MXPA00002568A - Solid oral dosage form comprising a combination of metformin and glibenclamide - Google Patents

Abstract

The present invention relates to a solid oral dosage form comprising a combination of metformin and glibenclamide in which the size of glibenclamide is such that the glibenclamide bioavailability is comparable to the glibenclamide bioavailability obtained with a separate administration of metformin and glibenclamide.

Description

SOLID ORAL DOSAGE FORM THAT COMPRISES A COMBINATION OF METFORMIN AND GLIBENCLAMIDE DESCRIPTION OF THE INVENTION 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 hyperglycemia, caused by insulin deficiency, insulin resistance and reduced glucose tolerance. There are two main groups of oral antidiabetic drugs: these are the sulfonylureas and the biguanides. The sulfonylureas act by stimulating the release of insulin and therefore are only effective with some residual activity of the pancreatic beta cell, examples of existing sulfonylureas being glyburide, glycazide, tolbutamide, glipizide, tolazamide, gliquidone and chlorpropamide. Biguanides, such as metformin, act by decreasing gluconeogenesis and increasing the peripheral utilization of glucose, and because they require endogenous insulin they are only effective with some residual activity of the pancreatic islet cell.

REF .: 33029 & amp; Jm? * 8Li £ k '- The initial treatment of non-insulin-dependent diabetes includes control of diet and exercise. Only after this has proved inadequate are oral antidiabetic drugs used, and this only to complement the effect of the diet, not to replace it. Monotherapy with an oral antidiabetic can be an effective treatment for many years. However, efficiency may decrease over the years. Because sulfonylureas and biguanides have complementary modes of action, combination therapy is now a form of established treatment for non-insulin-dependent diabetes. To improve acceptance by the patient, a combined tablet would be advantageous. The present invention relates to solid oral dosage forms comprising a combination of metformin and glibenclamide (also known as glyburide). WO 97/17975 has disclosed the combination of metformin with glibenclamide for the treatment of type II diabetes with a defined relationship between the two active ingredients required for optimal therapeutic effect. This prior art defines an optimal therapeutic relationship between metformin hydrochloride and glibenclamide of 100: 1, for example S "? ^^^^^^^^^^ e ^ j ^^^^ s ^^ t ^^^ ^^ í3¿ 500 mg metformin hydrochloride 5 mg of glibenclamide in a unit dose. This relationship allows a range of daily doses, based on the amount of tablets taken per day, which prevents a poor control of the disease by lower dose of any of the ingredients when joint administration is required, and avoids hypoglycemia by overdose of any of the components when they are administered together. The performance guarantee in clinical use, to derive a product having a good bioavailability of the glibenclamide component, is a key requirement for physicians wishing to treat patients with a combination formulation. Proper bioavailability implies that May 15 mg of glibenclamide formulated into a combination tablet with metformin is absorbed as acceptably similar and comparable speed to the glibenclamide dosed as single formulation of the same strength when dosed together with a unique entity formulation of metformin. This prior art does not teach how to formulate a combined product of metfor m with glibenclamide so as to ensure an appropriate bioavailability of the glyburide component. No reference is made to this respect in the case of metformin hydrochloride Sfc * ..j Sg? * cause of its high solubility in water and therefore the bioavailability of metformin from combined formulations will not be further analyzed. However, it is a very important aspect to consider in relation to glibenclamide, since it is a substance not very soluble in water (the solubility is 0.1 mg / ml in water at 25 ° C practically insoluble according to the definition of the USP). As such, its Solution Index after administration in a dosed form will influence the speed and degree of entry of the drug into the bloodstream (bioavailability). The control of the speed and degree of entry into the bloodstream is important for an appropriate therapeutic effect. Therefore, the reference presents an adequate ratio of the two active ingredients in a single dose form, to design how the two additional ingredients could be administered jointly and advantageously (on the basis of how they would be dosed in usual practice in association with the unique entity formulations currently in existence), without teaching how to guarantee that said combined formulation will act in terms of bioavailability of glibenclamide. This bioavailability should be as similar as possible ^^^^^^^^^^ gi ^^^^^^^^^ g ^^^^ n ^^^^^^^^ gj ^^^^^^^^^ H ^^^^ ^^^^ - ^ when the relevant doses of the two unique entity formulations are adhered together. In addition, when a combination tablet, using standard galenic procedures, is processed with standard generic glibenclamide in the combination tablet, a lower bioavailability was clear compared to the co-prescribed situation. It has now been discovered, using in vitro and in vivo tests, that the lower bioavailability is related to the particle size and granulometry of glibenclamide. It has been found that too small particles result in high levels of glibenclamide in blood with the consequent risk of hypoglycaemia, and that too large particles can not dissolve rapidly enough to give a bioavailability comparable to the co-prescribing situation. It is therefore necessary to have a well defined granulometry of glibenclamide in the combined form. The selection of a glibenclamide fraction of specific size allows the production of an oral dosage form comprising a combination of metformin and glibenclamide, and in particular a tablet, having a bioavailability of glibenclamide comparable to the bioavailability obtained with the ** &; - separate administration of metformin and glibenclamide, as judged by the area under the curve of the in vivo analyzes. The present invention provides in particular a tablet comprising a combination of metformin and glibenclamide, which has a bioavailability of glibenclamide comparable to the case of tablets administered jointly. In a first embodiment, the oral solid form such as a tablet, according to the invention, cons a combination of glibenclamide and metformin in which the size of the glibenclamide is such that at most 10% of the particles have less of 2 μm and at most 10% of the particles exceeds 60 μm. Preferably, the size of the glibenclamide is such that at most 10% of the particles are less than 3 μm and at most 10% of the particles exceed 40 μm. This specific particle size range of glibencla ida can be obtained by sifting or grinding by air jet. In a second embodiment, the solid oral dosage form comprises a combination of metformm and glibenclamide where the size of glibenclamide is such that at most 25% of the ^. ^^^ 1T --- ^^ M - ^^ tfawama k particles measured less than 11 μm and at most 25% of the particles measured more than 46 μm. Preferably, 50% of the particular ones measure less than 23 μm. Metformin can be used as a metformm salt, such as hydrochloride, fumarate, hydrobromide, p-chlorophenoxy acetate or embonate. The weight ratio between the salt of metformin and glibenclamide should preferably be between 50/1 and 250/1. Preferred compositions for the oral dosage form are provided in the following table, in which the ranges of the components are given. ^ - ^ r * ^ S -. ^^^ 'g * A composition for commercial coating film is used, for example Opadry (Clorcon, UK). The especially preferred compositions are the following: * A composition for commercial coating film is used, for example Opadry (Colorcon, UK). The tablet according to the present invention can be obtained by a process comprising: a) granulation by wet granulation of a mixture of metformin and glibenclamide; b) mixing the granules with an auxiliary to form tablets and diluents; and c) tabletting the mixture thus obtained by forming the tablets. Advaeously, the mixture used to form the granules comprises a granulator binder. This granulator binder is, in particular, a polyvinylpyrrolidone, such as, for example, a polyvinylpyrrolidone with a molecular weight of 45,000. The polyvinylpyrrolidone can be used in a proportion of 2-4% by weight with respect to the final tablet. After the granulation step, the granules can be sieved and dried. The granules are then mixed with a diluent and auxiliary tablet The diluent can be any material commonly used for the manufacture of tablets, such as microcrystalline cellulose The auxiliary tablet can be any material commonly used for the manufacture of tablets, as is the magnesium stearate.

The obtained tablets can then be coated with hydrophilic cellulose polymer and talcum. The hydrophilic cellulose polymer can be 2-hydroxypropylmethylcellulose. The invention will be illustrated by means of the following examples and tests.

Example 1 A metformin / glibenclamide tablet was prepared as follows: 66.6 g of polyvinylpyrrolidone are mixed with 246 g of purified water with a stirrer. 1500 g of metformin hydrochloride, 7.5 g of glibenclamide (with 10-90% of size range between 2 and 60 μm), 42 g of croscarmellose sodium and 284.4 g of microcrystalline cellulose are mixed in a granulator. The polyvinylpyrrolidone solution is added to the granulator and the wet mass is granulated. The granules are extruded through a 1 m mesh. The granules are emptied into a preheated fluidized bed dryer and dried. 97.5 g of microcrystalline cellulose are mixed with the granules using an oscillating mixer. Add 12 g of magnesium stearate to the oscillating mixer and mix. The mixture of granules is made into tablets using a suitable tableting press.

The tablets are coated with a coating of 2% hydroxypropylmethylcellulose in a coater.

Example 2 A tablet of metformin / glibenclamide was prepared as follows: 5.83 g of glibenclamide (with a size range of 10 to 90% comprised between 2 and 60 μm) are pre-mixed with 32.67 g of croscarmellose sodium. 46.67 g of polyvinylpyrrolidone are mixed with 93.33 g of purified water with a stirrer. The mixture of glibenclamide-croscarmellose sodium is mixed with 1166.6 g of metformin hydrochloride in a granulator. The polyvinylpyrrolidone solution is added to the granulator and the wet mass is granulated. The granules are emptied into a preheated fluidized bed dryer and dried. The particle size of the granules is reduced by passing through a 1 mm mesh. 131.83 g of microcrystalline cellulose are mixed in the granulator with the granules. 16.3 g of magnesium stearate are added to the granulator and mixed. The mixture of granules is made into tablets using a suitable tableting press. The tablets are coated with a coating of 2-hydroxypropylmethylcellulose at 2 - in a coater.

Test 1 In vivo bioavailability tests were performed with tablets prepared as indicated in example 2, using two batches of glibenclamide. The two batches had the following particle size range from 10 to 90%: lot A: 3.47-38.08 μm lot B: 15.63-91.6 μm The granulometry of batches A and B are illustrated in figure 1. Both were administered lots of tablets to healthy patients compared to co-administered glibenclamide (marketed under the Daonil brand) and metformin hydrochloride (16 patients for each group). The comparative concentrations of glibenclamide in a tablet comprising a combination of metformm and respectively lot A and lot B of glibenclamide and with co-administration are shown respectively in FIGS. 2 and 3. & ,; ~.

The area under the curve. { AUC) is: (AUC (ng / ml / h) Combination with lot A 790.5 Combination with lot B 353.0 co-administration 869.3 It appears that with the combination according to the invention with lot A, the AUC is substantially the same as in the case of co-administration, whereas in combination with the Lot B the AUC is more clearly distinct.

Test 2 A careful examination of glibenclamide levels in blood in humans after the administration of a series of formulations in tablets of metformin hydrochloride combined with glibenclamide (identified as Combo formulations 1, 2, 3 and 4), where the formulation it is ideative except for the particle size characteristics of the glibenclamide used, compared to the commercial reference formulations of metformin hydrochloride (Glucophage ^, Bristol-Myers Squibb) and glibenclamide Micronase'M, Upjohn) dosed together, allowed the definition of the particle characteristics for enclamide that would guarantee the - & * • iJiG & amp; amp; & S £ ß £ gS & amp; Adequate bioavailability of the enclamide component from the combined formulation. This means that control of the disease when treating patients with such a combination in the formulation for the first time will be predictable, based on prior medical knowledge of treatments that use any of the drugs individually. Alternatively, if patients have been subjected to prior stabilization of their disease by adding a commercial product such as Micronase ™ to the existing treatment on Glucophage ™ (or vice versa), the switch to a more convenient treatment using the combination in a single tablet ( and where appropriate bioavailability of the glyburide component) will maintain the desired level of disease control. The data from studies with metformin / gl ibenclamide hydrochloride tablets of different particle size characteristics allowed the development of a correlation between the particle size of the drug and the performance in vi vo. The properties of the glyburide lots used in the series of combined tablets used are shown in the following table: When four individual batches of identical composition of metformm / glyburide 500 / 2.5 mg hydrochloride tablets were prepared using each of these batches of enclamide and administered to humans, the following pharmacokinetic parameters were found by analyzing the plasma concentration curves -enclamide time: A reasonable correlation can be obtained between the particle size and the maximum geometric mean obtained in terms of plasma concentration of fM enclamide, Cmax, "^^ also with the mean geometric area under the plasma concentration-time curve of enclamide, AUC.From these correlations, the projected limits on the particle size for the glyburide that would give Cmax and AUC values predicted + 25% of a mean value for batches of the reference enclamide formulation, Micronase ™, used in the two in vivo studies was transformed into: subdim limits 25% subdiv. Limits 50th subdim limits 75% Cmax < 0-18 microns < 0.37 microns < 0-63 microns AUC < 0 -11 microns < 0-25 microns < 0-46 microns Adapting the Cmax and AUC requirements, the projected limits were then transformed into: subdim limits 25 * limits subdim. fifty? subdim limits 75% < 11 microns < 23 microns < 46 microns enclamide with these particle size characteristics has dust surface area values between 1.7 and 2.2 prg "1 as determined by nitrogen adsorption.Therefore, the material of these properties, when formulated as istoS is described in this work, it is distinguished from the material disclosed in US 3,979,520 which required enclamide of powder surface area of more than 3 nrg "1 (preferably between 5 and 10 prg-1) to yield a bioavailability of enclamide The enclamide of particle size properties such as those described in this work, when formulated as described herein, produces the bioavailability of appropriate enclamide in humans, as describes below.

Test 3 A batch of metfor in-enclamide hydrochloride tablets of 500/5 mg was prepared as follows. HE mixed by stirring enclamide (1.0 kg) with the size defined above with 2.8 kg of croscarmellose sodium and this mixture was then combined in a high-cut mixer with metformin hydrochloride (100 kg) to which 0.5% by weight of stearate had been added. of magnesium. This dry mix was wet granulated in a high-cut mixer - with 12.1 kg of an aqueous povidone solution (containing 4 kg of povidone). The wet granules were dried in a fluid bed dryer at 60 ° C to a defined moisture level. The dry granules (loss on drying 2-3% w / w) were reduced The size in an oscillator (screen aperture 1.0 mm) is then mixed by rotation with 10.8 kg of microcrystalline cellulose, followed by mixing with 0.9 kg. of lubricating magnesium stearate for tablets. The lubricant granules were compressed using 16mm x 8mm capsule-shaped tooling and the tablet cores were film coated (gained weight approximately 2% w / w) with the patented Opadry 32920 material to yield the yellow final tablets in the form of capsule. In a human pharmacokinetic study, one of these tablets was administered to volunteers or with a treatment consisting of the joint administration of a 500 mg Glucophage ™ and a 5 mg Micronase ™ tablet. Plasma glibenclamide levels were analyzed after administration and the following pharmacokinetics were found for this component: • ^ t & ** JtWtt The bioavailability of glibenclamide from the combined tablet is comparable to that of the formulation of the reference lick, Micronase ™. This would allow patients, conveniently, to take one tablet of the combined product instead of two tablets together of existing therapies, without worrying about possible results of low levels of glibenclamide in the blood that could appear with formulations of the prior art which cause loss of control of the disease.

Example 3 Instead of forming tablets, the granulate prepared for test 3 was filled into size 00 capsules to provide the product metformin hydrochloride / glibenclamide 500 mg / 5 mg or the product of 500 mg / 2.5 mg. The granulate was filled into size 1 capsules to provide the product of 250 mg / 2.5 mg.

These capsules presented acceptable physical properties providing an alternative to the tablets.

The formulations described in WO 97/17975 could not be introduced into capsules of a size that was acceptable to most patients due to the ^ j? Á * íáí ^^^ e ^^ s ^^ SjáSg greater amount used by the formulations described therein.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

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Claims (8)

1. Having described the invention as above, the claim contained in the following claims is claimed as property: 1. An oral solid dosage form, characterized in that it comprises a combination of metformin and glibenclamide in which the of glibenclamide is such that the bioavailability of glibenclamide is comparable to the bioavailability of glibenclamide obtained by a separate administration of metformin and glibenclamide.
2. 2. An oral solid dosage form, characterized in that it comprises a combination of metformin and glibenclamide in which the of the glibenclamide is such that at most 10% of the particles is less than 2 μm and at most 10% of the particles exceeds 60 μm.
3. 3. A solid oral dosage form according to claim 2, characterized in that the of the glibenclamide is such that a maximum of 10% of the particles is less than 3 μm and a maximum of 10% of the particles exceeds 40 μm .
4. 4. An oral solid dosage form, characterized in that it comprises a combination of metformin and glibenclamide in which the of the glibenclamide is such that at most 25% of the particles is less than 11 μm and at most 25% of the particles exceeds 96 μm.
5. 5. An oral solid dosage form, characterized in that 50% of the particles do not exceed 23 μm.
6. 6. An oral solid dosage form according to any one of claims 1 to 4, characterized in that the metformin is present as the metformin salt and the weight ratio between the salt of metformm and glibenclamide is between 50/1 and 250/1 .
7. 7. A solid oral dosage form according to any of claims 1 to 6, characterized in that it is a tablet.
8. 8. A tablet according to claim 7, characterized in that it is obtained by a process comprising: a) they were granulated by wet granulation of a mixture of metformin and glibenclamide; b) mixing the granules with a tablet aid; c) tabletting the mixture thus obtained forming tablets. SOLID ORAL DOSAGE FORM THAT COMPRISES A COMBINATION OF METFORMIN AND GLIBENCLAMIDE SUMMARY OF THE INVENTION The present invention relates to a solid oral dosage form comprising a combination of metformin and glibenclamide in which the volume of glibenclamide is such that the bioavailability of glibenclamide is comparable to the bioavailability of the glibenclamide obtained by a separate administration of metformin and glibenclamide.