SOLID DOSAGE FORM OF AN ANTIDIABETIC DRUG

Field of the invention

The present invention relates to solid dosage forms of an antidiabetic drug glyburide. More particularly, the present invention relates to solid dosage forms of antidiabetic drug glyburide with specific particle size and specific surface area.

The present invention also relates to solid dosage forms of antidiabetic drug glyburide with specific particle size in combination with Metformin HCl. The present invention also relates to a process for the preparation of solid dosage forms of antidiabetic drug glyburide with specific particle size and specific surface area.

Background of the invention

Glyburide, also known as glibenclamide, chemically known as 5-chloro- N- [2- [4- [ [ [(cyclohexy lamino)-carbony 1] amino] sulfony l]pheny 1] ethyl] -2- methoxybenzamide. Glyburide is a commercially available product indicated for the treatment of type II diabetes.

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 glyburide, gliclazide, tolbutamide, glipizide, tolazamide, gliquidone and chlorpropamide. The biguanidines, such as metformin, act by decreasing gluconeogenesis and by increasing peripheral utilization of glucose, and as they require endogenous insulin they are only effective with some residual pancreatic islet cell activity.

Because of the poor water solubility of glyburide, the rate of dissolution of the drug from a dosage form is a controlling factor in determining the rate and extent of drug absorption. The rate of dissolution depends on particle size and also the choice of excipients used in the formulation. Borchert (Pharmazie, 31 :307-309,1976) demonstrated the importance of this in- in vivo studies in rats

and dogs, which showed more extensive absorption of glyburide when a fine particle size material was evaluated against a. coarser material, the drug being administered as a suspension.

Glyburide is marketed commercially under the trade name MICRONA SE® and its combination with metformin is marketed under the trade name GLUCOVANCE®.

US patent Nos. 3,979,520 and 4,060,634 describe the use of micronized or high surface area, preferably 3 to 10 m2/g glyburide, in combination with various pharmaceutically acceptable excipients to obtain enhanced bioavailability.

US 4,916, 169 discloses micronized glyburide composition as a unit dose, containing one or more pharmaceutically acceptable excipients, the improvement which comprises spray-dried lactose as the preponderant excipient in said composition, being present therein at about not less that seventy percent (70%) by weight of the final composition.

US patent No. 5,922,769 discloses a combination of glibenclamide and metformin in a 1 : 100 weight ratio, so as to allow a daily dosage of 15 mg glibenclamide and 1500 mg metformin, used for the onset of diabetes to the most severe cases, particular in cases of secondary failure to a combination of glibenclamide-metformin HCl in a weight ratio higher than 1 : 100.

US patent No. 6,303,146 describes a dosage form comprising a combination of metformin and glibenclamide in which the size of the glibenclamide is such that at most 10% of the particles are less than 2μm and at most 10% of the particles are greater than 60 μm, so that the glibenclamide bioavailability is comparable to the glibenclamide bioavailability obtained with a separate administration of metformin and glibenclamide.

US patent No. 6,830,760 discloses a tablet composition comprising glyburide having the following particle size distribution characteristics: 25% undersize value between 3 and 11 μm, 50% undersize value between 6 and

23 μm, and 75% undersize value between 15 and 46 μm and a second drug, wherein the second drug being a drug that is useful for the treatment of type II diabetes.

In view of the importance of glyburide and its combination with metformin hydrochloride as a potential agent for the treatment of diabetes, we have developed new formulations, which are bioequivalent with respect to the marketed dosage forms.

Objective of the invention

Accordingly, the main objective of present invention is to provide solid dosage forms of glyburide, which comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parametes like dissolution, disintegration.

Yet another objective of the present invention is to provide simple, and efficient process for preparing solid dosage forms of glyburide on a commercial scale.

Summary of the invention

According to the main embodiment of the present invention, there is provided solid dosage forms of glyburide having the particle size distribution such that about 30% of the particles are less than 3 μm, about 50% of the particles are less than 5 μm, and about 90% of the particles are less than 30 μm.

Detailed description of the invention

In view of poor water solubility of glyburide, the rate of dissolution of the drug from a dosage form is a controlling factor in determining the rate and extent of drug absorption. The rate of dissolution depends on particle size and also the choice of excipients used in the formulation.

The glyburide of present invention has a defined particle size distribution. This particle size distribution provides an enhanced rate of dissolution of the glyburide compared to bulk glyburide and reproducible bioavailability in vivo.

The present invention also provides solid dosage forms of glyburide and combination of glyburide and at least one other antidiabetic agent selected from glycosidase inhibitors such as acarbose; thiazolidinediones such as rosiglitazone, pioglitazone; biguanides such as metformin hydrochloride; nateglinide or repaglinide.

The solid dosage form of the present invention is in the form of a capsule, single tablet containing glyburide and other active substance; tablet in tablet, bilayered tablet and the like.

The desired particle size distribution of the glyburide of the present invention is such that 90% of the particles are less than 30 μm. The desired particle size distribution is obtained by sieving or air jet milling. The particle size distribution is measured by a laser light scattering method. Glyburide having this particle size has specific surface area of about 1 to 3 m ² /g, as measured by BET method. The solid dosage forms of glyburide of the present invention, further comprises one or more pharmaceutically acceptable excipients such as diluents, binder, disintegrant, lubricants and the like, when formulated into tablets or capsule.

The preferred excipients, known in the art, would be those that allow drug release to occur without substantially influencing the rate of drug dissolution and absorption. Such excipients would be highly soluble in water, and hence dissolve rapidly when the dosage form is immersed in an aqueous environment. In this way, the poorly soluble glyburide is liberated as a finely divided suspension.

Dissolution of glyburide from this suspension, the rate of which is controlled by the particle size distribution of the suspension, is a prerequisite for absorption.

Hence, the absorption characteristics are defined by the particle size distribution of the glyburide

Suitable diluents of the present invention are selected from sugars such as sucrose, lactose, maltose and glucose; sugar alcohols such as mannitol, sorbitol

and xylitol; oligosaccharides such as maltodextrins; calcium phosphate-dibasic, calcium carbonate, cellulose-microcrystalline and the like or combinations thereof.

Suitable disintegrants of the present invention are selected from croscarmellose sodium, sodium starch glycollate, crospovidone and sodium alginate and the like.

The formulation may include binder such as povidone, low viscosity hydroxypropyl methylcellulose, starch, pregelatinized starch and the like.

Suitable lubricants of the present invention are magnesium stearate, hydrogenated vegetable oil, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate and the like.

The formulation may optionally include other excipients such as glidants, anti- adherents, colors, flavors, film coating components.

The present invention also provides a process for the preparation of solid dosage forms of glyburide and combination of glyburide and other antidiabetic agents. The different formulation processes that can be employed for making the disclosed formulations are dry granulation (slugging, compaction), wet granulation, and. direct compression.

The processing steps involved in making tablet dosage forms of glyburide are as given here : i) sifting and mixing glyburide of the desired particle size, metformin HCl, diluents, disintegrants in a rapid mixer granulator, ii) granulating the materials of step (i) using binder solution, drying the granules obtained in fluid bed dryer, iii) blending the granules of step (ii) with extragranular excipients and v) compressing the lubricated granules to obtain glyburide and metformin

HCl tablets.

The following examples further exemplify the inventions and are not intended to limit the scope of the inventions. Example 1 Single tablet containing glybiiride and metformin HCl

The particle size distribution of glyburide is : 30 % of the particles are less than 0.7 μm 50 % of the particles are less than 1.5 μm 90 % of the particles are less than 4.5 μm.

The processing steps that were involved in making tablet dosage forms of glyburide and metformin are as given here : i) sifted and mixed metformin HCl, glyburide, croscarmellose sodium and . microcrystalline cellulose in a rapid mixer granulator,

ii) granulated the materials of step (i) using binder solution of povidone in water, dried the granules in fluid bed dryer at 4O ⁰ C +5 ⁰ C, iii) sifted the granules & milled the retentions, iv) blended the granules of step (iii) with extragranular excipients and lubricated magnesium stearate and v) compressed the lubricated granules to obtain glyburide and metformin HCl tablets.

Dissolution Profile of Glyburide and Metformin HCl Tablets 5mg/500mg A) Metformin HCl Component

The tablets were subjected to an in vitro dissolution method to determine the rate at which the metformin HCl was released from the tablets. The tablets were placed into a dissolution medium of pH 6.8 phosphate buffer and stirred with paddles at 50 rpm (USP 2 apparatus). The dissolution profile is given in Table 1.

Table 1

B) Glyburide Component

The tablets were also subjected to an in vitro dissolution method to determine the rate at which the glyburide was released from the tablets. The tablets were placed into a dissolution medium of pH 9.5 borate buffer and stirred with paddles at 75 rpm (USP 2 apparatus) The dissolution profile is given in Table 2.

Table 2

Example 2 Glyburide Tablet

The particle size distribution of glyburide is 30 % of the particles are less than 2 μm 50 % of the particles are less than 4.5 μm 90 % of the particles are less than 20 μm.

i) sifted glyburide, dibasic calcium phosphate dihydrate, sodium alginate, microcrystalline cellulose and mixed in a suitable blender, ii) lubricated the blend of step (i), with talc and magnesium stearate and iii) compressed the lubricated blend of step (ii) to obtain tablets of glyburide.

The tablets were also subjected to an in vitro dissolution method to determine the rate at which the glyburide was released from the tablets. The tablets were placed into a dissolution medium of pH 9.5 borate buffer and stirred with paddles at 75 rpm (USP 2 apparatus). The dissolution profile is given in Table 3.

Table 3

In vivo bioequivalence studies were performed on 5mg tablets of glyburide prepared as per composition of example 2 as test and MICRONASE® 5 mg tablets as reference, under fasting conditions. The results are given in table 4.

Table 4

Example 3

Tablet in tablet containing glyburide and metformin HCl

Metformin HCI blend

i) sifted and mixed metformin HCl and povidone in . a rapid mixer granulator, the blend of step (i) was granulated with binder solution of povidone in water in rapid mixer granulator, iii) loaded the wet granules into fluid bed dryer, iv) dried the granules at 50 + 10 °C and ^' v) lubricated the granules of step (iv) with magnesium stearate.

Glyburide tablets prepared as per the procedure described in example 2 were loaded into one hoper and metformin HCl blend obtained above were loaded into second hoper and compressed the tablets to obtain tablet in tablet.