CA2001502A1

CA2001502A1 - Cyclosporin ophthalmic compositions

Info

Publication number: CA2001502A1
Application number: CA002001502A
Authority: CA
Inventors: Ronald E. Peeples
Original assignee: Individual
Current assignee: Individual
Priority date: 1988-10-26
Filing date: 1989-10-25
Publication date: 1990-04-26
Also published as: KR900005973A; NL8902657A; GR1000611B; IT8948485A0; IL92120A; PT92120A; AU626928B2; DK531289D0; SE8903583L; DK531289A; GB2224205A; NO894266L; NZ231131A; GB2224205B; FI895064A0; LU87613A1; AU4371589A; ZA898140B; GB8924040D0; GR890100690A

Abstract

ABSTRACT

Novel ophthalmic compositions comprising a cyclosporin, e.g.
Ciclosporin, as active ingredient, and a vegetable oil, preferably cor oil, and a petroleum jelly, preferably white petrolatum, as carrier.
The compositions are useful for topical ophthalmic application in the treatment of diseases or conditions affecting the eye, in particular interior structures or tissues of the eye, as well as of surrounding or associated organs or tissues.

Description

z CYCLOSPORIN OPE~T~LNIC COMPOSITIO~S

The present invention relaees to novel ophthalmic compositions, i.e.
pharmaceutical compositions for admini~tration to the eye9 comprising a cyclosporin as active ingredient and suitable for the treatment of diseases and conditions of the eye and surrounding areas The cyclosporins comprise a large and recognised class of peptide compounds having pharmaceutical utility, ~or example immunosuppressant, anti-inflammatory, and/or anti-parasitic activity and/or activity in abrogating tumor resistance to antineoplastic or cytostatic drug therapy. The cyclosporins include, for example, naturally occurring fungal metabolites, such as the cyclosporins 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.
US Patents Nos. 4,108,985; 4,210,581 and 4,220,641), l(D)-Ser]e--Ciclosporin (see USP 4,384,996), lO-acetyl-(D)Ser~8-Ciclosporin (see USP 4,764,503), [~-fluoro-(D~Ala]~-Ciclosporin (see UK Patent Application 2,206,119A), lVal~2-[(D)methylthio-Sar]3- and [Dihydro-MeBmt]l-[Val]2-[(D)methylthio-Sarl3-Ciclosporin [see USP
4,703,033] and very many more.

Of the cyclosporins, the most widely investigated to date is cyclosporin A, also known and referred to hereinafter as Ciclosporin and commercially available under the Registered Trade Mark SANDIMMUN
or SANDIMMUNE. Ciclosporin 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 successfullq and widely used in the suppression of organ tran~plant rejection. Ciclosporin has also been used systemically in the treatment of intraocular inflammatory or autoimmune diseases, such as uveitis. However, because of the side 5~

effects associated with systemic therapy, Ciclosporin has had only limited use in treating such cond~tions of the eye.

Effective topical administr~tion of Ciclosporin to the eye would reduce or eliminate to a large extent the systemic side ~ffects by restricting activity to ehe locus of the condition being treated and proposals to this effect have been made, (see e.g. USP ~,649,047).
However, utility and effectiveness of Ciclosporin in treating diseases and conditions of the eye has remained hindered by the lack of a suitable composition which is acceptable or effective for topical use.
A composition is required, which does not cau~e patient discomfort and which permits a convenient administration regimen9 that is, does not require unduly frequent administration, while providing adequate drug substance delivery both to the external and, in particular, the internal regions of the eye.

Similar considerations apply to other cyclosporins known from the art, e.g. proposed for use as immunosuppressants or anti-inflammatory agents, for example cyclosporin G, also known and referred to hereinafter as lNva]2-Ciclosporin.

The present invention provides novel ophthalmic compositions comprising a cyclosporin as active lngredient which meet difficulties hitherto encountered in the art, e.g. as described above. The compositions of the invention are intended for topical application, i.e. for application to or at the surface of the eye, e.g. to the cornea or corneal epithelium, or to the immediate areas surrounding the eye, for example the inner surfaces of the upper or lower lid.

Applied topically as aforesaid, the compositions of the invention are useful for the treatment of diseases or conditions of the eye or of the surrounding or associated organs or tissues, for example the tear glands and ducts, especially immune mediated or inflammatory diseases or conditions. More especially the compositions of the invention are useful for the treatment of diseases or conditions ~hich involve undesirably elevated immuno-response or inflammatory reaction or event s~

as a component or part of their etiology, in particular autoimmune disPases of the eye. Diseases and conditions which may be treated with the compositions of the invention include, for example uveitis (both anterior and posterior), chronic ker~titis, conjunctivitis (including in particular vernal conjunctivltis), vernal keratocon~unctivitis, keratoconjunctivitis sicca, and keratoplasty (i.e. use in relation to corneal transplant), as well as inflammatory or immune mediated conditions induced by ocular surgery in general. The compositions of the invention may also be employed for the induction or maintainance of tearing, for example where tear-function is impaired, e.g. in consequence of any disease or condition as aforesaid.

The ophthalmic compositions of the invention are surprisingly found to cause little or no irritation or patlent discomfort and to provide a therapeutic effece at convenient application rates ln the corneal and internal regions of the eye, including the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina, or sclera or in surrounding organs or tissues of the eye, for example the tear duct or tear gland.

~ore particularly the present invention provides in a first aspect:

A) An ophthalmic composition comprising a cyclosporin as active ingredient and comprising (1) an ophthalmically acceptable vegetable oil and (2) an ophthalmically acceptable petroleum jelly as carrier medium.

The compositions of the invention are intended for topical ophthalmic application, i.e. application to the surface of the eye, e.g. to the cornea or corneal epithelium, or to the immediate surrounding regions of the eye.

By "ophthalmically acceptable" is meant appropriate or allowable for administration to the eye, e.g. sa~e fcr topical ophthalmic application at dosages to be administered.

- 2~S~

Preferred cyclosporins for use in the compositions of th~ inv~ntion are cyclosporins having immunosuppressant or anti-inflammatory activity, e.g. as hereinbefore described, in particular Cicloqporin. A
further preferred cyclosporin for use in the compositions of the invention is [Nva~2-Ciclosporin. The compositions of the invention are suitably in the form of an ointment with the defined components (1 and ~2) comprising the ointment base.

The cyclosporin, e.g. Ciclosporin, is suitably present in the compositions of the invantion in an amount of from about 0.01 to abou~
lG%. (Unless otherwise indicated, all percentages herein and in the accompanying claims are by weight based on the total weight of the composition.) Preferably the cyclosporin is present in an amount of from about 0.05 to about 10%, especially from about 0.05 to about 5%, more preferably from about 0.1 to about 2.5%. Most preferably the cyclosporin is present in an amount of about 0.1, 0~5, 1.0 or 2.0%.

Component (1) [vegetable oil] is suitably present in the compositions of the invention in an amount of at least 25~. Suitably component (1) is present in an amount of from about 25 to about 65~, preferably from about 25 to about 45~, more preferably from about 35 to about 45~, and especially about 40 to about 45X.

Component (2) [petroleum iellY] is suitably present in the compositions of the invention in an amoun~ of at least 25~, preferably at least 50X. Suitably component (2) is present in an amount of from about 25 to about 65~, preferably from about S0 to about 65~, more preferably from about 50 to about 60~, and especially from about 50 to about 55%.

Components (1) and (2) are suitably present in the compositions of the invention in a ratio of from about 1:2 to 2:1 p.p.w., e.g. about 1:1 P-p.w. .

Component (1) may comprise any appropriate vegetable oil including, e.g. olive oil, arachis oil, corn oil, castor oil or sesame oil or 5C~2 - 5 _ 600-7089 mixtures thereof. Preferably however, component (1) comprises corn oil, e.g. as described in the ~ANDBOOK OF P~ IACEUTICAL EXCIPIENTS
~herein "RPE"), ~oint publication of the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, at page 91.

Component (2) may comprise any appropriate petroleum jelly product e.g. as available under the names white pretolatum (USP 8 United States Pharmacopoeia), white soft paraffin (BP/EP . British/European Pharmacopoeias), white pe~roleum ~elly or petrol~um ~elly or under the names petrolatum yellow (USP~, yellow soft paraffin (BP/EP), yellow petrolatum or yellow petroleum ~elly - for further definition see HPE, p.p. 194-195. Especially preferred as component (2) are white petrolatum products, e.g. having a Color (Maximum, Lovibond Color - 2"
Cell) = ca. 0.5 to 18Y, 0.5R.

Compositions in accordance with the invention also suitably comprise (3) an emulQifier. Suitable compon~ntY (3) include any ophthalmically acceptable emulsifier, e.g. as known in the art. Preferred emulsifiers for use in the compositions are non-ionic emulsifiers, in particular non-ionic lanolin derivatives or extracts, especially lanolin alcohols (see ~PE, p. 164) or sterol-based emulsifiers generally. Examples of suitable emulsifiers for use in the compositions of the invention are products such as known and commercially available under the Trade Name Amerchol, in particular the products Amerchol 400, C, CAB, H9, L-99, 4-500 and RC and especially Amerchol CAB. lFor further defin~tion of the above products see Fiedler, "Lexikon der Hilfstoffe, 3rd Edition (1989), p.p. 138-139].

Components (3) when present are suitably present in the compositions of the invention in an amount of from about 0.5 to about 10%, preferably from about 0.5 to about 5%, more preferably from about 1 to 2.5X, e.g. about 2%.

Compositions in accordance with the invention may also include any further components suitable for use in ophthalmic preparations, for 5~)2 example preserving or anti-microbial agents. In particular they will suitably comprise (4) a preserving agene, chlorobutanol (e.g. as anhydrous chlorobutonal) - see HPE, p.p. 72-73 - be$ng particularly suitable. Such additional components, e.g. components (4), when present will suitably be present in amounts of up to about 5.0%, more suitably up to about 2.0X, e.g. from about 0.01 to aboue 2.0% or to about 5.0%, preferably from about 0.1 to about 1.0%, e.g. ca. 0.5X.
Compositions in accordance with the present invention may thus suitably comprise, e.g. ~he following ingredients in the relative indicated amounts:

CYCLOSPORIN le.g. CICLOSPORIN
OR ~Nva] 2 -CICLOSPORIN] 0.01 to 10 ~ 25 to 65%
(2) _ 25 to 65~ preferably 50 to 65%
(3) 0.5 to lOX
(4) 0.1 t~ 5%

plus any further components to a total of 100%, whereby components (1) and (2) are preferably present in a ratio of about 1:2 to 2:1 p.p.w. 9 and whereby preferred ranges for individual components may independently be selected from those hereinbefore indicated. The following example is illustrative of the compositions of the invention.

~PLB

COMPONENT
CYCLOSPORIN (e.g. CICLOSPORIN) 2.0 ~
(l) CORN OIL 41.65%
(2) UHITE PETROLATUM 53.9 %
(3) NON-IONIC LANOLIN DERIVATIVES
(e.g. AMERC~OL CAB) 1.96Z
~4) C~LOROBUT~NOL (ANHYDROUS) 0.49%
TOTAL 100.0 %

o~

EquiYalent compositions comprising 0.1, 0.5 and 1% cyclosporin (e.g.
Ciclosporin) may be prepared by increasing each of the components (1) to (4) together by the required proportional amount.

The composition, which is in the form of an ointment, may be prepared by standard technin,ues, for example, by adding (1) to (2) and heating to about 35 to 60C to form a clear liquid, then dissolving (3) and (4) with stirring in the clear liquid to form she vehicle for the ointment. The Ciclosporin i9 dissolved by stirring in the 11quefied vehicle, after which the ointment is ready for final processing.
Alternatively, the Ciclosporin can be dissolved in (l) or a portion of (l) and the obtained solution then added eo the remaining ingredients before further processing. For production in large quantity the Ciclosporin is suitably dissolved in the mixture of (1) - (4) at elevated temperature using a high torque mixer. The ob~ained solution is then filtered asceptically and filled under sterile conditions into containers, e.g. ointment tubes, suitably con~aining up ~o ca. Sg, e.g. 3.5g ointment per container.

In production, compositions of the invention are preferably subjected to filtration, e.g. asceptic filtration, on completion of dissolution of the cyclosporin and before further processing.

Por therapeutic use, compositions of the invention will preferably be filled into containerc appropriate, e.g. adapted, devised or intended, for direct topical opththalmic application of the contents, for example ointment tubes as aforesaid having a closeable outlet of relatively small diameter and permitting ready application of the contents to or at the surface of ~he eye, e.g. in an amount of from about 0.05 to about 0.2 ml, e.g. of about 0.05 to about 0.1 ml.

Utility of the compositions of ~he invention may be demonstrated in animal test models, e.g. as hereinafter described, or in clinical trials.

2~5~;~

TEST HET~OD

The objective of the method is to determine the penetration into and reservoirs of radioactivity in various tissues of the rabbit eye, as well as systemic concentrations following a single topical application of compositions comprising tritiated Ciclosporin ("Ci-3H"), by investigation of distribution of Ci-3H in the eye tissues and obtained Ci-3H blood levels (systemic concentrations).

Ci-3H is prepared by introducing a tritium label at amino acid residue 1 (-MeBmt-) of Ciclosporin by standard techniques, for example, as described in Voges et al., "Synthesis and Applications of Isotopically Labeled Compounds", Ed. R.R. Muccino, Elsevier Press Ams~erdam, 371-376 (1986), ~n the article entitled "Tritiated Compounds for In-Vivo Investigation". Purity and ideneity are established by NMR
spectroscopy, TLC/radio-TLC, and reverse-phase ~PLC. A 1:10 dilution of Ci-3H with unlabeled Ciclosporin is used for testing.

For tasting, female New Zealand white rabbits ~Lab ~ab Co.) weighing 4 to 6 kilograms are used. The animals are housed in standard rabbit cages, fed a controlled diet (Purina Chow) and allowed water ad libitum. For approximately one hour ~ollowing application of test composition, the rabbits are kept in a normal upright position in a restrainer. Test compositions are administered in 20 ~1 or 19.9 mg dosages using a calibrated pipette.

Pipettes are carefully filled so that there are no air bubbles, and test composition is carefully expelled into the cupped inferior cul-de-sac of both rabbit eyes. The lids are then held together gently for one second and released. The eyes are visually monitored for any signs of irritation, irritation induced tearing or opacity in accordance with the Calgon modification of the Draize test using a dissection lamp instead of a slit lamp (Draize, J.H., Appraisal for the Safety of Chemicals in Foods, Drugs and Cosmetics, association of Food and Drug ~fficials of the United States, Texas State Department of Health, Austin, Texas, 1959. Modified by Calgon Consumer Products 2~s~

Research Labs, Toxicology, 1973.).

After dosing, groups of 3 rabbits are sacrificPd at 0.3, 1, 2, 4, 6, 12, 24, 48 and 96 hours. Ju~t prior to sacrifioe, blood samples are obtained from the marginal ear vein. The animals are ~hen sacrificed by in~ection of T-61 Euthanasia Solution (~oechst) into the marginal ear vein. Both eyes are rinsed with normal saline (0.9%NaCl) and enucleated without rupturing surrounding blood vessels. The ocular surface is carefully rinsed and dried with filter paper to remove any drug remaining in the tear fluid. The aqueous humor is removed by means of a 26 gauge 3/8 inch needle attached to a 0.2 milliliter (ml) pipette inserted at the corneal limbus. The cornea is excised at the limbus, following which the iris and ciliary body are dissected as a single sample. The lens is then removed, and an aliquot of the vitreous is collected. ~xcess vitreous i9 removed from the remaining tissues by blotting with filter paper. The choroid-retina is scraped from the sclera, and a sample oP the sclera is taken from the section closest to the opt~c nerve. To avoid contamination, clean instruments are used for the dissection of individual tissues. Each sample is rinsed and blotted on filter paper before being weighed into combustion cones. Blood samples (~200 ~1) are also weighed into combustion cones. The tissue and blood samples are air-dried prior to combustion in a Packard Tri-Carb~ Sample Oxidizer, Model 306 using MonophaseR-40 (Packard Instrument Co.). Following combustion, the radioactivity of the samples is determined by scintillation counting in a Packard Tri-Carb~ Liquid Scintillation Spectrometer, ~odel 460.

To determine specific activity, a 2.0 ~1 aliquot of test composition is dissolved in 100 ml of t.-butyl methyl ether, and 0.1 ml of the ether solution is assayed by the combus~ion method. Using the specific activity, the disintegrations per minute per gram (dpm/g) concentration of radioactivity in the tissues is converted to nanogram equivalents of Ciclosporin~gram of tissue or blood.

Radioactivity of all samples is determined within a statistical error of 7~ at a confidence level of 95~. This implies that any net counts lS02 per minut~ (cpm) YaIue less than ~ ~ould not be significantly diffe~ent from zero and corresponds to a detection limit of 34 picograms per gram (æg/g)-In one series of trials employlng the above test methodology, thefollowing compositions are compared:

TEST COMPOSITION A: Composition of Example 1 ln accordance with the present invention.

T~ST COMPOSITION B: Comparative composition, comprising Ciclosporin and components (2) to (4) in the same amounes a~ in Example 1 and 41.~5X mineral oil in place of corn oil as component (1).

TEST COMPOSITION C: Comparative composition comprising 2% Ciclosporin and 98~ castor oil.

(For the purposes of filling CO~POSITION B into pipettes, the composition is first warmed to 30C to facilitate filling and then allowed to cool to room temperature before application.) ~ESULTS

Figures 1 to 7 attached provide graphical representations for variation in c~ncentratlon of radio~ctiv~ty In each o~ the assayed eye tissues with time. In each graph, time is plotted along the abscissa (horizontally) in hours up to 96 hours: concentraion is plotted along the ordinate (vertically) in mg Eq of Ciclosporin~g of tissue, all values being normalised to a dose of 0.335 mg Ciclosporin/eye.

Results for composition A are represented by plots with solid circles.
Results for composition B are represented by plots with solid squares.
Results for composition C are represented by plots with open inverted triangles.

2~ 2 Fig. 1 provides results for the aqueous humor.
Fig. 2 provides results for the cornea.
Fig. 3 provides results for the iris/ciliary.
Fig. 4 provides results for the lens.
Fig. 5 provides results for the vitreous.
Fig. 6 provides results for the choroid/retina.
Fig. 7 provides results for the sclera.

Figs. l to 7 indicate a fairly rapid initial absorprion of Ciclosporin with all three formulations into the anterior and posterior tissue~ of the eye. Houever, peak concentrations in ~he cornea (Fig. 2), which appears to serve as a reservoir for other in~raocular tissues, was achieved ca. 3x as rapidly with composition A (ca. 2 hrs.) as compared with composition B (ca. 6 hrs.). Moreover, concentrations achieved in the cornea with composition A are markedly higher than with composition B. Composition C requires ca. 12 hours to achieve maximum concentration in the cornea.

The resultant and surprising increase in delivery to the deeper tissues of the eye is confirmed by r~sult~ for the aqueous humor (Fig.
1) where the achieved AUC (area under curve) for composition A for the 96 hour period is ca. 2x that achieved with composition B and >3x that achieved with composition C. [Actual AUC (96hr.) values (mg ~q/g normalised to 0.335 mg/eye = composition A - 636: composition B - 334:
composition C - 188.] The same pattern of advantage for composition A
is maintained with respect to the iris/ciliary (Fig. 3) and the lens (Fig. 4) Composition A is thus seen to be markedly and surprisingly superior to both compositons B and C with respect to delivery to anterior regions of the eye, in particular the cornea and to the aqueous/iris/ciliary.
Compositions of the invention are thus of particular advantage in the treatment of diseases or conditions of the eye affecting or as they affect these regions, for example, for use in relation to corneal transplant, to the treatment of uveitis and of kerotoconjunctivitis sicca.

s~

- 12 - 600-70~9 As regards the posterior segmen~ of the eye, ~hile superiority of composition A is less marked with respect to the vltreous and sclera (Figs. 5 and 7), it is notably superior in relation to the choroid/retina (Pig. 7), regions of the eye more typically involved in autoimmune diseases affecting or as they affect the posterior segment.
Thus composition A provides markedly superior peak delivery as well as superior and bet~er sustained total delivery to the choroid/retina.
Thus a recorded AUC value (96hr) in the choroid~retina (mg Eq/g normalised to 0.335 mg/eye) for composition A is 527 as compared with values of only 296 and 184 for compositions B and C respectively.

Composition A is thu9 further markedly and surprisingly superior to both compositions B and C with respect to delivery to the posterior segment of the eye, including the choroid/retina and is thus of particular advantage in the treatment of diseases and conditions of the eye affecting or as they affect these regions, for example for use in the treatment of posterior uveitis as well as other immune mediated or inflammatory retinopathies.

As will be noted from Figs. 1 to 7, comparative composition C is in all respects markedly inferior to both compositions A and B.

~he following table provides determined data for Ciclosporin blood level (systemic) concentration~. ~ng Eq/g normalised to 0.335 mg/eye).

L5~2 TIME COMPOSITION A COMPOSITIQN B COMPOSITION C
. _ ..... . _ ._ 0.50.05 + 0.04 O 0.12 + 0.12 10.97 + 1.091.36 ~ 0.560.04 ~ 0.04 21.56 i 0.710.~8 + 0.610.44 i 0.17 41.25 i 0.88 0.87 ~ 1.680.71 ~ 0.11 6Q.27 i 0.230.07 i 0.190.8~ ~ 0.48 12 O 1.30 i 3.520.46 ~ 0.27 24 O 0.57 ~ 1.5S0.63 ~ 0.50 4~ O 0.12 + 0.340.81 + 0.84 96 O O 0.18 + 0.05 .
AUC 5.96 30.68 54.49 (0-96h) As will be seen, systemic levels measured are relatively low for all three test compositions, but surpringly so for composition A in comparison with both B and C. Composition A thus appear a~ markedly superior both in t~rms of delivery to the eye and its tissues as well as in avoidance of systemic ~nvolvement.

Yisual observation of the eye treated with composition A in the modified Draize test showed no composition related irritation.

The advantageous the~apeutic properties of the compositions of the invention may ~lso be demon trated ln clinical trlals, ~or example on administrat~on to subJects exhibiting disease or conditions of the eye as hereinabove set forth.

For the purpose of such trials, or for practical therapeutic use, e.g.
in the treatment of uveitis (anterior or posterior), vernal conjunctivitis, vernal keratoconjunctivitis or keratoconjunctivitis sicca, composition of the invention, e.g. the composition of example 1, are suitably admlnistered at or to the surface of the eye in individual amounts e.g. of from ca. 0.1 to 0.2 ml from 1 to 4x daily, e.g. depending on the particular disease or condition to be treated, its clinical status and the effect desired. Marked improvement in - 14 - 600-70~9 condition as compared with e.g. untreated controls are observable with continuance of treatment, e.g. over a period o~ 1 to 2 weeks and upwards. The compositions of the invention are found to be well tolerated by subjects undergoing therapy, with no significant or unto~ard irritation.

In accordance with the foregoing and in a further series of embodiments the present invention al50 provides:

B) An ophthalmic composition as defined under (A) above in a container appropriate for ophthalmic application of said composition, e.g. as hereinbefore described, for example appropriate for application of said composition to or at the surface of the eye, e.g~ to the cornea or corneal epithelium;

C) A process for the production of an ophthalmic composition as defined under (A) above, which process comprises bringing a cyclosporin into intimate admixture, appropriately with the application of warming, e.g. to a ~emperature of from about 30 to about 60C, with component (1~ and component (2) and, optionally, a component (3) and a component (4) as hereinbefore defined, and optionally thereafter filling the obtained composition into an appropriate container, e.g. as defined for (B) above;

D) A method of treating a disease or condition of the eye or of the surrounding or aqsociated organs or tissues in a sub~ect in need thereof, in particular of treating immune mediated or inflammatory diseases or conditions of the eye or of the surrounding or associated organs or tissues, which method comprises ad~inistering a composition as defined under (A) above topically to the eye, e.g. to or at the surface of the eye, e.g. to the cornea or corneal epithelium; as well as E) A composition as defined under (A) above for use in a ~ethod as defined under (D) above, or a cyclosporin for use in the preparation of a composition as defined under (A) above, said 5;02 composition being for use in a method as defined under tD) above.

Particular sections, segments or tissues of the eye to which the method (D) is applicable are as hereinbefore described. Particular diseases or conditions of the eye to ~hich the method (D) is applicable are similarly as hereinbefore described.

Claims

1. An ophthalmic composition comprising a cyclosporin as active ingredient and comprising (1) an ophthalmically acceptable vegetable oil and (2) an ophthalmically acceptable petroleum jelly as carrier medium.

2. A composition according to claim 1 wherein the cyclosporin is Ciclosporin or [Nva]2-Ciclosporin.

3. A composition according to claim 1 or 2 wherein the cyclosporin is present in an amount of from about 0.01 to about 10%.

4. A composition according to claim 3 wherein the cyclosporin is present in an amount of from about 0.1 to about 2.5%.

5. A composition according to any one of claims 1 to 4 wherein component (1) is present in an amount of from about 25 to about 65X.

6. A composition according to any one of claims 1 to 5 wherein component (2) is present in an amount of from about 25 to about 65%.

7. A composition according to claim 6 wherein component (2) is present in an amount of from about 50 to about 65%.

8. A composition according to any one of claims 1 to 7 wherein components (1) and (2) are present in a ratio of from about 1:2 to 2:1 p.p.w.

9. A composition according to any one of claims 1 to 18 wherein component (1) comprises olive, arachis, castor, sesame or corn oil.

10. A composition according to any one of claims 1 to 9 additionally comprising (3) an ophthalmically acceptable emulsifier and (4) a preserving agent.

11. A composition according to claim 10 wherein component (3) is present in an amount of from about 0.5 to about 10% and component (4) is present in an amount of up to about 5.0%.

12. A method of treating a disease or condition of the eye or of the surrounding or associated organs or tissues in a subject in need thereof, which method comprises administering a composition according to any one of claims 1 to 11 topically to the eye.