AU626928B2 - Cyclosporin opthalmic compositions - Google Patents

Description

C2/ u928 COMMONWEALTH OF AUSTRALIA Pl&TJENTJLi C 152 COMPL.ETE SPECIFICAIIM NAME ADDRESS OF APPLICANT: Sandoz Ltd.

Lichtstrasse CH-4002 Basle Switzerland NAME(S) OF IN4VENTOR(S): Ronald Edward PEEPLES ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: "CYlosporin Ophthalmic Compositions" The following statement is a full dtscription of this invention, including the best method of performing it known to me/us:i I la The present invention relateJ to novel ophthalmic compositions, i.e.

pharmaceutical compositions for administration to the eye, 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, for example immunosuppressant, anti-inflammatory, and/or anti-parasitic activity S and/or activity in abrogating tumor resistance to antineoplastic or i 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), [(D)-Ser] 8 -Ciclosporin (see USP 4,384,996), [O-acetyl-(D)Ser] 8 -Ciclosporin (see USP 4,764,503), [P-fluoro-(D)Ala] 8 -Ciclosporin (see UK Patent Application 2,206,119A), [Val] 2 -[(D)methylthio-Sar] 3 and [Dihydro-MeBmt]l-[Val] 2 -[(D)methylthio-Sar]3-Ciclosporin [see USP 4,703,033] and very many more.

Of the cyclosporins, the most widely investigated to date is Icyclosporin A, also known and referred to hereinafter as Ciclosporin and commercially available under the Registered Trade Mark SANDIMMUN h 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 successfully and widely used in the suppression of organ transplant rejection. Ciclosporin has also been used systemically in the treatment of intraocular inflammatory or autoimmune diseases, such as uveitis. However, because of the side t 2 600-7089 effects associated with systemic therapy, Ciclosporin has had only limited use in treating such conditions of the eye.

Effective topical administration of Ciclosporin 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 e.g. USP 4,649,047).

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 cause patient discomfort and which permits a convenient administration regimen, 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 f o agents, for example cyclosporin G, also known and referred to o hereinafter as [Nva] 2 -Ciclosporin.

The present invention provides novel ophthalmic compositions comprising a cyclosporin as active ingredient which meet difficulties r 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 thc cornea or corneal epithelium, or to the immediate areas surrounding the eye, for example the inner surfaces of the upper or lower lid I Applied topically as aforesaid, the compositions of the invention are useful for the treatment of diseases or conditions of the eye or of the surround;nj 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 which involve undesirably elevated immuno-response or inflammatory reaction or event Fi 3 600-7089 as a component or part of their etiology, in particular autoimmune diseases 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 keratitis, conjunctivitis (including in particular vernal conjunctivitis), vernal keratoconjunctivitis, keratoconjunctivitis sicca, and keratoplasty 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 patient discomfort and to provide a therapeutic effect at convenient application rates in 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 o00 or tissues of the eye, for example the tear duct or tear gland.

More particularly the present invention provides in a first aspect: *Ott A) An ophthalmic composition comprising a cyclosporin as active ingredient and comprising an ophthalmically acceptable vegetable oil and 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. safe for topical ophthalmic application at dosages to be administered.

"I

I

4 600-7089 Preferred cyclosporins for use in the compositions of the invention are cyclosporins having immunosuppressant or anti-inflammatory activity, e.g. as hereinbefore described, in particular Ciclosporin. 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 comprising the ointment base.

The cyclosporin, e.g. Ciclosporin, is suitably present in the compositions of the invention in an amount of from about 0.01 to about (Unless otherwise indicated, all percentages herein and in the accompanying claims are by weight based on the total weight of the composition.) Preferably the cyclos .in is present in an amount of from about 0.05 to about 10%, especial.y from about 0.05 to about more preferably from about 0.1 to about Most preferably the cyclosporin is present in an a'r.'nt of about 0.1, 0.5, 1.0 or o.

Component [vegetable oil] is suitably present in the compositions of the invention in an amount of at least 25%. Suitably component (1) o, 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 Component [petroleum jelly] is suitably present in the compositions of the invention in an amount of at least 25%, preferably at least 50%. Suitably component is present in an amount of from I about 25 to about 65%, preferably from about 50 to about 65%, more preferably from about 50 to about 60%, and especially from about 50 to I about Components and are suitably present in the compositions of the invention in a ratio of from about 1:2 to 2:1 e.g. about 1:1 p.p.w..

Component may comprise any appropriate vegetable oil including, e.g. olive oil, arachis oil, corn oil, castor oil or sesame oil or SiI 5 600-7089 1

S

4* mixtures thereof. Preferably however, component comprises corn oil, e.g. as described in the HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (herein joint publication of the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, at page 91.

Component may comprise any appropriate petroleum jelly product, e.g. as available under the names white pretolatum (USP =United States Pharmacopoeia), white soft paraffin (BP/EP British/European Pharmacopoeias), white petroleum jelly or petroleum jelly or under the names petrolatum yellow (USP), yellow soft paraffin (BP/EP), yellow petrolatum or yellow petroleum jelly for further definition see HPE, p.p. 194-195. Especially preferred as component are white petrolatum products, e.g. having a Color (Maximum, Lovibond Color 2"1 Cell) ca. 0.5 to 18Y, Compositions in accordance with the invention also suitably comprise an emulsifier. Suitable components 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 HPE, 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. [For further definition of the above products see Fiedler, "Lexikon der Hilfstoffe, 3rd Edition (1989), p.p. 138-139].

Components when present are suitably present in the compositions of the invention in an amount of from about 0.5 to about preferably from about 0.5 to about more preferably from about 1 to e.g. about 2%.

Compositions in accordance with the invention may also include any further components suitable for use in ophthalmic preparations, for C

V

-6- 600-7089 example preserving or anti-microbial agents. In particular they will suitably comprise a preserving agent, chlorobutanol as anhydrous chlorobutonal) see HPE, p.p. 72-73 being particularly suitable. Such additional components, e.g. components when present will suitably be present in amounts of up to about more suitably up to about e.g. from about 0.01 to about 2.0% or to about preferably from about 0.1 to about e.g. ca. Compositions in accordance with the present invention may thus suitably comprise, e.g. the following ingredients in the relative indicated amounts: CYCLOSPORIN CICLOSPORIN OR [Nva] 2

-CICLOSPORIN]

(1) (2) (3) (4) 0.01 to 25 to 25 to 65% preferably 50 to 0.5 to 0.1 to o eq o op *00 000 plus any further components to a total of 100%, whereby components (1) and are preferably present in a ratio of about 1:2 to 2:1 p.p.w., 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.

It I

EXAMPLE

:rir p~t(

L

lli i

COMPONENT

CYCLOSPORIN CICLOSPORIN) CORN OIL WHITE PETROLATUM NON-IONIC LANOLIN DERIVATIVES AMERCHOL CAB) CHLOROBUTANOL (ANHYDROUS)

TO

2.0 41.65% 53.9 1.96% 0.49% TAL 100.0 -7 600-7089 Equivalent c.-mpositions comprising 0.1, 0.5 and 1% cyclosporin (e.g.

Ciclosporin) may be prepared by increasing each of the components (1) to together by the required proportional amount.

The composition, which is in the form of an ointment, may be prepared by standard techniques, for example, by adding to and heating to about 350 to 6000 to form a clear liquid, then dissolving and with stirring in the clear liquid to form the vehicle for the ointment. The Ciclosporin is dissolved by stirring in the liquefied vehicle, after which the ointment is ready for final processing.

Alternatively, the Ciclosporin can be dissolved in or a portion of and thcq obtained solution then added to the remaining ingredients before further processing. For production in large quantity the Ciclosporin is suitably dissolved in the mixture of at elevated temperature using a high torque mixer. The obtained solution is then filtered asceptically and filled under sterile conditions into 0 containers, e.g. ointment tubes, suitably containing up to ca. e.g. 3.5g ointment per container.

0 0 0 040 In production, compositions of the invention are preferably subjected ~0 to filtration, e.g. asceptic filtration, on completion of dissolution O 0: o of the cyclosporin and before further processing.

For therapeutic use, compositions of the invention will preferably be fil,led into containers 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 the 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 the invention may be demonstrated in arimal test models, e.g. as hereinafter described, or in clinical trials.

8 600-7089 TEST METHOD 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 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 Amsterdam, 371-376 (1986), in the article entitled "Tritiated Compounds for In-Vivo Investigation". Purity and identity are established by NMR spectroscopy, TLC/radio-TLC, and reverse-phase HPLC. A 1:10 dilution o of Ci-3H with unlabeled Ciclosporin is used for testing.

00 0* o 6 For testing, female New Zealand white rabbits (Lab Rab Co.) weighing 4 00 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 following application of test composition, the rabbitsi are kept in a normal upright position in a restrainer. Test compositions are administered in 20 pl or 19.9 mg dosages using a calibrated pipette.

SPipettes 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, Appraisal for the Safety of Chemicals in Foods, Drugs and Cosmetics, association of Food and Drug Officials of the United States, Texas State Department of Health, Austin, Texas, 1959. Modified by Calgon Consumer Products i 2 Fl I I 9 600-7089 Research Labs, Toxicology, 1973.).

After dosing, groups of 3 rabbits are sacrificed at 0.3, 1, 2, 4, 6, 12, 24, 48 and 96 hours. Just prior to sacrifice, blood samples are obtained from the marginal ear vein. The animals are then sacrificed by injection of T-61 Euthanasia Solution (Hoechst) 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 S° limbus, following which the iris and ciliary body are dissected as a single sample. The lens is then removed, and an aliquot of the So vitreous is collected. Excess vitreous is removed from the remaining a tissues by blotting with filter p.per. The choroid-retina is scraped 0 t0 from the sclera, and a sample of the sclera is taken from the section closest to the optic 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 pl) are also weighed into a0* combustion cones. The tissue and blood samples are air-dried prior to combustion in a Packard Tri-Carba Sample Oxidizer, Model 306 using t (Packard Instrument Following combustion, the 1 radioactivity of the samples is determined by scintillation counting in a Packard Tri-CarbR Liquid Scintillation Spectrometer, Model 460.

To determine specific activity, a 2.0 ul 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 combustion method. Using the specific A o 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 t r. 10 600-7089 per minute (cpm) value less than 3 would not be significantly different from zero and corresponds to a detection limit of 34 picograms per gram (pg/g).

In one series of trials employing the above test methodology, the following compositions are compared: TEST COMPOSITION A: Composition of Example 1 in accordance with the present invention.

TEST COMPOSITION B: Comparative composition, comprising Ciclosporin and components to in the same amounts as in Example 1 and 4 "41.65% mineral oil in place of corn oil as component 00aa TEST COMPOSITION C: Comparative composition comprising 2% Ciclosporin and 98% castor oil.

0 0 So0 (For the purposes of filling COMPOSITION B into pipettes, the composition is first warmed to 30 0 C to facilitate filling and then allowed to cool to room temperature before application.) o 0 6 00 0 0. s RESULTS 04 U I Figures 1 to 7 attached provide graphical representations for variation in concentration of radioactivity in each of 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.

ii lcslc~a 11 600-7089 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. 1 to 7 Undicate a fairly rapid initial absorprion of Ciclosporin with all three formulations into the anterior and posterior tissues of the eye. a'vever, peak concentrations in the cornea (Fig. which appears to serve as a reservoir for other intraocular tissues, was S, achieved ca. 3x as rapidly with composition A (ca. 2 hrs.) as compared with composition B (ca. 6 irs.). 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.

t b The resultant and surprising increase in delivery to the deeper tissues of the eye is confirmed by results 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 vith composition B and >3x that achieved with composition C. [Actual AUC (96hr.) values (mg Eq/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).

1 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.

jI Jl 12 600-7089 As regards the posterior segment of the eye, while superiority of composition A is less marked with respect to the vitreous and sclera (Figs. 5 and it is notably superior in relation to the choroid/retina (Fig. regions of the eye more typically involved in autoimmune diseases affecting or as they affect the posterlor segment.

Thus composition A provides markedly superior peak delivery as well as superior and better 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 thus 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 o in the treatment of posterior uveitis as well as other immune mediated 0.O0.4 or inflammatory retinopathies.

0 0 a As will be noted from Figs. 1 to 7, comparative composition C is in all respects markedly inferior to both compositions A and B.

00^ The following table provides determined data for Ciclosporin blood 0 level (systemic) concentrations. (ng Eq/g normalised to 0.335 mg/eye).

0 0o o 0 0 A i *1 -1 t- L I i 13 600-7089 TIME COMPOSITION A COMPOSITION B COMPOSITION C (hrs) 0.05 0.04 0 0.12 0.12 1 0.97 1.09 1.36 0.56 0.04 0.04 2 1.56 0.71 0.28 0.61 0.44 0.17 4 1.25 0.88 0.87 1.68 0.71 0.11 6 0.27 0.23 0.07 0.19 0.84 0.48 12 0 1.30 3.52 0.46 0.27 24 0 0.57 1.55 0.63 0.50 49 0 0.12 0.34 0.81 0.84 96 0 0 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 as markedly superior both in terms of delivery to the eye end its tissues as well.

i as in avoidance of systemic involvement.

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

The advantageous therapeutic properties of the compositions of the invention may also be demonstrated in clinical trials, for example on Administration 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 i conjunctivitis, vernal keratoconjunctivitis or keratoconjunctivitis sicca, composition of the invention, e.g. the composition of example 1, are suitably administered 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 I I Y 9 3 1- 14 600-7089 condition as compared with e.g. untreated controls are observable with continuance of treatment, e.g. over a period of 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 untoward irritation.

In accordance with the foregoing and in a further series of embodiments the present invention also provides: B) An ophthalmic composition as defined under 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 above, which process comprises bringing a *cyclospccin into intimate admixture, appropriately with the application of warming, e.g. to a temperature of from about 30° to about 60°C, with component and component and, optionally, a component and a component as hereinbefore defined, and optionally thereafter filling the obtained composition into an appropriate container, e.g. as defined for above; D) 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, in particular of treating immune mediated or inflammatory diseases or conditions of the eye or of the surrounding or associated organs or .issues, which method comprises administering a composition as defined under 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 above for use in a method as defined under above, or a cyclosporin for use in the preparation of a composition as defined under above, said

'N*

lmr~-olo l- 15 600-7089 composition being for use in a method as defined under above.

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

a* I

C

9 9 tt e -j tj i

I

Claims (11)

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

2. A composition according to claim 1 wherein the cyclosporin is Ciclosporin or [Nva]2-Ciclosporin. 000 0 ofa o 9 6 e a oea 0 o o c 000o 0o50 o I I t

3. A composition present in an

4. A composition present in an

5. A composition component (1) 6, A composition component: (2)

7. A composition present in an according to claim 1 or 2 wherein the cyclosporin is amount of from about 0.01 to about according to claim 3 wherein the cyclosporin is amount of from about 0.1 to about according to any one of claims 1 to 4 wherein is present in an amount of from about 25 to about according to any one of claims 1 to 5 wherein is present in an amount of from about 25 to about according to claim 6 wherein component is amount of from about 50 to about 4 Il-;~ IL 0r I Li I

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

9. A composition according to any one of claims 1 to 18 wherein component comprises olive, arachis, castor, sesame or corn oil. 17 A composition according to any one of claims 1 to 9 additionally comprising an ophthalmically acceptable emulsifier and a preservi._ Sent.

11. A composition according to claim 10 wherein component is present in an amount of from about 0.5 to about 10X and component is present in an amount of up to about

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. 0 0 0 t i -i h r CI 18

13. An ophthalmic composition or a method involving the ophthalmic composition, substantially as hereinbefore described with reference to the Examples. DATED this 27th day of May, 1992 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLISON CAVE e o o o a a e a o as 0 0 0 I t 0 Sea 4 0 a Bo s o a a s ir e i i t 1 it A j 4- j~ C-V C) 'k (,N 0 t 920527,dbda24,43715.res,18