WO1999004801A1

WO1999004801A1 - Use of sulfated glycosaminoglycans for treating of retinopathy

Info

Publication number: WO1999004801A1
Application number: PCT/EP1998/004929
Authority: WO
Inventors: Johan Wennemar Van Der Pijl; Herman Hendrik Pieter Jan Lemkes
Original assignee: Universiteit Leiden
Current assignee: Universiteit Leiden
Priority date: 1997-07-28
Filing date: 1998-07-23
Publication date: 1999-02-04
Anticipated expiration: 2000-01-28
Also published as: AU9160498A

Abstract

The invention relates to the use of a sulfated glycosaminoglycan and/or a synthetic functional analogue thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing of diabetic background retinopathy.

Description

USE OF SULFATED GLYCOSAMTNOGLYCANS FOR TREATING OF RETINOPATHY

The invention relates to the use of sulfated glycosaminoglycans and/or synthetic functional analogues thereof for the manufacture of a medicament for treating and preventing of retinopathy. Further the invention relates to a pharmaceutical composition for said use.

Patients with diabetes mellitus develop a number of physical disorders during the course of their disease. More than 90 % of all diabetes patients develop retinopathy, very often at last resulting in blindness. Worldwide, every year 30,000 to 40,000 people become blind due to diabetic retinopathy.

A severe disorder in diabetic retinopathy is so-called background retinopathy, which is caused by retinal leakage. Diabetes induces a deterioration of the condition of the basement membrane of the retinal capillary blood vessels resulting in increased permeability of the capillary blood vessels, which results, in turn, in increased leakage of proteins. This leads to swelling of the retina (oedema) and the formation of deposits of the proteins on the retina (hard exudates in diabetic maculopathy), which impaires the eyesight and may finally cause blindness.

Up until now, background retinopathy is usually treated by focal laser therapy (Arch.Ophthalmol. 103. 1796-806, 1985). A leaking capillary vessel is closed by singeing with a laser. This therapy stops the deterioration of the eyesight, but also irreversibly damages the capillary blood vessel treated. Moreover, areas of leakage close to the fovea are difficultly amenable to laser treatment; further visual loss can therefore not always be prevented. In addition, this therapy can only be performed with limited accuracy. Thus, partial loss of the eyesight may be a side effect of the treatment.

It has now been found that sulfated glycosaminoglycans and/or synthetic functional analogues thereof or pharmaceutically acceptable salts thereof can be used to treat and prevent retinopathy. This is in particular successful in diabetic background retinopathy, caused by increased permeability of capillary blood vessels on the retina.

The use of the sulfated glycosaminoglycans and/or synthetic functional analogues thereof or pharmaceutically acceptable salts thereof according to this invention results in effective improvement of the condition of the retina of diabetes patients with background retinopathy. In particular the progression of hard exudates stops and is even reversed. The use of this invention can be the only therapy used to treat to a patient, but it may also be an adjuvans treatment together with other therapies, such as focal laser therapy.

The class of sulfated glycosaminoglycans which can be used according to this invention comprises heparin, low molecular weight heparins (L WΗs) like dalteparin (Fragmin®), enoxaparin (Clexane®) and nadroparin (Fraxiparine®), and especially sulfated glycosaminoglycans for the major part consisting of heparan sulfate, in particular those described in EP 421,508 (66 % to 95 % heparan sulfate), of which the commercially available danaparoid sodium (danaparoid; Orgaran®, N.V. Organon, Oss, the Netherlands; Org 10172 (Thromb.Res., 27, 353-63, 1982)) is particularly preferred. Other compounds which may be used according to this invention are synthetic functional analogues of the above mentioned sulfated glycosaminoglycans, such as oligosaccharides as described in EP 84,999, EP 301,818, EP 529,715, US 5,378,829, and the like.

For use according to the invention, the sulfated glycosaminoglycan and/or a synthetic functional analogue thereof or a pharmaceutically acceptable salt thereof (shortly "active agent") may be administered enterally (e.g. orally or topically) or parenterally (e.g. via the subcutaneous or intravenous route). Preferably, but not limited to this route of administration, the active agent is administered as a subcutaneous injection to the mammal undergoing treatment. Preferably, the mammal is a human.

For humans preferably the dosage is 0,001-10 mg per kg body weight per treatment. More preferably, the active agent is administered at doses of between 1 mg and 150 mg, and most preferably between 30 mg and 100 mg, per patient per treatment. The active agent may be used alone or in combination with other therapeutic agents and may be presented as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition for treating and preventing of retinopathy comprising said active agent together with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The term "acceptable" means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, transdermal, transmucosal, local, or rectal administration, and the like, all in unit dosage forms for administration.

For oral adminstration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use. Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotone saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described. The invention is further illustrated by the following example. This should not be considered to be limiting in any way. EXAMPLE

Danaparoid sodium, as a representative compound for use according to the present invention, has been subject to a pilot clinical study in 9 patients with diabetes mellitus.

Medication: Danaparoid sodium is a mixture of sulfated glycosaminoglycans, consisting of 84% heparan sulfate, 12% dermatan sulfate and 4% chondroitin sulfate isolated from digested porcine intestinal mucosa. It has an average molecular weight of 4000-7000 d, and a specific anti-Xa activity of 1 1.0-17.0 U/mg. The elimination half-life of anti-Xa activity is ~ 25 h. The danaparoid sodium formulation used (Orgaran®) is a sterile aqueous solution containing danaparoid sodium (1250 anti Xa units per ml), sodium sulfite (1.5 mg/ml), sodium chloride to isotonic and hydrochloric acid to pH 7.0. In this study 0.6 ml ampoules were used.

Study: The study was designed as a phase II, randomized, double blind, placebo controlled, crossover study evaluating putative effects of danaparoid sodium on the rate of proteinuria in insulin dependent diabetic mellitus (IDDM) patients (J.Am.Soc.Nephrol. 8, 456-62, 1997). Nine patients, 8 males, 1 female (median age 35 years, interquartile range (IQR) 29-44 years), with IDDM (duration median 25 years, IQR 16-28 years) with macroalbuminuria (albumin excretion rate > 300 mg/24 h) due to diabetic nephropathy were studied. Mean arterial blood pressure was 105 mrnHg (median) (IQR 100-107); the use of angiotensin I converting enzyme inhibitors and other anti hypertensive medications was on a stable dosage at least 6 weeks prior to the start of the study and remained unchanged. Median HbAlc was 8.3% (IQR 7.7-9.8%). Six out of 9 patients had undergone pattern photocoagulation previously because of proliferative retinopathy. The other 3 patients had stable background retinopathy. At baseline, in 7 patients hard exudates were present in both eyes.

The patients were randomly assigned to one of the treatment orders: 750 anti-Xa units danaparoid sodium (0.6 ml), subcutaneously administered once daily for 6 weeks; a wash-out period of 4 weeks, followed by 6 weeks placebo (saline with sulfite) or the same scheme in the opposite direction. Fundus photography was performed at inclusion and at the end of the study. Seven field, red- free photographs of both eyes were obtained after mydriasis with a Zeiss camera. No bleeding complications were observed. To evaluate the course of signs of retinal leakage, a 45° photograph centered around the fovea was projected and all hard exudates were traced. Photographs were studied anonymous, masked for pre- or post-treatment assessment. Hard exudates were semi-quantitatively graded, ranging from 1+ (only minimal) to 5+ (extensive circinate).

Results: All patients have completed the study. The results are depicted in Figure 1.

No hard exudates developed in the 2 patients without hard exudates prior to the study. In 1 patient the level of hard exudates remained unchanged in both eyes. In 2 patients an improvement was seen in 1 eye , the other eye remaining unchanged. In 4 patients the degree of hard exudates improved in both eyes. So, in 14 eyes with hard exudates, an improvement was observed in 10 eyes (Wilcoxon matched-pairs signed ranks test, p = 0.005), 4 remaining unchanged, while no eye showed progression. There was no difference between patients with or without previous pattern photocoagulation.

Conclusion: Not only progression of hard exudates was stopped, but even a significant improvement was observed after the study treatment with danaparoid sodium. Treatment with danaparoid sodium alone or as a systemic adjuvans treatment together with focal laser treatment can therefore be considered as a benificial treatment of retinopathy, like active diabetic background retinopathy (such as retinal oedema, hard exudates and maculopathy).

Claims

1. A use of a sulfated glycosaminoglycan and/or a synthetic functional analogue thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing of diabetic background retinopathy.

2. The use according to claim 1, wherein the sulfated glycosaminoglycan and/or synthetic functional analogue thereof consists for the major part of heparan sulfate.

3. The use according to claim 2, wherein the sulfated glycosaminoglycan and/or synthetic functional analogue thereof consists for 66 % to 95 % of heparan sulfate.

4. The use according to claim 3, wherein the sulfated glycosaminoglycan is danaparoid sodium.

5. The use according to any one of claims 1-4, wherein the medicament is suitable for subcutaneous administration.

6. The use according to any one of claims 1-4, wherein the medicament is in a unit dosage form.

7. A method of treating or preventing of diabetic background retinopathy in a mammal, comprising the administration to said mammal of a therapeutically effective amount of a sulfated glycosaminoglycan and/or a synthetic functional analogue thereof of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition adapted for treating or preventing of diabetic background retinopathy comprising the sulfated glycosaminoglycan and/or a synthetic functional analogue thereof of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable auxiliaries.