SK171798A3 - Topical preparations containing immunosuppressive agents - Google Patents

Abstract

Therapeutic preparations for topical ophthalmic application, containing from 0.02 to 5.0 weight % of immunosuppressive agents belonging to the groups of monocyclic undecapeptides, macrolide lactones or corticosteroids, in a vehicle comprising up to 10 weight % of polyalkyleneglycol-polyurethane copolymers. Said copolymers consist preferably of poly(oxy-1,2-ethanediyl)- alpha -hydro- omega -hydroxypolymers with 1,1'-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1000 to 3000 in a hydrophilic vehicle and preferably of poly[oxy(methyl-1,2-ethanediyl)]- alpha -hydro- omega -hydroxypolymers with 1,1'-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1600 to 18000 in a lipophilic vehicle. Said therapeutic agents can further contain additional excipients common in topical administration forms.

Description

Topical preparations with immunosuppressants

Technical field

The invention relates to medicaments intended for topical ocular administration of lipophilic, immunosuppressive medicaments dissolved or dispersed in a physiologically acceptable vehicle containing excipients increasing the penetration of medicaments into ocular tissues.

BACKGROUND OF THE INVENTION

Topical ocular administration is considered to be the topical administration of the medicinal products to the conjunctival sac under the eyelid and cornea as well as subconjunctival and retrobulbar administration.

In addition to the anatomical and physiological properties of the eye, the efficacy of topically applied drugs for the treatment of ocular diseases is influenced in particular by the physicochemical properties of the drug and the nature of the dosage form and its composition. It is well known that drug transport into ophthalmic tissues is hampered by eye defense mechanisms such as increased lacrimation and blinking, which reduces drug concentration in the precoreal region. Drug absorption is facilitated by prolonged contact with the cornea and the ability of the drug to penetrate the cornea. The bioavailability of drugs after topical application to the eye is usually only 1 to 10% of the administered substance.

Typical lipophilic, immunosuppressive drugs that are used to treat ocular diseases are e.g. anti-inflammatory and immunosuppressive agents from the group of monocyclic poly-N-methylated undecapeptides, lactone macrolides or corticosteroids. Undecapeptide useful in the treatment of the eye is a group of cyclosporins, especially ciclosporin, [Nva] ² - ciclosporin, [Val] ² - ciclosporin and dihydro- [Val] ^{2-Ciclosporin.}

Macrolide antibiotics suitable for the treatment of ocular diseases are mainly tacrolimus and sirolimus. Tacrolimus and its structurally similar derivatives are collectively referred to as ascomycins, sirolimus and its structurally related derivatives are collectively referred to as rapamycins.

A group of corticosteroids used for topical application in ophthalmology are substances such as e.g. cortisone and hydrocortisone, prednisolone and methyl prednisolone, dexamethasone and fluorometalone.

The therapeutic efficacy of said cyclosporins in topical application has been shown in particular in risk of corneal transplants and autoimmune diseases such as keratoconjunctivitis sicca, chronic keratitis, Behcet's syndrome, Sjøgren's syndrome, endogenous uveitis, but also ulcerative diseases of the cornea such as. Morenov ulcer.

Macrolide antibiotics have been shown to be highly immunosuppressive in organ and tissue transplantation and are promising for keratoplastics. Corticosteroid drugs are used in the treatment of inflammations following ophthalmic surgery as well as inhibiting immunological reactions following corneal transplants.

All three classes of active compounds of the present invention are also administered systemically for the treatment of inflammatory and autoimmune eye diseases. However, due to the serious side effects of this treatment, systemic administration is only of limited use. In a rational topical application, side effects associated with systemic administration can be reduced or avoided by concentrating the activity of the formulation only on the site to be treated and its immediate surroundings.

Drugs from the N-methyl cyclic undecapeptide, macrolide lactone and corticosteroid groups are only slightly soluble in water or hydrophilic carriers physiologically acceptable for ophthalmic administration in their unionized form. This practically makes it difficult to prepare classic hydrophilic eye drops. By way of illustration, the water solubility of the cyclosporin group is in the range of 16-30 pg / ml at 25 ° C, with the more polar [Thr] ^{2 r} ciclosporin molecule being more water soluble than the less polar [NVa] ² -ciclosporin. The value of the partition coefficient P between the aqueous phase and the lipophilic phase represented by n-octanol can be used to mutually assess the lipophilicity of the active ingredients from the above groups. For corticosteroid drugs, e.g. log P between 1.2 (prednisolone) to 4.3 (flurbiprofen). In the cyclosporin group, the log P for immunosuppressive active agents is between 1.1 to 3.1. For ascomycins and rapamycins, partition coefficient values are not published, but can be assumed from the water solubility data to be comparable to cyclosporins.

One of the first patents dedicated to the ocular topical application of ciclosporin drugs as a method of treating phacoanaphylactic endoophthalmitides and uveitis in the anterior and posterior ocular segment or ocular diseases exhibiting reduced tear production is US Patents 4,649,047 and 4, 839,342. Both patents do not specify the dosage form and envisage the use of solutions, suspensions and ointments with a pharmaceutically acceptable vehicle containing vegetable, animal, mineral and silicone oils; liposomes, followed by alcohols, dimethylsulfoxide and polyoxyethylated castor oil. Said patents neither disclose weight ratios of suitable excipients, neither in the embodiments nor in the claims.

A group of corticosteroids, cyclosporins and antibiotics for ophthalmic application is referred to US Patent 4,865,846 protecting delivery systems in which drug solutions in a liquid or ointment base are present together with particles of biodegradable materials containing the same or other drugs, and a process for preparing these delivery systems. Exemplary embodiments of this patent show that the preparation of three-dimensional particles of 0.4 to 1.0 mm in size from bioerodible materials such as collagen, gelatin, polyvinyl alcohol and methylcellulose derivatives, suspending these particles in a liquid or ointment base, and a method of incorporating drugs into these bioerodible The particle size is very laborious and poorly suited for a validated manufacturing process.

Topical preparations for application to the eye and adjacent tissues containing cyclosporins in a vehicle composed of a mixture of vegetable oils and petrolatum are described in UK Patent 2,224,205. However, the medicaments produced by the processes described in this patent contain as emulsifiers substances based primarily on steroid sheep wool. At present, there is already a move away from the use of these substances for possible allergic and irritant effects of possible insecticidal residues contained in sheep wool fat.

Ophthalmic preparations with low concentrations of cyclosporin in an aqueous vehicle containing surfactants from the group of polyethoxylated fatty acid esters, polyethoxylated alkyl ethers and polyethoxylated alkyl phenyl ethers are described in International Application WO 93/23010. An emulsion ophthalmic formulation with specific affinity for lacrimal glands containing cyclosporins is described in International Application WO 95/31211.

Euacid and isotonic nanoemulsions suitable for application containing 0.01% to 5% of drugs, including corticoids and cyclosporins, are described in European patent application EP 0 696 452 A1. None of the above patents solve the particular problem of increasing drug penetration through the cornea into internal ocular structures such as aqueous humor, iris or uvea.

SUMMARY OF THE INVENTION

It is an object of the present invention to increase corneal permeability in topically applied drugs and to achieve therapeutically effective levels of the drug in the internal tissues of the eye using particularly suitable excipients in the pharmaceutical compositions. This task is particularly difficult for drugs that are very difficult to dissolve in body fluids and tissues. Substances that are very difficult to dissolve in water are considered to be substances which need 1000 to 10,000 parts by volume of water to dissolve 1 part by weight. Such drugs are in particular immunosuppressants from the group of monocyclic undecapeptides represented by ciclosporin or [Nva] ² -ciclosporin, from the group of lactones with a macrolide structure represented by sirolimus or tacrolimus and from the group of corticoids represented e.g. prednisolone or dexamethasone.

The present invention provides pharmaceutical preparations for topical ophthalmic applications, which according to the invention are characterized by the presence of 0.02 to 5.0% by weight of immunosuppressive drugs dissolved or dispersed in a physiologically acceptable vehicle containing up to 10% by weight of polyalkylene glycol-polyurethane copolymers of formula 1

° I II ₂ -O-) _n .- [CN ^^ \ _CH2 / \ NC - (- O-CH _r CH) _n -θ] -Η H '''' ^Hm

G) wherein n is 8 to 51, m is predominantly 1 to 4 and R is CH 3 or H.

From the chemical point of view, the correct CAS names of these substances are hereinafter abbreviated in the CTFA nomenclature:

CAS nomenclature CTFA nomenclature Poly (oxy 1,2-ethanediyl) -α-hydro- <o -hydroxy polymer with 1,1'-methylene-bis- (4-isocyanatocyclohexane) CAS no. 39444-87-6 PEG-8 / SMDI copolymer Poly [oxy (methyl 1,2-ethanediyl)]) - N -hydroxy- (O-hydroxy polymer with 1,1'-methylene-bis- (4-isocyanatocyclohexane) CAS no. 9042-82-4 CAS no. 9042-82-4 PPG-12 / SMDI copolymer copolymer PPG-51 / SMDI

In CTFA nomenclature, the abbreviations PEG and PPG refer to polyethylene glycol and polypropylene glycol and to SMDI the abbreviation is saturated methylenediphenyl diisocyanate.

These substances are circulated e.g. under the tradename Polyolprepolymer-2 (PPG-12 / SMDI copolymer); Polyolprepolymer-14 (PPG-51 / SMDI copolymer) and Polyolprepolymer-15 (PEG-8 / SMDI copolymer) and are manufactured by PENEDERM Incorporated.

In dermal use, these copolymers are known. They have a strong activity on the skin and form easily deposits in the stratum corneum. This creates long-lasting liquid reservoirs of drugs between the comeocytes and allows for a prolonged action of the drugs in the skin.

The use of polyol prepolymers in dermal and cosmetic compositions protects e.g. US Patents 4,971,800, 5,045,317 and 5,051,260.

Despite the significantly different anatomical composition of the skin from the anatomical composition of the ocular cornea, it was surprisingly found that polyalkylene glycol-polyurethane copolymers significantly increase penetration of very difficult-to-dissolve immunosuppressive drugs across the cornea. This phenomenon has been demonstrated in ophthalmic formulations when the aforementioned drugs are incorporated in the presence of said copolymers into both hydrophilic and hydrophobic, physiologically acceptable vehicles.

Surprisingly, it has also been found that the pharmaceutical compositions of the present invention containing polyalkylene glycol polyurethane copolymer excipients do not cause an increase in ocular irritation at useful concentrations up to 10% by weight, although there is a demonstrable increase in the penetration of therapeutically effective immunosuppressive drugs into the internal ocular structures. Also, histological examination of the ocular structures after repeated administration of the compositions of the invention does not indicate the possibility of their damage. In contrast, eye irritation and toxicity are already reported with 0.1% and higher concentrations of azone, a known substance used to improve the permeability of drugs to the cornea of the eye (Ismail IM et al., Pharm. Res., 9 (6), 817). (1992).

Achievement of favorable biological properties is contingent upon the qualitative properties of the copolymers of the invention, in particular residual concentrations of the unreacted diisocyanate component and the corresponding polyalkylene glycols. Typical properties of copolymers are shown in the following overview:

copolymer PPG-12 / SMDI copolymer PPG-51 / SMDI copolymer PEG-8 / SMDI mol. mass (weight average) 4000 18000 1800 viscosity mPa.s at 37 ° C 2500-4500 2500-6000 2500-5000 unreacted diisocyanate max. 0.1% max. 0.1% max. 0.1% residual PPG content PEG content max. 20% max. 20% max. 20% heavy metal content max. 20 ppm max. 20 ppm max. 20 ppm water content max. 0.1% max. 0.1% max. 0.1%

The polyalkylene glycol-polyurethane copolymers contain a mixture of oligomers whose representation is expressed as an index of "m" in the general formula, which is predominantly 1 to 4.

Typical molecular weight distributions determined by gel permeation chromatography apply to the various types of copolymers produced. For example, for PPG12 / SMDI, the molecular weight fraction is:

up to 23% (for peaks of 1500 to 2000) to 25% (for peaks of 2400 to 3300) to 45% (for peaks of £ 3700)

Both types of copolymers containing hydroxyl end groups in the polyalkylene glycol moiety significantly increase deposition of said drugs into the middle part of the cornea (stroma), which contains a high proportion of water. Due to the graduated lipophilicity of copolymer fractions of different molecular weights that very poorly water-soluble immunosuppressive drugs are not fixed only in the strongly lipophilic layer of the corneal epithelium consisting of only about 5 upper layers of living cells.

Lipophilic ophthalmic vehicles comprise both plant or animal triacylglycerols (e.g. castor oil, corn oil, sesame oil or fish oil) and hydrogenated forms thereof. Hydrocarbon mixtures such as e.g. saturated hydrocarbons hexamethyltetracosahexaene known as petrolatum or unsaturated branched hydrocarbons known as squalene, or its hydrogenated squalane form can also be introduced in limited amounts between triacylglycerols. Lipophilic vehicles also include structured lipids consisting of triglyceryl esters with medium acyl residues Cg to C12 in combination with long acyl residues C11 to C22. Also polyglyceryl esters of C14 to C22 fatty acids having a hydrophilic-lipophilic equation (HLB) of less than 6, having an oily character, are useful as non-irritating lipophilic ophthalmic vehicles. Likewise, fatty alcohols having a hydrocarbon chain length of C11 to C23 are useful for this purpose.

Hydrophilic ophthalmic vehicles for the compositions of the invention are comprised of water or alkylene glycols such as, in particular, glycerol or polyethylene glycols. Block copolymers of ethylene oxide with propylene oxide, also known as poloxamers or meroxapols, are also useful.

Both types of ophthalmic vehicles are also characterized in that they have a liquid or semi-solid consistency at temperatures of 15-37 ° C.

Additional excipients may be present in the vehicles of the topical ophthalmic formulations of the invention in an amount that is technologically necessary and their choice is contingent upon the choice of the particular dosage form. In the case of solutions, these are physiologically acceptable solvents and solubilizers of liquid or semi-solid consistency to the eye. In the case of emulsion and suspension dispersion preparations, these are additionally stabilizing additives of the phases present. In multi-dose ophthalmic packages, antimicrobial additives are common.

Since the molecular weight of the PEG-8 / SMDI copolymer does not exceed 3000, it is appropriate to take into account its contribution to the osmotic pressure value in formulations with a hydrophilic vehicle and to adjust the tonicity by conventional excipients of ionogenic or nonionic character if necessary.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings show graphically the effect of the addition of 1% PPG51 / SMD1 copolymer in the topical ophthalmic formulations of Example 3 on the absorption of ciclosporin into the cornea (graph 1) and its penetration into the iris (graph 2), aqueous humor (graph 3) and uvey (graph) 4). There was a significant increase in absorption in the groups of pigmented rabbit males and females. On average, the concentration of ciclosporin increased after 12 applications of one drop of the preparation to the eye as compared to controls as follows:

cornea 3,30x; iris 5.24x, aqueous humor 5.08x and uvea 5.2x.

Table 1 is also attached with an indication of the evaluation of the eye response.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate possible compositions of the formulation of the invention with drugs of all typical groups without being of any limitation.

Example 1

Eye drops 1% 2%

Ciclosporin 1,000 kg 2,000 kg PPG-12 / SMDI copolymer 1,00 kg 1,00 kg Diglyceryl monooleate 2,50 kg 5,00 kg chlorobutanol 0,50 kg 0,50 kg Corn oil up to 100,00 liters up to 100,00 liters

The PPG-12 / SMDI copolymer and diglyceryl monooleate are mixed with corn oil in a 100 L Steridose Systems AB magnetic stirrer. Freshly sublimed chlorobutanol and ciclosporin are dissolved in the mixture at ambient temperature. The solution is aseptically filtered into a sterilized container through a 0.2 gm membrane filter. It is filled into polyethylene containers of S ml volume on a BFS system.

Both concentration variants of the formulation were evaluated for eye irritation in rabbits according to the methodology described.

The eye drops of Example 1 containing 1% and 2% ciclosporin and their corresponding placebo without copolymer were evaluated for eye irritation by a methodology recommended by the ETAD toxicology committee.

Eye drops were tested on 6 New Zealand White rabbits each. The animals were of conventional quality weighing 2.19 to 4.62 kg corresponding to their age. Rabbits were housed individually in metal cages and acclimatized to vivarium conditions (temperature 22 + 2 ° C, relative air humidity 50 to 70%). The rabbits were fed a standard KKK / L feed and drinking water ad libitum.

The eye drops were applied in a single dose of 50 gl to each eye, divided into two successive portions of 25 μΙ. Eye condition (conjunctiva, cornea, iris and tear production) was monitored before and 24, 48 and 72 hours after application. A commercially available fluorescein solution under blue spot lighting was used to examine the cornea. After 24 hours, saline was applied to the eyes in the same manner and in the same amount. Changes in the conjunctiva, cornea, iris and tear production were evaluated according to the scheme given in Table I. The cumulative values of changes observed at 24, 48 and 72 hours in all 6 rabbits are as follows:

1% eye ί drops 2% eye drops agent placebo agent placebo Corneal changes [A x B x 51 0 0 0 0 Changes on the iris [A x 51 0 0 0 0 Changes to the conjunctiva [A of b of C] x 2 32 10 16 0 Final degree of irritation 1.78 0.56 0.89 0 Final report irritate irritate irritate irritate

Σ changes in cornea, iris and conjunctiva Result of irritation ---- [3x6]

Irritation classification: final grade 0 to 10 to 25 to 56 57 to 110 does not irritate easily irritating slightly irritating strongly irritating

Example 2

Eye drops A B (placebo)

Cidosporin 2,000 g 2,000 g PPG-51 / SMDI copolymer 2,000 g Decaglyceryl pentaoleate 5,000 g 5,000 g Tocopheryl linoleate 0,700 g 0,700 g Corn oil to 100,000 ml to 100,000 ml

The preparations were evaluated for tolerability at 19 days in dogs according to the described methodology with histopathological examination and the penetration of ciclosporin into ocular tissues was evaluated.

Ten Beagle dogs, 12-16 months old, were used in the experiment. The dogs were treated at regular intervals. They were treated with Canvac, Dohyvac-Parvo and Lyscelin during the respective period.

Animals were housed individually in pens of 0.9 x 1.0 m under conventional conditions. They were fed a standard Ro XIII pelleted diet at a daily dose of 300 g per dog. Drinking water was available to dogs ad libitum.

Test Preparations - According to Example 2, were applied four times a day to 5 dogs (test group) at 2-hour intervals on the cornea of each eye one drop by dropper from a standard package. After dropping, the corneal was spread by gently closing the lids. The control group (S dogs) received the same placebo. Both preparations were applied for 19 consecutive days. Ophthalmologic examinations were performed before and at the end of the application period. Eye tolerance was again assessed according to the scheme in Table 1, daily prior to the first application. The presence and magnitude of eventual corneal opacification (grade 0 to 4), iris irritation and condition (grade 0 to 2), conjunctival redness or swelling (grade 0 to 4), and secretion (grade 0 to 3) were assessed. Variants A and B were classified as non-irritant.

Two dogs were used for histopathological examination and 1 drop of the preparation of Example 2 was applied 4 times a day to the conjunctival sac of both eyes. In addition, the control dog was treated with placebo in the same manner. The experiment lasted 19 days.

One hour after the last administration, the dogs were sacrificed by bleeding under thiopental anesthesia. The eyeballs were carefully removed from the orbit and fixed in a 10% neutral form. A sharp razor blade was made through each eye with a incision that went from the optic nerve entrance to the corneal edge. A lamella with a width of about 8 mm containing the cornea, pupil, lens and optic nerve was then obtained from the larger eye segment. In addition to the eyeball, the tear gland was always removed from the outer orbit.

Histological preparations were made using standard paraffin technique, cut in thickness of about 6 gm and stained with hematoxylin-eosin, PAS method for mucopolysaccharides, cresyl violet, alcian blue, Van Gieson method and Halle-Muller technique.

In the histotopograms of both eye bulbs of the control dog or in both dogs treated with the preparation according to embodiment no. 2 no deviations were found in any ocular structure (cornea, belima, conjunctiva, choroid, retina, ciliary body, iris, lens, anterior and posterior ocular chambers, optic nerve, cross-sectional areas of the ocular muscles and peribulbar mesh). Neither the conjunctiva lining the posterior surface of the upper eyelid nor the lacrimal gland was changed.

Penetration into eye tissues

Groups of 4 Beagle dogs aged 12 to 16 months were used in the experiment. Three of them were administered to both eyes formulation A or B according to Example 2, specifically labeled with tritiated ciclosporin with an activity of 2 mCi / ml in an amount of 0.03 ml. The application was performed 4 times a day at two-hour intervals for two days, on the third day the preparation was applied 3 times. A total of 11 applications were performed. A fourth dog received the formulation of Example 2 at the same amount and frequency without specific labeling.

An hour after the last administration, the dogs were sacrificed by bleeding from large cervical vessels under thiopental anesthesia. Then both eyes were removed, including the conjunctiva and tear glands. The right eyes of all 4 dogs were sealed with 2% carboxymethylcellulose gel and frozen in a mixture of n-hexane and dry ice for autoradiographic examination. Samples of 25% of the individual tissues were taken from the left eyes, weighed and then dissolved in 1 ml of 25% KOH in 20% ethanol. Radioactivity measurements were performed on a Wallac Rackbet liquid scintillation spectrophotometer. Activity values (dpm) were calculated per ng of administered substance / g tissue.

A B

Avg. horses. (n = 3) Direction. Outgoing. Avg. horses. (n = 3) Direction. Outgoing. cornea 15,743.4 ± 2730.2 5,100.2 ± 1474.1 conjunctiva 4350,2. ± 192.3 750.0 ± 97.7 iris 633.5 ± 62.2 120.9 ± 44.5 Tear gland 146.6 ± 44.1 30.8 ± 23.0 Chamber water 62.0 ± 7.9 11.7 ± 3.4

In the vitreous, lens, belime and retina, the observed ciclosporin values were at background level.

Example 3

Eye drops A B

ciclosporin 2,00 g 2,00 g PPG-51 / SMDI copolymer 1,00 g Diglyceryl monooleate 4,00 g 5,00 g Corn oil up to 100,00 ml up to 100,00 ml

Both formulations were labeled with tritiated ciclosporin at a dose of 1 mBq / mg of active ingredient. Both preparations were administered to a group of 6 rabbits weighing 3 to 3.5 kg consisting of 3 males (M) and 3 females (F). Formulation A was instilled into the left eye always onto the cornea (not into the conjunctival sac).

The application was carried out every 15 minutes for 3 hours (12 applications in total) in the amount of 15 μΐ of the preparation using a micropipette (total 3.6 mg ciclosporin). 15 minutes after the last administration, the animals were sacrificed, the aqueous humor was removed from all eyes and the cornea, iris and uvea were dissected.

Tissue samples were weighed and adjusted to measure radioactivity on a Wallac Rackbet liquid scintillation spectrometer. Activity values (dpm) were converted to ng ciclosporin / g tissue concentrations.

The mean tissue concentration values of ciclosporin (n = 6) for both formulations are as follows:

A B cornea 14246.1 ng / g 5832.1 ng / g iris 915.9 ng / g 174.8 ng / g Chamber water 293.1 ng / g 57.8 ng / g uvea 107.4 ng / g ²⁰ · ³

Example 4

Eye ointment

[Nva] ² - ciclosporin 0.50 g PPG-51 / SMDI copolymer 2,00 g RRR-alpha-tocopherol 0.40 g Hydrogen castor oil 26.9 g (CUTINA® HR by HENKEL) Castor oil 70,00 g

The tocopherol, the copolymer and the active substance are dissolved at 60 ° C to a sterilized mixture of castor oil and hydrogenated oil. It is filtered hot under aseptic conditions and filled into a tube with an ophthalmic applicator.

Example 5

Eye drops

sirolimus 0.50 g PPG-12 / SMDI copolymer 1,00 g Sorbitan trioleate 2,00 g Askorbyl palmitate 0,02 g Soybean oil up to 100,00 ml

The prepared solution is filtered through a septum with 0.2 gm separation and filled into glass vials with an ophthalmic applicator.

Example 6

Eye drops

dexamethasone 0.100 g PEG-8 / SDMI copolymer 6,000 g PEG-50 stearate 5,000 g (Myrj® 53 by ICI) K ₂ HPO ₄ 0.061 g NaOH 0.1 M solution qs pH 6.9 Phenylethyl alcohol 0,300 g Sterile water up to 100,00 ml

The prepared solution is filtered through a 0.2 gm filter septum and filled into polyethylene containers with an ophthalmic applicator.

Industrial usability

The invention finds application in the pharmaceutical industry in the manufacture of topical ophthalmic preparations. The compositions of the invention are characterized by a high penetration of immunosuppressive drugs into the ocular tissues and a very good tolerability.

Claims (4)

PATENT CLAIMS Medicinal preparations for topical ocular administration, characterized in that they consist of 0.02 to 5.0% by weight of immunosuppressive drugs dissolved or dispersed in a physiologically acceptable vehicle containing up to 10% by weight of polyalkylene glycol-polyurethane copolymers of the formula I ROO ^R HO - (- CH-CH-Ο- a) _N - [CN ₂ -CH ^ ^ - ^ ^ -NC - (- O-CH ₂ -CH-) _n -O-] -H in which n = 8-51 m is predominantly 1 to 4 and R is CH 3 or hydrogen, optionally together with other excipients customary in topical dosage forms. Formulations according to claim 1, characterized in that, when using a hydrophilic vehicle, the polyalkylene glycol-polyurethane copolymers are poly (oxy-1,2-ethanediyl) -α-hydro-m-hydroxypolymers α1,1'-methylene-bis- (4- isocyanate cyclohexane) having an average molecular weight of 1000 to 3000. Formulations according to claim 1, characterized in that, when the lipophilic vehicle is used, the polyalkylene glycol-polyurethane copolymers are poly [oxy (methyl-1,2-ethanediyl)] -? -Hydroxyhydroxypolymers α1,1'-methylene-bis- (4 (isocyanate-cyclohexane) having an average molecular weight of 1600 to 18,000. Formulations according to claims 1 to 3, characterized in that they contain as immunosuppressive medicaments medicaments belonging to the groups of monocyclic undecapeptides or macrolide lactones or corticosteroids, used either singly or in mutually arbitrary mixtures. Formulations according to claims 1 to 4, characterized in that they contain, as immunosuppressive drugs, ciclosporin and / or [Nva] ² -ciclosporin in an amount of 0.1 to 3.0% by weight and / or tacrolimus and / or sirolimus in an amount of 0 % To about 2.0% by weight and / or dexamethasone and / or prednisolone in an amount of 0.02 to 1.0% by weight.