WO2013034174A1

WO2013034174A1 - Solid preparations of pioglitazone and glimepiride

Info

Publication number: WO2013034174A1
Application number: PCT/EP2011/065415
Authority: WO
Inventors: Özkan CAKMAK; Hülya SARAC; Naci BITIK; Mustafa Adiyaman
Original assignee: Zentiva Saglik Urunleri Sanayi ve Ticaret AS
Current assignee: Zentiva Saglik Urunleri Sanayi ve Ticaret AS
Priority date: 2011-09-06
Filing date: 2011-09-06
Publication date: 2013-03-14
Anticipated expiration: 2014-03-06

Abstract

The present invention relates to solid preparations and combinations of pioglitazone and glimepiride, and a method for their preparation. The method comprises granulating pioglitazone and glimepiride with other excipients individually, and blending the both granulates to obtain solid oral dosage forms with improved stability and dissolution profile.

Description

SOLID PREPARATIONS OF PIOGLITAZONE AND GLIMEPIRIDE

Field of the Invention

The present invention relates to solid preparations of insulin sensitizers and insulin secretagogues. More particularly, the invention is relating to the methods and preparations directed to pioglitazone and glimepiride combinations having improved dissolution profile.

Background of the Invention

Combining the existing oral antidiabetics for obtaining synergistic effect over sole use of the active ingredients is gaining increasing popularity in management of type II diabetes. Pioglitazone hydrochloride, having the general nomenclature of (±)-5-[[4-[2- (5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride is known as a muscle sensitivity enhancer against insulin, and is marketed under the trade name of Actos®. Glimepiride, known with the chemical name 1-[[p-[2-(3-ethyl-4- methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclo hexyl)-urea is an effective stimulator for insulin release, and is marketed under the trademark Amaryl®. These two active ingredients are subjected to numerous formulation attempts because of the increased effect of their combinations. They, however suffer of severe incompatibility in their dissolution profiles because of the considerably low dissolution rate of glimepiride in oral solid combinations. This is because the dissolution profile of glimepiride dramatically worsens by suppression of other ingredients of the combinations, hence single granulation for preparing such combinations is not preferable and is constituting major disadvantages of the commonly used processes of prior art. Further problems appear with low stability and high friability resulting in the fact that final product becomes incommodious before and after the oral uptake of solid dosage forms.

EP-A2-1 174135 discloses the combinations of the thiazolinediones and sulfonylureas without stating the problems mentioned above. To solve the aforementioned problems, production of the solid preparations as bilayer tablets in existence of a surfactant such as polysorbate 80 is known from the popular antidiabetics by Takeda Pharmaceuticals marketed as Duetact® in the USA and Tandemact® in EU. Polysorbate 80 is included to the glimepiride layer for increasing its dissolution performance and making it compatible with pioglitazone in their dissolution profiles. It is highly desired that both active ingredients are released with similar profile as in their corresponding monocomponent forms. To achieve this object, oral tablets are compressed in bilayer forms to physically separate the pioglitazone and glimepiride parts in order to maintain their dissolution profiles as in their individual formulations. This is however, not preferable because the production of the pharmaceutical formulations as bilayer tablets decreases the production capacity with at least 60-70% as compared to monolayer tablets. This production technique additionally needs more investment and qualified labor force rendering it disadvantageous in industrial scale. Therefore, compressing oral tablets in monolayer form without having the aforementioned technical problems is currently a challenge in the technical field. Moreover, eliminating the use of surfactants such as polysorbate is further objective of those skilled in the art as addition of surfactants has effect on tableting process, e.g. it apparently decreases tablet hardness and increases friability.

A further attempt, as for instance disclosed in WO-A2-2009/120844, involves preparation of the solid formulations in existence of cellulose derivatives, such as microcrystalline cellulose, as an alternative solubility enhancer for elimination of the friability problems associated with polysorbate.

WO-A2-2007/072992 provides another way of solving the dissolution problems by a solid preparation wherein pioglitazone is coated with lactose or sugar alcohol for tolerating late dissolution of glimepiride. The document also discloses multilayer tablets including combinations of pioglitazone and glimepiride. Moreover, the tablets in multilayer form suffer of the drawbacks as per mentioned above because of the need for extra coatings as well as polysorbate in solid preparations.

Thus, it is one of the objects of the present invention to provide a new solid preparation of pioglitazone and glimepiride with improved dissolution profile. A further object of the present invention is to provide new solid preparations wherein the use of a surfactant such as polysorbate is eliminated.

Another object of the present invention is to provide new solid preparations wherein problems of friability and complicated coatings as in the conventional mono- or bilayer tablets are eliminated.

Another object of the present invention is to provide a new method of producing pioglitazone-glimepiride combinations which is efficient and cost effective as compared to the conventional methods.

Still a further object of the present invention is to provide a new method for achieving the above objectives. These and other objectives that may be apparent to those skilled in the art in light of the description and appended claims are solved by a novel method including individual wet granulation steps as disclosed in claim 1.

Summary of the Invention

The invention is directed to the solid combinations of pioglitazone and glimepiride as well as a novel method for their production. Said method involves individually granulating the pioglitazone and glimepiride in certain excipients and then drying and blending the same into a homogenous mixture that has improved stability and dissolution profile. The resulting solid combinations exhibit good solubility especially in terms of the glimepiride part which is known as hardly soluble as compared to its individual formulations. With this novel approach production of tablets in monolayer forms becomes possible by virtue of the improved solubility of glimepiride in such combinations. The method and the eventual product are also advantageous with elimination of the surfactants such as polysorbate that increases friability of solid drugs.

Detailed Description of the Invention

The solid preparations of the present invention comprise a combination of pioglitazone and glimepiride that are individually prepared by wet granulation with other excipients prior to final blending, and are finally blended and compressed to obtain monolayer tablets having improved dissolution profile.

Thus, according to a first aspect of the present invention there is provided a novel method of preparing pioglitazone-glimepiride combinations, involving wet granulation of the active materials individually, and blending and optionally compressing the same into monolayer tablets.

In one of the granulation steps, pioglitazone is mixed with other excipients in the presence of purified water. Granules are then dried for decreasing the moisture content and milled for obtaining them in desired particle size. In the procedure above, pioglitazone HCI salt is particularly preferred, and is having a preferred particle size of less than 150μηι before being added to the granulation mixture. In a second wet granulation step, glimepiride is mixed with other excipients in the presence of purified water, and granules are then dried and milled similar to the procedure above. The preferred particle size of active agent glimepiride is less than 10 microns before being added to the granulation mixture. In both of the granulation steps, a high shear mixer granulator may well be used for obtaining homogenous mixtures. The excipients may be arranged such that at least one filler, binder and disintegrant as conventionally known in the pharmaceutical industry are combined in the high shear granulator. The binder and disintegrant materials may for instance be povidone and croscarmellose sodium respectively, although many other alternatives are available in the art and the reference books.

In a further step of the method the pioglitazone part granules and glimepiride part granules as obtained in the aforementioned granulation steps are blended to form a homogenous mixture. This blending step may also involve certain excipients such as disintegrants, fillers, diluents and lubricants. As a lubricant, magnesium stearate is particularly preferred.

In the final step of the method according to the present invention, the final blending mixture is compressed into monolayer tablets, for instance in a rotary tableting machine. In preferred dosage forms the formulations according to the present invention comprise 30mg pioglitazone + 4mg glimepiride or 30mg pioglitazone + 2mg glimepiride.

In average process equipment, monolayer tablets provide at least 60 to 70% more production rate as compared to that of the multilayer tablets. This is an indication of long felt need in the pharmaceutical industry because the conventional products, with bilayer or multilayer structure, considerably limit the production rates and need additional surfactants for elimination of the dissolution problems. The monolayer tablets do also exhibit improved content and mass uniformity as well known in the pharmaceutical technology.

The inventors noted that these problems are overcome by the method of the present invention which provides tablets having increased compatibility between pioglitazone and glimepiride in terms of stability and dissolution profiles. These effects are attributed to the individual wet granulation steps applied in the procedure. The specific particle sizes of the individual active ingredients are also thought to contribute to the rate of dissolution as mentioned above.

Further aspects and advantages of the present invention will be apparent to those skilled in the art upon reading the description above along with the following examples which are non-limiting to the scope of the invention.

Example 1

Preparation of oral tablets comprising pioglitazone and glimepiride Granulation I

For the granulation, purified water was transferred into a vessel. Lactose, Pioglitazone HCI, croscarmellose sodium and Povidone were put into a high shear mixer granulator. This powder mixture was mixed at low speed for homogenization before the granulation step. Purified water was added slowly into the powder mixture in the high shear mixer granulator and granulation was continued. The granules were then dried, and finally milled. Granulation II

For the granulation, purified water was transferred into a vessel. Lactose, Glimepiride, croscarmellose sodium and Povidone were put into a high shear mixer granulator. This powder mixture was mixed at low speed for homogenization before the granulation step. Purified water was added slowly into the powder mixture in the high shear mixer granulator and granulation was continued. The granules were then dried in oven. The granules were finally milled.

Blending and tableting

Pioglitazone part granules and Glimepiride part granules as obtained in the above procedures were blended together with microcrystalline cellulose and croscarmellose sodium. Magnesium stearate was then added to the powder mixture and final mixture was continued to be blended. The final mixture was then compressed into tablets in a rotary tableting machine to obtain monolayer tablets. The tablets obtained with the procedure above were having the following composition:

Table I. Formulation according to Example I

UNIT

INGREDIENTS FORMULA

(mg / tabl.)

Pioglitazone HCI

33,07

Glimepiride 4,00

Lactose (Hydrous) 212,96

Povidone 25 5,86

Croscarmellose Sodium 15,31

Microcrystalline Cellulose 27,00

Magnesium Stearate 1 ,80 Example 2

Tablets according to the formulation of Table I were prepared with a single granulation step wherein the active ingredients and other excipients with the same amounts as in Example 1 were put into a high shear granulator and purified water was added to the powder mixture followed by drying and milling. Compressed tablets were obtained in a rotary tableting machine in monolayer form.

Example 3

The procedure of Example 2 was repeated with the exception that polysorbate 80 was added to the granulation mixture to obtain the following formulation.

Table II. Formulation according to Example 3

Example 4

Dissolution profiles of the tablets

Tablets as obtained according to Examples 1 , 2 and 3, as well as the commercial tablets of Actos® 30 mg tablet (Pioglitazone, UK) and Amaryl® 4 mg tablet (Glimepiride, UK) were subjected to dissolution tests and their dissolution rates were compared with each other at different pH values, using dissolution apparatus type II (paddles), at 75 RPM and at 37°C, in 900 ml dissolution medium. The dissolution media applied in the following dissolution tests are arranged as prescribed in the European Pharmacopoeia (EP). Dissolution tests for pioglitazone part

Pioglitazone HCI has a pH dependent solubility profile and is having low solubility at aqueous basic media. Therefore, dissolution behaviors of Pioglitazone HCI samples at pH 6.8 (EP) are excluded in the following data.

Table III. Dissolution profiles at pH = 1 (0.1 N HCI)

Table IV. Dissolution profiles at pH = 4.5 (EP)

Dissolution tests for glimepiride part

Glimepiride has also pH dependent solubility, and is having low solubility at aqueous acidic media. Therefore, dissolution behaviors of Glimepiride samples at pH 1 (0.1 N HCI) and pH 4.5 (EP) are excluded in the following data. Table V. Dissolution profiles at pH = 6.8 (EP)

Table VI. Dissolution profiles at pH = 6.8 (EP) + 0.2 % SLS

It was observed with the above data that dissolution profile of pioglitazone content of the formulation according to example 1 showed no substantial difference with the reference product (ACTOS). This is an indication showing the fact that combination of example 1 did not have substantial effect in dissolution profile of pioglitazone.

Similarly the glimepiride part also had substantially the same or even slightly a better dissolution profile compared to the reference product proving that the combination of Example 1 did not affect the solubility of the glimepiride side despite the sample of Example 1 was actually in the form of a combination unlike the reference product (Amaryl) which consists of a sole active ingredient with additional excipients.

Further comparative tests were carried out at pH 6.8 in the presence of SLS wherein the tablets of Examples 1 , 2 and 3 were compared with respect to their dissolution profiles. Table VII. Dissolution profiles at pH SLS

The comparative data of Table VII shows that the tablets prepared with the two step granulation according to Example 1 had superior dissolution profile as compared to other tablets prepared with single granulation procedures according to Examples 2 and 3. The procedure of Example 1 was even advantageous by providing superior effects as compared to Example 3 that involves Polysorbate 80 as a surfactant. Thus, it was clearly shown that the tablets of the invention eliminate the need for extra surfactants and specific coatings, and provide oral tablets that have improved characteristics inherent to the preparation procedure.

Claims

A method for the preparation of the solid oral combination forms of pioglitazone and glimepiride comprising the steps of:

a. wet granulation of pioglitazone with an excipient selected from the group consisting of a filler, binder and disintegrant,

b. wet granulation of glimepiride with an excipient selected from the group consisting of a filler, binder and disintegrant,

c. individually drying the both granulates and blending the same to obtain a homogenous mixture,

d. adding an extragranular excipient selected from the group of a filler, binder, disintegrant, diluent and lubricant, and finally mixing and compressing the same into tablets.

2. A method according to claim 1 wherein the tablets are compressed in monolayer form.

3. A method according to claim 1 wherein the filler is lactose in hydrous form.

4. A method according to claim 1 wherein the method further comprises milling and sieving of the granules of active ingredients in step a) and step b) such that the particle size of the pioglitazone HCI is less than 150μηι whereas the particle size of the glimepiride is less than 10μηι.

5. A method according to claim 1 wherein the binder is povidone 25, the disintegrant is selected from croscarmellose sodium and microcrystalline cellulose, diluent is microcrystalline cellulose and lubricant is magnesium stearate.

6. A method according to claim 1 wherein the amounts of pioglitazone and glimepiride are arranged to obtain a solid oral dosage form of 30mg pioglitazone + 4mg glimepiride or 30mg pioglitazone + 2mg glimepiride.

7. A solid preparation obtainable by the method of any of the preceding claims.

8. A solid preparation according to claim 7 which is in the form of monolayer tablets.