MXPA96005599A - Specific emulsions for the lagrimal gland, for the topic application to the ocu tissue - Google Patents

Abstract

The present invention relates to a pharmaceutical composition in the form of a non-irritating emulsion which includes at least one cyclosporin in admixture or combination with a high fatty acid glyceride and polysorbate 80. More particularly, cyclosporin may be cyclosporin A and High fatty acid glyceride can be castor oil. The composition has been found to be of a high level of comfort and a low irritation potential, suitable for the delivery of medicaments to sensitive areas such as ocular tissues with improved absorption in the lacrimal gland. In addition, the composition has stability for up to nine months without the crystallization of the ciclospori

Description

SPECIFIC EMULSIONS FOR THE LAGRIMAL GLAND, FOR TOPICAL APPLICATION TO THE OCULAR TISSUE FIELD OF THE INVENTION The present invention relates in general to novel pharmaceutical compositions incorporating chemical substances which are very poorly soluble in water and is more particularly related to a novel ophthalmic emulsion which includes cyclosporins in a mixture with castor oil and Polysorbate 80 with a high level of comfort and a potential for low irritation.

BACKGROUND OF THE INVENTION Cyclosporins are a group of non-polar cyclic oligopeptides with a known immunosuppressive activity. In addition, as described in U.S. Pat. No. 4,839,342, cyclosporins (sometimes written in the literature as "cyclosporine" ("cyclosporin")), have been found to be effective in the treatment of keratoconj untivitis sicca (KCS or dry eye disease) medicated, immune , in a patient who suffers from it. As noted hereinabove, cyclosporins comprise a group of cyclic oligopeptides and the REF: 23572 the main target of them is cyclosporin A (C, "H .. ^ .. N .. ^ 0 .." which has been identified in the company of several other minor metabolites, cyclosporins B to l. A number of synthetic analogs have been prepared In general, commercially available cyclosporins may contain a mixture of several individual cyclosporins which all share a cyclic peptide structure consisting of eleven amino acid residues with a total molecular weight of about 1,200. but with different substituents or configurations of some of the amino acids, it should be noted that the reference to the term "Cyclosporin" or "cyclosporins" is used throughout the present specification to designate the cyclosporin component in the composition of the present invention. However, this specific reference is proposed to include any individual element of the cyclosporin group as well as mixtures of two or more individual cyclosporins, either natural or synthetic. The activity of the cyclosporins, as noted here above, is as an immunosuppressant and in the improvement or restoration of lacrimation of the laryngeal gland. This activity can be improved if it is possible to improve the absorption of cyclosporine in the lacrimal gland. The present invention provides a formulation and method that produces optimal concentrations of cyclosporin A in the lacrimal gland and other ocular surface tissues. Unfortunately, the solubility of cyclosporin in water is extremely low and as elaborated in U.S. Pat. No. 5,051,402, it has been considered not only difficult but practically impossible to prepare a pharmaceutical composition containing the cyclosporin dissolved in an aqueous medium. As reported, the solubility of cyclosporin in water is between about 20 Ztg / ml up to 30 tg / ml for cyclosporin A. Accordingly, formulations prepared up to now that incorporate cyclosporin have been prepared as oily solutions containing ethanol. However, these preparations limit the bioavailability to oral preparations and this is beld to be due to the separation of the cyclosporin as a solid immediately after it has come into contact with water, such as in the mouth or the eye of a patient. In the case of injectable cyclosporin preparations, they must first be diluted with physiological brine before intravenous administration but this probably leads to the precipitation of cyclosporin and therefore may be considered undesirable for intravenous administration. Surface active agents such as polyoxyethylated castor oil have been used as solubilizing agents to inject the preparations to prevent cyclosporin from being removed. However, this can also cause security problems (see U.S. Patent No. 5,051,402). The practical utility of cyclosporin could be greatly improved if its administration could be effective; for example, the effectiveness of cyclosporine in the treatment of ocular symptoms of Behcet's syndrome. However, if it is administered orally for the treatment of these symptoms, accompanying side effects due to systemic or systemic circulation may cause adverse reactions such as hypertrichosis or renal dysfunction. On the other hand, if the oily preparations containing cyclosporin are applied directly to the eyes, irritation or fogging of the visual field may result. This plus the difficulty in the formulation of cyclosporine limits its use in the formulations that could be useful during keratoplasty as well as in the treatment of herpetic keratitis and vernal conjunctivitis. Until now, as for example in U.S. Pat. No. 5,051,402, attempts have been made to dissolve enough cyclosporin in an aqueous solvent system to achieve an effective concentration for the treatment. Importantly, this solvent system does not contain any surface active agent such as polyethoxylated castor oil. Conceptually, the purpose of dissolving cyclosporine in an aqueous solvent system is to make possible the contact with body fluids which simply constitute the dilution of the aqueous solvent system which could successfully eliminate the immediate precipitation of cyclosporine when it is placed in contact with the water content of body fluids. For direct use in the eye, cyclosporin has been formulated with a number of pharmaceutically acceptable excipients, for example, animal oils, vegetable oils, an appropriate aqueous or organic solvent, a tear or drop solution, artificial, a natural polymer or synthetic or an appropriate membrane. Specific examples of these pharmaceutically acceptable excipients, which may be used singly or in combination, are olive oil, peanut oil, castor oil, mineral oils, gelatin or petroleum jelly, dimethyl sulfoxide, cremophor, liposomes, or products similar to liposomes or a silicone fluid, among others. In summary, a large amount of effort has been consumed to prepare a pharmaceutical composition containing cyclosporin dissolved in an aqueous medium or cyclosporin prepared as an oily solution. However, successful formulations are still sought to be achieved as evidenced by the lack of commercial products. As noted hereinbefore, it has been reported that cyclosporin has shown some solubility in oily preparations containing high fatty acid glycerides such as olive oil, peanut oil, and / or castor oil. These formulations often produce an unpleasant sensation when applied to the eye because of stimulation or viscosity which is characteristic of these oils. Another disadvantage of these formulations is that they contain a high concentration of oils, and the oils aggravate the symptoms of certain diseases of the ocular surface such as dry eyes, indicated by cyclosporin. Therefore, these oily formulations can not be clinically acceptable. Additionally, these formulations frequently suffer from physical instability due to the propensity of the cyclosporins to undergo a conformational change and to crystallize. The problem of crystallization has been detected in formulations containing corn oil or medium chain triglycerides. Finally, these formulations frequently have a low thermodynamic activity (degree of saturation) of cyclosporin, which leads to a bioavailability of the poorer drug. It may be possible to minimize the problems related to an unpleasant sensation and the aggravation of the syndrome by reducing the oil content and the dispersion of the oily phase in the water, in an emulsion. However, it is not an easy task to formulate an ophthalmic emulsion because an indispensable class of ingredients in an emulsion system are the emulsifiers, and most of the emulsifiers are highly irritating to the eyes. The present invention is directed to an emulsion system which uses elevated fatty acid glycerides but in combination with Polysorbate 80, which leads to an emulsion with a high level of comfort and a low potential for irritation, suitable for the supply of medicines to sensitive areas such as eye tissues. In addition, the present invention provides a pharmaceutical composition and method for eliciting the preferential absorption of cyclosporin in the lacrimal gland. That is, for a given drop-by-drop instillation or application of the composition in one eye, a larger amount of absorption occurs in the lacrimal gland for formulations made in accordance with the present invention than for the formulations used hitherto.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, a non-irritating pharmaceutical composition with a high level of comfort and a low irritation potential, suitable for delivery to sensitive areas such as ocular tissues, comprises cyclosporin mixed with an emulsifying amount of a high fatty acid glycerol and Polysorbate 80. More particularly, the composition may comprise cyclosporin A and the high fatty acid glyceride may comprise castor oil. Preferably, the weight ratio of the castor oil to the Polysorbate 80 is between about 0.3 to about 30 and a weight ratio of the cyclosporin to the castor oil is below 0.16. More preferably, the weight ratio of the castor oil to the Polysorbate 80 is between 0.5 and 12.5, and the weight ratio of the cyclospo- - a-brane to the castor oil is between 0.12 and 0.02. When the cyclosporin is dissolved in the oily phase according to the present invention, the emulsion is found to be physically stable during long-term storage. No crystallization of cyclosporin was appreciated after nine months at room temperature. In addition, the cyclosporin emulsion is formulated in such a way that the drug has a reasonably high thermodynamic activity, still without the problem of crystallization. Importantly, the composition of the present invention provides improved absorption of cyclosporin in the lacrimal gland of the eye. In this way, the activity of cyclosporine in the restoration of lachrymal gland tearing is increased. That is, since a larger amount of cyclosporine is absorbed in the lacrimal gland, a greater amount of cyclosporine is effective in producing tearing of the lacrimal gland than hitherto possible.

BRIEF DESCRIPTION OF THE DRAWINGS The advantages and features of the present invention will be better understood by the following description when considered in conjunction with the appended drawings, in which: Figure 1 is a bar graph of the conjunctival concentration of cyclosporin A after of a typical, single drop instillation or application of various formulations in a rabbit eye; Figure 2 is a graph or bar graph of the corneal concentration of cyclosporin A after a single topical instillation of various formulations in a rabbit eye; Figure 3 is a bar graph of the ciliary body concentration of cyclosporin A after a single topical instillation of various formulations in a rabbit eye; and Figure 4 is a bar graph or diagram of the concentration in the lacrimal gland of cyclosporin A after a single topical instillation of various formulations in a rabbit eye.

DETAILED DESCRIPTION OF THE INVENTION As noted herein above, cyclosporin is available as a mixture in which the main ingredient is cyclosporin A with smaller, but significant amounts, of other cyclosporins such as cyclosporins B to 1. However, also as noted hereinabove, the present invention can be applied to either the pure cyclosporin or a mixture of individual cyclosporins. The discovery on which the present invention is based is related to a combination of a high fatty acid glyceride and an emulsifying and dispersing agent, Polysorbate 80. The selection of these components could not have been anticipated based on the conventional reasoning. For example, although it is well known that cyclosporin can be used in combination with castor oil, this combination is irritating to sensitive tissues such as the eye. Accordingly, conventional teaching in the art is set apart from a formulation which utilizes a high fatty acid glyceride, such as castor oil, and cyclosporin. In other words, there is no way to deduce that the use of an emulsifying and dispersing agent such as Polysorbate 80 will reduce the potential irritation of an emulsion using castor oil. There are no examples of polysorbate in combination with castor oil which, when mixed with cyclosporine, produces an emulsion with a high level of comfort and a low irritation potential, suitable for the supply of the medicament to sensitive areas such as the eye tissues. The present invention achieves a state of stable solution of cyclosporin. This state of stable solution is another important performance characteristic that differentiates the present invention from conventional oily systems. Cyclosporine is notorious for its tendency to precipitate in conventional oily systems in which it initially dissolves completely. According to the present invention, the emulsions can be further stabilized using a polyelectrolyte, or polyelectrolytes if there is more than one, of the family of the crosslinked polyacrylates, such as carbomers and Pemulen. Pemulen is a polymeric emulsifier which has the CTFA name of Crosslinked Polymer or Crosslinked Acrylates / Alkyl Acrylate with C10-30 and is described in the monograph "Carbomer 1342" in USPXXII / NFXVII. In addition, the tonicity of the emulsions can be further adjusted using glycerin, mannitol, or sorbitol if desired. The pH of the emulsions can be adjusted in a conventional manner using sodium hydroxide to an almost physiological pH level and although buffering agents are not required, suitable buffering agents can include phosphates, citrates, acetates and borates. Although preferred drugs according to the present invention include cyclosporin, other chemical substances which are very poorly soluble in water such as indomethacin and steroids such as androgens, prednisolone, predni-solone acetate, f luorometolone, and the dexamethasone can be emulsified with castor oil and Polysorbate 80 leading to a composition with a low potential of irritation, similar. The invention is further illustrated by the following examples with all parts and percentages expressed by weight. The cyclosporin used in the examples was supplied by Sandoz.

Example 1 Example 2 Example 3 fifteen twenty Example 4 The formulations described in Examples 1-4 were made for the treatment of the syndrome of kerato-conjunctivitis sicca (dry eyes) with Examples 2, 3 and 4 without the active ingredient cyclosporin, used to determine the toxicity of the components emulsify-two. The formulations in Examples 1-4 were applied to the eyes of rabbits eight times a day for seven days and were found to cause only slight to mild discomfort and slight hyperepemia in the rabbit's eyes. Examination with a slotted lamp revealed no changes in the surface tissue. In addition, the castor oil emulsion containing cyclosporin, as described hereinabove in Examples 1A-1D, was also tested to verify ocular bioavailability in rabbits; and the therapeutic level of ciclosporin was found in the tissues of interest after dosing. This provides the rationale that cyclosporins in an ophthalmic delivery system are useful for treating dry eyes as described in U.S. Pat. No. 4,839,342. In addition, no difference in toxicity was found between the formulations with cyclosporins (Examples 1A-1D) and the formulations without cyclosporins (Examples 2-4). The formulations described in Examples 1-4 were found to be physically stable during long-term storage. With respect to formulations 1A-1D, no crystallization of the cyclosporins was observed after nine months at room temperature. In addition, other high fatty acid glycerides such as olive oil, peanut oil and the like can also be used with Polysorbate 80 with similar results with respect to biotoxicity. The following examples demonstrate the activity of the composition according to the present invention for an improved absorption of cyclosporin A in the lacrimal gland. materials 3 [Mebmt-H] -cyclosporin-A (lot # TRQ6553) was prepared by Amersham International (Buckinghamshire, England) with a radiochemical purity of -98% (by reverse phase HPLC) and a specific activity of 2.6 Ci / mmoles 3 (2.16 mCi / mg). The H tag is a metabolically stable position as shown by the asterisk. The radiolabelled CsA was supplied as a solution in ethanol (1 mCi / ml). All the organic solvents used in the procedures described in this study were "CLAR grade". All other chemicals and reagents were analytical grade unless otherwise stated. The compositions of the six formulations tested are listed in Table A.

TABLE A The radiolabel formulations were formulated to ensure that the radioactivity was homogeneous throughout the vehicle. The concentrations of the radioactivity expected from the formulations of the radiolabelled drug were 1-2 mCi / ml. The expected specific activity of the radiolabelled cyclosporin A (CsA) formulations was 0.5-2 mCi / mg. All test items were stored at room temperature.

Analysis of Test Drug Formulations The test formulations were analyzed in triplicate, by CLAR, to determine the CsA concentration and the radiochemical purity of the CsA dosing solutions (> 93%) before dosing. The radioactive concentrations of the test formulations were quantified by scintillation counting of the liquid phase (LSC).

Chromatographic conditions Pump: Beck'man Model 126 (Beckman Instruments, San Ramón, CA) Mobile phase: Acetonitrile: 0.03% H "P0, in water, pH 3 (65:35 v / v) J 4 Flow rate 1.0 ml / min Column Supercosil C8, 7.5 cm x 4.6 mm, 3 JT? (Supelco, Bellefonte, PA) Superguard LC-8 (Supelco) Column Heater (Bio-rad, Richmond, CA) at 60-70 ° C WISP 712B Injector (Waters Associates, Milford, MA) Detector 14, Radioisotope Detector 171 (Radio Isotope 171 Detector) (Beckman Instruments) Ready Flow III Twinkling Count (Beckman Instruments), Flow Rate of? 4 ml / min UV detector: Model 166 (Beckman Instruments), 202 nm Data Processor: Beckman System Gold (Beckman Instruments) Run Time: 15 min Hold Time: 6 min (cyclosporin A) Animals Female New Zealand albino rabbits were obtained and isolated for at least five days before the procedures. The animals were housed in rooms controlled both in temperature and humidity. Food and tap water were provided ad libitum. Fifty-eight rabbits (2-3 kg) were selected from the colony to minimize influence or predisposition. They were individually identified by ear tabs and appeared to be healthy.

Dosage The animals were divided into six groups of nine rabbits; each group was treated with one of the six formulations of CsA. During dosing, the lower eyelid of each rabbit was gently pulled away from the eye and 35 J - 1 of the formulation was administered into the lower conjunctival cul - de - sac (closed cavity) of each eye. After dosing, the upper and lower eyelids were kept closed manually during f > J 5 seconds and they are released. The animals were observed visually for signs of tearing or eye discomfort.

Sampling The tissues were collected at 20 minutes, 6 hours and 24 hours after the dose for each group. Three rabbits (six eyes) were used at each point or instant of time. At specific sampling intervals, the animals were euthanized by an intravenous injection of 0.5-1 ml of Eutha-6 (Western Supply Co., Arcadia, California) through the marginal ear vein. Each eye was then rinsed with a normal saline solution. The aqueous humor (? 200? 1) was removed by means of a 0.5 ml tuberculin syringe. The orbital lacrimal gland (? 400 mg), the upper and lower bulbar conjunctive bodies (^ 50 mg each), the corneal body (> 50 mg) and the iris-ciliary body (A / 50 mg) were dissected. . The dissected tissues were transferred to a dry blotting paper and weighed. Ocular tissue and aqueous humor samples from both eyes were collected from the four untreated animals that will be used as target samples.

Analysis of Radioactivity An aliquot of the aqueous humor (50-175 μ-) was directly taken into account in 10 ml of Ready-Solv HP by LSC. Tissue and blood samples were weighed in combustion cones prior to combustion in a Packard Tissue Oxuduzer Model 307 (Packard Co., Downers Grove, Illinois). After combustion of the tissue samples, the H20 was trapped in Monophase-S solution (Packard) and the radioactivity of the samples was determined by LSC in a Beckman Model 1801 or 3801 scintillation counter.

(Beckman Instruments, San Ramón, California).

Analysis of data The Excel program (version 4.0, Microsoft Corp., Redmond, Washington) was used for data analysis. The concentrations of the total radioactivity in the tissue samples was expressed as dpm / g or dpm / ml and converted to equivalents (eq) of ng, of CsA / g or mi, using the specific activity of the dosage formulations. The standard deviation (SD, average, or standard error of the mean (SEM) was calculated according to standard methods.) Radioactivity levels were not considered significant unless the dpm was greater than twice that of the background b = (white) Comparisons of drug concentrations of tissues at each point or time point for the formulations were determined by one-way ANOVA All statistical comparisons were made using StatView (version 1.03, Abacus Concepts, Inc. ., Berkeley, Calif.) The Fisher and Scheffe F tests were used to determine significant differences between the formulations at the 95% level (? = 0.05) The rejection criterion to exclude any atypical data was based on tests of standard atypical values No more than one outlier was removed from any data set.

Results and Discussion Concentrations of radioactivity in ocular tissues at 20 minutes, 6 hours, and 24 hours after a single topical application of various formulations are shown in Figures 1-4. In general, ocular tissue concentrations were greater at the more initial 20 minute time point as reported in previous single dose studies (2, 3). The concentration of radioactivity was highest in the conjunctiva and the cornea for each formulation. Concentrations in the relatively low aqueous humor and iris-ciliary body suggest low intraocular absorption of CsA, consistent with low corneal permeability of CsA of -1.0 x 10 cm / sec (6). The decline or decrease in radioactivity concentrations from the cornea was slower than those from the conjunctiva, the lacrimal gland, and the aqueous humor. The concentrations of the radioactivity of the blood observed (< 3 ng-eq / ml) were much lower than the CsA concentrations of the plasma of the conduit of 80-250 ng / ml observed after the oral dosage to humans (1 ). The dependence of the conjunctival and corneal penetration of the CsA on the formulation was interpreted in terms of the concentration of CsA in the formulation and the rate of CsA release from the formulation in a film for the drip application. Aqueous formulations demonstrated a greater propensity to release CsA for diffusion through the surface epithelium. Straight chain 0.2% castor oil was formulated below the solubility of CsA and therefore the rate of release could be hindered by the thermodynamic activity of the CsA less than the maximum (5). The ocular surface tissues contained a higher fraction of the CsA dose than the other tissues and were used to discriminate between the aqueous emulsion, and the straight chain castor oil formulations. The polyoxyl formulation 40 produced higher ocular surface tissue concentrations than the emulsions and straight chain castor oil. The emulsions were also effective in the delivery of CsA to the tissues of interest, the lacrimal gland, the cornea, and the conjunctiva. The castor oil emulsion showed higher lacrimal gland concentrations than the modified Sante and the migliol emulsion. Straight-chain castor oil showed the lowest concentrations in the superficial ocular tissues. Apparently, the factors that have an influence on the penetration of CsA in the lacrimal gland and the superficial tissues are different. Although a particular pharmaceutical composition in the form of a non-irritating emulsion has been described above for the purpose of illustrating the manner in which the invention can be used to take advantage, it should be appreciated that the invention is not limited thereto. Accordingly, any and all modifications, variations, or equivalent arrangements, which may be obvious to a person of ordinary skill in the art, should be considered within the scope of the present invention as defined in the appended claims.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (26)

R E I V I N D I C A C I O N S

1. A composition, characterized in that it comprises a non-irritating emulsion of at least one cyclosporin in admixture or combination with a high fatty acid glyceride, Polysorbate 80 and a stabilizing amount of the Pemulen emulsion in water, suitable for topical application to the ocular tissue.

2. The pharmaceutical composition according to claim 1, characterized in that cyclosporin comprises cyclosporin A.

3. The pharmaceutical composition according to claim 2, characterized in that the weight ratio of the high fatty acid glyceride to the Polysorbate 80 is between about 0.3 and about 30.

4. The pharmaceutical composition according to claim 3, characterized in that the high fatty acid glyceride comprises castor oil and the weight ratio of the cyclosporin to the castor oil is below about 0.16.

5. A pharmaceutical composition, characterized in that it comprises a non-irritating emulsion of at least one cyclosporin in admixture or combination with castor oil and Polysorbate 80 in water, suitable for topical application to ocular tissue.

6. The pharmaceutical composition according to claim 5, characterized in that cyclosporine comprises cyclosporin A.

7. The pharmaceutical composition according to claim 6, characterized in that the weight ratio of the castor oil to the Polysorbate 80 is between about 0.3 and about 30.

8. The pharmaceutical composition according to claim 7, characterized in that the weight ratio of cyclosporin to castor oil is below about 0.16.

9. The composition according to claim 1, characterized in that the high fatty acid glyceride and the Polysorbate 80 are present in an amount sufficient to prevent the crystallization of the cyclosporin for a period of up to about nine months.

10. A non-irritating, stable ophthalmic composition characterized in that it comprises cyclosporin in admixture or combination with an emulsifying amount of a high fatty acid glyceride and Polysorbate 80.

11. A pharmaceutical emulsion, characterized in that it comprises cyclosporin A, castor oil, p Pemulen, glyceride and water in sufficient amounts to prevent the crystallization of cyclosporin A for a period of up to about nine months, the pharmaceutical emulsion is suitable for Topical application to ocular tissue.

12. The pharmaceutical emulsion according to claim 11, characterized in that the cyclosporin A is present in an amount of between about 0.05 to about 0.40%, by weight, the castor oil is present in an amount of between about 0.625%, by weight, Polysorbate 80 is present in an amount of about 1.0%, by weight, the Pemulen is present in an amount of about 0. 05%, by weight, and the glyceride is present in an amount of about 2.2%, by weight.

13 A pharmaceutical emulsion, characterized in that it consists of between about 0.05% and about 0.40%, by weight, of cyclosporin A, between about 0.625% and about 5.0%, by weight, of castor oil, about 1.0%, by weight, of Polysorbate p 80, approximately 0.05%, by weight, of Pemulen, and approximately 2.2%, by weight, of glycerin in water with a pH between approximately 7.2 and 7.6, suitable for topical application to ocular tissue.

14. A pharmaceutical composition suitable for instillation or drop-wise application in an eye, the pharmaceutical composition is characterized in that it comprises a non-irritating emulsion of at least one cyclosporin and castor oil in an amount that causes improved absorption in the lacrimal gland.

15. The pharmaceutical composition according to claim 14, characterized in that cyclosporin comprises cyclosporin A.

16. The pharmaceutical composition according to claim 15, characterized in that the cyclosporin is present in an amount between about 0.20 and about 5.0% by weight.

17. The pharmaceutical composition according to claim 15, characterized in that it also comprises a stabilizing amount of the emulsion of Pemulen in water, suitable for topical application in the eye.

18. The pharmaceutical composition according to claim 17, characterized in that the cyclosporin is present in an amount of about 0.20% by weight, the castor oil is present in an amount of about 1.25% by weight, and the Pemulen is present in an amount of about 0.05% by weight.

19. The pharmaceutical composition according to claim 18, characterized in that it further comprises the Tween 80 in an amount of about 1.0% by weight, and glycerin in an amount of about 2.20% by weight.

20. A pharmaceutical composition suitable for instillation or drop-wise application in an eye, the pharmaceutical composition is characterized in that it comprises a non-irritating mixture of at least one cyclosporin and castor oil in an amount that causes an improved absorption in the lacrimal gland.

21. The pharmaceutical composition according to claim 20, characterized in that cyclosporin comprises cyclosporin A.

22. A method to cause an improved absorption of cyclosporin A in the lacrimal gland of an eye, the method is characterized in that it comprises the steps of: mixing cyclosporin A with castor oil; instill apply drop by drop the mixture in the eye

23. The method according to claim 22, characterized in that the mixing step includes forming an emulsion of cyclosporin A, castor oil and water.

24. A method to cause an improved absorption of cyclosporin A in the lacrimal gland of an eye, the method is characterized in that it comprises the steps of: forming an emulsion of cyclosporin A, p castor oil, Pemulen and water; and apply drop by drop or instill the emulsion in the eye.

25. The method according to claim 24, characterized in that the cyclosporin is present in an amount of about 0.20% by weight, the castor oil is present in an amount of about 1.25% by weight, and the Pemulen is present in an amount of about 0.05% by weight.

26. The method according to claim 24, characterized in that the emulsion further comprises the Tween 80 in an amount of about 1.0% by weight, and the glycerin in an amount of about 2.20% by weight.