KR20140146897A - Transparent eye drops composition comprising cyclosporin - Google Patents

Transparent eye drops composition comprising cyclosporin Download PDF

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Publication number
KR20140146897A
KR20140146897A KR1020130069815A KR20130069815A KR20140146897A KR 20140146897 A KR20140146897 A KR 20140146897A KR 1020130069815 A KR1020130069815 A KR 1020130069815A KR 20130069815 A KR20130069815 A KR 20130069815A KR 20140146897 A KR20140146897 A KR 20140146897A
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KR
South Korea
Prior art keywords
weight
transparent
composition
cyclosporin
parts
Prior art date
Application number
KR1020130069815A
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Korean (ko)
Inventor
이상필
Original Assignee
이상필
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Priority to KR1020130069815A priority Critical patent/KR20140146897A/en
Publication of KR20140146897A publication Critical patent/KR20140146897A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/014—Hydrolysed proteins; Derivatives thereof from animals from connective tissue peptides, e.g. gelatin, collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1751—Bactericidal/permeability-increasing protein [BPI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2305/00—Use of specific compounds during water treatment
    • C02F2305/04—Surfactants, used as part of a formulation or alone

Abstract

Provided in the present invenition is a transparent cyclosporine eye drops composition including cyclosporine, polyethylene glycol400, propylene glycol, and a surfactant, which is transparent in external appearance and does not have sense of foreign materials and stimulation to be used in prevention or treatment of dry eye.

Description

[0001] Transparent eye drops composition containing cyclosporin [

The present invention relates to a transparent ophthalmic solution composition containing cyclosporin and a pharmaceutical composition for preventing or treating dry eye syndrome, and more particularly to a transparent ophthalmic solution composition comprising cyclosporin, polyethylene glycol 400, propylene glycol and a surfactant, To a pharmaceutical composition for preventing or treating dry eye syndrome.

Dry eye syndrome is one of the most commonly encountered diseases in clinical practice. It is known to be a multifactorial disease with increased tear osmolarity, ocular discomfort accompanied by ocular surface inflammation, visual disturbance, and tear layer instability. The therapeutic approach has shifted attention to preserving the tear layer by releasing leukocytes at the stage of supplementing the aqueous layer of tears. Recently, cyclosporine eye drops have been used for immune and inflammatory responses.

The development of dry eye syndrome due to autoimmunity is caused by the infiltration of T lymphocytes activated by autoimmune reaction into the ocular surface and the main lacrimal gland, releasing a large amount of proinflammatory cytokines. Such inflammatory reactions are chronic progression, Of the epithelial cells.

Cyclosporine is a polymer peptide drug (molecular weight 1202) consisting of 11 amino acids, which inhibits the growth and differentiation of T-cells and thus has strong immunosuppressive activity. It is a drug effective for dry eye syndrome.

However, since cyclosporine is insoluble in water, it is generally used in a suspended form. However, it is preferable to provide a clear aqueous liquid form for use as an eye drop. In the case of a suspension type formulation, There is a difficulty in thorough examination, and it also causes discomfort to the eyes. Thus, a clear solution composition is the most desirable formulation for administration to the eye.

Accordingly, the inventor of the present invention has found that when using a cyclosporin eye drop suitable for use in eyes, it is possible to produce a transparent eye drop of cyclosporin which is transparent and less irritating to eyes when polyethylene glycol 400, propylene glycol and a surfactant are used, .

The present invention provides a transparent ophthalmic solution composition containing cyclosporin, which is apparently transparent, free of foreign objects and irritation, and useful for preventing or treating dry eye syndrome.

The present invention also provides a method for producing the transparent ophthalmic solution composition.

In order to solve the above problems, the present invention relates to a cosmetic composition comprising 1 part by weight of cyclosporin, 50 to 200 parts by weight of polyethylene glycol 400, 5 to 20 parts by weight of polyoxyl 40 hardened castor oil, 2 to 10 parts by weight of polysorbate 80, And a composition comprising water, a surfactant, and water.

The term " cyclosporin " used in the present invention refers to a drug that has a strong immunosuppressive activity by inhibiting the growth and differentiation of T-cells as a polymer peptide drug (molecular weight 1202) consisting of 11 amino acids. The cyclosporine is clinically used for the purpose of inhibiting the immune rejection reaction occurring in the graft recipient after transplantation of organs such as the kidney, liver, heart, bone marrow, pancreas, skin, cornea and tissue, Have been applied to diseases. In particular, the present invention is used for prevention or treatment of dry eye syndrome.

Cyclosporine is generally used in suspended form because it is insoluble in water. However, when it is used for eyedrops, it is difficult for the patient to use the suspension because the suspension gives a foreign body to the eyes. In the case of the suspension type formulation, it is difficult to perform complete examination in the eye drop of the aseptic preparation which is subjected to the complete examination at the time of manufacture. Accordingly, the present invention provides a transparent eye drop composition of cyclosporin by adding polyethylene glycol 400, propylene glycol and a surfactant.

The term 'polyethylene glycol 400' used in the present invention is an addition polymer of ethylene oxide and water, represented by HOCH 2 (CH 2 OCH 2 ) nCH 2 OH, wherein n is 7 to 9. Polyethylene glycol 400, which is used as a viscosity modifier in the present invention, is used to provide a clear ophthalmic solution composition of cyclosporin together with a surfactant.

The term 'propylene glycol' used in the present invention is a kind of alcohol made from propylene as a raw material and is represented by CH 3 CHOHCH 2 OH. Propylene glycol is used as a solubilizing aid in the present invention and is used to provide a clear eye drop composition of cyclosporin together with a surfactant.

The term " surfactant " used in the present invention means a substance commonly used for dissolving a water-insoluble substance in water, which has both a hydrophilic part and a hydrophobic part. In the present invention, polyoxyl 40 hardened castor oil and polysorbate 80 are used as a surfactant and polyethylene glycol 400 is used to provide a clear eye drop composition of cyclosporin. In order to improve the transparency of cyclosporin, it is more preferable to use polyoxyl 40 hardened castor oil and polysorbate 80.

The polyethylene glycol 400 and the surfactant used in the present invention are preferably used in an amount of 50-200 parts by weight and 5-20 parts by weight, respectively, based on 1 part by weight of the cyclosporin. When they are used within the above-mentioned range, the transparency is lowered. If they are each in excess of the above range, the viscosity is increased and a foreign matter is formed on the eyes. see. Preferably, the polyethylene glycol 400 is 50-200 parts by weight based on 1 part by weight of the cyclosporin. The content of propylene glycol is preferably 0.5 to 10 parts by weight based on 1 part by weight of cyclosporin. When the content of propylene glycol is less than 0.5 part by weight, there is a problem in the stability of the transparent eye drop. When the content of propylene glycol is more than 10 parts by weight, the osmotic pressure of the eye drops increases and the eye may be irritated.

Since the transparent ophthalmic solution composition according to the present invention is used for eyes, it is preferable that the pH is 7.2 to 7.5 in order to minimize irritation to the eyes. If the concentration is out of the above range, the acidic or basic property becomes stronger, which may cause irritation to the eyes. In order to adjust the pH, it is preferred to adjust using the sodium hydroxide, sodium chloride or a combination thereof in the present invention.

In addition, the transparent ophthalmic solution composition according to the present invention may further comprise 1-10 parts by weight of carboxymethyl cellulose sodium, 1 part by weight of cyclosporin, sodium carboxymethyl cellulose, sodium hyaluronate or omega 3 fatty acid. Sodium carboxymethylcellulose, sodium hyaluronate, or omega-3 fatty acids, which aid in the efficacy of cyclosporine, can be useful for dry eye syndrome.

The present invention also provides a pharmaceutical composition for preventing or treating dry eye syndrome comprising the above-mentioned transparent eye drop composition.

The term " dry eye syndrome " used in the present invention means that T lymphocytes activated by an autoimmune reaction infiltrate into the ocular surface and the main lacrimal gland and secrete a pro-inflammatory cytokine in a large amount. The inflammatory reaction is chronic, Which is caused by damage to the epithelial cells of the ocular surface.

The transparent eye drop cyclosporine according to the present invention inhibits T lymphocytes activated by the immune response and down-regulates the proinflammatory cytokine of the conjunctiva. In addition, the goblet cells in the conjunctiva are increased in the point of the cyclosporin and the proliferation of epithelial cells is suppressed. The use of cyclosporin transparent eye drops according to the present invention in patients with dry eye syndrome increases the basal tear secretion, improves angular conjunctival epithelium, increases the density of conjunctival goblet cells and the production of transforming growth factor (TGF) -β2, It is effective for the subjective symptoms such as improvement, irritation, decrease in the number of artificial tears, and so on, and thus it can be effectively used for preventing or treating dry eye syndrome.

The term "prophylactic " as used in the present invention means any action that inhibits or delays disease by the administration of the composition. The term "treatment" as used in the present invention means all the actions of improving or ameliorating symptoms of the disease upon administration of the composition. The pharmaceutical composition is prepared in the form of a transparent eye drop, and may further comprise suitable carriers, excipients and diluents commonly used.

The present invention also provides a method for preparing a composition, comprising the steps of: adding a surfactant to cyclosporin and dissolving the same (step 1); Adding polyethylene glycol 400 to water and dissolving (step 2); Adding the solution prepared in step 1 to the solution prepared in step 2 (step 3); And adjusting the pH of the solution prepared in step 3 to 7.2-7.5.

The kind and content of each component used in the above production method are the same as those described above.

The transparent ophthalmic solution composition according to one embodiment of the present invention is transparent in appearance and is suitable for examination of whole water of an aseptic preparation and confirmed to have no foreign body sensation and irritation in eyes and thus can be usefully used for prevention or treatment of dry eye syndrome .

INDUSTRIAL APPLICABILITY The transparent ophthalmic solution composition according to the present invention can be used for preventing or treating dry eye syndrome, which is apparently transparent and has no foreign body sensation and irritation to eyes.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Example 1

Polysilox 40 hardened castor oil, polysorbate 80 and propylene glycol were added to the cyclosporin and dissolved therein. Separately, polyethylene glycol 400 was dissolved in the water for injection (distilled water) and dissolved. Then, the cyclosporin solution prepared above was added thereto and stirred. Then, the pH was adjusted to 7.3 with sodium hydroxide, the whole volume was adjusted with water for injection (distilled water) Then, the mixture was filled in a container to prepare a cyclosporine transparent eye drop. The ingredients are shown in Table 1 below.

Serial Number ingredient mg / mL One Cyclosporine 0.5 2 Polyethylene glycol 400 73 3 Polyoxyl 40 hardened castor oil 7 4 Polysorbate 80 3 5 Propylene glycol 0.5 6 Sodium hydroxide Suitable amount 7 Injection water Suitable amount

Comparative Example 1

Polysorbate 80 was added to cyclosporin and dissolved. Mannitol was added to the water for injection and dissolved. Then, the cyclosporin solution prepared above was added thereto and stirred. The pH was adjusted to 7.3 with sodium hydroxide, the total volume was adjusted with water for injection (distilled water), and the mixture was filtered. To prepare a cyclosporin transparent eye drop. The components are shown in Table 2 below.

Serial Number ingredient mg / mL One Cyclosporine 0.5 2 Polysorbate 80 10 3 Di-mannitol 46 4 Sodium hydroxide Suitable amount 5 Injection water Suitable amount

Comparative Example 2

Polysorbate 80 and propylene glycol were added to the cyclosporin and dissolved therein. The cyclosporin solution prepared above was added to the water for injection (distilled water) and stirred. The pH was adjusted to 7.3 using sodium hydroxide, the whole volume was adjusted with water for injection (distilled water), and the mixture was filtered to prepare a cyclosporin transparent eye drop , And the respective components are shown in Table 2 below.

Serial Number ingredient mg / mL One Cyclosporine 0.5 2 Polysorbate 80 10 3 Propylene glycol 20 4 Sodium hydroxide Suitable amount 5 Injection water Suitable amount

Experimental Example

The compositions of Example 1, Comparative Example 1 and Comparative Example 2 were stored at 5 캜, 25 캜 and 40 캜 for 6 months, and their appearance was observed. The results are shown in Table 4.

Example 1 Comparative Example 1 Comparative Example 2 Store at 5 ℃ Start date Constellation transparent Constellation transparent Constellation transparent 2 months past Constellation transparent Constellation transparent Constellation transparent Four months Constellation transparent Constellation transparent Constellation transparent 6 months old Constellation transparent Constellation transparent Constellation transparent Storage at 25 ℃ Start date Constellation transparent Constellation transparent Constellation transparent 2 months past Constellation transparent Constellation transparent Constellation transparent Four months Constellation transparent Precipitation formation Precipitation formation 6 months old Constellation transparent Precipitation formation Precipitation formation Store at 40 ℃ Start date Constellation transparent Constellation transparent Constellation transparent 2 months past Constellation transparent Precipitation formation Precipitation formation Four months Constellation transparent Precipitation formation Precipitation formation 6 months old Constellation transparent Precipitation formation Precipitation formation

As shown in Table 4, the composition of Example 1 containing both polyethylene glycol and propylene glycol was transparent for 6 months at 25 ° C. and 40 ° C., but Comparative Example 1 containing no polyethylene glycol and propylene glycol and only propylene glycol Comparative Example 2 formed a precipitate upon storage at 25 占 폚 and 40 占 폚.

Therefore, it was confirmed that the present invention can be produced in the form of a cyclosporin transparent eye drop, by including both polyethylene glycol and propylene glycol.

Claims (8)

1 part by weight of cyclosporin, 50 to 200 parts by weight of polyethylene glycol 400, 5 to 20 parts by weight of polyoxyl 40 hardened castor oil, 2 to 10 parts by weight of polysorbate 80, 0.5 to 10 parts by weight of propylene glycol and water Lt; / RTI >
2. The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of sodium carboxy sodium per 1 part by weight of cyclosporin.
The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of sodium hyaluronate per part by weight of cyclosporine.
The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of omega-3 fatty acid relative to 1 part by weight of cyclosporine.
The composition of claim 1, wherein the composition is from pH 7.2 to pH 7.5.
6. The composition of claim 5, wherein the pH is adjusted with sodium hydroxide, sodium chloride or a combination thereof.
The composition according to claim 1, wherein the polyethylene glycol is 140 to 150 parts by weight based on 1 part by weight of cyclosporin.
A pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising the composition of any one of claims 1 to 6.

KR1020130069815A 2013-06-18 2013-06-18 Transparent eye drops composition comprising cyclosporin KR20140146897A (en)

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KR1020130069815A KR20140146897A (en) 2013-06-18 2013-06-18 Transparent eye drops composition comprising cyclosporin

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