WO2006054165A1

WO2006054165A1 - Pharmaceutical compositions of alendronic acid and processes for their preparation

Info

Publication number: WO2006054165A1
Application number: PCT/IB2005/003471
Authority: WO
Inventors: Kamal Mehta; Raveendra M. Pai; Rajeev Shanker Mathur
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-11-19
Filing date: 2005-11-18
Publication date: 2006-05-26
Anticipated expiration: 2007-05-19

Abstract

The present invention relates to pharmaceutical compositions of alendronic acid and pharmaceutically acceptable salts thereof, and processes for their preparation.

Description

PHARMACEUTICAL COMPOSITIONS OF ALENDRONIC ACID AND PROCESSES FOR THEIR PREPARATION

Field of the Invention

Background of the Invention

A variety of bisphosphonic acids have been disclosed as being useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: US 3,962,432; US 4,054,598; US 4,267,108; US 4,327,039; US 4,621,077; US 4,624,947; US 4,746,654; US 4,922,077; and WO 02/03963. Various methods for tablet formulation of bisphosphonic acids have been employed, however, they are not entirely satisfactory.

For example, the use of the common diluent lactose, when employed in a solid dosage form of an active ingredient having a basic nitrogen-containing functionality, can result in discoloration, chemical instability and loss of potency of the dosage form. The mechanism responsible for the incompatibility of lactose with basic nitrogen-containing active ingredients is believed to be due to the Maillard (or "browning") reaction in which the basic nitrogen (typically a primary or secondary amino group) of the active ingredient reacts with the "glycosidic" hydroxyl group of lactose ultimately resulting in the formation of brown pigmented degradation products. Other sugars having a "glycosidic" hydroxyl group, such as glucose, also stimulate this degradation when employed as excipients in dosage forms of basic nitrogen-containing actives. Degradation of the active ingredient is particularly pronounced in the presence of water and/or elevated temperature.

The above problem can be solved by making a composition which is free of such excipients.

Attempts have been made to formulate bisphosphonates bearing a basic nitrogen- containing functionality with lactose as a diluent by eliminating water from the formulation process. A dry mix process using anhydrous lactose as a diluent avoids the enhanced degradation which occurs in the presence of water. Solid dosage forms prepared by such a process are exemplified in US 5,882,656. Summarv of the Invention

In one general aspect there is provided a pharmaceutical composition suitable for oral administration to a human. The composition consists essentially of (a) from about 0.5% to about 60% by weight of alendronic acid or a pharmaceutically acceptable salt thereof; (b) from about 10% to about 95% by weight of microcrystalline cellulose; (c) from about 0.5% to about 20% by weight of a disintegrant selected from the group consisting of starch, modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and (d) from about 0.1% to about 10% by weight of lubricant/glidant selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydro genated vegetable oil, sodium stearyl fumarate, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof. The composition is optionally film coated.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the composition may be in the form of a tablet. The pharmaceutically acceptable salts may include ammonium salts, alkali metal salts, alkaline earth metal salts, salts with organic bases, N-methyl-D-glucamine, and salts with amino acids. The pharmaceutically acceptable salt may be the sodium salt. The sodium salt may be the monohydrate, trihydrate, anhydrous or other polymorphic form.

The lubricant/glidant may be one or more of colloidal silicon dioxide, magnesium stearate and talc.

In another general aspect there is provided a process for the preparation of a pharmaceutical composition. The process includes the steps of (a) blending alendronic acid or pharmaceutically acceptable salt thereof and microcrystalline cellulose, (b) optionally milling the blend, (c) mixing the blend of step a) with a disintegrant and lubricant/glidant, (d) optionally granulating the blend, (e) optionally blending the granules with extragranular excipients, (f) lubricating the blend of step a) or granules of step b), and (g) compressing into or filling into a suitable size solid dosage form.

Embodiments of the process may include one or more of the following features. For example, the extragranular excipients may be one or more of microcrystalline cellulose, disintegrant, glidant and lubricant. The granulation may be carried out by wet or dry granulation technique. The wet granulation may be carried out with a granulating fluid or solution/dispersion of binder. The dry granulation may be carried out by roller compactor or slugging.

The composition may consist essentially of (a) from about 0.5% to about 60% by weight of alendronic acid or a pharmaceutically acceptable salt thereof; (b) from about 10% to about 95% by weight of macrocrystalline cellulose; (c) from about 0.5% to about 20% by weight of a disintegrant selected from the group consisting of starch, modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and (d) from about 0.1% to about 10% by weight of lubricant/glidant selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sodium stearyl fumarate, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.

In another general aspect there is provided a method of treating or preventing osteoporosis comprising administering a pharmaceutical composition consist essentially of (a) from about 0.5% to about 60% by weight of alendronic acid or a pharmaceutically acceptable salt thereof; (b) from about 10% to about 95% by weight of microcrystalline cellulose; (c) from about 0.5% to about 20% by weight of a disintegrant selected from the group consisting of starch, modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and (d) from about 0.1% to about 10% by weight of lubricant/glidant selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sodium stearyl fumarate, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Description of the Invention

The inventors have developed pharmaceutical compositions suitable for oral administration to a human. The compositions include alendronic acid, microcrystalline cellulose, disintegrant and lubricant/glidant, wherein the composition is free of sugars. Microcrystalline cellulose used in the composition serves various functions such as diluent and lubricant, as well as binder. The increasing microcrystalline cellulose content in a composition results in lowering of the requirement for a diluent as microcrystalline cellulose also has good compressibility. Hence, in some cases it can completely replace the diluent, e.g., as in the case of this invention. Additionally, microcrystalline cellulose is not known to interact with alendronic acid. The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill and the like. The tablets can be prepared by techniques known in the art such as wet granulation, dry granulation and direct compression, and may contain a therapeutically useful amount of the alendronic acid or salts thereof and such excipients as are necessary to form the tablet by such techniques. Tablets and pills can additionally be given enteric coatings and other release-controlling coatings for the purpose of acid protection, easing swallowability, etc.

The pharmaceutically acceptable salts of alendronic acid include ammonium salts, alkali metal salts such as potassium and sodium (including, but not limited to, mono-, di- and tri-sodium) salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. The sodium salt may exist in any of the solid states, including the monohydrate, trihydrate, anhydrous, or any other polymorphic forms.

In one general aspect, the pharmaceutical composition may be prepared by a dry granulation technique comprising the steps of blending alendronic acid or pharmaceutically acceptable salts thereof, microcrystalline cellulose and disintegrant; dry granulating the blend by roller compactor or slugging; optionally blending with pharmaceutically acceptable inert excipients; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets; and, optionally, coating the tablets with film forming polymers and coating additives. In another general aspect, the pharmaceutical composition may be prepared by a direct compression technique comprising the steps of blending alendronic acid or pharmaceutically acceptable salts thereof, microcrystalline cellulose and disintegrant; lubricating the blend; directly compressing the lubricated blend into suitable sized tablets; and, optionally, coating with film forming polymers and coating additives. hi addition to the active ingredient, diluent, disintegrant and lubricant/glidant, the composition may comprise coloring agents. Coloring agents that may be used include any FDA approved colors for oral use.

The pharmaceutical composition may optionally be coated with functional and/or non-functional layers comprising film-forming polymers. Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating the tablets.

The invention is further illustrated by the following examples, which are for illustrative purpose only and should not be considered as limiting the scope of the invention. EXAMPLES 1-3

Process:

1. Sodium alendronate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sifted through a sieve and geometrically blended.

2. The blend of step 1 was passed through a roller compactor and the compacts were passed through a sieve.

3. Croscarmellose sodium, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a sieve and added to the blend of step 2 and thoroughly mixed.

4. Magnesium stearate was sifted through a sieve and added to the blend of step 3 and thoroughly mixed.

5. The blend of step 4 was compressed into tablets.

EXAMPLE 4-6

Process:

1. Sodium alendronate and microcrystalline cellulose were milled through a suitable sieve.

2. Croscarmellose sodium and magnesium stearate were sifted through sieve and geometrically blended.

3. The blend of step 1 was passed through a roller compactor and the compacts were passed through a sieve.

4. Croscarmellose sodium, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a sieve and added to the blend of step 2 and thoroughly mixed.

5. Magnesium stearate was sifted through a sieve and added to the blend of step 3 and. thoroughly mixed.^'

6. The blend of step 4 was compressed into tablets.

Upon stability testing of the tablets made according to the above examples, no discoloration was observed when the tablets were subjected to 40°C/75% relative humidity for six months.

While there have been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

Claims

We claim: 1 A pharmaceutical composition suitable for oral administration to a human, the composition consisting essentially of: a) from about 0.5% to about 60% by weight of alendronic acid or a pharmaceutically acceptable salt thereof; b) from about 10% to about 95% by weight of microcrystalline cellulose; c) from about 0.5% to about 20% by weight of a disintegrant selected from the group consisting of starch, modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and d) from about 0.1% to about 10% by weight of lubricant/glidant selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sodium stearyl fumarate, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof; wherein the composition is optionally film coated. 2. The pharmaceutical composition of claim 1 , wherein the composition is in the form of a tablet. 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salts include ammonium salts, alkali metal salts, alkaline earth metal salts, salts with organic bases, N-methyl-D-glucamine, and salts with amino acids. 4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable salt comprises the sodium salt. 5. The pharmaceutical composition according to claim 4, wherein the sodium salt comprises the monohydrate, trihydrate, anhydrous or other polymorphic form. 6. The pharmaceutical composition according to claim 1, wherein the lubricant/glidant comprise one or more of colloidal silicon dioxide, magnesium stearate and talc. 7. A process for the preparation of pharmaceutical composition, the process comprising the steps of: a) blending alendronic acid or pharmaceutically acceptable salt thereof and microcrystalline cellulose, b) optionally milling the blend, c) mixing the blend of step a) with a disintegrant and lubricant/glidant, d) optionally granulating the blend, e) optionally blending the granules with extragranular excipients, f) lubricating the blend of step a) or granules of step b), and g) compressing into or filling into a suitable size solid dosage form. 8. The process for the preparation of a pharmaceutical composition according to claim 7, wherein the extragranular excipients comprise one or more of microcrystalline cellulose, disintegrant, glidant and lubricant., 9. The process for the preparation of a pharmaceutical composition according to claim 7, wherein the granulation is carried out by wet or dry granulation technique. 10. The process for the preparation of a pharmaceutical composition according to claim 9, wherein the wet granulation is carried out with a granulating fluid or solution/dispersion of binder. 11. The process for the preparation of a pharmaceutical composition according to claim 9, wherein the dry granulation is carried out by roller compactor or slugging. 12. The process of the preparation of a pharmaceutical composition according to claim 9, wherein the composition consists essentially of: a) from about 0.5% to about 60% by weight of alendronic acid or a pharmaceutically acceptable salt thereof; b) from about 10% to about 95% by weight of microcrystalline cellulose; c) from about 0.5% to about 20% by weight of a disintegrant selected from the group consisting of starch, modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and d) from about 0.1% to about 10% by weight of lubricant/glidant selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sodium stearyl fumarate, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof. 13. A method of treating or preventing osteoporosis comprising administering a pharmaceutical composition according to claim 1.