DK163865B - Use of oestrogens for producing preparations to be used locally for treating increased pressure in the eye - Google Patents

Description

-1- DK 163865 B

This invention relates to the use of estrogens in the preparation of topical compositions for the treatment of elevated pressure in the eye.

Simplex glaucoma (chronic glaucoma) is, in general view, caused by an elevated intraocular pressure which, possibly in conjunction with decreased blood supply to the optic nerve of the papilla, causes a progressive loss of nerve fibers and thus visual field impairment.

The elevated intraocular pressure that most often follows the glaucoma is due to a mismatch between the production of ventricular fluid in the corpus ciliare and the drain to the bloodstream which takes place via the trabeculae at the ventricular angle, and is probably due to an age-related reduction in drainage capacity.

In Denmark, there are an estimated 50,000 people with simplex glaucoma, approx. 20,000 are diagnosed and undergoing treatment.

The disease occurs with increasing frequency in people over the age of 50, about as often in men as in women.

A treatment that addresses the probable primary cause of the disease, the progressive deterioration of the drainage capacity does not exist today, and the known treatment methods are usually unable to prevent progression of visual field defects over a number of years, often resulting in total blindness.

The known drugs for lowering intraocular pressure are characterized by a duration of action of a few hours, which means that the pressure during sleep and during periods of irregular drip, which often occur frequently, can rise to harmful heights. These pressure increases will not be recognized by normal examination procedure.

Furthermore, over the course of a few months or years, the pressure-reducing effect of the drugs will often be insufficient, which is why patients must be treated with many different substances with the following hassle and expense.

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The existing substances are all suffering from side effects of a lighter or more severe nature which often make treatment with one or more substances impossible.

From the journal "Experimental Eye Research" / Vol. 26, (1978) / pp. 599-610 / see, in particular, the abstract, pp. 601, 605 and 608, agents for reducing intraocular pressure for local application in the eye are known. substance with progesterone action. The effect occurs within one hour and is due to inhibition of ventricular fluid production, as is the case with the most commonly used antiglaucomatous agents such as timolol maleate and dipivephrine (beta-blocker and adrenergic, respectively). After daily use for 18 days tolerance development is not seen. The effect persists after each drip for up to 6 hours, corresponding to the conditions of timolol maleate and dipive fringe. Thus, the effect does not last for several weeks after cessation of treatment.

From the specification of DK Patent Application No. 2942/86, means for reducing the intraocular pressure for local application in the eye are known which contain an anabolic, androgenic substance. The substance penetrates through the cornea to the chamber fluid where, by concomitant topical application of corticosteroid (cortisol) preparations, it prevents the increase of resistance to fluid drainage and thus the increase of intraocular pressure that occurs with corticosteroid preparations alone.

When treated with anabolic androgens alone, a deterioration of the fluid flow is seen, cf. Table I, p. 7 and no effect on intraocular pressure, cf. p. 31.

Both local and systemic use of estrogens is common in a wide range of areas not related to the one mentioned here.

Intramuscular or oral but not topical use of combination preparations containing estrogens and progesterones has previously been shown to have an antihypertensive effect on the eye, but these results have been disputed and have never been widely accepted or used for treatment purposes.

Treatment of simplex glaucoma with estrogens alone has not been previously described, either with tablets, injection or topically.

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Ethinyl estradiol (mestranol), which is a synthetic estrogen, is reported in the journal "Experimental Eye Research", vol. 26, (1978), pp. 599-610, by administering a drop of 0.1% eye suspension to 8 rabbits, respectively. and 7 monkeys have a slight pressure-increasing effect in the short term, ie. within 4 hours. In similar trials with the synthetic estrogen-style booster role, no effect on short-term intraocular pressure was found. Short-term experiments of this kind are aimed at finding substances that reduce intraocular pressure via a reduction of the chamber fluid production, analogous to the action of the most commonly used antiglaucomatous agents such as timolol maleate and dipive fringe.

Since, according to common clinical knowledge, treatment-requiring conditions with low intraocular pressure do not exist, the above experiments have not been continued.

A clinical trial has, given the surprising results given above, that estrogens, by prolonged, local use, have a decreasing effect on intraocular pressure.

The course and results of the test:

Clinical trial report of viscous estradiol 1% eye drops Material, method and registered side effects 14 patients with the diagnosis of glaucoma simplex received the test preparation. The patients were treated in 2 series.

In the first series, 5 patients each evening received a drop of the test preparation in each eye while 2 patients received a placebo.

Of the 5 patients who received the test drug (estradiol eye drops), 3, 2 women and 1 man noticed, side effects in the form of slight tenderness of the nipples and, in the case of the man, also slight swelling similar to the mammary glands.

Of the first series, 2 women, one per gram of systemic estradiol side effects, the other one per gram of uncharacteristic conjunctival irritation.

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It was decided to continue the study as uncontrolled as it was now clear which preparation contained the active substance. Furthermore, the dose was lowered to one drop every other evening in each eye. This happened a month after the start of the first series.

Thus, the patients in the second series, a total of 7, received only one drop every second evening in each eye. In these, no side effects were seen, neither locally nor systemically.

One patient in the second series suffered a slight increase in intraocular pressure per gr, which necessitated adjunctive therapy.

results

The 11 patients who completed the study were given a series of initial pressure measurements and were then treated with the estradiol drops as described above.

With linear regression, a slight positive slope coefficient was found and a slight negative during treatment. This difference is not significant.

On average, a pressure of 21.5 / 20.9 rnmHg (hay / wt) was found before treatment and 19.4 / 18.9 mmHg during treatment, ie. an average decrease of approx. 2 mmHg which is significant (p <0.000005).

For pressure measurements made for 2-4 months after discontinuation of the test preparation, an average of 21.5 / 21.6 mmHg was found.

Probability that all estrogens have the same effect on intraocular pressure as estradiol.

When the requirement is formulated to include estrogens in a broader sense, it is because the effect of the eye agent is closely linked to the general effect of these substances on the connective tissue. The group of estrogens comprises substances of very different chemical composition and is precisely defined based on a common biological effect on different tissues, cf. e.g., Andres Goth: Medical Pharmacology, C.V. Mosby 1978.

The biological effect sought here is an increase in hyaluronic acid.

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the acid content of the chamber fluid and trabeculae under the assumption that hyaluronic acid in the eye has the function of keeping the drain open.

Estrogens are known from experiments to increase glycosaminoglycan and including hyaluronic acid synthesis in a variety of tissues. This effect is similar whether naturally occurring estrogens, eg estradiol, semi-synthetic estrogens, eg estradiol benzoate or purely synthetic estrogens eg diethyl-style booster, cf. G. Asboe-Hansen: "Hormones and Connective Tissue", Munksgaard 1966.

With the glaucoma simplex, as mentioned in the introduction, changes in the connective tissue of the trabecular plant occur, so that the flow of the chamber fluid deteriorates. Efforts to prevent this disease process are hampered by the fact that no analog animal experimental model exists. Thus, an elevated intraocular pressure may be induced by prolonged topical treatment with cortisol preparations as shown in the description of DK patent application no.

Therefore, an assessment of the effect of a given substance on glaucoma can only be done in clinical trials with glaucoma patients.

The clinical trial underpinning the present invention has been initiated on the basis of the above theoretical considerations regarding the biological effect of estrogens on connective tissue.

Conducting a similar clinical trial on glaucoma patients with a wide range of estrogen group representatives must be considered unethical as the common effect of estrogens on connective tissue must be likely to have a similar effect on eye pressure as the randomly selected representative, estradiol .

Claims (1)

In the use according to the invention, the following are obtained, cf. the above trial report and in-depth probability; 1. that the effect is elongated so that it occurs only after several weeks of use and lasts for several weeks after cessation, which is why no harmful pressure increases occur when omitting individual applications. 2. that the reduction of intraocular pressure is achieved by a single application every other day. 3. it does not cause significant systemic side effects as the absorbed dose is negligible. 4. it implies that the substance penetrates through the cornea to the chamber fluid, where it acts as a remedy or drain in the trabecular plant, even without prior drip with cortisol preparations. 5. To prevent gradual pressure rise by simplex glaucoma. PATENT REQUIREMENTS Use of estrogens for the preparation of topical preparations for the treatment of high pressure in the eye.