State of the art As is known, diabetes type 11 is a frequent metabolic illness, characterised by insulin-resistance and by deficit of insulin secretion, with consequent hyperglycaemia.

Accurate control of glycaemia, maintaining fasting values, as well as values after meals, close to normality is important for the long-term prevention of the chronic complications of diabetes.

In the case where a proper diet together with physical exercise prove in themselves insufficient to bring and maintain glycaemia within normal values, it is necessary to intervene on the patient with the aid of appropriate drugs.

The drugs that are commonly used in the treatment of hyperglycaemia in patients with diabetes type 11 can be divided into three major categories: a) drugs that stimulate insulin secretion, such as sulphonylureas and meglitinides.

As an alternative, also insulin can be administered by subcutaneous route; b) drugs that increase insulin sensitivity (metformin or thiazolidinediones) ; and c) drugs that slow down intestinal absorption of carbohydrates (acarbose).

The main scientific societies recommend starting treatment with an oral drug (preferably a sulphonylurea in patients of normal weight and mefformin in overweight patients); in the cases in which just one drug is not sufficient to maintain an adequate control of glycaemia, a second drug is added, reserving the treatment with insulin to the cases not adequately controlled with a combination of two oral drugs.

For the control of glycaemia various drugs belonging to the classes indicated above have been used, such as mefformin, glybenclamide, chlorpropamide, fenformin and glyclazide.

There are moreover known compositions containing two of the aforesaid active principles in combination.

In particular Galeone et al. Minerva Endocrinol, Vol. 23, no 3, September 1998 pages 71-75 and Guillausseau P. J. Diabetic Medicine Vol. 14, n° 9 September 1997 pages 798-802 describe the combined use of metformin and glyclazide in the treatment of type 2 diabetes.

However, in the above cited literature, both drugs were used at sub-maximal doses (1.5 g/day for metformin, 120 mg/day for glyclazide). Such low doses of the two drugs could be insufficient to obtain a proper reduction of cardiovascular risk in patient with type 2 diabetes.

The literature reports that both mefformin and glyclazide have a dose-dependent effect on blood glucose (in the 1-2,5 g/day range for metformin and in the 40-240 mg7day range for glyclazide).

However the effect of metformin on cardiovascular risk has been observed only for doses of 2,550 mg/day. Using the current formulations of glyclazide (80 mg) and mefformin (500, 850 or 1000 mg) combined treatment with the two drugs at appropriate doses requires a high number of tablets each day, this being a major obstacle for patients'compliance in long term treatments.

Detailed description of the invention It has now been surprisingly found, and forms the subject of the present invention, that pharmaceutical compositions for oral use containing as active principles mefformin and glyclazide in quantities comprised between 500---1000 mg for metformin and between 20-80 for glyclazide allow to overcome the above said problems.

In fact the use of formulations containing the reported doses of the two drugs surprisingly allow the combined treatment without increasing the number of tablets. In particular, tablets containing 850 mg of metformin and 40 or 80 mg of glyclazide would allow the administration of a full dose of metformin, and of an adequate dose of glyclazide, with only three tablets per day. It is particularly important to reach an adequate dose of metformin, because this drug has been shown to reduce cardiovascular risk in patients with type 2 diabetes when used at doses of 2,550 mg a day (850 mg three times a day) Moreover, studies currently in progress point to the fact that, in addition to the proven anti-hyperglycaemic properties, the compositions according to the

invention can contribute to the prevention of chronic, micro-and macro-vascular, complications of diabetes type il.

Since the haemovascular effects of glyclazide and metformin are expressed on different phases in the process of thrombogenesis and fibrinolysis, it is highly probable that there exists a synergetic effect due to the simultaneous administration of the two active principles. Consequently, the combination of the two molecules could specifically prevent the complications of diabetes type 11 to an extent greater than what might be expected on the basis of the reduction of glycaemia alone.

Preferred compositions are the ones containing 850, 850,500, 1000,1000 mg of metformin together with respectively 40,80, 80,40 and 80 mg of glyclazide.

Particularly preferred are the compositions according to the invention containing 850 mg of mefformin in association with 40 mg of glyclazide The compositions according to the present invention can be prepared using the techniques known in pharmacopoeia for the preparation of formulations for oral use, for example: tablets, capsules, pills, chewable tablets, preparations for sublingual absorption etc.

Particularly preferred are immediate-release tablets.

The excipients normally used are the ones used as binders (e. g., pre-gelatinized starch), diluents (e. g., microcrystalline cellulose), glidants (e. g., colloidal silica), <BR> <BR> wetting agents (e. g. , Tween 80), disgregating agents (e. g. , sodium<BR> amidoglycolate), lubricants (e. g. , magnesium stearate), and film-coating agents<BR> (e. g. , opadry oy s7163).

Particularly preferred are the formulations according to the invention in the form of high-disgregation tablets which enable immediate release of the active principles.

Particularly preferred tablets of this type are 950-mg tablets which contain (in addition to two active principles in the amounts indicated above) the following additives:

Microcrystalline cellulose : as required for 950 mg Pre-gelatinized starch: 60 mg Hydrated colloidal silica : 6 mg Tween 80 : 7 mg Sodium amidoglycolate : 59 mg Magnesium stearate: 5 mg Opadry oy s7163 : 30 mg The size of an industrial lot is approximately 350 000 tablets corresponding to 322 kg.

To prepare approximately 87 500 950-mg tablets (corresponding to approximately 80.5 kg of granulate) the following are loaded in a Graft Collette granulator : 43.750 kg of metformin, 17.65 kg of microcrystalline cellulose, 5.250 kg of pre- gelatinized starch, and 0.521 kg of hydrated colloidal silica. The above ingredients are mixed for 10 minutes.

Granulation is carried out with a solution consisting of 10.341 kg of water and 0.612 kg of Tween 80.

The granulate thus obtained, which has a somewhat pasty consistency due to the granulation with the water/Tween mixture, is passed through a rotary granulator provided with a basket having holes of a diameter of 3 mm, is dried in a fluid bed (RH = 1.3%) and is co-ground at 16 mesh with 5.163 kg of sodium amidoglycolate and 7.000 kg of glyclazide.

After the four sub-lots have been pooled together, the procedure continues with the addition of 1.750 kg of magnesium stearate, and finally with compression and film coating.

The compositions according to the invention can be used in the treatment of diabetes mellitus type 11 in patients who are not adequately controlled with metformin alone or with a sulphonylurea agent alone. In particular, patients not adequately controlled with mefformin alone could pass to metformin 850 mg + glyclazide 40 mg three times a day, which guarantees an effective dose of metformin with the addition of a small dose of glyclazide for stimulating insulin secretion. If this is not sufficient, they could pass to metformin 850 mg + glyclazide 80 mg three times a day, and possibly to metformin 1000 mg + glyclazide 80 mg three times a day. Patients not adequately controlled with a sulphonylurea agent alone could pass to glyclazide 80 mg + metformin 850 mg three times a day, so as to maintain a sufficiently high dose of sulphonylurea and add thereto the insulin- sensitising action of metformin.