WO2015005409A1 - Aqueous ophthalmic composition containing cyclosporine a - Google Patents

Aqueous ophthalmic composition containing cyclosporine a Download PDF

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Publication number
WO2015005409A1
WO2015005409A1 PCT/JP2014/068382 JP2014068382W WO2015005409A1 WO 2015005409 A1 WO2015005409 A1 WO 2015005409A1 JP 2014068382 W JP2014068382 W JP 2014068382W WO 2015005409 A1 WO2015005409 A1 WO 2015005409A1
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WO
WIPO (PCT)
Prior art keywords
composition
castor oil
concentration
cyclosporin
polyethylene glycol
Prior art date
Application number
PCT/JP2014/068382
Other languages
French (fr)
Japanese (ja)
Inventor
章吾 宮城
マデトジャ、ヤニ
チュウ、チョンジャン
Original Assignee
参天製薬株式会社
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Publication of WO2015005409A1 publication Critical patent/WO2015005409A1/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
    • A61K38/04—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an aqueous ophthalmic composition comprising cyclosporin A at a concentration of 0.01-0.08% (w / v), wherein the composition comprises polyethylene glycol and 1.0-5.0% (
  • the present invention relates to a composition containing a polyethoxylated castor oil derivative at a concentration of w / v) (hereinafter also referred to as “the present composition”).
  • Cyclosporin A is known to be effective in the treatment of various ophthalmic diseases because it suppresses cellular immunity, and has been reported to have a high therapeutic effect especially on dry eye.
  • Non-Patent Document 1 discloses an ophthalmic solution (RESTASIS (registered trademark) 0.05%) containing cyclosporin A as an active ingredient in a patient whose tear secretion is reduced due to ocular inflammation accompanied by dry keratoconjunctivitis (dry eye). It has been described to increase tear secretion. In fact, in the United States, an ophthalmic solution (RESTASIS (registered trademark) 0.05%) containing cyclosporin A as an active ingredient is widely used as a dry eye treatment.
  • RESTASIS registered trademark
  • Non-Patent Document 1 glycerin, castor oil, polysorbate 80, carbomer polymer type A, purified water, sodium hydroxide (to adjust pH) are added to RESTASIS (registered trademark) 0.05%. And its properties are disclosed to be emulsions. Further, Non-Patent Document 1, RESTASIS the (R) prior to the use of 0.05%, white, until opaque homogeneous emulsion is obtained, wherein also be necessary to invert several times ophthalmic solution vial Has been.
  • RESTASIS registered trademark
  • Patent Document 1 describes that the solubility of cyclosporine in water is extremely low, and it is practically impossible to obtain a preparation in which cyclosporine is dissolved in an aqueous medium (step 0005).
  • Patent Document 1 describes that surfactants such as polyethoxylated castor oil are used as a solubilizer in an injectable composition in order to suppress separation of cyclosporine. At the same time, it has been suggested that this causes safety problems (step 0007).
  • Patent Document 2 discloses an aqueous ophthalmic composition containing cyclosporin A, and it is disclosed that cyclosporin A is solubilized in water by adding a polysorbate surfactant and 1,5-hexanediol. (0071 and 0072 stages). In addition, it is described that the preparation of the invention described in Patent Document 2 is clear and does not form crystals or precipitates (Step 0073). However, Patent Document 2 also describes that cyclosporin A was not solubilized in water when PEG400 was added instead of 1,5-hexanediol (steps 0069 and 0070).
  • Non-Patent Document 2 cyclosporin A is soluble in vegetable oils such as olive oil.
  • a cyclosporin A solution based on olive oil is instilled, a burning sensation and irritation to the conjunctiva occur, and further, these side effects are It has been reported that it is due to the influence of the base (Non-Patent Document 2: page 4, right column, (b)).
  • Non-Patent Document 2 discloses that in an aqueous solution, CREMOPHOR (registered trademark) improves the corneal permeability of cyclosporin A, and benzalkonium is an ophthalmic solution at a concentration of 0.01% w / v. It is described that it is used as a preservative.
  • CREMOPHOR registered trademark
  • Patent Document 3 cyclosporin A, absolute ethanol, CREMOPHOR (R) composition comprising EL and PEG400 (Example 5), and cyclosporin A, benzyl alcohol, propylene glycol, consisting of PEG400 and CREMOPHOR (R) EL A composition (Example 14) is disclosed, but none contains water and is not a so-called aqueous composition.
  • An object of the present invention is an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), which is stable, has little eye irritation, and has a clear property. Is to provide a composition that is
  • the present inventors have used a polyethoxylated castor oil derivative and polyethylene glycol to provide a clear aqueous composition (solubilized preparation) containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v). It was found that can be obtained.
  • the present inventors show that the composition has high thermal stability when the concentration of the polyethoxylated castor oil derivative in the composition is 1.0 to 5.0% (w / v).
  • the present invention has also been found and the present invention has been completed. Furthermore, it was also revealed that the composition has lower eye irritation than conventional commercially available cyclosporine-containing ophthalmic solutions.
  • the present invention relates to an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), the composition comprising polyethylene glycol and 1.0 to 5.0.
  • composition preferably contains polyethylene glycol at a concentration of 0.5 to 5.0% (w / v).
  • a preferred polyethylene glycol is “PEG400”.
  • the composition preferably contains a polyethoxylated castor oil derivative at a concentration of 1.0 to 3.0% (w / v), and contains a polyethoxylated castor oil derivative at a concentration of 2.0%. Is particularly preferred.
  • a preferred polyethoxylated castor oil derivative is “polyoxyl 35 castor oil”.
  • the present composition may contain benzalkonium chloride at a concentration exceeding 0.005% (w / v), and may contain the benzalkonium chloride as the only preservative.
  • the composition does not substantially contain “oil” or “ethanol”, and more preferably does not substantially contain both “oil” and “ethanol”.
  • the present composition is an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), and the composition is 1.25% (w / v). Containing PEG400 at a concentration of 2.0, polyoxyl 35 castor oil at a concentration of 2.0% (w / v), and benzalkonium chloride at a concentration of greater than 0.005% (w / v). It is particularly preferable that the composition is not contained.
  • the present invention also includes the following steps: (A) dissolving the cyclosporin A in polyethylene glycol to obtain a solution; and (b) mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative and water. Also provided is a method for producing the composition.
  • the concentration of polyethylene glycol in the aqueous ophthalmic composition produced by this production method is preferably 0.5 to 5.0% (w / v).
  • the concentration of the polyethoxylated castor oil derivative in the aqueous ophthalmic composition produced by this production method is preferably 1.0 to 3.0% (w / v), and preferably 2.0%. Is particularly preferred.
  • step (b) of the production method the solution obtained in step (a) can be mixed with the polyethoxylated castor oil derivative, water and benzalkonium chloride.
  • concentration of benzalkonium chloride in the aqueous ophthalmic composition produced by the method is preferably greater than 0.005% (w / v).
  • the production method preferably does not include “the step of mixing cyclosporin A and oil” or “the step of mixing cyclosporin A and ethanol”, and more preferably, “the step of mixing cyclosporin A and oil” and “cyclosporin A”.
  • the step of mixing ethanol with ethanol is not included.
  • the present invention also includes the following steps: (A) dissolving cyclosporin A in PEG400 to obtain a solution; (B) mixing the solution obtained in step (a) with polyoxyl 35 castor oil, water and benzalkonium chloride; Containing cyclosporin A at a concentration of 0.05% (w / v), the concentrations of polyoxyl 35 castor oil, PEG 400 and benzalkonium chloride are 2.0% (w / v) and 1.25%, respectively. Also provided is a method for producing the above aqueous ophthalmic composition that is greater than (w / v) and greater than 0.005% (w / v).
  • cyclosporin A formulations such as RESTASIS (TM) 0.05% ophthalmic solution
  • a clear aqueous ophthalmic composition eye irritation is small
  • cyclosporine in the composition A composition having excellent thermal stability of A can be provided.
  • Cyclosporine A is a compound represented by the following formula (1).
  • Cyclosporine A can be produced according to a usual method in the field of synthetic organic chemistry, and is commercially available from SIGMA-ALDRICH. In the United States, an ophthalmic solution (RESTASIS (registered trademark) ophthalmic solution) containing cyclosporin A as an active ingredient is commercially available.
  • RESTASIS registered trademark
  • the composition has a concentration of 0.01-0.08% (w / v), preferably 0.03-0.06% (w / v), more preferably 0.05% (w / v).
  • Contains cyclosporin A cyclosporin A.
  • the present composition preferably contains cyclosporin A at that concentration as the only active ingredient and does not contain other active ingredients.
  • “clear” means that the composition is transparent, preferably colorless and transparent when the target composition is filled in a glass container (glass vial, glass ampoule, etc.) and visually confirmed. It means that.
  • a composition in which cyclosporin A is solubilized and / or dissolved is included in a “clear” composition.
  • ophthalmic composition means a composition used for topical ophthalmic administration.
  • a preferred “ophthalmic composition” is an eye drop.
  • aqueous ophthalmic composition means an ophthalmic composition based on water.
  • aqueous ophthalmic composition preferably more than 80% (w / v) of the composition is water, more preferably more than 90% (w / v) of the composition is water. is there.
  • the “aqueous ophthalmic composition” preferably does not substantially contain “oil” and “ethanol” described later.
  • Polyethylene glycol is a compound represented by the general formula HO— (CH 2 —CH 2 —O) n —H (n is an integer of 1 or more).
  • Preferred as the “polyethylene glycol” of the present invention is polyethylene glycol having an average molecular weight of 200 to 1,000.
  • Preferred examples of the “polyethylene glycol” of the present invention include polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), polyethylene glycol 1000 (PEG 1000), and the like.
  • the most preferred example of the “polyethylene glycol” of the present invention is PEG400.
  • the polyethylene glycol concentration in the composition is not particularly limited, but is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3.0 (w / v). Yes, and particularly preferably 1.25% (w / v).
  • polyethoxylated castor oil derivative of the present invention means a compound obtained by addition polymerization of castor oil with ethylene oxide, and the castor oil may not be hydrogenated, for example, “polyoxyl castor oil” Alternatively, the castor oil may be hydrogenated, for example, “polyoxyl hydrogenated castor”.
  • Polyoxyl castor oil is also called “polyoxyethylene castor oil” and “polyethoxylated castor oil”
  • polyoxyl hydrogenated castor oil is “polyoxyethylene hydrogenated castor oil” and “polyethoxylated hydrogenated castor oil”. Also called “oil”.
  • polyoxyl castor oil examples include “polyoxyl 35 castor oil” having an average addition mole number of ethylene oxide of about 35, or “polyoxyl 40 castor oil” having an average addition mole number of ethylene oxide of about 40. Or a mixture thereof, and “polyoxyl 35 castor oil” is preferable.
  • Polyoxyl 35 castor oil is also called polyoxyl castor oil, PEG-35 castor oil, and macrogoglycerol ricinoleate, and is marketed under the trade name “Cremophor (registered trademark) EL”.
  • Polyoxyl 40 castor oil which is commercially available under the trade name "Eumulgin (registered trademark) RO40", “Emulphor (registered trademark) EL-719".
  • Examples of the “polyoxyl hydrogenated castor oil” of the present invention include “polyoxyl 30 hydrogenated castor oil” having an average addition mole number of ethylene oxide of about 30, and “polyoxyl 40 hydrogenated castor oil” having an average addition mole number of ethylene oxide of about 40.
  • Polyoxyl 30 hydrogenated castor oil is a trade name of “Nikkol (registered trademark) HCO-30”
  • Polyoxyl 40 hydrogenated castor oil is “Cremophor (registered trademark) RH40”, “Nikkol (registered trademark)”.
  • HC-40 polyoxyl 50 hydrogenated castor oil
  • Nikkol registered trademark
  • HC-50 polyoxyl 60 hydrogenated castor oil
  • Nikkol registered trademark
  • the concentration of the polyethoxylated castor oil derivative in the composition is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / v), 2.0% ( Most preferred is w / v).
  • Benzalkonium chloride is a compound represented by the following general formula (2). [Wherein, R represents an alkyl group represented by C 8 H 17 to C 18 H 37 . ]
  • benzalkonium chloride shows the general formula (2), R is the “C 12 H 25" (hereinafter, “benzalkonium chloride (C12)" and also referred to) in is there.
  • the concentration of the benzalkonium chloride is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w). ), More preferably 0.0075 to 0.05% (v / w), still more preferably 0.0075 to 0.02% (v / w).
  • the concentration of benzalkonium chloride in the present composition is particularly preferably 0.01% (v / w).
  • “containing benzalkonium chloride at a concentration of more than 0.005% (w / v) as a preservative” means that the present composition is added to “benzalkonium chloride” at the concentration, It also means to contain “preservatives other than benzalkonium chloride", but preferably contains “benzalkonium chloride” as the only preservative, and "preservation other than benzalkonium chloride” It means not containing "agent”.
  • the “preservatives other than benzalkonium chloride” include benzethonium chloride, chlorhexidine gluconate, parabens, sorbic acid and salts thereof, chlorobutanol, boric acid, borax, chlorite, and the like. Can be mentioned.
  • the “oil” is not particularly limited as long as it is an “oil” that can be used for ophthalmic applications.
  • castor oil olive oil, orange oil, soybean oil, camellia oil, rapeseed oil, coconut oil ( coconut oil), eucalyptus oil, corn oil, safflower oil, egoma oil, cottonseed oil, wheat germ oil, peppermint oil, sunflower oil, sesame oil, corn oil, peanut oil, peanut oil, almond oil, jojoba oil, camellia oil, etc.
  • liquid vegetable oils animal oils such as lanolin and squalane; fish oils; mineral oils such as liquid paraffin and light liquid paraffin; medium chain fatty acid triglycerides.
  • the “polyethoxylated castor oil derivative” is not included in the “oil” of the present invention.
  • composition preferably does not substantially contain “oil” or “ethanol”, and more preferably does not substantially contain both “oil” and “ethanol”.
  • substantially free of oil and / or “substantially free of ethanol” affects properties of the composition (eg, whether it is clear) and stability. Means that no “oil” and / or “ethanol” is present in the composition.
  • additives other than the “polyethylene glycol”, “polyethoxylated castor oil derivative” and “benzalkonium chloride” can be blended.
  • the additives include isotonic agents such as glycerin, sodium chloride, potassium chloride; disodium hydrogen phosphate (disodium hydrogen phosphate dodecahydrate), sodium phosphate, sodium acetate, epsilon-aminocaproic acid, etc. Buffering agents of sodium; edetate sodium (including monosodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate and hydrates thereof), stabilizers such as sodium citrate, etc. Can do.
  • the pH of the present composition may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4-8.
  • composition can be formulated as a “unit dose formulation” that can be used once, or can be formulated as a “multi-dose formulation” that can be used repeatedly by adding benzalkonium chloride. .
  • the present composition can be used not only for dry eye (dry eye syndrome) but also for treating keratoconjunctival epithelial disorders associated with endogenous diseases such as Sjogren's syndrome and Stevens-Johnson syndrome.
  • the production method includes steps (a) of obtaining a solution by dissolving cyclosporin A in polyethylene glycol, and a step (b) of mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative and water.
  • step (b) the solution obtained in step (a) can also be mixed with polyethoxylated castor oil derivative, water and benzalkonium chloride.
  • step (b) in addition to the solution obtained in step (a), the polyethoxylated castor oil derivative, water, and benzalkonium chloride, part or all of the additives are mixed. You can also.
  • the concentration of cyclosporin A in the aqueous ophthalmic composition obtained by this production method is 0.01-0.08% (w / v), preferably 0.03-0.06% (w / v), more preferably 0.05% (w / v). Therefore, in the step (a), the same concentration is 0.01 to 0.08% (w / v), preferably 0.03 to 0.06% (w / v), more preferably 0.05% ( A quantity of w / v) of cyclosporin A and polyethylene glycol is mixed.
  • the concentration of polyethylene glycol in the aqueous ophthalmic composition obtained by this production method is not particularly limited, but is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3. 0 (w / v), most preferably 1.25% (w / v). That is, in step (a), the same concentration is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3.0 (w / v), and most preferably 1. Polyethylene glycol and cyclosporin A in an amount of 25% (w / v) are mixed.
  • the concentration of the polyethoxylated castor oil derivative in the aqueous ophthalmic composition obtained by the present production method is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / V), most preferably 2.0% (w / v). That is, in the step (b), the same concentration is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / v), and most preferably 2. It is preferable to mix the polyethoxylated castor oil derivative in an amount of 0% (w / v), the solution obtained in step (a) and water.
  • the concentration of ruconium chloride is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w), more preferably 0.0075 to 0.05% (v / w). w), more preferably 0.0075 to 0.02% (v / w), particularly preferably 0.01% (v / w).
  • the same concentration is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w), more preferably 0.0075 to 0.00.
  • Benzalkonium chloride in an amount of 05% (v / w), more preferably 0.0075 to 0.02% (v / w), particularly preferably 0.01% (v / w), and the step It is preferable to mix the solution obtained in (a), the polyethoxylated castor oil derivative, and water.
  • the method may include one or more steps other than the steps (a) and (b).
  • the “step of mixing cyclosporin A and oil” or “cyclosporin A and ethanol are mixed.
  • the step of mixing is not included, and more preferably, both of the step of mixing cyclosporin A and oil and the step of mixing cyclosporin A and ethanol are not included.
  • Cremophor (registered trademark) EL was further added to increase the Cremophor (registered trademark) EL concentration in the sample to 0.4% (w / v), and then the sample was filled into a glass ampule and visually observed. As a result, the properties of the sample were clear.
  • Comparative prescription 1 After dissolving 0.05 g of cyclosporin A in 1.25 g of PEG400, the obtained solution and Cremophor (registered trademark) EL 0.5 g, benzalkonium chloride (C12) 0.01 g, glycerin 1.2 g, phosphorus 0.6 g of disodium oxyhydrogen dodecahydrate and purified water were mixed. After dilute hydrochloric acid and / or sodium hydroxide was added to adjust the pH to 7.0, purified water was added to make 100 mL.
  • Cremophor registered trademark
  • Comparative prescription 2 It was prepared in the same manner as Comparative Formula 1 except that 0.1 g of sodium edetate was added.
  • Comparative prescription 3 (base of prescription 2) It was prepared in the same manner as Formula 2 except that cyclosporin A was not added.
  • Comparative Formulation 4 (RESTASIS (TM) 0.05% ophthalmic solution) Commercial RESTASIS using (R) 0.05% ophthalmic solution.
  • Prescription 2 (50 ⁇ L) was instilled into the left eye of a Japanese white rabbit 6 times at intervals of 90 minutes with Pipetteman, and the number of blinks per minute for 1 minute immediately after instillation 1 and the sixth was measured.
  • comparative formulation 3 (50 ⁇ L) was instilled into the contralateral eye of the rabbit 6 times at 90-minute intervals, and the number of blinks for 1 minute immediately after instillation 1 and 6th time was measured.
  • Comparative prescription 4 eye drops Comparative prescription 4 (50 ⁇ L) was instilled into the left eye of a Japanese white rabbit 6 times at intervals of 90 minutes with Pipetteman, and the number of blinks per minute for 1 minute immediately after instillation 1 and the 6th time was measured. The contralateral eye was untreated.
  • Test results The test results are shown in Table 2. Blink frequency of the formulation 2 instillation eye, compared Formulation 4 (RESTASIS (TM) 0.05% ophthalmic solution) may be fewer than that of eye drops eye shown.
  • Comparative prescription 5 Except that the amount of benzalkonium chloride added was 0.005 g, the same operation as Comparative Formula 1 used in the thermal stability test was performed to obtain Comparative Formula 5.
  • the preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 15th revision Japanese Pharmacopoeia (hereinafter, also simply referred to as “Japanese Pharmacopoeia”).
  • Escherichia Coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Candida albicans C. albicans
  • Candida albicans C. albicans
  • Candida albicans C. albicans
  • Test results The test results are shown in Table 3.
  • Cyclosporine-containing ophthalmic compositions of the present invention RESTASIS (R) on the conventional cyclosporin A formulations such as 0.05% ophthalmic solution is a clear aqueous composition varies, also preferred stability as ophthalmic composition It also has safety. Therefore, the cyclosporine-containing ophthalmic composition of the present invention can be suitably used for the treatment of dry eye and the like.

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Abstract

The problem addressed by the present invention is to provide an aqueous ophthalmic composition containing cyclosporine A at a concentration of 0.01-0.08% (w/v), and that is stable, has low eye irritation, and has the property of being clear. The ophthalmic composition containing cyclosporine A can be formulated as a clear aqueous composition by containing a polyethoxylated castor oil derivative and polyethylene glycol, and so concomitantly has favorable stability and safety as an ophthalmic composition. Consequently, the ophthalmic composition containing cyclosporine A can be used favorably in the treatment of dry eye and the like.

Description

シクロスポリンＡを含有する水性眼科用組成物Aqueous ophthalmic composition containing cyclosporin A
　本発明は、０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、該組成物がポリエチレングリコールおよび１．０～５．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有する組成物（以下、「本組成物」とも言う）に関する。 The present invention relates to an aqueous ophthalmic composition comprising cyclosporin A at a concentration of 0.01-0.08% (w / v), wherein the composition comprises polyethylene glycol and 1.0-5.0% ( The present invention relates to a composition containing a polyethoxylated castor oil derivative at a concentration of w / v) (hereinafter also referred to as “the present composition”).
　シクロスポリンＡは、細胞性免疫を抑制することから、種々の眼科疾患の治療に有効であることが知られており、特にドライアイに対して高い治療効果を有することが報告されている。 Cyclosporin A is known to be effective in the treatment of various ophthalmic diseases because it suppresses cellular immunity, and has been reported to have a high therapeutic effect especially on dry eye.
　非特許文献１には、乾性角結膜炎（ドライアイ）を伴う眼炎症によって涙液分泌が低下した患者において、シクロスポリンＡを有効成分とする点眼液（ＲＥＳＴＡＳＩＳ（登録商標）０．０５％）が、涙液分泌を増加させることが記載されている。実際、米国においては、シクロスポリンＡを有効成分とする点眼液（ＲＥＳＴＡＳＩＳ（登録商標）０．０５％）がドライアイ治療薬として広く使用されている。
　また、非特許文献１には、グリセリン、ヒマシ油、ポリソルベート８０、ｃａｒｂｏｍｅｒ ｃｏｐｏｌｙｍｅｒ ｔｙｐｅ Ａ、精製水、水酸化ナトリウム（ｐＨを調製するため）が、ＲＥＳＴＡＳＩＳ（登録商標）０．０５％に添加されており、その性状はエマルジョンであることが開示されている。さらに、非特許文献１には、ＲＥＳＴＡＳＩＳ（登録商標）０．０５％の使用前に、白色、不透明の均一なエマルジョンが得られるまで、該点眼液バイアルを数回反転させる必要があることも記載されている。 Non-Patent Document 1 discloses an ophthalmic solution (RESTASIS (registered trademark) 0.05%) containing cyclosporin A as an active ingredient in a patient whose tear secretion is reduced due to ocular inflammation accompanied by dry keratoconjunctivitis (dry eye). It has been described to increase tear secretion. In fact, in the United States, an ophthalmic solution (RESTASIS (registered trademark) 0.05%) containing cyclosporin A as an active ingredient is widely used as a dry eye treatment.
In Non-Patent Document 1, glycerin, castor oil, polysorbate 80, carbomer polymer type A, purified water, sodium hydroxide (to adjust pH) are added to RESTASIS (registered trademark) 0.05%. And its properties are disclosed to be emulsions. Further, Non-Patent Document 1, RESTASIS the (R) prior to the use of 0.05%, white, until opaque homogeneous emulsion is obtained, wherein also be necessary to invert several times ophthalmic solution vial Has been.
　特許文献１には、シクロスポリンの水への溶解性は極めて低く、水性媒体にシクロスポリンを溶解させた製剤を得ることは実際的には不可能であると記載されている（０００５段）。
　また、特許文献１には、シクロスポリンの分離を抑制するため、注射用組成物において、ポリエトキシ化ヒマシ油などの界面活性剤（ｓｕｒｆａｃｅ　ａｃｔｉｖｅ　ａｇｅｎｔｓ）を溶解剤として使用していることが記載されているが、同時に、これが安全性上の問題を引き起こすことも示唆されている（０００７段）。 Patent Document 1 describes that the solubility of cyclosporine in water is extremely low, and it is practically impossible to obtain a preparation in which cyclosporine is dissolved in an aqueous medium (step 0005).
In addition, Patent Document 1 describes that surfactants such as polyethoxylated castor oil are used as a solubilizer in an injectable composition in order to suppress separation of cyclosporine. At the same time, it has been suggested that this causes safety problems (step 0007).
　特許文献２には、シクロスポリンＡを含有する水性眼科用組成物が記載されており、ポリソルベート界面活性剤及び１，５－ヘキサンジオールを添加することで、シクロスポリンＡが水に可溶化することが開示されている（００７１および００７２段）。また、特許文献２記載の発明である製剤が、澄明であり、結晶や沈殿を形成しなかったことが記載されている（００７３段）。
　しかしながら、特許文献２には、１，５－ヘキサンジオールに換えてＰＥＧ４００を添加した場合には、シクロスポリンＡは水に可溶化しなかったことも記載されている（００６９および００７０段）。 Patent Document 2 discloses an aqueous ophthalmic composition containing cyclosporin A, and it is disclosed that cyclosporin A is solubilized in water by adding a polysorbate surfactant and 1,5-hexanediol. (0071 and 0072 stages). In addition, it is described that the preparation of the invention described in Patent Document 2 is clear and does not form crystals or precipitates (Step 0073).
However, Patent Document 2 also describes that cyclosporin A was not solubilized in water when PEG400 was added instead of 1,5-hexanediol (steps 0069 and 0070).
　非特許文献２には、シクロスポリンＡがオリーブ油などの植物油に可溶であるが、オリーブ油を基剤とするシクロスポリンＡ溶液を点眼すると、灼熱感や結膜に対する刺激が生じること、さらに、これらの副作用が基剤の影響によるものであることなどが報告されている（非特許文献２：４頁、右欄、（ｂ））。
　また、非特許文献２には、水性溶液において、ＣＲＥＭＯＰＨＯＲ（登録商標）が、シクロスポリンＡの角膜透過性を向上させこと、またベンザルコニウムが、０．０１％ｗ／ｖの濃度で、点眼液の保存剤として用いられることが記載されている。 In Non-Patent Document 2, cyclosporin A is soluble in vegetable oils such as olive oil. However, when a cyclosporin A solution based on olive oil is instilled, a burning sensation and irritation to the conjunctiva occur, and further, these side effects are It has been reported that it is due to the influence of the base (Non-Patent Document 2: page 4, right column, (b)).
Non-Patent Document 2 discloses that in an aqueous solution, CREMOPHOR (registered trademark) improves the corneal permeability of cyclosporin A, and benzalkonium is an ophthalmic solution at a concentration of 0.01% w / v. It is described that it is used as a preservative.
　特許文献３には、シクロスポリンＡ、無水エタノール、ＣＲＥＭＯＰＨＯＲ（登録商標）ＥＬおよびＰＥＧ４００からなる組成物（実施例５）、ならびにシクロスポリンＡ、ベンジルアルコール、プロピレングリコール、ＰＥＧ４００ならびにＣＲＥＭＯＰＨＯＲ（登録商標）ＥＬからなる組成物（実施例１４）が開示されているが、いずれも水を含有しておらず、いわゆる水性組成物ではない。 Patent Document 3, cyclosporin A, absolute ethanol, CREMOPHOR (R) composition comprising EL and PEG400 (Example 5), and cyclosporin A, benzyl alcohol, propylene glycol, consisting of PEG400 and CREMOPHOR (R) EL A composition (Example 14) is disclosed, but none contains water and is not a so-called aqueous composition.
ＵＳ ２００７／００１５６９１ Ａ１US 2007/0015691 A1 ＵＳ ２０１０／００１６２１９ Ａ１US 2010/0016219 A1 特表２００１－５１６３５１号公報Special table 2001-516351 gazette
　本発明の課題は、０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、安定であり、眼刺激性が小さく、その性状が澄明である組成物を提供することである。 An object of the present invention is an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), which is stable, has little eye irritation, and has a clear property. Is to provide a composition that is
　本発明者等は、ポリエトキシ化ヒマシ油誘導体およびポリエチレングリコールを用いることで、０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する澄明な水性組成物（可溶化製剤）が得られることを見出した。 The present inventors have used a polyethoxylated castor oil derivative and polyethylene glycol to provide a clear aqueous composition (solubilized preparation) containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v). It was found that can be obtained.
　さらに、本発明者等は、該組成物中のポリエトキシ化ヒマシ油誘導体の濃度を１．０～５．０％（ｗ／ｖ）とした場合に、該組成物が高い熱安定性を有することをも見出し、本発明を完成させるに至った。さらに、該組成物は、従来の市販のシクロスポリン含有点眼液より眼刺激性が低いことも明らかとなった。 Furthermore, the present inventors show that the composition has high thermal stability when the concentration of the polyethoxylated castor oil derivative in the composition is 1.0 to 5.0% (w / v). The present invention has also been found and the present invention has been completed. Furthermore, it was also revealed that the composition has lower eye irritation than conventional commercially available cyclosporine-containing ophthalmic solutions.
　すなわち、本発明は、０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、該組成物がポリエチレングリコールおよび１．０～５．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有する組成物である。 That is, the present invention relates to an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), the composition comprising polyethylene glycol and 1.0 to 5.0. A composition containing a polyethoxylated castor oil derivative at a concentration of% (w / v).
　また、本組成物は０．５～５．０％（ｗ／ｖ）の濃度のポリエチレングリコールを含有することが好ましい。なお、本発明において、好ましいポリエチレングリコールは「ＰＥＧ４００」である。 Further, the composition preferably contains polyethylene glycol at a concentration of 0.5 to 5.0% (w / v). In the present invention, a preferred polyethylene glycol is “PEG400”.
　また、本組成物は１．０～３．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有することが好ましく、２．０％の濃度のポリエトキシ化ヒマシ油誘導体を含有することが特に好ましい。なお、本発明において、好ましいポリエトキシ化ヒマシ油誘導体は「ポリオキシル３５ヒマシ油」である。 The composition preferably contains a polyethoxylated castor oil derivative at a concentration of 1.0 to 3.0% (w / v), and contains a polyethoxylated castor oil derivative at a concentration of 2.0%. Is particularly preferred. In the present invention, a preferred polyethoxylated castor oil derivative is “polyoxyl 35 castor oil”.
　また、本組成物は０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を含有することもでき、また上記ベンザルコニウム塩化物を唯一の防腐剤として含有することもできる。 Also, the present composition may contain benzalkonium chloride at a concentration exceeding 0.005% (w / v), and may contain the benzalkonium chloride as the only preservative.
　本発明において、本組成物は「油」または「エタノール」を実質的に含有しないことが好ましく、さらに好ましくは、「油」および「エタノール」の両者を実質的に含有しない。 In the present invention, it is preferable that the composition does not substantially contain “oil” or “ethanol”, and more preferably does not substantially contain both “oil” and “ethanol”.
　また、本組成物は、０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、該組成物が１．２５％（ｗ／ｖ）の濃度のＰＥＧ４００、２．０％（ｗ／ｖ）の濃度のポリオキシル３５ヒマシ油、および０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を含有し、油とエタノールを実質的に含有しない組成物であることが特に好ましい。 The present composition is an aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01 to 0.08% (w / v), and the composition is 1.25% (w / v). Containing PEG400 at a concentration of 2.0, polyoxyl 35 castor oil at a concentration of 2.0% (w / v), and benzalkonium chloride at a concentration of greater than 0.005% (w / v). It is particularly preferable that the composition is not contained.
　また、本発明は、次のステップ：
（ａ）シクロスポリンＡをポリエチレングリコールに溶解させて、溶液を得るステップ；および
（ｂ）ステップ（ａ）で得られた溶液とポリエトキシ化ヒマシ油誘導体および水を混合するステップ
を含む、上記の水性眼科用組成物の製造方法も提供する。 The present invention also includes the following steps:
(A) dissolving the cyclosporin A in polyethylene glycol to obtain a solution; and (b) mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative and water. Also provided is a method for producing the composition.
　本製造方法によって製造される水性眼科用組成物中のポリエチレングリコールの濃度は０．５～５．０％（ｗ／ｖ）であることが好ましい。 The concentration of polyethylene glycol in the aqueous ophthalmic composition produced by this production method is preferably 0.5 to 5.0% (w / v).
　また、本製造方法によって製造される水性眼科用組成物中のポリエトキシ化ヒマシ油誘導体の濃度は１．０～３．０％（ｗ／ｖ）であることが好ましく、２．０％であることが特に好ましい。 The concentration of the polyethoxylated castor oil derivative in the aqueous ophthalmic composition produced by this production method is preferably 1.0 to 3.0% (w / v), and preferably 2.0%. Is particularly preferred.
　本発明においては、本製造方法のステップ（ｂ）において、ステップ（ａ）で得られた溶液とポリエトキシ化ヒマシ油誘導体、水およびベンザルコニウム塩化物を混合することができ、この時、本製造方法によって製造される水性眼科用組成物中のベンザルコニウム塩化物の濃度は０．００５％（ｗ／ｖ）超であることが好ましい。 In the present invention, in step (b) of the production method, the solution obtained in step (a) can be mixed with the polyethoxylated castor oil derivative, water and benzalkonium chloride. The concentration of benzalkonium chloride in the aqueous ophthalmic composition produced by the method is preferably greater than 0.005% (w / v).
　本製造方法は「シクロスポリンＡと油を混合するステップ」または「シクロスポリンＡとエタノールを混合するステップ」を含まないことが好ましく、さらに好ましくは、「シクロスポリンＡと油を混合するステップ」および「シクロスポリンＡとエタノールを混合するステップ」の両者を含まない。 The production method preferably does not include “the step of mixing cyclosporin A and oil” or “the step of mixing cyclosporin A and ethanol”, and more preferably, “the step of mixing cyclosporin A and oil” and “cyclosporin A”. The step of mixing ethanol with ethanol is not included.
　また、本発明は、次のステップ：
（ａ）シクロスポリンＡをＰＥＧ４００に溶解させて、溶液を得るステップ；
（ｂ）ステップ（ａ）で得られた溶液とポリオキシル３５ヒマシ油、水およびベンザルコニウム塩化物を混合するステップを含む、
　０．０５％（ｗ／ｖ）の濃度のシクロスポリンＡを含有し、ポリオキシル３５ヒマシ油、ＰＥＧ４００およびベンザルコニウム塩化物の濃度が、それぞれ、２．０％（ｗ／ｖ）、１．２５％（ｗ／ｖ）および０．００５％（ｗ／ｖ）超である上記の水性眼科用組成物の製造方法も提供する。 The present invention also includes the following steps:
(A) dissolving cyclosporin A in PEG400 to obtain a solution;
(B) mixing the solution obtained in step (a) with polyoxyl 35 castor oil, water and benzalkonium chloride;
Containing cyclosporin A at a concentration of 0.05% (w / v), the concentrations of polyoxyl 35 castor oil, PEG 400 and benzalkonium chloride are 2.0% (w / v) and 1.25%, respectively. Also provided is a method for producing the above aqueous ophthalmic composition that is greater than (w / v) and greater than 0.005% (w / v).
　本発明によれば、ＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液などの従来のシクロスポリンＡ製剤とは異なり、澄明な水性眼科用組成物であって、眼刺激性が小さく、組成物中のシクロスポリンＡの熱安定性が優れた組成物を提供することができる。 According to the present invention, unlike the conventional cyclosporin A formulations such RESTASIS (TM) 0.05% ophthalmic solution, a clear aqueous ophthalmic composition, eye irritation is small, cyclosporine in the composition A composition having excellent thermal stability of A can be provided.
　シクロスポリンＡは、下記式（１）で示される化合物である。
Figure JPOXMLDOC01-appb-C000001
 Cyclosporine A is a compound represented by the following formula (1).
Figure JPOXMLDOC01-appb-C000001
　シクロスポリンＡは、有機合成化学分野における通常の方法に従って製造することができ、またＳＩＧＭＡ－ＡＬＤＲＩＣＨ社などにより市販されている。また、米国においては、シクロスポリンＡを有効成分として含有する点眼液（ＲＥＳＴＡＳＩＳ（登録商標）点眼液）が市販されている。 Cyclosporine A can be produced according to a usual method in the field of synthetic organic chemistry, and is commercially available from SIGMA-ALDRICH. In the United States, an ophthalmic solution (RESTASIS (registered trademark) ophthalmic solution) containing cyclosporin A as an active ingredient is commercially available.
　本組成物は、０．０１～０．０８％（ｗ／ｖ）、好ましくは０．０３～０．０６％（ｗ／ｖ）、さらに好ましくは０．０５％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する。本組成物は、当該濃度のシクロスポリンＡを唯一の有効成分として含有し、他の有効成分を含有しないことが好ましい。 The composition has a concentration of 0.01-0.08% (w / v), preferably 0.03-0.06% (w / v), more preferably 0.05% (w / v). Contains cyclosporin A. The present composition preferably contains cyclosporin A at that concentration as the only active ingredient and does not contain other active ingredients.
　本発明において、「澄明」とは、対象となる組成物をガラス製容器（ガラスバイアル、ガラスアンプルなど）に充填し、目視で確認した際に、該組成物が透明、好ましくは、無色かつ透明であることを意味する。シクロスポリンＡが可溶化されたおよび／または溶解した組成物は、「澄明な」組成物に含まれる。 In the present invention, “clear” means that the composition is transparent, preferably colorless and transparent when the target composition is filled in a glass container (glass vial, glass ampoule, etc.) and visually confirmed. It means that. A composition in which cyclosporin A is solubilized and / or dissolved is included in a “clear” composition.
　本発明において、「眼科用組成物」とは、眼局所投与に用いられる組成物を意味する。本発明において、好ましい「眼科用組成物」は点眼剤である。 In the present invention, “ophthalmic composition” means a composition used for topical ophthalmic administration. In the present invention, a preferred “ophthalmic composition” is an eye drop.
　本発明において、「水性眼科用組成物」とは水を基剤とする眼科用組成物を意味する。本発明の「水性眼科用組成物」においては、好ましくは該組成物の８０％（ｗ／ｖ）超が水であり、さらに好ましくは該組成物の９０％（ｗ／ｖ）超が水である。さらに、本発明において、「水性眼科用組成物」は、好ましくは、後述する「油」及び「エタノール」を実質的に含まない。 In the present invention, “aqueous ophthalmic composition” means an ophthalmic composition based on water. In the “aqueous ophthalmic composition” of the present invention, preferably more than 80% (w / v) of the composition is water, more preferably more than 90% (w / v) of the composition is water. is there. Further, in the present invention, the “aqueous ophthalmic composition” preferably does not substantially contain “oil” and “ethanol” described later.
　ポリエチレングリコールは、ＨＯ－（ＣＨ２－ＣＨ２－Ｏ）ｎ－Ｈの一般式（ｎは１以上の整数である）で示される化合物である。 Polyethylene glycol is a compound represented by the general formula HO— (CH 2 —CH 2 —O) n —H (n is an integer of 1 or more).
　本発明の「ポリエチレングリコール」として好ましいのは、平均分子量が２００～１０００のポリエチレングリコールである。本発明の「ポリエチレングリコール」の好ましい例としては、ポリエチレングリコール２００（ＰＥＧ２００）、ポリエチレングリコール３００（ＰＥＧ３００）、ポリエチレングリコール４００（ＰＥＧ４００）、ポリエチレングリコール６００（ＰＥＧ６００）、ポリエチレングリコール１０００（ＰＥＧ１０００）などを挙げることができるが、本発明の「ポリエチレングリコール」の最も好ましい例はＰＥＧ４００である。 Preferred as the “polyethylene glycol” of the present invention is polyethylene glycol having an average molecular weight of 200 to 1,000. Preferred examples of the “polyethylene glycol” of the present invention include polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), polyethylene glycol 1000 (PEG 1000), and the like. However, the most preferred example of the “polyethylene glycol” of the present invention is PEG400.
　本組成物中のポリエチレングリコール濃度については、特に限定はされないが、好ましくは０．５～５．０（ｗ／ｖ）であり、さらに好ましくは０．５～３．０（ｗ／ｖ）であり、１．２５％（ｗ／ｖ）であることが特に好ましい。 The polyethylene glycol concentration in the composition is not particularly limited, but is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3.0 (w / v). Yes, and particularly preferably 1.25% (w / v).
　本発明の「ポリエトキシ化ヒマシ油誘導体」は、ヒマシ油に酸化エチレンを付加重合させて得られた化合物を意味し、ヒマシ油は水素添加されていないもの、例えば「ポリオキシルヒマシ油」でよく、またはヒマシ油は水素添加されたもの、例えば「ポリオキシル硬化油ヒマシ」でもよい。なお、「ポリオキシルヒマシ油」は、「ポリオキシエチレンヒマシ油」、「ポリエトキシ化ヒマシ油」とも呼ばれ、「ポリオキシル硬化ヒマシ油」は、「ポリオキシエチレン硬化ヒマシ油」、「ポリエトキシ化硬化ヒマシ油」とも呼ばれる。
　本発明の「ポリオキシルヒマシ油」の例は、酸化エチレンの平均付加モル数が約３５である「ポリオキシル３５ヒマシ油」、または酸化エチレンの平均付加モル数が約４０である「ポリオキシル４０ヒマシ油」、あるいはそれらの混合物が挙げられ、「ポリオキシル３５ヒマシ油」が好ましい。
　なお、「ポリオキシル３５ヒマシ油」は、ポリオキシルヒマシ油、ＰＥＧ－３５ヒマシ油、リシノール酸マクロゴグリセロールとも呼ばれ、また、「Ｃｒｅｍｏｐｈｏｒ（登録商標）ＥＬ」の商品名で市販されている。「ポリオキシル４０ヒマシ油」は、「Ｅｕｍｕｌｇｉｎ（登録商標）ＲＯ４０」、「Ｅｍｕｌｐｈｏｒ（登録商標）ＥＬ－７１９」の商品名で市販されている。
　本発明の「ポリオキシル硬化ヒマシ油」の例は、酸化エチレンの平均付加モル数が約３０である「ポリオキシル３０硬化ヒマシ油」、酸化エチレンの平均付加モル数が約４０である「ポリオキシル４０硬化ヒマシ油」、酸化エチレンの平均付加モル数が約５０である「ポリオキシル５０硬化ヒマシ油」、または酸化エチレンの平均付加モル数が約６０である「ポリオキシル６０硬化ヒマシ油」、あるいはそれらの混合物が挙げられる。
　なお、「ポリオキシル３０硬化ヒマシ油」は、「Ｎｉｋｋｏｌ（登録商標）ＨＣＯ－３０」の商品名で、「ポリオキシル４０硬化ヒマシ油」は、「Ｃｒｅｍｏｐｈｏｒ（登録商標）ＲＨ４０」、「Ｎｉｋｋｏｌ（登録商標）ＨＣ－４０」の商品名で、「ポリオキシル５０硬化ヒマシ油」は、「Ｎｉｋｋｏｌ（登録商標）ＨＣ－５０」の商品名で、「ポリオキシル６０硬化ヒマシ油」は、「Ｎｉｋｋｏｌ（登録商標）ＨＣ－６０」の商品名で市販されている。 The “polyethoxylated castor oil derivative” of the present invention means a compound obtained by addition polymerization of castor oil with ethylene oxide, and the castor oil may not be hydrogenated, for example, “polyoxyl castor oil” Alternatively, the castor oil may be hydrogenated, for example, “polyoxyl hydrogenated castor”. “Polyoxyl castor oil” is also called “polyoxyethylene castor oil” and “polyethoxylated castor oil”, and “polyoxyl hydrogenated castor oil” is “polyoxyethylene hydrogenated castor oil” and “polyethoxylated hydrogenated castor oil”. Also called “oil”.
Examples of the “polyoxyl castor oil” of the present invention include “polyoxyl 35 castor oil” having an average addition mole number of ethylene oxide of about 35, or “polyoxyl 40 castor oil” having an average addition mole number of ethylene oxide of about 40. Or a mixture thereof, and “polyoxyl 35 castor oil” is preferable.
“Polyoxyl 35 castor oil” is also called polyoxyl castor oil, PEG-35 castor oil, and macrogoglycerol ricinoleate, and is marketed under the trade name “Cremophor (registered trademark) EL”. "Polyoxyl 40 castor oil", which is commercially available under the trade name "Eumulgin (registered trademark) RO40", "Emulphor (registered trademark) EL-719".
Examples of the “polyoxyl hydrogenated castor oil” of the present invention include “polyoxyl 30 hydrogenated castor oil” having an average addition mole number of ethylene oxide of about 30, and “polyoxyl 40 hydrogenated castor oil” having an average addition mole number of ethylene oxide of about 40. Oil "," polyoxyl 50 hydrogenated castor oil "having an average addition mole number of ethylene oxide of about 50, or" polyoxyl 60 hydrogenated castor oil "having an average addition mole number of ethylene oxide of about 60, or a mixture thereof. It is done.
“Polyoxyl 30 hydrogenated castor oil” is a trade name of “Nikkol (registered trademark) HCO-30”, and “Polyoxyl 40 hydrogenated castor oil” is “Cremophor (registered trademark) RH40”, “Nikkol (registered trademark)”. under the trade name of HC-40 "," polyoxyl 50 hydrogenated castor oil ", under the trade name" Nikkol (registered trademark) HC-50 "," polyoxyl 60 hydrogenated castor oil "," Nikkol (registered trademark) HC- 60 "under the trade name.
　本組成物中のポリエトキシ化ヒマシ油誘導体濃度は１．０～５．０％（ｗ／ｖ）であり、好ましくは１．０～３．０（ｗ／ｖ）であり、２．０％（ｗ／ｖ）であることが最も好ましい。 The concentration of the polyethoxylated castor oil derivative in the composition is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / v), 2.0% ( Most preferred is w / v).
　ベンザルコニウム塩化物は、下記一般式（２）で示される化合物である。
Figure JPOXMLDOC01-appb-C000002
　［式中、ＲはＣ８Ｈ１７～Ｃ１８Ｈ３７で表されるアルキル基を示す。］ Benzalkonium chloride is a compound represented by the following general formula (2).
Figure JPOXMLDOC01-appb-C000002
[Wherein, R represents an alkyl group represented by C 8 H 17 to C 18 H 37 . ]
　本発明の「ベンザルコニウム塩化物」として好ましいのは、上記一般式（２）においてＲが「Ｃ１２Ｈ２５」を示すもの（以下、「ベンザルコニウム塩化物（Ｃ１２）」ともいう）である。 Preferred as "benzalkonium chloride" of the present invention, shows the general formula (2), R is the "C 12 H 25" (hereinafter, "benzalkonium chloride (C12)" and also referred to) in is there.
　本組成物にベンザルコニウム塩化物を添加する場合、該ベンザルコニウム塩化物の濃度は０．００５％（ｖ／ｗ）超であり、好ましくは０．００５～０．１％（ｖ／ｗ）、より好ましくは０．００７５～０．０５％（ｖ／ｗ）、さらに好ましくは０．００７５～０．０２％（ｖ／ｗ）である。本組成物中のベンザルコニウム塩化物濃度としては、０．０１％（ｖ／ｗ）が特に好ましい。 When benzalkonium chloride is added to the composition, the concentration of the benzalkonium chloride is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w). ), More preferably 0.0075 to 0.05% (v / w), still more preferably 0.0075 to 0.02% (v / w). The concentration of benzalkonium chloride in the present composition is particularly preferably 0.01% (v / w).
　本発明において、「０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を防腐剤として含有する」とは、本組成物が当該濃度の「ベンザルコニウム塩化物」に加え、「ベンザルコニウム塩化物以外の防腐剤」をも含有することをも意味するが、好ましくは、「ベンザルコニウム塩化物」を唯一の防腐剤として含有し、「ベンザルコニウム塩化物以外の防腐剤」を含有しないことを意味する。なお、該「ベンザルコニウム塩化物以外の防腐剤」としては、ベンゼトニウム塩化物、クロルヘキシジングルコン酸塩、パラベン類、ソルビン酸およびその塩、クロロブタノール、ホウ酸、ホウ砂、亜塩素酸塩などを挙げることができる。 In the present invention, “containing benzalkonium chloride at a concentration of more than 0.005% (w / v) as a preservative” means that the present composition is added to “benzalkonium chloride” at the concentration, It also means to contain "preservatives other than benzalkonium chloride", but preferably contains "benzalkonium chloride" as the only preservative, and "preservation other than benzalkonium chloride" It means not containing "agent". The “preservatives other than benzalkonium chloride” include benzethonium chloride, chlorhexidine gluconate, parabens, sorbic acid and salts thereof, chlorobutanol, boric acid, borax, chlorite, and the like. Can be mentioned.
　本発明において、「油」とは、眼科用途に使用可能な「油」であれば特に制限はないが、例えば、ヒマシ油、オリーブ油、オレンジ油、ダイズ油、ツバキ油、ナタネ油、ヤシ油（ココナッツ油）、ユーカリ油、トウモロコシ油、サフラワー油、エゴマ油、綿実油、小麦胚芽油、ペパーミント油、ヒマワリ油、ゴマ油、コーン油、ラッカセイ油、ピーナッツ油、アーモンド油、ホホバ油、ツバキ油等の液体植物油；ラノリン、スクワラン等の動物油；魚油；流動パラフィン、軽質流動パラフィン等の鉱物油；中鎖脂肪酸トリグリセリドなどを挙げることができる。なお、前記「ポリエトキシ化ヒマシ油誘導体」は本発明の「油」には含まれない。 In the present invention, the “oil” is not particularly limited as long as it is an “oil” that can be used for ophthalmic applications. For example, castor oil, olive oil, orange oil, soybean oil, camellia oil, rapeseed oil, coconut oil ( Coconut oil), eucalyptus oil, corn oil, safflower oil, egoma oil, cottonseed oil, wheat germ oil, peppermint oil, sunflower oil, sesame oil, corn oil, peanut oil, peanut oil, almond oil, jojoba oil, camellia oil, etc. Examples include liquid vegetable oils; animal oils such as lanolin and squalane; fish oils; mineral oils such as liquid paraffin and light liquid paraffin; medium chain fatty acid triglycerides. The “polyethoxylated castor oil derivative” is not included in the “oil” of the present invention.
　本組成物は、「油」または「エタノール」を実質的に含有しないことが好ましく、さらに好ましくは、「油」および「エタノール」の両者を実質的に含有しない。 This composition preferably does not substantially contain “oil” or “ethanol”, and more preferably does not substantially contain both “oil” and “ethanol”.
　本発明において、「油を実質的に含まない」および／または「エタノールを実質的に含まない」とは、本組成物の性状（澄明であるか否かなど）や安定性などの物性に影響を与える濃度の「油」および／または「エタノール」が本組成物には含有されていないことを意味する。 In the present invention, “substantially free of oil” and / or “substantially free of ethanol” affects properties of the composition (eg, whether it is clear) and stability. Means that no “oil” and / or “ethanol” is present in the composition.
　本組成物には、前記「ポリエチレングリコール」、「ポリエトキシ化ヒマシ油誘導体」および「ベンザルコニウム塩化物」以外の添加剤を配合することもできる。該添加剤としては、グリセリン、塩化ナトリウム、塩化カリウムなどの等張化剤；リン酸水素二ナトリウム（リン酸水素二ナトリウム十二水和物）、リン酸ナトリウム、酢酸ナトリウム、イプシロン－アミノカプロン酸などの緩衝化剤；エデト酸ナトリウム（エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウムおよびこれらの水和物を含む）、クエン酸ナトリウムなどの安定化剤等を挙げることができる。 In the present composition, additives other than the “polyethylene glycol”, “polyethoxylated castor oil derivative” and “benzalkonium chloride” can be blended. Examples of the additives include isotonic agents such as glycerin, sodium chloride, potassium chloride; disodium hydrogen phosphate (disodium hydrogen phosphate dodecahydrate), sodium phosphate, sodium acetate, epsilon-aminocaproic acid, etc. Buffering agents of sodium; edetate sodium (including monosodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate and hydrates thereof), stabilizers such as sodium citrate, etc. Can do.
　本組成物のｐＨは眼科製剤として許容される範囲内にあればよいが、通常４～８の範囲内が好ましい。 The pH of the present composition may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4-8.
　本組成物は、一回使い切りの「ユニットドーズ製剤」として製剤化することもできるし、ベンザルコニウム塩化物を添加することで、繰り返し使用可能な「マルチドーズ製剤」として製剤化することもできる。 This composition can be formulated as a “unit dose formulation” that can be used once, or can be formulated as a “multi-dose formulation” that can be used repeatedly by adding benzalkonium chloride. .
　本組成物は、ドライアイ（眼球乾燥症候群）のみならず、シェーグレン症候群、スティーブンス・ジョンソン症候群などの内因性疾患に伴う角結膜上皮障害の治療にも用いることができる。 The present composition can be used not only for dry eye (dry eye syndrome) but also for treating keratoconjunctival epithelial disorders associated with endogenous diseases such as Sjogren's syndrome and Stevens-Johnson syndrome.
　本製造方法は、シクロスポリンＡをポリエチレングリコールに溶解させて、溶液を得るステップ（ａ）、およびステップ（ａ）で得られた溶液とポリエトキシ化ヒマシ油誘導体および水を混合するステップ（ｂ）を含むが、ステップ（ｂ）において、ステップ（ａ）で得られた溶液をポリエトキシ化ヒマシ油誘導体、水およびベンザルコニウム塩化物と混合することもできる。 The production method includes steps (a) of obtaining a solution by dissolving cyclosporin A in polyethylene glycol, and a step (b) of mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative and water. However, in step (b), the solution obtained in step (a) can also be mixed with polyethoxylated castor oil derivative, water and benzalkonium chloride.
　本製造方法においては、ステップ（ｂ）において、ステップ（ａ）で得られた溶液、ポリエトキシ化ヒマシ油誘導体、水、ベンザルコニウム塩化物に加えて、前記添加剤の一部または全部を混合することもできる。 In this production method, in step (b), in addition to the solution obtained in step (a), the polyethoxylated castor oil derivative, water, and benzalkonium chloride, part or all of the additives are mixed. You can also.
　本製造方法によって得られる水性眼科用組成物中のシクロスポリンＡ濃度は０．０１～０．０８％（ｗ／ｖ）、好ましくは０．０３～０．０６％（ｗ／ｖ）、さらに好ましくは０．０５％（ｗ／ｖ）である。したがって、前記ステップ（ａ）では、同濃度が０．０１～０．０８％（ｗ／ｖ）、好ましくは０．０３～０．０６％（ｗ／ｖ）、さらに好ましくは０．０５％（ｗ／ｖ）となる量のシクロスポリンＡとポリエチレングリコールを混合する。 The concentration of cyclosporin A in the aqueous ophthalmic composition obtained by this production method is 0.01-0.08% (w / v), preferably 0.03-0.06% (w / v), more preferably 0.05% (w / v). Therefore, in the step (a), the same concentration is 0.01 to 0.08% (w / v), preferably 0.03 to 0.06% (w / v), more preferably 0.05% ( A quantity of w / v) of cyclosporin A and polyethylene glycol is mixed.
　本製造方法によって得られる水性眼科用組成物中のポリエチレングリコールの濃度は特に限定はされないが、好ましくは０．５～５．０（ｗ／ｖ）であり、さらに好ましくは０．５～３．０（ｗ／ｖ）であり、最も好ましくは１．２５％（ｗ／ｖ）である。
すなわち、前記ステップ（ａ）では、同濃度が好ましくは０．５～５．０（ｗ／ｖ）であり、さらに好ましくは０．５～３．０（ｗ／ｖ）、最も好ましくは１．２５％（ｗ／ｖ）となる量のポリエチレングリコールとシクロスポリンＡを混合する。 The concentration of polyethylene glycol in the aqueous ophthalmic composition obtained by this production method is not particularly limited, but is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3. 0 (w / v), most preferably 1.25% (w / v).
That is, in step (a), the same concentration is preferably 0.5 to 5.0 (w / v), more preferably 0.5 to 3.0 (w / v), and most preferably 1. Polyethylene glycol and cyclosporin A in an amount of 25% (w / v) are mixed.
　また、本製造方法によって得られる水性眼科用組成物中のポリエトキシ化ヒマシ油誘導体の濃度は１．０～５．０％（ｗ／ｖ）であり、好ましくは１．０～３．０（ｗ／ｖ）であり、最も好ましくは２．０％（ｗ／ｖ）である。すなわち、前記ステップ（ｂ）では、同濃度が１．０～５．０％（ｗ／ｖ）であり、好ましくは１．０～３．０（ｗ／ｖ）であり、最も好ましくは２．０％（ｗ／ｖ）となる量のポリエトキシ化ヒマシ油誘導体と、前記ステップ（ａ）で得られた溶液および水を混合することが好ましい。 The concentration of the polyethoxylated castor oil derivative in the aqueous ophthalmic composition obtained by the present production method is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / V), most preferably 2.0% (w / v). That is, in the step (b), the same concentration is 1.0 to 5.0% (w / v), preferably 1.0 to 3.0 (w / v), and most preferably 2. It is preferable to mix the polyethoxylated castor oil derivative in an amount of 0% (w / v), the solution obtained in step (a) and water.
　前記ステップ（ｂ）において、前記ステップ（ａ）で得られた溶液をポリエトキシ化ヒマシ油誘導体、水およびベンザルコニウム塩化物と混合する場合、本製造方法によって得られる水性眼科用組成物中のベンザルコニウム塩化物の濃度は０．００５％（ｖ／ｗ）超であり、好ましくは０．００５～０．１％（ｖ／ｗ）、より好ましくは０．００７５～０．０５％（ｖ／ｗ）、さらに好ましくは０．００７５～０．０２％（ｖ／ｗ）、特に好ましくは０．０１％（ｖ／ｗ）である。すなわち、前記ステップ（ｂ）では、同濃度が０．００５％（ｖ／ｗ）超であり、好ましくは０．００５～０．１％（ｖ／ｗ）、より好ましくは０．００７５～０．０５％（ｖ／ｗ）、さらに好ましくは０．００７５～０．０２％（ｖ／ｗ）、特に好ましくは０．０１％（ｖ／ｗ）となる量のベンザルコニウム塩化物と、前記ステップ（ａ）で得られた溶液、ポリエトキシ化ヒマシ油誘導体とおよび水を混合することが好ましい。 In the step (b), when the solution obtained in the step (a) is mixed with a polyethoxylated castor oil derivative, water and benzalkonium chloride, the benza in the aqueous ophthalmic composition obtained by the production method The concentration of ruconium chloride is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w), more preferably 0.0075 to 0.05% (v / w). w), more preferably 0.0075 to 0.02% (v / w), particularly preferably 0.01% (v / w). That is, in the step (b), the same concentration is more than 0.005% (v / w), preferably 0.005 to 0.1% (v / w), more preferably 0.0075 to 0.00. Benzalkonium chloride in an amount of 05% (v / w), more preferably 0.0075 to 0.02% (v / w), particularly preferably 0.01% (v / w), and the step It is preferable to mix the solution obtained in (a), the polyethoxylated castor oil derivative, and water.
　また、本方法は、前記ステップ（ａ）および（ｂ）以外の一または複数のステップを含んでいても良いが、好ましくは、「シクロスポリンＡと油を混合するステップ」または「シクロスポリンＡとエタノールを混合するステップ」を含まず、さらに好ましくは、「シクロスポリンＡと油を混合するステップ」および「シクロスポリンＡとエタノールを混合するステップ」の両者を含まない。 The method may include one or more steps other than the steps (a) and (b). Preferably, the “step of mixing cyclosporin A and oil” or “cyclosporin A and ethanol are mixed. The step of mixing is not included, and more preferably, both of the step of mixing cyclosporin A and oil and the step of mixing cyclosporin A and ethanol are not included.
　以下に、性状確認試験、熱安定性試験、保存効力試験および安定性試験の結果を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 The results of the property confirmation test, thermal stability test, storage efficacy test and stability test are shown below, but these examples are for better understanding of the present invention and limit the scope of the present invention. is not.
［性状確認試験］ [Property confirmation test]
（試験方法および結果）
　シクロスポリンＡ ０．０５ｇをＰＥＧ４００ １．２５ｇに溶解させた後、得られた溶解液とＣｒｅｍｏｐｈｏｒ（登録商標）ＥＬ ０．０５ｇ、ベンザルコニウム塩化物 ０．００５ｇ、グリセリン １．２５ｇ、リン酸水素二ナトリウム十二水和物 ０．６ｇおよび精製水を混合し、０．０５％（ｗ／ｖ）の濃度のＣｒｅｍｏｐｈｏｒ（登録商標）ＥＬを含有する試料（１００ｍＬ）を得た。該試料の外観は、４時間撹拌後においても非澄明（白色）であった。一方、Ｃｒｅｍｏｐｈｏｒ（登録商標）ＥＬをさらに添加し、前記試料中のＣｒｅｍｏｐｈｏｒ（登録商標）ＥＬ濃度を０．４％（ｗ／ｖ）まで上昇させた後、該試料をガラスアンプルに充填し、目視で確認したところ、試料の性状は澄明であった。 (Test method and results)
After 0.05 g of cyclosporin A was dissolved in 1.25 g of PEG400, the resulting solution and Cremophor (registered trademark) EL 0.05 g, benzalkonium chloride 0.005 g, glycerol 1.25 g, dihydrogen phosphate mixing the sodium twelve dihydrate 0.6g and purified water to obtain 0.05% (w / v) of the concentration of Cremophor sample containing (R) EL (100 mL). The appearance of the sample was unclear (white) even after stirring for 4 hours. On the other hand, Cremophor (registered trademark) EL was further added to increase the Cremophor (registered trademark) EL concentration in the sample to 0.4% (w / v), and then the sample was filled into a glass ampule and visually observed. As a result, the properties of the sample were clear.
（考察）
　澄明なシクロスポリン含有水性組成物を得るには、ポリエチレングリコールおよび０．４％（ｗ／ｖ）以上の濃度のポリエトキシ化ヒマシ油誘導体を併用することが必要であることが示された。 (Discussion)
It has been shown that to obtain a clear cyclosporine-containing aqueous composition, it is necessary to use polyethylene glycol and a polyethoxylated castor oil derivative at a concentration of 0.4% (w / v) or higher in combination.
［熱安定性試験］ [Thermal stability test]
（試料調製）
処方１
　シクロスポリンＡ ０．０５ｇをＰＥＧ４００ １．２５ｇに溶解させた後、得られた溶解液とＣｒｅｍｏｐｈｏｒ（登録商標）ＥＬ ２ｇ、ベンザルコニウム塩化物 ０．０１ｇ、エデト酸ナトリウム ０．１ｇ、リン酸水素二ナトリウム十二水和物 ０．６ｇおよび精製水を混合した。希塩酸および／または水酸化ナトリウムを添加してｐＨ７．０とした後、精製水を加えて１００ｍＬとした。 (Sample preparation)
Formula 1
After 0.05 g of cyclosporin A was dissolved in 1.25 g of PEG400, the resulting solution and Cremophor (registered trademark) EL 2 g, benzalkonium chloride 0.01 g, sodium edetate 0.1 g, dihydrogen phosphate Sodium dodecahydrate 0.6g and purified water were mixed. After dilute hydrochloric acid and / or sodium hydroxide was added to adjust the pH to 7.0, purified water was added to make 100 mL.
比較処方１
　シクロスポリンＡ ０．０５ｇをＰＥＧ４００ １．２５ｇに溶解させた後、得られた溶解液とＣｒｅｍｏｐｈｏｒ（登録商標）ＥＬ ０．５ｇ、ベンザルコニウム塩化物（Ｃ１２） ０．０１ｇ、グリセリン １．２ｇ、リン酸水素二ナトリウム十二水和物 ０．６ｇおよび精製水を混合した。希塩酸および／または水酸化ナトリウムを添加してｐＨ７．０とした後、精製水を加えて１００ｍＬとした。 Comparative prescription 1
After dissolving 0.05 g of cyclosporin A in 1.25 g of PEG400, the obtained solution and Cremophor (registered trademark) EL 0.5 g, benzalkonium chloride (C12) 0.01 g, glycerin 1.2 g, phosphorus 0.6 g of disodium oxyhydrogen dodecahydrate and purified water were mixed. After dilute hydrochloric acid and / or sodium hydroxide was added to adjust the pH to 7.0, purified water was added to make 100 mL.
比較処方２
　エデト酸ナトリウム ０．１ｇを添加したことを除き、比較処方１と同様の方法で調製した。 Comparative prescription 2
It was prepared in the same manner as Comparative Formula 1 except that 0.1 g of sodium edetate was added.
（試験方法）
　それぞれ５ｍＬの処方１ならびに比較処方１および２を、タイプ６（ポリエチレン）チップおよびタイプ６（ポリプロピレン）キャップを有するタイプ６（低密度ポリエチレン）ボトル（５ｃｃ）に充填し、それぞれについて６０℃で４週間保存した。その後、シクロスポリンＡの含有量を高速液体クロマトグラフィー（ＨＰＬＣ）を用いて定量し、残存率を求めた。 (Test method)
Each 5 mL of Formula 1 and Comparative Formulas 1 and 2 are filled into Type 6 (low density polyethylene) bottles (5 cc) with Type 6 (polyethylene) tips and Type 6 (polypropylene) caps, each at 60 ° C. for 4 weeks. saved. Thereafter, the content of cyclosporin A was quantified using high performance liquid chromatography (HPLC) to determine the residual rate.
（結果）
　試験結果を表１に示す。なお、処方１ならびに比較処方１および２の性状は澄明であった。 (result)
The test results are shown in Table 1. The properties of Formula 1 and Comparative Formulas 1 and 2 were clear.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
（考察）
　安定なシクロスポリン製剤を得るためには、ポリエトキシ化ヒマシ油誘導体の濃度が重要であることが示された。 (Discussion)
It has been shown that the concentration of polyethoxylated castor oil derivative is important to obtain a stable cyclosporine formulation.
［眼刺激性試験］ [Eye irritation test]
（試料調製）
処方２
　エデト酸ナトリウムの代わりにグリセリン １．８ｇを添加したことを除き、前記熱安定性試験で用いた処方１と同様の方法で調製した。 (Sample preparation)
Formula 2
It was prepared in the same manner as Formula 1 used in the thermal stability test except that 1.8 g of glycerin was added instead of sodium edetate.
比較処方３（処方２の基剤）
　シクロスポリンＡを添加しないことを除き、処方２と同様の方法で調製した。 Comparative prescription 3 (base of prescription 2)
It was prepared in the same manner as Formula 2 except that cyclosporin A was not added.
比較処方４（ＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液）
　市販のＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液を用いた。 Comparative Formulation 4 (RESTASIS (TM) 0.05% ophthalmic solution)
Commercial RESTASIS using (R) 0.05% ophthalmic solution.
（試験方法）
処方２および比較処方３点眼群 (Test method)
Formula 2 and Comparative Formula 3 ophthalmic group
　処方２（５０μＬ）をピペットマンで日本白色ウサギの左眼に９０分間隔で６回点眼し、点眼１および６回目直後の１分間の瞬目回数を計測した。また、当該ウサギの対側眼には、比較処方３（５０μＬ）を９０分間隔で６回点眼し、同じく点眼１および６回目直後の１分間の瞬目回数を計測した。 Prescription 2 (50 μL) was instilled into the left eye of a Japanese white rabbit 6 times at intervals of 90 minutes with Pipetteman, and the number of blinks per minute for 1 minute immediately after instillation 1 and the sixth was measured. In addition, comparative formulation 3 (50 μL) was instilled into the contralateral eye of the rabbit 6 times at 90-minute intervals, and the number of blinks for 1 minute immediately after instillation 1 and 6th time was measured.
比較処方４点眼群
　比較処方４（５０μＬ）をピペットマンで日本白色ウサギの左眼に９０分間隔で６回点眼し、点眼１および６回目直後の１分間の瞬目回数を計測した。対側眼は無処置とした。 Comparative prescription 4 eye drops Comparative prescription 4 (50 μL) was instilled into the left eye of a Japanese white rabbit 6 times at intervals of 90 minutes with Pipetteman, and the number of blinks per minute for 1 minute immediately after instillation 1 and the 6th time was measured. The contralateral eye was untreated.
（試験結果）
　試験結果を表２に示す。処方２点眼眼の瞬目回数は、比較処方４（ＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液）点眼眼のそれよりも少ないことが示された。 (Test results)
The test results are shown in Table 2. Blink frequency of the formulation 2 instillation eye, compared Formulation 4 (RESTASIS (TM) 0.05% ophthalmic solution) may be fewer than that of eye drops eye shown.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
（考察）
　本組成物の眼刺激性は、市販のシクロスポリンＡ製剤（ＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液）よりも低いことが示された。 (Discussion)
Eye irritation of the composition, it was shown lower than the commercial cyclosporine A formulation (RESTASIS (TM) 0.05% ophthalmic solution).
［保存効力試験］ [Preservation efficacy test]
（試料調製）
処方１
　前記熱安定性試験と同様の方法で調製した。 (Sample preparation)
Formula 1
It was prepared by the same method as in the thermal stability test.
比較処方５
　ベンザルコニウム塩化物の添加量が０．００５ｇであることを除き、前記熱安定試験で用いた比較処方１と同様の操作を行い、比較処方５を得た。 Comparative prescription 5
Except that the amount of benzalkonium chloride added was 0.005 g, the same operation as Comparative Formula 1 used in the thermal stability test was performed to obtain Comparative Formula 5.
（試験方法）
　保存効力試験は、第十五改正日本薬局方（以下、単に「日本薬局方」ともいう）の保存効力試験法に準拠して行った。本試験では、試験菌として、Ｅｓｈｅｒｉｃｈｉａ　Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ　ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）、Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ　ａｕｒｅｕｓ（Ｓ．ａｕｒｅｕｓ）、Ｃａｎｄｉｄａ　ａｌｂｉｃａｎｓ（Ｃ．ａｌｂｉｃａｎｓ）およびＡｓｐｅｒｇｉｌｌｕｓ　ｂｒａｓｉｌｉｅｎｓｉｓ（Ａ．ｂｒａｓｉｌｉｅｎｓｉｓ）を用いた。 (Test method)
The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 15th revision Japanese Pharmacopoeia (hereinafter, also simply referred to as “Japanese Pharmacopoeia”). In this test, Escherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Candida albicans (C. albicans) were used as test bacteria. .
（試験結果）
　試験結果を表３に示す。 (Test results)
The test results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
（考察）
　本組成物に０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を添加することで、日本および米国薬局方の基準に適合する程度の保存効力が得られることが示された。 (Discussion)
The addition of benzalkonium chloride at a concentration of more than 0.005% (w / v) to this composition has been shown to provide storage efficacy to the extent that it meets Japanese and US Pharmacopoeia standards. .
　本発明のシクロスポリン含有眼科用組成物は、ＲＥＳＴＡＳＩＳ（登録商標）０．０５％点眼液などの従来のシクロスポリンＡ製剤とは異なり澄明な水性組成物である上、眼科用組成物としても好ましい安定性および安全性をも併せ持つ。したがって、本発明のシクロスポリン含有眼科用組成物はドライアイ等の治療に好適に使用できる。 Cyclosporine-containing ophthalmic compositions of the present invention, RESTASIS (R) on the conventional cyclosporin A formulations such as 0.05% ophthalmic solution is a clear aqueous composition varies, also preferred stability as ophthalmic composition It also has safety. Therefore, the cyclosporine-containing ophthalmic composition of the present invention can be suitably used for the treatment of dry eye and the like.

Claims (20)

  1. 　０．０１～０．０８％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、該組成物がポリエチレングリコールおよび１．０～５．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有する、組成物。 An aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.01-0.08% (w / v), wherein the composition comprises polyethylene glycol and 1.0-5.0% (w / v) A composition comprising a polyethoxylated castor oil derivative at a concentration of
  2. 　０．５～５．０％（ｗ／ｖ）の濃度のポリエチレングリコールを含有する、請求項１記載の組成物。 The composition according to claim 1, comprising polyethylene glycol at a concentration of 0.5 to 5.0% (w / v).
  3. 　１．０～３．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有する、請求項１記載の組成物。 The composition according to claim 1, comprising a polyethoxylated castor oil derivative at a concentration of 1.0 to 3.0% (w / v).
  4. 　２．０％（ｗ／ｖ）の濃度のポリエトキシ化ヒマシ油誘導体を含有する、請求項１記載の組成物。 The composition according to claim 1, comprising a polyethoxylated castor oil derivative at a concentration of 2.0% (w / v).
  5. 　さらに０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を含有する、請求項１記載の組成物。 The composition according to claim 1, further comprising benzalkonium chloride at a concentration exceeding 0.005% (w / v).
  6. 　ポリエチレングリコールがＰＥＧ４００である、請求項１記載の組成物。 The composition according to claim 1, wherein the polyethylene glycol is PEG400.
  7. 　ポリエトキシ化ヒマシ油誘導体がポリオキシル３５ヒマシ油である、請求項１記載の組成物。 The composition according to claim 1, wherein the polyethoxylated castor oil derivative is polyoxyl 35 castor oil.
  8. 　油を実質的に含有しない、請求項１記載の組成物。 The composition according to claim 1, substantially free of oil.
  9. 　エタノールを実質的に含有しない、請求項１記載の組成物。 The composition according to claim 1, substantially free of ethanol.
  10. 　０．０５％（ｗ／ｖ）の濃度のシクロスポリンＡを含有する水性眼科用組成物であって、該組成物が１．２５％（ｗ／ｖ）の濃度のＰＥＧ４００、２．０％（ｗ／ｖ）の濃度のポリオキシル３５ヒマシ油、および０．００５％（ｗ／ｖ）超の濃度のベンザルコニウム塩化物を含有し、油およびエタノールを実質的に含有しない、組成物。 An aqueous ophthalmic composition containing cyclosporin A at a concentration of 0.05% (w / v), wherein the composition is PEG 400, 2.0% (w A composition comprising polyoxyl 35 castor oil at a concentration of / v) and benzalkonium chloride at a concentration greater than 0.005% (w / v) and substantially free of oil and ethanol.
  11. 　次のステップ：
    （ａ）シクロスポリンＡをポリエチレングリコールに溶解させて溶液を得るステップ；および
    （ｂ）ステップ（ａ）で得られた溶液とポリエトキシ化ヒマシ油誘導体および水を混合するステップを含む、請求項１記載の水性眼科用組成物の製造方法。     Next steps:
    The method of claim 1, comprising the steps of: (a) dissolving cyclosporin A in polyethylene glycol to obtain a solution; and (b) mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative and water. A method for producing an aqueous ophthalmic composition.
  12. 　該組成物中のポリエチレングリコールの濃度が０．５～５．０％（ｗ／ｖ）である、請求項１１記載の方法。 The method according to claim 11, wherein the concentration of polyethylene glycol in the composition is 0.5 to 5.0% (w / v).
  13. 　該組成物中のポリエトキシ化ヒマシ油誘導体の濃度が１．０～３．０％（ｗ／ｖ）である、請求項１１記載の方法。 The method according to claim 11, wherein the concentration of the polyethoxylated castor oil derivative in the composition is 1.0 to 3.0% (w / v).
  14. 　該組成物中のポリエトキシ化ヒマシ油誘導体の濃度が２．０％（ｗ／ｖ）である、請求項１１記載の方法。 The method according to claim 11, wherein the concentration of the polyethoxylated castor oil derivative in the composition is 2.0% (w / v).
  15. 　次のステップ：
    （ａ）シクロスポリンＡをポリエチレングリコールに溶解させて溶液を得るステップ；および
    （ｂ）ステップ（ａ）で得られた溶液とポリエトキシ化ヒマシ油誘導体、水およびベンザルコニウム塩化物を混合するステップを含む、請求項５記載の水性眼科用組成物の製造方法。     Next steps:
    (A) dissolving cyclosporin A in polyethylene glycol to obtain a solution; and (b) mixing the solution obtained in step (a) with the polyethoxylated castor oil derivative, water and benzalkonium chloride. The manufacturing method of the aqueous ophthalmic composition of Claim 5.
  16. 　ポリエチレングリコールがＰＥＧ４００である、請求項１１記載の方法。 The method according to claim 11, wherein the polyethylene glycol is PEG400.
  17. 　ポリエトキシ化ヒマシ油誘導体がポリオキシル３５ヒマシ油である、請求項１１記載の方法。 The method according to claim 11, wherein the polyethoxylated castor oil derivative is polyoxyl 35 castor oil.
  18. 　水性眼科用組成物が油を含まない、請求項１１記載の方法。 The method according to claim 11, wherein the aqueous ophthalmic composition does not contain oil.
  19. 　水性眼科用組成物がエタノールを含まない、請求項１１記載の方法。 The method according to claim 11, wherein the aqueous ophthalmic composition does not contain ethanol.
  20. 　次のステップ：
    （ａ）シクロスポリンＡをＰＥＧ４００に溶解させて溶液を得るステップ；
    （ｂ）ステップ（ａ）で得られた溶液とポリオキシル３５ヒマシ油、水およびベンザルコニウム塩化物を混合するステップを含む、
    ０．０５％（ｗ／ｖ）の濃度のシクロスポリンＡを含有し、ポリオキシル３５ヒマシ油、ＰＥＧ４００およびベンザルコニウム塩化物の濃度が、それぞれ、２．０％（ｗ／ｖ）、１．２５％（ｗ／ｖ）および０．００５％（ｗ／ｖ）超である水性眼科用組成物の製造方法。     Next steps:
    (A) dissolving cyclosporin A in PEG400 to obtain a solution;
    (B) mixing the solution obtained in step (a) with polyoxyl 35 castor oil, water and benzalkonium chloride;
    Containing cyclosporin A at a concentration of 0.05% (w / v), the concentrations of polyoxyl 35 castor oil, PEG 400 and benzalkonium chloride are 2.0% (w / v) and 1.25%, respectively. A method for producing an aqueous ophthalmic composition that is (w / v) and greater than 0.005% (w / v).
PCT/JP2014/068382 2013-07-11 2014-07-10 Aqueous ophthalmic composition containing cyclosporine a WO2015005409A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109010270A (en) * 2018-09-03 2018-12-18 辅必成（上海）医药科技有限公司 A kind of ophthalmically acceptable cream of cationic materials preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0558906A (en) * 1991-09-06 1993-03-09 Sankyo Co Ltd Cyclosporin eye-lotion
JP2001516351A (en) * 1997-03-12 2001-09-25 アボツト・ラボラトリーズ Hydrophilic binary system for administration of cyclosporine
JP2011502989A (en) * 2007-11-01 2011-01-27 ボーシュ アンド ローム インコーポレイティド Non-aqueous water-miscible materials as vehicles for drug delivery

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0558906A (en) * 1991-09-06 1993-03-09 Sankyo Co Ltd Cyclosporin eye-lotion
JP2001516351A (en) * 1997-03-12 2001-09-25 アボツト・ラボラトリーズ Hydrophilic binary system for administration of cyclosporine
JP2011502989A (en) * 2007-11-01 2011-01-27 ボーシュ アンド ローム インコーポレイティド Non-aqueous water-miscible materials as vehicles for drug delivery

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109010270A (en) * 2018-09-03 2018-12-18 辅必成（上海）医药科技有限公司 A kind of ophthalmically acceptable cream of cationic materials preparation
CN109010270B (en) * 2018-09-03 2021-07-30 辅必成（上海）医药科技有限公司 Eye lotion prepared from cationic material

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