Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-07-14
2001-10-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S489000, C424S494000
Reexamination Certificate
active
06303146
ABSTRACT:
The present invention relates to solid oral dosage forms for the treatment of non-insulin dependent diabetes.
Non-insulin dependent diabetes is a metabolic disorder characterized by hyperglycaemia, which occurs due to insulin deficiency, insulin resistance and reduced glucose tolerance.
There are two main groups of oral antidiabetic drugs available: these are the sulphonylureas and the biguanidines. Sulphonylureas act by stimulating insulin release and are thus only effective with some residual pancreatic beta-cell activity, examples of sulphonylureas available are glibenclamide, gliclazide, tolbutamide, glipizide, tolazamide, gliquidone and chlorpropamide. The biguanidines, such as metformin, act by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose, and as they require endogenous insulin they are only effective with some residual pancreatic islet cell activity.
The initial treatment of non-insulin dependent diabetes involves diet control and exercise. Only after this has been shown to be inadequate are oral antidiabetic drugs used, and then only to complement the effect of diet and not replace it. Monotherapy with an oral antidiabetic can be an effective treatment for many years. However the efficiency can decrease with time. Due to sulphonylureas and biguanidines having complementary modes of action, combined therapy is now an established form of treatment for non-insulin dependent diabetes.
To improve patient compliance a combined tablet would be an advantage. The present invention relates to solid oral dosage forms comprising a combination of mefformin and glibenclamide (also named glyburide).
A combination of metformin with glibenclamide has been disclosed in WO 97/17975 for the treatment of type II diabetes with a defined ratio of the two active ingredients, which is a requirement in order to obtain an optimum therapeutic effect. This prior art defines an optimum therapeutic ratio of metformin hydrochloride to glibenclamide of 100:1, for example 500 mg of metformin hydrochloride with 5 mg glibenclamide in a single dosage unit. This ratio allows a range of daily doses, based on increasing the number of tablets taken per day, that avoid poor disease control through underdosing of either ingredient when there is a requirement for co-administration, and avoids hypoglycaemia by overdosing of either component when so co-administered. Assurance of performance in clinical use, which will derive from having a product exhibiting appropriate bioavailability of the glibenclamide component, is a key requirement for physicians wishing to treat patients with a combination formulation. Appropriate bioavailability implies that 5 mg of glibenclamide formulated into a combination tablet with metformin is absorbed to an acceptably similar extent, and at a comparable rate, to glibenclamide dosed as a single entity formulation of the same strength when dosed concurrently with a single entity formulation of metformin.
This prior art does not teach how to formulate a combination product of metformin with glibenclamide so as to assure appropriate bioavailability of the glibenclamide component. There is no issue in this respect in the case of metformin hydrochloride on account of its high water solubility and therefore the bioavailability of metformin from combination formulations will not be discussed further. It is however a very important aspect to consider for glibenclamide as this is a poorly soluble drug substance (solubility is 0.1 mg/ml in water at 25° C.—practically insoluble as defined by the USP).
As such, its rate of solution after administration of a dosage form will influence the rate and extent of entry of the drug into the bloodstream (bioavailability). The control of the rate and extent of entry into the bloodstream is important for appropriate therapeutic effect.
Hence, the reference discloses a suitable ratio of the two active ingredients in a single dosage form, in order to model how the two individual ingredients might be desirably co-administered (based on how they would be dosed according to usual practice associated with currently available single entity formulations), it does not teach how to assure that such a combination formulation will perform in terms of bioavailability of glibenclamide. This bioavailability should be as similar as possible to when the relevant doses of the two single entity formulations are co-administered.
In addition, when a combination tablet using standard galenic procedures is proceeded with standard generic glibenclamide in the combination tablet, a reduced bioavailability in comparison to the co-prescribed situation was apparent.
It has now been found using in-vitro and in-vivo testing that the reduced bioavailability is related to the particle size and the particle size distribution of the glibenclamide. It has been found that particles which are too small result in high glibenclamide blood levels with consequent risk of hypoglycaemia and particles which are too large cannot dissolve sufficiently rapidly to give comparable bioavailability with the co-prescribed situation. It is therefore necessary to have a closely defined particle size distribution of the glibenclamide in the combination form.
The selection of a specific size fraction of glibenclamide enables the production of a solid oral dosage form comprising a combination of metformin and glibenclamide, and in particular a tablet, exhibiting glibenclamide bioavailability comparable to the bioavailability obtained with the separated administration of metformin and glibenclamide, when judged by the area under the curve of the in-vivo analysis.
The present invention provides in particular a tablet comprising a combination of metformin and glibenclamide, exhibiting a comparable glibenclamide bioavailability to the co-administered tablets.
In a first embodiment, the solid oral form such as a tablet, according to the invention, contains a combination of glibenclamide and metformin in which the size of the glibenclamide is such that at most 10% of the particles are less than 2 &mgr;m and at most 10% of the particles are greater than 60 &mgr;m. Preferably, the size of the glibenclamide is such that at most 10% of the particles are less than 3 &mgr;m and at most 10% of the particles are greater than 40 &mgr;m. This specific particle size range of glibenclamide may be obtained by sieving or air jet milling.
In a second embodiment, the solid oral dosage form comprises a combination of metformin and glibenclamide in which the size of glibenclamide is such that at most 25% of the particles are less than 11 &mgr;m and at most 25% of the particles are greater than 46 &mgr;m.
Preferably, 50% of particles are less than 23 &mgr;m.
Metformin may be used as a salt of metformin, such as hydrochloride, fumarate, hydrobromide, p-chlorophenoxy acetate or embonate. The weight ratio of metformin salt to glibenclamide should preferably be between 50/1 to 250/1.
The preferred compositions for the oral dosage form is provided in the table below, with ranges on components being provided:
Amount of ingredient, mg per tablet
Product identity
Ingredient
500/5
500/2.5
250/1.25
Metformin hydrochloride
500.0
500.0
250.0
Glibenclamide
5.00
2.50
1.25
Croscarmellose sodium
6.0-30.0
6.0-30.0
3.0-15.0
Microcrystalline cellulose
30.0-120.0
30.0-120.0
15.0-60.0
Polyvinyl pyrrolidone
6.0-36.0
6.0-36.0
3.0-18.0
Magnesium stearate
0.6-15.0
0.6-15.0
0.3-7.5
Film coat*
9.0-24.0
9.0-24.0
4.5-12.0
*a commercially-available film coat composition is used, such as Opadry (Colorcon, UK).
The especially preferred compositions are as follows:
Amount of ingredient, mg per tablet
Product identity
Ingredient
500/5
500/2.5
250/1.25
Metformin hydrochloride
500.0
500.0
250.0
Glibenclamide
5.00
2.50
1.25
Croscarmellose sodium
14.0
14.0
7.0
Microcrystalline cellulose
54.0
56.5
28.25
Polyvinyl pyrrolidone
20.0
20.0
10.0
Magnesium stearate
1.2-12.0
1.2-12.0
0.6-6.0
Film coat*
9.0-24.0
9.0-24.0
4.5-12.0
*a commercially-available film coat composition is used, such as Opadry (Colorcon, UK).
The tablet ac
Bonhomme Yves
Cave Gillian
Nicholson Geoffrey
Nicholson Sarah J.
LIPHA
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
Tran S.
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