WO2001095913A1

WO2001095913A1 - Methods and compositions for the prevention of myopia

Info

Publication number: WO2001095913A1
Application number: PCT/SE2001/001339
Authority: WO
Inventors: Johan Stjernschantz; Bahram Resul
Original assignee: Synphora Ab
Priority date: 2000-06-13
Filing date: 2001-06-13
Publication date: 2001-12-20
Also published as: SE0002211D0; AU2001264522A1

Abstract

Exogenous prostaglandins and derivatives of prostaglandins as well as anti-inflammatory agents blocking prostaglandin synthesis are disclosed as useful for the prevention of the development of myopia. The prostaglandins should preferentially be administered topically on the eye, whereas the anti-inflammatory agents may be administered topically on the eye or orally. The administration may be continuous or intermittent.

Description

METHODS AND COMPOSITIONS FOR THE PREVENTION OF MYOPIA

The present invention concerns the field of ophthalmic medicine, the pharmacological treatment of myopia, and in particular novel methods and compositions for the treatment and/or prevention of myopia.

Background of the invention

Myopia, or nearsightedness, is a condition characterized by incorrect refractive power of the eye to focus the visual object on the retina. The most common form of nearsightedness is axial myopia, which is due to an excessive growth of the eye. Axial myopia is a very common condition with a prevalence of up to 20-30%, being particularly common in the Asian population, e.g. amongst Chinese and Japanese. Myopia can be corrected by negative glasses or contact lenses or by excimer laser re-shaping of the cornea. While the myopic refractive error usually can be adequately corrected, high degree myopia may be associated with serious complications such as retinal detachment, choroidal atrophy vitreous degeneration and low tension glaucoma.

The mechanism controlling the growth of the eye is poorly known, but recent research indicate that the role of the retina may in fact be important. However, it is not known in which way the retina controls the growth of the sclera, the outermost tunic of the eye. Several animal models of axial myopia have been established, and one of the most common models is form deprivation myopia of the chick. If the chick eye is covered by a translucent occluder for 1-2 weeks, there is a substantial enlargement of the eye, including an increase in the axial length. Consequently myopia follows. However, it should be emphasised that the chick eye differs anatomically in many respects from the primate and human eye; the sclera in the chick consists of two layers, an inner cartilaginous and an outer fibrous layer while the human sclera consists only of a fibrous layer. The sclera of the chick eye also contains ossicles, which the human eye does not. There are also other anatomical differences between the avian and the human eye. However, in spite of these differences the chick eye is usually regarded as an adequate model for myopia studies. Suturing the lids e.g. in new-born primates induces myopia in a similar way. Prior art

While it is rather well accepted that the retina controls the growth of the sclera, the underlying mediators for the growth are largely unknown. Atropine, a muscarinic cholinergic antagonist, has been shown to retard the development of myopia in many animal species and in man, and in addition endogenous transmitter substances such as dopamine and vasoactive intestinal polypeptide (NIP) may be important in the retinal control of eye growth. Information about experimental models of axial myopia and various transmitters that may be of importance in the control of eye growth can be found in different review articles e.g. Edwards (1996).

In addition to this, Stone, R. A. et al. (WO89/11854) have presented a method for inhibiting abnormal axial growth of the eye of a maturing mammal, comprising determining the concentration of a neurochemical, e.g. dopamine in the retina of said eye and administering effective amounts of said neurochemical, its agonist or its antagonist.

Summary of the invention

The present invention makes available methods and compositions for the pharmacological treatment of myopia, and in particular novel methods and compositions for the treatment and/or prevention of myopia according to the attached claims, which are hereby incorporated in their entirety.

Description of the invention

The present inventors have unexpectedly found that prostaglandins, and in particular prostaglandin F_2α (PGF_2α) seem to be involved in the control of the growth of the eye, and in the chick model form deprivation myopia could be significantly reduced by PGF_2α. This is very surprising since the myopia development in the chick has been reported to be based on active growth of the sclera. Similar, although weaker effects were also seen with latanoprost acid (13,14-dihydro-17-phenyl-18,19,20-trinor- PGF_2α), a PGF_2α analogue, and with prostaglandin E₂ (PGE₂). Since the elongation of the mammalian eye probably is based on stretching of the sclera rather than active growth, it seems quite possible that prostaglandins, which may affect the extracellular matrix, are also involved in the growth of the mammalian eye, but in the opposite way, causing excessive elongation of the eye globe leading to axial myopia.

Consequently, compounds that reduce the production of endogenous prostaglandins, both steroidal compounds and nonsteroidal anti-inflammatory drugs (NSAIDs) may retard myopia development in the primate including the human eye. Such compounds include inter alia corticosteroids, and drugs that block the COX enzymes.

Endogenous prostaglandins are naturally occurring fatty acids derived from arachidonic acid, which is a constituent of the phospholipids in the cell membranes. Arachidonic acid is released by phospholipases, in particular phospholipase A₂ (PLA₂). The enzyme is blocked by lipocortin, a protein which is induced by corticosteroids. After being released, arachidonic acid is converted to prostaglandin intermediates by the cyclo-oxygenase enzyme (COX). There are two COX isoenzymes COX-1, a constitutive enzyme, and COX-2, an inducible enzyme, typically induced during pathological conditions, such as inflammation and neoplastic processes. Common drugs that block the COX enzymes comprise the nonsteroidal anti-inflammatory drugs, e.g. celecoxib, rofecoxib, meloxicam, NS398 (COX-2 selective inhibitors), indomethacin, diclofenac, flurbiprofen, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac. Corticosteroids,^' in addition to blocking the effect of PLA2, also inhibit the transcription of the COX-2 gene.

The physiologically important prostaglandins comprise PGD₂, PGE₂, PGF_2α, PGI₂ (prostacyclin) and a related compound TxA₂ (thromboxane).

The structure of prostaglandins typically includes a cyclopentane ring, a carboxylic acid terminated side chain of 7 carbon atoms (α-chain) and a methyl terminated side chain of 8 carbon atoms (ω-chain). The side chains usually contain one or several double bonds. In the 2-series of prostaglandins for instance the α-chain contains a double bond between carbons 5 and 6 in cis configuration, while the ω-chain contains a double bond between carbons 13 and 14 in trans figuration. The substituents in the cyclopentane ring determine whether the prostaglandin is of the D, E or F type. The present invention accordingly relates to the use of prostaglandins or prostaglandin synthase inhibitors, in particular COX-1 and/or COX-2 inhibitors, for the prevention of the development of myopia. The drugs are preferentially applied topically on the eye in a suitable, physiologically acceptable formulation or administered orally, once or several times daily for different periods of time, and the treatment may continue for several years. Depending on the progression rate of the myopia the treatment may also be given intermittently e.g. once every second day, once a week, eveiy second week, or with even longer intervals. In humans the most likely drug to be effective is a COX-1 and COX-2 inhibitor, or a selective COX-2 inhibitor, the later comprising e.g. celecoxib, rofecoxib, meloxicam andNS-398, whereas unselective COX inhibitors comprise e.g. indomethacin, diclofenac, flurbiprofen, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac.

While the nonsteroidal anti-inflammatory agents currently are preferred, it cannot be excluded that corticosteroids could be used successfully as well and thus they are also encompassed by the present invention to prevent the development of myopia. Although the current invention largely is based on the use of nonsteroidal anti-inflammatory drags for the prevention of the development of axial myopia in the human eye, it should be emphasised that various exogenous prostaglandins may be useful as well, as demonstrated in the chick eye. Thus, e.g. PGF _α and latanoprost, a selective FP prostanoid receptor agonist, as well as PGE and their derivatives may be useful in the prevention of myopia.

The complexity of the elongation of the eye ball from biochemical and neurobiological perspectives has to be emphasised varying e.g. between the day and night, and currently it is not known exactly how the presence or absence of prostaglandins affect the formation of myopia. The fact that both the presence and absence (by blocking the prostaglandin synthesis) of prostaglandins may exert similar preventive or attenuating effect on myopia formation is in no way unique. A similar relationship between dopamine agonist and antagonist has previously been demonstrated e.g. by Stone et al. (supra).

The new medicaments, be it prostaglandin synthase inhibitors such as nonsteroidal anti- inflammatory drugs, or prostaglandin analogues, should be administered preferentially topically on the eye in suitable physiologically acceptable formulations. Such formulations depending on the active substance may be aqueous or oil solutions and various forms of gels, polymers as well as soluble or non-soluble drug inserts. The formulations furthermore may contain solubilizers such as polysorbate, or liposomes and substances increasing the viscosity such as polyvinylalcohole, polivinylpyrrolidone and hyaluronic acid. In addition the formulations may contain preservatives e.g. benzalkonium chloride and chlorhexidine etc, but formulations which are preservative-free in unit-dose packages may also be used. The active principle may also be formulated in ointments, which are applied locally on the eye.

It should also be emphasised that many drugs penetrate better into the ocular tissues as more lipophilic ester prodrugs. Such ester prodrugs have been utilised previously to enhance the penetration of prostaglandin analogues into the eye, but have seldom been used for the enhancement of the bioavailability of nonsteroidal anti-inflammatory drugs into the eye. Thus, prodrugs of NSAID agents with enhanced penetration into the ocular tissues are important. NSAID agents comprise e.g. indomethacin, acetylsalicylic acid, diclofenac, flurbiprofen, celecoxib, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac. Nepafenac is a topical ocular anti-inflammatory and analgesic substance, formulated as an amide prodrug. Prodrugs of the above substances, based on amide bonds, are also possible to utilise according to the present invention.

Example

Form deprivation myopia was induced in white leghorn chicks according to previous reported methods (Lauber, 1991). Briefly a translucent plastic occluder was mounted to cover one eye when the chicks were 2-3 days old. The other eye was kept as a control. The drugs were administered intravitreously into the eye twice a week with 3 day's interval. For the administration of the test drugs the occluder was removed for a few minutes.

The chicks wore the occluders for one week and thereafter the axial length of the eye was measured with ultrasound technique (A-2500 Scan., Sonomed Inc.). One group of animals received the vehicle (isotonic saline) only and served as control for the drug effects. The contralateral control eye of each animal always served as a control and in each animal the axial length of the occluded eye was compared to that of the non-occluded eye.

The following drugs were tested with the doses given in Table 1 : PGF_2α, PGE₂ and latanoprost. The drugs were injected intravitreously through a 30G needle inserted through the pars plana region into the vitreous. The injected volume was 10-20 μl.

The results of the experiments are presented in Table 1. It can be seen that PGF_2α at an intravitreal dose of 8 ng prevented most of the myopia development (p<0.01). If both PGF _α groups (8 ng and 80 ng) are pooled and the results are compared with the isotonic saline control the difference is highly statistically significant at the p= 0.0007 level. PGE₂ and latanoprost had similar but less pronounced effect. Thus, prostaglandins, and particularly PGF_2α administered intravitreously blocked in a very significant and consistent way the myopia development in the animal model used.

Table 1. Attenuating effect on myopia development of prostaglandin analogues injected intravitreously twice daily with 3 day's interval in chicks wearing occluder.

*) p<0.1; **) p<0.05; ***) p<0.01 (compared to vehicle group; t-test)

The results of the experiments can be interpreted in two ways:

Firstly, the prostaglandins administered to the eye may have a direct inhibitory effect on cell proliferation (Kishi et al., 1994), or they may inhibit the release of mediators, e.g. dopamine (Al-Zadjali et al., 1994), which could be important in the development of myopia (Stone et al., 1989). Accordingly, exogenous prostaglandins administered to the eye may prevent the elongation and growth of the eye as shown in the form deprivation model of the chick eye. It should be mentioned that in the chick model, the present inventors found subconjunctival administration of prostaglandins less effective than intravitreal administration, and topical application of prostaglandins was essentially without effect, which may be due to the peculiar anatomy of the avian eye.

Secondly, the mechanism underlying the prevention of myopia may be based on prostaglandin-induced increased catabolism of collagen and other connective tissue components as a results of e.g. matrix metalloproteinase activation. Such prostaglandin- induced catabolism e.g. in the sclera (Sagara et al., 1999) would counteract the active growth of the eye ball during form deprivation myopia in the chick. In the human eye, in contrast to the avian eye, the elongation of the eye is to a large extent, although perhaps not totally, based on stretching of the structures which requires softening of the tissue. Hence matrix metalloproteinases and other proteases activated by endogenous prostaglandins may be important in the mechanism leading to axial myopia in the human eye. Consequently, anti- inflammatory drags inhibiting cyclo-oxygenase and thereby prostaglandin synthesis can be anticipated to slow down or prevent axial myopia in humans, but not in the chick model since anti-inflammatory drugs would inhibit the production of endogenous prostaglandins, and prostaglandins if anything have been shown to retard the growth of the chick eye (Table 1).

Thus in the absence of appropriate clinical studies, currently it cannot be stated with certainty that prostaglandins have no retarding effect on myopia development in humans as they have in the chick, but it is much more likely that inhibition of endogenous prostaglandin production in humans is more effective in preventing myopia.

In support of the experimental data presented in Table 1 the present inventors have recently found, using immunohistochemical techniques, that the FP prostanoid receptor (receptor for PGF2a and latanoprost) is abundantly expressed in the retina, choroid and fibrous layer of the sclera in the chick eye. This may explain the very good effect of PGF2a in the chick eye. Also the EP3 prostanoid receptor (receptor for PGE2) was found to be expressed in the chick retina whereas the EP1 receptor (another receptor for PGE2) was sparsely distributed. In addition, using immunohistochemical technique, the present inventors have found evidence for the presence of the COX-1 and possibly COX-2 enzymes in the chick retina.

The present inventors have also recently found evidence for constitutive expression of the COX-2 enzyme in the primate retina and optic nerve head using immunohistochemical technique. Some staining indicative of COX-2 expression was also found at least in the anterior part of the sclera. Thus it is conceivable that activation of the COX-2 enzyme leading to production of endogenous prostaglandins may be important in the patho genesis of the elongation of the human eye. Consequently, inhibition of COX-2 and possibly COX-1 in the human eye can be anticipated to slow down or even prevent altogether the pathological elongation of the eye in axial myopia. Accordingly, the present invention relates to the use of exogenous prostaglandins and derivatives of prostaglandins as well as to the use of anti-inflammatory agents blocking prostaglandin synthesis for the prevention of the development of myopia. Such prostaglandins should be administered topically on the eye at a dose range of 0.1-100 μg/administration once or several times per day continuously or intermittently. The dose of the anti-inflammatory drug may vary between 10 μg and 1000 μg and the drugs should be administered topically on the eye continuously or intermittently. It should also be emphasised that the anti- inflammatory agent may be administered orally, e.g. as tablets, the dose varying from 10 mg to 1000 mg. In some cases it may even be possible to combine the administration of the prostaglandin with the anti-inflammatory drug.

Although the invention has been described with regard to its preferred embodiments, which constitute the best mode presently known to the inventors, it should be understood that various changes and modifications as would be obvious to one having the ordinary skill in this art may be made without departing from the scope of the invention as set forth in the claims appended hereto.

Claims

1. A method for the treatment and/or prevention of myopia, characterized in that a composition containing a prostaglandin or prostaglandin derivative is administered to the eye.

2. The method according to claim 1 , characterized in that the prostaglandin is chosen among the following compounds: PGF_2α, PGE₂, latanoprost, travoprost, bimatoprost, isopropyl unoprostone, or a derivative of any one of these compounds.

3. A method for the prevention of myopia, characterized in that a composition containing a steroidal or nonsteroidal anti-inflammatory drug or a prodrug of the latter is administered to the eye.

4. A method according to claim 3, characterized in that the composition is applied topically to the eye.

5. A method according to claim 3, characterized in that the composition is administered orally.

6. The method according to claim 3, characterized in that the nonsteroidal anti- inflammatory drug is chosen among the following compounds: celecoxib, rofecoxib, meloxicam and NS398 (COX-2 selective inhibitors), indomethacin, diclofenac, flurbiprofen, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac.

7. The use of a prostaglandin or prostaglandin derivative for the manufacture of a medicament for the prevention and/or treatment of myopia.

8. The use according to claim 7, characterized in that the prostaglandin is chosen among the following compounds: PGF_2α, PGE₂, latanoprost, travoprost, bimatoprost, isopropyl unoprostone, or a derivative of any one of these compounds.

9. A composition comprising a pharmaceutically effective amount of a prostaglandin or prostaglandin derivative in a physiologically acceptable vehicle for use as a medicament for the prevention of myopia.

10. The composition according to claim 7, characterized in that the prostaglandin is chosen among the following compounds: PGF_2α, PGE , latanoprost, travoprost, bimatoprost, isopropyl unoprostone, or a derivative of any one of these compounds.

11. The use of a steroidal or nonsteroidal anti-inflammatory drag or a prodrug of the latter for the manufacture of a medicament for the prevention and/or treatment of myopia.

12. The use according to claim 11, characterized in that the nonsteroidal anti- inflammatory agent is chosen from the following group of substances: celecoxib, rofecoxib, meloxicam or NS398 (COX-2 selective inhibitors), indomethacin, diclofenac, flurbiprofen, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac.

13. A composition containing a pharmaceutically effective amount of a steroidal or nonsteroidal anti-inflammatory drug or a prodrug of the latter in a physiologically acceptable vehicle for use as a medicament for the prevention of myopia.

14. The composition according to claim 13, characterized in that the nonsteroidal anti- inflammatory agent is chosen from the following group of substances: celecoxib, rofecoxib, meloxicam or NS398 (COX-2 selective inhibitors), indomethacin, diclofenac, flurbiprofen, naproxen, ibuprofen, sulindac, ketorolac, ketoprofen, mefenamic acid, and nepafenac.