the pore; Or a polypeptide having increased binding ability with a substance that increases its activity or expression, whereby a polypeptide having epithelial or endothelial cell growth promoting ability; Or substances which increase their activity or expression may be released in a sustained manner. This may be, for example, the surface of the porous silica particles modified with an alkoxysilane having a hydrophilic substituent.
  • the water-soluble substance may have a water solubility of 10 g / L or more at 1 atmosphere and 25 ° C., but is not limited thereto.
  • Polypeptides having an ability to promote supported epithelial or endothelial cell growth Or a polypeptide having an activity that promotes epithelial or endothelial cell growth with porous silica particles when the substance that increases its activity or expression is charged, and the surface and / or inside of the pores are charged with opposite charges; Or a polypeptide having increased binding ability with a substance that increases its activity or expression, whereby a polypeptide having epithelial or endothelial cell growth promoting ability; Or substances which increase their activity or expression may be released in a sustained manner.
  • This may be, for example, the surface-modified porous silica particles with an alkoxysilane having an acidic group or a basic group.
  • polypeptides having epithelial or endothelial cell growth promoting ability if the substance that increases its activity or expression is positively charged at neutral pH, the surface of the particles and / or the interior of the pores may be negatively charged at neutral pH, whereby porous silica particles and epithelial or endothelial cells Polypeptides having growth promoting capacity; Or polypeptides having increased ability to bind to substances that increase their activity or expression to promote epithelial or endothelial cell growth; Or substances which increase their activity or expression may be released in a sustained manner.
  • the porous silica particles may be surface-modified with an alkoxysilane having an acidic group such as a carboxyl group (-COOH) and a sulfonic acid group (-SO 3 H).
  • polypeptides having epithelial or endothelial cell growth promoting ability may be surface-modified with an alkoxysilane having a basic group such as an amino group or another nitrogen-containing group.
  • Polypeptides having epithelial or endothelial cell growth promoting ability may be released for a period of, for example, 7 days to 1 year or more, depending on the type of treatment required, the release environment, and the porous silica particles used.
  • porous silica particles of the present invention can be 100% degraded as biodegradable, so that the polypeptide having an ability to promote epithelial or endothelial cell growth supported thereon; Or a substance that increases its activity or expression can be released 100%.
  • composition of the present invention has a wound healing effect, comprising: a polypeptide having a supported epithelial or endothelial cell growth promoting ability; Or it may be an effect achieved by stably delivering a substance that increases its activity or expression in the body, and released to the target in a sustained manner, thereby promoting the expression of factors such as vascular endothelial growth factor (VEFG).
  • VEFG vascular endothelial growth factor
  • composition of the present invention may further comprise a pharmaceutically acceptable carrier, and may be formulated with the carrier.
  • pharmaceutically acceptable carrier refers to a carrier or diluent that does not stimulate the organism and does not inhibit the biological activity and properties of the administered compound.
  • Acceptable pharmaceutical carriers in compositions formulated in liquid solutions are sterile and biocompatible, which include saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.
  • Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • compositions of the present invention are applicable in any formulation and may be prepared in oral or parenteral formulations.
  • Pharmaceutical formulations of the present invention may be oral, rectal, nasal, topical (including the cheek and sublingual), subcutaneous, vaginal or parenteral (intramuscular, subcutaneous). And forms suitable for administration by inhalation or insufflation.
  • composition of the present invention is administered in a pharmaceutically effective amount. Effective dose levels depend on the type of disease, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent medications, and other factors well known in the medical field. Can be determined.
  • the pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
  • the dosage of the composition of the present invention varies widely depending on the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of the disease, and the appropriate dosage is, for example, Depending on the amount of drug accumulated in the body and / or the specific efficacy of the carrier of the invention used. For example, it may be 0.01 ⁇ g to 1 g per kg of body weight, and may be administered once or several times per unit period in daily, weekly, monthly or yearly unit periods, or may be administered continuously for a long time using an infusion pump. Can be. The number of repeated doses is determined in consideration of the time the drug stays in the body, the drug concentration in the body, and the like. Even after treatment according to the course of the disease treatment, the composition can be administered for relapse.
  • composition of the present invention may further contain a compound which maintains / increases the solubility and / or the solubility of one or more active ingredients or the active ingredients exhibiting the same or similar function in the treatment of wounds. It may also optionally further comprise anti-inflammatory agents, antiviral agents and / or immunomodulators and the like.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the present invention also relates to a method of treating a wound.
  • the wound treatment method of the present invention comprises a polypeptide having epithelial or endothelial cell growth promoting ability; Or administering to the individual porous silica particles carrying a substance that increases their activity or expression.
  • Polypeptides having epithelial or endothelial cell growth promoting ability; Or a substance which increases its activity or expression may be in the above-mentioned range.
  • the porous silica particles may be in the ranges exemplified above, or may be prepared by methods / conditions within the ranges exemplified above.
  • the subject may be a mammal, including a human, and specifically a human.
  • a polypeptide having an epithelial or endothelial cell growth promoting ability; Or a substance which increases its activity or expression can be formulated in a method within the ranges described above in the form of a composition.
  • the method of administration is not limited and includes, for example, oral, rectal, nasal, topical (including buccal and sublingual), subcutaneous, vaginal or parenteral (muscle) Intravenous, subcutaneous and intravenous) or by inhalation or insufflation.
  • the present invention is a polypeptide having an epithelial or endothelial cell growth promoting ability; Or to a pharmaceutical composition for treating wounds of porous silica particles carrying a substance which increases the activity or expression thereof.
  • Polypeptides having epithelial or endothelial cell growth promoting ability; Or a substance which increases its activity or expression may be in the above-mentioned range.
  • the porous silica particles may be in the ranges exemplified above, or may be prepared by methods / conditions within the ranges exemplified above.
  • porous silica particles of the present invention may be abbreviated as 'DegradaBALL or DDV'.
  • Example 1 Porous Silica Particles (DDV or DegradaBALL)
  • reaction solution was then centrifuged at 8000 rpm for 10 minutes at 25 ° C. to remove the supernatant, centrifuged at 8000 rpm for 10 minutes at 25 ° C., and washed five times with alternating ethanol and distilled water.
  • the reaction was carried out starting at 25 ° C. and warming up at a rate of 10 ° C./min, then slowly cooling at a rate of 1-10 ° C./min in the autoclave.
  • the cooled reaction solution was centrifuged at 8000 rpm for 10 minutes at 25 ° C. to remove the supernatant, and centrifuged at 8000 rpm for 10 minutes at 25 ° C. and washed five times with ethanol and distilled water.
  • the porous silica particles prepared in 2) were put in a glass vial, heated at 550 ° C. for 5 hours, and cooled slowly to room temperature after completion of the reaction to prepare particles.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that the reaction conditions at the time of pore expansion were changed to 140 ° C. and 72 hours.
  • Porous silica particles were prepared in the same manner as in Example 1-1- (1), except that a 5-fold large container was used, and each material was used in 5-fold volume.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 920 ml of distilled water and 850 ml of methanol were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 800 ml of distilled water, 1010 ml of methanol, and 10.6 g of CTAB were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 620 ml of distilled water, 1380 ml of methanol, and 7.88 g of CTAB were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 2.5 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 4.5 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 11 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in 1-1- (1), except that 12.5 mL of TMB was used for pore expansion.
  • Example 1-1- (1) -2 In the same manner as in Example 1-1- (1) -2), the small pore particles were reacted with TMB, cooled, and centrifuged to remove the supernatant. Thereafter, centrifuged under the same conditions as in Example 1-1- (1) -2), washed three times with alternating ethanol and distilled water, and then dried under the same conditions as in Example 1-1- (1) -2). Powdery porous silica particles (pore diameter 10-15 nm, particle diameter 200 nm) were obtained.
  • N-Hydroxysuccinimide 200 mg was dispersed in 30 mL of PBS and allowed to react for 12 hours while stirring at room temperature. The product is then washed and dried.
  • reaction solution of the previous step remains inside the pore, so that the inside of the pore is not modified.
  • the cooled reaction solution was centrifuged at 8000 rpm for 10 minutes to remove the supernatant, centrifuged at 8000 rpm for 10 minutes at 25 ° C, and washed five times with alternating ethanol and distilled water.
  • Example 1-1- (4) The porous silica particles of Example 1-1- (4) were reacted with (3-Aminopropyl) triethoxysilane (APTES) to charge with a positive charge.
  • APTES (3-Aminopropyl) triethoxysilane
  • porous silica particles were dispersed in a 10 mL toluene in a 100 mL round bottom flask with a bath sonicator. Then 1 mL of APTES was added and stirred at 400 rpm and stirred at 130 ° C. for 12 hours.
  • Example 1-1- (1) The porous silica particles of Example 1-1- (1) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), except that 0.4 ml of APTES was added and the reaction time was 3 hours.
  • APTES (3-Aminopropyl) triethoxysilane
  • Example 1-1- (9) The porous silica particles of Example 1-1- (9) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), and the other method was the method of 1-2- (1) -1). Modified in the same manner as
  • Example 1-1- (10) The porous silica particles of Example 1-1- (10) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), and modified in the same manner as in the method of 1-2- (1) -1). It was.
  • APTES (3-Aminopropyl) triethoxysilane
  • Example 1-1- (1) The porous silica particles of Example 1-1- (1) were reacted with Trimethoxy (propyl) silane to introduce a propyl group into the surface and the pores, and 0.35ml of Trimethoxy (propyl) silane was added instead of APTES, followed by reaction for 12 hours. Modification was carried out in the same manner as in Example 1-2- (1) except for the above.
  • Example 1-1- (1) The porous silica particles of Example 1-1- (1) were reacted with Trimethoxy-n-octylsilane to introduce propyl groups on the surface and inside of the pores, and 0.5ml of Trimethoxy-n-octylsilane was added instead of APTES, and reacted for 12 hours. Modification was carried out in the same manner as in Example 1-2- (1) except for the above.
  • Example 1-1- (1) The porous silica particles of Example 1-1- (1) were negatively charged by reacting with succinic anhydride, using DMSO (dimethyl sulfoxide) instead of toluene, and adding 80 mg of succinic anhydride instead of APTES. The reaction was stirred at room temperature for an hour, and the same modification as in Example 1-2- (1) -1) was performed except that DMSO was used instead of distilled water.
  • DMSO dimethyl sulfoxide
  • Example 1-2- (1) -1 It was modified in the same manner as in Example 1-2- (1) -1), except that 1.1 mL of MPTES was used instead of APTES.
  • Example 1-2- (3) -2 100 mg of the porous silica nanoparticles of Example 1-2- (3) -2) were dispersed in 1 mL of 1 M aqueous sulfuric acid solution and 20 mL of 30% hydrogen peroxide solution, and stirred at room temperature to induce an oxidation reaction. Oxidized to groups. After the same washing and drying in the same manner as in Example 1-2- (1) -1).
  • FIG. 1 is a photograph of porous silica particles of Example 1-1- (1)
  • FIG. 2 is a photograph of porous silica particles of Example 1-1- (2). You can see that it was created
  • Figure 3 is a photograph of the small pore particles of Example 1-1- (1)
  • Figure 4 is a comparison photograph of the small pore particles of Example 1-1- (1) and 1-1- (3), spherical It can be seen that the small pore particles of evenly generated.
  • the surface area and pore volume of the small pore particles of Example 1-1- (1) and the porous silica particles of Examples 1-1- (1), (7), (8) and (10) were calculated.
  • the surface area was calculated by Brunauer-Emmett-Teller (BET) method, and the pore size distribution was calculated by Barrett-Joyner-Halenda (BJH) method.
  • Example 1-1- (1) 2.1 1337 0.69
  • Example 1-1- (7) 4.3 630 0.72
  • Example 1-1- (8) 6.9 521 0.79
  • Example 1-1- (1) 10.4 486 0.82
  • Example 1-1- (10) 23 395 0.97
  • porous silica particles are biodegraded and nearly decomposed after 360 hours.
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles into a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • porous silica particle powder was dissolved in 5 ml of SBF (pH 7.4). Thereafter, 5 ml of the porous silica particle solution was placed in a permeable membrane having pores having a diameter of 50 kDa shown in FIG. 7. 15 ml of SBF was added to the outer membrane, and the SBF of the outer membrane was replaced every 12 hours. Decomposition of the porous silica particles was performed at 37 ° C. with 60 rpm horizontal stirring.
  • porous silica particles of the example have a significantly larger t than the control.
  • t which has a ratio of absorbance 1/2 of the positively charged particles, was 24 or more.
  • lactoferrin protein a protein consisting of the sequence of SEQ ID NO: 1 was used.
  • the particles the particles of Example 1-2- (3) -4) having a methylphosphonate group introduced on the surface thereof were used.
  • the plasmid DNA amplified the promoter portion from the pCMV vector to prepare a KanaR2-ColE1-CMV promoter portion.
  • the LTF encoding portion was amplified by PCR from the human cDNA library to prepare an LTF ORF of about 3 kb in length (pLEM-hLTF-101, SEQ ID NO: 2).
  • particles of Example 1-2- (1) -1) in which amino groups were introduced into the surface and the pores were used.
  • C2C12 cells were incubated for 24 hours after seeding 5.0 ⁇ 10 4 cells in a 12-well plate. Then, pre-starvation treatment was performed for 12 hours in Serum-free medium. Cells were treated with 200 ⁇ g / mL LTF protein after replacement with 0.1% FBS containing medium. According to the time (0, 1, 2, 3, 6, 12, 24, 48 hours) the cells trizol treatment to extract mRNA, and VEGF mRNA expression was confirmed by PCR.
  • C2C12 cells were seeded in a 12-well plate by 5.0 ⁇ 10 4 cells and incubated for 24 hours. Then, pre-starvation treatment was performed for 12 hours in Serum-free medium.
  • LTF pDNA @ DDV complexes in which 1 ⁇ g of LTF plasmid DNA was loaded on 20 ⁇ g of DDV, were treated with cells for 4 hours under serum-free conditions.
  • HEK-293T cells were seeded in a 12-well plate by 5.0 ⁇ 10 4 cells and incubated for 24 hours.
  • 1.0 ⁇ g of LTF pDNA was added to 20.0 ⁇ g of DDV to prepare an LTF pDNA @ DDV complex, and the cells were treated with serum-free conditions for 4 hours (mock was treated with only 1.0 ⁇ g of LTF pDNA).
  • the medium was replaced with a medium containing 1% FBS and incubated for 48 hours. After 48 hours, the medium in which HEK-294T cells were cultured was harvested.
  • HT-1080 cells were seeded by 2.0 ⁇ 10 3 cells in a 96-well plate and incubated for 24 hours. Then, pre-starvation treatment was performed for 12 hours in Serum-free medium. Cells harvested from HEK-293T cells treated with Serum-free medium, 10% FBS medium, 1% FBS medium + Mock HEK-294T cells, 1% FBS medium + 50% LTF pDNA DDV, respectively, The media collected from HEK-293T cells treated with 25% LTF pDNA DDV are treated.
  • the cells were multiplied and treated with 10% CCK-8 solution. The cells were incubated for 1 hour and then absorbed at 450 nm.
  • HT-1080 cell line As a result, the proliferation rate of HT-1080 cell line was very low in culture with 1% FBS, but HT-1080 cell line with conditioned medium induced cell proliferation in a form similar to that of culture solution with 10% FBS. 14).
  • the bar graph shows 24, 48, 72 and 96 hours in order from the left.
  • the degree of proliferation of the cells was confirmed by treating the HT-1080 cells with lactoferrin protein supported on DDV.
  • HT-1080 cells were seeded by 3.0 ⁇ 10 3 cells in a 96-well plate and incubated for 24 hours. After washing the cells once with 1 ⁇ PBS, DDV (0, 12.5, 25, 50, 100, 200, 400 ⁇ g / mL) carrying FBS-free medium, 10% FBS medium, 1% FBS + lactoferrin protein, respectively, DDV (0, 12.5, 25, 50, 100, 200, 400 [mu] g / mL) carrying FBS-free medium + lactoferrin protein was treated to cells and incubated for 48 hours. After 48 hours, the cells were washed once with 1 ⁇ PBS, treated with 10% CCK-8 solution, and incubated for 1 hour. Afterwards, the absorbance was confirmed at 450 nm to determine how proliferated the cells were.
  • Recombinant LTF protein loaded on DDV was treated to PAM-212 cells to confirm the extent of cell proliferation.
  • PAM-212 cells were seeded by 2.0 ⁇ 10 3 cells in a 96-well plate and incubated for 24 hours. Cells were washed once with 1 ⁇ PBS, then FBS-free media, 10% FBS, 1% FBS + lactoferrin protein (100 ⁇ g / mL), DDV carrying 1% FBS + lactoferrin protein (100 ⁇ g / mL), respectively. 1% FBS was treated with the cells. Cells were washed once with 1 ⁇ PBS at 48 and 96 hours, respectively, and 10% CCK-8 solution was incubated for 1 hour after treatment with the cells. And the absorbance was confirmed at 450 nm wavelength to determine how proliferated the cells were.
  • VEGF protein and lactoferrin protein supported on DDV were treated with HUVEC cells to confirm the effect of inducing the cells into vascular form.
  • the prepared composition 50 ⁇ l was injected into the skin around the wound, and a circular silicone cover (outer diameter: 30 mm, inner diameter: 5 mm) was closed around the wound and sutured with a surgical thread for observation and management.
  • a Tegaderm film was attached onto the wound, and the wound was wound with a pressure bandage.
  • the skin was collected at the wound site and the tissues were fixed with 4% PFA.
  • the tissues were made into frozen blocks, sliced to 7 mm thick, stained, and placed on a glass slide for observation under a microscope.

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Abstract

La présente invention concerne une composition pharmaceutique permettant de traiter des plaies avec une excellente efficacité par administration prolongée hautement efficace d'un polypeptide présentant l'aptitude à favoriser la croissance de cellules épithéliales ou endothéliales ou d'une substance destinée à augmenter l'activité ou l'expression du polypeptide.
PCT/KR2019/009531 2018-07-31 2019-07-31 Préparation pharmaceutique de cicatrisation de plaies WO2020027571A1 (fr)

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EP19845244.3A EP3845218A4 (fr) 2018-07-31 2019-07-31 Préparation pharmaceutique de cicatrisation de plaies
CN201980050585.9A CN112533590A (zh) 2018-07-31 2019-07-31 用于使伤口愈合的药物组合物
JP2021504531A JP7140431B2 (ja) 2018-07-31 2019-07-31 傷治療用の医薬組成物

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KR1020190092942A KR102316726B1 (ko) 2018-07-31 2019-07-31 상처 치료용 의약 조성물
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07196529A (ja) * 1993-12-29 1995-08-01 Morinaga Milk Ind Co Ltd 創傷治癒剤、化粧料および養毛剤
KR20140010285A (ko) * 2012-07-16 2014-01-24 서울대학교산학협력단 약물전달용 조성물 및 이를 이용한 약물전달방법
KR20150014560A (ko) * 2013-07-29 2015-02-09 서강대학교산학협력단 ｐＨ-반응성 키토산-코팅 다공성 실리카 나노입자
KR20160011565A (ko) * 2014-07-22 2016-02-01 주식회사 레모넥스 생리활성 물질 또는 단백질 전달용 조성물 및 이의 용도
KR20180091768A (ko) * 2017-02-06 2018-08-16 주식회사 레모넥스 생리활성물질 전달체

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Publication number Priority date Publication date Assignee Title
JPH07196529A (ja) * 1993-12-29 1995-08-01 Morinaga Milk Ind Co Ltd 創傷治癒剤、化粧料および養毛剤
KR20140010285A (ko) * 2012-07-16 2014-01-24 서울대학교산학협력단 약물전달용 조성물 및 이를 이용한 약물전달방법
KR20150014560A (ko) * 2013-07-29 2015-02-09 서강대학교산학협력단 ｐＨ-반응성 키토산-코팅 다공성 실리카 나노입자
KR20160011565A (ko) * 2014-07-22 2016-02-01 주식회사 레모넥스 생리활성 물질 또는 단백질 전달용 조성물 및 이의 용도
KR20180091768A (ko) * 2017-02-06 2018-08-16 주식회사 레모넥스 생리활성물질 전달체

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