ORAL BISPHOSPHONATE FORMULATIONS

INTRODUCTION

Aspects of the present application relate to methods for inhibiting bone resorption in a mammal while minimizing the occurrence of potential for adverse gastrointestinal effects. Further aspects of the present application relate to oral formulations containing bisphosphonate drugs, methods for manufacturing the same, and uses thereof. In aspects, the present application further relates to oral formulations of bisphosphonates comprising alendronate or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof.

A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, periodontal disease, and tooth loss. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Bone characterized by weakened mechanical strength is much more susceptible to fracture, even under stresses that would otherwise be tolerated by normal bone. In the United States alone, some 8 million women and 2 million men suffer from osteoporosis. Many more are at increased risk for osteoporosis because they have low bone mass. The risk of suffering from osteoporosis increases with age, particularly in those over the age of 50.

Osteoporosis results from a disorder in bone remodeling, which is the process by which bone tissue is continually renewed and repaired. In bone remodeling, osteoclasts resorb old or damaged bone, while osteoblasts synthesize a new bone matrix. In patients who suffer from osteoporosis, the rate of bone resorption undesirably exceeds the rate of bone formation, either because too much bone is resorbed or too little bone is formed. Because disorders associated with bone loss are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.

Drugs used in the treatment of bone resorption disorders act by inhibiting bone resorption. Among such anti-resorptive agents are bisphosphonate compounds. Bisphosphonates are synthetic analogues of pyrophosphates, which are naturally occurring regulators of bone turnover. Bisphosphonates (also called diphosphonates) are a class of drugs having a common P-C-P»backbone (two phosphonate groups covalently linked to a carbon) that prevent the loss of bone mass and are used to treat osteoporosis and similar diseases. There are numerous bisphosphonates which have been identified as having utility as pharmaceutical agents which inhibit bone resorption. These include: (4-amino-1-hydroxybutylidene)bis-phosphonate [alendronate]; (cycloheptylamino)methylene]bis-phosphonate[cimadronate]; (dichloromethylene)-bis-phosphonate [clodronate]; (l-hydroxyethylidene)-bis-phosphonate [etidronate]; [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate [ibandronate]; (6-amino-1 -hydroxyhexylidene)-bis-phosphonate [neridronate]; [3-(dimethylamino)-1 -hydroxy-propylidene]-bis-phosphonate [olpadronate]; (3-amino-1 -hydroxypropylidene)-bis-phosphonate [pamidronate]; [1 -hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate [risedronate]; [[(4-chlorophenyl)thio]methylene]-bis-phosphonate [tiludronate] and [1-hydroxy-2-(1 H-imidazol-1 -yl)ethylidene]-bis-phosphonate [zoledronate].
A variety of bisphosphonic acids have been disclosed as being useful in the treatment and prevention of diseases involving bone resorption. Representative publications include U.S. Patent Nos. 3,962,432, 4,054,598, 4,267,108, 4,327,039, 4,621,077, 4,624,947, 4,746,654, and 4,922,077.

Despite their therapeutic benefits, the administration of bisphosphonate compounds for the treatment of bone resorption disorders in solid oral dosage forms suffers from several major drawbacks. First, bisphosphonate compounds are very poorly absorbed from the gastrointestinal tract into the blood of a patient (i.e., have low bioavailability). In fact, typically only about 0.5% to about 5% of the total bisphosphonate active ingredient is absorbed from an oral dosage formulation such as a solid tablet. Once in the blood stream, typically only about 20% to about 50% of the bisphosphonate becomes bound to the bone surfaces. The bioavailability of bisphosphonate is further reduced under highly acidic gastric conditions, which occur when the patient has eaten food or consumed an acidic beverage (e.g., coffee, tea, or orange juice).

The bioavailability of the bisphosphonates is further affected by the delivery system. Solid delivery systems such as capsules and tablets must be ingested with sufficient liquid to disintegrate the dosage form. Once the dosage form is inside the stomach or small intestine of a patient, it has to disintegrate into small particles, and the active ingredient has to be solubilized such that it can be absorbed into the plasma of the patient. The disintegration and solubilization processes for solid dosage forms delay the bioavailability of the active ingredient.

Further, oral bisphosphonates are known to cause esophageal irritation and erosion, upset stomach, and inflammation unless the oral dosage form is taken with a full glass of water and the patient remains upright for at least half hour after taking the medication.

The combination of these problems has led to complicated regimen that attempts to optimize bioavailability of the bisphosphonate while minimizing the gastrointestinal problems. Thus, current regimen require the patient to: (a) remain strictly upright for at least 30 minutes after taking the bisphosphonate composition so as to minimize esophageal irritation: and (b) wait as much as 2 hours after dosing before eating.

U.S. Patent Nos. 5,994,329, 6,015,801, 6,225,294, and 6,333,316 disclose methods for inhibiting bone resorption comprising the administration of histamine H2 receptor blockers and/or proton pump inhibitors about 30 minutes to about 24 hours prior to the administration of bisphosphonates. The local tissue irritation and ulceration associated with the administration of bisphosphonates may be mitigated by the administration of drugs that suppress gastric acid production. The proton pump inhibitors react with acid (are activated) to form thiophilic sulfenamide or sulfenic acid components. Once activated, the compounds irreversibly bind to the sulfhydryl group of cysteine residues thus halting acid production. The H2 receptor blockers inhibit acid production by competing with histamine in binding to H2 receptors.

U.S. Patent Nos. 5,853,759 and 7,488,496 describe effervescent compositions of bisphosphonates. These teach that an effervescent liquid limits the amount of time in which the bisphosphonate is in contact with the esophageal tissue, thus minimizing the risk of irritation. Second, the administration of bisphosphonate as an effervescent composition results in improved bioavailability of the bisphosphonate compared to non-effervescent bisphosphonate formulations. Third, the effervescent formulations are particularly advantageous for elderly patients who may experience difficulty in swallowing tablets, but can more easily swallow a liquid formulation.

U.S. Patent No. 7,473,684 describes bisphosphonate formulations comprising an antifoaming agent such as a polydimethylsiloxane to reduce reflux and esophageal irritation. The antifoaming agent is present in the formulation to limit the formation of foams in the stomach. The associated concomitant decrease in the volume of stomach contents, and additionally barrier properties of some preferred antifoaming agents, will reduce the likelihood of stomach acid reflux and therefore esophageal irritation.

Despite the availability of the foregoing approaches, there remains a need for compositions and drug administration regimen for treating bone resorption disorders, which are less complicated and more convenient than those presently commonly used. Moreover, there remains a need for pharmaceutical compositions that can deliver a bisphosphonate drug for treating bone resorption disorders while reducing likelihood of stomach acid reflux and therefore esophageal irritation.

SUMMARY
Aspects of the present application relate to methods for inhibiting bone resorption in a mammal while minimizing the occurrence of potential for adverse gastrointestinal effects. Further aspects of the present application relate to oral formulations of bisphosphonate drugs, methods for manufacturing the same, and uses thereof. In aspects, the present application further relates to oral solid formulations of bisphosphonates comprising alendronate or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof.

An aspect provides oral solid pharmaceutical formulations of bisphosphonate drugs that have an improved bioavailability of bisphosphonate, and/or reduced side effects, compared to existing oral solid formulations of bisphosphonates.

An aspect provides oral solid pharmaceutical formulations of bisphosphonates that have acid mediating capacity and undergo rapid disintegration, or undergo rapid dissolution, upon contact with fluids such as water, saliva, and gastric juice.

An aspect provides oral solid pharmaceutical formulations of bisphosphonates, which, when orally administered to a mammal, raises the pH of the gastric juices of the stomach of the mammal to pH values about 3 or higher.

An aspect provides oral solid pharmaceutical formulations of bisphosphonates, which, when dispersed in water, produce pH values about 3 to about 8.

An aspect of the present application relates to oral solid pharmaceutical formulations of bisphosphonates, wherein the formulations further comprise a pro-kinetic agent and/or an antacid, in combination with a bisphosphonate.

An aspect involves sequential administration of a pro-kinetic agent and/or an antacid about 30 minutes to about 24 hours prior to administration of bisphosphonates, or simultaneous administration of pro-kinetic agent and/or an antacid, together with a bisphosphonate.

An aspect of the present application relates to oral solid pharmaceutical formulations of bisphosphonates, wherein a formulation may be any of tablets, capsules, granules, pellets, beads, admixtures, or powders.
An aspect relates to oral solid pharmaceutical formulations of bisphosphonates, wherein the formulations may optionally be enteric coated.

An aspect provides oral tablet formulations of bisphosphonates, which may be immediate-release tablets, dispersible tablets, effervescent tablets, fast-disintegrating tablets, freeze-dried tablets, fast-dissolving tablets, chewable tablets, sub-lingual tablets, or buccal tablets.

An aspect of the present application relates to effervescent compositions of alendronate or a pharmaceutical acceptable salt thereof, wherein the composition has a total weight in the range of 1500 mg to about 6000 mg.

An aspect of the present application relates to effervescent formulations of alendronate or a pharmaceutically acceptable salt thereof, wherein the formulation does not contain citric acid as an acidic component of an effervescing couple.

An aspect of the present application relates to effervescent formulations of alendronate or a pharmaceutical^ acceptable salt thereof, wherein effervescing components of the formulation comprise tartaric acid as an acidic component of an effervescing couple.

An aspect of the application relates to effervescent formulations of alendronate or a pharmaceutically acceptable salt thereof, wherein effervescing components of the formulation do not comprise a carbonate or bicarbonate salt as an alkaline component of an effervescing couple.

An aspect of the present application is directed to oral solid pharmaceutical formulations of bisphosphonates, wherein the formulations comprise a basifying/alkalinizing agent.

An aspect provides rapidly dispersible or immediate-release tablets of alendronate or a pharmaceutically acceptable salt thereof, wherein the tablets further comprise sodium carbonate or bicarbonate as a basifying/alkalinizing agent.

An aspect provides effervescent formulations of bisphosphonates, wherein the formulations comprise reactants that do not evolve carbon dioxide.

An aspect provides effervescent formulations of alendronate or a pharmaceutically acceptable salt thereof, wherein the formulations comprise reactants that evolve oxygen, or gases other than carbon dioxide, that are safe for human consumption.

An aspect of the present application relates to oral solid pharmaceutical formulations of bisphosphonates, wherein a bisphosphonate is any of alendronate, cimadronate, clodronate, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, zoledronate, pharmaceutically acceptable salts and esters thereof, and mixtures thereof.

An aspect of the present application relates to oral solid pharmaceutical formulations of bisphosphonates, wherein the formulations are useful for treating and or preventing any one or more of the conditions or disease states: osteoporosis, which can include post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, and idiopathic osteoporosis; Paget's disease; abnormally increased bone turnover; periodontal disease; tooth loss; localized bone loss associated with periprosthetic osteolysis; bone fractures; metastatic bone disease; hypercalcemia of malignancy; and multiple myeloma.

DETAILED DESCRIPTION

Aspects of the present application relate to methods for inhibiting bone resorption in a mammal, while minimizing the occurrence of adverse gastrointestinal effects. Aspects of the present application relate to oral formulations containing bisphosphonate drugs, methods for manufacturing the same, and uses thereof. In aspects, the present application further relates to oral solid formulations of bisphosphonates, comprising alendronate or a pharmaceutically acceptable salt thereof, methods for manufacturing the same, and uses thereof.

As used throughout this application, the term "bisphosphonate" is intended to include the chemically related bisphosphonic acid drugs and their pharmaceutically acceptable salts, and any of various crystalline and amorphous polymorphic forms. Some examples of salts of bisphosphonic acids include ammonium salts, alkali metal salts such as potassium and sodium (including mono-, di- and tri-sodium) salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and salts with amino acids such as arginine, lysine, etc.

In embodiments, a bisphosphonate drug can be any of alendronate, cimadronate, clodronate, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, zoledronate, pharmaceutically acceptable salts and esters thereof, and mixtures thereof.

The term "alendronate" includes the bisphosphonic acid and its salts. It includes crystalline, hydrated crystalline, and amorphous forms of alendronate. It specifically includes alendronate sodium and alendronate monosodium trihydrate.

The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosage formulations of any shapes and sizes, whether coated or uncoated.

The term "capsule" as used herein refers to a hard or soft gelatin capsule filled with any of tablets, mini-tablets, granules, pellets, powders, etc. of the present application.

The term "effervescing couple" refers to a combination of substances, such as an acidic source and an alkaline source, that react to produce a gas.

Effervescent drug formulations can offer enhanced dissolution and absorption of active ingredients resulting in increased bioavailability. Frequently, active ingredients are absorbed better from effervescent formulations as compared to directly administered solid tablet formulations. Effervescent tablets also can be larger in size, allowing for higher drug loading as well as combination drug loading. Because the tablets are to be dispersed or dissolved in aqueous media, they are easier to swallow than dry solid tablet formulations. Furthermore, effervescent compositions can be formulated without polyvalent metal ions (e.g., Ca+2 and Mg+2), which can bind to bisphosphonate compounds rendering them insoluble and unabsorbable.

Embodiments of the present compositions advantageously provide at least one, at least two, or at least three of the following properties: quick dissolution upon introduction into water; pleasant taste; clear aqueous composition after dissolution; and acceptable crush resistance after tableting.

The pharmaceutical compositions can comprise any suitable amount of the bisphosphonates in order to produce effective blood concentrations of a bisphosphonate in a mammal (e.g., a human) to which the bisphosphonate is administered. Typically, about 0.1% or more (e.g., about 0.25% or more, or about 1% or more) of a bisphosphonate drug, based on the total weight of the composition, is present in the pharmaceutical compositions. For example, the pharmaceutical compositions can comprise about 0.25% to about 35% of a bisphosphonate, based on the total weight of the composition. In some embodiments, about 1.5% or more (e.g., about 3% or more, or about 5% or more) and about 30% or less (e.g., about 20% or less) of a bisphosphonate, based on the total weight of the composition, is present in the pharmaceutical compositions.

The pharmaceutical compositions can be administered to a mammal following a continuous dosing schedule. The continuous schedule can be daily, once weekly, twice weekly, three times weekly, bi-weekly, monthly, bi-monthly, and with other frequencies.

The actual amount of bisphosphonate present in an effervescent composition depends at least in part on the specific bisphosphonate and the dosing schedule chosen. When the bisphosphonate is alendronate, typically about 1 mg or more and about 500 mg or less bisphosphonate is present, such as about 5 mg to about 200 mg. When the bisphosphonate is risedronate, typically about 1 mg or more and about 200 mg or less bisphosphonate is present, such as about 2 mg to about 50 mg. When the bisphosphonate is etidronate, typically about 70 mg or more and about 2000 mg or less bisphosphonate is present, such as about 100 mg to about 500 mg (e.g., about 200 mg to about 400 mg). When the bisphosphonate is tiludronate, typically about 50 mg or more and about 1000 mg or less bisphosphonate is present, such as about 100 mg to about 500 mg. When the bisphosphonate is ibandronate, typically about 0.1 mg or more and about 200 mg or less bisphosphonate is present, such as about 1 mg to about 50 mg.

Moreover, if the absorption of the active agents into the blood stream is improved (e.g., by 3 times, 5 times, or even 10 times) through the use of an effervescent composition of the application, as compared to a traditional tablet or capsule formulation containing the same amount of the active agent, the amount of the active agent present in the effervescent composition can be reduced from the amount required in other tablet or capsule formulations (e.g., the amounts set forth above). Thus, the effervescent composition of the application optionally may contain only 35 wt. % or less (e.g., about 25 wt. %, or about 15 wt. %, or less) than the amount by weight of active agent required in traditional tablet or capsule formulations without changing the amount of the active agent present in the bloodstream of a mammal.

The ability to reduce the amount of active bisphosphonate a dosage form without reducing the amount absorbed into the bloodstream of the mammal is a significant step towards reducing the overall cost of the dosage forms.

For example, when the bisphosphonate is to be administered weekly, twice weekly, bi-weekly, monthly, or bi-monthly, the amount of bisphosphonate present in an effervescent composition of the application can be less than that required for tablet formulations for similar dosing schedules. When the bisphosphonate is alendronate, typically the weekly dosage is only about 8 mg to about 16 mg, or about 10 mg to about 15 mg. The monthly dosage of alendronate typically is about 30 mg to about 200 mg, or about 50 mg to about 120 mg. The dosage for bi-monthly administration of alendronate typically is about 50 mg to about 500 mg, or about 100 mg to about 300 mg. When the bisphosphonate is etidronate, the monthly dosage typically is about 400 mg to about 800 mg, or about 500 mg to about 700 mg. The dosage for bi-monthly administration of etidronate typically is about 800 mg to about 1600 mg, or about 1000 mg to about 1500 mg. When the bisphosphonate is ibandronate, the monthly dosage typically is about 50 mg to about 90 mg, or about 60 mg to about 85 mg. The dosage for bi-monthly administration of ibandronate typically is about 100 mg to about 300 mg, or about 125 mg to about 250 mg. When the bisphosphonate is residronate, the monthly dosage typically is about 20 mg to about 140 mg, or about 50 mg to about 100 mg. The dosage for bi-monthly administration of etidronate typically is about 100 mg to about 300 mg, or about 120 mg to about 200 mg.

The bisphosphonate active ingredient of a composition can be finely milled to enhance systemic absorption of the bisphosphonate. Finely milled particles of the bisphosphonate result in greater surface area being exposed to an absorption medium, thereby maximizing absorption. Desirably, the bisphosphonate is milled to particle sizes about 100 urn or less, or about 4 urn to about 100 urn. In embodiments, the bisphosphonate is milled to have particle sizes about 5 um to about 70 urn, or about 10 urn to about 50 um.

Acidic and alkaline effervescent components can be present in the effervescent compositions in any suitable amounts. In embodiments, the relative amounts of acid component and alkaline effervescent component are such that the effervescent composition, when dispersed or dissolved in an aqueous fluid, produces a buffer solution. For purposes of clarity, the phrase "effervescent composition completely dissolves" is intended to mean that the acid component and the alkaline effervescent component are substantially completely dissolved in the aqueous fluid, even though other components (e.g., the bisphosphonate or a microencapsulated bisphosphonate) are incompletely dissolved or may not be dissolved.

A buffer solution is produced when an acid component reacts with an alkaline effervescent component to produce a solution containing the acid component and/or the alkaline effervescent component in equilibrium with the fully deprotonated salt of the acid component. For example, when the acid component is citric acid and the alkaline component is sodium bicarbonate, the buffer would consist of an acid form of citric acid and sodium citrate (e.g., the fully deprotonated salt of citric acid). Typically, the buffered solution has pH values about 3 to about 6.5, or about 3.5 to about 6.5, or about 4 to about 6.5. In embodiments, the buffered solution has pH values about 3.5 to about 6, or about 4 to about 6. In embodiments, the buffered solution has pH values about 4 to about 5.5, or about 4.5 to about 5.5. For example, in some embodiments the buffered solution contains an amount of fully deprotonated salt of the acid component that is at least about 1.5 times, or at least about 1.75 times, or at least about 2 times the amount of acid equivalents (e.g., equivalents of acid groups within the acid component). In embodiments, the amount of acid equivalents is not zero.

Suitable acidic effervescing couple components include, but are not limited to, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides, acid salts (e.g., sodium salts and potassium salts), mixtures of acid salts, acid salts of disodium dihydrogen pyrophosphate, acid citrate salts (e.g., monosodium citrate and disodium citrate), and other related organic acids and their salts, including any combinations thereof. The use of non-sodium acid components is desirable for use with patients requiring electrolyte maintenance, e.g., hypertensive and other cardiac patients.

In embodiments of the application, the acid source is chosen from acid sources that are also sequestering agents. This is an important consideration because bisphosphonates, particularly alendronate, can be potent sequestering agent for divalent cations, especially Ca+2 and Mg+2. If either of these cations is present, the alendronate will sequester them, rendering the alendronate less bioavailable. Acid sources that also act as sequestering agents include citric acid and tartaric acid, and

mixtures thereof. Any excess citric acid or tartaric acid in the formulation binds to the cations and prevents their complexation with alendronate.

Suitable alkaline effervescing couple components include, but are not limited to, carbonate salts, bicarbonate salts, and mixtures thereof. In embodiments, an alkaline effervescing component is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, potassium bicarbonate, sodium glycine carbonate, calcium carbonate, calcium bicarbonate, L-lysine carbonate, arginine carbonate, or any combinations thereof.

A carbonate source in embodiments does not contain divalent cations that could be sequestered by the bisphosphonate. Such carbonate sources include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and sodium glycine carbonate.

In embodiments, an acid source is present in quantities equal or greater than a carbonate source, on a molecular equivalent basis. For example, when citric acid is the acid source and sodium bicarbonate is the carbonate source, mole ratios of citric acid to bicarbonate are at least about 1:3. In embodiments, there is an excess of citric acid, as this not only helps to efficiently generate the effervescence, but also acts to sequester cations that might otherwise complex with alendronate, and the excess can also act as a flavor enhancer. In an illustration of an excess acid source, mole ratios of citric acid to bicarbonate range from about 1:1 to about 3:1. When sodium carbonate is used as the source of carbonate, an equivalence with citric acid will require a mole ratio of 2 moles citric acid to 3 moles carbonate. Analogous ratios can be calculated for any source of acid and carbonate, and in embodiments the carbonate source may be present as a mixture of a bicarbonate and a carbonate.

In embodiments, an acid component is present in an effervescent composition in amounts about 25% to about 75%, based on the total weight of the composition, and an alkaline effervescing component is present in the effervescent composition in amounts about 20% to about 60%, based on the total weight of the composition. In embodiments, the amount of citric acid may be less than about 20% (e.g., about 1% to about 15%, or about 5% to about 10%) based on the total weight of the acid component and the alkaline effervescing component. The amount of carbonate salt may be less than about 20% (e.g., about 0.1% to about 10%, or about 1% to about 7%) based on the total weight of the acid component and the alkaline effervescing component. The amount of bicarbonate salt may be less than about 60% (e.g., about 25% to about 50%, or about 30% to about 45%) based on the total weight of the acid component and the alkaline effervescing component.

In embodiments, weight ratios of bicarbonate salt to carbonate salt will be controlled to optimize performance of the effervescent formulation. In such embodiments, the amount of a bicarbonate salt is at least about 4 times (e.g., preferably at least about 6 times, or more preferably at least about 8 times) the amount by weight of a carbonate salt.

In embodiments, administration of a buffer solution produced upon dissolution of the effervescent composition in water to a mammal (e.g., a human) produces a stomach contents pH in the mammal at least about 3 (e.g., about 3.5 or higher), or at least about 4 (e.g., about 4.5 or higher). The buffer solution can be capable of mediating the pH of a patient's stomach contents for at least about 10 minutes or longer (e.g., about 15 minutes or longer). In embodiments, the buffer solution is capable of mediating the pH of a patient's stomach contents for about 30 minutes or longer (e.g., up to about 45 minutes or longer).
Pharmaceutical formulations of the present application may be in the form of tablets, capsules, granules (synonymously, "beads" or "particles" or "pellets"), or powders.

In embodiments, an effervescent composition optionally further comprises an anti-ulcer agent. The anti-ulcer agent can be a ^-antagonist, a proton pump inhibitor, or a combination thereof. The H2-antagonist can be any suitable H2-antagonist, for example, ranitidine, cimetidine, famotidine, nizatidine, or any combinations thereof. In embodiments, a H2-antagonist is ranitidine or cimetidine. When used, a H2-antagonist will be present in an effervescent composition in an amount of about 3% to about 60% (e.g., about 8% to about 40%) based on the total weight of the composition. In embodiments, a H2-antagonist is present in an effervescing composition dosage unit in amounts about 2 mg to about 500 mg, depending on the specific antagonist drug selected. When the H2-antagonist is cimetidine, it can be present at about 25 mg to about 400 mg (e.g., about 50 mg to about 350 mg). When the H2-antagonist is famotidine, it can be present at about 2 mg to about 50 mg (e.g., about 5 mg to about 30 mg). When the H2-antagonist is nizatidine, it can be present at about 25 mg to about 350 mg (e.g., about 50 to about 300 mg). Other amounts also are useful.

Suitable proton pump inhibitors include omeprazole, lansoprazole, rabeprazole, pantoprazole, their stereoisomers, and any combinations thereof. In embodiments, a proton pump inhibitor is present in amounts from about 0.5% to about 60% by weight of the composition (e.g., about 5% to about 40%). A proton pump inhibitor drug can be present in effervescing composition dosage units in amounts about 5 mg to about 100 mg, depending on the specific proton pump inhibitor used. For example, when the proton pump inhibitor is omeprazole, it is present in amounts about 10 mg to about 30 mg. When the proton pump inhibitor is lansoprazole, it is present in amounts about 2 mg to about 30 mg (e.g., about 5 mg to about 20 mg). When the proton pump inhibitor is rabeprazole, it is present in amounts about 5 mg to about 60 mg (e.g., about 10 to about 45 mg). When the proton pump inhibitor is pantoprazole, it is present in amounts about 5 mg to about 50 mg (e.g., about 10 mg to about 35 mg). Other amounts also are useful.

The pH range of a buffered aqueous solution resulting from dissolution of the effervescent composition is frequently in the range of about 3 to about 6.5 (e.g., about 4 to about 6.5, or about 5 to about 6.5). In order to avoid decomposition of many acid-sensitive active agents, it is useful to maintain pH values higher than the pKg of the active agent, such as pH values at least 0.7 pH units above the pKa, or at least 1 pH unit above the pKa of the active agent. For example, when the effervescent composition comprises an anti-ulcer agent, such as omeprazole, it is desirable to maintain pH values above the pKg of the anti-ulcer agent. The pKa of omeprazole is about 3.9, thus an effervescent composition of the invention comprising omeprazole desirably has a buffered pH at least about 5. The upper limit for the buffer pH is ultimately limited by the tolerance of the stomach lining for alkaline solutions. Typically, the upper limit of the stomach tolerance is about pH 10. However, the upper pH limit may further be limited by the pH tolerance of the ingredients included in the effervescent formulation.

The pharmaceutical compositions of the present application may further comprise prokinetic agents. Prokinetic agents are drugs that enhance gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. Prokinetic agents that can be used for the purposes of the present application include, but are not limited to, metoclopramide, domperidone, and the like.

Formulations of the present application can be prepared using conventional methods that are well-known in the art. Granules can be formed by any processes, using operations such as one or more of dry granulation, wet granulation, extrusion-spheronization, and the like. In embodiments, granulation of an active ingredient, optionally with one or more pharmaceutically acceptable excipients such as diluents or fillers, may be carried out using equipment such as planetary mixers, double cone blenders, rapid mixer granulators (RMG), single pot processors, fluid bed processors, and the like. Alternatively, powder blends may be compacted using a roller compactor and then milled to produce granules that are suitable for compression. The granules obtained may further be compressed into tablets or filled into capsules using techniques known in the art. Alternatively, tablets may be prepared by a direct compression technique, using powder blends. Alternatively, any of technologies known in the art, such as freeze-drying, spray drying, mass extrusion, and molding may also be used to prepare formulations in accordance with the present application. For soluble powder formulations, the composition of the powder is similar to that of the tablet, except that a lubricant is generally present in lesser amounts and the binder chosen is a dry binder. In embodiments, the powder is granulated.

Equipment suitable for processing the pharmaceutical formulations of the present application include rapid mixer granulators, planetary mixers, double cone blenders, mass mixers, ribbon mixers, single pot processor, fluid bed processors, mechanical sifters, homogenizers, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

A single pot processor enables completion of entire granulation process (dry blending, wetting, granulation, drying, and milling) in one machine, so no product transfers are required, significantly reducing risks of product exposure to the atmosphere.

Different types of rapidly dissolving solid oral dosage forms and various technologies for the production of such dosage forms currently known in the art can be used to formulate the compositions. For instance, OraSolv®, DuraSolv®, FlashTab®, Zydis®, WowTab®, FastMelt®, FlashDose®, NanoCrystal®, and QuickSolv® are well known dosage form technologies that can be used for the purposes of this application, with suitable modifications.

Formulations of the application can contain any desired number of pharmaceutical excipients, including those from categories such as diluents, binders, disintegrants, lubricants, glidants, flavoring agents, sweeteners, etc., as will be appreciated by those skilled in the art. Certain representative excipients are described below for illustration, but many others will also be useful and the present disclosure is not limited to using only those described.

Various useful fillers or diluents include, but are not limited to, starches, lactose, mannitol (e.g., Pearlitol™ SD200), cellulose derivatives, confectioner's sugar 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 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. Various 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™ PH101, PH102, PH301, PH302 and PH-F20, PH-112 microcrystalline cellulose 114, microcrystalline cellulose 112, and silicified microcrystalline cellulose (e.g., Prosolv™ products supplied by JRS Pharma). Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include, but are not limited to, hydroxypropyl celluloses, also called HPC (e.g., Klucel™ LF and Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (e.g., Methocel™ products) and useful in various grades, polyvinylpyrrolidones, also called PVP or povidones (such as grades K25, K29, K30, and K90), copovidones (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol™ products), methylcelluloses, polymethacrylates, and starches.

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not 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 hydroxypropylcelluloses 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.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

In certain embodiments, super-disintegrants may be used to provide rapid disintegration of the formulation on contact with aqueous fluids such as water or saliva. Super-disintegrants provide quick disintegration due to combined effect of swelling and water absorption by the formulation. Examples of super-disintegrants are croscarmellose (e.g., Ac-Di-Sol™ by FMC BioPolymer), crospovidone (e.g., Kollidon™ CL, Kollidon CL-F, Kollidon CL-SF, and Kollidon CL-M from BASF), and sodium starch glycolate.

The compositions of the present application may also include a basifying agent to provide an acid mediating effect on the gastric pH, to facilitate better absorption and thereby enhance the bioavailability of the administered bisphosphonate. Suitable basifying agents include, for example, pharmaceutically acceptable amine bases such as triethanolamine, salts of carboxylic acids such as sodium acetate, sodium citrate, and potassium sorbate, carbonates such as sodium bicarbonate, anhydrous sodium carbonate, potassium carbonate, and potassium bicarbonate, sodium glycine carbonate, calcium carbonate, calcium bicarbonate, L-lysine carbonate, arginine carbonate, and any combinations of two or more thereof. In some embodiments, a basifying agent is sodium bicarbonate, potassium bicarbonate, sodium carbonate, or a combination thereof.

The compositions of the present application also may include a stabilizing agent that prevents precipitation of drug in the solution. For this purpose, water-soluble polymers such as, for example, polyvinyl alcohols, polyvinylpyrrolidones, polyvinylpyrrolidone/polyvinyl acetate copolymers, polyethylene glycols, polyethylene glycol/polypropylene glycol copolymers polyvinylpyrrolidone/polyvinyl acetate copolymers, and cellulose ethers, such as hydroxypropyl methylcelluloses, are suitable.

The composition may further include a solubilizing agent, which aids in the transition of the bisphosphonate from the gastrointestinal tract to the blood by solubilizing the bisphosphonate and facilitating its transfer into the mucosal interface of the gastrointestinal tract. A solubilizing agent can be any suitable solubilizing agent, for example, a polyvinylpyrrolidone, a polyethylene glycol, a dextran, or any combinations thereof. The polyvinylpyrrolidone and polyethylene glycol can have any suitable molecular weights. For example, a polyvinylpyrrolidone can have a molecular weight of about 20,000 g/mol to about 40,000 g/mol, or about 25,000 g/mol to about 35,000 g/mol, or about 28,000 g/mol to about 32,000 g/mol. A polyethylene glycol can have a molecular weight of about 2000 g/mol to about 10,000 g/mol (e.g., about 4000 g/mol, about 6000 g/mol, or about 8000 g/mol). A dextran can be any suitable branched poly-D-glucoside having predominantly a-1,6 glycosidic bonds. In some embodiments, a solubilizing agent comprises a combination of a polyvinylpyrrolidone and a polyethylene glycol.

Typically, the solubilizing agent is present in an effervescent composition in amounts about 0.1% or more based on the weight of the composition, for example, about 0.1% to about 10% (e.g., about 1% to about 5%) based on the weight of the composition. A polyvinylpyrrolidone and/or about 20 mg to about 100 mg polyethylene glycol can be present in an effervescent composition. When the solubilizing agent is a
dextran, about 1% to about 20%, or about 5% to about 15% (e.g., about 10%) dextran, based on the weight of the composition, can be present in an effervescent composition.

The compositions may further utilize a lubricant, which is mixed with powder blends or applied to compression dies before the granular mixture is compressed into effervescent tablets. Lubricants include hydrogenated or partially hydrogenated vegetable oils such as corn oil, canola oil, cottonseed oil, sesame oil, soybean oil, grape seed oil, sunflower oil, safflower oil, olive oil, peanut oil, and combinations thereof. Lubricants can also include calcium stearate, magnesium stearate, zinc stearate, polyoxyethylene monostearate, talc, polyethylene glycols, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, and any combinations thereof. Lubricants can form a hydrophobic coating on an effervescent tablet and affect the dissolution rate of the tablet.

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variation, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and any combinations thereof.

The compositions of the invention desirably have a pleasant taste. The taste of a pharmaceutical composition is important as it enhances the willingness of patients to utilize the dosage form. Many active agents, such as bisphosphonates and anti-ulcer agents, have an objectionable taste that should be masked by the formulation in which the active agents are delivered. Therefore, the effervescent composition can include a sweetener, a flavorant, or a combination thereof.

A sweetener can be any suitable natural or artificial sweetener, or a combination of natural and artificial sweeteners. Useful natural sweeteners include sucrose, glucose, dextrose, invert sugar, fructose, glycyrrhizic acid, and mixtures thereof. Typically, a natural sweetener is present in an effervescent composition in amounts about 10% to about 50% (e.g., about 20% to about 40%), based on the weight of the composition. Useful artificial sweeteners include saccharin, aspartame, chloro-derivatives of sucrose such as sucralose, cyclamate, acesulfame-K, sugar alcohols such as sorbitol, mannitol, and xylitol, and any mixtures thereof. Typically, an artificial sweetener is present in an effervescent composition in amounts up to about 5% (e.g., about 0.1 to about 2.5%), based on the weight of the composition. The effective concentrations of a sweetener are determined by the strength of its sweetness, solubility, and masking ability for a specific active ingredient. For example, when the sweetener is aspartame, about 10 mg to about 50 mg is present in an effervescent composition. When the sweetener is saccharin, about 10 mg to about 30 mg is present in an effervescent composition. When the sweetener is acesulfame-K, about 10 mg to about 50 mg is present in an effervescent composition. When the sweetener is xylitol, about 100 mg to about 400 mg is present in an effervescent composition. When the sweetener is Splenda™, about 10 mg to about 50 mg is present in an effervescent composition. Other amounts also are useful.

A flavorant can be a natural or artificial flavorant. Typically, the flavorant is present in the composition in an amount of about 0% to about 10% (e.g., about 1% to about 7.5%), based on the weight of the composition. Useful flavorants include volatile oils, synthetic flavor oils, oleoresins, plant extracts (e.g., green tea flavor), and any combinations thereof. Specific flavorants include citrus oils such as lemon, orange, grape, lime and grapefruit, fruit essences such as apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot, and other fruit flavors. Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon, lime), decanal (orange, lemon), C8-aldehydes (citrus fruits), Cg-aldehydes (citrus fruits), Ci2-aldehydes (citrus fruits), tolylaldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), 2-dodecenal (citrus, mandarin), and any mixtures thereof. A flavorant typically is present in an effervescent composition in amounts about 10 mg to about 100 mg.

The compositions of the present application may optionally contain a coloring agent. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, iron oxides, silicon dioxide, and zinc oxide, combinations thereof, and the like.

Typically, the compositions of the application, other than effervescent compositions, can have a total weight of about 100 mg or more. In embodiments, the total weight of these compositions can range from about 100 mg to about 1500 mg.

Effervescent compositions of the application frequently have total weights of about 1500 mg or more (e.g., about 2000 mg or more). In embodiments, the effervescent compositions have total weights of about 2500 mg or more, such as total weights of about 2000 mg to about 6000 mg (e.g., about 3500 mg to about 5000 mg).

Compositions of the application, when formulated as dispersible, fast-dissolving, or effervescent compositions, can have disintegration times of about 300 seconds or less upon immersion into about 120 ml_ of water. Embodiments of such compositions provide an aesthetically pleasing fluid that is substantially free or totally free of un¬dissolved excipients.

The pharmaceutical compositions of the present application are useful in the therapeutic or prophylactic treatment of disorders involving calcium or phosphate metabolism and associated diseases. Examples of these diseases include osteoporosis (including estrogen deficiency, immobilization, and glucocorticoid induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcimia, metastatic bone disease, peridontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, hardening of the arteries (sclerosis), arthritis, bursitis, neuritis, and tetany.
The following examples are presented to illustrate certain specific aspects and embodiments of the present application, but are not intended to limit the scope of the disclosure in any manner.

EXAMPLES l-XI
Ingredients for the examples are listed in Table 1.
Tablets are manufactured by sifting the ingredients (except PEG 6000) through a sieve and blending. The blended material is then lubricated by blending with PEG 6000 and the lubricated blend is compressed using 25 mm round plain punches. All of the manufacturing activities are performed under conditions of relative humidity £25% and temperatures £25°C.

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

We claim:

1. An pharmaceutical composition comprising: (a) 50 mg to 120 mg alendronate (b) tartaric, and (c) an alkaline effervescing component which is a carbonate salt or a bicarbonate salt, wherein the composition has a total weight of 3500 mg to about 6000 mg and when dissolved in water produces a solution having a buffered pH of about 4 to about 6.5 and has buffering capacity sufficient to mediate the pH of a patient's stomach for at least 15 minutes.

2. An pharmaceutical composition comprising: (a) 50 mg to 120 mg alendronate (b) sodium citrate, and (c) an alkaline effervescing component which is a carbonate salt or a bicarbonate salt, wherein the composition has a total weight of 3500 mg to about 6000 mg and when dissolved in water produces a solution having a buffered pH of about 4 to about 6.5 and has buffering capacity sufficient to mediate the pH of a patient's stomach for at least 15 minutes.

3. An pharmaceutical composition comprising: (a) 50 mg to 120 mg alendronate (b) citric acid, and (c) an alkaline effervescing component which is a carbonate salt or a bicarbonate salt, wherein the composition has a total weight less than 3500 mg and when dissolved in water produces a solution having a buffered pH of atleast 6.5 and has buffering capacity sufficient to mediate the pH of a patient's stomach for at least 15 minutes.

4. The composition of claim 1-3, wherein the pharmaceutical composition comprises a carbonate salt or a bicarbonate salt or combination thereof.

5. The composition of claim 1-3, wherein the acid component and the alkaline component are at least partially reacted with each other during granulation with the bisphosphonate.

6. The composition of claim 1-3, further comprising a solubilizing agent.

7. The composition of claim 6, wherein the solubilizing agent is selected from the group consisting of polyvinylpyrrolidones, polyethylene glycols, dextrans, and combinations thereof.

8. The composition of claim 7, wherein the bisphosphonate is selected from the group consisting of etidronate, risedronate, ibandronate, alendronate, and combinations thereof.

9. The composition of claim 1-3, wherein the bisphosphonate is alendronate and said buffering capacity sufficient to mediate the pH of a patient's stomach for at least 30 minutes or more.

10. An effervescent composition comprising: (a) 50 mg to 120 mg of a bisphosphonate

(b) citric acid, and (c) an alkaline effervescing component which is a carbonate salt or a bicarbonate salt, wherein the composition has a total weight less than 3500 mg and when dissolved in water produces a solution having a buffered pH of about 4 to about 6.5 and has buffering capacity sufficient to mediate the pH of a patient's stomach for at least 15 minutes.