Field of The Invention
The present invention relates to solid dosage forms of bisphosphonic acid derivatives. Jn particular, the invention relates to solid dosage forms comprising bisphosphonic acid or a pharmaceutically acceptable salt thereof and a salt of monovalent metal ion.
The present invention also relates to a process for the preparation of solid dosage forms comprising bisphosphonic acid or a pharmaceutically acceptable salt thereof and a salt of monovalent metal ion.
Background Of The Invention
Various bisphosphonic acid derivatives are well known for use in the treatment of diseases involving bone resorption.
The bisphosphonic acids that are available in the market for the treatment and prevention of osteoporosis include risedronate marketed under the trade name ACTONEL®, ibandronate marketed under the trade name BONIVA®, alendronate marketed under the trade name FOSAMAX®, pamidronate marketed under the trade name AREDIA®, etidronate marketed under the trade name DIDRONEL® and tiludronate marketed under the trade name SKELID®.
Alendronate sodium is chemically known as (4-amino-1 -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 and is marketed under the trade name BONIVA® (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, stearic acid and colloidal silicon dioxide.
Risedronate sodium is chemically known as [l-hydroxy-2-(3-pyridinyl) ethylidene] bis [phosphonic acid] monosodium salt and marketed under the trade name ACTONEL® (Procter & Gamble) supplied as tablets containing 5, 30, 35 and 75 mg of free acid. Commercially available risedronate tablets contain risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate as active ingredient and excipients such as crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide.
Given below are the patents/patent publications, which disclose pharmaceutical compositions of bisphosphonic acids.
US Patent No. 5,358,941, 5,681,590, 5,882,656, 6,090,410, 6,194,004, 6,406,714 and 6,517,867 discloses compositions of bisphosphonate comprising anhydrous lactose; microcrystalline cellulose; croscarmallose sodium; and magnesium stearate and the preparation include dry mixing of bisphosphonate with a diluent, binder, disintegrant, and lubricant and then compressing the resultant mixture into a tablet.
US 5,405,994, 5,739,381 disclose an oral pharmaceutical composition comprising an effective amount of disodium tiludronate monohydrate and pharmaceutically acceptable carrier.
US 5,656,288 disclose a process of making an oral pharmaceutical composition comprising disodium tiludronate tetrahydrate and a pharmaceutically acceptable carrier comprising sodium lauryl sulfate.
US 6,096,342 disclose 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 6,194,004 discloses a pharmaceutical composition which comprises of 0.5 to 40% by weight of a bisphosphonic acid or a pharmaceutically acceptable salt thereof and 60% to 99.5% by weight of excipients which include diluents, where the diluent was selected from anhydrous lactose and hydrous fast flow lactose and said composition is coated.
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 6,419,955 discloses 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. Similarly, US 6,692,764 discloses a process for the preparation of uncoated tablet mainly comprising of bisphosphonate as a sole binder, microcrystalline cellulose, lactose, croscarmellose sodium and magnesium stearate by means of wet granulation.
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 that includes an intragranular phase comprising a bisphosphonic acid derivative and at least one carbohydrate alcohol, together with an aqueous binder.
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 2006/046100 discloses a composition comprising alendronic acid or pharmaceutically acceptable salt thereof, non-reducing sugar or sugar alcohol, disintegrant and lubricant, wherein the process includes direct compression and dry granulation.
The above prior art references discloses various compositions for bisphosphonic acid with various excipients such as lactose, microcrystalline cellulose. However, still there is a need to develop compositions of bisphosphonate avoiding lactose, which might interact with nitrogen containing groups and results in discoloration of the product.
In our continuous efforts to develop solid bioequivalent dosage forms of bisphosphonate, we found that can be developed using salt of a monovalent metal ion.

Objective Of The Present Invention
Accordingly, the main objective of the present invention is to provide solid dosage forms comprising bisphosphonic acid or a pharmaceutical acceptable salt thereof.
Yet another objective of the present invention is to provide solid dosage forms of bisphosphonic acid or a pharmaceutical acceptable salt in such a way that it will comply with the reference product in terms of in vivo parameters for bioequivalence such as Cmax, AUC, Tmax and in vitro parameters like dissolution, disintegration etc.
Yet another objective of the present invention is to provide process for the preparation of solid dosage forms comprising bisphosphonic acid or a pharmaceutical acceptable salt thereof.
Summary Of The Invention
Accordingly, the present invention provides solid dosage forms comprising bisphosphonic acid or its pharmaceutically acceptable salts and a salt of monovalent metal ion.
Detailed Description Of The Invention
In an embodiment, the solid dosage forms of bisphosphonic acid or its pharmaceutically acceptable salts further comprise one or more pharmaceutically acceptable excipients.
In yet another embodiment, the salt of monovalent metal ion used is selected from sodium chloride, potassium chloride, potassium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate and the like or combinations thereof and is in the range from about 10 to about 60% by weight of the composition.
In an embodiment, bisphosphonic acid or its pharmaceutically acceptable salts of the present invention may in the form of amorphous or a crystalline solid.

In another embodiment, the particle size of bisphosphonic acid or its pharmaceutically acceptable salts used is in the range of about 5 microns to 200 microns.
The term bisphosphonic acids include alendronic acid, ibandronic acid, risedronic acid, clodronic acid, etidronic acid, tiludronic acid, paraidronic acid and their pharmaceutically acceptable salts thereof.
In another embodiment, the pharmaceutically acceptable excipients comprise diluents, disintegrants, binders, lubricants, glidants and the like.
In yet another embodiment, the amount of bisphosphonic acid used may be in the range from 2 to 400 mg.
The pharmaceutically acceptable salts of the present invention include sodium, potassium, calcium, magnesium and the like.
Suitable diluents used according to the present invention are selected from sucrose, dextrose, mannitol, sorbitol, starch, dibasic calcium phosphate, micro crystalline cellulose, silicified micro crystalline cellulose and the like or combinations thereof and may be used in the range of about 5 to 50% by weight of the composition.
Suitable binders used according to the present invention are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch and the like or combinations thereof
Suitable disintegrants used according to the present invention are selected from modified starches or modified celluloses, sodium starch glycolate, crospovidone, croscarmellose sodium and the like or combinations thereof and may be used in the range of about 1 to 10% by weight of the composition.
Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.
Suitable glidant's include talc, silicon dioxide, cornstarch and the like.

Salts of multivalent ions and the products containing calcium or multivalent cations (such as aluminium, magnesium and iron etc.) including milk, food and other antacids are likely to interfere with absorption of ibandronate.
In another embodiment of the present invention, the solid oral dosage forms include tablets or capsules.
The tablets may be uncoated or optionally coated with film coating composition. The coating solution mainly comprises of film forming polymers and one or more of plasticizers, opacifier, anti tacking agents and the like. The coating according to the present invention is applied by solubilizing or suspending the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylenechloride and the like or mixtures thereof.
Suitable film forming polymers used according to the present invention is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose hydroxyethyl cellulose and the like.
Suitable plasticizers used according to the present invention are selected from diethyl phthalate, triacetin, polyethylene glycol and the like.
Suitable opacifier used according to the present invention is titanium dioxide.
In a preferred embodiment of the present invention, the solid dosage forms comprises bisphosphonic acid selected from alendronic acid, ibandronic acid and risedronic acid; 10 to 60% by weight of monovalent metal ion selected from sodium chloride, potassium chloride and potassium carbonate; 5 to 50% by weight of diluents selected from sucrose, dextrose, micro crystalline cellulose and silicified micro crystalline cellulose and 1% to 10% by weight of disintegrants selected from sodium starch glycolate, crospovidone and croscarmellose sodium.
In another embodiment of the present invention, the solid dosage forms comprising bisphosphonic acid or its pharmaceutically acceptable salt and a salt

of monovalent metal ion, may be prepared by direct compression, dry
granulation using slugging or compaction and wet granulation.
The wet granulation process comprises the steps of
i). blending bisphosphonate, salt of monovalent metal ion and one or more
pharmaceutically acceptable excipients,
ii). granulating the blend of step (i) using binder solution,
iii). drying the granules obtained in step (ii),
iv). blending the dried granules with extragranular excipients followed by
lubrication and
v). compressing the lubricated blend to obtain tablets.
Suitable solvents used for granulation are selected from water, ethanol, acetone, methylene chloride, methanol, and isopropanol or a combination thereof.
The solid dosage forms of the present invention are useful in the therapeutic or prophylactic treatment of disorders in calcium and phosphate metabolism and associated diseases such as osteoporosis, osteodystrophy, Paget's disorder, myositis, ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany.
The following examples further exemplify the invention and are not intended to limit the scope of the invendon. 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.



given below:
1. Ibandronate sodium, sodium chloride, a portion of microcrystalline
cellulose and crospovidone were blended,
2. granulated the blend of step (1) using binder solution of povidone in
purified water,
3. dried the granules obtained in step (2),
4. blended the granules of step (3) with remaining portion of microcrystalline cellulose and crospovidone, colloidal silicon dioxide,
5. lubricated the blend of step (4) with sodium stearyl fumarate,
6. compressed the blend of step (5) into tablets,
7. coated the tablets to obtain film-coated tablet.
The solid dosage forms as described in example 2 was prepared by similar procedure as described in example 1.

The solid dosage form of ibandronate prepared according to the present invention were tested for drug release in 500 ml water having 0.1 N HCi for 1

hours using USP apparatus 2 with paddle speed at 50 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for ibandronate content. The dissolution profile is given in Table I below:

We claim:
1. A solid dosage form comprising bisphosphonic acid or its
pharmaceutically acceptable salts and a salt of monovalent metal ion.
.2. The dosage form as claimed in claim 1, wherein the sah of monovalent
metal ion used is selected from sodium chloride, potassium chloride, potassium
carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate or a
combination thereof.
3. The dosage form as claimed in claim 1, further comprises one or more diluents, disintegrants, binders, lubricants and glidants.
4. The dosage form as claimed in claim 3, wherein the diluent is selected from sucrose, dextrose, mannitol, sorbitol, starch, dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose or a combination thereof
5. The dosage form as claimed in claim 3, wherein the disintegrant is selected from modified starches or modified celluloses, sodium starch glycolate, cross-linked polyvinylpyrrolidone, croscarmellose sodium or a combination thereof
6. The dosage form as claimed in claim 3, wherein the binder is selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch or a combination thereof.
7. The dosage form as claimed in claim 3, wherein the lubricant is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate or a combination thereof
8. The dosage form as claimed in claim 1, wherein the particle size of bisphosphonic acid or its pharmaceuticaHy acceptable salts used is in the range of about 5 microns to 200 microns.
9. The dosage form as claimed in claim 1, wherein the amount of bisphosphonic acid used may be in the range from 2 to 400 mg.

10. A process for the preparation of solid dosage form comprising
bisphosphonic acid or its pharmaceutically acceptable salts and a salt of
monovalent metal ion, comprises the steps of
i). blending bisphosphonate, salt of monovalent metal ion and one or more
pharmaceutical acceptable excipients,
ii). granulating the blend of step (i) using binder solution,
iii). drying the granules obtained in step (ii),
iv). blending the dried granules with extragranular excipients followed by
lubrication and
v). compressing the lubricated blend to obtain tablets.