Field of the Invention
The present invention relates to surface-modified particles of ibandronate and process of preparation thereof.
Background of the Invention
Bisphosphonates (also known as diphosphonates) are a family of compounds which is associated with the treatment and prevention of diseases related to high bone resorption, viz. osteoporosis, Paget's disease, metastatic bone cancer. These compounds bind with the naturally occurring cells in the bone that are responsible for causing the breakdown of bone tissue (osteoclasts), thereby destroying them, slowing the bone absorption process and inhibiting their detrimental effects on bone density levels. Bisphosphonate drugs are divided into two main categories: nitrogenous or nitrogen containing bisphosphonates and non-nitrogenous or non-nitrogen containing bisphosphonates. The non-nitrogenous bisphosphonates include drugs like tiludronate, etidronate and clodronate and the nitrogenous bisphosphonates are alendronate, pamidronate, risedronate, zoledronate, olpadronate, neridronate and ibandronate to name a few.
Ibandronate is a comparatively newer bisphosphonate that has been approved for use and is chemically known as 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid. It is marketed in the form of ibandronate sodium monohydrate and is commercially available from F. Hoffmann-La Roche Ltd, Basel (Switzerland) under the proprietary name of BONIVA®/BONVIVA® 2.5mg and 150mg tablets and 3mg/3mL strength intravenous injection. Ibandronate is also available under the trade name BONDRONAT® as a 50mg strength tablet and 6mg/6mL strength concentrate for intravenous infusion. Presently, ibandronate is indicated for use in (a) the treatment or prevention of osteoporosis in postmenopausal women; (b) the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases; and (c) the treatment of tumour-induced hypercalcaemia with or without metastases. The US Patent No. 4,927,814 discloses ibandronate and its use in the treatment or prophylaxis of calcium metabolism disturbance or disease.
The prior art records several documents describing ibandronate formulations, for example US Patent Number 6,419,955 illustrates process for the preparation of 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 fluidized-bed granulator with adjuvants to form a granulate; drying the granulate in the fluidized-bed granulator; and processing the granulate to produce the

pharmaceutical composition in unit dosage form, such that the said method can reduce the loss of active substance or the diminution in content of active substance in the formulation to less than 6% by weight. The problem of ibandronate induced gastro- and oesophageal irritation is rectified in US Patent No.6,143,326, wherein solid oral formulations consisting of a core containing ibandronate are provided, which is coated with an adjuvant coating free of ibandronate. The coating either dissolves independently of the pH value or is removed from the solid oral formulation upon contact with digestive juice, and in this way, relatively rapid disintegration of the drug form and release of ibandronate within a short period of time are both ensured. Consequently, high local concentrations of the ibandronate are achieved. Further, the PCT application WO/2004/56373 describes high dose formulations containing ibandronate and process for their preparation, wherein the process comprises of spray granulating a mixture of ibandronate, a filler and the entire amount of the disintegrant to be used in the preparation of the tablet with a solution of a binder in purified water, drying the spray granulated material; mixing the dried spray granulated material with a mixture consisting of additional filler, a lubricant, and a flow regulator wherein said mixture was previously passed through a fine sieve, to yield a final blend; and finally compressing the final blend into tablets.
Ibandronate exhibits severe stickiness which is an inherent property of the drug and this brings forth several limitations from the manufacturing point of view, for example, sticking, picking of particles containing ibandronate to punch and/or die surface of conventional compression tools or adhesion to hopper surface or the adherence of particles containing ibandronate to form agglomerates and other surface irregularities. Consequently, an imperfect final composition with significant negative impacts in content uniformity is obtained. The US Patent Number 6,294,196 tries to address this problem, and discloses formulations containing solid dosage form containing ibandronate in the inner phase and less than 5% by weight stearic acid in the outer phase, relative to the total weight of the dosage form of administration. The use of stearic acid on one hand results in providing a sufficient lubricant effect, so that the tablet or capsule filler does not stick to the processing machines, and on the other hand the granulated active substance does not become water-repellent.
However, in the present case, varying the amount of lubricants or using different types of lubricants did not alleviate the sticking problem. Further, preparing a formulation free of any binder/adhesive also did not yield any favourable results. Hence, there still persists a need to develop a convenient and efficacious manufacturing procedure for formulating ibandronate compositions which would be free of the hereinbefore discussed tribulations associated with such compositions. Therefore, herein a method to modify the surface characteristics of

particles comprising ibandronate is disclosed, which serves as a solution to eradicate the said manufacturing related difficulties and in turn helps in the development of an improved quality finished product.
Summary of the Invention
In one general aspect, it relates to surface-modified particles of ibandronate comprising of an adsorbate which comprises of ibandronate, a pharmaceutically acceptable polymer and optionally, a pharmaceutically acceptable carrier.
In another general aspect, it relates to surface-modified particles of ibandronate comprising of an adsorbate which comprises of ibandronate, a pharmaceutically acceptable polymer and optionally a pharmaceutically acceptable carrier, wherein the said particles are further formulated into a solid dosage form.
In another general aspect, it relates to a process of preparation of surface-modified particles of ibandronate comprising of an adsorbate which comprises of ibandronate, a pharmaceutically acceptable polymer and optionally a pharmaceutically acceptable carrier, wherein the process comprises
(a) dissolving ibandronate and a pharmaceutically acceptable polymer or a blend
thereof in a suitable solvent; and
(b) adsorbing the solution of step (a) onto a pharmaceutically acceptable carrier.
In another general aspect, it relates to a process of preparation of surface-modified particles of ibandronate comprising of an adsorbate which comprises of ibandronate, a pharmaceutically acceptable polymer and optionally a pharmaceutically acceptable carrier, wherein the process comprises
(a) dissolving a pharmaceutically acceptable polymer in a suitable solvent; and
(b) adsorbing the solution of step (a) onto ibandronate or a blend of ibandronate and
a pharmaceutically acceptable carrier.
Detailed Description of the Invention
The term "surface-modified particles of ibandronate" encompasses granules, pellets, microparticles, minitablets or beads comprising therapeutically effective amount of ibandronate which has been processed or have been subject to surface modification techniques, as opposed to the unmodified particles comprising therapeutically effective amount of ibandronate obtained by following the conventional aqueous wet granulation, non-aqueous wet granulation, dry granulation, roller compactation or direct compression

procedures known from the art. The modified surface of the particles is neither caused by any chemical alteration or modification of ibandronate nor is a consequence of formation of a new or separate surface or layer which is an effect of a chemical interaction between ibandronate and pharmaeeutically acceptable polymer and/or a pharmaceutically acceptable carrier or any other pharmaceutically acceptable excipients. The surface modifications of the said particles may be attributed to the alteration brought about in the physical properties of the outer layer of the said particles, wherein the surface of the unmodified ibandronate particles is partially or completely adsorbed onto a pharmaceutically acceptable polymer and/or a pharmaceutically acceptable carrier to form an adsorbate.
The surface-modified particles may further be processed into solid dosage forms and includes all standard pharmaceutical solid dosage forms and may be in the form of coated or uncoated tablets, multilayer tablets, hard gelatin capsules, soft gelatin capsules, pills, and the like.
The term "therapeutically effective amount" as used herein, is understood to mean the effective dose of ibandronate which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliatively on the condition. The dose may range from about 0.1 to about SOOmg of ibandronate. The recommended dose of BONIVA® or BONVIVA® which is 2.5mg once daily or 150mg once monthly or BONDRONAT® which is 50mg once daily, may be considered as a standard dose. Ibandronate, as referred to herein means ibandronic acid or a pharmaceutically acceptable form of ibandronate, including without limitation, the free acid (ibandronic acid), and its pharmaceutically acceptable salts, enantiomers, solvates, hydrates, polymorphs and complexes thereof. In one embodiment, the monosodium monohydrate salt of ibandronic acid is used in a therapeutically effective amount of 150mg.
The term "pharmaceutically acceptable polymer" as referred to herein, includes without limitation all hydrophilic and hydrophobic polymers. It includes homopolymers and copolymers of N-vinyl lactams, e.g. N-vinyl-2-pyrrolidone (polyvinyl pyrrolidone), crosslinked N-vinyl-2-pyrrolidone, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate; cellulose esters and cellulose ethers, e.g. hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethyl methylcellulose, ethylcarboxyethyl cellulose, sodium carboxymethyl cellulose; cellulose phthalates or succinates; polyacrylates and polymethacrylates; polyvinylalcohol; polyacrylamides; vinyl acetate polymers e.g. polyvinyl acetate; high molecular weight polyalkylene oxides such as polyethylene oxide; polyethylene glycols; sodium alginate; cellulose acetate, and the like or

combinations thereof. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
The term "pharmaceutically acceptable carrier" as used herein, may be exemplified as, but are not limited to, sugars and saccharides like lactose, dextrose, sucrose, fructose, maltose; sugar alcohols like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starch and pregelatinized starch; dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like or combinations thereof. In one embodiment, the pharmaceutically acceptable carrier is lactose, microcrystalline cellulose or the combinations thereof. The combination product of lactose and microcrystalline cellulose, like those available from Meggle-Pharma under the brand name Cellactose® may also be used. Lactose may be anhydrous lactose or lactose monohydrate.
Suitable solvents that may be used for the preparation of the surface-modified particles as described herein includes without limitation, water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like.
Optionally, the solid dosage form comprising the surface-modified ibandronate particles as well the surface-modified ibandronate particles itself may further comprise of other pharmaceutically acceptable excipients. The term "other pharmaceutically acceptable excipients" as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), binder(s), disintegrant(s), lubricants(s), glidants(s) or combinations thereof.
Diluents may be exemplified as, but are not limited to, lactose, sucrose, mannitol, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, dihydrated or anhydrous dibasic calcium phosphate and the like or combination thereof.
Binders that may be used include, but are not limited to, starch derivatives like corn starch and pregelatinized starch; cellulose ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum and other such materials routinely used in the art of solid dosage form manufacturing.

Disintegrants may be selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, alginates, carboxymethyl starches, methacrylic acid divinylbenzene copolymer salts and microcrystalline cellulose.
A suitable lubricant with optimum anti-adherent property may be used which includes without limitation magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Other pharmaceutically acceptable excipients like sweeteners, stabilizers, antioxidants colouring agents, plasticizers may also be included.
The solid dosage form may further be coated using conventional coating compositions, for example Opadry and the like.
The surface-modified ibandronate particles may be prepared in a Fluidized Bed Granulator, which offers a number of advantages. For example, it allows processing at ambient temperatures for thermosensitive materials, and also helps in generation of low-density, free-flowing granules. Further, a drug substance can be added as a solid or by a solution. Therefore, formation of an adsorbate for the preparation of said surface-modified particles would be advantageous in a Fluidized Bed Granulator.
In one embodiment, surface-modified ibandronate particles may be prepared by the process which comprises
(a) dissolving a blend of ibandronate and polyvinylpyrrolidone in water; and
(b) adsorbing the solution of step (a) onto lactose.
In another embodiment, surface-modified ibandronate particles may be prepared by the process which comprises
(a) dissolving polyvinylpyrrolidone in a water; and
(b) adsorbing the solution of step (a) onto ibandronate.
In another embodiment, surface-modified ibandronate particles may be prepared by the process which comprises
(a) dissolving polyvinylpyrrolidone in water; and

(b) adsorbing the solution of step (a) onto a blend of ibandronate and lactose.
In another embodiment, surface-modified ibandronate particles may be prepared by the process which comprises
(a) dissolving a blend of ibandronate and polyvinylpyrrolidone in water; and
(b) adsorbing the solution of step (a) onto a blend of microcrystalline cellulose and
lactose.
In another embodiment, surface-modified ibandronate particles may be prepared by the process which comprises
(a) dissolving a blend of ibandronate and polyvinylpyrrolidone in purified water;
(b) suspending a blend of lactose and crosslinked polyvinylpyrrolidone in the solution of
step (a);
(c) drying the suspension of step (b) to obtain an adsorbate; and
(d) sizing the adsorbate of step (c) to obtain surface-modified ibandronate particles.
In another embodiment, solid dosage forms comprising surface-modified ibandronate particles, may be prepared by process which comprises
(a) blending the said particles with crosslinked polyvinylpyrrolidone, microcrystalline
cellulose, colloidal silicon dioxide and sodium stearyl fumarate; and
(b) processing the blend of step (a) to tablets or capsules using appropriate tooling.
Solid dosage forms comprising surface-modified ibandronate particles free of sticking, picking and/other manufacturing related difficulties and process of preparation thereof described herein is further illustrated by the following examples, but, these should not be construed as limiting the scope of invention.

Examples 1-9

(Table Removed)
Procedures: Example 1
A blend of ibandronate sodium monohydrate and polyvinylpyrrolidone was dissolved in purified water. This solution was sprayed onto a blend of lactose and crosslinked polyvinylpyrrolidone in a Fluid Bed Granulator. The adsorbate so formed was dried and sized to obtain surface-modified ibandronate sodium monohydrate particles. The said particles were further blended with microcrystalline cellulose, colloidal silicon dioxide, crosslinked polyvinylpyrrolidone, and sodium stearyl fumarate to obtain a homogeneous blend. The said blend was compressed using appropriate tooling into tablets. No sticking or picking observed while processing.
Example 2
Polyvinylpyrrolidone was dissolved in purified water and this solution was sprayed onto a blend of ibandronate sodium monohydrate, lactose, microcrystalline cellulose and crosslinked polyvinylpyrrolidone in a Fluid Bed Granulator. The adsorbate so formed was dried and sized to obtain surface-modified ibandronate sodium monohydrate particles. The said particles were further blended with microcrystalline cellulose, colloidal silicon dioxide, crosslinked polyvinylpyrrolidone, and magnesium stearate to obtain a homogeneous blend. The said blend was compressed using appropriate tooling into tablets. No sticking or picking observed while processing.
Example 3
Polyvinylpyrrolidone was dissolved in purified water and this solution was sprayed onto ibandronate sodium monohydrate in a Fluid Bed Granulator. The adsorbate so formed was dried and sized to obtain surface-modified ibandronate sodium monohydrate particles. The said particles were further blended with lactose, microcrystalline cellulose, colloidal silicon dioxide, crosslinked polyvinylpyrrolidone, and stearic acid to obtain a homogeneous blend. The said blend was compressed using appropriate tooling into tablets. No sticking or picking observed while processing.
Example 4
A blend of ibandronate sodium monohydrate and polyvinylpyrrolidone was dissolved in purified water. This solution was sprayed onto lactose in a Fluid Bed Granulator. The adsorbate so formed was dried and sized to obtain surface-modified ibandronate sodium monohydrate particles. The said particles were further blended with microcrystalline cellulose, colloidal silicon dioxide, crosslinked polyvinylpyrrolidone, and stearic acid to obtain

a homogeneous blend. The said blend was compressed using appropriate tooling into tablets. No sticking or picking observed while processing.
Example 5
Polyvinylpyrrolidone was dissolved in purified water and this solution was sprayed onto a blend of ibandronate sodium monohydrate and lactose in a Fluid Bed Granulator. The adsorbate so formed was dried and sized to obtain surface-modified ibandronate sodium monohydrate particles. The said particles were further blended with microcrystalline cellulose, colloidal silicon dioxide, crosslinked polyvinylpyrrolidone, and stearic acid to obtain a homogeneous blend. The said blend was compressed using appropriate tooling into tablets. No sticking or picking observed while processing.
Example 6
Ibandronate sodium monohydrate was blended with lactose and the inner phase portion of microcrystalline cellulose in a Rapid Mixer Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the outer phase portion of microcrystalline cellulose, crosslinked polyvinylpyrrolidone, stearic acid and colloidal silicon dioxide. The final blend was compressed into tablets using appropriate tooling. Sticking and picking was observed while processing.
Example 7
Ibandronate sodium monohydrate was blended with lactose and the inner phase portion of microcrystalline cellulose in a Rapid Mixer Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the outer phase portion of microcrystalline cellulose, crosslinked polyvinylpyrrolidone, stearic acid and colloidal silicon dioxide. The final blend was compressed into tablets using appropriate tooling. Sticking and picking was observed while processing.
Example 8
Ibandronate sodium monohydrate was blended with polyvinylpyrrolidone & microcrystalline cellulose in a Rapid Mixer Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with lactose, crosslinked polyvinylpyrrolidone, stearic acid and colloidal silicon dioxide. The final blend was compressed into tablets using appropriate tooling. Sticking and picking was observed while processing.

Example 9
Ibandronate sodium monohydrate was blended with microcrystalline cellulose, lactose and polyvinylpyrrolidone. The blend was compacted using a roller compactor. The mass obtained was suitably sized to obtain granules. The granules were then further blended with crosslinked polyvinylpyrrolidone, stearic acid and colloidal silicon dioxide. The final blend was compressed into tablets using appropriate tooling. Sticking and picking was observed while processing.

WE CLAIM:
1. Surface-modified particles of ibandronate comprising of an adsorbate which comprises
of ibandronate, a pharmaceutically acceptable polymer and optionally, a
pharmaceutically acceptable carrier.
2. A process of preparation surface-modified particles of ibandronate according to claim
1, wherein the process comprises of

(a) dissolving ibandronate and a pharmaceutically acceptable polymer in a
suitable solvent; and
(b) adsorbing the solution of step (a) onto a pharmaceutically acceptable carrier.
3. A process of preparation surface-modified particles of ibandronate according to claim
1, wherein the process comprises of
(a) dissolving a pharmaceutically acceptable polymer in a suitable solvent; and
(b) adsorbing the solution of step (a) onto ibandronate or a blend of ibandronate
and a pharmaceutically acceptable carrier.

4. The surface-modified particles according to claim 1, wherein the pharmaceutically
acceptable polymer is selected from the group consisting of polyvinylpyrrolidone,
crosslinked polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone and vinyl acetate,
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl
cellulose, ethyl cellulose, hydroxyethyl methylcellulose, ethylcarboxyethyl cellulose,
sodium carboxymethyl cellulose, cellulose phthalates or succinates, polyacrylates,
polymethacrylates, polyvinylalcohol, polyacrylamides; vinyl acetate polymers; high
molecular weight polyalkylene oxides such as polyethylene oxide; polyethylene glycols,
sodium alginate, cellulose acetate, and the like or combinations thereof.
5. The surface-modified particles according to claim 4, wherein the pharmaceutically
acceptable polymer is polyvinylpyrrolidone.

6. The surface-modified particles according to claim 1, wherein the pharmaceutically
acceptable carrier is selected from the group consisting of lactose, dextrose, sucrose,
fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, powdered cellulose,
microcrystalline cellulose, starch, pregelatinized starch, dicalcium phosphate, tribasic
calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like or
combinations thereof.
7. The surface-modified particles according to claim 6, wherein the pharmaceutically
acceptable carrier is selected from microcrystalline cellulose, lactose and a
combination thereof.
8. The surface-modified particles of ibandronate according to claim 1, wherein the said
particles further comprises one or more of other pharmaceutically acceptable
excipients selected from the group consisting of diluent(s), binder(s), disintegrant(s),
lubricants(s), and glidants(s).
9. The surface-modified particles of ibandronate according to claim 1, wherein the said
particles are further formulated into a solid dosage form.
10. Surface-modified particles of ibandronate, wherein the said particles comprise of an
adsorbate comprising of ibandronate, a pharmaceutically acceptable polymer and
optionally a pharmaceutically acceptable carrier and process of preparation thereof,
substantially as described and illustrated by examples herein.