Cyclosporin compositions

Details Cyclosporin compositions Cyclosporin compositions

2001-08-27

2003-06-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S078040, C424S488000

Reexamination Certificate

active

06582718

ABSTRACT:

This invention relates to ophthalmic compositions, particularly eye-drop formulations, comprising a cyclosporin as active ingredient and being suitable for the treatment of diseases of the eye and surrounding areas.
The cyclosporins comprise a large and recognized class of peptide compounds having pharmaceutical utility, for example immunosuppressant, anti-inflammatory, and/or anti-parasitic activity and/or activity in abrogating tumor resistance to anti-neoplastic or cytostatic drug therapy. The cyclosporins include, for example, naturally occurring fungal metabolites, such as the cyclosporin A, B, C, D and G, as well as a wide variety of synthetic and semi-synthetic cyclosporins, for example the dihydro- and iso-cyclosporins (see e.g. U.S. Pat. Nos. 4,108,985; 4,210,581 and 4,220,641), [(D)-Ser]
8
-Ciclosporin (see U.S. Pat. No. 4,384,996), [0-acetyl, (D)-Ser]
8
-Ciclosporin (see U.S. Pat. No. 4,764,503), [&bgr;-fluoro-(D)Ala]
8
-Ciclosporin (see UK Patent Application 2,206,119A), [Val]
2
-[(D)methylthio-Sar]
3
- and [Dihydro-MeBmt]
1
-[Val]
2
-[(D)methylthio-Sar]
3
-Ciclosporin [see U.S. Pat. No. 4,703,033], [0-(2-hydroxyethyl)-(D)Ser]
8
-Ciclosporin, and [3′-deshydroxy-3′-keto-MeBmt]
1
-[Val]
2
-Ciclosporin and many more.
Of the cyclosporins, the most widely investigated to date is cyclosporin A, being commercially available under the Registered Trade Mark SANDIMMUN or SANDIMMUNE. Cyclosporin A has been shown to suppress selectively a variety of T-lymphocyte functions, including prevention of maturation and expression of sensitized T-lymphocytes in cell mediated immune responses, and is now successfully and widely used in the suppression of organ transplant rejection. Cyclosporin A has also been used systemically in the treatment of intraocular inflammatory or autoimmune diseases, such as uveitis. However, because of the side effects associated with systemic therapy, Cyclosporin A has had only limited use in treating conditions of the eye.
Effective topical administration of Cyclosporin A to the eye would reduce or eliminate to a large extent the systemic side effects by restricting activity to the locus of the condition being treated and proposals to this effect have been made, (see for example U.S. Pat. No. 4,649,047). However, utility and effectiveness of Cyclosporin A in treating diseases and conditions of the eye has been hindered until now by the lack of suitable eye-drops which are acceptable to the eye. Eye-drops are required which do not cause patient discomfort and which permit a convenient administration regimen and do not require unduly frequent administration, while providing adequate drug substance delivery both to the external and, in particular, the internal regions of the eye. A further difficulty is the very poor solubility of cyclosporin A in water. This leads often to precipitation of cyclosporin A from aqueous-based eye-drops causing strong irritation of the eye.
Efforts have been made to overcome these difficulties by dissolving cyclosporin A in vegetable oils (Ophthalmology, 96, 1144-1150 (1989)) and by clatherating cyclosporin A with cyclodextrin (Japanese unexamined Patent Publication SHO-64-85921/1989).
In oily solution, however, cyclosporin A is poorly distributed in the eyes (Folia Ophthalmologica Japonica, 40, (5), 902-908 (1989)), and a high concentration (2%) of cyclosporin A is needed for clinical treatment (Ophthalmology, 96, 1144-1150 (1989)). Further, these oily eye drops tend to cause a disagreeable feeling to the eyes.
Also, whereas cyclosporin eye-drops solubilized by clatherating with cyclodextrin certainly have an improved distribution in the eyes (Folia Ophthalmologica Japonica, 40, (5), 902-908 (1989)), the dissolved cyclosporin A is however again precipitated. As indicated by experiments in rabbits, this provokes strong irritation in at least the anterior part of eyes and induces redness and edema of conjunctival palpebrae and secretion from the conjunctiva, causing problems for application of cyclosporin A in this form.
There is thus an urgent need to develop a topical, ophthalmic formulation which causes less irritation to the eyes, has a better distribution of cyclosporin A in the eyes and has no problems of precipitation of cyclosporin.
In an attempt to solve these problems, studies have been conducted with various surfactants which are currently used for formulating medical substances with low solubility in water, especially the most commonly used surfactants polysorbate 80 and polyoxyethylene hydrogenated castor oil. However, polysorbate 80 was found to have a poor solubilizing effect, when used for the preparation of eye-drops, and the dissolution of cyclosporin was not sufficient. Polyoxyethylene hydrogenated castor oil was found to strongly irritate the eyes when used in eye-drops.
Thus these commonly used surfactants proved not to be successful for the preparation of eye-drops which contain a high concentration of cyclosporin and have decreased irritation to the eyes.
Surprisingly these difficulties may be overcome by formulating the cyclosporin in a surfactant selected from polyoxyethylene fatty acid esters, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers, or mixtures thereof.
Accordingly in one aspect this invention provides an ophthalmic composition comprising a cyclosporin, especially cyclosporin A, and a surfactant selected from polyoxyethylene fatty acid esters, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers, or mixtures thereof.
The ophthalmic compositions are preferably formulated as eye-drop formulations. Preferably they are aqueous based.
With these ophthalmic compositions, very good therapeutic results may be obtained even when the cyclosporin is present in low concentrations; for example within the range of from about 0.005 to about 1.0% (w/v), preferably about 0.005 to about 0.1% (w/v), and, more desirably from about 0.01 to about 0.075% (w/v). As used in this specification, 1% (w/v) is equivalent to 1 g per 100 ml.
Preferred polyoxyethylene fatty acid esters are based on saturated fatty acids, preferably not containing any substituent. The chain length may be from 14 to 22 carbon atoms, preferably 16 to 18 carbon atoms. A preferred fatty acid is stearate. Preferably the ester is a mono ester. Preferably the polymerization number of the polyoxyethylene moiety is from about 20 to about 60. A preferred example is polyoxyl 40 stearate. An example is the polyoxyl 40 stearate known under the brand name Myrj 52 (available from Atlas Chemie, Essen, Germany).
Preferred polyoxyethylene aralkyl esters are based on a phenol substituted by one or more alkyl groups; the alkyl groups for example having from 4 to 10 carbon atoms, preferably 8 or 9 carbon atoms. Preferably the phenyl group has only one alkyl group as substituent. Preferably the polymerization number of the polyoxyethylene moiety is from about 1 to about 50, more preferably around 40. A preferred example has properties as laid down in the Cosmetic, Toiletry & Fragrance Association, Inc (CTFA) cosmetic ingredients directory. Examples are octoxynols, for example those known under the brand name “Triton” and obtainable from Rohm and Haas, Philadelphia, USA.
Preferred polyoxyethylene alkyl ethers are based on fatty alcohols having, for example, from 4 to 20 carbon atoms. Preferably the polymerization number of the polyoxyethylene moiety is from 10 to 60. An example is the polyoxyethylene alkyl ether known as Cetomacrogol 1000 which has an acid value of less than 0.5 a hydroxyl value of 40 to 52.5 and an refractive index of 1.448 to 1.452.
The preferred surfactant is a polyoxyethylene fatty acid ester and more preferably polyoxyl 40 stearate.
Preferably the weight ratio of surfactant to cyclosporin is from about 10:1 to about 50:1.
The concentration of surfactant in the ophthalmic compositions is desirably within the range of from about 0.1% to about 3.0% (w/v), and, more desirably from abo

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