JPH0558906A - Cyclosporin eye-lotion - Google Patents

Abstract

PURPOSE:To provide a safe eye-lotion containing cyclosporin and a specific surfactant and not giving any irritation when used. CONSTITUTION:The objective aqueous eye-lotion solution contains (A) cyclosporin preferably in an amount of 0.2-2.0mg/ml, especially 0.2-1.5mg/ml, and (B) one kind or more of surfactants selected from polysorbate, polyoxyethylene-hardened caster oil and a polyoxyethylene fatty acid ester preferably in an A:B weight ratio of 1:5 to 1:200, especially 1:20 to 1:100. The eye-lotion solution is, if necessary, mixed with a polyhydric alcohol (e.g. glucose, fructose or polyethylene glycol), separately injected into vials, frozen at -40 deg.C in a lyophilizer, and subsequently vacuum-dried at a shelf temperature of 10 deg.C therein for approximately 48hr to obtain the lyophilized product. The lyophilized product mixed with the polyhydric alcohol exhibit especially good solubility and appearance when again dissolved, and give the solution not having any difference from the solution before lyophilized.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an eye drop preparation containing cyclosporin, which is safe and does not cause irritation during use.

[0002]

2. Description of the Prior Art Nine types of cyclosporins, A to I, are known to date. All of these are cyclic peptides having a molecular weight of about 1200 and consisting of 11 amino acids, (hereinafter, "cyclosporin" in the present invention,
Included are each of these peptides and mixtures of each of these peptides. ) Medically useful immunosuppressive, antifungal, anti-inflammatory action, etc. (Merck Index, 2748, 396 pages, 10)
Edition: Helv.Chim.Acta, 60, 1568-1578 (1977
Year): Helv.Chim.Acta, Volume 65, 1655-1677 (1982)
Year) etc.).

[0003] At present, cyclosporin preparations (having cyclosporin A as a main component) are commercially available and used as an immunosuppressant in the form of orally administered drugs and injections (trade name "Sandimune";"Recently"). New Drug "139-
144 pages, 38 collections, 1987 edition). However, since the solubility of cyclosporine in water is extremely low at 20 to 30 μg / ml, the above injection is prepared as a surfactant solution containing ethanol, and the oral administration is prepared as an oil solution preparation.

Recently, Kanai et al. (Abstracts of the 93rd Annual Meeting of the Japanese Society of Ophthalmology, p. 239, “On the immunosuppressive effect of cyclosporine ophthalmic solution after corneal transplantation”) have been shown to be useful as an immunosuppressant, especially in the ophthalmic field. Ophthalmological Society Magazine, 93rd
It was confirmed by the special edition of the special edition, issued on April 5, 1989.

As the cyclosporin eye drop preparation, for example, a method using cyclosporine with α-cyclodextrin (JP-A-64-85921), intermediate fatty acid mono and / or
Alternatively, a method using diglyceride (JP-A-2-49733).
No.), vegetable oil or mineral oil (Japanese Patent Publication No. 3-
No. 503159) is known.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have completed the present invention by discovering a cyclosporin ophthalmic solution which does not cause irritation or clouding of the visual field.

[0007]

The present invention comprises (I) 1) cyclosporine and 2) one or more surfactants selected from polysorbate, polyoxyethylene hydrogenated castor oil and polyoxyethylene fatty acid ester. Aqueous eye drop aqueous solution formulation, and (II)
It consists of 1) cyclosporine and 2) an eye drop formulation obtained by freeze-drying an aqueous solution containing one or more surfactants selected from polysorbate, polyoxyethylene hydrogenated castor oil and polyoxyethylene fatty acid ester.

That is, the following conditions (1) Solubility in cyclosporine for the purpose of solubilizing cyclosporin only with a surfactant, (2) buffer, osmotic pressure adjusting agent, preservative in the solubilized cyclosporin solution , And the like, changes in appearance over time, (3) Eye irritancy test with rabbit eye drops after solubilization and dilution with water to eye drop concentration,
As a result of various studies on the surfactant satisfying the requirement, polysorbate, polyoxyethylene hydrogenated castor oil, and polyoxyethylene fatty acid ester unexpectedly showed excellent effects as compared with other surfactants.

Examples of the polysorbates used in the present invention include polysorbates 20, 40, 80 and the like. Preferably polysorbate 80
Is.

Examples of the polyoxyethylene hydrogenated castor oil used in the present invention include polyoxyethylene hydrogenated castor oil 40, 60, 80, 100 and the like. Polyoxyethylene hydrogenated castor oil 60 is preferred.

Examples of the polyoxyethylene fatty acid ester used in the present invention include polyoxyethylene fatty acid monostearate (40) and monolaurate (1
0), monooleate (10) and the like. Preferred is polyoxyethylene fatty acid monostearate (40).

The use ratio (weight ratio) of the cyclosporin of the present invention and the surfactant is preferably 1: 5 to 1: 200.
And more preferably 1:20 to 1: 100.

The concentration of cyclosporin in the water of the present invention is preferably 0.1 to 2.0 mg / ml, more preferably 0.2.
The lyophilized ophthalmic formulation of the present invention, which is ˜1.5 mg / ml, contains a polyhydric alcohol such as glucose, fructose, maltose, sucrose, sorbitol, xylitol, mannitol as an excipient in the solubilized solution as required. One or a mixture of two or more sugars such as; polyethylene glycol 500 to polyethylene glycol 30000; The use ratio (weight ratio) of cyclosporine and polyhydric alcohol is preferably 1: 5 to 1: 200, more preferably 1:20 to
It is 1: 100.

In the present invention, in these basic forms, inorganic salts such as sodium chloride and potassium chloride as osmotic pressure adjusting agents or sugars such as glucose, mannitol and sorbitol; benzalkonium chloride and chlorobutanol as antifungal agents; In addition, it is within the technical level in the art to improve the formulation by adding sodium citrate, sodium phosphate or the like as a buffer, and is included in the present invention.

The aqueous solution preparation for eye drops of the present invention can be produced by dissolving cyclosporin in the above-mentioned surfactant and then adding water to dilute it to an eye drop concentration. The thus-obtained aqueous solution preparation may be adjusted to a pH of about 6.0 with a buffer if necessary, and then separated into eyedrop containers under aseptic conditions for use.

The freeze-dried eye drop preparation of the present invention is dissolved by adding a polyhydric alcohol to the solubilized solution as needed. Then, it can be manufactured by dispensing in a vial, freezing to −40 ° C. in a freeze dryer, and vacuum drying at a shelf temperature of 10 ° C. for about 48 hours. The freeze-dried agent thus obtained can be dissolved in a solution containing a mildew-proofing agent and an osmotic pressure adjusting agent at the time of use and transferred to an eye drop container for use.

[0017]

EXAMPLES Examples and test examples will be given below, but these are for explaining the present invention, and the present invention is not limited thereto.

The cyclosporin used in the examples and test examples is supplied from Sandoz Ltd. of Switzerland and is the same as the commercially available "Sandymune" (trade name) main agent.

Example 1. 0.5 g of cyclosporine was dissolved in 20 g of polyoxyethylene hydrogenated castor oil (60) while heating. After confirming the dissolution, water for injection was gradually added to solubilize the cyclosporin / activator. Further, 8 g of sodium chloride as an osmotic pressure adjusting agent and an appropriate amount of antifungal agent were added, and the total amount was adjusted to 1000 ml. It was aseptically filtered with a membrane filter, dispensed into an eye drop container, and then used.

Example 2. 2 g of cyclosporine 0.5 g
It was dissolved in 0 g of polysorbate 80. Water for injection 1000 m
was gradually added to obtain a cyclosporin homogeneous aqueous solution.
Then, 20 g of glucose was added and dissolved as an excipient, and freeze-dried by a usual method. At the time of use, it was dissolved in sterile water for injection and used.

Example 3. 2 g of cyclosporine 0.5 g
Dissolved in 0 g polysorbate 80. A fungicide was added and the product was stored in a non-water state. At the time of use, it was dissolved and diluted to a use concentration with 1000 ml of water for injection in which 9 g of sodium chloride was dissolved as an osmotic pressure adjusting agent, and the solution was applied to the eye drop.

Example 4. Cyclosporine 0.5 g to polyoxyethylene fatty acid monostearate (40) 20 g
After dissolving in, 100 ml of water for injection was added to obtain a uniform solution.
Separately, dissolve 10 g maltose in 100 ml water for injection,
Add cyclosporin homogeneous solution to 100% with water for injection
It was set to 0 ml. This was dispensed into a vial and then frozen at -40 ° C in a freeze dryer. Further, freeze-drying was carried out at a shelf temperature of 10 ° C for 48 hours and at 30 ° C for 10 hours to obtain a freeze-dried preparation of cyclosporine. When using, dissolve in sterile water for injection,
It was put to use.

Example 5. Cyclosporine (1.0 g) was dissolved in 20 g of polyoxyethylene hydrogenated castor oil (60) while heating. 900 ml of water for injection was gradually added to this to obtain a uniform solution. 40 g polyethylene glycol 4000
Is dissolved in a uniform solution and dissolved in water for injection to a total volume of 1000 m.
l This was dispensed into a vial and then frozen at −50 ° C. in a freeze dryer. Further, freeze-drying was performed at a shelf temperature of 0 ° C. for 48 hours and at a shelf temperature of 30 ° C. to obtain a freeze-dried cyclosporin preparation. At the time of use, it was dissolved in a solution in which benzalkonium chloride as a mildew-proofing agent and potassium chloride as an osmotic pressure adjusting agent were dissolved, and then transferred to an eye drop container for use.

Test Example 1. The solubility, time-dependent stability and eye irritation of cyclosporine in various surfactants were investigated by a conventional method. The results are shown in the table.

[0025]

[Table] ·········· Surfactant Cyclosporine Time-dependent Eye irritation Solubility Stability・ ・ ・ ・ ・ ・ ・ ・ ・ Polysorbate 80 ○ ○ ○ POE hydrogenated castor oil (60) ○ ○ ○ POE Fatty acid monostearate (40) ○ ○ ○ POE fatty acid ether (25) ○ ○ △ Pluronic F68 (trade name) ○ × ― Purified egg yolk lecithin × × ― Sucrose fatty acid lauryl ester × × ― Polyglycerin lauryl ester ○ × ― ・ ・..................... POE = polyoxyethylene

[0026]

[Effects of the Examples] Cyclosporine aqueous solution formulations were prepared by dissolving cyclosporin only with the selected surfactant, and then gradually adding water for injection to a solubilizing concentration to reach a working concentration of 25-50.
A 0-fold dilution gave a clear aqueous solution. The diluted solution was stored at room temperature for 6 months or longer, but it was found that precipitation or precipitation did not occur and it could be sufficiently used for eye drops. It was confirmed that the freeze-dried preparation of cyclosporine was superior in stability over time to the state of an aqueous solution and that there was almost no decrease in the content of cyclosporine. Regarding the re-solubility, when polyhydric alcohols were added, the solubility and appearance at the time of re-dissolution were particularly good, and no difference from the solution state before freeze-drying was observed.

[0027]

The cyclosporin aqueous solution preparation and the freeze-dried preparation of the present invention exhibit excellent effects for eye drops.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area A61K 47/44 G 7329-4C

Claims (2)

[Claims] 1. An ophthalmic aqueous solution formulation comprising 1) cyclosporine and 2) one or more surfactants selected from polysorbate, polyoxyethylene hydrogenated castor oil and polyoxyethylene fatty acid ester. 2. An eye drop preparation obtained by freeze-drying an aqueous solution comprising 1) cyclosporine and 2) one or more surfactants selected from polysorbate, polyoxyethylene hydrogenated castor oil and polyoxyethylene fatty acid ester.