WO2003030903A1

WO2003030903A1 - The use of tizanidine for treating metabolic disorders related to abnormal insulin secretion

Info

Publication number: WO2003030903A1
Application number: PCT/GB2002/004501
Authority: WO
Inventors: Hazel Judith Bardsley
Original assignee: Arachnova Therapeutics Ltd
Current assignee: Arachnova Therapeutics Ltd
Priority date: 2001-10-05
Filing date: 2002-10-04
Publication date: 2003-04-17
Anticipated expiration: 2004-04-05
Also published as: GB0123991D0

Abstract

Tizanidine is useful for the treatment or prevention of a metabolic disorder characterised by defective or abnormal insulin secretion where inhibition of that insulin secretion is beneficial.

Description

THE USE OF TIZANIDINE FOR TREATING METABOLIC

DISORDERS RELATED TO ABNORMAL INSULIN

SECRETION

Field of the Invention

This invention relates to new therapeutic uses for tizanidine, a known compound. Background of the Invention

Type 2 diabetes mellitus (formerly known as non-insulin-dependent diabetes) features early onset of insulin resistance. This leads to greater than normal levels of insulin or hyperinsulinemia, with resultant elevation of blood glucose when the pancreas can no longer keep up with increased insulin requirements. Often, patients with hyperinsulinemia and diabetes also have hypertension, obesity and dyslipidemia, all occurring in a disorder constellation often referred to as "syndrome X" or "metabolic syndrome".

In type 2 diabetes, it has also been found that the pancreas exhibits defective insulin secretion. This is often characterised by decreased first phase insulin response, abnormal pulsatile insulin release, an increased ratio of proinsulin to insulin and reduced orderliness of insulin secretory pattern.

Abnormal insulin secretion and hyperinsulinemia are associated with great morbidity. In these conditions, it may be desirable to inhibit insulin secretion. For example, in morbidly obese patients with hyperinsulinemia, diazoxide, a potent inhibitor of insulin secretion, can accelerate weight loss versus control without any deleterious effects on blood glucose; see Alemzadeh et al, J. Clin. Endocrinol. and Metab. (1998) 83:1911-5.

Currently, there are few agents other than potassium channel openers that can inhibit insulin secretion. Some alpha 2 agonists can inhibit insulin secretion but these agents are also associated with unwanted reduction in blood pressure and other side-effects. Imidazoline drugs potentiate glucose-induced insulin secretion from isolated islets incubated in vitro and are also effective when administered to experimental animals in vivo.

The compound tizanidine, i.e.5-chloro-N-(4,5-dihydro-1 H-imidazolyl-2-yl)- 2,1 ,3-benzothiadiazol-4-amine; see US-A-3843668 and US-A-4053617), has alpha 2 agonist properties and is used as a skeletal muscle relaxant. Tizanidine has been found to bind to kidney imidazoline receptors with approximately 20 times more affinity than the alpha 2 adrenoceptors; see Muramatsu etal, Japan

J. Pharmacol. (1992) 59: 457-459.

Summary of the Invention

Surprisingly, it has been found that tizanidine is able to cause a dose- dependent decrease in insulin secretion. According to the invention, tizanidine can be used for the treatment or prevention of a metabolic disorder characterised by defective or abnormal insulin secretion where inhibition of that insulin secretion is beneficial.

Description of the Drawings Figures 1 to 3 are each graphs of insulin secretion (i.e. "IS", ng/islet/h) against concentration of tizanidine ("IT]", μM).

Description of Preferred Embodiments

By means of the invention, a number of diseases characterised by abnormal insulin secretion can be treated. These include type 2 diabetes, obesity, metabolic syndrome or syndrome X, polycystic ovary syndrome, hyperinsulinemia, dyslipidemia, drug-induced weight gain, congestive heart disease, glucose intolerance, renal disease, type 1 diabetes and persistent hyperinsulinemic hypoglycemia of infancy.

The active compound can be formulated in any suitable manner together with a conventional diluent or carrier. The active compound is preferably administered by the oral route; other suitable routes of administration include sublingual/buccal, transdermal, intramuscular, intranasal, rectal, parenteral, subcutaneous, pulmonary and topical. An effective dose of the active agent will depend on the nature and degree of the complaint, the age and condition of the patient and other factors known to those skilled in the art. A typical daily dosage is 0.01 to 1000 mg.

A pharmaceutical composition containing the active ingredient may be in the form of a sublingual tablet or patch. Suitable compositions for oral use include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups and elixirs.

Suitable additives include sweetening agents, flavouring agents, colouring agents and preserving agents. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated, to form osmotic therapeutic tablets for controlled release. Hard gelatin capsules may include an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; soft gelatin capsules may include water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The active compound may be tizanidine itself or a derivative, such as a salt or metabolite thereof. A prodrug form may also be used.

The study on which the invention is based will now be described, with reference to the accompanying drawings. Study

Islets of Langerhans were isolated from male Wistar rats (180-200 g body weight) by collagenase digestion of the excised pancreas. Islets were hand- picked under a binocular dissecting microscope to minimise their contamination with exocrine tissue. Islets were used within 2 hours of the death of the animal and were incubated in groups of 3 in bicarbonate-buffered saline solution (pH 7.4) supplemented with 2 mM Ca and 1 mg/ml bovine serum albumin. Islets were incubated for 1 hour at 37°C, after which samples of the medium were removed for measurement of insulin secretion by radioimmunoassay.

Initial studies were designed to investigate the effects of increasing concentrations of the agent on insulin secretion in response to 20 mM glucose (a maximally stimulating concentration). The results (Fig. 1 ) revealed that tizanidine induced a dose-dependent inhibition of insulin secretion over the concentration range 10-1000 nM. The EC₅₀ for this response varied between 50-100 nM, and complete inhibition was seen at 1 μM. In further experiments, islets of Langerhans were isolated from male Wistar rats and incubated in vitro in the presence of either 7mM glucose or 10 mM glucose plus increasing concentrations of tizanidine. Following incubation for 1 hour at 37°C, the medium was sampled and insulin measured by radioimmunoassay. Each experiment was repeated on two separate occasions with 6 replicate incubations in each case. The results are shown in Figs. 2 (7 mM glucose) and 3 (10 mM glucose), respectively. Again, in each case, a dose- dependent decrease in insulin secretion was seen.

Claims

I . Use of tizanidine for the manufacture of a medicament for the treatment or prevention of a metabolic disorder characterised by defective or abnormal insulin secretion where inhibition of that insulin secretion is beneficial.

2. Use according to claim 1 , wherein the disorder is type 2 diabetes.

3. Use according to claim 1 , wherein the disorder is obesity.

4. Use according to claim 1 , wherein the disorder is metabolic syndrome or syndrome X.

5. Use according to claim 1 , wherein the disorder is polycystic ovary syndrome.

6. Use according to claim 1 , wherein the disorder is hyperinsulinemia.

7. Use according to claim 1 , wherein the disorder is dyslipidemia.

8. Use according to claim 1 , wherein the disorder is drug-induced weight gain.

9. Use according to claim 1 , wherein the disorder is congestive heart disease.

10. Use according to claim 1 , wherein the disorder is glucose intolerance.

I I . Use according to claim 1 , wherein the disorder is renal disease. 12. Use according to claim 1 , wherein the disorder is type 1 diabetes. 13. Use according to claim 1 , wherein the disorder is persistent hyperinsulinemic hypoglycemia of infancy.