KR102146704B1 - Cyclosporin a containing microstructures for transdermal and intradermal drug delivery - Google Patents

Abstract

The present invention discloses a microstructure containing cyclosporine A. Microstructures containing cyclosporine A according to an embodiment of the present invention is a microstructure; And a coating layer formed by coating a cyclosporine A drug solution containing cyclosporine A on the surface of the microstructure, wherein the cyclosporine A drug solution is transdermal or intradermal drug delivery through autoimmune diseases, inflammatory diseases, and It is characterized in that it treats or prevents at least one disease of the transplant rejection reaction.

Description

Cyclosporin A (CsA) transdermal and intradermal drug delivery microstructure {CYCLOSPORIN A CONTAINING MICROSTRUCTURES FOR TRANSDERMAL AND INTRADERMAL DRUG DELIVERY}

The present invention relates to a microstructure for transdermal and intradermal drug delivery containing cyclosporine A (CsA), and transdermal and intradermal drug delivery including cyclosporine A (CsA) capable of administering cyclosporine A (CsA) through skin penetration It relates to a microstructure.

Cyclosporine A (see Fig. 40) is a high molecular peptide drug consisting of 11 amino acids, which exhibits strong immunosuppressive activity by inhibiting the growth and differentiation of T-cells, and according to the structure of its constituent amino acid residues, cyclosporine A and cyclosporine B , Cyclosporine C, Cyclosporine D, Cyclosporine G, etc., but in fact, cyclosporine A, whose pharmacological activity and clinical application cases are the most widely used, is most widely used.

Cyclosporine A was discovered in 1976 in the fungus Tolypocladium inflatum by Borel et al., and it was discovered that it inhibits lymphocyte growth.As an immunosuppressant, it was attracted attention as a drug that opened a new horizon in the field of organ transplantation. come.

Cyclosporine A has a cyclic structure of 11 amino acids, of which 7 amino acids are present in N-methylated form, and the remaining 4 amino acids are not N-methylated, so the hydrogen bonded to this nitrogen atom is an intramolecular carbonyl group. It has a peculiar structure that forms hydrogen bonds, and because of this, it is a poorly soluble drug that is hardly soluble in water because it has strong intramolecular attraction and relatively difficult to interact with water molecules.

Cyclosporine A (C ₆₂ H ₁₁₁ N ₁₁ O ₁₂ ) has a relatively large molecular weight of 1,202,63, and is very hydrophobic, although its clinically useful, so it has a solubility in water (7.3 µg/ml, 37°C). Because it is low (J. Pharm. Pharmcol., 43, 28-289, 1991), when administered orally, the bioavailability is less than 30% and the absorption rate is very low (Drug Delivery System 1, 1-7, 1986).

In order to improve this problem, many prior art have been patented. In addition, the bioavailability rate is greatly affected by the amount of bile secretion, lipid intake, and other conditions of the patient to be administered, so the deviation between patients is very large, about 5 to 50%, and even in the same patient, there is a large deviation during the same treatment period. .

The side effects of long-term administration of cyclosporine A include nephrotoxicity and hepatotoxicity. In the case of nephrotoxicity, the glomerular filtration rate decreases in a dose-dependent manner, causing chronic irreversible loss of renal nephron, and the unique properties of cyclosporine A, low bioavailability, and large gaps in individual absorption rates are effective drugs by maintaining a constant blood concentration. It is acting as a major difficulty in drug administration planning to suppress the onset and side effects, that is, to maintain the life of transplant patients.

In particular, it is more difficult if the patient to be administered is in a state in which organs involved in metabolism and excretion of drugs such as liver or kidney are transplanted. Accordingly, formulation studies are being conducted to improve the above-described problems of cyclosporine to increase the treatment coefficient.

For example, a comparison of the pharmacokinetic parameters after oral administration of cyclosporine-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) and Sandimmune Neoral® showed that the PLGA NP formulation was compared with the latter's rapid Cmax and 3-day release pattern. It was found that the absorption rate was controlled and the drug concentration in the blood was maintained over 5 days, and the drug reduction was also gentle.

This pharmacokinetic pattern of PLGA nanoparticles ultimately contributes to the insignificant blood urea nitrogen (BUN), plasma creatinine (PC) and malondialdehyde (MDA) concentrations and histopathological nephrotoxicity than that of the existing Sandimmune Neoral®. (Journal of Controlled Release 119 (2007) 197-206).

These formulation studies are mainly studies on the solubilization of cyclosporine A, and there are various forms such as microspheres, powder compositions by adsorption, inclusion complexes, and solid dispersions, as well as methods using a mixture of vegetable oil and surfactant.

For example, U.S. Patent No. 4,38,307, relates to a solution for cyclosporine A. A technology is patented in which a three-component composition of Labrafil as a surfactant and olive oil and ethanol as a solvent is used. Korean Patent No. 10-0446170 relates to a pre-concentrate of a cyclosporine A-containing microemulsion consisting of a hydrophilic phase, a hydrophobic phase and a surfactant, and as a hydrophilic phase, a low molecular weight mono- or poly-oxy-alkanediol (C1-5), Microemulsions using tetrahydrofurfuryl di- or partial-ether, 1,2-propylene glycol, transcutol, glycofurol, etc., and intermediate fatty acid triglycerides and fatty acid saccharide monoesters as hydrophobic phase. Descriptions of topical preparations in the form of preconcentrates and emulsions are described.

Korean Patent Publication No. 2003-0065831 relates to a sustained-release pharmaceutical composition containing cyclosporine A. More specifically, it relates to a biodegradable polymer and a cyclosporine A-containing sustained-release pharmaceutical composition essentially comprising a cyclosporine A and a release controlling agent enclosed therein.

Korean Patent Laid-Open Publication No. 10-1990-0012625 describes a composition consisting of cyclosporine A as an active ingredient, monoester per fatty acid, and a diluent or carrier, which is prepared in a solid dosage form suitable for oral administration. No. 0173349 relates to a cyclosporine A-containing solid dispersion composition, characterized in that it contains cyclosporine A and two surfactants: a solubilizing surfactant and a stabilizing surfactant.

Korean Patent Registration No. 10-1819310 discloses cyclosporin A or a pharmaceutically acceptable salt thereof; It relates to a pharmaceutical formulation containing a hydrophilic polymer in the group consisting of surfactants, co-surfactants, oils, and combinations thereof, and a preparation method thereof. Even if a small amount of oil, surfactant, co-surfactant is used, the dissolution rate is maintained or precipitated. Present the agent to be inhibited.

Korean Patent Registration No. 10-0300252 relates to a pharmaceutical composition containing cyclosporine A as an active ingredient, and specifically, a pharmaceutical containing a cyclosporine A-containing solid microemulsion prepared by dispersing a cyclosporine A-containing microemulsion in an enteric carrier. It relates to the composition. The solid microemulsion prepared as described above does not dissolve in the trauma such as artificial gastric juice, but dissolves in the artificial intestinal fluid to form a microemulsion having fine particles again, thereby rapidly releasing cyclosporine.

Korean Patent Registration No. 10-0304326 is a single component or two selected from the group consisting of 1) cyclosporine A as an active ingredient, 2) alkyl esters of polycarboxylic acids as lipophilic solvents, and esterified compounds of carboxylic acids and polyols. The above mixed ingredients, 3) oil, and 4) relates to a microemulsion pre-concentrate composition containing a surfactant, and Korean Patent No. 10-1492447 is an active ingredient by mixing cyclosporine A, a non-aqueous solvent, an emulsifier, and an aqueous solvent. A nanoemulsion eye drop composition that increases the solubility of cyclosporine A and improves the stability of the eye drop composition and a method for preparing the same are proposed.

Cyclosporine A is widely used as an immunosuppressive agent used for the treatment and prevention of various autoimmune diseases, inflammatory diseases and transplant rejection diseases in humans and animals. However, it is poorly soluble in itself, has a first pass effect in the liver, and P-glycoprotein efflux. This drug has a low bioavailability, and these pharmacokinetic parameters vary greatly depending on the degree of bile acid distribution between patients and the patient's condition. In addition, at high concentrations, it is a drug that has a narrow therapeutic window, which is concerned about kidney and liver toxicity, and when administered orally, the drug reaches the highest drug concentration (Cmax) in the blood within a short period of time and then rapidly decreases, and the drug characteristics of large individual deviations. It contributes greatly to side effects. In the meantime, research on various formulations and formulations has been conducted to improve this through various research on formulations, but fundamental improvement has not been made.

Cyclosporine A (CsA) is an autoimmune and inflammatory psoriasis (psoriasis), psoriatic arthritis (psoriatic arthritis), nail psoriasis (nail psoriasis), atopic dermatitis (atopic dermatitis), etc. Alopecia areata, urticarial, dry eyes, Sjφgren's syndrome, rheumatoid arthritis, Behcet disease, Pemphigus vulgaris, lichen planus (Lichen planus) is also widely used, but when administered systemically, it is limitedly used due to side effects such as kidney and liver toxicity (J Am Acad Dermatol. 2010;63(6):925-46, J Drugs Dermatol. 2012 ;11(8):979-87).

In particular, in the case of skin lesions such as psoriasis, atopic dermatitis, and alopecia areata, penetration of cyclosporine A (CsA) into the skin through transdermal administration has the potential to significantly reduce systemic side effects. Various efforts were made, such as the development of various formulations, sonophoresis, iontophoresis, and physical drug delivery by electroporation, but were not successful due to the high molecular weight of cyclosporine A (CsA) (J. Control.Release 50 (1998) 61-70.J. Control.Release 199 (2015)190-197, Int. J. Pharma. 326 (2006) 32-38.Biointerphases 12 (2017).

In addition, intralesional injection, in which cyclosporine A (CsA) is injected directly into the skin, which is a lesion, has been reported to be effective in treating psoriasis, but is not used due to discomfort such as pain caused by injection (J. Am. Acad. Dermatol. 22 (1990) 94-100).

Looking at the CsA microstructure prior art, there are prior art with a similar purpose, but most of the inventions have not been specifically presented through animal experiments by producing several actual CsA microneedles listed in some texts, preventing and treating in vivo intradermal psoriasis.

Korean Patent Laid-Open Publication No. 10-2010-0037389 discloses a method for preparing a solid microstructure capable of controlling multiple drug release by mixing microparticles or nanoparticles and/or a drug carrier in an emulsion formulation with a biocompatible/biodegradable material, and thereby It is about the manufactured solid microstructure.

Korean Patent Registration No. 10-1633137 relates to a liposome-microstructure including a liposome containing a carrier drug and a method for manufacturing the same, and the present invention can deliver a water-soluble or fat-soluble drug by enclosing it in the liposome. Drugs that were not easily absorbed can be delivered into the body through the skin. A liposome capable of drug delivery is provided with a microstructure of a microstructure, and this liposome-microstructure utilizes the drug delivery characteristics of the liposome to selectively and locally stabilize the drug on the desired site such as cancer, muscle, and cells. Can be delivered.

In Korean Patent Application Laid-Open No. 10-2015-0119204, a microneedle is a means for transdermally administering a drug, and the physiologically active substance is an immunosuppressive drug, but cyclosporine A is not specified.

Korean Patent Registration No. 10-1314091 relates to an electro-microneedle assembly in which a soluble microstructure and an electrotransmissive electrode are integrated into one structure for transdermal gene delivery in a treatment site, and a method of manufacturing the same, and is treated through a microneedle array. Transdermal genetic material delivered into the site is characterized by an immunosuppressant, more specifically cyclosporine A.

However, the invention is not directly mentioned and specifically manufactured through the examples, and is not specified in the claims. The main invention is a gene penetration method, which expects that proteins/peptides will pass without evidence or examples, but it is far from the present invention completed through specific examples and animal experiments as disclosed in the present invention.

Korean Patent No. 10-1712413 relates to a method of applying a microneedle applicator to the skin to treat an area of the skin and/or to deliver an active agent to the skin. The active ingredient or active agent delivered transdermally through the microneedle applicator is characterized by being formed of an immunosuppressive agent (eg, cyclosporine A), but essentially relates to a microneedle applicator. Treatment and prevention of diseases through a cyclosporine A microneedle The description of is not specified.

Korean Patent Publication No. 10-2011-0086854 relates to a microneedle array that replaces subcutaneous injection for rapid and painless delivery of injectable drug formulations. The microneedles facilitate transdermal delivery of therapeutic agents or sampling of fluid through the skin. As a specific microscopic structure associated with an array designed to penetrate the stratum corneum for the purpose, a material delivered through the microneedle is formed as an immunosuppressant. However, this is a method that connects the liquid drug layer to the skin through hollow MN, and is not related to the solid microneedle.

Korean Patent Publication No. 10-2013-0094214 relates to a composite microneedle array including a microneedle and a film superimposed on the microneedle, including the composite microneedle array according to any one of claims 1 to 7 Although a transdermal patch is specified, the material delivered transdermally through a microneedle array is characterized by being formed as an immunosuppressant, but there is no specific example of cyclosporine A, and is essentially an invention of a microneedle type.

International Patent Publication No. WO2016/155891 places the biodegradable polymer PLGA part in which the drug is dispersed in the sharp part of the tip of the microneedle, and the upper part of this part is connected to the water-soluble polymer PVP, and these needles are adhesive tape. Although the invention of the microneedle structure attached to the skin is proposed, the PVP layer melts immediately after penetration into the skin, and the PLGA drug layer is released into the skin, and these structures have the characteristics of slow-release drug delivery with biodegradability. Here, the invention is unfinished because cyclosporine has not been able to concretely specify the invention through production and experimentation.

Korean Patent Registration No. 10-0446170, "Pharmaceutical composition containing cyclosporine" Korean Patent Laid-Open Patent No. 10-1990-0012625, "Cyclosporingalene formulation" Korean Patent Registration No. 10-1819310, "Pharmaceutical composition containing cyclosporine" Korean Patent Registration No. 10-1492447, "Nanoemulsion ophthalmic composition containing cyclosporine and its manufacturing method" Korean Patent Laid-Open Patent No. 10-2003-0065831, "Sustained-release pharmaceutical composition containing cyclosporine" Korean Patent Registration No. 10-0304326, "Cyclosporine-containing microemulsion pre-concentrate composition" Korean Patent Registration No. 10-0300252, "Pharmaceutical composition containing cyclosporine-containing solid microemulsion" Korean Patent Registration No. 10-0173349, "Cyclosporine-containing solid dispersion composition" Korean Patent Registration No. 10-1794377, "Complex microneedle array including nanostructures" Korean Patent Registration No. 10-1712413, "Microneedle applicator including counter assembly" Korean Patent Registration No. 10-1633137, "Liposome for drug delivery-microstructure and its manufacturing method" Korean Patent Laid-Open Patent No. 10-2015-0119204, "Microneedle coating composition and microneedle device" Korean Patent Registration No. 10-1314091, "Electro-microneedle aggregate for transdermal gene delivery and manufacturing method thereof" Korean Patent Publication No. 10-2010-0037389, "Solid microstructure capable of controlling multiple drug release and its manufacturing method" Korean Patent Application Publication No. 10-2011-0086854, "Hollow microneedle array and method" Korean Patent Laid-Open Patent No. 10-2013-0094214, "Complex microneedle array including nanostructures" International Publication No. WO2016/155891, "MICRONEEDLE PATCH FOR DELIVERING AN ACTIVE INGREDIENT TO SKIN" US Patent No. 4386307, "Galenical compositions"

The embodiment of the present invention is a novel drug delivery method that solves the shortcomings of existing oral formulations and has the advantages of microstructures through research on microstructure formulations and formulations containing cyclosporine A (CsA), in vivo animal skin penetration, and in vivo psoriasis model. It is intended to provide a method of preventing and treating autoimmune diseases and inflammatory diseases.

Specifically, embodiments of the present invention a) increase the bioavailability because there is no liver first pass effect and P-glycoprotein efflux, b) because it is delivered through the skin, the drug concentration without a rapid increase or decrease in the drug in the blood It makes it possible to maintain a gentle and long-lasting maintenance, c) minimizing systemic exposure of drugs by delivering CsA to a local disease target through microstructures without pain, minimizing side effects such as nephrotoxicity and hepatotoxicity, , Joints, scalp. Maintaining sufficient drug concentration in local areas such as the eyeballs, psoriasis, psoriatic arthritis, nail psoriasis, atopic dermatitis, alopecia areata, urticarial, Local autoimmune and inflammatory diseases such as dry eyes, Sjφgren's syndrome, rheumatoid arthritis, Behcet disease, Pemphigus vulgaris, and Lichen planus To provide a drug delivery system for preventing and treating cyclosporine A (CsA).

In an embodiment of the present invention, in order to deliver drugs to local autoimmune and inflammatory diseases without pain locally, a small hole is made on the surface of the skin through various cyclosporine A microstructures including microneedles. Through a study on a drug delivery system that delivers CsA, we aim to provide a technology for intralesional drug administration with a therapeutic concentration of drugs to local lesions while minimizing systemic exposure to CsA.

An embodiment of the present invention is to reduce side effects caused by conventional oral or injection drugs by designing a transdermal absorber through a microstructure containing cyclosporine A.

An embodiment of the present invention is a systemic autoimmune disease with minor side effects through continuous maintenance of blood drug concentration without rapid increase and decrease in blood drug, high bioavailability compared to oral administration through transdermal drug delivery to humans and animals, systemic To provide a microstructure containing a painless cyclosporine A (CsA) used for the treatment and prevention of inflammatory diseases and transplant rejection diseases.

Microstructures containing cyclosporine A according to an embodiment of the present invention is a microstructure; And a coating layer formed by coating a cyclosporine A drug solution containing cyclosporine A on the surface of the microstructure, wherein the cyclosporine A drug solution is an autoimmune disease, an inflammatory disease, and a transdermal or intradermal drug delivery. At least one of the transplant rejection reactions can be treated or prevented.

The microstructure containing cyclosporine A is a systemic autologous system characterized by a high bioavailability compared to oral administration through transdermal drug delivery to humans or animals, and minor side effects through continuous maintenance of drug concentration in blood without rapid increase or decrease in blood drug. It may be a microstructure containing a painless cyclosporine A used for the treatment and prevention of immune diseases, systemic inflammatory diseases and transplant rejection diseases.

The microstructures containing cyclosporin A are human and animal graft-versus-host disease, rheumatoid arthritis, psoriasis, and tendon through local intradermal drug delivery. Psoriatic arthritis, nail psoriasis, atopic dermatitis, alopecia areata, urticarial, dry eyes, Sjφgren's syndrome, nummular keratitis, adenovirus Adenoviral keratoconjunctivitis, systemic mastocytosis, Kimura disease, Pyoderma gangrenosum, Dyshidrotic eczema, Chronic urticarial, Behcet disease, Behcet disease Pityriasis rubra pilaris, Dermatomyositis, Pemphigus vulgaris, Epidermolysis bullosa acquisita, Lichen planus, Lichen planus, Hydradenitis suppurativa, crystals It may include at least one of Seongyangjin (Prurigo nodularis) and sclerosis (Systemic sclerosis).

The microstructure containing cyclosporine A contains a cyclosporine A chemical solution, a biocompatible material and an additive,

The microstructure containing the cyclosporine A is a microneedle, a microspike, a microblade, a microknife, a microfiber, a microprobe, a microbarb, a microarray or a microelectrode, more preferably a microneedle, a microspike , Microblade, microknife, microfiber, microprobe, and at least one of microvalve may be included.

The biocompatible material is hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxy Carboxymethyl chitin, fibrin, agarose, pullulan, polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), glucose, lactose, fructose, galactose, mannose, Maltose, lactulose, maltose, sucrose, trehalose, raffinose, melgitose, melibiose, xylobiose, cellobiose, stachyose, sorbitol, mannitol, cellobiose, gentibiose gentiobiose), erythritol, xylitol, lasitol, maltitol, gluconic acid, aldonic acid including γ-lactone, lactone derivatives of gluconic acid, gluconic acid γ -Lactone derivatives of aldonic acid, including lactones, ribaraic acid, arabinaric acid and aldaric acid including galactaric acid, arabinaric acid (arabinaric acid) and a lactone derivative of aldaric acid including galactaric acid, glucuronic acid, galaccuronic acid, and mannuronic acid. Uronic acid, starch, vegetable gums, crystalline cellulose, heparin, hyaluronic acid, chitin, chitosan, dextran, alginate, tragacanta, agar, carrageenan, hydroxypropylmethylcellulose (HPMC) ), ethyl cellulose (EC), carboxymethylcellulose (CMC), hydroxypropyl cellulose (HPC, hydroxy propyl cellulose), hydroxypropyl methylcellulose (HPMC), polycaprolactone (PCL, polycaprolactone), polyvinyl pyrrolidone (PVP poly vinyl pyrrolidone), polyvinyl alcohol, polyethylene glycol (PEG, polyethylene glycol), polyvinyl caprolactam-polyvinyl acetatepolyethyleneglycol graft copolymer (brand name: Soluplus), silk, gelatin, poly-γ-glutamic acid, poly (methylvinylether/maleic anhydride)(PMVE/MA), polyvinylpyrrolidone-polyvinyl alcohol (PVP-PVA), poly(vinylpyrrolidone-co-methacrylic acid)(PVP-MAA), PVP-cyclodextrin(PVP-CD), Poly(methylvinylether/ maleic anhydride)-polyethylene glycol (PMVE/MA-PEG), poly(2-hydroxyethyl methacrylate)(PHEMA), poly(styrene)-block-poly(acrylic acid) (PS-b-PAA), Gantrez, acrylate modified HA (m-HA), Polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycarbonate, polystyrene (PS), carbomer, Polyoxyethylene (PEO, polyethylene oxide), polypropylene oxide (PPO, poly propylene oxide), polyvinyl methyl ether (PVME, poly vinyl methyl ether), polymethyl acrylate (PMA, poly (methyl) acrylate)s, polyester amide, poly (butyric acid), acrylic amide, Acrylic acid, polyanhydride, polyorthoester, polyetherester, poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, Acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, polyethylene glycol (PEG), polymetha Acrylates, polyhydroxyalkanoates (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydrosoxylate-co-valerate); PHBV), poly(3-hydroxyproprionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), poly(4-hydroxybutyrate), poly (4-hydroxyvalerate), poly(4-hydroxyhexanoate), poly(esteramide), polycaprolactone, polylactide (PLA), polydioxa, poly(glycolic acid-co-trimethylene) Carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acid), polycyanoacrylate, poly(trimethylene carbonate), poly(iminocarbonate), poly(tyrosine carbonate), polycarbonate, poly( Tyrosine arylate), polyalkylene oxalate, polyphosphagens, PHA-PEG, polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, poly Propylene, polystyrene, polyvinyl acetal dietylamino acetate, polyvinyl acetate, polyvinyl butyral, polyvinyl formal, vinyl chloride-propylene-vinyl acetate (vinylchloride-propylene-vinylacetate) copolymer, vinyl chloride-vinylacetate copolymer, cumaroneindene polymer, dibutylaminohydroxypropyl ether, ethylene-vinyl acetate ( ethylene-vinylacetate) copolymer, at least one of glycerol distearate, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid (2-methyl-5-vinylpyridine methacrylate-methacrylic acid) copolymer It may include.

The additive includes a surfactant, and the surfactant is polyoxyethylene glycolated natural oils, polyoxyethylene glycolated hydrogenated vegetable oils, reoxyethylene glycolated natural castor oil, reoxyethylene glycolated hydrogenated castor oil, Cremophor Reaction products of natural or hydrogenated vegetable oils including Cremophor RH 40, Cremophor RH 60, Cremophor EL, Nikkol HCO-40, and Nikkol HCO-60 with ethylene glycol, poly Mono-lauryl of oxyethylene sorbitan fatty acid, tri-lauryl of polyoxyethylene sorbitan fatty acid, palmityl, stearyl, oleyl esters, polyoxyethylene (20) sorbitan mono-urate (trade name Tween 20 ), polyoxyethylene sorbitan fatty acid esters containing polyoxyethylene (20) sorbitan mono-palmitate (trade name Tween 40) or reoxyethylene (20) sorbitan mono-oleate (trade name Tween 80), ceti Polyoxyethylene fatty acid esters including all HE (Cetiol HE), polyoxyethylene fatty acid esters, Myrj, Mirz 52 or polyoxyethylene stearic acid esters, Pluronic or Mcalix ( Emkalyx) polyoxyethylene-polyoxypropylene copolymers polyoxyethylene-polyoxypropylene block copolymers including poloxamer, dioctyl succinate, dioctyl sodium sulfosuccinate, di-[2 -Ethylhexyl]-succinate, sodium lauryl sulfate, phospholipids, lecithin, soy lecithin, alkali metal salts or bile salts containing sodium taurochorate, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 BS or natural vegetable oil triglycerides containing Labrasol and transesterification products of polyalkylene polyols, mono-glycerides, di-glycerides, mono/ Di-glyceride, caprylic acid, caprylic acid/capric acid mono-glyceride caprylic acid/capric acid di-glyceride, vito Esterification products of capric acid and glycerol including Imwitor or Imbitor 742, sorbitan mono-laurate, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, Sorbitan mono-oleate, sorbitan tri-oleate, sorbitan fatty acid esters including span, pentaerythrit-diolyate, pentaerythrit-distearate, pentaerythrit-monolaurate , Pentaerythritol fatty acid esters including pentaerythrit-polyglycol ether or pentaerythrit-monostearate, polyalkylene glycol ethers, pentaerythrite fatty acid esters, sterols and derivatives thereof, cholesterol, cholesterol Derivatives, phytosterols, sitosterol, campesterol, stigmasterol and ethylene oxide additives thereof, generol, soya sterol, soya sterol derivative, polyethylene glycol mono-fatty acid ester, di-fatty acid ester, polyethylene glycol dicapryl Polyethylene glycol dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol isostearate, polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, Solutol HS 15 (Solutol HS 15), polyethylene Glycol Hydroxystearate, Miglyol 840, Propylene Glycol Caprylic-Capric Diester, Myvatex, Myvaplex, Myverol, Monoglyceride, Glycerol Mono Olate, glycerol monopalmitate and glycerol monostearate, Myvacet mono-acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, stearate, laurate, oleate, polyethylene Glycol Monooleate, MYO, Myo-2, Myo-6, Myo-10, Succinic acid di-alpha tocopheryl polyethylene glycol 1000, cetrimide (alkyltrimethylam monium bromide (Cetrimide), hexadecyltrimethylammonium bromide (CTAB), benzalkonium chloride, benzethonium chloride, docusate sodium salt, sodium dodecyl sulfate (SDS) ) May include at least one of.

The additive includes a mechanical strength control additive, and the mechanical strength control additive is trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melesitos, dextran, sorbitol, xylitol , Palatinite, mannitol, poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyether ester ( polyetherester), polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non -Degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefin (chlorosulphonate polyolefins), polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG ), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and at least any of a copolymer of monomers forming these polymers It can contain one.

The additive includes a viscosity control additive, and the viscosity control additive is polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), and hydroxypropyl Methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), polyvinyl acetate, hyaluronic acid (HA), polyacrylic acid, polyacrylamide, polymethacrylic acid, polyvinyl acetate and polyvinyl caprolactam. It may include at least one of PEG copolymers (Soluplus), gelatin, and derivatives of these substances, or mixtures thereof.

The additive includes a disintegration control additive, and the disintegration control additive is cyclodextrin, trehalose, maltose, lactose, lactulose, proctose, starch glycolate sodium, bicarbonate, croscarmellose sodium, crospovidone, starch and these It may contain at least any one of a mixture of.

The cyclosporine A chemical solution contains a solution of cyclosporine A dissolved in a solvent, and the solvent is ethanol, butanol, isobutanol, isopropanol, propanol, methanol, Ethylene bromide, Acetone, Chloroform, 2-ethylhexanol, Methyl ethyl ketone, Ethylene chloride, Methyl isobutyl ketone isobutyl ketone), methylene chloride, dichloromethane, methyl isopropyl ketone, tetrachloroethylene, mesityl oxide, carbon tetrachloride, Trichloroethylene, propylene glycol, dimethylformamide, 1,4-dioxane (1,4-Dioxane), butyl ether, dimethylformamide, ethyl ether (Ethyl ether), diisopropyl ether, dimethyl sulfoxide, tetrahydrofuran, tert-butyl methyl ether, pyridine, acetonitrile (Acetonitrile), ethyl acetate (Ethyl acetate), cyclohexane (Cyclohexane), toluene (Toluene), hexane (Hexane), and at least one of xylene (Xylene) may be included.

The cyclosporine A drug solution may be a cyclosporine A self-emulsifying drug delivery system (SEDDS, Self emulsifying drug delivery system).

The cyclosporine A self-emulsifying drug delivery system may include a hydrophilic or lipophilic solvent, an oil, a surfactant, and a hydrophilic polymer.

The hydrophilic or lipophilic solvent is mono-oxy-alkanediol, poly-oxy-alkanediol, C1 to C5 alkyl, C1 to C5 alkanol ethanol, tetrahydrofurfuryl di-ether, tetrahydrofurfuryl moiety- Ether, diethylene glycol monoethyl ether, Transcutol, tetrahydrofurfuryl alcohol polyethylene glycol, Glycofurol, 1,2-propylene glycol, dimethylisosorbide, propylene carbonate and polyoxyethylene-polyoxy Propylene block copolymer, Pluronic L10, Pluronic L31, Pluronic L35, Pluronic L43, Pluronic L101, Pluronic ) 31R1 and poloxamer 124, triacetin and triethyl citrate alone or a mixture thereof and a mixture of propylene carbonate, alkyl esters of polycarboxylic acids, esterification of carboxylic acids and polyols Compounds (carboxylic acid esters of polyols), triethyl citrate, tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate, triacetin ( triacetin) may contain at least one of.

The oil is castor oil, MCT (Medium Chin Triglyceride oil), corn oil, cotton seed oil, sesame oil, soya oil, cassia Casia oil, cinnamon oil, almond oil, arachis oil, safflower oil, linseed oil, rapeseed oil, Borage oil, primrose oil, peanut oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil ), eucalyptus oil, lavender oil, coconut oil, orange oil, lemon oil, anise oil, clove oil, super -Super-refined oil, super-refined corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil, crossential, concentrated borage oil, vegetable oil Esterification reaction product, as a triglyceride of intermediate fatty acids, Sepol 860 (SEFOL 860), Sepol 870, Sepol 880, Miglyol 810, Miglyol 812, Miglyol 818, Migly Miglyol 840, Labrapak CC, GMO AV1 (GMO AV1), ATMOS 300, GMOrphic 80, DL-a-Tocopheryl acetate ), Labrafil M 2130 CS, Imwitor 742, Myvac et), Myvaplex, Myverol, Generol, Myritol 318, Captex 300, Captex 355, Capmul MCM EP, C8 , I8, Neobee M5, Mazol 1400, Maisine 35-1, Crossential GLO E50; concentrated borage oil ethyl ester)[Croda Corporation], Nikkol EOO (ethyl olive oleate), ethyl oleate, isopropyl myristate, oleic acid in liquid form, linoleic acid in liquid form, ethyl linoleate , Isopropyl palmitate, Isopropylmyristate, Plurol Oleique CC 497, polyglyceryl oleate, Plurol Stearique, Polyglyceryl palmitostearate, DGMO-C, diglyceryl monooleate, tetraglin 1-O, tetraglyceryl monooleate (tetraglyceryl monooleate), Hexaglyn 1-O, hexaglyceryl monooleate, Hexaglyn 5-O, hexaglyceryl pentaoleate, Decaglyn 5-O, decaglyceryl pentaoleate, Decaglyn 10-O, decaglyceryl decaoleate, squalene, Hexamethyltetracosahexaenes, hydrogenated squalene, omega-3 essential fatty acids (EFAs), eicosapentaenoic acid, docosahexaenoic acid, ethyl Oil in esterified form, Incromega F 2250, Incromega F2628, ethyl esterified oil, Incromega E2251, Incromega F2573, Incromega TG2162, Incromega TG2779, Incromega TG2928, oleic acid, linoleic acid ), linolenic acid, or a derivative thereof.

The surfactants are polyoxyethylene glycolated natural vegetable oils, polyoxyethylene glycolated hydrogenated vegetable oils, polyoxyethylene glycolated natural castor oil, polyoxyethylene glycolated hydrogenated castor oil, Cremophor RH 40, cremophor Morphoa RH 60, Cremophora EL, Nikkol HCO-40, Nikkol HCO-60, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid mono-lauryl, polyoxyethylene Sorbitan fatty acid tri-lauryl, palmityl, stearyl, oleyl esters, Tween, polyoxyethylene (20) sorbitan mono-laurate (Tween 20), polyoxyethylene (20) sorb Non-non-palmitate (Twin 40), polyoxyethylene (20) sorbitan mono-oleate (Twin 80), polyoxyethylene fatty acid esters, Cetiol HE, Myrj, Mirz 52), polyoxyethylene-polyoxypropylene copolymers, Pluronic, Emkalyx, polyoxyethylene-polyoxypropylene block copolymers, poloxamer, dioctyl succinate, dioctyl Sodium sulfosuccinate, di-[2-ethylhexyl]-succinate, sodium lauryl sulfate, phospholipids, lecithin, soy lecithin, bile salts, alkali metal salts, sodium taurochorate, natural vegetable oil triglycerides and polyalkylenes Ester group transfer reaction product with polyol, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 BS, Labrasol, mono-glyceride, di -Glyceride, mono/di-glyceride, caprylic acid, esterification reaction product of capric acid with glycerol, caprylic acid/capric acid mono-glyceride, caprylic acid/capric acid di-glyceride, Imbitor, Imbitor 742, sorbitan fatty acid esters, sorbitan mono-laurate, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, bovine Rbitan mono-oleate, sorbitan tri-oleate, span, pentaerythritol fatty acid esters, polyalkylene glycol ethers, pentaerythrite fatty acid esters, pentaerythrit-diolate, pentaerythrite -Distearate, pentaerythrit-monolaurate, pentaerythrit-polyglycol ether, pentaerythrit-monostearate, sterols, sterol derivatives, cholesterol, cholesterol derivatives, phytosterols, Sitosterol, campesterol, stigmasterol, ethylene oxide addition of sitosterol, ethylene oxide addition of campesterol, ethylene oxide addition of stigmasterol, generol, soya sterol, soya sterol derivative, polyethylene glycol mono-fatty acid ester, polyethylene glycol Di-fatty acid ester, polyethylene glycol dicaprylate, polyethylene glycol dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol isostearate, polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, solutol HS 15 (Solutol HS 15), polyethylene glycol hydroxystearate, Miglyol 840 (Miglyol 840), propylene glycol caprylic-capric acid diester, Myvatex, Myvaplex, Miberol ( Myverol), monoglyceride, glycerol monooleate, glycerol monopalmitate, glycerol monostearate, Myvacet, mono-acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, Bound stearate, laurate, oleate, polyethylene glycol monooleate, MYO, myo-2, myo-6, myo-10, succinic acid di-alpha tocopheryl polyethylene glycol 1000, cetrimide (alkyltrimethylammonium bromide ( Cetrimide)), hexadecyltrimethylammoniumbromide (CTAB), chloride It may include at least one of benzalkonium chloride, benzethonium chloride, docusate sodium salt, and sodium dodecyl sulfate (SDS).

The hydrophilic polymer is hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose Acetate phthalate, hydroxypropylene methylcellulose or hydroxypropylene methylcellulose phthalate and cellulose derivatives, propylene oxide or derivatives thereof, polyvinylpyrrolidone (PVP), K12, K15, K17, K25, K30, K60, K90, K120, vinylpyrrolidone-vinyl acetate, polyethylene glycol, polyvinylalcohol, polyvinylacetate, polyvinylacetate phthalate ), polymethacrylate, polymethacrylate polymer (trade name: Eudragit), polyacrylic acid, derivatives of polymethacrylate (eg, carbomer) and polyvinyl capro It may include at least one of lactam-polyvinyl acetate-polyethylene glycol graft copolymer (polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer, brand name: Soluplus).

It may include a cyclosporine A inclusion body, which is a drug delivery body of the particles encapsulated with the cyclosporin A by the encapsulation component in the cyclosporine A drug solution.

The encapsulating components are serum albumin, gelatin, lecithin, collagen, iron oxide, casein, polycaprolactone, polylactide (PLA), Polymethyl metha acrylate (PMMA), poly alkyl cyano acrylate (PACA), poly methyl cyano acrylate (PMCA), polylactide (Poly D, L-Lactide), polyacrylamide, poly(methylvinylether-co-maleic anhydride, PVM/MA) Eudragit, polyglycolide (PGA) ), poly(lactide-co-glycolide; PLGA), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyalkyl cellulose, maltose, chitosan, polyester, polyhydroxyalkanoate (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydrosoxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate) ; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4- Hydroxyhexanoate), poly(esteramide), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, Poly(amino acid), polycyanoacrylate, poly(trimethylene carbonate), poly(iminocarbonate), poly(tyrosine carbonate), polycarbonate, poly(tyrosine arylate), polyalkylene oxalate, polyphospha Gens, PHA-PEG, polyvinylpyrrolidone, polybutadiene, polyhigh Hydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl foam, vinyl chloride-propylene -Vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, cumaroneindene polymer, dibutylaminohydroxypropyl ether, ethylene-vinyl acetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylic Rate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, stearic acid, behenic acid, cellulose, cellulose derivatives, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, Contains at least one of glycogen, chitin, chondroitin, dextrin, keratin sulfate, tallow, whale wax, beeswax, paraffin wax, castor wax, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, and glycogen can do.

The cyclosporine A inclusion body contains a stabilizer, and the stabilizer is a cellulose compound including carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA). ) Or polyvinyl-based compounds containing polyvinylpyrrolidone (PVP), acrylic compounds containing carbomers, gum compounds containing gellan gum or Xanthan gum, hyaluronic acid (HA), sodium hyaluronate (SodiumHyaluronate), sodium alginate (Sodium Alginate), dextran (Dextran) and didodecyldimethylmalonium bromide (Didodecyldimethylammonium Bromide) may contain at least any one of.

The cyclosporine A chemical solution may contain a cyclosporine A liposome.

The cyclosporine A liposome contains a phospholipid, and the phospholipid is phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithin, phosphatidic acid, sphingomyelin, lipofectin, cephalin, cardiolipin dipalmitoyl Phosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, diolephosphatidylglycerol, dimyristoylphosphatidylglycerol, hexadecylphosphocholine, di Stearoylphosphatidylcholine, distearoylphosphatidylglycerol, dioleylphosphatidylethanolamine, palmitoylstearoylphosphatidylcholine, palmitoylstearoylphosphatidylglycerol, monooleoylphosphatidylethanolamine, 1-palmitoyl-2-oleoyl -sn-glycero-3-phosphatidylcholine, polyethylene glycol distearoylphosphatidylethanolamine, dipalmitoylphosphatidylserine, 1,2-dioleoyl-sn-glycero-3-phosphatidylserine, dimyristoylphosphatidylserine , Distearoylphosphatidylserine, dipalmitoylphosphatidic acid, 1,2-dioleoyl-sn-glycero-3-phosphatidic acid, dimyristoylphosphatidic acid, distearoylphosphatidic acid, Dipalmitoylphosphatidylinositol, 1,2-dioleoyl-sn-glycero-3-phosphatidylinositol, dimyristoylphosphatidylinositol, and distearoylphosphatidylinositol, and at least one of distearoylphosphatidylinositol may be included.

The cyclosporine A liposome contains an internal phase viscosity increasing agent, and the internal phase viscosity increasing agent is polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene. -Vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefin (chlorosulphonate polyolefins), polyethylene oxide, polyvinyl Pyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and these It may include at least one of a copolymer of monomers forming a polymer.

The cyclosporine A liposome contains a mechanical strength increasing agent, and the mechanical strength increasing agent is trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melesitos, dextran, sorbitol, and Silitol, palatinite, mannitol, poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyether Ester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate , Non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefins (chlorosulphonate polyolefins), polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol Among the copolymers of (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and monomers forming these polymers It may include at least any one.

The cyclosporine A chemical solution may contain cyclosporine A lipid particles including at least one of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC).

The cyclosporine A chemical solution contains lipids in cyclosporine A lipid particles, and the lipids include glyceryl behenate (Compritol 888 ATO), glyceryl stearate (Imwitor 900), and trypalmitin. Glycerol (tripalmitin glycerol) (Dynasan 116), glyceryl palmitostearate (Precirol ATO 5), glyceryl palmitate (Cetyl palmitate), stearic acid (Stearic acid), tripalmitin (Tripalmitin), car Caprylic/-capric triglyceride (Miglyol® 812 and 810, Labrafac??, Softison 378 ), vitamin E (Vitamin E), vitamin E derivatives (TOS, TPGS), Lauroyl Polyoxylglycerides (Gelucire® 44) /14), monoacylglycerols (Monoacylglycerols) (Myverol 18-99 K), soy lecithin (Soy lecithin) (Epikuron??200), and at least one of squalene (Squalene) may be contained.

The cyclosporine A chemical solution contains a surfactant among cyclosporine A lipid particles, and the surfactant is polyoxyethylene glycolated natural vegetable oils, polyoxyethylene glycolated hydrogenated vegetable oils, polyoxyethylene glycolated natural castor oil, polyoxyethylene Glycolized hydrogenated castor oil, Cremophor RH 40, Cremophor RH 60, Cremophor EL, Nikkol HCO-40, Nikkol HCO-60, polyoxyethylene sorbitan fatty acid esters , Mono-lauryl of polyoxyethylene sorbitan fatty acid, tri-lauryl of polyoxyethylene sorbitan fatty acid, palmityl, stearyl, oleyl ester, Tween, polyoxyethylene (20) sorbitan Mono-laurate (Tween 20), polyoxyethylene (20) sorbitan mono-palmitate (Twin 40), polyoxyethylene (20) sorbitan mono-oleate (Twin 80), polyoxyethylene fatty acid esters, Cetiol HE, Myrj, Mirz 52), polyoxyethylene-polyoxypropylene copolymers, Pluronic, Emkalyx, polyoxyethylene-polyoxypropylene block Copolymers, poloxamer, dioctyl succinate, dioctyl sodium sulfosuccinate, di-[2-ethylhexyl]-succinate, sodium lauryl sulfate, phospholipids, lecithin, soy lecithin, bile salts, alkali Metal salt, sodium taurochorate, ester group transfer reaction product of natural vegetable oil triglyceride and polyalkylene polyol, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 BS, Labrasol, mono-glyceride, di-glyceride, mono/di-glyceride, caprylic acid, esterification product of caprylic acid with glycerol, caprylic acid/capric acid mono -Glyceride, caprylic/capric acid di-glyceride, Imbitor, Imbitor 742, sorbitan fatty acid esters, sorbitan mono-laurei T, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, sorbitan mono-oleate, sorbitan tri-oleate, span, pentaerythritol fatty acid esters, polyalkyl Ene glycol ethers, pentaerythrite fatty acid esters, pentaerythrit-diolate, pentaerythrit-distearate, pentaerythrit-monoraurate, pentaerythrit-polyglycol ether, pentaerythrit-monostea Rate, sterols, sterol derivatives, cholesterol, cholesterol derivatives, phytosterols, sitosterol, campesterol, stigmasterol, ethylene oxide additive of sitosterol, ethylene oxide additive of campesterol, ethylene oxide additive of stigmasterol , Generol, soya stearate, soya sterol derivative, polyethylene glycol mono-fatty acid ester, polyethylene glycol di-fatty acid ester, polyethylene glycol dicaprylate, polyethylene glycol dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol iso Stearate, polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, Solutol HS 15, polyethylene glycol hydroxystearate, Miglyol 840 (Miglyol 840), propylene glycol car Pryl-capric diester, Myvatex, Myvaplex, Myverol, Monoglyceride, Glycerol Monooleate, Glycerol Monopalmitate, Glycerol Monostearate, Myvacet , Mono-acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, bound stearate, laurate, oleate, polyethylene glycol monooleate, MYO, Myo-2, Myo- 6, myo-10, succinate di-alpha tocopheryl polyethylene glycol 1000, cetrimide (alkyltrimethylammonium bromide (Cetrimide)), cetrimide Monium bromide (hexadecyltrimethylammonium bromide (CTAB), benzalkonium chloride) benzethonium chloride, docusate sodium salt, and at least one of sodium dodecyl sulfate (SDS) may be included. have.

The cyclosporine A chemical solution may include a composition in which cyclosporine A is dissolved in a non-aqueous solvent, an emulsifier, and a stabilization agent.

The non-aqueous solvent is vegetable oil, castor oil, coconut oil, cinnamon oil, corn oil, olive oil, cottonseed oil, soybean oil, fatty acid esters consisting of 14 to 20 carbon atoms, lauric acid, myristic acid, palmitic acid, palmitoic acid, Stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, eicosapentaenoic acid, ethyl oleate, isopropyl myristate, fatty acid ester glycerol consisting of 6 to 12 carbon atoms, Labrapak PG or Labrapak lipo Fatty acid ester glycerides including fillet WL 1349, caprylic acid-capric acid triglycerides including Miglyol 812, caprylic acid-caprylic acid-linoleic acid triglycerides including Miglyol 818, It may further include at least any one of fatty acid esters consisting of 14 to 20 carbon atoms and glycerides of fatty acid esters consisting of 6 to 12 carbon atoms.

The emulsifier is a reaction product of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene glycolated natural castor oil, polyoxyethylene glycolated hydrogenated castor oil (trade name: Cremophor, BASF; HCO,: NIKKOL ), polyoxyethylene-sorbitan-fatty acid esters, mono lauryl, trilauryl, palmityl, stearyl esters or oleyl esters (trade name: Tween, ICI), polyoxyethylene fatty acid Esters, polyoxyethylene stearic acid esters (trade names: Mirage (Myrj, ICI, etc.), polyoxyethylene-polyoxypropylene copolymer, Pluronic, Emkalyx (BASF), polyoxyethylene- Polyoxypropylene block copolymer (Poloxamer, BASF), sodium dioctylsulfosuccinate, sodium lauryl sulfoate, phospholipids, soy lecithin, propylene glycol mono-fatty acid, propylene glycol di-fatty acid esters, propylene glycol dica Prylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol caprylic-capric acid diester (Miglyol 840, Huls), Trans-esterification reaction product of natural vegetable oil triglyceride and polyalkylene polyol, Labrafil M (manufactured by Gattefosse), mono-glyceride, di-glyceride, mono/di-glyceride, car Pryl/capric acid mono-glyceride, caprylic/capric acid di-glyceride (Imwitor, Huls), sorbitan fatty acid esters, sorbitan monolauryl (trade name: Span), Sorbitan monopalmityl, sorbitan monostearyl, sterols, sterol derivatives, cholesterol, phytosterol, sitosterol, pentaerythrate-fatty acid ester, pentaerythritol fatty acid ester, polyalkylene glycol ester, pentaeryth-dioleate, penta Eryth-distearate, pentaeryth-monolaurate, pentaeryth-poly It may further include at least one of glycol ether and pentaeryth-monostearate.

The stabilizer is a cellulose compound including carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), or polyvinylpyrrolidone (PVP). Polyvinyl compounds containing, acrylic compounds containing carbomer, gum compounds containing gellan gum or Xanthan gum, hyaluronic acid (HA), sodium hyaluronate (Sodium Hyaluronate) , Sodium alginate (Sodium Alginate) and dextran (Dextran) may further include at least one of.

The cyclosporine A chemical solution contains cyclodextrin containing the cyclodextrin, and the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, or glucosyl cyclodextrins of each of these, Maltosyl cyclodextrin, methyl cyclodextrin, hydroxyethyl cyclodextrin, and at least one of hydroxypropyl cyclodextrin may be further included.

The cyclodextrin containing the cyclosporine A uses a dissolution aid, and the dissolution aid further comprises at least one of ethanol, glycerin, polyethylene glycol, polypropylene glycol, polyethylene oxide, polypropylene oxide and polyoxyethylene sol metal can do.

It is an amphiphilic polymer micelle containing the cyclosporine A in an amphiphilic polymer material as the cyclosporine A chemical solution,

The amphiphilic polymer material is N-phthaloylcarboxymethylchitosan, Poly(2-ethylhexyl acrylate)-b-poly(acrylic acid), Poly(tert-butyl acrylate)-b-poly(2-vinylpyridine), Poly(ethylene oxide)-b -polycaprolactone, Poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone), Poly(e-caprolactone)-b-poly(methacrylic acid), Poly(ethyleneglycol)-b-poly (e-caprolactone-co-trimethylenecarbonate), Poly(aspartic acid)-b-polylactide, Poly(ethylene glycol)-block-poly(aspartate-hydrazide), Poly(N-isopropyl acrylamide-co-methacryl acid)-g- poly(D,L-lactide), Stearic acid-grafted chitosan oligosaccharide, Pluronic F127, Poloxamer 407(Pluronic F127), Poloxamer 188(Pluronic F68), Methoxy poly(ethylene glycol)-poly(ε-caprolactone)(MPEG-PCL ), Methoxy-poly(ethylene glycol)(MPEG), hexyl-substituted poly(lactides)(hexPLA)(polymers of MPEG-PLA and MPEG-hexPLA), Poly(butylene oxide)-poly(ethyleneoxide)-poly(butylene oxide ), Polyhydroxyethylaspartamide (PHEA), Methoxy (polyethylene glycol)-block-polycaprolactone (MePEG-b-PCL), Methox y poly(ethylene) glycol(MPEG), Poly(ethylene oxide)-poly(propylene oxide)(PEO-PPO-PEO) block copolymers, Hexadecyloxypropyl, Methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide), Pluronic P123(P123) ), Da-tocopheryl polyethylene glycolsuccinate(TPGS), N-isopropylacrylamide(NIPAAM), Tetronic® 701(T701), Synperonic® PE/F127(F127), Synperonic® PE/P84(P84), Poly(propylene oxide) (PPO ), poly(ethylene oxide)(PEO), PEG-b-PCL, cationic polyelectrolyte chitosan(CH), Poly(ethylene oxide)-poly(propylene, oxide)-poly(ethylene oxide)((PEO-PPO-PEO) , polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer, trade name: Soluplus), complex of sodium lauryl sulfate and Soluplus, methoxy-capped poly(ethylene glycol)-block-poly(epsilon-caprolactone) (mPEG-b-PCL) and Poly( At least one of ethylene glycol)-b-poly(D,L-lactic acid) may be further included.

According to an embodiment of the present invention, a new drug delivery that has the advantages of microstructures and solves the shortcomings of existing oral formulations through research on microstructure formulations and formulations containing cyclosporine A (CsA), in vivo animal skin penetration, and in vivo psoriasis model. Methods and methods of preventing and treating autoimmune diseases and inflammatory diseases can be provided.

Specifically, according to an embodiment of the present invention, a) increases the bioavailability because there is no liver first pass effect and no P-glycoprotein efflux, and b) because it is delivered through the skin, a drug without a rapid increase or decrease in blood drug It makes it possible to maintain the concentration for a long time while maintaining a gentle concentration, and c) by delivering CsA to a local disease target through a microstructure without pain, minimizing the systemic exposure of the drug to minimize side effects such as nephrotoxicity and liver toxicity, Oral cavity, joints, scalp. Maintaining sufficient drug concentration in local areas such as the eyeballs, psoriasis, psoriatic arthritis, nail psoriasis, atopic dermatitis, alopecia areata, urticarial, Local autoimmune and inflammatory diseases such as dry eyes, Sjφgren's syndrome, rheumatoid arthritis, Behcet disease, Pemphigus vulgaris, and Lichen planus Cyclosporine A (CsA) drug delivery system that prevents and treats can be provided.

According to an embodiment of the present invention, in order to deliver the drug locally to local autoimmune and inflammatory diseases without pain, small holes are made on the skin surface through various cyclosporine A microstructures including microneedles. Through a drug delivery system study, it is possible to provide intralesional drug administration technology with a therapeutic concentration of drugs to local lesions while minimizing systemic exposure to CsA.

According to an embodiment of the present invention, by designing a transdermal absorber through a microstructure containing cyclosporine A, side effects caused by conventional oral or injection drugs may be reduced.

According to an embodiment of the present invention, a systemic autoimmune disease having a high bioavailability compared to oral administration through transdermal drug delivery to humans and animals, a systemic autoimmune disease having minor side effects through continuous maintenance of blood drug concentration without a rapid increase or decrease in blood drug, It is possible to provide a microstructure containing a painless cyclosporin A (CsA) used for the treatment and prevention of systemic inflammatory diseases and transplant rejection diseases.

1 is an image showing a local psoriasis inhibitory effect after intradermal administration of a SEDDS A formulation coated microneedle containing cyclosporine A.
FIG. 2A is a graph showing a blood cyclosporine A concentration-time profile administered using a microneedle containing cyclosporin A, and FIG. 2B is a graph showing a blood cyclosporine A concentration-time profile administered orally.
3 is an image showing a skin sampling method and a ratio of tissues used in fabrication of a tissue slide.
FIG. 4 is an image showing the results of staining histopathology of the psoriasis preventing effect according to Example 1. FIG.
5 is a graph showing an epidermal thickness measuring result of the psoriasis preventing effect according to Example 1. FIG.
6 is an image showing the results of staining histopathology of the psoriasis treatment effect according to Example 1. FIG.
7 is a graph showing an epidermal thickness measuring result of a psoriasis treatment effect according to Example 1. FIG.
8 is a graph showing a comparison of epidermal thickness measuring results of the psoriasis preventing effect and the psoriasis treatment effect according to Example 1. FIG.
FIG. 9A is an optical microscope image showing a coating layer coated once on the microneedle surface of Example 1, and FIG. 9B is an optical microscope image showing a coating layer coated once on the microneedle surface of Example 2. 9C is an optical microscope photograph showing a coating layer coated twice on the surface of the microneedle of Example 1, and FIG. 9D is an optical microscope photograph showing a coating layer coated twice on the surface of the microneedle of Example 2. 9E is an optical microscope photograph showing a coating layer coated three times on the surface of the microneedle of Example 1, and FIG. 9F is an optical microscope showing a coating layer coated three times on the surface of the microneedle of Example 2. It shows a picture.
10A is a scanning electron microscope photograph showing a coating layer coated once on the microneedle surface of Example 1, and FIG. 10B is a scanning electron microscope photograph showing a coating layer coated once on the microneedle surface of Example 2. 10C is a scanning electron microscope photograph showing a coating layer coated twice on the microneedle surface of Example 1, and FIG. 10D is a scanning electron microscope photograph showing a coating layer coated twice on the microneedle surface of Example 2 An electron microscope photograph is shown, and FIG. 10E is a scanning electron microscope photograph showing a coating layer coated three times on the microneedle surface of Example 1, and FIG. 10F is a coating layer coated three times on the microneedle surface of Example 2. It shows a scanning electron microscope picture showing.
FIG. 11A is an image showing the insertion ratio of the microneedles of Example 1 coated twice on pig skin, and FIG. 11B is the insertion ratio of the microneedles of Example 2 coated twice on pig skin Is an image showing, and FIG. 11C is an image showing the insertion ratio of the microneedle of Example 1 coated three times on pig skin, and FIG. 11D is the microneedle of Example 2 coated three times on pig skin. This is an image showing the insertion ratio.
12 is a schematic diagram showing equipment for coating a microneedle.
Figure 13a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug solution (HPC general formulation), 13b is an optical microscope measurement of a microneedle coated twice with a cyclosporine A drug solution (HPC general formulation) This is an image showing the results, and 13c is an image showing the measurement results under an optical microscope of a microneedle coated three times with a cyclosporine A chemical solution (HPC general formulation).
14 is an image showing the optical microscopic measurement results of a microneedle coated with a cyclosporine A chemical solution (SEDDS A formulation) three times.
15 is an image showing a visual observation result according to Example 4.
FIG. 16 is an image showing the results of H&E staining histopathology of the dryness prevention effect according to Example 4, and FIG. 17 is an epidermal thickness measuring result of the psoriasis prevention effect according to Example 4. It is a graph shown.
FIG. 18 is an image showing the results of H&E staining histopathological speculum of the psoriasis treatment effect according to Example 4, and FIG. 19A is an epidermal thickness measuring result of the psoriasis treatment effect according to Example 4. 19B is a graph showing the comparison of epidermal thickness measuring results of the psoriasis preventing effect and the psoriasis treatment effect according to Example 4. FIG.
Figure 20a is an image showing the optical microscope measurement results of a microneedle coated three times with cyclosporine A drug (SEDDS A formulation + Sodium starch glycolate), 20b is cyclosporine A drug (SEDDS A formulation + Sodium starch glycolate) three times This is an image showing the measurement results of the coated microneedle under a scanning electron microscope.
Figure 21a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SEDDS A formulation + Croscarmellose sodum), 21b is a cyclosporine A drug (SEDDS A formulation + Croscarmellose sodum) is coated three times This is an image showing the measurement results of the microneedle under a scanning electron microscope.
Figure 22a is an image showing the optical microscope measurement results of a microneedle coated three times with a coating layer (SEDDS A formulation + Crospovidone), 22b is a scanning electron microscope measurement of a microneedle coated with a coating layer (SEDDS A formulation + Crospovidone 3 times) This is an image showing the result.
Figure 23a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation), and Figure 23b is an optical microscope of a microneedle coated twice with a cyclosporine A drug (SEDDS B formulation) An image showing the measurement result, FIG. 23C is an image showing the optical microscope measurement result of a microneedle coated three times with a cyclosporine A drug (SEDDS B formulation), and FIG. 23D is a cyclosporine A drug (SEDDS B formulation) 3 This is an image showing the scanning electron microscope measurement results of the microneedle coated once.
24 is an image showing a visual observation result according to Example 8.
FIG. 25 is an image showing the results of H&E staining histopathology of the dryness prevention effect according to Example 8, and FIG. 26 is an epidermal thickness measuring result of the psoriasis prevention effect according to Example 8. It is a graph shown.
FIG. 27 is an image showing the results of H&E staining histopathology of the dry treatment effect according to Example 8, and FIG. 28 is an image showing the results of epidermal thickness measuring of the psoriasis treatment effect according to Example 8. FIG. 29 is a graph showing the comparison of epidermal thickness measuring results of the dryness preventing effect and the psoriasis treatment effect according to Example 8. FIG.
Figure 30a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Gelatin), and Figure 30b is a microneedle coated with a cyclosporine A drug (SEDDS B formulation + Gelatin) twice. An image showing the measurement result of the needle under an optical microscope, FIG. 30C is an image showing the measurement result of a microneedle coated three times with a cyclosporine A chemical solution (SEDDS B agent + Gelatin), and FIG. 30D is an image showing the measurement result of a cyclosporine A chemical solution ( SEDDS B formulation + Gelatin) is an image showing the scanning electron microscope measurement results of the microneedle coated three times.
Figure 31a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Gelatin+gelucire), and FIG. 31B is a cyclosporine A drug (SEDDS B formulation + Gelatin+gelucire) coated twice Figure 31c is an image showing the optical microscope measurement results of the microneedles, and Figure 31c is an image showing the optical microscope measurement results of the microneedles coated three times of cyclosporine A chemical solution (SEDDS B formulation + Gelatin + gelucire), Figure 31d is a cyclosporine A chemical solution (SEDDS B formulation + Gelatin + gelucire) is an image showing the measurement results of the microneedles three times coated microneedle.
Figure 32a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Aerosil), and Figure 32b is a microneedle coated twice with a cyclosporine A drug (SEDDS B formulation + Aerosil) It is an image showing the measurement result with an optical microscope, FIG. 32C is an image showing the optical microscope measurement result of a microneedle coated three times of cyclosporine A chemical solution (SEDDS B agent + Aerosil), and FIG. 32D is an image showing cyclosporine A chemical solution (SEDDS B agent + Aerosil) is an image showing the measurement results of a microneedle coated three times with a scanning electron microscope.
Figure 33a is an image showing the optical microscope measurement results of the microneedle coated once with cyclosporine A chemical solution (PLGA), and Figure 33b shows the optical microscope measurement results of the microneedle coated twice with cyclosporine A chemical solution (PLGA) Figure 33c is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (PLGA), and Figure 33d is a scanning electron of a microneedle coated three times with a cyclosporine A chemical solution (PLGA) It is an image showing the microscopic measurement result.
Figure 34a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporin A drug (PLGA + eudragit formulation), and Figure 34b is a microneedle coated with a cyclosporine A drug (PLGA + eudragit formulation) twice It is an image showing the measurement result with an optical microscope, FIG. 34C is an image showing the optical microscope measurement result of a microneedle coated three times with a cyclosporine A chemical solution (PLGA + eudragit formulation), and FIG. Formulation) is an image showing the measurement results of a microneedle coated three times with a scanning electron microscope.
Figure 35a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (PLGA+ Carbopomer formulation), and Figure 35b is an optical microscope of a microneedle coated twice with a cyclosporine A drug (PLGA+ Carbopomer formulation) It is an image showing the measurement result, Figure 35c is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (PLGA + Carbopomer formulation), Figure 35d is a cyclosporine A drug (PLGA + Carbopomer formulation) is 3 This is an image showing the scanning electron microscope measurement results of the microneedle coated once.
Figure 36a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (NLC C), and Figure 36b is a scanning electron microscope measurement of a microneedle coated three times with a cyclosporine A chemical solution (NLC C) This is an image showing the result.
Figure 37a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (NLC L), and Figure 37b is a scanning electron microscope measurement of a microneedle coated three times with a cyclosporine A chemical solution (NLC L) This is an image showing the result.
Figure 38a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SLN I formulation), and Figure 38b is a scanning electron of a microneedle coated three times with a cyclosporine A drug (SLN I formulation) It is an image showing the microscopic measurement result.
Figure 39a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SLN P formulation), and Figure 39b is a scanning electron of a microneedle coated three times with a cyclosporine A drug (SLN P formulation) It is an image showing the microscopic measurement result.
40 is an image showing the chemical formula of cyclosporine A.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings and contents described in the accompanying drawings, but the present invention is not limited or limited by the embodiments.

The terms used in the present specification are for describing exemplary embodiments and are not intended to limit the present invention. In this specification, the singular form also includes the plural form unless specifically stated in the phrase. As used in the specification, "comprises" and/or "comprising" refers to the presence of one or more other components, steps, actions and/or elements, and/or elements, steps, actions and/or elements mentioned. Or does not exclude additions.

As used herein, "embodiment", "example", "side", "example" and the like should be construed as having any aspect or design described better or advantageous than other aspects or designs. Is not.

In addition, the term'or' means an inclusive OR'inclusive or' rather than an exclusive OR'exclusive or'. That is, unless stated otherwise or unless clear from context, the expression'x uses a or b'means any one of natural inclusive permutations.

In addition, the singular expression ("a" or "an") used in this specification and the claims generally means "one or more" unless otherwise stated or unless it is clear from the context that it relates to the singular form. Should be interpreted as.

The terms used in the description below have been selected as general and universal in the related technology field, but there may be other terms depending on the development and/or change of technology, customs, preferences of technicians, and the like. Therefore, terms used in the following description should not be understood as limiting the technical idea, but should be understood as exemplary terms for describing embodiments.

In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, detailed meanings will be described in the corresponding description. Therefore, terms used in the following description should be understood based on the meaning of the term and the contents throughout the specification, not just the name of the term.

Meanwhile, terms such as first and second may be used to describe various components, but the components are not limited by terms. The terms are used only for the purpose of distinguishing one component from another.

In addition, when a part such as a film, layer, region, configuration request, etc. is said to be "on" or "on" another part, not only is it directly above another part, but also another film, layer, region, component in the middle thereof. This includes cases where such as are interposed.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present specification may be used as meanings that can be commonly understood by those of ordinary skill in the art to which the present invention belongs. In addition, terms defined in a commonly used dictionary are not interpreted ideally or excessively unless explicitly defined specifically.

Meanwhile, in describing the present invention, if it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the subject matter of the present invention, the detailed description thereof will be omitted. In addition, terms used in the present specification are terms used to properly express an embodiment of the present invention, which may vary according to the intention of users or operators, or customs in the field to which the present invention belongs. Accordingly, definitions of these terms should be made based on the contents throughout the present specification.

Microstructures containing cyclosporine A according to an embodiment of the present invention is a microstructure; And a coating layer formed by coating a cyclosporine A drug solution containing cyclosporine A on the surface of the microstructure, wherein the cyclosporine A drug solution is transdermal or intradermal drug delivery through autoimmune diseases, inflammatory diseases, and At least one of the transplant rejection reactions can be treated or prevented.

Therefore, according to an embodiment of the present invention, a novel microstructure formulation and formulation study containing cyclosporine A (CsA), in vivo animal skin penetration, and in vivo psoriasis model solves the shortcomings of existing oral formulations and has the advantages of microstructures. It can provide a method of drug delivery and a method of preventing and treating autoimmune diseases and inflammatory diseases.

Specifically, according to an embodiment of the present invention, a) increases the bioavailability because there is no liver first pass effect and no P-glycoprotein efflux, and b) because it is delivered through the skin, a drug without a rapid increase or decrease in blood drug It makes it possible to maintain the concentration for a long time while maintaining a gentle concentration, and c) by delivering CsA to a local disease target through a microstructure without pain, minimizing the systemic exposure of the drug to minimize side effects such as nephrotoxicity and liver toxicity, Oral cavity, joints, scalp. Maintaining sufficient drug concentration in local areas such as the eyeballs, psoriasis, psoriatic arthritis, nail psoriasis, atopic dermatitis, alopecia areata, urticarial, Local autoimmune and inflammatory diseases such as dry eyes, Sjφgren's syndrome, rheumatoid arthritis, Behcet disease, Pemphigus vulgaris, and Lichen planus Cyclosporine A (CsA) drug delivery system that prevents and treats can be provided.

According to an embodiment of the present invention, in order to deliver the drug locally to local autoimmune and inflammatory diseases without pain, small holes are made on the skin surface through various cyclosporine A microstructures including microneedles. Through a drug delivery system study, it is possible to provide intralesional drug administration technology with a therapeutic concentration of drugs to local lesions while minimizing systemic exposure to CsA.

According to an embodiment of the present invention, by designing a transdermal absorber through a microstructure containing cyclosporine A, side effects caused by conventional oral or injection drugs may be reduced.

According to an embodiment of the present invention, a systemic autoimmune disease having a high bioavailability compared to oral administration through transdermal drug delivery to humans and animals, a systemic autoimmune disease having minor side effects through continuous maintenance of blood drug concentration without a rapid increase or decrease in blood drug, It is possible to provide a microstructure containing a painless cyclosporin A (CsA) used for the treatment and prevention of systemic inflammatory diseases and transplant rejection diseases.

1 is an image showing a local psoriasis inhibitory effect after intradermal administration of a SEDDS A formulation coated microneedle containing cyclosporine A.

Referring to Figure 1, after topical administration of the SEDDS A formulation coated microneedle containing cyclosporine A to the skin of an animal (Mice (BALB/c, male 10-12 weeks old), psoriasis was induced by continuously applying Imiquimod, a psoriasis-inducing substance. Thereafter, psoriasis inhibitory effect (normal), psoriasis-inducing control site, and epidermal thickness measurement through histopathology at the site where the SEDDS A formulation coated microneedle containing cyclosporine A was administered to the psoriasis-causing site ( As a result of comparing epidermal hyperplasia), it can be seen that there is a psoriasis inhibitory effect on the intradermal administration site of the microneedle coated with the SEDDS A formulation containing cyclosporine A.

Hereinafter, with reference to Examples 1 to 24, the characteristics of the present invention will be described.

Example 1: Cyclosporine A Chemical solution (HPC general formulation) Fabrication of dissolving microstructures containing biocompatible substances and additives, and experiments on pharmacokinetics (Pk) and inhibitory effects on intradermal psoriasis

A soluble cyclosporine A (CsA) microneedle (MN) was prepared using a polydimethylsiloxane (PDMS) mold. CsA and hydroxypropyl cellulose (Hydroxypropyl cellulose) (HPC, MW 80kD) were mixed in a weight ratio of 1:9 to 20% in a methanol molding solution. After applying the molding solution to the mold, go through a centrifugation process (2588g for 30min (Combi-514R, Hanil Science Industrial, South Korea) to fill the cavity ((600μm long and 250μm wide) in the PDMS mold) and then dry it. Thus, a soluble CsA microneedle was obtained.

The obtained MN was confirmed in its shape through a scanning electron microscope, and after applying it for 10 s with a force of 50N against the actual porcine skin, dyed with trypan blue solution (Sigma-Aldrich) and permeated skin ( blue dots) as a percentage of the total number of needles, it could be seen that more than 90% of the skin was pierced by MN.

<Pharmacokinetic study after oral administration of cyclosporine A (CsA) in the same amount as dissolving cyclosporine A microneedle>

Four Eight-week-old Sprague-Dawley (SD) rats are 10% CsA MN per Mouse and 50N for 30 s with a dermaplast band-aid and clip to penetrate the skin and remove the clip for 30 minutes. Attached to the liver skin. After that, collect the needle and calculate the amount of CsA that has penetrated into the skin (441.18μg/kg), and the oral preparation (CsA 3.529mg, Cremophore EL 2600mg, ethanol) so that the same amount of CsA is administered to the other 4 rats. 1.32ml, saline 4ml) was orally administered as Sonde.

After administration, 50ul of internal standard material is added to 100ul of sampled blood, and 1.2ml of MTBE (methyl tertiary-butyl ether) is added after vortexing. After vortexing, shake for 10 minutes. Centrifuge at 4℃ and 13000g in a centrifuge for 3 minutes, take 1ml of MTBE layer, transfer to another tube, and dry under nitrogen stream at 40℃ hit block. In the pretreatment process after extraction, 200ul reconstituted solution (MeOH:DW=4:1) was added, vortexed, filtered, and injected into LC/MS/MS for analysis.

Table 1 is a table showing the names of instruments used for LC/MS/MS analysis.

[Table 1]

FIG. 2A is a graph showing a blood cyclosporine A concentration-time profile administered using a microneedle containing cyclosporin A, and FIG. 2B is a graph showing a blood cyclosporine A concentration-time profile administered orally.

2A and 2B, as a result of pharmacokinetic analysis, a microneedle containing cyclosporine A (Dissolving CsA microneedle; 10% CsA) is 8 hours of reaching the maximum blood concentration (Tmax), and the maximum drug concentration (Cmax). , The average area under the concentration (AUC) of the drug was 8 o'clock, 15.9 ng/ml, and 686, respectively, whereas when administered orally, it was 2 o'clock, 18.2 ng/ml, and 254.44. It was found that the average distribution area of the needle was 2.7 times larger than that of oral administration, and the blood concentration was maintained very gently and relatively longer than that of oral administration.

In addition, Figures 2a and 2b show preferred pharmacokinetic parameters of transdermal administration of dissolving cyclosporin A microneedle compared to oral administration of CsA in the same dose.

In addition, as a result of the comparison of the pharmacokinetic and the same dose of CsA oral administration with the transdermal administration of the dissolving cyclosporine A microneedle, the bioavailability was significantly higher in the microneedle administration group, and the blood concentration also increased very slowly compared to oral administration. It decreases, showing that the blood concentration is relatively long-lasting.

<Psoriasis Inhibition Animal Experiment After Intradermal Administration of Dissolving CsA Microneedle>

Using imiquimod (Imiquimod; Aldara cream containing 5% IMQ (iNOVA Pharmaceuticals Pty Ltd.) Aldara Cream) to treat psoriatic disease Mice (BALB/c, male 10-12 weeks old) through cyclosporine A microneedle As a result, the effect of preventing and treating psoriasis that minimizes side effects was confirmed (J Immunol. 2009, 182(9):5836-45, PLOS One. 2015,10(9):e0137890).

The preventive effect administration method is as follows.

1) Epilation of the back of a mouse

2) One microneedle was administered to the center of the epilated back plate (5 minutes by hand, 35 minutes by Tegaderm, 40 minutes in total)

3) Apply 62.5mg of Aldara Cream (5% IMQ) after administration

4) Wrapped with Tegaderm and placed one mouse per cage

5) Re-apply IMQ every 3 days (repeat twice)

6) Histopathoscopic examination of skin sampling and H&E staining after death

The therapeutic effect administration method is as follows.

1) mouse back hair removal

2) Aldara Cream (5% IMQ) 62.5mg applied

3) Wrapped with Tegaderm and placed one mouse per cage

4) Re-apply IMQ every 3 days

5) After re-applying 2 additional times (total of 3 applications), a microneedle is administered to the center of the epilated back (5 minutes by hand, 35 minutes by Tegaderm, 40 minutes in total)

6) After administration, reapply 62.5mg of Aldara Cream (5% IMQ), wrap it with Tegaderm, and place it in the cage

7) Histopathoscopic examination of skin sampling and H&E staining after death

3 is an image showing a skin sampling method and a ratio of tissues used in fabrication of a tissue slide.

The skin sampling method and the ratio of the tissue used in the production of the tissue slide were performed as shown in FIG. 3.

Histological analysis was carried out as follows.

1) Biopsy of the skin at the site where psoriasis was induced and the skin at the site where the microneedle was administered at random, 10 pieces each

2) After H&E staining (hematoxylin and eosin staining), tissue microscopic examination

3) TOMORO Scope Eye 3.6?? Epidermal thickness measuring using software

4) Identification of statistical significance (Origin Pro 8 software analysis)

Staining histopathoscopic results were confirmed as follows.

1) Intradermal Administration of Dissolving CsA Microneedle to Prevent Psoriasis (x40)

FIG. 4 is an image showing the results of staining histopathology of the psoriasis preventing effect according to Example 1. FIG.

Table 2 is a table showing the results of epidermal thickness measuring of the psoriasis preventing effect, and FIG. 5 is a graph showing the results of epidermal thickness measuring of the psoriasis preventing effect according to Example 1.

[Table 2]

Referring to Tables 2, 4, and 5, it can be seen that the epidermal layer of the tissue at the site of psoriasis and the tissue at the site of administration of the needle is thicker than that of the tissue at the normal site (138 μm ±10.7 and 51.5 μm ±6.17, respectively vs. 21.24μm ±0.72; both P<0.001).

In addition, in the case of tissues administered with a cyclosporine A microneedle at the same time when IMQ was induced, it was confirmed that the thickness of the epidermal layer decreased significantly compared to the surrounding non-administered portion (138 μm ±10.7 vs. 51.5 μm ±6.17; P<0.001 ) To confirm the psoriasis prevention effect.

2) Effect of Intradermal Administration of Dissolving Cyclosporine A Microneedle on Psoriasis Treatment (x40)

6 is an image showing the results of staining histopathology of the psoriasis treatment effect according to Example 1. FIG.

Table 3 is a table showing the results of epidermal thickness measuring of the psoriasis treatment effect according to Example 1, and FIG. 7 shows the results of epidermal thickness measuring of the psoriasis treatment effect according to Example 1. It is a graph.

[Table 3]

Referring to Table 3, FIGS. 6 and 7, it was confirmed that the epidermal layer of the tissue at the site of psoriasis-induced and the dissolution cyclosporine A microneedle was thickened compared to the epidermal layer of the tissue at the normal site (92.94 μm ±3.18 and 53.9 μm) ±3.60, respectively vs. 21.2μm ±0.69; both P<0.001), so that psoriasis was well induced, and in the case of tissues administered with MN after psoriasis induction, it was confirmed that the thickness reduction decreased to a significant level compared to the epidermal layer of the surrounding area without administration. (92.94μm ±3.18 vs. 53.9μm ±3.60; P<0.001) confirmed that the psoriasis treatment effect.

8 is a graph showing a comparison of epidermal thickness measuring results of the psoriasis preventing effect and the psoriasis treatment effect according to Example 1. FIG.

Referring to FIG. 8, on average, it can be seen that the level of inhibitory effect on psoriasis induced by MN and the level of treatment effect were similar, and the effect was significant. In addition, it can be seen that there are differences in tissues and individuals in the induction of psoriasis.

Example 2: Cyclosporine A Medicine and Fabrication of coated microneedles containing cyclosporine A containing biocompatible materials and additives

Table 4 is a table showing the shape of the microneedle according to Example 2.

[Table 4]

Microneedles according to Example 2 used Examples 1 and 2.

In order to compare Examples 1 and 2 of the microneedle, a solvent (50% Ethanol aqueous solution), a polymer (Hydroxypropyl cellulose, HPC), and a dye (trypan blue) were used to coat and dry, followed by optical microscopy and scanning electrons. Microscopic photographs were compared, and the ratio of microneedles inserted by insertion into pig skin was compared.

The coating solution was prepared by completely dissolving 150 mg of HPC and 5 mg of trypan blue in 1 mL of 50% ethanol aqueous solution using a sonicator, vortexor, and homogenizer. .

The coating solution was repeatedly coated three times on a microneedle array disc using a device, and dried at room temperature in a desiccator for 24 hours.

FIG. 9A is an optical microscope image showing a coating layer coated once on the microneedle surface of Example 1, and FIG. 9B is an optical microscope image showing a coating layer coated once on the microneedle surface of Example 2. 9C is an optical microscope photograph showing a coating layer coated twice on the surface of the microneedle of Example 1, and FIG. 9D is an optical microscope photograph showing a coating layer coated twice on the surface of the microneedle of Example 2. 9E is an optical microscope photograph showing a coating layer coated three times on the surface of the microneedle of Example 1, and FIG. 9F is an optical microscope showing a coating layer coated three times on the surface of the microneedle of Example 2. It shows a picture.

9A to 9F, the sharpness of the state after coating the microneedle of Example 2 3 times is the sharpness of the state after coating the microneedle of Example 2 3 times. It can be seen that it is better.

10A is a scanning electron microscope photograph showing a coating layer coated once on the microneedle surface of Example 1, and FIG. 10B is a scanning electron microscope photograph showing a coating layer coated once on the microneedle surface of Example 2. 10C is a scanning electron microscope photograph showing a coating layer coated twice on the microneedle surface of Example 1, and FIG. 10D is a scanning electron microscope photograph showing a coating layer coated twice on the microneedle surface of Example 2 An electron microscope photograph is shown, and FIG. 10E is a scanning electron microscope photograph showing a coating layer coated three times on the microneedle surface of Example 1, and FIG. 10F is a coating layer coated three times on the microneedle surface of Example 2. It shows a scanning electron microscope picture showing.

Referring to FIGS. 10A to 10F, the sharpness of the state after coating the microneedle three times in Example 2 is the sharpness of the state after coating the microneedle three times in Example 2 ( sharpness).

Table 5 is a table comparing the height of the microneedle according to the number of coatings.

[Table 5]

Referring to Table 5, after coating, it can be seen that the heights of the microneedles of Examples 1 and 2 are substantially similar.

Table 6 is a table comparing the amount of trypan blue of microneedles according to the number of coatings.

[Table 6]

Referring to Table 6, after coating, the amount of trypan blue after coating the microneedle of Example 1 twice is similar to the amount of trypan blue after coating the microneedle of Example 2 three times. Can be seen.

FIG. 11A is an image showing the insertion ratio of the microneedles of Example 1 coated twice on pig skin, and FIG. 11B is the insertion ratio of the microneedles of Example 2 coated twice on pig skin Is an image showing, and FIG. 11C is an image showing the insertion ratio of the microneedle of Example 1 coated three times on pig skin, and FIG. 11D is the microneedle of Example 2 coated three times on pig skin. This is an image showing the insertion ratio.

Table 7 is a table showing the results of the microneedle insertion ratio of Examples 1 and 2 according to the number of coatings.

[Table 7]

Referring to FIGS. 11A to 11D and Table 7, the insertion ratio of the microneedles of Example 1 coated three times is about 62%, and the insertion ratio of the microneedles of Example 2 coated three times (insertion ratio) Is about 77%, and it can be seen that the insertion ratio of the microneedle in Example 2 is about 15% higher.

12 is a schematic diagram showing equipment for coating a microneedle.

Referring to FIG. 12, a circular microneedle array disk is prepared and a viscous composition is prepared. In addition, after the viscous composition is placed flat on a support (reserver, depth 600 µm), the microneedle array is uniformly pressed against the support so that the viscous composition is applied to the microneedle. After coating, dry at room temperature for 20 minutes, coat again, and repeat a total of 3 times. Finally, after coating 3 times, put in a desiccator and dry at room temperature for 24 hours.

Example 3: Cyclosporine A Chemical solution (HPC general formulation) and Fabrication of coated microneedles containing cyclosporine A containing biocompatible materials and additives

CsA 30 mg, hydroxypropyl cellulose (Hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich) 150 mg is completely dissolved in 1-propanol (1-propanol anhydrous, Sigma-aldrich) 1 mL. The prepared microneedle array disk is mounted on a coating equipment and coated with a pre-made viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 13a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug solution (HPC general formulation), 13b is an optical microscope measurement of a microneedle coated twice with a cyclosporine A drug solution (HPC general formulation) It is an image showing the result, and 13c is an image showing the measurement result of an optical microscope of a microneedle coated three times with a cyclosporine A chemical solution (HPC general formulation).

13A to 13C, it can be seen that the coating layer is well coated on the microneedle.

Example 4: Cyclosporine A Chemical solution (SEDDS A formulation) and Of the present invention comprising biocompatible materials and additives In the examples Coating containing cyclosporine A according to Micro needle Evaluation of suppression of psoriasis after preparation and intradermal administration

Corn oil-mono-di-triglycerides (Maisin CCⓡ, Gattefosse) 318 mg, Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenatedcastor oil (Kolliphor® RH40, BASF) 383.7 mg, Propylene (propylene glycol, Junsei) 94.7 mg, ethanol ( Ethanol) (Ethanol HPLC grade, Honeywell) 94.7 mg and DL-α-tocopherol 1 mg (DL-α-tocopherol, Daejung) were mixed, CSA 100 mg was mixed, and sonication was performed for 30 minutes to make SEDD A formulation.

Dissolve 92 mg of the SEDDS A formulation containing cyclosporine A in 1 mL of 1-propanol, and dissolve 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich. Then, the prepared microneedle array disk is mounted on a coating equipment, and a viscous composition of the SEDDS A formulation containing cyclosporine A is put in a carrier, dried at room temperature for 20 minutes, and coated again for a total of 3 times. Finally, after coating three times, drying in a desiccator at room temperature for 24 hours to obtain a coated microneedle manufactured by SEDDS A formulation containing cyclosporine A.

14 is an image showing the optical microscopic measurement results of a microneedle coated with a cyclosporine A chemical solution (SEDDS A formulation) three times.

14, the height of the coating according to Example 4 is 462.17 ± 8.10 ㎛.

[Psoriasis Inhibitory Effect after Intradermal Administration of SEDDS A Formulation Coated Microneedle]

15 is an image showing a visual observation result according to Example 4.

Referring to FIG. 15, as a result of skin observation, the psoriasis-causing site exhibited redness, which is a characteristic of psoriasis, compared to normal skin, and psoriasis was well induced. It can be seen that it is effective in preventing and treating psoriasis as it can be judged with the naked eye, such as suppression of flushing at the site of SEDDS MN administration.

1) Effect of preventing psoriasis after intradermal administration of SEDDS A agent coated microneedle (MN) (x40)

FIG. 16 is an image showing the results of H&E staining histopathology of the dryness prevention effect according to Example 4, and FIG. 17 is an epidermal thickness measuring result of the psoriasis prevention effect according to Example 4. It is a graph shown.

16 and 17, it was confirmed that the epidermal layer of the tissue at the site of psoriasis induction and the tissue at the site of administration of Formulation 2 MN was thicker than that of the tissue at the normal site (98.9μm ±5.7 and 38.5μm ±3.2, respectively vs. Psoriasis was successfully induced by 21.3μm ±0.6; both P<0.001).

In the case of tissues administered with SEDDS A drug MN at the time of IMQ induction, it was confirmed that the decrease in epidermal thickness decreased to a significant level compared to the surrounding area (98.9μm ±5.7 vs. 38.5μm ±3.2; P<0.001, an average of about 60um in thickness reduction. ), it was found that there is a psoriasis prevention effect.

2) Effect of treatment of psoriasis after intradermal administration of SEDDS A drug-coated microneedle (MN) (x40)

FIG. 18 is an image showing the results of H&E staining histopathological speculum of the psoriasis treatment effect according to Example 4, and FIG. 19A is an epidermal thickness measuring result of the psoriasis treatment effect according to Example 4. 19B is a graph showing the comparison of epidermal thickness measuring results of the psoriasis preventing effect and the psoriasis treatment effect according to Example 4. FIG.

18 to 19B, in the case of tissues administered with SEDDS A agent-coated MN after psoriasis induction, it was confirmed that the decrease in epidermal layer thickness was significantly reduced compared to the surrounding non-administered portion (91.5 μm ± 2.2 vs. 69.5 μm ± 2.4). ; P<0.001) to prove the treatment effect.

In addition, in the case of SEDDS A-coated MN, on average, when MN was administered simultaneously with IMQ psoriasis induction, the effect of reducing the epidermal layer was greater than the effect of MN administration after psoriasis induction (38.5μm ±3.2 vs. 69.5μm ±2.4). It can be seen that it represents.

Example 5: Cyclosporine A Medicinal solution ( SEDDS A formulation + Sodium starch glycolate ), and biocompatible materials and additives

92 mg of the SEDDS A formulation of Example 4 was dissolved in 1 mL of 1-propanol (1-propanol anhydrous, Sigma-aldrich), and 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich) was dissolved. Sodium starch glycolate (Explotab, JRS) 20 mg is evenly dispersed in the prepared solution.

Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 20a is an image showing the optical microscope measurement results of a microneedle coated three times with cyclosporine A drug (SEDDS A formulation + Sodium starch glycolate), 20b is cyclosporine A drug (SEDDS A formulation + Sodium starch glycolate) three times This is an image showing the measurement results of the coated microneedle under a scanning electron microscope.

Referring to FIGS. 20A and 20B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (SEDDS A formulation + Sodium starch glycolate) 3 times has a coating height of 463.80 ± 10.84 μm.

Example 6: Cyclosporine A Medicinal solution ( SEDDS A formulation + Croscarmellose sodum ), and biocompatible materials and additives

92 mg of the SEDDS A formulation of Example 4 was dissolved in 1 mL of 1-propanol, and 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich was dissolved. 20 mg of Croscarmellose sodium (Solutab EDP, Blanver) is evenly dispersed in the solution. Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 21a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SEDDS A formulation + Croscarmellose sodum), 21b is a cyclosporine A drug (SEDDS A formulation + Croscarmellose sodum) is coated three times This is an image showing the measurement results of the microneedle under a scanning electron microscope.

Referring to FIGS. 21A and 21B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (SEDDS A formulation + Croscarmellose sodum) three times has a coating height of 434.36 ± 11.73 μm.

Example 7: Cyclosporine A Medicinal solution ( SEDDS A formulation + Crospovidone ), and biocompatible materials and additives

92 mg of the SEDDS A formulation of Example 4 was dissolved in 1 mL of 1-propanol, and 150 mg of hydroxypropyl cellulose (Hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich) was dissolved, and crospovidone (polyplasdone® XL-10, Ashland ) 20 mg is evenly dispersed in the solution. Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 22a is an image showing the optical microscope measurement results of a microneedle coated three times with a coating layer (SEDDS A formulation + Crospovidone), 22b is a scanning electron microscope measurement of a microneedle coated with a coating layer (SEDDS A formulation + Crospovidone 3 times) This is an image showing the result.

Referring to FIGS. 22A and 22B, it can be seen that the coating height of the microneedle coated with the coating layer (SEDDS A formulation + Crospovidone) 3 times has a coating height of 429.32 ± 6.08 μm.

Example 8: cyclosporine A Chemical solution (SEDDS B formulation) and Containing cyclosporin A containing biocompatible substances and additives Micro needle Production and Intradermally Inhibitory effect of psoriasis after (intradermal) administration

Mono-di-glycerides (Labrafil M 1944 CS, Gattefosse) 300 mg, Macrogolglycerol hydroxystearate/Polyoxyl 35 hydrogenatedcastor oil (Kolliphor® EL, BASF) 466.7 mg, Diethylene glycol monoethyl ether (Transcutol P, Gattefosse) 233.3 mg after mixing CsA 160 mg And made by sonication for 30 minutes. Dissolve 116 mg of the formulation in 1 mL of 1-propanol, and dissolve 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich.

Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 23a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation), and Figure 23b is an optical microscope of a microneedle coated twice with a cyclosporine A drug (SEDDS B formulation) It is an image showing the measurement result, Figure 23c is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SEDDS B formulation), Figure 23d is a cyclosporine A drug (SEDDS B formulation) is 3 This is an image showing the scanning electron microscope measurement results of the microneedle coated once.

23A to 23D, the coating height of the microneedle coated once with the cyclosporine A chemical solution (SEDDS B preparation) is 445.80 ± 18.59 μm, and the microneedle coated with the cyclosporine A chemical solution (SEDDS B preparation) twice. The coating height of is 461.64 ± 10.64 μm, and it can be seen that the coating height of the microneedles coated three times with cyclosporine A chemical solution (SEDDS B formulation) is 479.37 ± 9.69 μm.

[Inhibitory Effect of SEDDS B Drug Coated MN on Psoriasis After Intradermal Administration]

24 is an image showing a visual observation result according to Example 8.

Referring to FIG. 24, as a result of skin condition confirmation and skin observation, it can be seen that psoriasis was well induced and the preventive and therapeutic effects of the MN administration site appeared with the naked eye.

1) Effect of preventing psoriasis after intradermal administration of SEDDS B formulation coated microneedle (MN) (x40)

FIG. 25 is an image showing the results of H&E staining histopathology of the dryness prevention effect according to Example 8, and FIG. 26 is an epidermal thickness measuring result of the psoriasis prevention effect according to Example 8. It is a graph shown.

Table 8 is a table showing the results of measuring epidermal thickness of the dryness preventing effect according to Example 8.

[Table 8]

Referring to FIGS. 25, 26, and 8, it was confirmed that the reduction in epidermal layer thickness decreased to a significant level in the case of tissues to which the SEDDS B formulation-coated MN was simultaneously administered at the time of IMQ induction compared to the surrounding non-administered portion (90.4 μm ±3.4 vs. 33.0μm ±1.2; P<0.001).

In addition, it can be seen that the psoriasis-preventing effect of the SEDDS B formulation coated MN, which showed an average thickness reduction of about 60 μm, was evident at the level of the epidermal layer of normal tissue.

2) Effect of treatment of psoriasis after intradermal administration of SEDDS B formulation coated microneedle (MN) (x40)

FIG. 27 is an image showing the results of H&E staining histopathology of the dry treatment effect according to Example 8, and FIG. 28 is an image showing the results of epidermal thickness measuring of the psoriasis treatment effect according to Example 8. FIG. 29 is a graph showing the comparison of epidermal thickness measuring results of the dryness preventing effect and the psoriasis treatment effect according to Example 8. FIG.

Table 9 is a table showing the results of measuring epidermal thickness of the dry treatment effect according to Example 8.

[Table 9]

Referring to Figures 27 to 29, in the case of SEDDS B formulation coated MN, on average, it can be seen that MN is administered at the same time as IMQ psoriasis induction and when MN is administered after psoriasis induction shows a similar reduction (about 50-60um). I can. In addition, it can be seen that there is a difference in the degree of induction of psoriasis caused by tissue and individual differences.

Example 9: Cyclosporine A Chemical solution (SEDDS B formulation + Gelatin) and Fabrication of coated microneedles containing biocompatible materials and additives

After mixing 1000 mg of agent B of Example 5, 2000 mg of Gelatin (Gelatin-G, Geltech), and 50 mL of D.W, spray-dried using a mini spray dryer (B-290, Buchi). Disperse 217.55 mg of the SEDDS B-Gelatin formulation in 1 mL of 1-propanol and dissolve 100 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich.

Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 30a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Gelatin), and Figure 30b is a microneedle coated with a cyclosporine A drug (SEDDS B formulation + Gelatin) twice. An image showing the measurement result of the needle under an optical microscope, FIG. 30C is an image showing the measurement result of a microneedle coated three times with a cyclosporine A chemical solution (SEDDS B agent + Gelatin), and FIG. 30D is an image showing the measurement result of a cyclosporine A chemical solution ( SEDDS B formulation + Gelatin) is an image showing the scanning electron microscope measurement results of the microneedle coated three times.

Referring to Figures 30a to 30d, the coating height of the microneedles coated once with cyclosporine A chemical solution (SEDDS B agent + Gelatin) is 441.03 ± 21.90 μm, and cyclosporine A chemical solution (SEDDS B agent + Gelatin) is coated twice It can be seen that the coating height of the microneedles is 444.42 ± 14.98 μm, and the coating height of the microneedles coated with cyclosporine A chemical solution (SEDDS B agent + Gelatin) three times is 466.55 ± 16.01 μm.

Example 10: cyclosporine A Medicinal solution ( SEDDS Agent B + Gelatin+ gelucire ), and biocompatible materials and additives

After mixing 1000 mg of agent B of Example 5, 2000 mg of Gelatin (Gelatin-G, Geltech), 70.9 mg of Lauroyl polyoxyl-32 glycerides (gelucire 44/14, Gattefosse) and 50 mL of DW, a spray dryer B (Mini spray dryer B -290, Buchi). Disperse 217.55 mg of SEDDS B-Gelatin-Gelucire formulation in 1 mL of 1-propanol, dissolve 100 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich, and mount the prepared microneedle array disk on the coating equipment. The carrier is coated with a viscous composition. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 31a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Gelatin + gelucire), Figure 31b is a cyclosporine A drug (SEDDS B formulation + Gelatin + gelucire) is 2 It is an image showing the optical microscope measurement result of the microneedle coated twice, and FIG. 31C is an image showing the measurement result of the microneedle coated three times with cyclosporine A chemical solution (SEDDS B formulation + Gelatin+gelucire), FIG. 31d is an image showing the measurement results of a microneedle coated with a cyclosporine A chemical solution (SEDDS B formulation + Gelatin + gelucire) three times with a scanning electron microscope.

31A to 31D, the coating height of the microneedle coated once with the cyclosporine A drug (SEDDS B formulation + Gelatin+gelucire) is 409.79 ± 17.86 μm, and the cyclosporine A drug (SEDDS B formulation + Gelatin+gelucire) is coated once. The coating height of the microneedles coated twice is 424.37 ± 24.84 μm, and the coating height of the microneedles coated three times with cyclosporine A chemical solution (SEDDS B formulation + Gelatin + gelucire) is 442.19 ± 36.00 μm. .

Example 11: Cyclosporine A Chemical solution (SEDDS B formulation + Aerosil) and Fabrication of coated microneedles containing biocompatible materials and additives

Mixing 1000 mg of agent B of Example 5, 1250 mg of fumed silica (Aerosil® 200 pharma), 100 mL of 20% ethanol (Etanol HPLC grade, Honeywell), and using a spray dryer (Mini spray dryer B-290, Buchi) Spray drying. Disperse 163.13 mg of SEDDS B-Aerosil formulation in 1 mL of 1-propanol and dissolve 100 mg of hydroxypropyl cellulose. The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 32a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (SEDDS B formulation + Aerosil), and Figure 32b is a microneedle coated with a cyclosporine A drug (SEDDS B formulation + Aerosil) twice. An image showing the measurement result of the needle under an optical microscope, FIG. 32C is an image showing the measurement result of a microneedle coated three times with cyclosporine A chemical solution (SEDDS B agent + Aerosil), and FIG. 32D is an image showing the measurement result of cyclosporine A chemical solution ( SEDDS B formulation + Aerosil) is an image showing the scanning electron microscope measurement results of the microneedle coated three times.

Referring to Figures 32a to 32d, the coating height of the microneedle coated once with cyclosporine A chemical solution (SEDDS B agent + Aerosil) is 360.18 ± 26.12 μm, and cyclosporine A chemical solution (SEDDS B agent + Aerosil) is coated twice It can be seen that the coating height of the microneedles is 385.93 ± 37.56 μm, and the coating height of the microneedles coated with cyclosporine A chemical solution (SEDDS B formulation + Aerosil) three times is 485.68 ± 64.22 μm.

Example 12: cyclosporine A Chemical solution (SEDDS C formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

Propylene carbonate (Propylene carbonate 99.5%, SAMCHUN) 150 mg, poloxamer 124 (Kollisolvⓡ P124, BASF) 70 mg, Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenatedcastor oil (Kolliphor® RH40, BASF) 370 mg, Carprylic/capric glycerides (Labac lipophile WL 1349, Gattefosse) 200 mg, mono-di-glyceride (Labarfil M 1944 CS, Gattefosse) 120 mg, DL-α-tocopherol 1 mg (DL-α-tocopherol, Daejung) 3 mg, then CsA 100 mg and sonication 30 minutes I made it.

Dissolve 101 mg of SEDDS C formulation in 1 mL of 1-propanol and 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich. Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Example 13: Cyclosporine A Chemical solution (SEDDS D formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

Corn oil-mono-di-triglycerides (Maisin CCⓡ, Gattefosse) 160 ul, Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenatedcastor oil (Kolliphor® RH40, BASF) 190 ul, Propylene (propylene glycol, Junsei) 50 ul, Ethanol (Ethanol HPLC grade) , Honeywell) 50 ul was mixed, CSA 100mg was mixed, and sonication was performed for 30 minutes. Dissolve 100 ul of this formulation in 1 mL of 1-propanol and dissolve 150 mg of hydroxypropyl cellulose avg. Mw. ~80,000, Aldrich.

Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Example 14: cyclosporine A Chemical liquid (PLGA) and Fabrication of coated microneedles containing biocompatible materials and additives

Dissolve 50mg of PLGA and 10mg of CSA in 3mL of Methylene chloride (Methylene chloride, Fisher). Dissolve 100mg Polyvinyl alcohol (PVA, Polyvinyl alcohol MW. 85,000~12,4000, sigma) in D.W to prepare 10mL PVA aqueous solution (1% w/v). Mix the two solutions and tip sonication for 1 minute. During sonication, put a beaker containing the solution in an ice bath and proceed at 40% amplitude under sonication (Vibra cell 505, Sonics) conditions.

The sonicated formulation solution is homogenized in a high-pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics) at 500 bar 10 cycles, and then diluted with 40 mL of PVA aqueous solution (0.36% w/v) to stabilize the formulation solution. Stir at room temperature at 700 rpm for 4 hours to evaporate dichloromethane, and then make a formulation solution with mannitol (Pearlitol 25 C, Roquette) 5 times the amount of CsA added. Freeze-drying at -20˚C to obtain nanoparticles.

Add 110 mg of PLGA particle formulation to 1 mL of purified water, and disperse evenly, and then completely dissolve 100 mg of carboxymethyl cellulose sodium salt (carboxymethyl cellulose sodium salt, Sigma) and 10 mg of tween 80. Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 33a is an image showing the optical microscope measurement results of the microneedle coated once with cyclosporine A chemical solution (PLGA), and Figure 33b shows the optical microscope measurement results of the microneedle coated twice with cyclosporine A chemical solution (PLGA) Figure 33c is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (PLGA), and Figure 33d is a scanning electron of a microneedle coated three times with a cyclosporine A chemical solution (PLGA) It is an image showing the microscopic measurement result.

33A to 33D, the coating height of the microneedles coated with the cyclosporine A chemical solution (PLGA) once is 495.54 ± 39.91 μm, and the coating height of the microneedles coated with the cyclosporine A chemical solution (PLGA) twice is 497.58. ± 34.37 μm, and it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (PLGA) three times is 512.44 ± 33.24 μm.

Example 15: cyclosporine A Chemical solution (PLGA+eudragit formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

PLGA+eudragit formulation PLGA 37.5mg, Ammonio methacrylate (Eudragit® RS 100) 12.5 mg, CSA (10mg) is dissolved in Methylene chloride (Methylene chloride, Fisher) 3mL. Dissolve 100mg Polyvinyl alcohol (PVA, Polyvinyl alcohol MW. 85,000~12,4000, sigma) in D.W to prepare 10mL PVA aqueous solution (1% w/v). Mix the two solutions and tip sonication for 1 minute. During sonication, put a beaker containing the solution in an ice bath and proceed at 40% amplitude under sonication (Vibra cell 505, Sonics) conditions.

The sonicated formulation solution is homogenized in a high pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics) at 500 bar 10 cycles, and then diluted with 40 mL of PVA aqueous solution (0.36% w/v) to stabilize the formulation solution. Dichloromethane is evaporated by stirring at 700 rpm for 4 hours at room temperature. Then, make a formulation solution with mannitol (Pearlitol 25 C, Roquette) 5 times the amount of CSA added. Freeze-drying at -20˚C to obtain nanoparticles.

Add 110 mg of PLGA-Eudragit particle formulation to 1 mL of purified water, and disperse evenly, then completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich). The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Figure 34a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporin A drug (PLGA + eudragit formulation), and Figure 34b is a microneedle coated with a cyclosporine A drug (PLGA + eudragit formulation) twice An image showing the measurement result under an optical microscope, FIG. 34C is an image showing the optical microscope measurement result of a microneedle coated three times with a cyclosporine A chemical solution (PLGA+eudragit formulation), and FIG. Formulation) is an image showing the measurement results of a microneedle coated three times with a scanning electron microscope.

34A to 34D, the coating height of the microneedle coated once with the cyclosporine A chemical solution (PLGA + eudragit formulation) is 522.23 ± 4.46 μm, and the microneedle coated with the cyclosporine A drug solution (PLGA + eudragit formulation) twice It can be seen that the coating height of the needle is 521.96 ± 4.09 μm, and the coating height of the microneedle coated with the cyclosporine A chemical solution (PLGA + eudragit formulation) three times is 514.57 ± 4.82 μm.

Example 16: cyclosporine A Chemical solution (PLGA+ Carbopomer formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

Dissolve PLGA (50mg) and CSA (10mg) in 3mL of Methylene chloride (Methylene chloride, Fisher). Dissolve 100mg Polyvinyl alcohol (PVA, Polyvinyl alcohol MW. 85,000~12,4000, sigma) in DW to make 10mL PVA aqueous solution (1% w/v), and then add 20mg of Carbomer (Sunpol 940, Sunfine Gloal) and dissolve it. Prepare the solution. Mix the two solutions and tip sonication for 1 minute. During sonication, put a beaker containing the solution in an ice bath and proceed at 40% amplitude under sonication (Vibra cell 505, Sonics) conditions.

After homogenizing the sonicated formulation solution in a high pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics) at 500 bar 10 cycles, 5 mg of carbopol was added to 40 mL of PVA aqueous solution (0.36% w/v) to stabilize the formulation solution. Dilute by adding the solution. Dichloromethane is evaporated by stirring at 700 rpm for 4 hours at room temperature. After that, make a formulation solution with mannitol (Pearlitol 25C, Roquette) 5 times the amount of CSA added.

Freeze-drying at -20˚C to obtain nanoparticles. Add 125 mg of PLGA-Cabomer particle formulation to 1 mL of purified water, and disperse evenly, then completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich). Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 35a is an image showing the optical microscope measurement results of a microneedle coated once with a cyclosporine A drug (PLGA+ Carbopomer formulation), and Figure 35b is an optical microscope of a microneedle coated twice with a cyclosporine A drug (PLGA+ Carbopomer formulation) It is an image showing the measurement result, Figure 35c is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (PLGA + Carbopomer formulation), Figure 35D is a cyclosporine A drug (PLGA + Carbopomer formulation) is 3 This is an image showing the scanning electron microscope measurement results of the microneedle coated once.

35A to 35D, the height of the coating of the microneedle coated once with the cyclosporine A chemical solution (PLGA+ Carbopomer formulation) cannot be checked, and the height of the microneedle coated with the cyclosporine A chemical solution (PLGA+ Carbopomer formulation) twice. It can be seen that the coating height is 507.28 ± 3.59 μm, and the coating height of the microneedle coated with the cyclosporine A chemical solution (PLGA+ Carbopomer formulation) three times is 518.62 ± 4.92 μm.

Example 17: cyclosporine A Chemical solution (NLC C) and Fabrication of coated microneedles containing biocompatible materials and additives

Dissolve 200mg Glycerol distearate (Precirol ATO 5, Gattefosse), 400mg propylene glycol monocaprylate (Capryol 90, Gattefosse), and 18mg CSA in a water bath. Add 10 mL of preheated 2% Polysorbate 80 (tween® 80, sigma-aldrich) aqueous solution to the lipid layer by boiling water with the lipid layer, and tip sonication (Vibra cell 505, Sonics) under the condition of 40% amplitude and 4 minutes. The sonicated formulation solution is homogenized for 10 cycles at 500bar using a high pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics).

Cool down in an ice bath for 5 minutes and give enough time to form particles. After that, make a formulation solution with mannitol (Pearlitol 25C, Roquette) 5 times the amount of CsA added. Freeze-dried to obtain a powdered formulation.

Add 192.3 mg of the NLC-C particle formulation to 1 mL of purified water, and disperse evenly, and then completely dissolve 100 mg of Carboxymethyl cellulose sodium salt (Sigma). Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 36a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (NLC C), and Figure 36b is a scanning electron microscope measurement of a microneedle coated three times with a cyclosporine A chemical solution (NLC C) This is an image showing the result.

36A and 36B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (NLC C) three times is 513.58 ± 4.13 μm.

Example 18: cyclosporine A Chemical solution (NLC L) and Fabrication of coated microneedles containing biocompatible materials and additives

NLC-L. 200mg Glycerol distearate (Precirol ATO 5, Gattefosse), 400mg Carprylic/capric glycerides (Labrafac lipohphile WL 1349, Gattefosse), 18mg CsA are dissolved in a water bath. Add 10 mL of a 2% polysorbate 80 (tween® 80, Sigma-aldrich) aqueous solution preheated by boiling water along with the lipid layer to the lipid layer. Tip sonication (Vibra cell 505, Sonics) under the condition of 40% amplitude and 4 minutes.

The sonicated formulation solution is homogenized for 10 cycles at 500bar using a high pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics). Cool down in an ice bath for 5 minutes and give enough time to form particles. After that, a formulation solution containing mannitol (Pearlitol 25C, Roquette) 5 times the amount of CsA added is prepared and lyophilized to obtain a powdered formulation.

Add 108.7 mg of NLC-L particle formulation to 1 mL of purified water, and disperse evenly, and then completely dissolve 100 mg of Carboxymethyl cellulose sodium salt (Sigma). Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 37a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A chemical solution (NLC L), and Figure 37b is a scanning electron microscope measurement of a microneedle coated three times with a cyclosporine A chemical solution (NLC L) This is an image showing the result.

Referring to FIGS. 37A and 37B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (NLC L) three times is 523.85 ± 9.65 μm.

Example 19: cyclosporine A Chemical solution (SLN I formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

200mg Glycerol monostearate (Kolliwax GMS II, BASF) and 18mg CSA are dissolved in a water bath. Add 10 mL of preheated 2% polysorbate 80 (tween® 80) aqueous solution by boiling water along with the lipid layer to the lipid layer. Tip sonication (Vibra cell 505, Sonics) under the condition of 40% amplitude and 4 minutes. The sonicated formulation solution is homogenized for 10 cycles at 500 bar using a high pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics).

Cool down in an ice bath for 5 minutes and give enough time to form particles. After that, a formulation solution containing mannitol (Pearlitol 25 C, Roquette) 5 times the amount of CsA added is prepared and lyophilized to obtain a powder form formulation. Add 167 mg of SLN-I particle formulation to 1 mL of purified water, and disperse evenly, and completely dissolve 100 mg of Carboxymethyl cellulose sodium salt (Sigma).

Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 38a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SLN I formulation), and Figure 38b is a scanning electron of a microneedle coated three times with a cyclosporine A drug (SLN I formulation) It is an image showing the microscopic measurement result.

38A and 38B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (SLN I formulation) three times is 511.96 ± 9.09 μm.

Example 20: cyclosporine A Chemical solution (SLN P formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

200mg Glycerol distearate (Precirol ATO 5, Gattefosse) and 18mg CSA are dissolved in a water bath. Add 10 mL of a 2% polysorbate 80 (tween® 80, sigma-aldrich) aqueous solution preheated by boiling water along with the lipid layer to the lipid layer. Tip sonication (Vibra cell 505, Sonics) under the condition of 40% amplitude and 4 minutes. The sonication-completed formulation solution is homogenized for 10 cycles at 500bar using a high-pressure emulsifier (M-110P Microfludizer high sheer processor, Microfludics).

Cool down in an ice bath for 5 minutes and give enough time to form particles. After that, a formulation solution with mannitol (Pearlitol 25 C, Roquette) added 5 times the amount of CSA added is prepared and lyophilized to obtain a powder form formulation.

Add 176 mg of SLN-P particles to 1 mL of purified water, disperse evenly, and completely dissolve 100 mg of Carboxymethyl cellulose sodium salt (Sigma). Then, the prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. After the last 3 coatings, dry in a desiccator at room temperature for 24 hours.

Figure 39a is an image showing the optical microscope measurement results of a microneedle coated three times with a cyclosporine A drug (SLN P formulation), and Figure 39b is a scanning electron of a microneedle coated three times with a cyclosporine A drug (SLN P formulation) It is an image showing the microscopic measurement result.

Referring to FIGS. 39A and 39B, it can be seen that the coating height of the microneedle coated with the cyclosporine A chemical solution (SLN P formulation) three times is 513.40 ± 1.13 μm.

Example 21: cyclosporine A Chemical solution (Liposome preparation) and Fabrication of coated microneedles containing biocompatible materials and additives

Mix Methylene chloride (Methylene chloride, Fisher)/Methanol (Methanol HPLC grade, Honeywell) at 9:1 (v/v). 150mg Sodium deoxycholate (sodium deoxycholate, Sigma-aldrich), 600mg Soybean phosphatidylcholine (Lecitin from soybean, Santa cruz biotechnology), and 150mg CsA are mixed and dissolved in 16 mL of Methylene chloride/Methanol solvent. A thin film is obtained by drying under reduced pressure in an evaporator (Rotary evaporator N1000, Eyela). Heat to 50 °C and dissolve the film obtained above in 15 mL of D.W.

After that, 750mg of mannitol (Pearlitol 25 C, Roquette), which is 5 times the amount of CsA added, is added and freeze-dried at -20°C. In 1 mL of purified water, add Liposome preparation and disperse evenly, then completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich).

The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Example 22: cyclosporine A Chemical solution (Cyclodextrin formulation) and Fabrication of coated microneedles containing biocompatible materials and additives

6g α-cyclodextrin (α-Cyclodextrin, BTC Korea), 2g γ-cyclodextrin (γ-Cyclodextrin, BTC Korea), 40mg EDTA (EDTA, Sigma-aldrich), 168mg CSA 1.4% PVA (Polyvinyl alcohol MW. 85,000~12) ,4000, sigma) solution in 33.6mL. Tip sonication (Vibra cell 505, Sonics) at 40% amplitude for 2 minutes.

After that, freeze-dry at -20 °C. After adding the Cyclodextrin formulation to 1 mL of purified water and dispersing it evenly, completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich). The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Example 23: cyclosporine A Dry emulsion and Fabrication of coated microneedles containing biocompatible materials and additives

Dissolve 150mg Glycerol mono-oleates (Peceol, Gattefosse) and 150mg CSA in 45mL ethanol (EthanolHPLC grade, Honeywell). Add 7.5mg of Polyvinyl Pyrrolidone (Kollidon K-25, BASF) to the prepared solution. A thin film is obtained by drying under reduced pressure in an evaporator (Rotary evaporator N1000, Eyela). Heat to 50 °C and dissolve the film obtained above in 15 mL of D.W. After that, 750mg of mannitol (Pearlitol 25 C, Roquette), which is 5 times the amount of CsA added, is added and freeze-dried at -20°C. Add dry emulsion formulation to 1 mL of purified water and disperse evenly, then completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich). The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

Example 24: cyclosporine A Chemical solution (Polymeric Nanomicelle) and Fabrication of coated microneedles containing biocompatible materials and additives

Dissolve 4500mg Polyvinyl caprolactam-polyvinylacetate-polyoxyethylene graft copolymer (Soluplus, BASF) and 150mg CSA in 60mL ethanol. A thin film is obtained by drying under reduced pressure in an evaporator (Rotary evaporator N1000, Eyela). After heating to 50 °C, dissolve the film obtained above in 15 mL of D.W, add 750 mg of mannitol (Pearlitol 25 C, Roquette), which is 5 times the amount of CsA, and freeze-dry at -20 °C. After adding the polymeric nanoparticle formulation to 1 mL of purified water and dispersing it evenly, completely dissolve 70 mg of Carboxymethyl cellulose sodium salt (Carboxymethyl cellulose sodium salt, Sigma) and 10 mg of Polysorbate 80 (Tween® 80, Sigma-aldrich).

The prepared microneedle array disk is mounted on a coating equipment and coated with a viscous composition on a carrier. After coating, it is dried at room temperature for 20 minutes and then coated again to coat a total of 3 times. Finally, after coating 3 times, dry in a desiccator at room temperature for 24 hours.

As described above, although the present invention has been described by the limited embodiments and drawings, the present invention is not limited to the above embodiments, and various modifications and variations from these descriptions are those of ordinary skill in the field to which the present invention belongs. This is possible.

Therefore, the scope of the present invention is limited to the described embodiments and should not be defined, but should be defined by the claims to be described later as well as equivalents to the claims.

Claims (33)

Micro structure; And
Coating layer formed by coating a cyclosporine A chemical solution containing cyclosporine A on the surface of the microstructure
Including,
The coating layer further includes a biocompatible material and an additive,
The cyclosporine A drug solution treats or prevents at least one of autoimmune diseases, inflammatory diseases, and transplant rejection through transdermal or intradermal drug delivery,
The cyclosporine A chemical solution contains methanol, ethanol, or propanol as a solvent,
The biocompatible material includes hydroxypropyl cellulose (HPC),
The microstructure containing cyclosporine A, characterized in that the micro-needle.
The method of claim 1,
The microstructure containing cyclosporine A is a systemic autologous system characterized by a high bioavailability compared to oral administration through transdermal drug delivery to humans or animals, and minor side effects through continuous maintenance of drug concentration in blood without rapid increase or decrease in blood drug. Microstructure containing painless cyclosporine A used for the treatment and prevention of immune diseases, systemic inflammatory diseases, and transplant rejection diseases.
The method of claim 1,
The microstructures containing cyclosporin A are human and animal graft-versus-host disease, rheumatoid arthritis, psoriasis, and tendon through local intradermal drug delivery. Psoriatic arthritis, nail psoriasis, atopic dermatitis, alopecia areata, urticarial, dry eyes, Sjφgren's syndrome, nummular keratitis, adenovirus Adenoviral keratoconjunctivitis, systemic mastocytosis, Kimura disease, Pyoderma gangrenosum, Dyshidrotic eczema, Chronic urticarial, Behcet disease, Behcet disease Pityriasis rubra pilaris, Dermatomyositis, Pemphigus vulgaris, Epidermolysis bullosa acquisita, Lichen planus, Hydradenitis suppurativa, crystallization Seongyangjin (Prurigo nodularis) and scleroderma (Systemic sclerosis) is used for treatment or prevention of at least any one of the microstructure containing cyclosporine A.
delete delete The method of claim 1,
The additive comprises a surfactant,
The surfactants are polyoxyethylene glycolated natural oils, polyoxyethylene glycolated hydrogenated vegetable oils, reoxyethylene glycolated natural castor oil, reoxyethylene glycolated hydrogenated castor oil, Cremophor RH 40, Cremophor A reaction product of natural or hydrogenated vegetable oils including RH 60, Cremophor EL, Nikkol HCO-40, and Nikkol HCO-60 with ethylene glycol, mono-ra of polyoxyethylene sorbitan fatty acid Uryl, tri-lauryl, palmityl, stearyl, oleyl esters of polyoxyethylene sorbitan fatty acids, polyoxyethylene (20) sorbitan mono-urate (trade name Tween 20), polyoxyethylene (20) sorb Polyoxyethylene sorbitan fatty acid esters containing non-non-palmitate (trade name Tween 40) or reoxyethylene (20) sorbitan mono-oleate (trade name Tween 80), Cetiol HE, polyoxy Polyoxyethylene fatty acid esters including ethylene fatty acid esters, Myrj, Mirz 52 or polyoxyethylene stearic acid esters, polyoxyethylene including Pluronic or Emkalyx- Polyoxypropylene copolymers Polyoxyethylene-polyoxypropylene block copolymers including poloxamer, dioctyl succinate, dioctyl sodium sulfosuccinate, di-[2-ethylhexyl]-succinate, sodium Bile salts including lauryl sulfate, phospholipids, lecithin, soy lecithin, alkali metal salts or sodium taurochorate, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 Ester group transfer reaction product of natural vegetable oil triglyceride and polyalkylene polyol including BS or Labrasol, mono-glyceride, di-glyceride, mono/di-glyceride, caprylic acid, Caprylic/Capric acid mono-glycerides Caprylic/Capric acid di-glycerides, Imwitor or Imbitor 742 Esterification reaction product of capric acid and glycerol containing, sorbitan mono-laurate, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, sorbitan mono-oleate, sorbitan Non-non-tri-oleate, sorbitan fatty acid esters including span, pentaerythrit-dioleate, pentaerythrit-distearate, pentaerythrit-monolaurate, pentaerythrit-polyglycol ether Or pentaerythritol fatty acid esters, polyalkylene glycol ethers, pentaerythritol fatty acid esters, sterols, cholesterols, phytosterols, sitosterol, campesterol, stigmasterol including pentaerythritol-monostearate And its ethylene oxide additive, generol, soya sterol, polyethylene glycol mono-fatty acid ester, di-fatty acid ester, polyethylene glycol dicaprylate, polyethylene glycol dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol isostea Polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, Solutol HS 15 (Solutol HS 15), polyethylene glycol hydroxystearate, Miglyol 840 (Miglyol 840), propylene glycol capryl -Capric acid diester, Myvatex, Myvaplex, Myverol, monoglyceride, glycerol monooleate, glycerol monopalmitate and glycerol monostearate, Myvacet mono -Acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, stearate, laurate, oleate, polyethylene glycol monooleate, MYO, Mio-2, Mio-6, Mio -10, succinic acid di-alpha tocopheryl polyethylene glycol 1000, alkyltrimethylammonium bromide (Cetrimide), hexadecyltrimet hylammonium bromide (CTAB), benzalkonium chloride, benzethonium chloride, docusate sodium salt, sodium dodecyl sulfate (SDS), characterized in that it contains at least one of Microstructure containing cyclosporine A.
The method of claim 1,
The additive comprises a mechanical strength control additive,
The mechanical strength control additives include trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melesitos, dextran, sorbitol, xylitol, palatinite, mannitol, poly(lactide). ), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, polycaprolactone, poly Esteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinylacetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, Polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefins (chlorosulphonate polyolefins), polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), poly methacrylate, hydroxypropylmethyl Cyclosporine A comprising at least one of cellulose (HPMC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), carboxymethylcellulose, cyclodextrin, and a copolymer of monomers forming such a polymer. Containing microstructures.
The method of claim 1,
The additive comprises a viscosity control additive,
The viscosity control additives are polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose. (CMC-Na), polyvinyl acetate, hyaluronic acid (HA), polyacrylic acid, polyacrylamide, polymethacrylic acid, PEG copolymer containing polyvinyl acetate and polyvinyl caprolactam (Soluplus), gelatin And a microstructure containing cyclosporine A, characterized in that it comprises at least any one of a mixture thereof.
The method of claim 1,
The additive includes a disintegration control additive,
The disintegration control additive includes at least one of cyclodextrin, trehalose, maltose, lactose, lactulose, fructose, sodium starch glycolate, bicarbonate, croscarmellose sodium, crospovidone, starch, and mixtures thereof. Microstructure containing cyclosporine A, characterized in that.
delete The method of claim 1,
The cyclosporine A chemical solution is a microstructure containing cyclosporine A, characterized in that the cyclosporine A self-emulsifying drug delivery system (SEDDS, Self emulsifying drug delivery system).
The method of claim 11,
The cyclosporine A self-emulsifying drug delivery system is a microstructure containing cyclosporine A, characterized in that it contains a hydrophilic or lipophilic solvent, an oil, a surfactant, and a hydrophilic polymer.
The method of claim 12,
The hydrophilic or lipophilic solvent is mono-oxy-alkanediol, poly-oxy-alkanediol, C1 To C5 alkyl, C1 to C5 alkanol ethanol, tetrahydrofurfuryl di-ether, tetrahydrofurfuryl moiety-ether, diethylene glycol monoethyl ether, Transcutol, tetrahydrofurfuryl alcohol polyethylene glycol , Glycofurol, 1,2-propylene glycol, dimethyl isosorbide, propylene carbonate and polyoxyethylene-polyoxypropylene block copolymer, Pluronic L10, Pluronic L31, flu Pluronic L35, Pluronic L43, Pluronic L101, Pluronic 31R1 and Poloxamer 124, triacetin and triethylcitrate alone or mixtures thereof and propylene Mixtures with carbonates, alkyl esters of polycarboxylic acids, carboxylic acid esters of polyols, triethyl citrate, tributyl citrate (tributyl citrate), acetyltributyl citrate (acetyltributyl citrate), acetyltriethyl citrate (acetyltriethyl citrate), a microstructure containing cyclosporine A, characterized in that it contains at least any one of triacetin (triacetin).
The method of claim 12,
The oil is castor oil, MCT (Medium Chin Triglyceride oil), corn oil, cotton seed oil, sesame oil, soya oil, cassia Casia oil, cinnamon oil, almond oil, arachis oil, safflower oil, linseed oil, rapeseed oil, Borage oil, primrose oil, peanut oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil ), eucalyptus oil, lavender oil, coconut oil, orange oil, lemon oil, anise oil, clove oil, super -Super-refined oil, super-refined corn oil, borage oil, sesame oil, primrose oil, peanut oil, olive oil, crossential, concentrated borage oil, vegetable oil Esterification reaction product, as a triglyceride of intermediate fatty acids, Sepol 860 (SEFOL 860), Sepol 870, Sepol 880, Miglyol 810, Miglyol 812, Miglyol 818, Migly Miglyol 840, Labrapak CC, GMO AV1 (GMO AV1), ATMOS 300, GMOrphic 80, DL-a-Tocopheryl acetate ), Labrafil M 2130 CS, Imwitor 742, Myvac et), Myvaplex, Myverol, Generol, Myritol 318, Captex 300, Captex 355, Capmul MCM EP, C8 , I8, Neobee M5, Mazol 1400, Maisine 35-1, Crossential GLO E50; concentrated borage oil ethyl ester)[Croda Corporation], Nikkol EOO (ethyl olive oleate), ethyl oleate, isopropyl myristate, oleic acid in liquid form, linoleic acid in liquid form, ethyl linoleate , Isopropyl palmitate, Isopropylmyristate, Plurol Oleique CC 497, polyglyceryl oleate, Plurol Stearique, Polyglyceryl palmitostearate, DGMO-C, diglyceryl monooleate, tetraglin 1-O, tetraglyceryl monooleate (tetraglyceryl monooleate), Hexaglyn 1-O, hexaglyceryl monooleate, Hexaglyn 5-O, hexaglyceryl pentaoleate, Decaglyn 5-O, decaglyceryl pentaoleate, Decaglyn 10-O, decaglyceryl decaoleate, squalene, Hexamethyltetracosahexaenes, hydrogenated squalene, omega-3 essential fatty acids (EFAs), eicosapentaenoic acid, docosahexaenoic acid, ethyl Esterified form of oil, Incromega F2 250, Incromega F2628, ethyl esterified oil, Incromega E2251, Incromega F2573, Incromega TG2162, Incromega TG2779, Incromega TG2928, oleic acid, linoleic acid ) And linolenic acid (linolenic acid), characterized in that it contains at least one of the microstructures containing cyclosporine A.
The method of claim 12,
The surfactants are polyoxyethylene glycolated natural vegetable oils, polyoxyethylene glycolated hydrogenated vegetable oils, polyoxyethylene glycolated natural castor oil, polyoxyethylene glycolated hydrogenated castor oil, Cremophor RH 40, cremophor Morphoa RH 60, Cremophora EL, Nikkol HCO-40, Nikkol HCO-60, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid mono-lauryl, polyoxyethylene Sorbitan fatty acid tri-lauryl, palmityl, stearyl, oleyl esters, Tween, polyoxyethylene (20) sorbitan mono-laurate (Tween 20), polyoxyethylene (20) sorb Non-non-palmitate (Twin 40), polyoxyethylene (20) sorbitan mono-oleate (Twin 80), polyoxyethylene fatty acid esters, Cetiol HE, Myrj, Mirz 52), polyoxyethylene-polyoxypropylene copolymers, Pluronic, Emkalyx, polyoxyethylene-polyoxypropylene block copolymers, poloxamer, dioctyl succinate, dioctyl Sodium sulfosuccinate, di-[2-ethylhexyl]-succinate, sodium lauryl sulfate, phospholipids, lecithin, soy lecithin, bile salts, alkali metal salts, sodium taurochorate, natural vegetable oil triglycerides and polyalkylenes Ester group transfer reaction product with polyol, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 BS, Labrasol, mono-glyceride, di -Glyceride, mono/di-glyceride, caprylic acid, esterification reaction product of capric acid with glycerol, caprylic acid/capric acid mono-glyceride, caprylic acid/capric acid di-glyceride, Imbitor, Imbitor 742, sorbitan fatty acid esters, sorbitan mono-laurate, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, bovine Rbitan mono-oleate, sorbitan tri-oleate, span, pentaerythritol fatty acid esters, polyalkylene glycol ethers, pentaerythrite fatty acid esters, pentaerythrit-diolate, pentaerythrite -Distearate, pentaerythrit-monolaurate, pentaerythrit-polyglycol ether, pentaerythrit-monostearate, sterols, cholesterol, phytosterols, sitosterol, campesterol, stigmasterol, sitosterol Of ethylene oxide, campesterol of ethylene oxide, stigmasterol of ethylene oxide, generol, soya sterol, polyethylene glycol mono-fatty acid ester, polyethylene glycol di-fatty acid ester, polyethylene glycol dicaprylate, polyethylene glycol Dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol isostearate, polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, Solutol HS 15, polyethylene glycol hydroxystearate Rate, Miglyol 840, propylene glycol caprylic-capric acid diester, Myvatex, Myvaplex, Myverol, monoglyceride, glycerol monooleate, glycerol Monopalmitate, glycerol monostearate, Myvacet, mono-acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, bound stearate, laurate, oleate, polyethylene glycol mono Olate, MYO, Mio-2, Mio-6, Mio-10, succinic acid di-alpha tocopheryl polyethylene glycol 1000, cetrimide (alkyltrimethylammonium bromide (Cetrimide)), hexadecyltrimethylammonium bromide (CTAB) ), benzalkonium chloride benzeto chloride A microstructure containing cyclosporine A, characterized in that it contains at least one of benzethonium chloride, docusate sodium salt, and sodium dodecyl sulfate (SDS).
The method of claim 12,
The hydrophilic polymer is hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose Acetate phthalate, hydroxypropylene methylcellulose, hydroxypropylene methylcellulose phthalate, propylene oxide, polyvinylpyrrolidone (PVP), K12, K15, K17, K25, K30, K60, K90, K120, Vinylpyrrolidone-vinyl acetate, polyethylene glycol, polyvinylalcohol, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate (Polymethacrylate), polymethacrylate polymer (trade name: Eudragit), polyacrylic acid and polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer, trade name: Soluplus ) Microstructure containing cyclosporine A, characterized in that it comprises at least any one of.
The method of claim 1,
A microstructure containing cyclosporine A, characterized in that it comprises a cyclosporine A inclusion body, which is a drug delivery body of particles in which the cyclosporine A is enclosed by a component encapsulated with the cyclosporine A chemical solution.
The method of claim 17,
The encapsulating components are serum albumin, gelatin, lecithin, collagen, iron oxide, casein, polycaprolactone, polylactide (PLA), Polymethyl metha acrylate (PMMA), poly alkyl cyano acrylate (PACA), poly methyl cyano acrylate (PMCA), polylactide (Poly D, L-Lactide), polyacrylamide, poly(methylvinylether-co-maleic anhydride, PVM/MA) Eudragit, polyglycolide (PGA) ), poly(lactide-co-glycolide; PLGA), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyalkyl cellulose, maltose, chitosan, polyester, polyhydroxyalkanoate (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydrosoxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate) ; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4- Hydroxyhexanoate), poly(esteramide), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, Poly(amino acid), polycyanoacrylate, poly(trimethylene carbonate), poly(iminocarbonate), poly(tyrosine carbonate), polycarbonate, poly(tyrosine arylate), polyalkylene oxalate, polyphospha Gens, PHA-PEG, polyvinylpyrrolidone, polybutadiene, polyhigh Hydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl foam, vinyl chloride-propylene -Vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, cumaroneindene polymer, dibutylaminohydroxypropyl ether, ethylene-vinyl acetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylic Rate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, stearic acid, behenic acid, cellulose, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin , Chondroitin, dextrin, keratin sulfate, tallow, whale wax, beeswax, paraffin wax, castor wax, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, and glycogen. Microstructure containing cyclosporine A
The method of claim 17,
The cyclosporine A inclusion body contains a stabilizer,
The stabilizer is a cellulose compound including carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP). Polyvinyl compounds including, acrylic compounds including carbomer, gum compounds including gellan gum or Xanthan gum, hyaluronic acid (HA), sodium hyaluronate (SodiumHyaluronate), A microstructure containing cyclosporine A, characterized in that it contains at least one of sodium alginate, dextran, and didodecyldimethylammonium bromide.
The method of claim 1,
A microstructure containing cyclosporine A, characterized in that it contains cyclosporine A liposomes as the cyclosporine A chemical solution.
The method of claim 20,
The cyclosporine A liposome contains a phospholipid,
The phospholipids are phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithin, phosphatidic acid, sphingomyelin, lipofectin, cephalin, cardiolipin dipalmitoylphosphatidylcholine, 1,2-dioleoyl- sn-Glycero-3-phosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, diolelphosphatidylglycerol, dimyristoylphosphatidylglycerol, hexadecylphosphocholine, distearoylphosphatidylcholine, distearoylphosphatidyl Glycerol, dioleylphosphatidylethanolamine, palmitoylstearoylphosphatidylcholine, palmitoylstearoylphosphatidylglycerol, monooleoylphosphatidylethanolamine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine, Polyethylene glycol distearoylphosphatidylethanolamine, dipalmitoylphosphatidylserine, 1,2-dioleoyl-sn-glycero-3-phosphatidylserine, dimyristoylphosphatidylserine, distearoylphosphatidylserine, dipalmi Toylphosphatidic acid, 1,2-dioleoyl-sn-glycero-3-phosphatidic acid, dimyristoylphosphatidic acid, distearoylphosphatidic acid, dipalmitoylphosphatidylinositol, 1,2- Dioleoyl-sn-glycero-3-phosphatidylinositol, dimyristoylphosphatidylinositol, and a microstructure containing cyclosporine A, characterized in that it comprises at least one of distearoylphosphatidylinositol.
The method of claim 20,
The cyclosporine A liposome contains an internal phase viscosity increasing agent,
The internal viscosity increasing agent is polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable poly Urethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefin (chlorosulphonate polyolefins), polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), poly Including at least one of methacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and a copolymer of monomers forming these polymers Microstructure containing cyclosporine A, characterized in that.
The method of claim 20,
The cyclosporine A liposome contains a mechanical strength increasing agent,
The mechanical strength increasing agent is trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melegitos, dextran, sorbitol, xylitol, palatinite, mannitol, poly(lactide). ), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, polycaprolactone, li Esteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, Polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate, polyolefins (chlorosulphonate polyolefins), polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethyl Cyclosporine A comprising at least one of cellulose (HPMC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), carboxymethylcellulose, cyclodextrin, and a copolymer of monomers forming such a polymer. Containing microstructures.
The method of claim 1,
Cyclosporine A containing cyclosporine A lipid particles comprising at least one of a solid lipid nanoparticle (SLN) and a nanostructured lipid carrier (NLC) as the cyclosporine A chemical solution Microstructure.
The method of claim 24,
The cyclosporine A chemical solution contains lipids in cyclosporine A lipid particles,
The lipids are glyceryl behenate (Compritol 888 ATO), glyceryl stearate (Imwitor 900), tripalmitin glycerol (Dynasan 116), glyceryl palmitostearate (glyceryl palmitostearate) (Precirol ATO 5), glyceryl palmitate (Cetyl palmitate), stearic acid, tripalmitin, caprylic/-capric triglyceride (Miglyol® 812 and 810, Labrafac ™, Softison 378 ), Vitamin E (Vitamin E), Lauroyl Polyoxylglycerides (Gelucire® 44/14), Monoacylglycerols (Monoacylglycerols) (Myverol 18-99 K), Soy lecithin (Epikuron™ 200) and Squalene A microstructure containing cyclosporine A, characterized in that it contains at least any one of (Squalene).
The method of claim 24,
The cyclosporine A chemical solution contains a surfactant in cyclosporine A lipid particles,
The surfactants are polyoxyethylene glycolated natural vegetable oils, polyoxyethylene glycolated hydrogenated vegetable oils, polyoxyethylene glycolated natural castor oil, polyoxyethylene glycolated hydrogenated castor oil, Cremophor RH 40, cremophor Morphoa RH 60, Cremophora EL, Nikkol HCO-40, Nikkol HCO-60, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid mono-lauryl, polyoxyethylene Sorbitan fatty acid tri-lauryl, palmityl, stearyl, oleyl esters, Tween, polyoxyethylene (20) sorbitan mono-laurate (Tween 20), polyoxyethylene (20) sorb Non-non-palmitate (Twin 40), polyoxyethylene (20) sorbitan mono-oleate (Twin 80), polyoxyethylene fatty acid esters, Cetiol HE, Myrj, Mirz 52), polyoxyethylene-polyoxypropylene copolymers, Pluronic, Emkalyx, polyoxyethylene-polyoxypropylene block copolymers, poloxamer, dioctyl succinate, dioctyl Sodium sulfosuccinate, di-[2-ethylhexyl]-succinate, sodium lauryl sulfate, phospholipids, lecithin, soy lecithin, bile salts, alkali metal salts, sodium taurochorate, natural vegetable oil triglycerides and polyalkylenes Ester group transfer reaction product with polyol, Labrafil, Labrafil M 1944 CS, Labrafil M 2123 CS, Labrafil WL 2609 BS, Labrasol, mono-glyceride, di -Glyceride, mono/di-glyceride, caprylic acid, esterification reaction product of capric acid with glycerol, caprylic acid/capric acid mono-glyceride, caprylic acid/capric acid di-glyceride, Imbitor, Imbitor 742, sorbitan fatty acid esters, sorbitan mono-laurate, sorbitan mono-palmitate, sorbitan mono-stearate, sorbitan tri-stearate, Sorbitan mono-oleate, sorbitan tri-oleate, span, pentaerythritol fatty acid esters, polyalkylene glycol ethers, pentaerythrite fatty acid esters, pentaerythrit-diolate, pentaerythrite -Distearate, pentaerythrit-monolaurate, pentaerythrit-polyglycol ether, pentaerythrit-monostearate, sterols, cholesterol, phytosterols, sitosterol, campesterol, stigmasterol, sitosterol Of ethylene oxide, campesterol of ethylene oxide, stigmasterol of ethylene oxide, generol, soya sterol, polyethylene glycol mono-fatty acid ester, polyethylene glycol di-fatty acid ester, polyethylene glycol dicaprylate, polyethylene glycol Dilaurate, polyethylene glycol hydroxystearate, polyethylene glycol isostearate, polyethylene glycol laurate, polyethylene glycol ricinoleate, polyethylene glitol stearate, Solutol HS 15, polyethylene glycol hydroxystearate Rate, Miglyol 840, Propylene Glycol Caprylic-Capric Diester, Myvatex, Myvaplex, Myverol, Monoglyceride, Glycerol Monooleate, Glycerol Monopalmitate, glycerol monostearate, Myvacet, mono-acetylated monoglyceride, di-acetylated monoglyceride, polyethylene glycol fatty acid esters, bound stearate, laurate, oleate, polyethylene glycol mono Olate, MYO, Mio-2, Mio-6, Mio-10, succinic acid di-alpha tocopheryl polyethylene glycol 1000, cetrimide (alkyltrimethylammonium bromide (Cetrimide)), hexadecyltrimethylammonium bromide (CTAB) , Benzalkonium chloride chloride A microstructure containing cyclosporine A, characterized in that it contains at least one of benzethonium chloride, docusate sodium salt, and sodium dodecyl sulfate (SDS).
The method of claim 1,
A microstructure containing cyclosporine A, comprising a composition in which cyclosporine A is dissolved in a non-aqueous solvent, an emulsifier, and a stabilizer as the cyclosporine A chemical solution.
The method of claim 27,
The non-aqueous solvent is vegetable oil, castor oil, coconut oil, cinnamon oil, corn oil, olive oil, cottonseed oil, soybean oil, fatty acid esters consisting of 14 to 20 carbon atoms, lauric acid, myristic acid, palmitic acid, palmitoic acid, Stearic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, eicosapentaenoic acid, ethyl oleate, isopropyl myristate, fatty acid ester glycerol consisting of 6 to 12 carbon atoms, Labrapak PG or Labrapak lipo Fatty acid ester glycerides including fillet WL 1349, caprylic acid-capric acid triglycerides including Miglyol 812, caprylic acid-caprylic acid-linoleic acid triglycerides including Miglyol 818, A microstructure containing cyclosporine A, further comprising at least one of fatty acid esters consisting of 14 to 20 carbon atoms and glycerides of fatty acid esters consisting of 6 to 12 carbon atoms.
The method of claim 27,
The emulsifier is a reaction product of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene glycolated natural castor oil, polyoxyethylene glycolated hydrogenated castor oil (trade name: Cremophor, BASF; HCO,: NIKKOL ), polyoxyethylene-sorbitan-fatty acid esters, mono lauryl, trilauryl, palmityl, stearyl esters or oleyl esters (trade name: Tween, ICI), polyoxyethylene fatty acid Esters, polyoxyethylene stearic acid esters (trade names: Mirage (Myrj, ICI, etc.), polyoxyethylene-polyoxypropylene copolymer, Pluronic, Emkalyx (BASF), polyoxyethylene- Polyoxypropylene block copolymer (Poloxamer, BASF), sodium dioctylsulfosuccinate, sodium lauryl sulfoate, phospholipids, soy lecithin, propylene glycol mono-fatty acid, propylene glycol di-fatty acid esters, propylene glycol dica Prylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol caprylic-capric acid diester (Miglyol 840, Huls), Trans-esterification reaction product of natural vegetable oil triglyceride and polyalkylene polyol, Labrafil M (manufactured by Gattefosse), mono-glyceride, di-glyceride, mono/di-glyceride, car Pryl/capric acid mono-glyceride, caprylic/capric acid di-glyceride (Imwitor, Huls), sorbitan fatty acid esters, sorbitan monolauryl (trade name: Span), Sorbitan monopalmityl, sorbitan monostearyl, sterol, cholesterol, phytosterol, sitosterol, pentaerythrate-fatty acid ester, pentaerythritol fatty acid ester, polyalkylene glycol ester, pentaeryth-dioleate, pentaeryth-dis Thearate, pentaeryth-monolaurate, pentaeryth-polyglycol ether and Microstructures containing cyclosporine A, characterized in that it further comprises at least one of pentaeryth-monostearate.
The method of claim 27,
The stabilizer is a cellulose compound including carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), or polyvinylpyrrolidone (PVP). Polyvinyl compounds containing, acrylic compounds containing carbomer, gum compounds containing gellan gum or Xanthan gum, hyaluronic acid (HA), sodium hyaluronate (Sodium Hyaluronate) , Sodium alginate (Sodium Alginate) and dextran (Dextran), characterized in that it further comprises at least one of the microstructures containing cyclosporine A.
The method of claim 1,
The cyclosporine A chemical solution contains cyclodextrin containing the cyclosporine A,
The cyclodextrins are α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin or their respective glucosyl cyclodextrin, maltosyl cyclodextrin, methyl cyclodextrin, hydroxyethyl cyclodextrin and hydro Microstructure containing cyclosporine A, characterized in that it further comprises at least any one of cypropyl cyclodextrin.
The method of claim 31,
Cyclodextrin containing the cyclosporine A uses a dissolution aid,
The dissolution aid is ethanol, glycerin, polyethylene glycol, polypropylene glycol, polyethylene oxide, polypropylene oxide, and a microstructure containing cyclosporine A further comprising at least one of a polyoxyethylene sol metal.
The method of claim 1,
It is an amphiphilic polymer micelle containing the cyclosporine A in an amphiphilic polymer material as the cyclosporine A chemical solution,
The amphiphilic polymer material is N-phthaloylcarboxymethylchitosan, Poly(2-ethylhexyl acrylate)-b-poly(acrylic acid), Poly(tert-butyl acrylate)-b-poly(2-vinylpyridine), Poly(ethylene oxide)-b -polycaprolactone, Poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone), Poly(e-caprolactone)-b-poly(methacrylic acid), Poly(ethyleneglycol)-b-poly (e-caprolactone-co-trimethylenecarbonate), Poly(aspartic acid)-b-polylactide, Poly(ethylene glycol)-block-poly(aspartate-hydrazide), Poly(N-isopropyl acrylamide-co-methacryl acid)-g- poly(D,L-lactide), Stearic acid-grafted chitosan oligosaccharide, Pluronic F127, Poloxamer 407(Pluronic F127), Poloxamer 188(Pluronic F68), Methoxy poly(ethylene glycol)-poly(ε-caprolactone)(MPEG-PCL ), Methoxy-poly(ethylene glycol)(MPEG), hexyl-substituted poly(lactides)(hexPLA)(polymers of MPEG-PLA and MPEG-hexPLA), Poly(butylene oxide)-poly(ethyleneoxide)-poly(butylene oxide ), Polyhydroxyethylaspartamide (PHEA), Methoxy (polyethylene glycol)-block-polycaprolactone (MePEG-b-PCL), Methox y poly(ethylene) glycol(MPEG), Poly(ethylene oxide)-poly(propylene oxide)(PEO-PPO-PEO) block copolymers, Hexadecyloxypropyl, Methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide), Pluronic P123(P123) ), Da-tocopheryl polyethylene glycolsuccinate(TPGS), N-isopropylacrylamide(NIPAAM), Tetronic® 701(T701), Synperonic® PE/F127(F127), Synperonic® PE/P84(P84), Poly(propylene oxide) (PPO ), poly(ethylene oxide)(PEO), PEG-b-PCL, cationic polyelectrolyte chitosan(CH), Poly(ethylene oxide)-poly(propylene, oxide)-poly(ethylene oxide)((PEO-PPO-PEO) , polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer, brand name: Soluplus), complex of sodium lauryl sulfate and Soluplus, methoxy-capped poly(ethylene glycol)-block-poly(epsilon-caprolactone) (mPEG-b-PCL) and Poly( Microstructures containing cyclosporine A, characterized in that it further comprises at least one of ethylene glycol)-b-poly(D,L-lactic acid).

Images