Field of the invention

The invention relates to latonoprost for use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure, systems for systemic (periphery, extraocular), continuous, subcutaneous or transdermal administration of latanoprost to reduce intraocular pressure and the new pharmaceutical form of the latonoprost.

State of the art

Latanoprost is a drug used in medicine to lower the intraocular pressure in patients with chronic glaucoma.

Intraocular pressure is the pressure inside the eye. Measurement of intraocular pressure is an elementary diagnostic method frequently used in ophthalmology. Apart from patient’s age, long-term increase of intraocular pressure, known as ocular hypertension, is the main risk factor of chronic glaucoma, known as primary open-angle glaucoma. I n the course of this disease retinal ganglion cells and their axons forming the optic nerve are progressively dying out, leading to irreversible total loss of vision. It is estimated that the number of patients with primary open angle glaucoma at risk of vision loss will amount to over 65 million throughout the world in 2020 (Kapetanakis W, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol. 2016;100:86-93).

In primary open-angle glaucoma reduction of intraocular pressure is the only way to stop or slow down retinal and optic nerve damage, thereby maintaining efficient patient’s vision. Known pharmacological methods for lowering the intraocular pressure consist in administration to the conjunctival sac of eye drops containing agents lowering intraocular pressure. Currently, eye drops with prostaglandin F2alpha (PGF2a) derivatives are the first-line treatment. Eye drops with one of four such derivatives are available on the market: latanoprost, travoprost and tafluprost that are esters, or bimatoprost that is an amide. These include reference medicines and numerous forms of generic drugs and variants that differ in the content and/or type of excipients, such as preservatives and additives needed to increase solubility.

Of the four PGF2a derivatives used in clinical practice, latanoprost is the most frequently administered. This substance is the prodrug exhibiting low pharmacological activity, activated by hydrolysis to latanoprost acid. When eye drops with latanoprost are administered to the conjunctival sac, deposit of this prodrug is formed in the cornea and its slow activation by enzymatic hydrolysis occurs. Latanoprost acid, active form of this drug, interacts with prostanoid FP receptors in ocular tissues (Sjoquist B, Basu S, Byding P, Bergh K, Stjernschantz J. The pharmacokinetics of a new antiglaucoma drug, latanoprost, in the rabbit. Drug Metab Dispos 1998;26:745-54). Reduction of intraocular pressure results from increased outflow of aqueous humour from eye anterior chamber to blood, while the production rate of aqueous humour remains the same (Dinslage S, Hueber A, Diestelhorst M, Krieglstein G. The influence of Latanoprost 0.005% on aqueous humour flow and outflow facility in glaucoma patients: a double-masked placebo-controlled clinical study. Graefes Arch Clin Exp Ophthalmol. 2004; 242:654-660). PGF2a derivatives, in particular latanoprost, used in the form of eye drops, are considered almost perfect drugs intended for lowering intraocular pressure. No accumulation in the organism even with long-term administration and no systemic side effects are their main advantages. It should be noted that daily dose of latanoprost administered as eye drops into the conjunctival sac amounts to approx. 1.5 pg, but latanoprost does not show toxicity also when administered systemically at significantly higher doses. According to Pfizer, manufacturer of Xalatan, a reference drug containing latanoprost, LD ₅ o (median lethal dose that will cause death of 50% of study animals after single administration) of latanoprost amounts to more than 2 mg/kg in case of a rat. Oral administration of a daily dose of 0.2 mg/kg for 2 years to rats and intravenous administration of a daily dose of 1 pg/kg for 13 weeks to dogs do not cause any noticeable harmful effects (www.pfizer.com/files/products/ material safety data/ LATANOPROST%2QSOLUTION.pdf).

Administration of prostaglandin analogues in form of eye drops has, however, significant disadvantages and limitations. First of all, it should be noted that in order to reduce intraocular pressure and prevent or slow down progression of glaucoma eye drops containing lipophilic prostaglandin F2a analogues have to be applied every day for the rest of patient’s life; and taking of eye drops for such a long time is inconvenient and difficult to adhere to, and often practically impossible. Meta-analysis of studies assessing compliance with medical orders in the treatment of glaucoma has shown that the majority of patients are unable to chronically administer eye drops that lower intraocular pressure (Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension, an evidence-based review. Ophthalmology 2005; 112:953-961 ). Newer study revealed that already in the first year of treatment only less than half of patients with chronic glaucoma adhered to a medical order to administer eye drops every day (Belhassen M, Laforest L, Licaj I, Van Ganse E. Early adherence to anti-glaucoma therapy: An observational study. Therapie 2016; 71 :491-499). In younger patients failure to adhere to medical orders related to daily administration of eye drops may be mainly of psychological nature, but older patients are simply not able to administer the medicine on their own due to health reasons, such as hand tremors.

Furthermore, long-term use of eye drops with PGF2a derivatives leads to burdensome local side effects that discourage and often prevent continuation of therapy. These include conjunctival hyperaemia, dry eyes and eye surface damage. Although latanoprost-containing eye drops are better tolerated than eye drops with other PGF2a derivatives (Aim A. Latanoprost in the treatment of glaucoma. Clin Ophthalmol. 2014;8:1967-1985), studies reveal that exposure of ocular tissues to latanoprost damages corneal stromal cells (Shen JW, Shan M, Peng YY, Fan TJ. Cytotoxic effect of latanoprost on human corneal stromal cells in vitro and its possible mechanisms. Curr Eye Res 2017; 42:534-541 ). Other studies show that long-term local use of latanoprost-containing eye drops leads to changes in eyeball share and formation of the so-called keratoconus (Honda N, Miyai T, Nejima R, Miyata K, Mimura T, Usui T, Aihara M, Araie M, Amano S. Effect of latanoprost on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 on the ocular surface. Arch Ophthalmol. 2010;128:466-471 ).

As mentioned above, latanoprost is a prodrug that needs to be activated by transformation to acidic form. It is believed that such activation is catalysed by an esterase present in the cornea, leading to an increase in the concentration of the active form (acid) in the aqueous humour in the eye anterior chamber and ocular tissues. After topical administration of eye drops latanoprost is supposed to increase outflow of aqueous humour to the blood, reaching FP receptors in the eye that are responsible for this effect from thecornea’s side. Studies in healthy volunteers showed that bulk (from 77% to 88%) of latanoprost dose administered to the eye surface is absorbed into the blood, where 90% of the drug binds to plasma albumins, but plasma half-live of latanoprost is then equal only to 17 minutes (Sjoquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol. 2002; 47, Suppl 1 :S6- 12). Therefore it is believed that latanoprost absorbed into blood after being administered to the conjunctival sac is so rapidly metabolised and eliminated from the organism that it has no impact on pharmacodynamic effect of lowering the intraocular pressure. For the above reasons, it is believed that in order to achieve a pharmacodynamic effect, i.e. lowered intraocular pressure, latanoprost has to be administered to eye surface adjacent to the cornea, or possibly subconjunctivally, or to the anterior eye chamber. Importantly, for this reason no studies on systemic administration of latanoprost in order to decrease intraocular pressure have been conducted.

Solutions known from the prior art, related to administration of lipophilic PGF2a prostaglandin analogues to lower intraocular pressure, developed in order to increase patients’ tolerability of long-term treatment of glaucoma and improve adherence to therapy, , are focused on pharmaceutical forms that increase duration of action of medicine administered topically. This effect is achieved using systems for topical administration of a drug on eye surface, into eye area or directly into eyeball. Contact lenses delivering latanoprost to corneal surface or bioresorbable polymer implants containing latanoprost implanted into anterior chamber and release it into aqueous humour are examples of systems used for long-term administration of this substance (Aref AA. Sustained drug delivery for glaucoma: current data and future trends. Curr Opin Ophthalmol 2017;28:169-174). Subconjunctival implantation of latanoprost-containing liposomes undergoing slow biodegradation which results in continuous delivery of latanoprpost to the eye surface is a solution that makes it possible to reduce intraocular pressure in a long-term perspective and avoid daily administration of eye drops (Natarajan JV, Ang M, Darwitan A, Chattopadhyay S, Wong TT, Venkatraman SS. Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye. Int J Nanomedicine 2012;7:123-31 ).

Taking into account prior art, it should be concluded that route of administration of lipophilic esters of PGF2alpha prostaglandin analogues other than their local administration into the eye area is unknown in treatment of ocular hypertension and chronic glaucoma. Moreover, no pharmaceutical forms of drugs intended for reduction of intraocular pressure are known that could be used to administer lipophilic esters of PGF2a derivatives, such as latanoprost, systemically in a continuous, subcutaneous or transdermal manner. In particular, systems for systemic administration of latanoprost in form of transdermal patches or biodegradable implants implanted under the skin in areas distant from eyeball, for example on the surface of the abdomen or forearm, are not currently known.

Detailed description of the invention

The invention relates to new pharmaceutical forms of latanoprost for use in prevention and/or treatment of chronically elevated intraocular pressure and its consequences, such as primary open-angle glaucoma, i.e. systems for continuous, systemic (extraocular) administration of latanoprost subcutaneously or transdermally.

The invention relates to latanoprost for use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure, wherein latanoprost is in the form suitable for systemic, subcutaneous or transdermal administration and is administered extraocularly, systemically subcutaneously or transdermally in order to reduce intraocular pressure.

Preferably, latanoprost for use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure is in the form for subcutaneous administration, which is selected from microspheres resin comprising drug, biodegradable sustained-release polymer comprising drug, subcutaneous implant of biodegradable polymer comprising drug , liposomes comprising latanoprost for subcutaneous administration, the micropump implantable subcutaneously.

Preferably, latanoprost for use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure for transdermal administration is in the form of transdermal patch.

Preferably, latanoprost for use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure for use in the treatment of diseases associated with chronically elevated intraocular pressure selected from ocular hypertension, chronic glaucoma.

Latanoprost in the preferred use in the treatment and/or prevention of diseases associated with chronically elevated intraocular pressure is released at a daily dose of no more than 45 pg into human organism.

The invention also relates to a system comprising latanoprost, wherein the system is in the form suitable for systemic, extraocular, continuous, subcutaneous or transdermal administration of latanoprost for use in the treatment and/or prevention of diseases associated with elevated intraocular pressure in order to reduce intraocular pressure.

Preferred system for said use is in the form for subcutaneous administration of the latanoprost and is selected from microspheres comprising drug made of a biodegradable sustained-release polymer, subcutaneous implant of biodegradable polymer comprising drug, liposomes comprising latanoprost for subcutaneous administration, micropump implantable subcutaneously.

The preferred system for said use is in the form for transdermal administration of the latanoprost and is in the form of a transdermal patch.

The preferred system for said use is for use in diseases associated with chronically elevated intraocular pressure, i.e. ocular hypertension, chronic glaucoma.

The preferred system for said use releases latanoprost dose of no more than 45 pg into human organism throughout one day. The invention also relates to new pharmaceutical forms of latanoprost for use in the prevention and/or treatment of chronically elevated intraocular pressure and consequences thereof, which is primary open-angle glaucoma, chronic glaucoma there is the system for systemically continuous subcutaneous administration of latanoprost in the form of the system for latanoprost administration to a human in a continuous manner, systemically, subcutaneously or transdermally. which release latanoprost dose of no more than 45 pg into human organism throughout a day.

The preferred pharmaceutical form of latanoprost is the system for subcutaneous administration which is selected from - microspheres comprising drug biodegradable sustained- release polymer, subcutaneous implant of biodegradable polymer comprising drug , liposomes comprising latanoprost for subcutaneous administration, a micropump implantable subcutaneously.

The preferred system for latanoprost administration is the system for transdermal administration in the form of a transdermal patch for administration of latanoprost.

The preferred pharmaceutical form of latanoprost for latanoprost administration is the system for continuous subcutaneous administration of latanoprost which is selected from a microspheres resin comprising latanoprost made of biodegradable sustained-release polymer, the subcutaneous implant of biodegradable polymer comprising latanoprost, liposomes comprising latanoprost- for subcutaneous administration, micropump implantable subcutaneously that releases latanoprost in a continuous manner.

The preferred pharmaceutical form of latanoprost for latanoprost administration is the system for subcutaneous continuous administration of latanoprost in the form of a transdermal patch.

The inventors have conducted experiments consisting in single administration of 20 pl _¬ ot Xalatan (Pfizer) or Monoprost (Thea) solution with 0.02% of latanoprost into the conjunctival sac of one eye of unanaesthetized rats previously habituated (accustomed) to intraocular pressure measurements performed using a rebound tonometer. Afterwards, intraocular pressure in both eyes was measured at hourly intervals. An anticipated reaction, which consisted in reduced intraocular pressure, was noted in an eye to which eye drops were administered. Surprisingly, it turned out that a comparable decrease of intraocular pressure takes place in an eye opposite to the one which received eye drops (Fig. 1 ). The phenomenon of lowering intraocular pressure in both eyes after one-side administration of latanoprost-containing eye drops proves that the effect of lowering intraocular pressure in an observed eye can be induced by administering latanoprost-containing drop in area other than conjunctival sac of this eye. In further experiments inventors revealed that the effect of lowering intraocular pressure in both eyes occurs after subcutaneous injection of latanoprost-containing eye drops in an area distant from eyeballs, i.e. under the skin on torso’s side. A comparable effect of lowering intraocular pressure is also achieved after application of latanoprost-containing eye drops on skin surface in an area distant from eyeballs, i.e. on the back.

Lowering of intraocular pressure by means of subcutaneous or epidermal administration of lipophilic prostaglandin F2alpha derivative, i.e. latanoprost, in an area distant from an eye would be a substantial progress in the treatment of ocular hypertension and chronic glaucoma, making it possible to avoid administration of the medicine into the conjunctival sac or other ocular areas which are particularly sensitive. However, such ways of lowering intraocular pressure would not eliminate burdensome need to administer the drug every day.

In search of preferable and patient-friendly solution that would eliminate the need to administer PGF2a derivative ester every day, the inventors conducted experiments involving continuous systemic subcutaneous administration of lipophilic prostaglandin F2 alpha derivatives using miniature osmotic pumps implanted under the skin on the back and making intraocular pressure measurements in subsequent days. Subcutaneous drug administration using a miniature osmotic pump is a model of continuous drugs administration from a reservoir placed under the skin, and if a drug is lipophilic and penetrates through the skin, this experimental design is also a model of continuous drug administration on skin surface using a patch. The experimental design used and the results obtained are discussed in detail below as the first embodiment of the solution according to this application.

The inventors have investigated the effect of continuous, systemic, extraocular administration of lipophilic F2a prostaglandin derivatives other than latanoprost, i.e. travoprost, tafluprost and bimatoprost, on intraocular pressure using miniature osmotic pumps implanted under the skin on rats’ backs based on measurements of intraocular pressure in subsequent days. Intraocular pressure was lowered only if latanoprost was administered systemically and extraocularly.

Based on the results of the said experiments, this application discloses new pharmaceutical forms of latanoprost the application of which is at least equally effective in reducing intraocular pressure but at the same time is devoid of disadvantages of known pharmaceutical forms of this drug which are administered locally on an eye, into an eye or to eye area. Systems for systemic, continuous, subcutaneous or transdermal administration of latanoprost, such as subcutaneous implants made of biodegradable polymer or transdermal patches are examples of these pharmaceutical forms. Systemic administration of latanoprost using the system according to the invention makes it possible to overcome said drawbacks that are associated with the use of the previously known pharmaceutical forms of latanoprost. First of all, both latanoprost-comprising transdermal patches and biodegradable implants implanted subcutaneously ensure continuous administration of the drug into the patient’s organism despite the fact that the drug administration system is not administrated every day (in contrast to eye drops) but much less frequently, for example twice or once a week (a patch) or once a month or once in three months (a polymer implanted transdermally). Substantially less frequent dosing will improve therapy adherence and continuous administration of the drug will ensure better control of intraocular pressure. This is of particular importance not only in younger patients who, for psychological reasons, may not regularly administer eye drops into the conjunctival sac every day for longer periods of time, but especially in older patients who are not able to administer eye drops on their own due to their health condition. Methods of systemic administration of latanoprost will decrease the proportion of patients with chronic glaucoma who do not adhere to medical advice, improving the efficacy of chronic glaucoma treatment. Second, subcutaneous implantation of a polymer carrier with the drug or placing a patch on the skin in an area distant from an eye will make it possible to avoid manipulation in the close area of the eyeball needed if solutions based on implantation of bioresorbable preparations containing PGF2alpha prostaglandin analogues into anterior chamber or contact lenses with the drug are used. Third, it is possible to avoid adverse effects caused by long-term administration of latanoprost to the eye or to the eye’s surface, e.g. hyperemic conjunctiva, dry eye syndrome, ocular surface damage, etc.

Publication cited herein and references provided therein are also listed as references.

Brief description of the drawings

For a better understanding of the invention, it has been illustrated in the embodiments and drawings that

Fig. 1. shows changes of intraocular pressure (IOP) in both eyes after one-sided administration of eye drops containing latanoprost into the conjunctival sac of one eye. Each point is the mean value of the results of experiments conducted in 7 animals. A - effects of administration of Xalatan (Pfizer), B - effects of administration of Monoprost (Thea). Full lines link pressure measurement results in an eye to which a drop was administered, whereas broken lines link results for the second eye to which no drug was administered. In all cases changes were time-dependent (according to the ANOVA statistical test the probability of the accidental nature of the relationship is P<0.0001 ). The dotted line links the results obtained in parallel experiments after administration of solvent for Xalatan (Pfizer) into an eye; in this case changes of intraocular pressure over time are not statistically significant (P>0.05).

Fig. 2. shows a diagram illustrating the location of system 1 used to administer latanoprost in the form of a miniature osmotic pump Alzet placed under the skin of rat’s back for systemic drug administration.

Fig. 3. presents the results of intraocular pressure (IOP) measurements taken once a day at the same time just before and after placing a miniature osmotic pump 1 Alzet under skin on the back that administers a solution containing lipophilic PGF2alpha derivative subcutaneously for 7 consecutive days. Individual points are average values obtained in 5 experiments. According to the ANOVA statistical test, the probability of the accidental character of the relationship of intraocular pressure and time is statistically significant (not accidental) only after administration of latanoprost (P<0.0001 ); in case of other drugs it is P>0.05.

Fig. 4. presents the results of intraocular pressure (IOP) measurements taken once a day at the same time just before and after placing a miniature osmotic pump 1 Alzet under back’s skin that administers a solution containing latanoprost (Xalatan, Pfizer, thicker line) or a solvent (thinner line) subcutaneously for 7 consecutive days. Each point is an average value obtained in measurements performed in 5 animals. According to the ANOVA statistical test, the probability of the accidental character of the relationship of intraocular pressure and time is P<0.001 for latanoprost and P> 0.05 for the solvent.

Embodiments of the invention

The following examples are given only to illustrate the invention and to explain its particular aspects, and not to limit it. They should not be equated with its entire scope that was defined in the below claims.

Unless otherwise indicated, in the following examples materials and methods typical of the field were used or manufacturer’s instructions for specific materials and methods were followed.

Example 1. Effect of systemic continuous administration of latanoprost subcutaneously on intraocular pressure in rat

Experiments were performed on Wistar rats with body weight of approx. 300 g habituated (accustomed) to intraocular pressure measurements performed using a rebound tonometer intended for studies on rodents. On day 0, after intraocular pressure measurement, system 1 for continuous administration in form of Alzet pump with a capacity of 200 pl_ and administration time of 7 days was filled with a solution of eye drops containing 50 pg/mL of latanoprost (Xalatan, Pfizer or Monoprost, Thea), 15 pg/mL of tafluprost (Taflotan, Santen), 40 pg/mL of travoprost (Travatan, Novartis) or 0.3 mg/mL of bimatoprost (Lumigan, Allergan). Alzet pumps filled with the drug were placed under the skin on animals’ back between 12p.m. and 1 p.m. as shown on Fig. 2. Afterwards, for 10 consecutive days, animals had their intraocular pressure measured once a day at the same time between 12 p.m. and 1 p.m. The one-way ANOVA test and Dunnett’s post hoc test were used in statistical analysis.

Results are shown on Fig. 3. Implantation of an osmotic pump 1 administering latanoprost at a dose of 1.0 mI_ per hour resulted in a decrease in intraocular pressure noticeable already after the first day of drug administration and reaching its maximum intensity after 4 days. Pressure returned to control values 3 days after drug discontinuation. Unexpectedly, it turned out that a comparable effect of reduced intraocular pressure was not achieved after systemic continuous administration of equivalent doses of eye drops containing the other two lipophilic esters of PGF2alpha derivatives used to treat glaucoma, i.e. travoprost and tafluprost, and the effect of systemic continuous administration PGF2alpha derivative amide, i.e. bimatoprost, was also significantly weaker.

In order to exclude the possibility that the intraocular pressure is decreased due to continuous systemic administration of additives present in latanoprost-containing eye drops in the next experiment the effect of Xalatan (Pfizer) eye drops and a solvent used to solubilize latanoprost in this pharmaceutical form have been compared. The results of this experiment shown in Fig. 4 excluded such possibility.

In the said experiments daily dose of latanoprost administered to a rat in a continuous manner was 4 pg/kg. In accordance with generally adopted rules (Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016,7:27- 31 ) in order to calculate human equivalent dose (HED), a dose for a rat (expressed in micrograms per kilogram of body weight) should be divided by 6.2, then multiplied by the average human body weight, which is usually equal to 70 kg. Predicted dose of latanoprost the continuous systemic administration of which will result in a significant decrease in intraocular pressure in humans amounts to 45 pg/24 hours. Such dose of latanoprost can be conveniently administered using system 1 for administration of latanoprost in the form of a transdermal patch once or twice per week. Taking into account that lipophilicity of latanoprost is similar to lipophilicity of estradiol (partition coefficient octanol/water logP for both substances amounts approx to 4), a solution described in patent US 8,231 ,906 (Mantelle) for estradiol or other similar solutions known from prior art intended for transdermal administration of lipophilic drugs using patches can be used for this purpose. Example 2. Preparation of a transdermal patch for systemic administration of latanoprost

A transdermal patch (transdermal therapeutic system) for systemic administration of lipophilic prostaglandin F2alpha analogues (PGF2alpha), e.g. latanoprost in order to decrease intraocular pressure have been prepared. This transdermal patch is for delivering the active substance at a constant rate though skin over a given period of time. In order to ensure constant release rate over given period of time, the transdermal patch consists basically of an outer impermeable layer and a reservoir with the active substance. The membrane system consists also of a membrane that controls release of the active substance and makes it possible to place a patch on the skin, whereas the matrix system is placed directly on the skin without additional membrane. Patches available on the market also have a removable protective layer attached to the adhesive part of the patch.

The transdermal patch made according to the invention consists of a matrix reservoir of the active substance which contains latanoprost at 10% w/w in a mixture of crosslinked polymer: hydroxypropyl methylcellulose (HMPC), binding agent: polyvinyl pyrrolidone (PVP), plasticizer: propylene glycol and permeation modifier: DMSO. The patch was made using solvent evaporation technology, which consists in spreading a mixture of excipients and the active substance on the surface of glass Petri dish and forming solid patch though slow evaporation of a solvent at room temperature for 12 hours. The resulting patch is smooth, flexible, homogeneous and does not brittle during use.

The literature and experiments made it possible to determine an optimal qualitative and quantitative composition of a matrix mixture in the following proportions:

1.5 g of HMPC

0.5 of PVP

5% propylene glycol

6% DMSO

Water : methanol 3:1

That is why patches placed on the skin constant rate deliver microgram amounts of latanoprost to the blood for several dozen days. The determination of the amount of latanoprost delivered over a given period of time is within competences of an expert in the field and is based on the relationship matrix type/latanoprost concentration in the matrix/surface of patch used.

Example 3. Preparation of microspheres for systemic administration of latanoprost

A system 1 for administration of latanoprost in form of microspheres consisting of D,L- lactide and epsilon-caprolactone copolymer, containing 20% of latanoprost, have been prepared according to the method described in Buntner B, Nowak M, Kasperczyk J, Ryba M, Grieb P, Walski M, Dobrzynski P, Bero M. The application of microspheres from the copolymers of lactide and epsilon- caprolactone to the controlled release of steroids. J Control Release 1998;56: 159- 67. Said microspheres contain latanoprost instead of beta-estradiol. Such microspheres implanted subcutaneously will exhibit comparable kinetics of drug delivery to the blood, because physicochemical properties of latanoprost, molecular weight in particular, are similar to physicochemical properties of systemically active steroid hormones, such as 17beta-estradiol. That is why after being implanted under the skin they deliver micrograms of latanoprost in a continuous manner for several dozen days. Example 4. Preparation of implants for systemic administration of latanoprost

Implant based on lactide-glycolide copolymer

Long-acting (depot) implants based on lactide-glycolide copolymer for subcutaneous administration have been made using a typical technology based on lactide-glycolide copolymer containing latanoprost. In this way, system 1 for administration of latanoprost was developed. The implant were developed with the use of known dry extrusion method from poly(D,L-lactide-co- glycolide) polymer by blending poly(D,L-lactide-co-glycolide) polymer (D,L-lactide/glycolide molar ratio: 54/51 to 46/49% mol) with latanoprost solution in a ball mill. The resulting mixture was then extruded through a 1 mm diameter nozzle using a screw extruder. The resulting extrudates containing prostaglandin F2alpha (PGF2alpha) analogues (theoretical core filling 30% w/w) were cut into implants of specific length and sterilised by gamma irradiation. The implant is completely biodegradable.