Field of The Invention
The present invention relates to a solid dosage form of bisphosphonic acid derivatives. In particular, the invention relates to a solid dosage form comprising Ibandronic acid or a pharmaceutical acceptable salt thereof and silicified microcrystalline cellulose.
The present invention also relates to a process for the preparation of solid dosage form comprising Ibandronic acid or a pharmaceutical acceptable salt thereof and silicified microcrystalline cellulose.
Background Of The Invention
Ibandronate sodium is a nitrogen containing bisphosphonate that inhibit osteoclast-mediated bone resorption and is chemically known as 3-(N-methyl-N-pentyl)amino-1 -hydroxypropane-1,1 -diphosphonic acid, monosodium salt, monohydrate.
Ibandronate sodium is marketed under the trade name Boniva® in the US. Ibandronate sodium is also marketed in Europe as Bondronate® for the prevention of skeletal events {pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases. It is supplied as film coated tablets containing 2.5mg and 150 mg of free acid as well as in the form of intravenous injectable. Commercially available Ibandronate tablets contain Ibandronate monosodium monohydrate as active ingredient and excipients such as lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, stearic acid and colloidal silicon dioxide.
Ibandronaie acid and its salts are described in US 4,927,814 for the treatment of bone diseases and particular disorders in the calcium metabolism such as hypercalcaemia, osteoporosis, tumor osteolysis or Paget's disease. It is freely soluble in water and practically insoluble in organic solvent.
Ibandronate, being a bisphosphonate compound, is poorly absorbed from the gastrointestinal tract. To enhance the bioavailability, Ibandronate has been administered via intravenous route. However, intravenous administration is

costly and inconvenient. If oral administration of the bisphosphonate is desired, relatively high doses must be administered to compensate the low bioavailability from the gastrointestinal tract.
Following patents / patent publications disclose various compositions of Ibandronate.
US 6,294,196 discloses a solid pharmaceutical dosage form comprising of Ibandronoic acid or a physiologically compatible salt thereof which is about 0.2% to 30% by weight of the dosage form with pharmaceutical adjuvants like lactose, microcrystalline cellulose, polyvinyl pyrrolidone in the inner phase and that of outer phase comprises of lubricant like stearic acid which is about less than 5% by weight of the dosage form.
US patent Nos. 5,358,941, 5,681,590, 5,882,656, 6,090,410, 6,194,004, 6,406,714 and 6,517,867 disclose oral tablet formulations that comprise 0.5 to 40% by weight of bisphosphonate and from about 60 to 99.5% by weight of excipient consisting essentially of anhydrous lactose, microcrystalline cellulose, croscarmallose sodium, and magnesium stearate.
US 6,143,326 discloses a pharmaceutical formulation comprising a tablet core containing about 0.1 to 100 mg of Ibandronate, a coating consisting of methylhydroxypropylcellulose, titanium dioxide, polyethylene glycol, talc and or lactose.
Similarly US 6,194,004 discloses a pharmaceutical composition 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 where the diluent was selected from anhydrous lactose and hydrous fast flow lactose and said composition is coated.
US 6,419,955 disclose a process for the preparation of Ibandronate tablet that comprises granulating the Ibandronate with other pharmaceutical acceptable excipients in presence of water by means of fluidised-bed granulator wherein the pharmaceutical excipient is lactose, microcrystalline cellulose and polyvinyl pyrrolidone etc.

Similarly, US 6,692,764 discloses a process for the preparation uncoated tablet mainly comprising of bisphosphonate as a sole binder, microciystalline cellulose, lactose, croscarmellose sodium and magnesium stearate by means of wet granulation.
US 2004/0121007 discloses a pharmaceutical composition containing Ibandronic acid, povidone, lactose monohydrate, cellulose microcrystalUne, crospovidone, stearic acid, silica anhydrous colloidal and finally covered by a film coat.
US 2006/0210639 discloses bisphosphonate composition comprising: (a) particles of bisphosphonate having an effective average particle size of less than about 2000 nm and one surface stabilizer selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, a non-ionic surface stabilizer and an ionic surface stabilizer.
US 2007/0049557 discloses a solid pharmaceutical dosage form comprising bisphosphonate including Ibandronate or a pharmaceutically acceptable salt thereof along with a modified amino acid carrier.
US 2007/0065507 discloses a formulation comprising a bisphosphonate in combination with an antifoaming agent in an amount effective to reduce foam formation in a patient's stomach.
US 2007/0117781 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 and further disclose that the formulation doesn't contain lactose.
WO 99/15155 discloses an oral solid dosage form comprising of dichloromethylene bisphosphonic acid as an active agent and silicified microcrystalline cellulose.
The above prior art references disclose compositions for bisphosphonic acid derivatives with various excipients such as lactose, microcrystalline cellulose. However, it is seen that the exposure of microcrystalline cellulose to moisture during wet granulation process may lead to reduction of the

compressibility of this excipient, so a large amount of such excipient is needed to obtain an acceptably compressed final product which in turn makes the final product more difficult to swallow and thus reducing the patient compliance. Similarly, the use of lactose may interact with nitrogen containing groups and results in discoloration of the product. Hence, there exists a need to develop a solid composition of Ibandronate to overcome the above problem.
In our continuous efforts to develop solid dosage forms of Ibandronate, we found that the use of silicified microcrystalline cellulose, which combines the excellent compactibility of microcrystalline cellulose with superior flow properties, produces tablets that are easily compressible.
Objective Of The Present Ipvention
Accordingly, the main objective of the present invention is to provide solid dosage form comprising Ibandronic acid or a pharmaceutical acceptable salt thereof.
Yet another objective of the present invention is to provide a solid dosage form of Ibandronic acid or a pharmaceutical acceptable salt in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration and etc.
Yet another objective of the present invention is to provide process for the preparation of solid dosage form comprising Ibandronic acid or a pharmaceutical acceptable salt thereof.
Summary Of The Invention
Accordingly, the present invention provides a solid dosage form of Ibandronic acid or its pharmaceutically acceptable salts comprising of about 10 to 90% of silicified microcrystalline cellulose, 0.5 to 10% of disintegrant and 0.5 to 7.5% of binder.
Detailed Description Of The Invention
In an embodiment, Ibandronic acid or its pharmaceutically acceptable salts of the present invention may in the form of amorphous, crystalline solid or a mixture of both.

Silicified microcrystalline cellulose is an agglomerate of microciystalHne cellulose and silicon dioxide in which the microcrystalline cellulose and silicon dioxide are in intimate association with each other, but there is no chemical interaction between the two materials. In general it is achieved by spray drying a suspension of microcrystalline cellulose and silicon dioxide.
Silicified microcrystalline cellulose is 30% to 40% more compactible than microcrystalline cellulose. In addition to that it also provides harder, less friable tablet and also eliminate capping. The use of silicified microcrystalline cellulose provides a nondusting alternative to glidants.
In yet another embodiment, the silicified microcrystalline cellulose used may be in the range of about 10% to about 90% by weight of the composition. More preferably, the silicified microcrystalline cellulose may be used in the range of about 30% to about 80% of the composhion.
Yet another embodiment of the present invention, the mean particle size of the Ibandronic acid or its pharmaceutically acceptable salts is in the range of about 10 to about 2Q0|j.m. More preferably, the mean particle size of Ibandronic acid or its pharmaceutically acceptable salts present in the range of about 50 to about 150 ^m.
The desired particle size is measured by either sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, or by other techniques
In another embodiment, the present invention further comprises one or more pharmaceutically acceptable excipients selected from diluents, lubricants and glidants.
In yet another embodiment, the amount of Ibandronic acid used may be in the range from 2 to 200 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, microcrystalline cellulose,

dihydrated or anhydrous dibasic calcium phosphate and the like or combinations thereof.
Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium steatyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.
Suitable glidant's include talc, silicon dioxide, cornstarch and the like.
Suitable binders used according to the present invention are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch and the like.
Suitable disintegrants used according to the present invention are selected from starch, sodium starch glycolate, carboxymethylcellulose and its salts, cross linked polyvinylpyrrolidone, croscarmellose sodium and the like.
In another embodiment, the solid oral dosage form includes tablets or capsules.
The solid oral dosage forms of the present invention when prepared by granulation process comprises an intragranular portion comprising Ibandronic acid, silicified microcrystalHne cellulose and other excipients and extragranular portion comprising silicified microcrystalHne cellulose and other excipients, wherein said intragranular portion comprises less than 70% by weight of the dosage form and extragranular portion comprises more than 25% by weight of the dosage form.
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, opacifiers, 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, bis-2-thyl hexyl phthalate, triacetin, polyethyleneglycol and the like.
Suitable antitacking agents of the present invention are selected from talc, sodium lauryl sulfate, colloidal silicon dioxide, glyceryl magnesium stearate, and the like and mixtures thereof
In a preferred embodiment of the present invention, the solid dosage form of Ibandronate sodium comprises of about 30% to 70% of silicified microcrystalline cellulose; 0.5% to 7% of disintegrants such as crosspovidone, croscarmellose sodium; 0.5% to 5% of binders such as povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and 0.5% to 5% of lubricants such as magnesium stearate and sodium stearyl stearate.
In another embodiment, the oral solid dosage form of Ibandronic acid or its pharmaceutically acceptable salts comprising of about 10 to 90% of silicified microcrystalline cellulose, 0.5 to 10% of disintegrants and 0.5 to 7.5% of binders, may be prepared by direct compression, dry granulation using slugging or compaction and wet granulation. The direct compression process comprises the steps of
i). blending Ibandronic acid or its pharmaceutically acceptable salts, silicified microcrystalline cellulose, disintegrant, binder with one or more pharmaceutical acceptable excipients, ii). lubricating the blend of step (i), iii). compressing the lubricated blend to obtain tablets and iv). optionally coating the core tablets. Similarly, the slugging process comprises the steps of,
i). blending Ibandronate sodium, silicified microcrystalline cellulose, disintegrant, binder with one or more pharmaceutical acceptable excipients.

ii). lubricating the blend obtained in step (i) followed by slugging,
iii). milling the slugs obtained in step (ii),
iv). blending the milled slugs with extragranular excipients,
v). lubricating and compressing the blend to obtain tablets.
Similarly, the wet granulation process comprises the steps of,
i). blending Ibandronate sodium, silicified microcrystaJline cellulose,
disintegrant 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.
Suitable solvents used for preparing binder include water, ethanol, acetone, methylene chloride, methanol, and isopropanol or a combination thereof.
The solid oral dosage forms of the present invention are usefiil 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, periodontaJ 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 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.

We claim:
1. Solid dosage form of Ibandronic acid or its pharmaceutically acceptable salts comprising of about 10 to 90% of silicified microcrystalline cellulose, 0.5 to 10% of disintegrant and 0.5 to 7.5% of binder.
2. The dosage form as claimed in claim 1, wherein the disintegrant is selected from starch, sodium starch glycolate, carboxymethylcellulose and its salts, cross linked polyvinylpyrrolidone, croscarmellose sodium or a combination thereof.
3. The dosage form as claimed in claim 1, wherein the binder is selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch or a combination thereof
4. The dosage form as claimed in claim 1, ftirther comprises diluents, lubricants and glidants.
5. The dosage form as claimed in claim 4, 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.
6. The dosage form as claimed in claim 4, wherein the glidant is selected from talc, silicon dioxide, cornstarch or a combination thereof
7. The dosage form as claimed in claim 1, wherein the amount of Ibandronic acid used is in the range from 2 to 200 mg.
8. The dosage form as claimed in claim 1, is in the form of tablets or capsules
9. Solid dosage form of Ibandronate sodium comprising from about 30%) to 70% of silicified microcrystalline cellulose; 0.5% to 7% of disintegrants such as crosspovidone. croscarmellose sodium; 0.5% to 5% of binders such as povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and 0.5% to 5% of lubricants such as magnesium stearate and sodium stearyl stearate.

10. Solid dosage form of Ibandronic acid or its pharmaceutically acceptable salts comprising of about 10 to 90% of silicified microcrystalline cellulose, 0.5 to 10% of disintegrants and 0.5 to 7.5% of binders, prepared by direct compression, slugging or wet granulation.