Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

The invention is concerned with the use of derivatives of a specific diastereomer of prostaglandin F_ , , viz. 11 epi, alpha for the treatment of glaucoma or ocular hypertension. The invention furthermore also relates to ophthalmological compositions containing an active amount of these prosta¬ glandin derivatives.

Glaucoma is an ocular disorder characterized by elevated intraocular pressure, excavation of the optic nerve head and gradual loss of the vision field. An abnormally high intra¬ ocular pressure will have a generally detrimental effect on the eye; and there are clear indications that this is probably the main factor causing degenerative changes of the retina in glaucoma patients. However, the pathophysiological mechanism underlying open-angle glaucoma is still unknown. If not treated successfully the disease will usually proceed to blindness sooner or later, its course towards that stage being characterized by a slow but progressive loss of vision.

The intraocular presεur IOP (abbr. of intraocular p_ressure) is usually defined by the formula

IOP = P + F x R (1) e

where P is the pressure in the epiεcleral veins, generally considered to be around 9 mm Hg; F is a measure of aqueous humor flow rate; and R is the resistance to aqueous humor outflow through the trabecular meshwork and adjacent tissue into Schlemm's canal.

Another path along which the aqueous humor may flow, in addition to the Schlemm's canal path, is via the ciliary muscle into the suprachoroidal space and then out of the eye through the sclera. This uveoscleral path has been described

by e.g. Bill (1975) . The pressure gradient along this path is very insignificant as compared to the gradient in the first mentioned case over the interior wall of Schlemm's canal and adjacent tissue. The flow-limiting step along the uveoscleral path is believed to reside in the flow from the anterior chamber into the suprachoroidal space.

A more complete formula is the following:

where P and R have the same meanings as above; F represents the total outflow of aqueous humor; and F represents that portion thereof which goes via the uveoscleral path.

In humans the IOP will normally be within the range of from 12 to 22 mm Hg. At higher values, e.g. exceeding 22 mm Hg, there is a risk that the eye may be affected. In a special form of glaucoma, the so-called low-tension glaucoma, lesions will occur at intraocular pressure levels which are generally regarded as physiological. Possibly this may be due to an increased pressure sensitivity of the eye of such an individual. Also the opposite type of phenomenon is known, i.e. some individuals may have an abnormally high intraocular pressure without any noticeable distinct defects in their vision field or optic nerve head. Such conditions are usually named "ocular hypertension".

Glaucoma treatments may be given by means of drugs, laser or surgery. In the case of drug treatments, the purpose is to achieve a reduction of either the flow (F) or the resistance (R) , which will result in a lower IOP according to formula (1) above; or alternatively the purpose may be to increase the flow via the uveoscleral path - w ^τ hich too will be a means of lowering the pressure as can be seen from formula (2) . Cholinergic agonists like for instance pilocarpine reduce the intraocular pressure mainly by increasing the outflow through Schlemm's canal.

Interest in prostaglandins as IOP- reducing substances has been growing substantially for quite some time; the mechanism underlying their effect probably being an increased uveoscleral outflow (Crawford et al. 1987, and Nilsεon et al. 1987) . These substances on the other hand do not appear to have any effect on either the formation of aqueous humor or the conventional outflow through Schlemm's canal (Crawford et al. 1987) .

The use of prostaglandins and derivatives thereof is described in for example US 4599353 and EP 87103714.9.

With respect to the practical usefulness of some of the previously described prostaglandins and derivatives as suitable as drugs for treating glaucoma or ocular hyper¬ tension, a limiting factor is their property of causing superficial irritation and vasodilatation in the conjunctiva. It is probable moreover that prostaglandins have an irritant effect on the sensory nerves of the cornea. Thus local side effects will arise in the eye already when the amounts of prostaglandin administered are quite small - that is, already when the doses are lower than those that would be desirable for achieving maximum pressure reduction. It has thus been found for instance that for this reason it is clinically impossible to use PGF~ , , -1-isopropyl ester in the amount that would give maximum pressure reduction. Prostaglandins being naturally occurring autacoids are very potent pharmacologically and affect both sensory nerves and smooth muscle of the blood vessels. Since the effects caused by - administrations of PGF2-,al.,p,ha and its esters to the ey ^J e comprise in addition to pressure reduction also irritation and hyperemia (increased blood flow) the doses currently practicable in clinical tests are necessarily very low. The irritation exp^erienced when PGF2„al.p,ha or its esters are applied consists mainly in a feeling of grittiness or of having a foreign body in one's eye, this being usually accompanied by increased lacrimation.

We have now found, surprisingly, that a diastereomer of prostaglandin PGF ₂ , , , viz. 11 epi, will lower the eye pressure without causing any substantial irritation. In this stereoisomer the hydroxyl at carbon atom 11 lies above the cyclopentane ring. This isomer of PGF„ , , has been known heretofore; it is a metabolite of PGD„ (Liston and Roberts 1985, Pugiiese et al. 1985) . The 11 epi PGF ₂ . , -1-isopropyl ester which as far as we know has not been described hereto¬ fore will give rise to hyperemia in the conjunctiva to about the same extent as the PGF_ , , -1-isopropyl ester, but this will not xnvolve any hazard or inconvenience as long as irritation problems are absent.

The present invention thus relates to 1-alkyl or i-alkylaryl esters of 11 epi PGF- , , to be used for treating glaucoma or ocular hypertension. The alkyl chain of the 1-alkyl esters comprises 1-10, preferably 1-7, and especially 1-5 carbon atoms. The 1-alkylaryl esters have an aryl group monosubεtituted by a lower alkyl chain. This lower alkyl chain has 1-5 carbon atoms. In an embodiment currently preferred, the 11 epi PGF„ _. , -1-iεopropyl ester is used.

Furthermore , the invention relates to compositions for the treatment of glaucoma or ocular hypertension, said compositions containing an effective intraocular pressure reducing amount of at least one 11 ep ^c i PGF_al,p,ha-1-ester defined as above, in an ophthalmologically compatible vehicle. The term "effective amount" here means that the composition contains about 0.1-10 Ug _r especially 1-10 ,ug of the active substance.

The ophthalmologically compatible vehicle which may be employed for preparing compositions of this invention compriεeε aqueous solutions as e.g. physiological salines, oil solutions or ointments. The vehicle furthermore may contain ophthalmologically compatible preservatives such as e.g. benzalkonium chloride, surfactantε like e.g. Tweeπ ^" 8G, lipoεorces or polymers, for example methyl cellulose, pclyvinyl

alcohol, polyvinyl pyrrolidone and hyaluronic acid; these may be used for the purpose of increasing the viscosity. Furthermore, it is also posεible to uεe εoluble or inεoluble drug inεertε when the drug is to be administered.

The invention moreover relates to a method for treating glaucoma or ocular hypertension. The method consists in contacting a composition aε aforesaid with the eye in order to reduce eye pressure and to maintain said pressure on a reduced level. The composition contains 0.1-10 ,ug , especially

1-10 /,ug,' of the active substance i.e. the 11 ep ^i PGF2„al.p,ha ester; the treatment may advantageously be carried out in that one drop of the composition, corresponding to about 30 ,ul, is administered about 1 to 4 times to the patient's eye.

The invention is illustrated by means of the following non-limitative examples.

Experiments

1. Synthesis of 11 epi PGF ₂ , , -1-isopropyl ester

20 mg (0,056 mmol) of 11 epi PGF„ _. , (Cayman Chemicals, US) were disεolved in acetone at room temperature. To thiε solution were added 54.5 mg (0.336 mmol) of diazabicycloundecene (DBu) and 76.15 mg (0.448 mmol) of propyl iodide, whereupon the mixture was left to εtand at room temperature for 8 hours. The solvent was removed in vacuo, the residue then being disεolved in 50 ml of ethyl acetate, waεhed with 20 ml of water, 20 ml of 3 % citric acid and 5 % εodiu hydrogen carbonate; thereafter the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and

the residue was purified by means of column chromato- graphy on silica gel, with ethyl acetate - acetone (1:1) as the eluent. The yield of the product was about 76 %, and its purity waε tested by means of thin layer chromatography and NMR.

2. Preparation of eye drops containing 11 epi PGF . , - 1-isopropyl ester

PGF2„al,ph, a-1-isop ^r ro ^r py ^J l ester or 11 ep^i PGF2„al.p,ha-1-iεo- propyl ester produced according to Example 1 waε mixed with an eye drop solution containing 0.5 % Tween 80 as a micelle-forming substance plus 0.01 % benzalkonium chloride as a preservative to 50 ,ug/ml concentration. Healthy volunteers received in one of their eyes one drop (30 ,ul) containing 1.5 ,ug of either PGF„ . , - 1-isopropyl eεter or 11 epi PGF„ . , -1-iεopropyl ester, and in the other eye one drop of the vehicle without any added prostaglandin compound, this other eye being the contralateral control eye. Feelings of irritation and hyperemia in the conjunctiva were then recorded during a period of two hours. Eye pressures were measured 2, 4, 6 and 8 hours after administration of 11 epi PGF_ , ,let-i-isopropyl ester, and 4 and hours after administration of PFG 2~al,ph, a-1-iεop^ropvl ester. With proεtaglandin eye reducing effect in the eye is expected to be achieved 6-8 hours after administration of the preparation.

Eye pressure was measured by means of applanation tonometry, either with Godmann's applanation tonometer or with a pneumatonometer (Digilab Mode -30RT) , after anestheεia of the cornea with oxybuprocaine dropε or with a mixture of oxybuprocaine and fluoreεcein. Reεultε could be read only after measurements were complete.

Feelings of irritation in the eye i.e. grittiness were claεεified by scores ranging from 0 to 3 where 0 = no irritation, 1 = slightly irritating, 2 = moderately irritating and 3 = highly irritating. Hyperemia in the conjunctiva was assessed only visually.

The results of the tests performed on healthy volunteers with 11 ep^i PGF2_al_,p,ha-1-isop^ropy ^J l eεter and and II.

Application of 1.5 ,ug of 11 epi ^PGF 2 _a ι _Dh administered as the 1-isopropyl ester in a particular vehicle and ap^plication of 1.5 I,ug ^ PGF2„al.ph,a administered as the

1-isopropyl ester in the same vehicle resulted in 1-2 mm Kg pressure reduction in normotensive individuals 4 to 8 hours after application, as compared to the control eye (Table I) . The pressure reduction was statistically significant on a P<0.05 to P<0.02 level.

This presεure reduction may appear to be a εmall one, but it is a well-known fact that normotensive individuals will generally show fairly little reaction in response to pressure reducing drugs. This is true also of e.g. pilocarpine and timolol. As can be seen from Table II, irritation after application of 1.5 ,ug 11 epi PGF„ . . was felt to be considerably less than the irritation felt upon application of 1.5 ,ug PGF„ , , when each had been administered in the form of its 1-isopropyl ester. This is very important from a clinical point of view, since it may thus be espected that the drug will be used in doses high enough to bring about a maximal reduction of eye presεure.

References

Bill, A (1975) . Blood circulation and fluid dynamics in the eye. Physiol. Rev. 55: 383-417.

Crawford, K, Kaufman, P L, och True Gabel, B'A (1987) . Pilocarpine antagonizes PGF ₂ -induced ocular hypotension: Evidence for enhancement of uveoscleral outflow by PGF~ . Invest. Ophthalmol. Vis Sci p. 11.

Liston, T och Roberts, L J (1985) . Transformation of prosta¬ glandin D„ to 9alpha,llbeta- (15S) -trihydroxyproεta- (5Z,13E) - dien-1-oic acid (9alpha,llbeta-proεtaglandin F„) : A unique biologically active prostaglandin produced enzymatically in vivo in humans. Proc Natl Acad Sci US 82 p. 6030-6034.

Nilsson, S F E, Stjernεchantz, J, och Bill, A (1987) . PGF ___-δ. increases uveoscleral outflow. Invest. Ophthalmol. Vis Sci Suppl p. 284.

Pugliese G et al (1985) . Hepatic Transformation of Proεtaglandi D„ to a New Proεtanoid, 9alpha,llbeta-Proεtaglandin F. , That Inhibitε Platelet Aggregation and Conεtricts Blood Vesεels. J Biol Chem 260(27) p. 14621-14625.

TAB E I

0 h ? h 4 b 6 h 8 h

Prostaglandin n Exp. Contr. Diff. Exp. Contr. Diff. Exp. Contr. Diff. Exp. Contr. Diff. Exp. Contr. Diff. (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg)

X) xx)

11 epi PGF -1- 14.7 + 14.5 + 0.3 + 13.7 + 15.1 + -1.4 + 13.4 + 14.5 + -1.1 + 11.8 + 13.8 + -1.9 12.1 + 13.3 + -1.2 +

2alpha isopropyl ost r 2.2 1.6 0.7 7.0 .1.5 0.7 1.6 1.4 0.4 2.0 1.2 1.1 1.0 1.0 0.3

x)

PCF -1- 15.6 + 17.4 i -1.8 + 15.0 + 16.9 + -1.9 +

?.alpha isopropyl cster 0.8 1.3 0.7 0.4 1.3 1.1

Eye pressure reducing effect of 11 epi PGF_ , , -1-iεopropyl ^{J t} 2alpha ester and PGF„ , , -1-isopropyl ester on normotensive 2alpha indivi uals after local application of a 30 ul eye drop c ntaining 1.5 ug of the active substance calculated as free acid. Contralateral control eyes were treated with vehicle alone.

xx ) = p > 0.02

9 33

TABLE I I

Time after application

Prostaglandin 15' 30' 45' 60' 120"

xx ) xxx)

11 epi-PGF„ , . -1- 0.4 + 0.2 0.2 + 0.2 0.0 + 0.0 0.0 + 0.0 0.0 + 2alpha isopropyl ester

- ^?GF - . _ 1.5 + 0.4 1.7 + 0.2 + 0.2 1.3 + 0.2 0.! 2alph _a ^-1_ isopropyl ester

xxx) p < 0.01

Feeling of pain (grittiness) in the eye of normotensive individuals after local application of 1.5 ,ug 11 epi PGF ₂ , -l-isopropyl ester or 1.5 ,ug PGF , -1-iεopropyl ester calculated as free acid. A scale of scores ranging from 0 to 3 was uεed for pain aεseεsment.