NL8902657A - CYCLOSPORIN CONTAINING OPHTHALMIC PREPARATIONS. - Google Patents

Description

Cyclosporine containing ophthalmic preparations.

The present invention relates to new ophthalmic preparations, i.e., pharmaceutical preparations for administration to the eye, which contain a cyclosporin as an active ingredient and are suitable for the treatment of diseases and conditions of the eye and surrounding areas.

The cyclosporins comprise a large and recognized group of peptide compounds of pharmaceutical utility, for example an immunosuppressive, anti-inflammatory and / or anti-parasitic and / or anti-tumor resistance activity against anti-neoplastic or cytostatic drug therapy. Cyclosporins include, for example, naturally occurring fungal metabolites such as cyclosporins A, B, C, D and G, as well as a wide variety of synthetic and semisynthetic cyclosporins, for example the dihydro- and iso-cyclosporins (see, for example, US patents 4,108,985, 4,210,581 and 4,220,641), [(D) -Ser] 8-Ciclosporin (see ICEP 4,384,996), [0-Acetyl- (D) Ser] 8-Ciclosporin (see USP 4,764 .503), [0-Fluoro- (D) Ala8-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 USP 4,703,033] and much more.

Of the cyclosporins, the most researched today is cyclosporin A, which is also known and will hereinafter be referred to as Ciclosporin and is commercially available under the registered trademark SANDIM-MUN or SANDIMUNE. Ciclosporin has been shown to selectively suppress a variety of T lymphocyte functions, including preventing maturation and expressing 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 for the treatment of intraocular inflammation or autoimmune diseases, such as uveitis. However, due to the occurrence of side effects associated with systemic therapy, Ciclosporin has had only limited use in the treatment of such eye disorders.

Effective topical administration of Ciclosporin to the eye will greatly reduce or eliminate systemic side effects by limiting its action to the area of the condition being treated and proposals have already been made for this (see, for example, USP 4,649,047). However, the use and effectiveness of Ciclosporin in treating diseases and conditions of the eye continued to be hampered by the lack of an appropriate formulation acceptable or effective for external use. A formulation is desired which does not inflict discomfort on the patient and which allows an appropriate administration regimen, i.e., does not require a troublesome multiple administration, while still providing appropriate drug delivery to both the external and, in particular, the internal areas of the eye takes place.

Similar considerations apply to the other cyclosporins known in the art, for example, which have been proposed for use as immunosuppressive or anti-inflammatory agents, for example cyclosporin G, which is also known and will hereinafter be referred to as [Nva] 2-Ciclosporin.

The present invention provides new ophthalmic compositions containing a cyclosporin as an active ingredient, which overcome the hitherto encountered problems in the art, for example as described above. The compositions according to the invention are intended for external application, that is, for application to or near the surface of the eye, for example the cornea or corneal epithelium, or to the areas directly around the eye, for example the internal surfaces of the top - or lower eyelid.

Applied externally, the preparations according to the invention, as already mentioned above, are useful for the treatment of diseases or disorders of the eye or of the surrounding or associated organs or tissues, for example the lacrimal glands and lacrimal ducts, in particular immune mediated, or inflammatory diseases or disorders. More particularly, the compositions of the invention are useful for treating diseases or conditions involving an undesirably high immunor sponge or inflammatory response or occurrence, as part or part of their ethiology, in particular autoimmune diseases of the eye . Diseases and conditions that can be treated with the compositions of the invention include, for example, uveitis (both anterior and posterior), chronic keratitis, conjunctivitis (especially spring conjunctivitis), spring keratocon junctivitis, dry keratoconjunctivitis and keratoplasty (i.e., application in connection with corneal transplantation), as well as inflammation or immunity induced by eye surgery in general. The compositions of the invention may also be used to induce or maintain the tear function, for example, if the tear function is compromised, for example, as a result of an aforementioned disease or condition.

The ophthalmic compositions of the invention surprisingly appear to cause little or no irritation or discomfort to the patient and to produce a therapeutic effect at appropriate application rates in the cornea and interior parts of the eye, including the anterior chamber, posterior chamber, vitreous, aqueous fluid, vitreous fluid, cornea, iris / ciliary, lens, choroid / retina or sclera or in the surrounding organs or tissues of the eye, e.g. tear duct or lacrimal gland.

More particularly, the present invention provides in a first aspect: A) an ophthalmic composition containing a cyclosporin as an active ingredient and (1) an ophthalmically acceptable vegetable oil and (2) an ophthalmically acceptable petroleum jelly as a carrier medium.

The compositions of the invention are intended for topical ophthalmic administration, for example, administration to the surface of the eye, for example, to the cornea or corneal epithelium, or to the immediately surrounding areas of the eye.

By "ophthalmically acceptable" is meant suitable or acceptable for ocular administration, for example, safe for topical ophthalmic administration in the dosages to be administered.

Cyclosporins recommended for use in the compositions of the invention are cyclosporins having an immunosuppressive or anti-inflammatory activity, as described, for example, above, especially Ciclosporin. Another recommended cyclosporine for use in the compositions of the invention is [Nva] 2-Ciclosporin. The preparations according to the invention are suitable in the form of an ointment with the defined components (1) and (2) present in 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 10% (unless otherwise indicated, all percentages herein and the appended claims are percentages by weight, based on total weight of the preparation). It is recommended that the cyclosporine be present in an amount from about 0.05 to about 10%, especially from about 0.05 to about 5%, especially from about 0.1 to about 2.5%. It is most recommended that the cyclosporine be present in an amount of about 0.1; 0.5; 1.0 or 2.0%.

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

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

The components (1) and (2) are suitably present in the compositions of the invention in an amount of from about 1: 2 to 2: 1 p.p.w., for example from about 1: 1 p.p.w.

Component (1) may contain any suitable vegetable oil, including, for example, olive oil, peanut oil, corn oil, castor oil or sesame oil or mixtures thereof. However, it is recommended that component (1) contains corn oil, as described, for example, in the HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (herein "ΗΡΕ"), a joint publication of the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, pp. 91.

Component (2) may contain any suitable Vaseline product, for example, those available under the names white petrolatum (USP = the Pharmacopoeia of the United States, white soft paraffin (BP / EP = British European Pharmacopeia, white petrolatum or petrolatum or under the names yellow petrolatum (USP), yellow soft paraffin (BP / EP), yellow petrolatum or yellow petrolatum, for further definitions see HPE pages 194 and 195. Particularly recommended as component (2) are white petrolatum products, for example with a color (Maximum, Lovibond color -2 "cell) = approximately 0.5 to 18Y, 0.5R.

The compositions according to the invention also suitably (3) contain an emulsifier. Suitable ingredients (3) include any ophthalmic acceptable emulsifier, such as those known in the art. Recommended emulsifiers for use in the compositions are nonionic emulsifiers, especially nonionic lanolin derivatives or extracts, especially lanolin alcohols (see HPE, page 164) or generally sterol based emulsifiers. Examples of suitable emulsifiers for use in the compositions according to the invention are the known products which are commercially available under the trade names 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 aforementioned products, see Fiedler, "Lexikon der Hilfstoffe, 3rd edition (1989), pp. 138-139].

The 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%, especially from about 1 to 2, 5%, for example about 2%.

The compositions of the invention may also contain any other ingredient suitable for use in ophthalmic compositions, for example, preservatives or anti-microbial agents. In particular, they will conveniently (4) contain a preservative, chlorobutanol (e.g., as anhydrous chlorobutanol) - see HPE, pp. 72-73, which is particularly suitable. Such additional ingredients, e.g., ingredients (4), if present, will conveniently be present in amounts up to about 5.0%, more suitably up to about 2.0%, e.g. from about 0.01 to about 2.0 % or up to about 5.0%, preferably from about 0.1 to about 1.0%, for example from about 0.5%.

Thus, compositions of the present invention may suitably contain, for example, the following ingredients in the stated relative amounts:

CYCLOSPORINE [for example, CICLOSPORINE

Or [Nva] 2-CICLOSPORINE] 0.01 to 10% (1) _25 to 65% (2) _25 to 65%, preferably 50 to 65% (3) _0.5 to 10% (4) _0.1 up to 5% plus any other ingredients up to 100% total, with ingredients (1) and (2) preferably being present in a ratio of about 1: 2 to 2: 1 ppw, with the recommended ranges for the individual ingredients being independent can be selected from the aforementioned. The following example illustrates the compositions of the invention.

Example

Component CYCLOSPORINE (eg CICLOSPORINE) 2.0% (1) Corn oil 41.65% (2) White petrolatum 53.9% (3) Non-ionic lanolin derivatives (eg AMERCHOL CAB) 1.96% (4) Chlorobutanol (aqueous) 0.49%

Total 100.0%

Equivalent preparations containing 0.1; Containing 0.5 and 1% cyclosporine (e.g. Ciclosporin) can be obtained by increasing each of the components (1) to (4) together with the required proportional amount.

The preparation, in the form of an ointment, can be prepared by standard methods, for example, by adding (1) to (2) and heating at about 35-60 ° C, to form a clear liquid and then (3) and (4) dissolving in the clear liquid with stirring to form the carrier for the ointment. The Ciclosporin is dissolved by stirring it in the liquefied carrier, after which the ointment is ready for final processing. Also, the Ciclosporin can be dissolved in (1) or part of (1) and the resulting solution then added to the other ingredients before further processing. To prepare a large amount, the Ciclosporin is suitably dissolved in the mixture of (1) - (4) at an elevated temperature, using a high torque mixer. The resulting solution was then sterile filtered and placed under sterile conditions into containers, for example tubular ointment, suitably containing up to about 5 g, for example 3.5 g, of ointment per container.

In the preparation, the preparations according to the invention are preferably filtered, for example sterile filtered, at the end of the dissolution of the cyclosporine and before further processing.

For therapeutic use, the compositions of the invention will preferably be placed in suitable containers, which are, for example, adapted, designed or intended for direct, external, ophthalmic use of the contents, for example tubing ointment, as mentioned above, with a sealable opening with a relatively small diameter allowing easy administration of the contents thereof on or at the surface of the eye, for example in an amount of from about 0.05 to about 0.2 ml, for example from about 0.05 to about 0, 1 ml, allows.

The utility of the compositions of the invention can be demonstrated by animal models, as described below, or in clinical studies.

Research method.

The purpose of the method is to investigate the penetration and reservoirs of radioactivity in various tissues of the rabbit eye, as well as systemic concentrations, after a single external administration of preparations containing tritiated Ciclosporin ("Ci-3H"), by examination of the distribution of Ci-3H in the eye tissues and the obtained Ci-3H blood levels (systemic concentrations).

Ci-3H was prepared by introducing a tritium label into the amino acid residue 1 (-MeBmt-) of Ciclosporin according to standard methods, as described, for example, by Voges and Med., "Synthesis and Applications of Isotopic Cally Labeled Compounds", Ed. R.R. Muccino, Elsevier Press Amsterdam, 371-376 (1986), in the article entitled "Tritia-ted Compounds for In-Vivo Investigation". Purity and identity were determined by NMR spectroscopy, TLC / radio-TLC, and reverse phase HPLC. A 1:10 dilution of Ci-3H with unlabeled Ciclosporin was used for the study.

New Zealand white female rabbits (Lab Rab Co.) weighing 4-6 kg were used for the study. The animals were housed in standard rabbit cages and fed an adjusted diet (Purina Chow) and obtained ad libitum water. The rabbits were forced to be held in a normal, upright position for approximately 1 hour after administration of the test composition. The preparations to be tested were administered in doses of 20 μΐ or 19.9 mg using a calibrated pipette.

The pipettes were carefully filled so that no air bubbles were present and the preparation to be tested was carefully expelled into the cup-shaped bottom blind pocket of both rabbit eyes. The eyelids were then gently compressed for 1 second and released again. The eyes were visually monitored for any signs of irritation, irritation-induced tear formation, or opacity according to the Calgon modification of the Draize test using a split lamp instead of a slit lamp (Draize, JH, 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 Research Labs, Toxicology, 1973.) ·

After dosing, groups of three rabbits were sacrificed at 0.3; 1; 2; 4; 6; 12; 24; 48 and 96 hours. Just before this, blood samples were taken from the marginal ear vein. The animals were then sacrificed by injecting T-61 Euthanasia Solution (Hoechst) into the marginal ear vein. Both eyes were rinsed with normal saline (0.9% NaCl) and removed without rupturing the surrounding blood vessels. The ocular surface was rinsed carefully and dried with filter paper to remove any drug remaining in the tear fluid. The aqueous liquid was removed using a 3/8 inch 26 gauge needle attached to a 0.2 milliliter (ml) pipette inserted into the corneal rim. The cornea was excised at the edge, after which the iris and the ciliary body were excised as a single sample. Then the lens was removed and a proportional fraction of the vitreous was collected. The excess of the vitreous was removed from the remaining tissues by dabbing with filter paper. The choroid retina was scraped from the sclera, and a sample of the sclera was taken from the portion closest to the optic nerve. To avoid contamination, clean tools were used to cut out the individual tissues. Each sample was rinsed and dried with filter paper before weighing into combustion cones. Blood samples from (*> 200 μΐ) were also weighed into combustion cones. The tissue and blood samples were first air dried and then burned in a Packard Tri-CarbR Sample Oxidizer, Model 306 using MonophaseR-40 (Packard Instrument Co.). After burning, the radioactivity of the sample was determined by scintillation counting in a Packard Tri-CarbR liquid scintillation spectrometer, Model 460.

To determine the specific activity, a 2.0 µl fraction of the preparation to be tested was dissolved in 100 ml of t-butyl methyl ether and 0.1 ml of the ether solution was treated by the combustion method. Using the specific activity, the disintegrations per minute per gram (ppm / g) concentration of the radioactivity in the tissues were converted into nanogram equivalents of Ciclosporin / gram of tissue or blood.

The radioactivity of all samples was determined within a statistical error of 7% with a confidence of 95%. This means that any net count per minute (cpm) value less than 3 will not differ significantly from 0 and corresponds to a detection limit of 34 picograms per gram (pg / g).

In a series of tests using the research methodology described above, the following preparations were compared:

Test Preparation Ai Preparation of Example 1 of the present invention.

Test Preparation B: Comparable preparation containing Ciclosporin and components (2) to (4) in the same amounts as in Example 1 and 41.65% mineral oil instead of corn oil as component (1).

Study preparation C: Comparable preparation containing 2% Ciclosporin and 98% castor oil.

(To fill pipettes with formulation B, the formulation was first heated to 30 ° C to facilitate filling and then allowed to cool to room temperature before use).

Results.

In the attached drawings 1-7, graphical representations of the variation in concentration of the radioactivity in each of the eye tissues examined are plotted against time. In each graph, the time along the abscissa (horizontal) in hours to 96 hours and the concentration along the ordinate (vertical) in mg Eq of Ciclosporin / g of tissue are plotted, with all values normalized to a dose of 0.335 mg Ciclosporin / eye.

The results of formulation A are represented by solid circle curves, those for formulation B by solid square curves, and the results of formulation C are represented by open inverted triangles curves.

Fig. 1 gives the results for the aqueous liquid, fig. 2 the results for the cornea, fig. 3 the results for the iris / cilia, fig. 4 the results for the lens, fig. 5 the results for the vitreous body, fig. 6 the results for the choroid / retina and Fig. 7 gives the results for the sclera.

Figures 1-7 show that a fairly rapid initial absorption of Ciclosporin occurs in all three preparations in the anterior and posterior tissues of the eye. However, peak concentrations in the cornea (Fig. 2) that appear to serve as a reservoir for the other tissues in the eye were obtained about three times faster with formulation A (approximately 2 hours) relative to formulation B (approximately 6 hours). In addition, the concentrations obtained in the cornea with preparation A are markedly higher than with preparation B. Preparation C takes about 12 hours to give the maximum concentration in the cornea.

The obtained and surprising increase in delivery to the deeper tissues of the eye was confirmed by results for the aqueous liquid (Fig. 1), where the obtained AUC (area under the curve) for formulation A for the 96 hour period was approximately is twice that obtained with preparation B and> 3x that obtained with preparation C. [Actual AUC (96 hours) values (mg Eq / g) normalized to 0.335 mg / eye = preparation A -636: preparation B-334 and formulation C-188.] The same pattern of the benefit of formulation A was retained with respect to the iris / cilia (Fig. 3) and the lens (Fig. 4).

Thus, it appears that formulation A is surprisingly clearly superior to both formulations B and C with respect to delivery to the anterior parts of the eye, in particular the cornea and the aqueous portion / iris / cilia. Thus, the compositions of the invention have particular advantages in the treatment of diseases or conditions of the eye affecting these areas, for example, for use in connection with corneal transplants, the treatment of uveitus and of dry kerotoconjunctivitis.

As for the posterior segment of the eye, it is noted that while the superiority of preparation is less pronounced in the vitreous and sclera (Figs. 5 and 7), it is clearly better in the choroid / retina (Fig. 7), parts of the eye more typically involved in autoimmune diseases that affect or will affect the posterior segment. Thus, Formulation A provides markedly superior peak release, as well as superior and longer-lasting total release to the choroid / retina. For example, a registered AUC value (96 hours) in the choroid / retina (mg Eq / g normalized to 0.335 mg / eye) for formulation A 527 was compared to the values of only 296 and 184 for formulations B and C. respectively.

Thus, preparation A is further clear and surprisingly superior to both preparations B and C in delivery to the posterior segment of the eye, including choroid / retina, and is thus of particular interest in the treatment of diseases and conditions of the eye affecting these areas infest or will infest, for example, for the treatment of posterior uveitis, as well as other retinopathies through immunity or inflammation.

As can be seen from Figures 1-7, the comparative preparation C is clearly worse in all respects than both preparations A and B.

The following table indicates the determined values for ciclosporin blood (systemic) concentrations (ng Eq / g normalized to 0.335 mg / eye).

Time Preparation A Preparation B Preparation C

(hours) 0.5 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 48 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 can be seen, the determined systemic values are relatively low for all three preparations tested, but surprisingly also for preparation A compared to both B and C. Thus preparation A appears to be clearly better in terms of delivery to the eye and its tissues. as for avoiding systemic development.

Visual evaluation of the eye treated with preparation A according to the modified Draize test showed no irritation attributable to the preparation.

The beneficial therapeutic properties of the compositions of the invention can also be demonstrated in clinical trials, for example, when administered to patients exhibiting diseases or conditions of the eyes, as described above.

For such studies, or for practical therapeutic application, for example, to treat uveitis (anterior or posterior), spring conjunctivitis, spring keratoconjunctivitis, or dry keratoconjunctivitis, the compositions of the invention, e.g., the composition of Example 1, are suitably administered on or with the surface of the eye in discrete amounts of, for example, about 0.1 to 0.2 ml, 1-4 times a day, for example depending on the special disease or condition to be treated, its clinical status and the desired effect. A marked improvement in the condition over untreated controls, for example, was seen with continued treatment, for example, over a period of 1 to 2 weeks or longer. The compositions of the invention have been found to be well tolerated by patients undergoing therapy without significant or unpleasant irritation.

According to the foregoing and according to further series of embodiments, the invention also provides: B) An ophthalmic preparation as defined under (A) above in a container suitable for ophthalmic administration of this preparation, for example as described above, for example suitable for administration of this preparation on or on the surface of the eye, for example the cornea or corneal epithelium.

c) A method of preparing an ophthalmic preparation, as defined under (A) above, which method comprises intimately mixing a cyclosporine, suitably under heating, e.g., at a temperature of about 30 to about 60 ° C, with component ( 1) and component (2) and, optionally, a component (3) and a component (4), as described above, and, if desired, subsequently filling a suitable container, as defined, for example, in (B) above, with the resultant preparation.

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 treating immunity-mediated or inflammatory diseases or conditions of the eye or the surrounding or associated organs or tissues, which method comprises topically administering a preparation as defined under (A) above to the eye, for example at or on the surface of the eye, for example on the cornea or corneal epithelium, and E) a preparation as defined in (A) above for use in a method as defined in (D) above, or a cyclosporine for use in the preparation of a preparation as defined in (A) above, which preparation is used in a method as defined under (D) above.

Special parts, segments or tissues of the eye to which the method (D) can be applied have been described above. Particular diseases and conditions of the eye in which method (D) can be used have also been described above.

Claims (14)

An ophthalmic preparation containing a cyclosporin as an active ingredient, characterized in that the preparation also contains (1) an ophthalmically acceptable vegetable oil and (2) an ophthalmically acceptable petroleum jelly as the carrier medium. A preparation according to claim 1, characterized in that the cyclosporine is Ciclosporin or [Nva] 2-Ciclosporin. A composition according to claim 1 or 2, characterized in that the cyclosporine is present in an amount from about 0.01 to about 10%. A formulation according to claim 3, characterized in that the cyclosporine is present in an amount from about 0.1 to about 2.5%. A formulation according to any one of claims 1-4, characterized in that component (1) is present in an amount from about 25 to about 65% A preparation according to any one of claims 1 to 5, characterized in that component (2) is present in an amount from about 25 to about 65%. A composition according to claim 6, characterized in that component (2) is present in an amount from about 50 to about 65%. A preparation according to any one of claims 1-7, characterized in that the components (1) and (2) are present in a ratio of about 1: 2 to 2: 1 p.p. wt. A preparation according to any one of claims 1-8, characterized in that component (1) comprises olive oil, peanut oil, castor oil, sesame oil or corn oil. A formulation according to any one of claims 1-9, characterized in that it additionally contains (3) an ophthalmically acceptable emulsifier and (4) a preservative. A composition according to claim 10, characterized in that 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%. Method for treating a disease or condition of the eye or the surrounding or associated organs or tissues in a patient in need of such treatment, characterized in that a composition according to any one of claims 1-11 is applied externally on the eye. 13. Method as described in the description and / or examples. 14. Preparations as described in the description and / or examples.