PHARMACEUTICAL COMPOSITIONS COMPRISING IBANDRONIC ACID

INTRODUCTION

The present invention relates to pharmaceutical compositions comprising Ibandronic acid, including salts, solvates, hydrates, polymorphs, prodrugs, metabolites, enantiomers, and mixtures thereof. The invention also relates to processes for preparing and methods of using the compositions.

Further, the invention relates to pharmaceutical compositions comprising ibandronic acid or its salts, at least one disintegrant, and optionally at least one disintegration enhancing component.
Osteoporosis is a disease of bone in which the amount of bone is decreased and the strength of trabecular bone is reduced, cortical bone becomes thin and bones are susceptible to fracture. Bisphosphonates are also commonly used in the prophylaxis and treatment of osteoporosis and corticosteroid-induced osteoporosis.

Bisphosphonates are synthetic analogues of natural pyrophosphate that inhibit osteoclast activity and decrease bone turnover and resorption.

Ibandronic acid is a nitrogen-containing bisphosphonic acid. Ibandronic acid has chemical names 3-(A/-methyl-W-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, or [1-hydroxy-3-(methyl-pentyl-amino)-1-phosphono-propyl]phosphonic acid, with the molecular formula C9H23NO7P2 and a molecular weight of 319.229. Ibandronic acid is a white to off white powder. It is freely soluble in water and practically insoluble in organic solvents.
Ibandronic acid has the structural formula below.
Ibandronic acid inhibits osteoclast-mediated bone resorption. The action of ibandronic acid on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Ibandronic acid inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass. It may also be used to treat hypercalcemia (elevated blood calcium levels).

Ibandronic acid sodium salt is available in tablet and injectable dosage form products, marketed under the name BONIVA®. The inactive ingredients for tablet dosage form consist of lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid, colloidal silicon dioxide, and purified water. The tablet film coating contains hypromellose, titanium dioxide, talc, polyethylene glycol 6000, and purified water.

BONIVA® injection is available as a sterile, clear, colorless, ready-to-use solution in a prefilled syringe that delivers 3.375 mg of ibandronate monosodium salt monohydrate in 3 mL of solution, equivalent to a dose of 3 mg of ibandronic acid. Inactive ingredients include sodium chloride, glacial acetic acid, sodium acetate and water.

Ibandronic acid derivatives and pharmaceutical compositions thereof are disclosed in U.S. Patent No. 4,927,814; U.S. Patent Nos. 6,294,196; 6,143,326; 6,623,755; 6,692,764 and 6,372,728. U.S. Patent Application Publication Nos. 2004/0121007; 2005/0089573 and 2004/0147484 disclose compositions of bisphosphonates.
International Application Publication Nos. WO 2005/063218, WO 2005/030177, WO 01/32185, and WO 00/61111 and India Patent Application No. 2474/CHENP/2004 disclose pharmaceutical compositions of ibandronic acid or its salts.
It has been reported that absorption of ibandronate occurs in the upper gastrointestinal tract. Further time required to reach maximum plasma concentration ranges from about 0.5 to about 2 hours in postmenopausal women. Hence rapid or fast release of ibandronate from the formulation may be desired to facilitate its absorption.

Various polymorphic forms ibandronic acid or its salt can be used to prepare the pharmaceutical composition of the instant invention. However it is important to stabilize the polymorphic form in the pharmaceutical composition such that no polymorphic conversion occurs during the shelf life of the product.

Thus there is a need to provide simple, effective and stable formulations of ibandronate that permit a rapid release of the active ingredient from the formulation.

SUMMARY

The present invention relates to pharmaceutical compositions comprising ibandronic acid, including salts, solvates, hydrates, polymorphs, prodrugs, metabolites, enantiomers, and mixtures thereof. The invention also relates to processes for preparing such stable pharmaceutical compositions comprising ibandronic acid or its salts and methods of using the same.

In an embodiment the invention relates to pharmaceutical compositions comprising:

a) ibandronic acid, or its salts, or hydrates thereof;

b) at least one disintegrant; and

c) optionally, at least one disintegration enhancing component.

In an embodiment the invention relates to pharmaceutical compositions comprising:

a) ibandronic acid or its salts, or hydrates thereof;

b) at least one disintegrant comprising one or more of crospovidone, croscarmelfose sodium, sodium starch gfycolate, hydroxypropyl cellulose, and a starch or starch derivative; and

c) optionally, a disintegration enhancing component comprising one or more of a carbonate salt of an alkali metal, a carbonate salt of an alkaline earth metal, a bicarbonate salt of an alkali metal, and a bicarbonate salt of an alkaline earth metal.

In another embodiment the invention includes rapid-disintegrating compositions comprising ibandronic acid or its salts, or hydrates thereof.

In an embodiment the invention includes method of enhancing disintegration of ibandronic acid or its salts, or hydrates thereof wherein the method comprises the use of at least one disintegrant and optionally at least one disintegration enhancing component, in the composition.

In an embodiment the invention includes pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof, at least one disintegrant and optionally at least one disintegration enhancing component, wherein ibandronic acid or is salt has an in vitro dissolution profile with a similarity factor (F2) of at least 50 to 100, compared to a dissolution profile of Boniva® tablets.

In an embodiment the invention relates to compositions having weight ratios of ibandronic acid or its salts, or hydrates thereof to a disintegration enhancing component in the range of about 1:50 to about 50:1, or about 1:30 to about 30:1.

In an embodiment the invention includes stable pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof.

In an embodiment, the invention includes processes of preparing pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof.

In an embodiment, the invention includes methods of using pharmaceutical compositions comprising ibandronic acid or salts thereof.

BRIEF DESCRIPTION OF FIGURES

Figure 1 shows comparative X-ray powder diffraction ("XRD") patterns for ibandronate sodium p Form (A), composition prepared according to Example 1 (B), and a similarly prepared composition but without ibandronate sodium fi Form (P).

Figure 2 shows comparative X-ray powder diffraction ("XRD") patterns for ibandronate sodium (5 Form (A), a composition prepared according to Example 1 (B), and a similarly prepared composition but without ibandronate sodium p Form (P) after storing at accelerated stability testing conditions of 40 °C/75% RH for about 1 month.

Figure 3 shows comparative X-ray powder diffraction ("XRD") patterns for a composition prepared according to Example 10 (A), ibandronate sodium p Form (B), and a similarly prepared composition but without ibandronate sodium p Form (C).

Figure 4 shows comparative X-ray powder diffraction ("XRD") patterns for a composition prepared according to Example 10 (A), ibandronate sodium p Form (B), and a similarly prepared composition but without ibandronate sodium p Form and packed in an aluminium desiccant/aluminium in triple laminated aluminium pouch, stored at accelerated stability testing conditions of 40°C/75% RH for about 6 months (C).

Figure 5 shows comparative X-ray powder diffraction ("XRD") patterns for a composition prepared according to Example 10 (A), ibandronate sodium p Form (B), and a similarly prepared composition but without ibandronate sodium p Form, packed in PVC-Aclar in triple laminated aluminium pouch, and at accelerated conditions of 40°C/75% RH for about 6 months (C).

Figure 6 shows comparative X-ray powder diffraction ("XRD") patterns for a composition prepared according to Example 10 (A), ibandronate sodium p Form (B), and a similarly prepared composition but without ibandronate sodium p Form, packed in a HDPE 40 cc bottle, after storage at accelerated stability testing conditions of 40 °C/75% RH for about 6 months (C).

Figure 7 shows comparative X-ray powder diffraction (uXRDn) patterns for compositions prepared according to Example 10 (A), ibandronate sodium p Form (B), and a similarly prepared composition but without any ibandronate sodium p Form, packed in PVC-PVCD in triple laminated aluminium pouches, after storage at accelerated stability testing conditions of 40 °C/75% RH for about 6 months (C).

DETAILED DESCRIPTION

The present invention relates to pharmaceutical compositions comprising ibandronic acid, including salts, solvates, hydrates, polymorphs, prodrugs, metabolites, enantiomers, and/or mixtures thereof. The invention also relates to processes for preparing pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof, and methods of using the same.

Bisphosphonic acids such as Ibandronic acid inhibit osteoclast-mediated bone resorption. The action of ibandronic acid on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone.

Ibandronic acid inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass. It may also be used to treat hypercalcemia (elevated blood calcium levels).

Pharmaceutically acceptable salts of Ibandronic acid include, but are not limited to: salts formed by reaction with inorganic bases, such as ammonium salts, alkali metal salts such as potassium and sodium (including mono-, di-, tri- sodium) salts, and alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine salts; and salts formed by reaction with amino acids such as arginine, lysine, etc.

The term "ibandronic acid" includes salts, polymorphs, either crystalline or amorphous, solvates, hydrates, enantiomers, racemic mixtures, prodrugs, metabolites, and mixtures thereof.

Different forms may provide different properties, such as solubility (which could be important in dosage form design and in terms of bioavailability and/or bioequivatence), stability advantages, etc.

Some polymorphs of drug substances suffer from the drawbacks of conversion to other crystalline forms on storage resulting in concomitant change, not only in the physical form and shape of the drug crystals, but also the associated changes in distinct physical properties.

Generally, the molecules will revert to a more thermodynamically stable form, often a form with lower solubility. Such a thermodynamically stable form may sometimes result in a reduced or suboptimal bioavailability, especially for oral administration. However such an unstable polymorphic form needs to be stabilized, so that no polymorphic conversion occurs during the shelf life of the product ensuring substantially intact physicochemical characteristics of the pharmaceutical composition.

Ibandronic acid or its salts, and hydrates thereof, exist in different polymorphic forms such as Form I, Form V, Form VIM, Form Alpha (a Form) and Form Beta (0 Form) etc.

In embodiments, the invention includes pharmaceutical compositions comprising 3 Form of ibandronate sodium.

In embodiments, the compositions of the present invention have been designed to enhance the disintegration and dissolution of ibandronic acid or its salts, or hydrates thereof, and provide rapid and targeted delivery of active substance to the upper gastrointestinal tract.

In the upper gastrointestinal tract, the rapidly disintegrating tablet cores of the present invention disintegrate into tiny particles, which are distributed throughout the stomach and thus reduce local irritation of the gastric mucosa. From the tiny particles, the active substance is rapidly released, thereby providing optimal conditions for relatively good absorption of the active substance in the gastrointestinal tract. Rapid disintegration provides rapid dissolution of the active susbtance in the stomach such that sufficiently high concentration of active substance is provided which is needed for optimum absorption in the stomach. Thus, the compositions provide a patient-friendly dosage form.

In an embodiment the invention relates to pharmaceutical compositions comprising:

a) ibandronic acid or its salts, or hydrates thereof;

b) at least one disintegrant; and

c) optionally, at least one disintegration enhancing component.

The selection of suitable combinations of disintegrants and optionally disintegration enhancing components provides rapid disintegration of the pharmaceutical compositions in the gastric juices. The rapidly-disintegrating composition disintegrates into tiny particles which are (due to fast disintegration) distributed throughout the stomach. In this way, local irritation of the gastric mucosa is minimized in comparison to pharmaceutical compositions which disintegrate at a slower rate in the stomach.

Non-limiting examples of useful disintegrants include carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not being limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses- Examples of low-substituted hydroxypropyicelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.), starches or derivatives such as pregelatinized starch. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, pectinic acid, alginic acid, etc.

Non limiting examples of useful disintegration enhancing components include but are not limited to basic alkali metal salts, basic alkaline earth metal salts and basic ammonium salts, for example in the form of the carbonates, hydrogen carbonates, phosphates, hydrogen phosphates, oxides, hydroxides, citrates, tartrates, and acetates of sodium, potassium, ammonium, etc. Various specific salts include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, magnesium carbonate, calcium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, tricalcium phosphate, sodium acetate, potassium acetate, etc., and salts with basic amino acids, such as lysine and arginine, and the like.

In an embodiment the invention relates to compositions having weight ratios of ibandronic acid or its salts, or hydrates thereof, to a disintegrant and optionally a disintegration-enhancing component in the range of about 1:50 to about 50:1, or about 1:30 to about 30:1.
In another embodiment the invention relates to compositions comprising a disintegrant and optionally a disintegration enhancing component in the range of about 0.1% to about 50%, or about 0.5% to about 25%, or about 1 % to about 10%, by weight of the total composition.
In yet another embodiment the invention includes compositions having weight ratios of disintegrant to disintegration enhancing component in the range of about 1:10 to about 10:1, or from about 1:7.5 to about 7.5:1.

In an embodiment a disintegrant and optionally a disintegration enhancing component is present in an intra-granular portion of the composition.
In another embodiment a disintegrant and optionally a disintegration-enhancing component is in an extra-granular portion of the composition.

In an embodiment the invention includes solid oral dosage forms of ibandronic acid or its salts, or hydrates thereof, including dosage forms such as tablets, capsules, pills, granules, powders, and the like.

For solid dosage forms there are various important physical parameters of ibandronic acid or its salts, or hydrates thereof, as well as that of final blends containing ibandronic acid or its salts, or hydrates thereof and excipients, impacting the properties of dosage forms, such as moisture content (determined by techniques such as Karl Fischer ("KF") apparatus or an infrared moisture balance), bulk density and tapped density, compressibility index, Hausner ratio (such as determined by USP density apparatus), flow property (such as determined by a Flowdex apparatus), etc. These physical parameters could affect the processes for preparation of the compositions.

Bulk density is defined as a property of particulate materials. It is the mass of many particles of the material divided by the volume they occupy. The volume includes the space between particles as well as the space inside the pores of individual particles. The bulk density of powders is usually reported both as "freely settled" and "tapped" densities (where the tapped density refers to the bulk density of the powder after a specified compaction process, usually involving vibration of the container). A useful method for determining the properties is Test 616, "Bulk and Tapped Density," United States Pharmacopeia 29, United States Pharmacepeial Convention, Inc., Rockville Maryland, 2005 ("USP").
In an embodiment the present invention relates to pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof having a bulk density of ibandronic acid or its salts, or hydrates thereof in the range of about 0.1 to about 0.85 g/mL
In another embodiment the present invention present invention relates to pharmaceutical compositions comprising ibandronic acid or its salts, hydrates thereof having a tapped density of ibandronic acid or its salts, hydrates thereof in the range of about 0.2 to about 0.95 g/mL.

In yet another embodiment the invention relates to pharmaceutical compositions wherein the bulk density of final blends of ibandronic acid or its salts, or hydrates thereof with excipients is in the range of about 0.35 to about 0.7 g/mL.
A further embodiment relates to pharmaceutical compositions wherein the tapped density of final blends of ibandronic acid or its salts, or hydrates thereof with excipients is in the range of about 0.45 to about 0.9 g/mL.

A "final blend" is a mixture of components, immediately prior to its conversion into a pharmaceutical dosage form.

Uniform particle size distributions of ibandronic acid or its salts, or hydrates thereof and also the final blends are desired for preparing a solid oral dosage form.
The particle size distribution of a material is generally described in terms of parameters D10, D50, D90l D[4,3] that are used routinely to describe the particle size or size distribution. Values are expressed as volume or weight or surface percentages. Dx as used herein is defined as the size of particles where x volume or weight percent of the particles have sizes less than the value given. D[4.3] for example is the volume mean size of the ibandronic acid or its salt or other powder compositions. Dgofor example means that 90% of the particles are below a particle size.

In an embodiment, the present invention relates to the use of particle size distributions of ibandronic acid or its salts, hydrates thereof, wherein D10 is in the range of about 0.5 to about 30 urn, D50 is in the range of about 10 to about 70 urn, and Dgo is in the range of about 50 to about 500 urn.

In an embodiment the invention relates to pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof wherein the water content of the composition is not more than about 10% w/w of the composition, as measured by KF.
In order to prepare solid oral dosage forms, the compositions further comprise at least one pharmaceutically acceptable excipient. The pharmaceutical^ acceptable excipients that can be used include, but are not limited to, diluents, binders, glidants, lubricants, solvents, colourants, film forming polymers and coating adjuvants.

Diluents include, but are not limited to, starches, lactose, mannitol, cellulose derivatives and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different grades of starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to canmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include but are not limited to hydroxypropylcelluloses (Klucel™ LF), hydroxypropyl methylcelluloses (Methocel™), polyvinylpyrrolidones or povidones (PVP-K25, PVP-K29, PVP-K30), powdered acacia, gelatin, guar gum, carbomers (Carbopol™), methylcelluloses, polymethacrylates, and starches.

Various useful glidants or antisticking agents include but are not limited to talc, silica derivatives, and colloidal silicon dioxide.
Various useful lubricants to assist in tableting, etc. include, but are not limited to, stearic acid derivatives such as magnesium stearate, sodium stearyl fumarate, calcium stearate, etc., talc, macrogol (polyethylene glycol), hydrogenated esters of fatty acids with glycerine, glyceryl behenate, hydrogenated castor oil, and mixtures thereof.

In one embodiment, the invention includes the use of sodium stearyl fumarate as a lubricant.
In another embodiment, the invention includes compositions comprising lubricant in an amount from about 0.1 % w/w to about 10% w/w.

In another embodiment, the invention includes the use of more than about 5% w/w of stearic acid as a lubricant.

Various solvents that are useful in processing include but are not limited to, water, lower alcohols like methanol, ethanol, and isopropanol, acidified ethanol, acetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformarnide, and tetrahydrofuran.

Flavoring agents, which can be used in the present invention, include, but are not limited to, natural or synthetic or semi-synthetic flavors like menthol, fruit flavors, citrus oils, peppermint oil, spearmint oil, oil of wintergreen (methyl salicylate), etc.

Various useful colorants include but are not limited to Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, and iron oxides.

It is known that bisphosphonic acids, including ibandronic acid or its salts, including hydrates thereof, give rise to irritation of the upper gastrointestinal tract. In order to overcome these problems, orally administered dosage forms frequently are coated. Film-forming polymers are frequently used for coating.

Various useful film-forming agents include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc., insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrytic acids, polyvinylalcohols,
polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, and waxes and fat substances.

In the case of polymethacrylates, cationic copolymerizates of dimethylaminoethyl methacrylate with neutral methacrylic esters (Eudragit™ E), copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups (described in "Ammonio Methacrylate Copolymer Type A or Type B" USP/NF, Eudragit™ RL and RS, respectively), and copolymerizates of ethyl acrylate and methyl methacrylate with neutral character (in the form of an aqueous dispersion, described in "Polyacrylate Dispersion 30 Per Cent" Ph. Eur., Eudragit™ NE 30 D) are useful.
Anionic copolymerizates of methacrylic acid and methyl methacrylate (described in "Methacrylic Acid Copolymer, Type C" USP/NF, Eudragit™ L and S, respectively, or in the form of the Eudragit™ L 30 D aqueous dispersion), acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc. may be used for film coatings.

The coating may be applied using methods such as film coating, press coating, tablet coating, encapsulating or microencapsulating.
If required, the films may contain additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, and the like.
Various useful plasticizers include but are not limited to castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also mixtures of plasticizers may be utilized. The type of plasticizer generally depends upon the type of coating agent.
An opacrfier like titianium dioxide may also be present. When coloured tablets are desired then the colour is normally applied in the coating. Consequently, colouring agents and pigments may be present in the film coating. Various colouring agents include but are not limited to iron oxides, which can be red, yellow, black or blends thereof.

Anti-adhesives are normally used in film coating processes to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc.
Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., camauba wax, candelilla wax and white wax). In an embodiment, polyethylene glycols having molecular weights of 3,000-20,000 are employed.
In addition to above the coating ingredients, sometimes pre-fonmulated commercial coating products such as Opadry™ White OY 58900 (contains hydroxypropyl methylcellulose, PEG 6000, and titanium dioxide), Lusterclear™, etc. will be used. Lustreclear is a combination of microcrystalline cellulose and carrageenan. The commercially available products are either provided as dispersions in a liquid, or are solids that can be dispersed in a suitable liquid before use.

In certain embodiments, the pharmaceutical compositions of the present invention may be processed using any of the techniques of direct compression, dry granulation, wet granulation, extrusion/spheronization, melt granulation, fluid bed granulation, etc.

In an embodiment, the invention includes processes for preparing pharmaceutical compositions, wherein an embodiment of a process comprises:

1) Sifting the active substance, and intra-granular and extra-granular excipients through a suitable sieve.

2) Geometrically mixing the active substance with intra-granular excipients.

3) Optionally, blending the step 2) materials with extra-granular excipients and compressing into tablets, or optionally the active substance and excipients are subjected to roll compaction, and then the compacted material is milled through a sieve to obtain granules.

4) Placing step 3) materials into a granulator and mixing.

5) Dissolving or dispersing a binder in a suitable solvent.

6) Granulating the step 4) dry mix material using the binder from step 5.

7) Drying the wet granules.

8) Sizing the dried granules through a sieve.

9) Blending the dried granules from step 8) or milled granules from step 3) with sifted extragranular excipients.

10) Lubricating the step 9) blend with lubricant by blending.

11) Compressing the final blend of step 10) into tablets using a compression machine.

12) Optionally coating the tablets using a coating solution or dispersion.

13) Alternatively, filling the final blend of step 10) into empty hard gelatin capsules.
In embodiments, the invention includes the use of dry processing for preparing pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof.

In embodiments, a process of preparation of the pharmaceutical composition of ibandonic acid or its salt is selected such that inclusion of moisture can be minimized in the pharmaceutical composition, as inclusion of moisture may lead to polymorphic conversion of the active.
In embodiments, the invention includes the use of non-aqueous granulation for preparing pharmaceutical compositions comprising ibandronic acid or its salts, or hydrates thereof.

In an embodiment, the invention relates to pharmaceutical compositions in the form of tablets having hardness from about 4 KP to about 15 KP.

In an embodiment, the invention includes amounts of active substance in pharmaceutical dosage forms at an amount more than about 36% w/w.
The pharmaceutical compositions of the present invention comprise from about 1 mg to about 500 mg of ibandronic acid or its salts, including hydrates thereof, per unit dosage form.
In an embodiment, the invention includes the use of packaging materials such as containers and lids of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc. The packages containing the formulations of the present invention might optionally contain a desiccant, oxygen absorbent, or both. In an embodiment, the packages according to the present invention may be flushed with nitrogen or inert gas before placing the formulation in the pack.

In an embodiment the invention relates to stable compositions comprising ibandronic acid or its salts, hydrates thereof.

The term "stable" for purposes of the present invention relates to either physical or polymorphic or chemical stability or both. The 'stability' according to the present invention refers to physical stability, chemical stability and/or polymorphic stability of the active ingredient during manufacture and also during the shelf life of the product. Physical stability may be determined by using analytical techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and infrared (IR) absorption spectroscopy.

In an embodiment the invention relates to pharmaceutical compositions comprising ibandronic acid or its salts, hydrates thereof, wherein an XRPD pattern of the contained ibandronic acid or its salt after stability testing is substantially the same as its initial XRPD pattern.

In another embodiment pharmaceutical compositions of the invention contain p crystalline form of ibandronic acid monosodium salt which is substantially free of crystalline forms 'B' and 'A' after exposure to the accelerated storage conditions of 40°C/75%RH for a period of 6 months.

In yet another embodiment, pH of pharmaceutical compositions comprising ibandronic acid monosodium salt is in the range from about 3 to about 7, initially and after the accelerated storage conditions of 40°C/75% RH for a period of 6 months.

In yet another embodiment the pharmaceutical compositions of the present invention show loss on drying (LOD) of not more than 15%, or not more than 10%, of the composition initially, and after exposure to the accelerated storage conditions of 40°C/75% RH for a period of 6 months.

In an embodiment the pharmaceutical compositions of the present invention show total impurities of not more than about 0.5%, or not more than about 0.2%, of the label drug content, after storage at the accelerated storage conditions of 40°C/75% RH over a period of 6 months.

The foregoing impurity criteria are for products that are stored in their usual commercial packaging, such as ,but not limited to, one of the packaging systems described in an example.

In a separate embodiment, the pharmaceutical compositions of the present invention disintegrate within not more than about 15 minutes, or within not more than about 10 minutes, after immersion in an aqueous medium.

The dosage forms so prepared can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopoeial Convention, Inc, Rockville, Maryland, 2005, to determine the rate at which the active substance is released from the dosage forms, and the content of active substance can be determined in solutions using techniques such as high performance liquid chromatography.

In an embodiment the pharmaceutical composition of the present invention possess a dissolution profile such that at least 90% of the drug is dissolved in not more than about 120 minutes, or not more than about 90 minutes, or not more than about 60 minutes, in USP apparatus II (paddles) at 50 rpm, in 500 ml of purified water (degassed) at 37°C ± 0.5°C.

The pharmaceutical dosage forms of the present invention are intended for oral administration to a patient in need thereof.

In an embodiment the invention includes pharmaceutical compositions wherein ibandronic acid or salts thereof are replaced with any other bisphosphonic acid such as alendronic acid, zoledronic acid, residronic acid, pamidronic acid, etidronic acid, etc., and salts thereof.

Certain specific aspects and embodiments of the invention will be further described in the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES Examplel: Ibandronic acid 150 mg tablets.

Ingredient mg/Tablet
Intra-granular
Ibandronate sodium (p Form) $ 160.33
Microcrystalline cellulose (Avicel™ PH112)98.47
Croscarmellose sodium 10
Colloidal silicon dioxide 6
Sodium stearyl fumarate 4.6
Extra-granular
Microcrystalline cellulose (Avicel™ PH112)8.4
Croscarmellose sodium 10
Colloidal silicon dioxide 2
Sodium bicarbonate 11.2
Sodium stearyl fumarate 9
Film coating
Opadry White OY58900 @ 9.6
Isopropyl alcohol (IPA)* 100
Methylene chloride (MC)* 55

$ 160.33 mg of ibandronate sodium p form is equivalent to 150 mg of ibandronic acid.

@ Opadry™ White OY 58900 contains hydroxypropyl methylcellulose, PEG 6000, and titanium dioxide and is supplied by Colorcon.

** Avicel™ PH 112 supplied by FMC Corporation

* Evaporates during processing.

Manufacturing process:

1) Intra-granular components ibandronate sodium, Avicel™ PH 112, croscarmellose sodium, and colloidal silicon dioxide were sifted through an ASTM #40 mesh sieve, and the sifted materials were blended for about 10 minutes.

2) Sodium stearyl fumarate (intra-granular) was sifted through an ASTM #60 mesh sieve.

3) Step 1) materials were blended with step 2).

4) Blend of step 3) was compressed to form slugs.

5) Step 4) slugs were milled through a 10 mm screen in a comminuting mill to form granules, so that all the granules are passed through an ASTM #16 mesh sieve.

6) The extra-granular materials Avicel™ PH 112, croscarmellose sodium, colloidal silicon dioxide, and sodium bicarbonate were sifted through an ASTM #40 mesh sieve and then were blended with granules of step 5).

7) Sodium stearyl fumarate (extra-granular) was sifted through an ASTM #60 mesh sieve.

8) Step 6) materials were blended with step 7).

9) Lubricated blend of step 7) was compressed into tablets.

10) Opadry White OY58000 was dispersed in a mixture of IPA and MC with stirring and stirred for about 45 minutes.

11) The compressed tablets of step 9) were film coated using coating dispersion of step 10).

The tablets prepared were subjected to in vitro dissolution testing performed in USP apparatus II (paddles) at 50 rpm, in 500 ml of purified water (degassed) at 37°C ± 0.5°C, and compared with the reference product Boniva® 150 mg. The results are tabulated in Table 1, where the values are cumulative percentages of the contained drug that dissolved.

Table 1

Time (minutes) Reference Example 1
5 66 55
10 92 87
15 96 97
30 101 100
45 105 103

Examples 2-3: Ibandronic acid 150 mg tablets.

Ingredient Example 2 Example 3
Intra-granular
Ibandronate sodium (p Form)176 176.4
Microcrystalline cellulose(Avicel PH112)82.8 82.4
Croscarmellose sodium 10 10
Colloidal silicon dioxide 6 6
Sodium stearyl fumarate 4.6 4.6
Extra-granular
Microcrystalline cellulose(Avicel PH112)19.6 8.4
Crospovidone 10 -
Croscarmellose sodium - 10
Colloidal silicon dioxide 2 2
Sodium bicarbonate - 11.2
Sodium stearyl fumarate g g

Manufacturing process: similar to that of Example 1, omitting the coating.

The tablets prepared were subjected to in vitro dissolution testing performed in USP apparatus II (paddles) at 50 rpm, in 500 ml of purified water (degassed) at 37°C ± 0.5°C. The results are tabulated in Table 2, where the values are cumulative percentages of the contained drug that dissolved.

Table 2

Time (minutes) Example 2 Example 3
5 27 55
10 49 87
15 83 97
30 - 100
45 — 103

Examples 4-6: Ibandronic acid 150 mg tablets.

Ingredient mg/Tablet

Example 4 Example 5 Example 6
Intra-granular
Ibandronate sodium ((3 Form)176 176.4 176.4
Microcrystailine cellulose(Avicel PH112)82.8 82.4 98
Croscarmellose sodium 10 10 10
Colloidal silicon dioxide 6 6 6
Sodium stearyl fumarate 4.6 4.6 4.6
Extra-granular
Microcrystailine cellulose (Avicel PH112)6.8 8.4 -
Croscarmellose sodium 10 10 5
Colloidal silicon dioxide 2 2 3
Sodium bicarbonate 12.8 - 13
Sodium carbonate - 12.8 -
Sodium stearyl fumarate 9 9 9
Film coating
Opadry White OY58900 @ 9.6 9.6 9.6
Isopropyl alcohol (IPA)*100 100 100
Methylene chloride (MC)*55 55 55

* Evaporates during processing.

Manufacturing process: similar to that of

Example 1.

The tablets prepared were subjected to in vitro dissolution testing. Dissolution conditions were the same as in Example 2 and dissolution results are tabulated in Table 3, where the values are cumulative percentages of the contained drug that dissolved.

Table 3

Time (minutes) Example 4 Example 5 Example 6
5 54 73 74
10 82 95 95
15 92 95 97
30 94 - 98
45 95 - 99

Examples 7-8: Ibandronic 150 mg tablets.

Ingredient mg/Tablet

Example 7 Example 8
Intra-granular
Ibandronate sodium (fS Form) 176.4 176.4
Lactose monohydrate 20 20
Microcrystalline cellulose (Avicel™ PH101)70 70
Povidone K-30 23 23
Methylene chloride (MC)*230 230
Extra-granular
Microcrystalline cellulose (Avicel PH101)43.1 13
Croscarmellose sodium 30 45
Colloidal silicon dioxide 3.75 3.6
Sodium bicarbonate - 15
Sodium stearyl fumarate 3.75 4
Film coating
Opadry White OY58900 12 12
Isopropyl alcohol (IPA)*125 125
Methylene chloride (MC)*70 70

* Evaporates during processing.
Manufacturing process:

1) Intra-granular components ibandronate sodium p form, lactose monohydrate,and Avicel™ PH101 were sifted through an ASTM #40 mesh sieve.

2) Binder solution was prepared by dissolving povidone K-30 in methylene chloride.

3) Ingredients of step 1) were granulated with binder solution of step 2).

4) Granules of step 3) were dried in fluid bed drier at 40 °C, until loss on drying was between 6 -9 % w/w at 105 °C.

5) Dried granules were sifted through an ASTM #20 mesh sieve.

6) Extra-granular Avicel PH102, croscarmellose sodium, colloidal silicon dioxide and sodium bicarbonate were sifted through an ASTM #40 mesh sieve.

7) Granules from step 5) were blended with step 6) for about 10 minutes.

8) Sodium stearyl fumarate (extra-granular) was sifted through an ASTM #60 mesh sieve and blended the material from step 7) for about 15 minutes.

9) Lubricated blend of step 8) was compressed into tablets.

10) Opadry White OY58900 was dissolved in a mixture of IPA and MC with stirring and stirred for about 45 minutes.

11) The tablets of step 9) were coated using Opadry dispersion of step 10).

The tablets prepared were subjected to in vitro dissolution testing. Dissolution conditions were the same as in Example 2 and dissolution results are tabulated in Table 4, where the values are cumulative percentages of the contained drug that dissolved.

Table 4

Time (minutes) Example 7 Example 8
5 23 65
10 45 97
15 60 98
30 81 98
45 87 99

The tablets of Example 8 were packed in aluminium/aluminium foil blisters with desiccant and stored at 40 °C/75 % RH for about 1 month. XRD analysis was performed on tablets at initial as well as 1 month samples.

Figure 1 shows comparative X-ray powder diffraction ("XRPD") patterns for ibandronate sodium p Form (A), composition prepared according to example 1 (B), similarly prepared composition but without ibandronate sodium p Form (C).

Figure 2 shows comparative XRPD patterns for ibandronate sodium p Form (A), composition prepared according to Example 1 (B), and a similarly prepared composition but without ibandronate sodium p Form (C) after storing at accelerated stability testing conditions of 40 °C/75% RH for about 1 month.

Examples 9-10: Ibandronic 150 mg tablets.

Ingredient rngfTablet

Example 9 Example 10
Intra-granular
Ibandronate sodium (p Form) 168.75 -
Ibandronate sodium (p Form) - 160.33
Lactose monohydrate 18.75 20
Microcrystalline cellulose (Avicel™ PH 101)75 -
Povidone K-30 18.75 12.8
Water* q.s. -
Methylene chloride (MC)* - 115.2
Extra-granular
Microcrystalline cellulose (Avicel PH 101)60 90.07
Crospovidone 26.25 16
Croscarmellose sodium - 16
Colloidal silicon dioxide 3.75 1.6
Sodium stearyl fumarate 3.75 3.2
Film coating
Opadry White OY58900 11.25 9.6
Isopropyl alcohol (IPA)* - 97.5
Methylene chloride (MC)* - 52.5
Water* q.s. -
Imprinting
Opacode black (S-1-17823) - q.s.
Isopropyl alcohol (IPA) - q.s.

* Evaporates during processing.

Manufacturing process:

1) Intra-granular ibandronate sodium, lactose monohydrate, and Avicel™ PH101
(if required) were sifted through an ASTM #40 mesh sieve, and mixed in a rapid mixture granulator.

2) Binder solution was prepared by dissolving povidone K-30 in water or methylene chloride.

3) Ingredients of step 1) were granulated with binder solution of step 2).

4) Granules of step 3) were dried in fluid bed dryer at 40 °C, until loss on drying was between 6-9 % w/w at 105 °C.

5) Dried granules of step 4) were sifted through an ASTM #20 mesh sieve.

6) Extra-granular Avicel PH101, crospovidone, croscarmellose sodium (if required), and colloidal silicon dioxide were sifted through an ASTM #40 mesh sieve.

7) Granules from step 5) were blended with step 6) for about 10 minutes

8) Sodium stearyl fumarate (extra-granular) was sifted through an ASTM #60 mesh sieve and blended with the material from step 7) for about 15 minutes.

9) Lubricated blend of step 8) was compressed into tablets.

10) Opadry White OY58900 was dissolved in water, or in IPA and MC, with stirring, and stirring was continued for about 45 minutes.

11) The tablets of step 9) were coated using Opadry dispersion of step 10).

12) The coated tablets of step 11) were imprinted using Opacode black (S-1 -17823) solution in IPA.

The tablets prepared were subjected to in vitro dissolution testing. Dissolution conditions were the same as in Example 2 and dissolution results are tabulated in Table 4, where the values are cumulative percentages of the contained drug that dissolved.

Table 4

Time (minutes) Example 9 Example 10
5 62 63
10 84 94
15 89 97
30 94 99
45 100 100

The tablets of Example 10 were packed in four different kinds of packing materials:
aluminium/aluminium foil with desiccant, PVC film with Aclar laminated with on hard tampered aluminium foil, PVC film coated with PVDC and laminated on aluminium foil, and 40cc HDPE bottles, and stored at 40 °C/75 % RH for about 6 months. XRD analysis was performed for tablets at initial as well as 6 month samples. The XRDs as shown in Figures 3-7 do not show any polymorphic conversion or any detectable impurity in the stability sample over 6 months. Thus, the pharmaceutical composition of Example 10 is stable over a period of 6 months with all of the different packaging conditions.

CLAIMS:

1. A pharmaceutical composition, comprising:

a) ibandronic acid, its salt, or a hydrate thereof;

b) at least one disintegrant; and

c) optionally, at least one disintegration enhancing component.

2. A pharmaceutical composition of claim 1, wherein a disintegrant comprises one or more of carmellose calcium, croscarmellose and salts thereof, a crospovidone, and a low-substituted hydroxypropylcellulose.

3. A pharmaceutical composition of claim 1, wherein a disintegration enhancing agent comprises one or more of sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, magnesium carbonate, calcium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, tricalcium phosphate, sodium acetate, and potassium acetate.

4. A pharmaceutical composition of claim 1, wherein a weight ratio of ibandronate to the total of disintegrant and optional disintegration-enhancing agent is in the range of about 1:50 to about 50:1, or about 1:30 to about 30:1.

5. A pharmaceutical composition of claim 1, wherein the pharmaceutical composition additionally comprises one or more of lactose monohydrate, microcrystalline cellulose, a polyvinylpyrrolidone, colloidal silicon dioxide, and sodium stearyl fumarate.

6. A pharmaceutical composition of claim 1, comprising ibandronate monosodium present as least 90% of beta polymorphic form, substantially free of polymorphic form 'B'.

7. A pharmaceutical composition of claim 1, wherein the composition has intra-granular and extra-granular components, such that the ratio of intra-granular component to extra-granular component ranges from about 80:20 to about 60:40.

8. A pharmaceutical composition of claim 1, wherein the ibandronic acid, salt, or hydrate has a particle size distribution wherein about 50% of the particles have particle sizes in the range of about 20 urn to about 70 urn, and 90% of the particles have particle sizes less than about the range of about 60 pm to about 200 pm.

9. A process of preparing a pharmaceutical composition of claim 1 comprising ibandronic acid, or a salt or hydrate thereof, in amount providing about 150 mg of ibandronic acid equivalent, wherein the process comprises a step of direct compression, dry granulation, wet granulation, extrusion/spheronization, melt granulation, or fluid bed granulation

10. A process of claim 10, wherein the process includes aqueous or non-aqueous granulation.