Cyclosporin nanomolecular aggregate, eye drop composition containing the same, and method for producing the same

Abstract

The present invention relates to a cyclosporine nanomolecular aggregate and an eye drop composition containing the same. More specifically, the present invention relates to a cyclosporine nanomolecular aggregate that has excellent storage stability and is delivered to target tissues (cornea and conjunctiva) more efficiently at a lower concentration than conventional formulations, and an eye drop composition containing the same.

Description

[Technical Field]

[0001] The present invention relates to a cyclosporine nanomolecular aggregate, an eye drop composition containing the same, and a method for producing the same. More specifically, the present invention relates to a cyclosporine nanomolecular aggregate, which has the effect of reducing the amount of excipients used by up to 90%, thereby reducing the amount of excipients used that cause eye irritation symptoms and thereby reducing side effects, by producing an eye drop composition containing the same and a method for producing the same, by producing an eye drop composition containing the same, which has the effect of reducing the amount of excipients used that cause eye irritation symptoms, while reducing the amount of excipients used by up to 90%, by reducing the amount of excipients used that cause eye irritation symptoms and thereby reducing side effects. [Background technology]

[0002] There are various treatments for dry eye, including artificial tears, cyclosporine eye drops, topical steroid eye drops, and autologous serum. Among these, cyclosporine is a fungal peptide component that specifically suppresses the activity of T-helper cells in the ocular surface tissue and blocks the production of IL-2, an immune-mediated inflammatory cytokine. Cyclosporine in the form of eye drops reduces lymphocyte influx into the lacrimal gland and effectively reduces apoptosis.

[0003] A representative prior art drug, 0.05% cyclosporine (Restasis, Allergan, Inc.), is a microemulsion eye drop prepared by mixing cyclosporine with polysorbate 80, castor oil, carbomer 1342, etc. An emulsion is a state in which two immiscible liquids are dispersed in another liquid in the form of small droplets at a fixed ratio. A microemulsion is a water-oil-surfactant mixture in which the components in the emulsion reach a phase equilibrium state through thermodynamic self-assembly. In equilibrium, microemulsions are influenced by various thermodynamic factors, such as temperature and composition, resulting in the coexistence of particles with various shapes, including lamellar sheets and hexahedrons. The particle sizes within the microemulsion vary widely, ranging from 67 to 2,489 nm. These properties result in the overall solution appearing as a bluish suspension. Therefore, cyclosporine prepared as a microemulsion has the disadvantage of causing eye irritation due to the non-uniform particle size of the suspension emulsion, and Restasis has the disadvantage of low bioavailability reaching the ocular surface. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 8,642,556 Summary of the Invention [Problem to be solved by the invention]

[0005] To solve the above problems, the present invention provides a cyclosporine nanomolecular aggregate and an eye drop composition containing the same, which can reduce the amount of cyclosporine, an active ingredient, used to 1 / 5 to 2 / 5 of that used in the prior art, while minimizing excipients that cause eye pain by up to 90% when preparing an eye drop composition.

[0006] The present invention also provides methods for producing cyclosporine nanomolecular aggregates and eye drop compositions containing the same. [Means for solving the problem]

[0007] The present invention provides a molecular associate in which cyclosporine is physically bound, and when the molecular associate is formed in a composition containing water, the molecular associate has an aggregated structure in the composition.

[0008] Furthermore, according to one embodiment of the present invention, there is provided a molecular association, wherein the molecular association has an average particle size of 1.0 to 10 nm or less.

[0009] Furthermore, according to one embodiment of the present invention, a molecular association can be provided in which the total amount of softening material is 1.5% or less of the initial amount after 6 months under long-term storage conditions at a temperature of 5°C ± 3°C.

[0010] Furthermore, according to one embodiment of the present invention, a molecular association can be provided in which the total amount of softening material is 1.5% or less of the initial amount after 6 months under accelerated conditions of 25°C±2°C / 70%±5%.

[0011] The present invention also provides a composition for producing an ophthalmic solution, comprising the molecular association, a surfactant, a solubilizing agent, and purified water.

[0012] According to one embodiment of the present invention, there is provided a composition for producing an ophthalmic solution, wherein the molecular association is contained in an amount of 0.001 to 0.04 wt % based on the total content of the composition.

[0013] According to one embodiment of the present invention, there is provided a composition for producing an ophthalmic solution, wherein the molecular association is contained in an amount of 0.001 to 0.02 wt % based on the total content of the composition.

[0014] According to one embodiment of the present invention, there is provided a composition for preparing an ophthalmic solution, which contains a surfactant in an amount of 0.001 to 0.5 wt % based on the total content of the composition.

[0015] According to one embodiment of the present invention, there is provided a composition for preparing an ophthalmic solution, which contains a surfactant in an amount of 0.01 to 0.1 wt % based on the total content of the composition.

[0016] According to one embodiment of the present invention, there is provided a composition for preparing an ophthalmic solution, which contains a solubilizer in an amount of 0.001 to 0.1 wt % based on the total content of the composition.

[0017] In addition, according to an embodiment of the present invention, there may be provided a composition for preparing an ophthalmic solution, wherein the surfactant is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, alcohol, amine oxide, block polymer, carboxylate alcohol, alkylphenol ethoxylate carboxylic acid / fatty acid, ethoxylate alcohol, ethoxylate alkylphenol, ethoxylate arylphenol, ethoxylate fatty acid, ethoxylate, fatty ester or oil, fatty ester, fatty acid methyl ester ethoxylate, glycerol ester, glycol ester, lanolin derivative, lecithin, lecithin derivative, lignin, lignin derivative, methyl ester, monoglyceride, monoglyceride derivative, polyethylene glycol, polymer surfactant, propoxylate and ethoxylate fatty acid, alcohol or alkylphenol, protein-derived surfactant, saccharosin derivative, sorbitan derivative, sucrose, sucrose derivative, glucose ester, and glucose ester derivative.

[0018] Furthermore, according to an embodiment of the present invention, there may be provided a composition for preparing an ophthalmic solution, wherein the solubilizer is at least one selected from the group consisting of castor oil, canola oil, C12-15 alkyl benzoate, almond oil, aluminum monostearate, cetostearyl alcohol, cholesterol, coconut oil, cyclomethicone, dimethicone, ethylene glycol stearate, glycerin, glyceryl monooleate, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, hydrogenated lanolin, lecithin, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, oleyl oleate, petrolatum, polydicaine, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, soybean oil, sunflower oil, wax, xylitol, and zinc acetate.

[0019] According to an embodiment of the present invention, there is provided an eye drop composition further comprising at least one selected from the group consisting of a viscosity adjuster, an osmotic pressure adjuster, and a pH adjuster.

[0020] According to one embodiment of the present invention, there is provided an eye drop composition, wherein the viscosity modifier is contained in an amount of 0.001 to 0.5 wt % based on the total content of the composition.

[0021] According to another embodiment of the present invention, there is provided an eye drop composition, wherein the osmotic pressure adjusting agent is contained in an amount of 0.5 to 10.0 wt % based on the total content of the composition.

[0022] According to one embodiment of the present invention, there is provided an eye drop composition, wherein the content of the viscosity modifier is 0.5 to 2.5 times the content of the molecular association.

[0023] According to one embodiment of the present invention, the viscosity modifier may be selected from the group consisting of acacia, agar, alanic acid, alginic acid, aluminum monostearate, attapulgite, bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carmellose, carrageenan, cellulose, microstearate, cetostearyl alcohol, chitosan, corn syrup, cyclomethicone, dextrin, egg phospholipids, ethyl cellulose, gelatin, magnesium aluminum silicate, maltitol solution, maltodextrin, medium chain triglyceride, methylcellulose, pectin, polycarbophil, polydextrose, polyethylene oxide, polyvinyl alcohol, potassium alginate, povidone, propylene glycol alginate, pullulan, dental type silica, hydrophobic colloidal silica, silicon dioxide, colloidal silica, sodium alginate, monolauroyl and sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, corn starch, hydroxypropyl corn starch, pregelatinized hydroxypropyl corn starch, starch P, hydroxypropyl starch P, pregelatinized hydroxypropyl starch P, potato starch, gellan gum, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, isomalt, α-lactalbumin, kaolin, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, tapioca starch, wheat starch, sucrose, sucrose palmitate, tragacanth, vitamin E propylene glycol succinate, and xanthan gum.

[0024] According to another embodiment of the present invention, there is provided an eye drop composition, wherein the osmotic pressure adjuster is at least one selected from the group consisting of glycerin, sorbitol, mannitol, dextrose, and sucrose.

[0025] According to another embodiment of the present invention, the pH adjuster is at least one selected from the group consisting of acetic acid, adipic acid, ammonia solution, ammonium carbonate, ammonium chloride, ammonium phosphate, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, citric acid, diethanolamine, fumaric acid, glycine, hydrochloric acid, α-lactalbumin, lactic acid, lysine hydrochloride, malic acid, maleic acid, methionine, monoethanolamine, sodium glutamate, nitric acid, phosphoric acid, potassium citrate, potassium hydroxide, potassium metaphosphate, potassium phosphate, propionic acid, racemethionine, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate, succinic acid, sulfuric acid, tartaric acid, and tetrolamine.

[0026] According to another embodiment of the present invention, there is provided an eye drop composition, wherein the molecular associate is contained in an amount of 0.001 to 0.04 wt % of the total content of the composition, and wherein the change in total content over a period of 6 months under long-term storage conditions of 25°C ± 2°C / 40% ± 5% is 90.0 to 110.0%.

[0027] According to another embodiment of the present invention, there is provided an eye drop composition, wherein the molecular associate is contained in an amount of 0.001 to 0.04 wt % of the total content of the composition, and wherein the change in total content after 6 months at intermediate conditions of 30°C ± 2°C / 65% ± 5% is 90.0 to 110.0%.

[0028] According to another embodiment of the present invention, there is provided an eye drop composition, wherein the molecular associate is contained in an amount of 0.001 to 0.04 wt % of the total content of the composition, and wherein the change in total content over 6 months under accelerated conditions of 40°C±2°C / 25%±5% is 80.0 to 110.0%.

[0029] According to one embodiment of the present invention, the eye drop composition can provide an eye drop composition that exposes the cornea and conjunctiva three times or more when applied to the eyeball.

[0030] According to another embodiment of the present invention, the amount of the eye drop composition that flows into the bloodstream of the entire body other than the ocular tissues when administered to the eye is 0.02% or less of the total administered amount.

[0031] The present invention provides a method for producing a molecular associate in which cyclosporine is physically bound, comprising the steps of: 1) introducing a cyclosporine solution into silica and then repeatedly draining the cyclosporine; 2) filtering the drained solution and concentrating the filtrate by vacuum distillation; 3) filtering the concentrated residual liquid phase and crystallizing it; and 4) filtering, washing, and drying the crystallized solid. [Effects of the Invention]

[0032] The present invention reduces the active ingredient cyclosporine by 1 / 5 to 2 / 5 while reducing the amount of excipients that cause ocular irritation by up to 90%, enabling efficient delivery to target tissues (cornea and conjunctiva) at lower concentrations. Furthermore, the amount of drug that enters the bloodstream and flows into the systemic tissues other than the ocular tissues (target tissues) is low, at less than 0.02% of the total administered dose, both in single and repeated instillation administrations. Furthermore, the drug achieves and maintains an extremely small particle size of 2 nm, demonstrating storage stability. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows the results of a comparative pharmacokinetic evaluation of cyclosporine A, the main drug ingredient, after single or repeated instillation of a control formulation, Allergan's Restasis (0.05%), and the eye drops of Example 3 of the present invention (0.01% and 0.02%) into rabbit eyes, and the intracorneal distribution of the drug was confirmed. [Figure 2]FIG. 1 shows the results of a comparative pharmacokinetic evaluation of cyclosporine A, the main drug ingredient, after single or repeated instillation of a control formulation, Allergan's Restasis (0.05%), and the eye drops of Example 3 of the present invention (0.01% and 0.02%) into the rabbit eyeballs, and the distribution in the conjunctiva was confirmed. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention presents a cyclosporine nanomolecular aggregate that can be efficiently delivered to target tissues (cornea and conjunctiva) at lower concentrations by reducing the amount of cyclosporine active ingredient by 1 / 5 to 2 / 5 compared to conventional technologies, while reducing the amount of excipients that cause ocular irritation by up to 90%. Furthermore, the present invention also presents a cyclosporine nanomolecular aggregate that has the advantage of showing low blood flow into the systemic ocular tissues (the target tissues of the drug)—less than 0.02% of the total administered dose—both in single and repeated instillation. Furthermore, the present invention presents a cyclosporine nanomolecular aggregate that achieves and maintains an extremely small particle size of 2 nm, demonstrating storage stability.

[0035] This will be explained in more detail below.

[0036] term In the present invention, the term "eye drops" means the administration of a liquid formulation in the form of drops onto the external surface of the eye.

[0037] In the present invention, the term "eye drops" relates to a pharmaceutical liquid preparation that is administered in the form of drops onto the external surface of the eye and exerts a localized effect on the posterior segment of the eye.

[0038] In the present invention, the term "composition for producing an ophthalmic solution" refers to an intermediate composition produced before producing an ophthalmic composition, which further contains a surfactant, a solubilizer, water, etc. in addition to the molecular associate. An ophthalmic solution can be produced by further adding a viscosity adjuster, an osmotic pressure adjuster, a pH adjuster, etc. to this intermediate composition.

[0039] In the present invention, the term "exposure amount" refers to the amount of the active ingredient of cyclosporine that reaches the cornea and conjunctiva.

[0040] In the present invention, the term "efflux" refers to the amount of cyclosporine that does not remain in the target site, such as the cornea and conjunctiva of the eyeball, but flows into the blood vessels, bloodstream, etc.

[0041] In the present invention, the term "softening agent" refers to a type of impurity that may be produced during the synthesis of raw materials or the manufacturing process of finished pharmaceutical products. Such softening agents must be contained in final pharmaceutical products only at levels below the standard and are used to verify quality.

[0042] In the present invention, the terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal, in vitro or in situ, or cells thereof, that are amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.

[0043] As used herein, the term "composition" refers to a mixture of at least one compound of the present invention with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients.

[0044] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount to provide a desired biological result. The result may be a reduction and / or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0045] In the present invention, the term "efficacy" refers to the maximum effect (Emax) achieved within the assay method.

[0046] Cyclosporin nanomolecular aggregates of the present invention The present invention provides a molecular associate in which cyclosporine is physically bound, and when the molecular associate is formed in a composition containing water, the molecular associate has an aggregated structure in the composition.

[0047] In the present invention, the average particle size of the molecular aggregate may be 1.0 to 10 nm, preferably 1.5 nm or more, 2.0 nm or more, or 7.0 nm or less, 5.0 nm or less, or 3.0 nm or less. The average particle size of the molecular aggregate can be measured through a diffraction experiment, preferably using a Zetasizer or small angle neutron scattering (SANS). Images can also be measured using transmission electron microscopy. If the average particle size of the molecular aggregate exceeds 10 nm, dispersibility decreases, resulting in reduced transparency and transmittance. The lower limit of the average particle size of the structure is not particularly limited, but a particle size of about 0.5 nm or more can be used.

[0048] In addition, the molecular associate according to the present invention has excellent storage stability. Unlike typical nano-sized dispersed particles, which are easily susceptible to aggregation or Ostwald ripening and therefore have poor storage stability, the molecular associate and composition according to the present invention exhibit little change in the amount of softening agent under long-term, intermediate, or accelerated storage conditions, thereby exhibiting excellent stability. The change rate refers to the average change rate calculated by averaging the change rates for each month up to the specified period.

[0049] As described above, it can be seen that the molecular association of the present invention has excellent stability.

[0050] Specifically, the molecular association may have a total softening substance content of 1.5% or less, preferably 1.0% or less, and more preferably 0.5% or less, of the initial amount after 6 months under long-term storage conditions at a temperature of 5°C ± 3°C.

[0051] Furthermore, the molecular association may have a total softening substance content of 1.5% or less, preferably 1.0% or less, and more preferably 0.5% or less, of the initial amount after 6 months under accelerated conditions of 25°C±2°C / 70%±5%.

[0052] Composition for producing ophthalmic solution of cyclosporin nanomolecular aggregate of the present invention The present invention provides a composition for preparing an ophthalmic solution, the composition further comprising a surfactant, a solubilizer, and purified water. The composition for preparing an ophthalmic solution is supplied to a user who intends to prepare an ophthalmic solution, and then the user can add additional components of the ophthalmic composition described below to prepare an ophthalmic solution.

[0053] The molecular association may be contained in an amount of 0.001 to 0.04% by weight, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and preferably 0.03% by weight or less, more preferably 0.02% by weight or less, based on the total content of the composition for producing an ophthalmic solution.

[0054] In the composition for preparing an ophthalmic solution of the present invention, the surfactant may further include at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, alcohol, amine oxide, block polymer, carboxylate alcohol, alkylphenol ethoxylate carboxylic acid / fatty acid, ethoxylate alcohol, ethoxylate alkylphenol, ethoxylate arylphenol, ethoxylate fatty acid, ethoxylate, fatty ester or oil, fatty ester, fatty acid methyl ester ethoxylate, glycerol ester, glycol ester, lanolin derivative, lecithin, lecithin derivative, lignin, lignin derivative, methyl ester, monoglyceride, monoglyceride derivative, polyethylene glycol, polymer surfactant, propoxylate and ethoxylate fatty acid, alcohol or alkylphenol, protein-derived surfactant, saccharosin derivative, sorbitan derivative, sucrose, sucrose derivative, glucose ester, and glucose ester derivative.

[0055] In the composition for producing ophthalmic solutions of the present invention, a significantly smaller amount of surfactant can be used than in conventional compositions for producing ophthalmic solutions. Specifically, the surfactant may be contained in an amount of 0.01 to 0.1 wt %, preferably 0.03 wt % or more, more preferably 0.05 wt % or more, and preferably 0.09 wt % or less, more preferably 0.08 wt % or less, based on the total content of the composition.

[0056] If the surfactant content is higher than the above range, there are problems such as a strong burning sensation and increased toxicity upon administration to the cornea and conjunctiva, and if the surfactant content is lower, there are problems such as difficulty in maintaining the size of the produced droplets and reduced permeability to cells.

[0057] The composition for preparing an ophthalmic solution of the present invention may further include at least one solubilizer selected from the group consisting of castor oil, canola oil, C12-15 alkyl benzoate, almond oil, aluminum monostearate, cetostearyl alcohol, cholesterol, coconut oil, cyclomethicone, dimethicone, ethylene glycol stearate, glycerin, glyceryl monooleate, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, hydrogenated lanolin, lecithin, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, oleyl oleate, petrolatum, polydicaine, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, soybean oil, sunflower oil, wax, xylitol, and zinc acetate.

[0058] In the composition for producing ophthalmic solutions of the present invention, a significantly smaller amount of solubilizer can be used than in conventional compositions for producing ophthalmic solutions. Specifically, the solubilizer may be contained in an amount of 0.001 to 0.1 wt %, preferably 0.01 wt % or more, more preferably 0.02 wt % or more, and preferably 0.05 wt % or less, more preferably 0.03 wt % or less, based on the total content of the composition.

[0059] If the content of the solubilizer is higher than the above range, blurred vision and burning sensation may occur, while if the content is lower than the above range, corneal epithelial permeability may decrease.

[0060] Ophthalmic composition of cyclosporin nanomolecular aggregates of the present invention The present invention provides an eye drop composition, wherein the composition for producing an eye drop solution further comprises at least one selected from the group consisting of a viscosity adjuster, an osmotic pressure adjuster, and a pH adjuster.

[0061] In the eye drop composition of the present invention, the osmolality adjusting agent may further comprise one or more selected from the group consisting of glycerin, sorbitol, mannitol, dextrose, and sucrose.

[0062] In the eye drop composition of the present invention, the osmotic pressure adjusting agent may be contained in an amount of 0.5 to 10% by weight based on the total content of the composition.

[0063] In the eye drop composition of the present invention, the viscosity adjuster is selected from the group consisting of acacia, agar, alanic acid, alginic acid, aluminum monostearate, attapulgite, bentonite, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carmellose, carrageenan, cellulose, microstearate, cetostearyl alcohol, chitosan, corn syrup, cyclomethicone, dextrin, egg phospholipids, ethylcellulose, gelatin, aluminum magnesium silicate, maltitol solution, maltodextrin, medium chain triglyceride, methylcellulose, pectin, polycarbophil, polydextrose, polyethylene oxide, polyvinyl alcohol, potassium alginate, povidone, propylene glycol alginate, pullulan, dental type silica, hydrophobic colloidal silica, silicon dioxide, colloidal silica, and sodium alginate. , sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, corn starch, hydroxypropyl corn starch, pregelatinized hydroxypropyl corn starch, starch P, hydroxypropyl starch P, pregelatinized hydroxypropyl starch P, potato starch, gellan gum, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, isomalt, α-lactalbumin, kaolin, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, tapioca starch, wheat starch, sucrose, sucrose palmitate, tragacanth, vitamin E propylene glycol succinate, and xanthan gum.

[0064] In the eye drop composition of the present invention, the viscosity modifier may be contained in an amount of 0.001 to 0.5 wt % based on the total content of the composition. If the content of the viscosity modifier is higher than this range, problems such as eye irritation, pain or discomfort, and eyelid crusting may occur, while if the content is lower, problems such as dry eye may occur.

[0065] The content of the viscosity modifier may be 0.5 to 2.5 times the content of the molecular associate. When the content ratio of the viscosity modifier to the molecular associate satisfies the above range, there is an advantage that no burning sensation occurs.

[0066] In the eye drop composition of the present invention, the pH adjuster may further comprise one or more selected from the group consisting of acetic acid, adipic acid, ammonia solution, ammonium carbonate, ammonium chloride, ammonium phosphate, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, citric acid, diethanolamine, fumaric acid, glycine, hydrochloric acid, α-lactalbumin, lactic acid, lysine hydrochloride, malic acid, maleic acid, methionine, monoethanolamine, sodium glutamate, nitric acid, phosphoric acid, potassium citrate, potassium hydroxide, potassium metaphosphate, potassium phosphate, propionic acid, racemethionine, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate, succinic acid, sulfuric acid, tartaric acid, and tetrolamine.

[0067] In the eye drop composition of the present invention, the pH adjuster may be contained in an amount appropriate for adjusting the pH.

[0068] Even when the above-mentioned additional components are added, the ophthalmic composition of the present invention may contain the molecular associate in an amount of 0.001 to 0.04 wt %, preferably 0.005 wt % or more, more preferably 0.01 wt % or more, and preferably 0.03 wt % or less, more preferably 0.02 wt % or less, based on the total content of the composition.

[0069] In addition, the molecular associate contained in the ophthalmic composition according to the present invention has excellent storage stability. Unlike typical nano-sized dispersed particles, which are easily exposed to aggregation or Ostwald ripening and have poor storage stability, the molecular associate and composition contained in the ophthalmic composition according to the present invention exhibit little change in the molecular associate under long-term, intermediate, or accelerated storage conditions, thereby exhibiting excellent stability. The change rate refers to the average change rate calculated by averaging the change rates for each month up to the specified period.

[0070] As described above, it can be seen that the molecular association of the present invention has excellent stability.

[0071] Specifically, the molecular aggregate contained in the eye drop composition may be present in an amount of 0.001 to 0.04 wt % relative to the total content of the composition, and the change in the total content over 6 months under long-term storage conditions of 25°C±2°C / 40%±5% may be 80.0 to 110.0%, preferably 90.0 to 110.0%.

[0072] Furthermore, the molecular aggregate contained in the eye drop composition may be present in an amount of 0.001 to 0.04 wt % relative to the total content of the composition, and the change in the total content over 6 months under intermediate conditions of 30°C±2°C / 65%±5% may be 80.0 to 110.0%, preferably 90.0 to 110.0%.

[0073] Furthermore, in the eye drop composition, the molecular aggregate contained in the eye drop composition may be contained in an amount of 0.001 to 0.04 wt % relative to the total content of the composition, and the change in the total content over 6 months under accelerated conditions of 40°C±2°C / 25%±5% may be 80.0 to 110.0%, preferably 90.0 to 110.0%.

[0074] The eye drop composition of the present invention contains a molecular association of cyclosporine, the active ingredient, in an amount of 0.001 to 0.04 wt % relative to the total content of the composition, which is significantly lower than that of eye drop compositions of the prior art. However, the active ingredient cyclosporine can be efficiently present in the cornea and conjunctiva, and as a result, when the eye drop composition is administered to the eye, the amount of exposure of the cornea and conjunctiva may be at least two times, preferably at least three times, more preferably at least four times, and most preferably at least five times.

[0075] Furthermore, when the eye drop composition according to the present invention is administered into the eye, the amount of the eye drop composition that flows into the bloodstream throughout the body other than the ocular tissues may be 0.02% or less, preferably 0.01% or less, and more preferably 0.005% or less of the total administered amount.

[0076] Method for producing the cyclosporin nanomolecular aggregate and the ophthalmic composition of the present invention The molecular associate of cyclosporin A according to one embodiment of the present invention can be prepared by applying shear stress to a solution containing cyclosporin A, which is a precursor of the molecular associate.

[0077] The shear stress applied to the solution containing cyclosporin A, which is the precursor of the molecular association, may be mechanical shear stress.

[0078] The mechanical shear stress may be applied by passing the solution through a silica-filled column or filter paper. Mechanical shear stress will be specifically described below.

[0079] More specifically, the present invention provides a method for producing a molecular associate in which cyclosporine is physically bound, comprising the steps of: 1) introducing a cyclosporine solution into silica and then repeatedly draining the cyclosporine; 2) filtering the drained solution and concentrating the filtrate by vacuum distillation; 3) filtering the concentrated residual liquid phase and crystallizing it; and 4) filtering, washing, and drying the crystallized solid.

[0080] First, the method for producing a molecular association of the present invention includes the steps of: 1) introducing a cyclosporine solution into silica, and then repeatedly releasing the cyclosporine.

[0081] According to one embodiment of the present invention, the mechanical shear stress may be applied by passing a solution containing cyclosporine A, the precursor of the molecular associate, through a column packed with silica. When the solution containing cyclosporine A passes through a column packed with silica or the like, it passes through a physically narrow region, and as a result, the precursor of the molecular associate, cyclosporine A, is subjected to very high shear stress.

[0082] The silica may be spherical or angular, but is not limited to this shape.

[0083] The average particle size of the silica may be 1.0 to 50 μm, specifically, 1.5 μm or more, 2 μm or more, or 40 μm or less, 30 μm or less, 20 μm or less, 10 μm or less, or 5 μm or less. If the size of the silica is less than 1.0 μm or exceeds 50 μm, even if the solution containing cyclosporine A passes through a column packed with silica, no shear stress is applied, and there is a possibility that the molecular aggregates will not change.

[0084] A negative pressure of 0.1 bar to 1.0 bar or 0.2 bar to 0.9 bar can be applied to the bottom of the silica-packed column. If the negative pressure applied to the bottom of the silica-packed column is less than 0.1 bar, the time required for the cyclosporine A-containing solution to pass through the column increases, which may delay the production time of the cyclosporine A molecular associate of the present invention. If the negative pressure applied to the bottom of the silica-packed column is more than 1.0 bar, the time required for the cyclosporine A-containing solution to pass through the column decreases, which may shorten the production time of the cyclosporine A molecular associate of the present invention, but may increase production costs due to the need for an additional pumping device.

[0085] According to another embodiment of the present invention, the mechanical shear stress may be applied by passing the solution containing cyclosporine A through one or more filter papers. When passing through the one or more filter papers, the precursor of the molecular association, cyclosporine A, passes through a physically narrow area and is subjected to very high shear stress.

[0086] The filter paper may be a single filter paper or two or more filter papers. When the filter paper is two or more filter papers, the filter papers may be stacked. When the filter paper is two or more filter papers, the filter paper may provide a higher shear stress than when a single filter paper is used.

[0087] The pore size of the filter paper may be 0.1 to 5.0 microns or 0.3 to 4.5 microns. If the pore size of the filter paper is less than 0.1 micron, the amount of the bile acid-containing solution passing through or filtered by the filter paper may be too small, which may reduce the production rate of the cyclosporine A molecular aggregate according to the present invention. If the pore size of the filter paper is more than 5.0 microns, the bile acid-containing solution may simply pass through the filter paper, which may result in ineffective application of shear stress.

[0088] The method for producing a molecular association of the present invention further comprises the step of 2) filtering the effluent and concentrating the filtrate by vacuum distillation. The filtering, vacuum distillation, and concentration methods can be any methods commonly used in the industry without any particular limitations.

[0089] The method for producing a molecular association of the present invention further comprises the steps of: (3) filtering the concentrated residual liquid phase and then crystallizing the filtered liquid phase; the filtering and crystallization methods can be any methods commonly used in the industry without any particular limitations.

[0090] The method for producing a molecular association of the present invention further comprises the step of 4) filtering, washing, and drying the crystallized solid. The filtering, washing, and drying may be performed by methods commonly used in the industry without any particular limitations.

[0091] The present invention will be described in more detail below through examples of the present invention, but it is to be understood that the present invention is not limited to these examples. [Example]

[0092] Example 1. Preparation of cyclosporine nanomolecular aggregate (SCAI-001) 1) 0.33 kg of cyclosporine A API (hereinafter referred to as CsA) was weighed out.

[0093] 2) 22.38 kg of 94.5% ethanol (hereinafter referred to as ethanol) was weighed separately.

[0094] 3) The ethanol prepared in 2) above was added to the CSA prepared in 1) above, and the mixture was stirred for 1 hour using a stirrer to prepare a CsA solution in advance.

[0095] 4) 16.70 kg of ethanol was weighed separately.

[0096] 5) Grace SYLOID 244FP was sieved using a 425 μm mesh.

[0097] 6) After weighing 1.67 kg of 425 μm silica, the ethanol from 4) was added and thoroughly wetted with a medicine spoon.

[0098] 7) Separately, 33.40 kg of EtOH 94.5% was weighed out.

[0099] 8) A Buchner funnel was placed on the Erlenmeyer flask and a 1.0 μm paper filter was placed on the funnel.

[0100] 9) After wetting a 1.0 μm paper filter with EtOH, the vacuum pump was turned on to adsorb it to the bottom of the funnel, and then the wetted silica from 6) above was slowly poured into it.

[0101] 10) When about 0.5 cm of silica liquid remained on top, the vacuum pump was stopped, the filtrate was discarded, and a new flask was placed in.

[0102] 11) The CSA solution prepared in 3) above was slowly poured onto the packed silica in several portions, taking care not to dig into the silica.

[0103] 12) When about 0.5 cm of the silica upper layer remained, the EtOH prepared in 7) was poured in two portions of 16.70 kg each.

[0104] 13) The filtrate from 12) was filtered using a 0.45 μm membrane filter (PVDF).

[0105] 14) The filtered filtrate was concentrated to 2.34 kg using a rotary vacuum evaporator (28°C, 80 to 180 rpm, 20 mbar).

[0106] 15) 0.33 kg of EtOH 94.5% was weighed out twice.

[0107] 16) The concentrated solution (2.34 kg) was filtered using a 0.22 μm membrane filter (PVDF). The CSA concentrate adhering to the filter was washed with the EtOH prepared in 15).

[0108] 17) Separately, 0.33 kg of EtOH 94.5% was weighed out.

[0109] 18) Purified water was filtered through a 0.22 μm (PVDF) membrane filter to prepare 100.20 kg.

[0110] 19) An overhead stirrer and impeller were set up to prepare for crystallization, and the concentrate from 16) was slowly added dropwise to the purified water from 18) for 40 minutes.

[0111] 20) After the dropwise addition was completed, the concentrated solution of 16) was washed with the EtOH prepared in 17) and added.

[0112] 21) The mixture of 20) was stirred for 2 hours and then allowed to stand for 1 hour.

[0113] 22) Purified water was filtered through a 0.22 μm (PVDF) membrane filter, and 5.01 kg was prepared separately.

[0114] 23) The mixture from 21) was poured into a glass filter (G3) and the crystallized solid was filtered.

[0115] 24) The purified water prepared in 22) was added to the mixture of 21) to wash the crystallized solid.

[0116] 25) The filtered crystallized solid was filtered under reduced pressure using a vacuum pump for about 1 hour, and then dried in a vacuum dryer (50°C, -0.1 bar).

[0117] 26) The moisture content was checked by KF, and if it was less than 2.5%, a solubility test was performed.

[0118] 27) When the value of 26) was met, the mixture was filtered using a 500 μm mesh sieve to obtain cyclosporine nanomolecular aggregates (SCAI-001).

[0119] The specific results are shown in Table 1 below.

[0120] [Table 1]

[0121] [Table 2]

[0122] Example 2. Preparation of a composition for producing an ophthalmic solution containing cyclosporine nanomolecular aggregates (SCAI-001) 1) After weighing 40 g of cyclosporine and 40 g of castor oil into an STS reactor, 8 kg of 95% ethanol (hereinafter referred to as ethanol) was added and dissolved for 1 hour while maintaining the internal temperature at 10-25°C. Separately, 8 kg of ethanol and 400 g of silica were weighed into a G / L reactor and stirred uniformly for 30 minutes. The wetting silica in the G / L reactor was slowly filtered through a Nutsche filter until the ethanol reached a surface thickness of 1-2 cm, forming a silica packed bed. The filtrate was then discarded.

[0123] 2) The solution from the STS reactor is filtered through a packed-bed Nutsche filter, then filtered through a housing filter (10 inch, 0.45 μm PES) and transferred to the G / L reactor in 1), and the filter is washed with 12 kg of ethanol before being transferred.

[0124] 3) 60 kg of ethanol and 0.16 kg of polysorbate 80 were added to the G / L reactor of 2) and stirred for 1 hour.

[0125] 4) Separately, 300 kg of PW (purified water) was added to an STS reactor, and the reaction solution from the G / L reactor in 3) was added dropwise for over 1 hour. After the addition was completed, the mixture was stirred for 30 minutes.

[0126] 5) The reaction solution in the STS reactor was subjected to primary vacuum concentration at an internal temperature of 30°C or less. After primary concentration was complete, the reaction solution in the STS reactor was filtered through a housing filter (10 inch, 0.45 μm PES) to remove precipitates. The filtrate filtered through the housing filter was subjected to secondary concentration at an internal temperature of 35°C or less. After secondary concentration was complete, the secondary concentrate was subjected to in-process inspections for cyclosporine concentration and residual ethanol testing (cyclosporine concentration: 1.0 mg / mL ± 10%, residual ethanol 5000 ppm or less). After in-process inspection was complete, the concentrate in the STS reactor was filtered through a housing filter (10 inch, 0.2 μm PES), and 22.78 kg was divided and packaged in LDPE sterile water bottles to obtain a composition for producing an ophthalmic solution containing SCAI-001.

[0127] Example 3. Ophthalmic composition containing cyclosporine nanomolecular aggregate (SCAI-001) 1) Manufacturing We conducted formulation research on an ophthalmic composition containing SCAI-001 as the active ingredient, and produced stability samples and clinical samples through contract manufacturing.

[0128] A dosage form study was completed using only the supplemental ingredients used in the Allergan product Restasis.

[0129] Using the molecular associates and compositions for preparing eye drops obtained in Examples 1 and 2, eye drop compositions were prepared as shown in Table 3 below.

[0130] [Table 3]

[0131] 2) Evaluation results After preparation of the eye drops, the evaluation results are shown in Table 4. After preparation, no precipitation occurred in any of the experimental groups of Compositions 1 to 6, and all were confirmed to be transparent.

[0132] It was confirmed that the zeta measurement values ​​differed depending on the amount of carbomer, and that as the amount of carbomer increased, the zeta results became unstable and the viscosity of the sample increased rapidly.

[0133] Among these, composition 4 was confirmed to be a composition that is easy to produce and can ensure stability.

[0134] [Table 4]

[0135] 3) Clinical sample production Stability samples and clinical samples were prepared through a contractor capable of producing disposable eye drops, and the details are summarized in Table 5 below.

[0136] [Table 5]

[0137] Experimental Example 1. Stability test of eye drop composition containing cyclosporine nanomolecular aggregate (SCAI-001) 1. Pharmaceutical raw materials SCAI-001 is a refrigerated drug, and stability tests were conducted on one manufacturing unit (Batch. SCAI-22E01) under accelerated and long-term storage conditions. For refrigerated drug storage, the accelerated test was conducted at a temperature of 25°C ± 2°C and humidity of 70% ± 5%, while the long-term test was conducted at a temperature of 5°C ± 3°C, and stability was confirmed at the initial stage and 1 month, 2 months, 3 months, and 6 months. The stability test results are as follows:

[0138] 1.1 Long-term storage conditions The test criteria for long-term storage conditions and the results are shown in Table 6. As a result of the stability test, all test items met the criteria for 6 months under long-term storage conditions, and no changes over time were observed, indicating stability.

[0139] [Table 6]

[0140] 1.2 Acceleration conditions The test criteria and results under accelerated conditions are shown in Table 7 below. The stability test results showed that the total amount of softening agents increased by approximately 0.6% over the initial period under accelerated conditions for 6 months, but still met the criteria. Other test items also met the criteria, and no changes were observed over time, indicating stability.

[0141] [Table 7]

[0142] 2. The finished pharmaceutical products were Composition 4, a 0.02% ophthalmic solution composition prepared in Example 3, and Composition 6, a 0.01% ophthalmic solution composition. Stability tests were conducted on one batch per volume for research purposes to confirm stability when stored at room temperature. Packaged in LDPE material, the pharmaceutical products were stored at room temperature and stability tests were conducted under accelerated conditions (40°C ± 2°C, 25% ± 5% humidity), intermediate conditions (30°C ± 2°C, 65% ± 5%), and long-term storage conditions (25°C ± 2°C, 40% ± 5%). The test periods were 6 months under accelerated conditions, 12 months under intermediate conditions, and 24 months under long-term storage. Currently, stability has been confirmed for up to 6 months.

[0143] 2.1 Stability test results for 0.02% ophthalmic solution composition (composition 4) 2.1.1 Long-term storage conditions The long-term storage criteria and the results are shown in Table 8. As a result of the stability test, all test items met the criteria for the long-term storage conditions for 6 months, and no changes were observed over time, indicating stability.

[0144] [Table 8]

[0145] 2.1.2 Midterm Examination Conditions The intermediate test criteria and results are shown in Table 9. The results of the stability test showed that the content was within the criteria for 6 months under the intermediate conditions, but a significant change was observed, with a decrease of approximately 10% compared to the initial content. The other items met the criteria.

[0146] [Table 9]

[0147] 2.1.3 Accelerated test conditions The accelerated test criteria and results are shown in Table 10. As a result of the stability test, significant changes were observed in the content results over a 6-month period under accelerated test conditions. The content decreased by approximately 20% compared to the initial test results, failing to meet the criteria.

[0148] [Table 10]

[0149] 2.2 Stability test results for 0.01% ophthalmic solution composition (composition 6) 2.2.1 Long-term storage conditions The long-term storage criteria and the results are shown in Table 11. As a result of the stability test, all test items met the criteria for the long-term storage conditions for 6 months, and no changes over time were observed, indicating stability.

[0150] [Table 11]

[0151] 2.2.2 Midterm Examination Conditions The interim test criteria and results are shown in Table 12. As a result of the stability test, all test items met the criteria for the interim condition over 6 months, and no changes over time were observed, indicating stability.

[0152] [Table 12]

[0153] 2.2.3 Accelerated test conditions The accelerated test criteria and results are shown in Table 13. As a result of the stability test, the content results were within the criteria for 6 months under the accelerated test conditions, but a significant change was observed, with a decrease of approximately 8% compared to the initial test results.

[0154] [Table 13]

[0155] Experimental Example 2. PK / PD study of ophthalmic composition containing cyclosporine nanomolecular aggregate (SCAI-001) The 0.02% ophthalmic solution composition (Composition 4) and the 0.01% ophthalmic solution composition (Composition 6) prepared in Example 3, as well as a control eye drop formulation (Restasis, 0.05%) as Comparative Example 1, were administered to NZW rabbits in single or repeated instillations (12-hour intervals, 7 days) to evaluate the pharmacokinetic distribution in ocular tissues and blood. 50 μL of the control and test formulations were instilled into the left and right eyes of the rabbits, and the animals were euthanized at each time point, after which blood and various tissue samples were collected. For the single instillation study, samples were collected 30 minutes and 1, 3, 6, 12, 24, 48, and 72 hours after instillation. For the repeated instillation study, samples were collected 1, 6, 24, and 72 hours after the final instillation on Day 7. Blood and nine types of ocular tissue samples (cornea, conjunctiva, aqueous humor, lens, iris, vitreous humor, sclera, choroid, and retina) were collected from two rabbits at each sampling time point. Drug components in each sample were extracted and their concentrations were analyzed using a Sciex QTRAP6500 mass spectrometer.

[0156] Using the analysis function of Phoenix WinNonlin software, the main pharmacokinetic parameters were calculated from the quantitative analysis results of the animal experiments, and the intraocular absorption, distribution, and elimination patterns of the examples of the present invention over time after administration were compared with those of the control formulation (Restasis).

[0157] The control formulation, Restasis (0.05%), and the 0.02% ophthalmic solution compositions, Composition 4, and Composition 6, 0.01% ophthalmic solution compositions prepared in Example 3 of the present invention, were administered to rabbit eyes either once or repeatedly, and their intraocular distribution was examined. The pharmacokinetics of the Examples and Comparative Examples were compared by measuring the amount of Cyclosporine A, the main component of the drug, transported into the blood and ocular tissues over time after ophthalmic administration. The LC / MS analytical method used in the analysis of the Examples and Comparative Examples was first validated, and then sample analysis was performed under consistent analytical conditions. For quantitative analysis, sample standard solutions prepared by diluting Cyclosporine A standards at various concentrations were subjected to organic solvent extraction or solid phase extraction (SPE). The drug concentrations in whole blood and ocular tissues were calculated using the calibration curves for each biological sample analyzed. The results are summarized in Tables 14 and 15 and Figures 1 and 2.

[0158] Table 14 below shows blood and tissue PK parameters for SCAI-001 (0.01%, 0.02%) and Restasis (0.05%) from a single ocular administration study.

[0159] [Table 14A] [Table 14B]

[0160] Table 15 below shows the blood and tissue PK variables and accumulation rates relative to a single eye drop of SCAI-001 (0.01%, 0.02%) and Restasis (0.05%) from a repeated eye drop study.

[0161] [Table 15A] [Table 15B]

[0162] In a single ophthalmic administration study, the drug exposure levels analyzed based on AUClast were confirmed to be highest in the cornea and conjunctiva, which are the drug targets, for both the control and test formulations. The specific exposure levels were as follows: (14,501.73 h*ng / g and 7,139.55 h*ng / g for Composition 6, a 0.01% ophthalmic solution composition prepared in Example 3; 21,979.46 h*ng / g and 9,437.89 h*ng / g for Composition 4, a 0.02% ophthalmic solution composition prepared in Example 3; and 13,257.85 h*ng / g and 6,855.43 h*ng / g for the control ophthalmic solution formulation (Restasis, 0.05%) used as Comparative Example 1). In tissues other than the cornea and conjunctiva, the highest levels of exposure were in the iris, followed by the sclera, choroid, retina, and aqueous humor (AH). On the other hand, concentrations below the lowest limit of quantification were detected in the vitreous humor (VH) and lens.

[0163] In particular, it was confirmed that the Examples had higher corneal and conjunctival exposure levels after a single administration, despite the lower instillation volume compared to the comparative example, Restasis (during dose normalization of AUClast, the corneal and conjunctival exposure levels were 5.47-fold and 5.21-fold higher for Composition 6, a 0.01% ophthalmic solution composition prepared in Example 3, and 3.98-fold and 3.44-fold higher for Composition 4, a 0.02% ophthalmic solution composition prepared in Example 3, compared to Restasis (0.05%)).

[0164] In whole blood, the examples reached Cmax within 1 hour and were detected at concentrations below the minimum limit of quantification for most of the time period except for Cmax.

[0165] In the repeated eye drop administration test, the drug exposure amount analyzed based on AUClast was confirmed to be highest in the cornea in both the comparative example and the examples (Composition 6, a 0.01% eye drop composition prepared in Example 3, 77,677.25 h*ng / g; Composition 4, a 0.02% eye drop composition prepared in Example 3, 85,080 h*ng / g; Comparative example 1, a control eye drop formulation (Restasis, 0.05%), 42,546 h*ng / g), followed by the conjunctiva, iris, sclera, lens, choroid, AH, and retina. In the VH, concentrations below the lowest limit of quantitation were detected. In the repeated ophthalmic administration test, the corneal and conjunctival exposure levels were also higher in the Examples than in the Comparative Examples, despite the lower doses (during dose normalization of AUClast, the corneal and conjunctival exposure levels were 9.13-fold and 4.06-fold higher for the 0.01% ophthalmic solution composition, Composition 6, and 5.00-fold and 2.69-fold higher for the 0.02% ophthalmic solution composition, Composition 4). In whole blood, the test formulation was confirmed to reach Cmax within 1 hour, and was detected at concentrations below the lowest quantitation limit for most time periods except for Cmax. In the repeated ophthalmic administration test, drug accumulation was confirmed in all biological samples except for the conjunctiva and whole blood, with the accumulation rate ranging from 72.58 to 1255.43%.

[0166] After administration, Composition 6, a 0.01% ophthalmic solution composition prepared in Example 3, was distributed in higher concentrations in the cornea, conjunctiva, iris, and choroid than the control eye drop formulation (Restasis, 0.05%), Comparative Example 1. Composition 4, a 0.02% ophthalmic solution composition prepared in Example 3, was distributed in higher concentrations in all tissues than Comparative Example 1. This indicates that the active ingredient of the drug is delivered more efficiently to target tissues in the eye at lower doses in the Examples than in the Comparative Examples. Furthermore, the amount of Cyclosporine A exposed in the cornea and conjunctiva accounted for 96.52-98.05% of the total amount of Cyclosporine A detected in all tissues in the single-administration test and 94.73-96.01% in the repeated-administration test.

[0167] In conclusion, in the Examples of the present invention, after administration, the majority of the drug was present in the target tissues, the cornea and conjunctiva, and was delivered to the target tissues more efficiently at a lower concentration than in the Comparative Examples. The amount of drug that flowed into the bloodstream throughout the body other than the ocular tissue, which is the target tissue of the drug, was low, at 0.02% or less of the total administered amount, both in single and repeated instillation.

Claims

1. a molecular association in which cyclosporine is physically bound, When the molecular association is formed from a composition containing water, In the composition, the molecular association has an aggregated structure. Molecular association.

2. 2. The molecular association according to claim 1, wherein the molecular association has an average particle size of 1.0 to 10 nm.

3. 2. The molecular associate according to claim 1, wherein the amount of total softening substances remaining in the molecular associate after six months under long-term storage conditions at a temperature of 5°C±3°C is 1.5% or less of the initial amount.

4. 2. The molecular association according to claim 1, wherein the amount of total softening substances remaining after six months under accelerated conditions of 25°C±2°C / 70%±5% is 1.5% or less of the initial amount.

5. A composition for producing an ophthalmic solution, comprising the molecular association of claim 1, a surfactant, a solubilizing agent, and purified water.

6. 6. The composition for producing an ophthalmic solution according to claim 5, wherein the molecular association is contained in an amount of 0.001 to 0.04% by weight based on the total content of the composition.

7. 6. The composition for producing an ophthalmic solution according to claim 5, wherein the molecular association is contained in an amount of 0.001 to 0.02% by weight based on the total content of the composition.

8. 6. The composition for producing an ophthalmic solution according to claim 5, wherein the surfactant is contained in an amount of 0.001 to 0.5% by weight based on the total content of the composition.

9. 6. The composition for producing an ophthalmic solution according to claim 5, wherein the surfactant is contained in an amount of 0.01 to 0.1% by weight based on the total content of the composition.

10. 6. The composition for producing an ophthalmic solution according to claim 5, wherein the solubilizer is contained in an amount of 0.001 to 0.1% by weight based on the total content of the composition.

11. 6. The composition for preparing an ophthalmic solution according to claim 5, wherein the surfactant is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, alcohols, amine oxides, block polymers, carboxylate alcohols, alkylphenol ethoxylate carboxylic acids / fatty acids, ethoxylated alcohols, ethoxylated alkylphenols, ethoxylated arylphenols, ethoxylated fatty acids, ethoxylates, fatty esters or oils, fatty esters, fatty acid methyl ester ethoxylates, glycerol esters, glycol esters, lanolin derivatives, lecithin, lecithin derivatives, lignin, lignin derivatives, methyl esters, monoglycerides, monoglyceride derivatives, polyethylene glycol, polymeric surfactants, propoxylated and ethoxylated fatty acids, alcohols or alkylphenols, protein-derived surfactants, saccharosin derivatives, sorbitan derivatives, sucrose, sucrose derivatives, glucose esters, and glucose ester derivatives.

12. 6. The composition for preparing an ophthalmic solution according to claim 5, wherein the solubilizer is at least one selected from the group consisting of castor oil, canola oil, C12-15 alkyl benzoate, almond oil, aluminum monostearate, cetostearyl alcohol, cholesterol, coconut oil, cyclomethicone, dimethicone, ethylene glycol stearate, glycerin, glyceryl monooleate, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, hydrogenated lanolin, lecithin, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, oleyl oleate, petrolatum, polydicaine, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, soybean oil, sunflower oil, wax, xylitol, and zinc acetate.

13. The composition for producing an ophthalmic solution according to claim 5, An eye drop composition further comprising at least one selected from the group consisting of a viscosity adjuster, an osmotic pressure adjuster, and a pH adjuster.

14. The eye drop composition according to claim 13, wherein the viscosity adjuster is contained in an amount of 0.001 to 0.5% by weight based on the total content of the composition.

15. 14. The eye drop composition according to claim 13, wherein the osmotic pressure adjusting agent is contained in an amount of 0.5 to 10.0% by weight based on the total content of the composition.

16. 14. The eye drop composition according to claim 13, wherein the content of the viscosity adjuster is 0.5 to 2.5 times the content of the molecular association.

17. The viscosity adjuster may be acacia, agar, alanic acid, alginic acid, aluminum monostearate, attapulgite, bentonite, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carmellose, carrageenan, cellulose, microstearate, cetostearyl alcohol, chitosan, corn syrup, cyclomethicone, dextrin, egg phospholipids, ethyl cellulose, gelatin, aluminum magnesium silicate, maltitol solution, maltodextrin, medium chain triglyceride, methylcellulose, pectin, polycarbophil, polydextrose, polyethylene oxide, polyvinyl alcohol, potassium alginate, povidone, propylene glycol alginate, pullulan, dental type silica, hydrophobic colloidal silica, silicon dioxide, colloidal silica, sodium alginate, or sorbitan monolaurate. , sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, corn starch, hydroxypropyl corn starch, pregelatinized hydroxypropyl corn starch, starch P, hydroxypropyl starch P, pregelatinized hydroxypropyl starch P, potato starch, gellan gum, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, isomalt, α-lactalbumin, kaolin, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, tapioca starch, wheat starch, sucrose, sucrose palmitate, tragacanth, vitamin E propylene glycol succinate, and xanthan gum.

18. 14. The eye drop composition according to claim 13, wherein the osmotic pressure adjusting agent is at least one selected from the group consisting of glycerin, sorbitol, mannitol, dextrose, and sucrose.

19. 14. The eye drop composition according to claim 13, wherein the pH adjuster is at least one selected from the group consisting of acetic acid, adipic acid, ammonia solution, ammonium carbonate, ammonium chloride, ammonium phosphate, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, citric acid, diethanolamine, fumaric acid, glycine, hydrochloric acid, α-lactalbumin, lactic acid, lysine hydrochloride, malic acid, maleic acid, methionine, monoethanolamine, sodium glutamate, nitric acid, phosphoric acid, potassium citrate, potassium hydroxide, potassium metaphosphate, potassium phosphate, propionic acid, racemethionine, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate, succinic acid, sulfuric acid, tartaric acid, and trolamine.

20. The molecular association is contained in an amount of 0.001 to 0.04% by weight based on the total content of the composition; 14. The eye drop composition according to claim 13, wherein the change in total content over a 6-month period under long-term storage conditions of 25°C±2°C / 40%±5% is 90.0 to 110.0%.

21. The molecular association is contained in an amount of 0.001 to 0.04% by weight based on the total content of the composition; 14. The eye drop composition according to claim 13, wherein the change in total content after 6 months at intermediate conditions of 30°C±2°C / 65%±5% is 90.0 to 110.0%.

22. The molecular association is contained in an amount of 0.001 to 0.04% by weight based on the total content of the composition; 14. The eye drop composition according to claim 13, wherein the change in total content over 6 months under accelerated conditions of 40°C±2°C / 25%±5% is 80.0 to 110.0%.

23. 14. The eye drop composition according to claim 13, wherein the amount of the cornea and conjunctiva exposed when the eye drop composition is administered is three times or more.

24. 14. The eye drop composition according to claim 13, wherein the amount of the eye drop composition that flows into the bloodstream of the entire body other than the ocular tissues when administered to the eye is 0.02% or less of the total administered amount.

25. A method for producing a molecular association in which cyclosporine is physically bound, 1) introducing a cyclosporine solution into silica, and then repeatedly discharging the cyclosporine; 2) filtering the effluent and then concentrating the filtrate by vacuum distillation; 3) filtering the concentrated residual liquid phase and then crystallizing it; and 4) filtering, washing and drying the crystallized solid; Method for producing molecular associations.

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