SOLID DOSAGE FORMS OF BISPHOSPHONIC ACIDS

Field of the invention

The technical field of the present invention relates to oral dosage forms of bisphosphonic acid or its pharmaceutically acceptable salts. More particularly, the present invention relates to oral dosage forms of bisphosphonic acid or its pharmaceutically acceptable salts prepared by wet granulation process.

Background of the invention

Various bisphosphonic acid derivatives are well known for use in the treatment of diseases involving bone resorption. These bisphosphonic acids include alendronic acid, risedronic acid, pamidronic acid, ibandronic acid, clodronic acid, etidronic acid, tiludronic acid and other such therapeutic agents belonging to this class of compounds, and their salts and solvates.

Various bisphosphonic acids available in the market for the treatment and prevention of osteoporosis include alendronate sodium marketed under the trade name FOSAMAX ^® , risedronate marketed under the trade name ACTONEL ^® , ibandronate marketed under the trade name BONIVA ^® , pamidronate marketed under the trade name AREDIA ^® , etidronate marketed under the trade name DIDRONEL ^® and tiludronate marketed under the trade name SRELID ^® .

Alendronate sodium is chemically known as (4-amino-l- hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Alendronate sodium is marketed under the trade name FOSAMAX ^® (Merck) supplied as tablets containing 5, 10, 35, 40 and 70 mg of free alendronic acid. Commercially available alendronate tablets contain alendronate monosodium salt trihydrate as active ingredient and excipients such as microcrystalline cellulose, anhydrous lactose, croscarmellose sodium and magnesium stearate.

Ibandronate sodium is chemically known as 3-(N-methyl-N-pentyl) amino- l-hydroxypropane-l,l-diphosphonic acid, monosodium salt that inhibits

osteoclast-mediated bone resorption. Ibandronate is marketed under the trade name BONIV A ^® (Roche) supplied as film coated tablets containing 2.5 and 150 mg of free acid. Commercially available ibandronate tablets contain ibandronate monosodium as active ingredient and excipients such as lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid and colloidal silicon dioxide.

Risedronate sodium is chemically known as [l-hydroxy-2-(3- pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Risedronate sodium is marketed under the trade name ACTONEL ^® (Procter & Gamble) supplied as tablets containing 5, 30 35 and 75mg of free acid. Commercially available risedronate tablets contain anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate as active ingredient and excipients such as crospovidone, ferric oxide red (35-mg tablets only), ferric oxide yellow (5 and 35-mg tablets only), hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide

The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular granulation is one of the most prevalent methods.

Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation. Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling.

Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic liquids or mixtures thereof, are used in wet granulation to produce granules. The advantages of wet granulation include improvement of the cohesiveness and comparability of powders, increase in density, good distribution provides uniform content of micronized or finely milled

low-dosage drugs, reduction of dust and airborne contamination, and prevention of segregation of components.

Given below are the patents/patent publications, which disclose pharmaceutical compositions of bisphosphonic acids.

US 5,358,941 discloses compositions of alendronate comprising anhydrous lactose; microcrystalline cellulose; croscarmallose sodium; and magnesium stearate and the preparation include dry mixing of alendronate with a diluent, binder, disintegrant, and lubricant and then compressing the resultant mixture into a desired tablet form.

US 6,096,342 discloses a pharmaceutical composition comprising, from 0.15% to 40.00% by weight of a risedronate and from 60.00% to 99.75% by weight of excipients comprising: lactose monohydrate, microcrystalline cellulose, crospovidone, and magnesium stearate. This patent further discloses the process of' preparation of tablets by mixing excipients with risedronate and then compressing mixture into tablets.

US 6,294,196 discloses a pharmaceutical composition in solid unit dosage form, said dosage form comprising an inner phase containing as the active substance ibandronic acid, or a physiologically compatible salt or hydrate thereof, said active substance being present in the dosage form in an amount of from about 0.2% to 30% by weight of the dosage form, and an outer phase containing stearic acid in an amount of about less than 5% by weight of the dosage form, wherein said inner phase comprises about at least 80% by weight of the dosage form and said outer phase comprises from about. 0.1% to 20% by weight of the dosage form. This patent further discloses the process for the preparation of said dosage form by wet granulation using water as granulating agent.

US 6,692,764 describes process for the preparation of a tablet containing an active ingredient, which is the sole binder, selected from the group consisting of: alendronic acid and other bisphosphonic acids or a pharmaceutically acceptable salt thereof; which process comprises: (1) forming a powder blend of the active

ingredient with diluents, wherein said active ingredient is the sole binder, (2) wet granulating the powder blend with water to form granules, (3) drying the granules to remove water, and (4) compressing the dried granules mixture into a desired tablet form.

US 6,419,955 describes process for preparing an ibandronate-containing pharmaceutical composition in unit dosage form, said composition containing up to 50 mg of ibandronate per unit dose, comprising granulating the ibandronate in the presence of water in a fluidised-bed granulator with adjuvants to form a granulate; drying the granulate in the fluidised-bed granulator; and processing the granulate to produce the pharmaceutical composition in unit dosage form, wherein the adjuvants comprise lactose in an amount of from about 25 to about 75% by weight of the composition, microcrystalline cellulose in an amount of from about 10 to about 20% by weight of the composition, and polyvinyl pyrrolidone in an amount of from about 2 to about 3% by weight of the composition.

US 6,465,017 discloses process for the preparation of tablets comprising alendronate and the process include forming a powder blend of inert pharmaceutical excipients; (b) granulation of the powder with an aqueous solution comprising alendronic acid; and (c) drying the granules to obtain a granulate.

WO 2005/030177 discloses an oral formulation which includes an intragranular phase comprising a bisphosphonic acid derivative and at least one carbohydrate alcohol, together with an aqueous binder.

WO 2006/046100 discloses a composition comprising alendronic acid or salt; non-reducing sugar or sugar alcohol; disintegrant and lubricant, wherein the process include direct compression and dry granulation.

WO 2006/018033 discloses a pharmaceutical composition comprising from 40 to 70% by weight of bisphosphonic acid or a pharmaceutically acceptable salt thereof and from 30 to 60% by weight of excipients, said excipients comprising a diluent selected from the group consisting of cellulose derivatives, starch and inorganic phosphates.

WO 2006/054165 discloses compositions comprising alendronic acid, microcrystalline cellulose, disintegrant and lubricant wherein the process includes dry granulation or wet granulation using granulating fluid or solution or dispersion of binder.

The above prior art references disclose various compositions of bisphosphonic acids prepared by direct compression or dry granulation or wet granulation using water as granulating agent with drug alone as binder or the use of additional binder solution. Some of the above prior art references further disclose that discoloration of tablets will occur in formulations manufactured by wet granulation. During our continuous efforts, it was observed that discolaration of tablets can be minimized and the stability can be improved using mixture of aqueous and non-aqueous solvent system for granulation process. There is no disclosure of using mixture of aqueous and nonaqueous solvent system for granulation in the prior art.

The inventors of the present invention have endeavored to develop a stable and bioequivalent composition comprising bisphosphonic acid prepared by wet granulation technique.

Objective of the invention

Accordingly, the main objective of the present invention is to provide oral dosage forms of bisphosphonic acids or its pharmaceutically acceptable salts prepared by simple and cost effective wet granulation process.

Yet another objective of the present invention is to provide oral dosage forms of bisphophonic acids prepared by wet granulation process in such a way that the dosage forms will comply with the reference product in terms of in vivo parameters like C _max , 1^ _13x and AUC and in vitro parameters like dissolution, disintegration and etc.

Summary of the invention

Accordingly, the present invention provides oral dosage forms comprising bisphosphonic acid or its pharmaceutically acceptable salts prepared by a process, which comprises the steps of: i) granulating bisphosphonic acid and one or more intragranular excipients using a mixture of aqueous and nonaqueous solvent system, ii) drying the granules and iii) formulating the dried granules obtained in step (ii) into solid dosage form.

Detailed description of the invention

In an embodiment of the present invention, the bisphosphonic acid includes alendronic acid, risedronic acid, pamidronic acid, ibandronic acid, clodronic acid, etidronic acid, tiludronic acid and their pharmaceutically acceptable salts and solvates.

The pharmaceutically acceptable salts of bisphosphonic acids according to present invention include sodium, potassium, calcium and magnesium.

In another embodiment of the present invention, the intragranular excipients include diluent, binder, disintegrant and surfactant.

In another embodiment, the oral solid dosage form comprises about 1% to about 40%w/w of bisphosphonic acid, 5% to about 80% w/w of diluent, about 1% to about 5% w/w of disintegrant, about 0.5% to about 5.0% w/w of binder as intragranular excipients.

In yet another embodiment of the present invention, the granulation is carried out using a mixture of aqueous and nonaqueous solvent system with or without binder.

In another embodiment, the dried granules are mixed with extra granular excipients such as diluent, disintegrant and lubricant before processing into solid dosage forms.

In another embodiment, the oral solid dosage form comprises 1% to about 40% w/w of diluent, about 1% to about 5% w/w of disintegrant and about 0.5% to about 5% w/w of lubricant as extra granular excipients.

Suitable diluents used according to the present invention are selected from spray-dried monohydrate or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dihydrated or anhydrous dibasic calcium phosphate and the like or combination thereof.

Suitable binders used according to the present invention are selected from the group comprising of hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch and the like.

Suitable disintegrants used according to the present invention are selected from modified starches or modified celluloses, algins, gums, carboxymethylcellulose and its salts, crospovidone and the like.

Suitable surfactants used according to the present invention are selected from sodium lauryl sulphate, polyethylene glycol, polysorbates and the like.

Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumerate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.

The aqueous and nonaqueous solvents of the present invention are selected from water and isopropyl alcohol, ethanol, methylene chloride, acetone and the like or mixture thereof.

The lubricated granules are then compressed into tablets, filled in capsules or sachets as powder for oral suspension. The tablets may be uncoated or optionally coated.

The film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent, plasticizer and antisticking agent.

Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixture thereof.

The solubilizing agent of the present invention may be selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene- propylene glycol copolymer (poloxamer), polyoxyethylene stearates (Macrogol- stearate), poly sorbates, propylene glycol, and the like or mixture thereof.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.

In yet another embodiment, the present invention also provides method of treating osteoporosis, menopausal osteoporosis, osteodystrophy, paget's disease, myositis ossificans, bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, sclerosis, arthritis, bursitis, neuritis and tetany by administering solid dosage forms prepared according to present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1

The processing steps involved in manufacturing compositions given in example 1 are given below: i) Alendronate sodium, microcrystalline cellulose, dextrose, sodium starch glycollate, were sifted and blended, ii) binder solution of povidone with a mixture of isopropyl alcohol and water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii), iv) dried the granules obtained in step (iii) and blended with extragranular microcrystalline cellulose and sodium starch glycolate, v) lubricated the blend of step (iv) with magnesium stearate and vi) compressed the lubricated blend to obtain tablets or filled into capsules.

The compositions given in examples 2-9 were prepared using similar procedure as described in example 1. Example 2

Example 3

Example 9

Tables given below show the comparative dissolution profile of alendronate tablets and FOSAMAX ^® carried out in purified water as medium according to the procedure described in the USP, Apparatus USP 11/900 ml, Paddle, @ 50 rpm speed. The release profile (% of drug released in minutes) is given in tables 1-3.

Table 1

Table 2