WO2006020009A1

WO2006020009A1 - Solid oral dosage form of a bisphosphonate containing a chelating agent

Info

Publication number: WO2006020009A1
Application number: PCT/US2005/025145
Authority: WO
Inventors: Richard John Dansereau; David Ernest Burgio, Jr.
Original assignee: The Procter & Gamble Company
Priority date: 2004-07-23
Filing date: 2005-07-15
Publication date: 2006-02-23

Abstract

A method comprising orally administering to a human or other mammal a solid oral dosage form comprising a pharmaceutical composition which may be administered to a human or other mammal in need thereof with water that is considered at least moderately hard, said pharmaceutical composition comprising a bisphosphonate or a pharmaceutically acceptable acid, salt, ester, solvate, or polymorph thereof and at least one chelating agent wherein the amount of bisphosphonate is greater than the equivalent weekly dose of said bisphosphonate suitable for the treatment of osteoporosis is useful for treating or preventing osteoporosis and other bone metabolic disorders.

Description

SOLID ORAL DOSAGE FORM OF A BISPHOSPHONATE CONTAINING A CHELATING AGENT

FIELD OF THE INVENTION The present invention relates to oral formulations of bisphosphonates and their methods of use in the treatment and prevention of a variety of disorders, including bone disorders such as osteoporosis, arthritis, and cancer. The methods of the present invention comprise administering to a human or other mammal in need thereof a solid oral dosage form comprising a pharmaceutical composition which may be administered with water that is at least moderately hard, said pharmaceutical composition comprising a bisphosphonate or a pharmaceutically acceptable acid, salt, ester, solvate, or polymorph thereof and at least one chelating agent, wherein the amount of bisphosphonate is greater than the equivalent weekly dose of said bisphosphonate suitable for the treatment of osteoporosis. The present invention also relates to pharmaceutical compositions of bisphosphonates and kits for carrying out these methods.

BACKGROUND OF THE INVENTION

A number of pathological conditions exist which can affect humans or other mammals and involve calcium and phosphate metabolism. Such conditions may be divided into two broad categories: (1) Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss or excessively high calcium and phosphate levels in the fluids of the body. Such conditions are sometimes referred to herein as patholological hard tissue demineralizations. or (2) Conditions which cause or result from deposition of calcium and phosphate anomalously in the body. These conditions are sometimes referred to herein as pathological calcifications. The first category includes osteoporosis, a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Essential quantities of cancellous bone are lost, marrow and bone spaces become larger, resulting in reduced cancellar bone strength. Compact or bone also becomes less dense and fragile. Another condition in the first category is Paget's disease (osteitis deformans). In this disease, dissolution of normal bone occurs which is then haphazardly replaced by soft, poorly mineralized tissue such that the bone becomes deformed from pressures of weight bearing, particularly in the tibia and femur. Hyperparathyroidism, hypercalcemia of malignancy, and osteolytic bone metastases are conditions also included in the first category. The second category, involving-conditions manifested by anomalous calcium and phosphate deposition, includes myositis ossificans progressiva, calcinosis universalis, and such afflictions as arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions which predispose involved tissue to deposition of calcium phosphates. The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue due to an imbalance in the normal resorption/formation cycle of bone within the bone remodeling unit. In general, there are two types of osteoporosis: primary and secondary. Secondary osteoporosis is the result of an identifiable disease process or agent. For example, glucocorticoid steroids are known to induce osteoporosis. See, for example, American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, "Recommendations for the Prevention and Treatment of Glucocorticoid- Induced Osteoporosis," Arthritis & Rheumatism, Vol. 44(7): 1496-1503 (July 2001); B.P. Lukert, M.D., F.A.C.P. "Glucocorticoid-Induced Osteoporosis," Primer in the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 4th Ed. 292-96, Publication of the American Society for Bone and Mineral Research, Murray J. Favus, M.D. Editor, Dept of Medicine, The University of Chicago Medical Center, Chicago, Illinois. Approximately 85% of all osteoporosis is primary osteoporosis. See, for example, Marjorie M. Luckey, M.D., "Evaluation of Postmenopausal Osteoporosis," Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 4th Ed. 273-77, Murray J. Favus, M.D. Editor, Dept of Medicine, The University of Chicago Medical Center, Chicago, Illinois; and "Osteoporosis Prevention, Diagnosis, and Therapy," JAMA, Vol. 285(6): 785-95 (Feb. 14, 2001). Such primary osteoporosis includes postmenopausal osteoporosis, age- associated osteoporosis (affecting a majority of individuals over the age of 70 to 80) and idiopathic osteoporosis.

For some osteoporotic individuals, the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result. Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency. Many compositions and methods are described for the "treatment" of osteoporosis. Many of these include the use of bisphosphonates or other bone-active phosphonates. See, for examples, J.Y. Reginster et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis," Osteoporosis International, (2000) 11: 83-91; Steven T. Harris, MD et al., "Effects of Risedronate Treatment of Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial," JAMA, October 13, 1999, Vol. 282(14): 1344-52. Risedronate, or l-hydroxy-2-(3-pyridinyl)-ethylidene-l,l- bisphosphonic acid, is a member of the class of compounds known as bisphosphonates. See U.S. Pat. No. 5,583,122, to Benedict et al., issued Dec. 10, 1996.

Continuous and cyclic administration of bisphosphonates alone or with other medicaments such as parathyroid hormone, calcium, and vitamin D have also been suggested as a therapy for osteoporosis. See, for example American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, "Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis," Arthritis & Rheumatism, Vol. 44(7): 1496-1503 (July 2001); J.Y. Reginster, et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis," Osteoporosis International, 11: 83-91 (2000); Steven T. Harris, MD, et al., "Effects of Risedronate Treatment of Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial," JAMA, Vol. 282 (14): 1344-52 (Oct. 13, 1999).

Adverse gastrointestinal effects have been associated with bisphosphonates as a class. Further, although calcium supplements are recommended for those at risk or suffering from osteoporosis, calcium-containing foods or supplements interfere with the absorption, and thus the efficacy, of bisphosphonates if taken simultaneously. To overcome these effects, patients taking bisphosphonates are instructed to take their medication with water and without food. Patients are further instructed to remain upright for thirty minutes after taking a bisphosphonate, and to take a calcium supplement at a different time of the day, or on a day when the patient is not taking a dose of a bisphosphonate.

These instructions can prove burdensome or difficult to remember for a patient who regularly takes a bisphosphonate. Thus, a less frequent dosing regimen would enhance patient convenience, which could lead to greater patient compliance with complicated treatment regimens associated with bisphosphonates.

Less frequent dosing regimens of bisphosphonates require higher unit doses of bisphosphonates to be administered periodically to the patient. The use of bisphosphonates in the treatment of other disorders such as osteoarthritis and cancer may also require higher unit doses of bisphosphonates than what is administered in the treatment of osteoporosis or Paget' s disease. However, it recently has been observed that absorption of higher unit doses of bisphosphonates - that is, doses of bisphosphonates exceeding the amount present in a weekly equivalent unit dose suitable for the treatment of osteoporosis - may be diminished when the patient takes the bisphosphonate with hard water. This "hard water effect" is observed when the patient takes the higher dose of a bisphosphonate with water that is considered at least moderately hard. In the past, others have perhaps sought to overcome interferences with the absorption of higher dose bisphosphonates by administering more of the bisphosphonate active ingredient per dose. See, for example, U.S. Pat. Pub. 2003/0225039A1, by Bauss et al., published Dec. 4, 2003; U.S. Pat. Pub. 2003/0139378A1, by Daifotis et al., published July 24, 2003.

It has now been found, however, that interference with the absorption of bisphosphonates due to the mineral content in hard water may be overcome by the addition of a chelating agent to a pharmaceutical composition comprising a higher dose of a bisphosphonate. While not desiring to be bound by theory, it is believed that the chelating agent present in the pharmaceutical composition complexes with the polyvalent cations in hard water and minimizes the chelation and precipitation of cations by the bisphosphonate active ingredient. Thus, the presence of the chelating agent minimizes the precipitation of the bisphosphonate out of solution. The pharmaceutical compositions comprising higher doses (i.e., greater than weekly doses) of bisphosphonates of the present invention can thus be taken with water that is considered at least moderately hard without resulting in a decrease in absorption of the bisphosphonate as compared with the absorption observed in lower doses of bisphosphonates (i.e., unit doses of bisphosphonates suitable for administration on a weekly or more frequent basis). SUMMARY OF THE INVENTION

The present invention relates to a method for treating or preventing a bone disorder, osteoarthritis or cancer in a human or other mammal in need thereof comprising orally administering to said human or other mammal a solid oral dosage form comprising a pharmaceutical composition which may be administered with water that is at least moderately hard, said pharmaceutical composition comprising a bisphosphonate or a pharmaceutically acceptable acid, salt, ester, solvate, or polymorph thereof and at least one chelating agent, wherein the amount of bisphosphonate is greater than the weekly dose of said bisphosphonate suitable for the treatment of osteoporosis. The invention further relates to pharmaceutical compositions and kits suitable for use with the methods of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Water hardness refers to a measure of the polyvalent cations (ions with a charge greater than +1) present in water. Common polyvalent cations present in hard water include calcium (Ca ) and magnesium (Mg ); iron (Fe ) and manganese (Mn ) may also be present at lower levels. Water hardness is generally expressed in units of milligrams per liter (mg/L) or parts per million (ppm) of CaCO₃ (calcium carbonate). Generally, waters with a total hardness in the range of 0 to 60 mg/L are termed soft; from 61 to 120 mg/L moderately hard; from 121 to 180 mg/L hard; and above 180 mg/L very hard. See Briggs, J.C. et al, Quality of Rivers of the United States, 1975 Water Year - Based on the National Stream Quality Accounting Network (NASQAN): U.S. Geological Survey Open-File Report 78-200, p. 436 (1977).

The terms "bisphosphonate" and "diphosphonate," as used herein, include any pharmaceutically active form of a bisphosphonate, including, but not limited to, acids, salts, esters, polymorphs, solvates, and derivatives thereof. The bisphosphonates of the present invention include those preferred compounds containing a nitrogen atom. Non- limiting examples of bisphosphonates useful herein include the following: l-hydroxy-2- (3-pyridinyl)-ethylidene-l,l-bisphosphonic acid (risedronate) as described in U.S. Pat. No. 5,583,122, to Benedict et al., issued Dec. 10, 1996; U.S. Pat. No. 6,410,520 B2, to Cazer et al., issued Jun. 25, 2002; 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid (alendronic acid or alendronate) as described in U.S. Pat. No. 4,621,077, to Rosini et al., issued Nov. 4, 1986; U.S. Pat. No. 6,281,381 Bl, to Finkelstein et al., issued Aug. 28, 2001; U.S. Pat. No. 6,008,207, to Brenner et al., issued Dec. 28, 1999; U.S. Pat. No. 5,849,726, to Brenner et al., issued Dec. 15, 1998; U.S. Pat. Pub. 2001/0021705 Al, by Brenner et al., published Sept. 13, 2001; U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski, issued May 28, 1991; 3- amino-l-hydroxypropylidene-l,l-bisphosphonic acid (pamidronate) as described in U.S. Pat. No. 4,639,338, to Stahl et al., issued Jan. 27, 1987; (4-chloroρhenyl)thiomethane- 1,1-diphosphonic acid (tiludronate) as described in U.S. Pat. No. 4,876,248 to Breliere et al., issued Oct. 24, 1989; l,l-dichloromethylene-l,l-diphosphonic acid (clodronate) as described in U.S. Pat. No. 4,859,472, to Demmer et al., issued Aug. 22, 1989; cycloheptylaminomethylene- 1,1 -bisphosphonic acid (cimadronate), as described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990; l-hydroxy-3-(N-methyl-N- pentylamino)propylidene-l,l-bisphosphonic acid (ibandronate), which is described in U.S. Pat. No. 4,927,814, issued May 22, 1990; l-hydroxy-2-(imidazol-l-yl)ethane-l,l- bisphosphonic acid (zoledronate) as described in U.S. Pat. No. 4,777,163, to Bosies et al., issued Oct. 11, 1988; and l-(N-phenylaminothiocarbonyl)methane- 1,1 -bisphosphonic acid. In one embodiment of the invention, the bisphosphonate is selected from the group consisting of risedronate, alendronate, pamidronate, tiludronate, cimadronate, ibandronate, clodronate, zoledronate, and salts, esters, polymorphs, and solvates thereof, and combinations thereof.

The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those of ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate active ingredient in the present invention is on an anhydrous monosodium salt basis, unless otherwise indicated herein. For example, the phrase "about 150 mg risedronate" means that the amount of the bisphosphonate compound selected is calculated based on 150 mg of anhydrous risedronate monosodium salt.

A "pharmaceutically-acceptable salt" is a cationic salt formed at any acidic (e.g., hydroxamic or carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in WO 87/05297, by Johnston et al., published Sept. 11, 1987. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. The term "pharmaceutically acceptable ester," as used herein, refers to an ester of a bisphosphonate that does not interfere with the bone resorption inhibition activity of the bisphosphonate or that is readily converted by an animal to yield the bisphosphonate.

The term "solvate," as used herein, refers to a compound formed by the chemical combination of a solvent and another substance in a specific molecular ratio. In one embodiment of the invention, the solvent is water and the resulting solvate is a hydrate. Non-limiting examples of pharmaceutically acceptable solvates of bisphosphonates include the hemipentahydrate and monohydrate forms, as described in U.S. Pat. No. 6,410,520, to Cazer et al., issued June 25, 2002. The term "polymorph," as used herein, refers to the existence of a substance in an alternate form having different physical and/or chemical properties. Non- limiting examples of polymorphs of bisphosphonates include crystal form variations such as plates and needles.

Such salts, esters, solvates, and polymorphs are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of these given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt, ester, solvate, or polymorph over another for reasons of solubility, stability, formulation ease, and the like. Determination and optimization of such salts, esters, solvates, and polymorphs is within the purview of the skilled artisan's practice. The amount of bisphosphonate active ingredient contained in the oral dosage forms of the present invention will depend on the particular bisphosphonate selected and the continuous dosing schedule upon which the bisphosphonate is dosed to the patient. One embodiment of the invention comprises a method for treating osteoporosis in a mammal in need thereof comprising orally administering to said mammal a solid oral dosage form comprising a unit dose of a pharmaceutical composition comprising a bisphosphonate or a pharmaceutically acceptable acid, salt, ester, solvate, or polymorph thereof and at least one chelating agent, wherein the amount of bisphosphonate is greater than the unit dose of said bisphosphonate suitable for the treatment of osteoporosis on a once weekly basis.

The term "equivalent weekly dose," as used herein, means the unit dose of a pharmaceutical composition suitable for administration once, i.e., one time per week, in the treatment of osteoporosis. For example, the equivalent weekly dose of risedronate for the treatment of osteoporosis is about 35 mg risedronate on an anhydrous monosodium salt weight basis; the equivalent weekly dose of alendronate for the treatment of osteoporosis is about 70 mg alendronate on an alendronic acid weight basis.

When the bisphosphonate is risedronate, a unit dose of a pharmaceutical composition of the present invention may comprise at least about 75 mg risedronate. In one embodiment of the invention, the pharmaceutical composition comprises from about

75 mg to about 200 mg risedronate. In another embodiment, the pharmaceutical composition comprises from about 100 mg to about 150 mg risedronate. In yet another embodiment of the invention, the pharmaceutical composition comprises about 75 mg, about 100 mg, or about 150 mg risedronate.

The term "unit dose" or "unit dosage" means one or more dosage forms containing an amount of pharmaceutical active or nutrient suitable for administration in one single dose, according to sound medical practice. The present invention is particularly useful for the administration of unit doses in the form of tablets, capsules, caplets and sachets.

The term "combined unit dose of calcium and vitamin D," as used herein, means a single unit dose comprising both calcium and vitamin D.

The term "IU," as used herein, means International Units. One microgram of vitamin D is approximately 40 International Units. The term "nutrient," as used herein, means any nutritional or dietary supplement including but not limited to vitamins, minerals, amino acids, herbs or other botanicals, or concentrates, metabolites, constituents, extracts, or combinations of the same.

The preferred nutrients to be administered in the bisphosphonate treatment regimen are calcium and/or vitamin D. Oral forms of calcium suitable for use in the present invention include capsules, compressed tablets, chewable tablets, and the like.

Typical salt forms of calcium suitable for use in the present invention include but are not limited to calcium carbonate, calcium citrate, calcium malate, calcium citrate malate, calcium glubionate, calcium gluceptate, calcium gluconate, calcium lactate, dibasic calcium phosphate, and tribasic calcium phosphate. In one embodiment of the invention, calcium can be administered at doses of 400 mg to 1500 mg of calcium per day. In another embodiment of the invention, calcium can be administered at doses of 400 mg to 1500 mg of calcium per day, on the days in between the days when the patient takes a unit dose of pharmaceutical active. If a calcium supplement and a bisphosphonate are dosed on the same day, the patient should take the bisphosphonate and the nutrient at different times of the day. For example, the patient may take a unit dose of a bisphosphonate in the morning, and a calcium supplement 4 hours later. The term "vitamin D," as used herein, refers to any form of vitamin D that may be administered to a mammal as a nutrient. Vitamin D is metabolized in the body to provide what is often referred to as "activated" forms of vitamin D. The term "vitamin D" can include activated and non-activated forms of vitamin D, as well as precursors and metabolites of such forms. Precursors of these activated forms include vitamin D₂ (ergocalciferol, produced in plants) and vitamin D₃ (cholecalciferol, produced in skin and found in animal sources and used to fortify foods). Vitamins D₂ and D₃ have similar biological efficacy in humans. Non-activated metabolites of vitamins D₂ and D₃ include hydroxy lated forms of vitamins D₂ and D₃. Activated vitamin D analogs cannot be administered in large doses on an intermittent schedule, due to their toxicity in mammals. However, non-activated vitamin D₂, vitamin D₃, and their metabolites may be administered in larger doses than "active" forms of vitamin D on an intermittent basis, without toxicity. In one embodiment of the invention, vitamin D can be administered at doses of 100 IU to 10,000 IU of vitamin D per day. In another embodiment of the invention, vitamin D can be administered at doses of 100 IU to 10,000 IU of vitamin D per day, on the days in between the days when the patient takes a unit dose of a bisphosphonate.

In another embodiment of the invention, the nutrient is a unit dose comprising both calcium and vitamin D. In one embodiment, the unit dose comprises about 500 mg calcium and about 400 IU to about 440 IU vitamin D, to be administered daily. In a further embodiment, the unit dose comprises about 500 mg calcium and about 400 IU to about 440 IU vitamin D, to be administered on the days in between the days when the patient takes the unit dose of a bisphosphonate. If a calcium-containing supplement and a bisphosphonate are dosed on the same day, the patient should take the bisphosphonate and the nutrient at different times of the day. For example, the patient may take a unit dose of a bisphosphonate in the morning, and a calcium-containing supplement 4 hours later.

Pharmaceutical Compositions

The present invention further relates to a solid oral dosage form comprising a pharmaceutical composition which may be administered to a human or other mammal in need thereof with water that is at least moderately hard, said pharmaceutical composition comprising:

(a) a bisphosphonate; and

(b) from about 10 mg to about 1000 mg of at least one chelating agent;

wherein the amount of bisphosphonate is greater than the equivalent weekly dose of said bisphosphonate suitable for the treatment of osteoporosis.

The pharmaceutical compositions of the present invention comprise a chelating agent. The term "chelating agent," as used herein, means a molecule containing two or more electron donor atoms that can form coordinate bonds to a single metal ion. The term "chelating agent" is understood to include the chelating agent as well as salts thereof. For example, the term "chelating agent" includes citric acid as well as its salt forms.

The most common and widely used chelating agents coordinate to metal atoms through oxygen or nitrogen donor atoms, or both. Other less common chelating agents coordinate through sulfur in the form of -SH (thiol or mercapto) groups. After the first coordinate bond is formed, each successive donor atom that binds creates a ring containing the metal atom. A chelating agent may be bidentate, tridentate, tetradentate, etc., depending upon whether it contains two, three, four, or more donor atoms capable of binding to the metal atom. See Kirk-Othmer Encyclopedia of Chemical Technology (4th ed. 2001).

Suitable chelating agents include any pharmaceutically-acceptable chelating agent or combinations thereof. Non-limiting examples of chelating agents suitable for use in the present invention include EDTA, citric acid, malic acid, tartaric acid, lactic acid, aspartic acid, glutamic acid, lysine, sodium hexametaphosphate, and combinations thereof. In one embodiment of the present invention, the chelating agent is EDTA, citric acid, or sodium hexametaphosphate. The amount of chelating agent present in the oral dosage form of the present invention will depend on the particular chelating agent selected and the amount of bisphosphonate active ingredient present in the oral dosage form. Generally, the oral dosage forms of the present invention will contain a safe and effective amount of a chelating agent suitable for achieving the desired chelating effect. In one embodiment, the oral dosage form contains from about 10 mg to about 1000 mg of a chelating agent per unit dose. In another embodiment, the oral dosage forms contain from about 10 mg to about 500 mg of a chelating agent per unit dose. When the chelating agent is EDTA, the preferred range is from about 10 mg to about 500 mg, preferably from about 25 mg to about 250 mg per unit dose. When the chelating agent is citric acid or any other chelating agent, the preferred range is from about 25 mg to about 1000 mg, preferably from about 50 mg to about 500 mg per unit dose.

The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically-acceptable excipients. The term "pharmaceutically- acceptable excipient," as used herein, means any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of risedronate. Pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, diluents, binders, disintegrants, solvents, co-solvents, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents. Flavoring agents and dyes and pigments among those useful herein include those described in Handbook of Pharmaceutical Excipients (4th ed., Pharmaceutical Press 2003).

Suitable co-solvents include, but are not limited to, ethanol, isopropanol, and acetone. Suitable surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters, sodium lauryl sulfate, Tween 80®, and lanolin esters and ethers. Suitable preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chlorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben.

Suitable fillers include, but are not limited to, starch, lactose, sucrose, maltodextrin, and microcrystalline cellulose.

Suitable plasticizers include, but are not limited to, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil, acetylated monoglycerides, and triacetin.

Suitable polymers include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and ethylcellulose.

Suitable lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc. The pharmaceutical compositions of the present invention may optionally comprise a film coating. Excipients suitable for use in a film coating include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, lactose, polyethylene glycol, talc, silicon dioxide, titanium dioxide, and polyvinyl alcohol. In one embodiment of the present invention, the pharmaceutical compositions may be formulated such that the chelating agent is released from the oral dosage form prior to the release of the bisphosphonate. For example, the chelating agent may be released from the oral dosage form in the stomach before the bisphosphonate is released in the stomach. This may be accomplished by a variety of techniques known to the skilled artisan. For example, a layer tablet may be prepared wherein the chelating agent and the appropriate excipients are incorporated into a first layer and the bisphosphonate is incorporated into a second layer. The chelating agent dissolves rapidly in the stomach over approximately 15 to 30 minutes and the bisphosphonate dissolves from the tablet over approximately 30 minutes to 1 hour.

Kits The kits of the present invention are particularly useful for administering one or more unit doses of a solid oral dosage form comprising a pharmaceutical composition of the invention comprising a bisphosphonate and at least one chelating agent according to an appropriate continuous dosing schedule. Such kits comprise one or more unit doses of a bisphosphonate and a means for facilitating compliance with methods of this invention. In one embodiment, a kit of the present invention is useful for administering a unit dose of a pharmaceutical composition of the present invention according to a continuous dosing schedule of one or two consecutive days per month. The term "continuous," as used herein, means at regular specified intervals. For example, a continuous frequency of once a month means that the active is given one day each month for an unspecified period of time or for as long as treatment is necessary.

The kits of the invention provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner. The compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention. Such compliance means includes instructions, packaging, and dispensing means, and combinations thereof. The kits can also comprise a means for aiding the memory, including but not limited to a listing of the days of the week, numbering, illustrations, arrows, Braille, calendar stickers, reminder cards, or other means specifically selected by the patient. Examples of packaging and dispensing means are well known in the art, including those described in U.S. Pat. No. 4,761,406, Flora et al, issued Aug. 2, 1988; and U.S. Patent 4,812,311, Uchtman, issued Mar. 14, 1989. Examples of particular arrangements of unit doses include those described in U.S. Pate. No. 6,047,829, Johnstone et al., issued April 11, 2000 and U.S. Pat. Appl. Serial No. 10/789525, by Cawthray et al., filed Feb. 27, 2004. Optionally, the kits may comprise at least one unit dose of a pharmaceutical composition of the present invention and at least one unit dose of an accompanying nutrient.

The following are non-limiting examples of embodiments of the present invention.

EXAMPLES Example 1 A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 150 mg risedronate and 500 mg citric acid, to be taken once monthly. The patient takes the oral unit dose the first day of each calendar month with a 6-ounce glass of moderately hard tap water. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to her baseline biopsy.

Example 2

A 70 kg man diagnosed with osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 100 mg risedronate and 250 mg sodium hexametaphosphate, to be taken once monthly. The patient takes the oral dosage form the last day of each calendar month with a 4-ounce glass of hard tap water. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to his baseline biopsy.

Example 3 A 62 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition to be taken on consecutive days twice monthly. Each unit dose of the pharmaceutical composition comprises 75 mg risedronate and 250 mg citric acid. The patient takes a unit dose of the pharmaceutical composition once per day with an 8-ounce glass of moderately hard tap water on the Saturday and Sunday of the first weekend of each calendar month. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to her baseline biopsy.

Example 4

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 280 mg alendronate and 750 mg citric acid, to be taken once monthly. The patient takes the oral dosage form the first day of each calendar month with an 8-ounce glass of moderately hard tap water. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to her baseline biopsy. Example 5

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 100 mg ibandronate and 250 mg sodium hexametaphosphate, to be taken once monthly. The patient takes the oral dosage form the first day of each calendar month with an 8-ounce glass of hard tap water. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to her baseline biopsy.

Example 6

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 150 mg ibandronate and 150 mg citric acid, to be taken once monthly. The patient takes the oral dosage form the first day of each calendar month with an 8-ounce glass of hard water. An increase in lumbar spine mone mineral density is observed at one year.

Example 7

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition comprising 150 mg risedronate, 150 mg citric acid, and 100 mg EDTA, to be taken once monthly. The patient takes the oral unit dose the first day of each calendar month with an 8-ounce glass of hard tap water. A biopsy of iliac crest bone is taken at two years and reveals an increase in mean wall thickness of the remodeling units compared to her baseline biopsy.

Example 8 The solutions are prepared as follows:

Solution A: To 500 ml of purified water at 37⁰C under constant agitation, 150 mg risedronate sodium is added and allowed to dissolve for 30 minutes. A sample is withdrawn, filtered and analyzed for drug content. Then, 12 ml concentrated calcium chloride solution is added in order to simulate very hard water (about 250 mg/liter final concentration, expressed as calcium carbonate) and the pH is adjusted with concentrated hydrochloric acid or sodium hydroxide to a pH of 6. The pH is designed to simulate the pH in the small intestine where the drug is absorbed. After 2 hours, a sample is withdrawn, filtered, and analyzed for drug content.

Solution B: To 500 ml of purified water at 37⁰C under constant agitation, 250 mg of sodium hexametaphosphate is added and dissolved. Then, 150 mg of risedronate sodium is added and allowed to dissolve for 30 minutes. A sample is withdrawn, filtered and analyzed for drug content. 12 ml concentrated calcium chloride solution is then added in order to simulate very hard water (about 250 mg/liter final concentration, expressed as calcium carbonate) and the pH is adjusted with concentrated hydrochloric acid or sodium hydroxide to a pH of 6. After 2 hours, a sample is withdrawn, filtered, and analyzed for drug content.

After 2 hours, the amount of risedronate sodium remaining in solution in Solution A is approximately 35% of the initial value. However, after 2 hours the risedronate sodium in Solution B remains essentially completely in solution. Example 9

Film-Coated Tablets Containing Risedronate and EDTA

Film-coated tablets containing risedronate and EDTA are made by preparing a coating composition and compressed tablets containing risedronate and EDTA, and then applying said coating composition to said tablets. A film- coating composition is prepared in the form of a suspension containing the following excipients, per tablet:

A. Film-Coating Suspension

Ingredients:

Dri-Klear® (dry) 8.67 mg (manufactured by Chr. Hansen,

DK-2970 Horsholm, Denmark) Chroma-Tone White 2.88 mg

(manufactured by Chr. Hansen, DK-2970 Horsholm, Denmark) Purified Water 100 mg

Dri-Klear is a mixture of hydroxypropylmethylcellulose, hydroxyproplycellulose, polyethylene glycol, and silicon dioxide. Chroma-Tone White is a mixture of hydroxyproplycellulose and titanium dioxide.

The coating suspension is prepared as follows: 1. Add the Dri-Klear to hot purified water, 60-80° C, with agitation. 2. Cool the Dri-Klear solution to 40° C. or below, with continual mixing until all the Dri-Klear is dissolved.

3. Add the Chroma-Tone White to purified water with mixing. Disperse with the use of a high shear mixer for 10-25 minutes.

4. Add the pigment suspension (step 3) to the polymer solution (step 2) and mix. Continue mixing until ready for use.

5. Load the core tablets into a 48 inch side vented coating pan.

6. Preheat the tablets until the exhaust temperature reaches approximately 35° C. and begin spraying. Apply the coating suspension using an inlet air temperature of 40-60° C. at a rate of 300-400 g/minute. 7. Cool the tablets and discharge.

A coating weight gain of 3% (total solids) is applied by spraying the above composition onto compressed tablets containing risedronate and EDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA The film-coating suspension prepared in Part A above is sprayed onto 75 mg risedronate tablets, each tablet weighing 385 mg and each containing: Active Ingredients:

Risedronate sodium 75.0 mg*

Chelant:

Disodium EDTA 150 mg

Excipients

Microcrystalline cellulose 149.5 mg

Sodium starch glycolate 9 mg

Stearic acid 1.5 mg * This amount is calculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows: The tablets are prepared by sieving the risedronate active ingredient and the EDTA with half of the microcrystalline cellulose into a twin shell blender. The blend is then mixed until uniform. Then, half of the stearic acid is added and the blend is mixed further. The blend is then roller compacted and milled. The remaining microcrystalline cellulose and sodium starch glycolate are added and mixed until uniform. The remaining stearic acid is then added and mixed until adequate lubrication is achieved. Tablets are then compressed on a rotary tablet press.

Example 10 Caplet Shaped, Film-Coated Ibandronate Tablet

Film-coated tablets containing ibandronate and citric acid are made by preparing a coating composition and compressed tablets containing ibandronate and citric acid, and then applying said coating composition to said tablets.

A film- coating composition is prepared in the form of a suspension containing the following excipients, per tablet:

A. Film-Coating Suspension

Ingredients:

Opadry® (dry) 25 mg

(manufactured by Colorcon, West Point, PA.)

Red iron oxide 0.4 mg

Purified Water 175 mg

Opadry is a commercial film-coating mixture manufactured by Colorcon, West Point, PA. The coating suspension is prepared as follows: 1. Add the Opadry to room temperature purified water with agitation.

2. Mix until all the Opadry is dissolved.

3. Add the red iron oxide to purified water with mixing. Disperse with the use of a high shear mixer for 5 minutes.

4. Add the red iron oxide suspension (step 3) to the polymer solution (step 2) and mix. Continue mixing until ready for use.

5. Load the core tablets into a 48 inch side vented coating pan. 6. Preheat the tablets until the exhaust temperature reaches approximately 40° C. and begin spraying. Apply the coating suspension using an inlet air temperature of 40-60° C. at a rate of 250-350 g/minute.

7. Cool the tablets and discharge. A coating weight gain of 4% (total solids) is applied by spraying the above composition onto compressed tablets containing ibandronate and citric acid, prepared in Part B below.

B. Compressed Tablets Containing Ibandronate and citric acid The film-coating suspension prepared in Part A is sprayed onto 150 mg ibandroante tablets, each tablet weighing 645 mg and each containing: Active Ingredients:

Ibandronate Sodium 150 mg*

Chelant: Citric acid 250 mg

Excipient

Microcrystalline Cellulose 109.5 mg

Croscarmellose Sodium 25.0 mg

Lactose 100 mg Magnesium stearate 0.5 mg

Polyvinylpyrrolidone 10 mg

Purified Water 100.0 mg

* This amount is calculated on a ibandronate free acid basis. Tablets having the composition set forth above are prepared as follows: The ibandronate sodium, citric acid, microcrystalline cellulose, croscarmellose sodium, lactose and polyvinylpyrrolidone are passed through a mill and added to a blender equipped with an intensifier bar. The mixture is blended for approximately ten minutes with the intensifier bar on and granulated with purified water for 15 minutes. The mixture is dried overnight at 30°C, passed through a mill. The magnesium stearate is screened and added to the blender. The blend is mixed for approximately 3 minutes with the intensifier bar off. The blend is compressed into tablets using a suitable tablet press.

Example 11 Film-Coated Tablets Containing Risedronate and Sodium hexamataphosphate

Film-coated tablets containing risedronate and Sodium hexamataphosphate are made by preparing a coating composition and compressed tablets containing risedronate and sodium hexamataphosphate, and then applying said coating composition to said tablets.

A film- coating composition is prepared in the form of a suspension containing the following excipients, per tablet: A. Film-Coating Suspension

Ingredients: Hydroxypropylmethylcellulose 10 mg

(dry)

Polyethylene glycol 6000 2.0 mg

Titanium dioxide 2.0mg

Yellow iron oxide 0.1 mg Purified Water 100 mg

The coating suspension is prepared as follows:

1. Add the hydroxypropylmethylcellulose to hot purified water, 60-80° C, with agitation.

2. Cool the hydroxypropylmethylcellulose solution to 40° C. or below, with continual mixing until all the hydroxypropylmethylcellulose is dissolved.

3. Add the polyethylene glycol 6000 with agitation.

4. Add the yellow iron oxide and titanium dioxide to purified water with mixing. Disperse with the use of a high shear mixer for 10-25 minutes.

5. Add the pigment suspension (step 3) to the polymer solution (step 2) and mix. Continue mixing until ready for use.

6. Load the core tablets into a 48 inch side vented coating pan.

7. Preheat the tablets until the exhaust temperature reaches approximately 35° C. and begin spraying. Apply the coating suspension using an inlet air temperature of 40-60° C. at a rate of 300-400 g/minute. 8. Cool the tablets and discharge. A coating weight gain of 3% (total solids) is applied by spraying the above composition onto compressed tablets containing risedronate and Sodium hexamataphosphate, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and Sodium hexamataphosphate

The film-coating suspension prepared in Part A above is sprayed onto 150 mg risedronate tablets, each tablet weighing 470 mg and each containing: Active Ingredients:

Risedronate sodium 150 mg* Chelant:

Sodium hexamataphosphate 150 mg

Excipients

Corn starch 150 mg

Crospovidone 15 mg Stearic acid 5 mg

* This amount is calculated on a risedronate anhydrous monosodium salt basis. Tablets having the composition set forth above are prepared as follows: The tablets are prepared by sieving the risedronate active ingredient and the sodium hexamataphosphate with half of the corn starch into a twin shell blender. The blend is then mixed until uniform. Then, half of the stearic acid is added and the blend is mixed further. The blend is then is roller compacted and milled. The remaining corn starch and the crospovidone are added and mixed until uniform. The remaining stearic acid is then added and mixed until adequate lubrication is achieved. Tablets are then compressed on a rotary tablet press. Example 12

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribed a solid oral dosage form of a pharmaceutical composition of Example 9, to be taken two consecutive days once monthly. The patient takes the oral unit dose the first and second day of each calendar month with an 8-ounce glass of hard tap water. An increase in lumbar spine mone mineral density is observed at one year. All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

What is claimed is:

1. A solid oral dosage form comprising a pharmaceutical composition which may be administered to a human or other mammal in need thereof with water that is at least moderately hard, said pharmaceutical composition comprising:

(a) a bisphosphonate; and

(b) from 10 mg to 1000 mg of at least one chelating agent; wherein the amount of bisphosphonate is greater than the equivalent weekly dose of said bisphosphonate suitable for the treatment of osteoporosis.

2. The pharmaceutical composition of Claim 1 wherein the bisphosphonate is selected from the group consisting of risedronate, alendronate, pamidronate, tiludronate, cimadronate, ibandronate, clodronate, zoledronate, and salts, esters, polymorphs, solvates, and combinations thereof, preferably wherein the bisphosphonate is risedronate.

3. The pharmaceutical composition of Claims 1 Or 2 claims wherein the pharmaceutical composition comprises at least 75 mg risedronate.

4. The pharmaceutical composition of Claims 1 or 2 wherein the pharmaceutical composition comprises 100 mg risedronate.

5. The pharmaceutical composition of Claims 1 or 2 wherein the pharmaceutical composition comprises 150 mg risedronate.

6. The pharmaceutical composition of any one of the preceding Claims wherein the chelating agent is selected from the group consisting of EDTA, citric acid, malic acid, tartaric acid, lactic acid, aspartic acid, glutamic acid, lysine, sodium hexametaphosphate, and combinations thereof, preferably wherein the chelating agent is selected from the group consisting of EDTA, citric acid, sodium hexametaphosphate, and combinations thereof.

7. The pharmaceutical composition of any one of the preceeding claims wherein the pharmaceutical composition is in the form of a tablet or caplet.

8. The pharmaceutical composition of any one of the preceeding claims wherein the pharmaceutical compositions is film coated.

9. A use of any one of the compositions of claims 1-8 for the treatment of a bone disorder in a human or other mammal in need thereof, preferably for the treatment of osteoporosis.

10. A kit for facilitating compliance with a bisphosphonate treatment regimen comprising one or more unit doses of a pharmaceutical composition according to Claims 1-8.

11. The kit of Claim 10 further comprising at least one unit dose of a nutrient, preferably wherein the nutrient is selected from the group consisting of calcium, vitamin D, a combined unit dose of calcium and vitamin D or mixtures thereof.

12. The kit of Claims 10 or 11, further comprising a means for aiding the memory.