ORAL BISPHOSPHONATE FORMULATIONS

INTRODUCTION

Aspects of the present application relate to pharmaceutical preparations containing bis-phosphate drugs, for oral administration. Further aspects relate to pharmaceutical formulations comprising improved bioavailability of bis-phosphate drugs and the processes for preparing the formulations.

Bisphosphonates are a family of drugs used to prevent and treat bone fractures, osteoporosis, Paget's disease, metastatic bone cancer, and other bone diseases with high bone resorption. Bisphosphonates bind to bone hydroxyapatite and slow down bone-eroding cells known as osteoclasts. This effect allows the bone-building cells known as osteoblasts to work more effectively. A general formula for the acid forms of bisphosphonate drugs is shown below, and the substituent groups are listed in the table.

Some of the bisphosphonate drugs are more commonly used in salt form, e.g., as their alkali metal salts, and/or as various hydrates.

Some of the limitations with conventional bisphosphonates include irritation of the upper gastrointestinal tract (GIT), such as esophageal ulcers, and low bioavailability. As a result, conventional bisphosphonates require a specific dosing regimen so that the patient can absorb some of the drug properly and avoid side effects. Because foods, beverages, medications and calcium interfere with absorption, conventional bisphosphonates must be administered on an empty stomach and, depending on the particular bisphosphonate, must wait from 30 minutes to two hours before consuming any food, beverages (other than water), medications or calcium supplements. As esophageal ulcers are a known side effect, dosing regimens for conventional bisphosphonates specify that patients consume an entire glass of water with the dosage form and avoid assuming a horizontal orientation, such as by lying down, within 30 to 60 minutes after administration.

The specific characteristics of alendronate served to exemplify the members of the class of bisphosphonates and the issues associated with them. Alendronate is a white, crystalline, odorless, non-hygroscopic bisphosphonate prepared by chemical synthesis. Alendronate monosodium trihydrate has a molecular weight of 325.1. Alendronate is approved in the U.S. for the prevention and treatment of osteoporosis in men and postmenopausal women, and for the treatment of Paget's disease of bone and glucocorticoid induced osteoporosis in both sexes. Like other bisphosphonates, alendronate binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts. Alendronate reduces bone turnover in human and animal models and decreases activation frequency, reducing bone resorption in both cortical and trabecular bone and ultimately increasing bone density and strength.

The oral bioavailability of alendronate is very low and independent of the dose (5-80 mg), averaging 0.76% in women and 0.59% in men. Pre-systemic metabolism does not occur. Following oral administration of conventional forms of alendronate, 40% of the dose absorbed is excreted in the urine within 8 hours and a further 5% is excreted over the next 64 hours. Sixty to seventy percent of the absorption occurs within 1 hour of dosing. Bioavailability is markedly reduced by coincident consumption of food (85%-90%) and even consumption of coffee or orange juice will impair absorption by as much as 60% or more. Coincident medication will also reduce absorption, as any calcium-containing compounds and multivalent cations will bind to the bisphosphonate. Elevation of gastric pH above 6 is associated with a twofold increase in alendronate absorption. Alendronate is not metabolized and is excreted unchanged with renal clearance comparable to the glomerular filtration rate.

Bisphosphonate compositions and oral dosage forms with improved systemic bioavailability which are not subject to the dosing restrictions of conventional bisphosphonates would represent a considerable benefit for patients. As a result, new strategies for delivering drugs across the GIT cell layers are needed, particularly for bisphosphonates.

Numerous potential absorption enhancers have been identified. For instance, medium chain glycerides have demonstrated the ability to enhance the absorption of hydrophilic drugs across the intestinal mucosa, see Pharmaceutical Research (1994), 11,1148-54. However, the importance of chain length and/or composition is unclear and therefore their mechanism of action remains largely unknown. Sodium caprate has been reported to enhance intestinal and colonic drug absorption by the para-cellular route, see: Pharmaceutical Research (1993) 10, 857-864; and Pharmaceutical Research (1988), 5, 341-346.

U.S. Patent No. 4,656,161 discloses a process for increasing the enteral absorbability of heparin and heparinoids by adding non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkyl-phenol or a sorbitan or glycerol fatty acid ester.

U.S. Patent No. 5,229,130 discloses a composition which increases the permeability of skin to a transdermally administered pharmacologically active agent formulated with one or more vegetable oils as skin permeation enhancers. Dermal penetration is also known to be enhanced by a range of sodium carboxylates, see International Journal of of Pharmaceutics (1994), 108,141-148. Additionally, the use of essential oils to enhance bioavailability is known, see U.S. Patent No. 5,66,386 and others. It is taught that the essential oils act to reduce either, or both, cytochrome P450 metabolism and P-glycoprotein regulated transport of the drug out of the blood stream back into the gut.

U.S. Patent No. 7,704,977 discloses oral administration of zoledronic acid using an enhancer, wherein the enhancer is a medium chain fatty acid or a salt of a medium chain fatty acid having a carbon chain length of from 6 to 20 carbon atoms, is solid at room temperature.

International Application Publication No: WO 2011/094531 discloses pharmaceutical compositions comprising a therapeutically effective amount of a therapeutically active ingredient; at least one water soluble enhancer, e.g., a medium chain fatty acid or a salt, ester, ether, or derivative of a medium chain fatty acid and has a carbon chain length of from about 4 to about 20 carbon atoms; and a saccharide, the pharmaceutical compositions comprise a therapeutically effective amount of a therapeutically active ingredient; at least one water soluble enhancer, e.g., a medium chain fatty acid or a salt, ester, ether, or derivative of a medium chain fatty acid and has a carbon chain length of from about 4 to about 20 carbon atoms; and a saccharide.

Often, however, the enhancement of drug absorption correlates with damage to the intestinal wall. Consequently, limitations to the widespread use of GIT enhancers are frequently determined by their potential toxicities and side effects. Additionally and especially with respect to peptide, protein or macromolecular drugs, the "interaction" of the GIT enhancer with one of the transport pathways should be transient or reversible, such as a transient interaction with or opening of tight junctions so as to enhance transport via the para-cellular route.

Provision of a solid oral dosage form which would facilitate the administration of a drug together with an enhancer is desirable. The advantages of solid oral dosage forms over other dosage forms include ease of manufacture, the ability to formulate different controlled release and extended release formulations and ease of administration. Administration of drugs in solution form does not readily facilitate control of the profile of drug concentration in the bloodstream. Solid oral dosage forms, on the other hand, are versatile and may be modified, for example, to maximize the extent and duration of drug release and to release a drug according to a therapeutically desirable release profile. There also are advantages relating to convenience of administration, thereby increasing patient compliance, and to costs of manufacturing associated with solid oral dosage forms.

SUMMARY
Aspects of the present application relate to pharmaceutical formulations comprising bisphosphonate drugs, and to the preparation thereof.

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is not a medium chain fatty acid or its derivative.

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is a medium chain fatty acid or its derivative, but not including any of, sodium laurate, and sodium caprate. sodium caprylate

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is not a medium chain fatty acid or its derivative. In embodiments, an enhancer is an ionic, nonionic, or lipophilic surfactant, a fatty alcohol, a bile salt or bile acid, a micelle, a chelator, etc.

In embodiments, formulations comprise zoledronic acid and a water-soluble enhancer, without a saccharide.

In embodiments, formulations comprise a bisphosphonate drug that is a free acid form or biologically acceptable salt of alendronate, clodronate, etidronate, incadronate, ibandronate, minodronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, or zoledronate.

In embodiments, a bisphosphonate formulation is an enteric coated instant release solid oral dosage form, which provides improved oral bioavailability and minimizes the risk of local irritation of the upper GIT. In specific embodiments, a bisphosphonate is zoledronic acid.

The formulations can be tablets, multi-particulates, or capsules. Multi-particulates can be packaged, such as in sachets, compressed to form tablets, or can be contained in capsules. Tablets can be single layer or multilayered tablets having compressed multi-particulates in one, all, or none of the layers. Embodiments of dosage forms are controlled release dosage forms and delayed release dosage forms. Dosage forms can be coated with a polymer, such as a drug release rate-controlling polymer, such as a delayed release polymer. The polymer can also be compressed together with an enhancer and the drug to form a matrix dosage form, such as a controlled release matrix dosage form. A polymer coating can then optionally be applied to the matrix dosage form.

Aspects of the application include processes for making bisphosphonate drug dosage forms, methods for the treatment of a medical condition by administering the dosage forms to a patient, and uses of a drug and enhancer in the manufacture of a medicament.

DETAILED DESCRIPTION

In this application, the bisphosphonate drug class is being represented by zoledronic acid, having the chemical name (1-hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and the formula CsH^NaC^-HkO. However, this is done solely for the sake of brevity and the disclosure is not intended to be limited to the use of only zoledronic acid, as its principles also can be applied to other bisphosphonates.

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is not a medium chain fatty acid or its derivative.

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is a medium chain fatty acid or its derivative, but not including any of sodium caprylate, sodium laurate, and sodium caprate.

In embodiments, formulations comprise zoledronic acid and an enhancer to promote absorption of the zoledronic acid, wherein the enhancer is not a medium chain fatty acid or its derivative. In embodiments, an enhancer is an ionic, nonionic, or lipophilic surfactant, a fatty alcohol, a bile salt or bile acid, a micelle, a chelator, etc.

In embodiments, formulations comprise zoledronic acid and a water-soluble enhancer, without a saccharide.

As used in this application, the singular forms "a", "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an enhancer" includes mixtures of two or more enhancers, reference to "a drug" includes mixtures of two or more drugs, etc.

As used herein, the term "drug" includes any drug, including conventional drug compounds and analogs thereof, appropriate for administration to an animal, including a human. The term "drug" also explicitly includes those entities that are poorly absorbed via the oral route including hydrophilic or macromolecular drugs such as peptides, proteins, oligosaccharides, polysaccharides or hormones including, but not limited to, insulin, calcitonin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoietin (EPO), interferons, somatropin, somatotropin, somatostatin, insulin-like growth factor (somatomedins), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), thyrotropin releasing hormone (TRH), growth hormone releasing hormone (GHRH), antidiuretic hormone (ADH) or vasopressin and analogues thereof such as for example desmopressin, parathyroid hormone (PTH), oxytocin, estradiol, growth hormones, leuprolide acetate, goserelin acetate, naferelin, buserelin, factor VIII, interleukins such as interleukin-2, and analogues thereof and anti-coagulant agents such as heparin, heparinoids, low molecular weight heparin, hirudin and analogues thereof, bisphosphonates including alendronate, clodronate, etidronate, incadronate, ibandronate, minodronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, and zoledronate, pentassacharides including anti-coagulant pentassacharides, antigens, and the like. As used herein, the terms "drug" and "bisphosphonate" include all forms thereof, including optically pure enantiomers or mixtures, racemic or otherwise, of enantiomers as well as derivative forms such as, for example, salts, acids, esters, and the like. The drug may be provided in any suitable phase state including as a solid, liquid, solution, suspension, and the like. When provided in solid particulate form, the particles may be of any suitable sizes and morphology, and may assume one or more crystalline, semi-crystalline, and/or amorphous forms.

The drug can be included in nano- or micro-particulate drug delivery systems in which the drug is, or is entrapped within, encapsulated by, attached to, or otherwise associated with, a nano- or micro-particle.

For purposes of this application, "medium chain" describes aliphatic fatty acids having un-branched chains of about 6 to about 12 carbon atoms. The chains may be saturated or partially unsaturated.

As used herein, a "therapeutically effective amount" refers to amounts of drug that elicits a therapeutically useful response in treating an existing medical condition, and/or preventing or delaying the onset of a medical condition in an animal, such as a mammal, including a human.

As used herein, the term "enhancer" refers to a water soluble compound or mixture of compounds, which is capable of increasing the transport of a therapeutically active ingredient (e.g., absorption), particularly a hydrophilic and/or macromolecular therapeutically active ingredient, through gastrointestinal tract tissues and into the blood, in an animal such as a human. The term "water soluble" as used herein includes compounds that are soluble or miscible in water at concentrations of at least about 0.5 mg/mL, e.g., at least 1, 2, 5, or 10 mg/mL, at room temperature. Enhancers include, without limitation, surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitines and alkanoylcholines, N-acetylated a-amino acids and N-acetylated non-a-amino acids, such as sodium 8-[N-(2-hydroxybenzoyl)amino]caprylate (SNAC) and sodium 10-[N-(2 hydroxybenzoyl)amino]decanoate (SNAD), and chitosans and other mucoadhesive polymers, including salts and other derivatives of such compounds. In embodiments, an enhancer is a water soluble compound that increases the bioavailability of a therapeutically active ingredient by at least 5%, e.g., at least 10, 20, 30,40, or 50%, when orally administered in a pharmaceutical formulation comprising a therapeutically active ingredient, as compared to a pharmaceutical formulation that does not include an enhancer.

A saccharide may be included in the formulations of the present application. As used herein, "saccharides" include sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, iactitol, pentitol, and hexitol. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldose, and ketose. Exemplary disaccharides include, but are not limited to, sucrose, isomalt, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, maltotriose, raffinose, and maltotetraose.

A "medium chain fatty acid derivative" includes fatty acid salts, esters, ethers, acid halides, amides, anhydrides, carboxylate esters, and nitrites, as well as glycerides such as mono-, di-, and tri-glycerides. The carbon chain may be characterized by various degrees of saturation. In other words, the carbon chain may be, for example, fully saturated or partially unsaturated (i.e., containing one or more carbon-carbon multiple bonds). Medium chain fatty acid derivatives encompass also medium chain fatty acids wherein the end of the carbon chain opposite the acid group (or derivative) is also functionalized with one of the above mentioned moieties (i.e., an ester, ether, acid halide, amide, anhydride, carboxylate esters, nitrile, or glyceride moiety). Such difunctional fatty acid derivatives thus include, for example, diacids and diesters (the functional moieties being of the same kind) and also difunctional compounds comprising different functional moieties, such as amino acids and amino acid derivatives, for example a medium chain fatty acid or an ester or a salt thereof comprising an amide moiety at the opposite end of the fatty acid carbon chain to the acid or ester or salt thereof.

As used herein, a "therapeutically effective amount of an enhancer" refers to an amount of enhancer that enhances gastrointestinal delivery of the drug to the underlying circulation and allows for the uptake of a therapeutically effective amount of the drug following oral administration. It has been shown that the effectiveness of an enhancer in enhancing the gastrointestinal delivery of poorly permeable drugs is dependent on the site of administration, the site of optimum delivery being dependent on the drug and enhancer.

As used herein, the term "rate controlling polymer material" includes hydrophilic polymers, hydrophobic polymers, and mixtures of hydrophilic and hydrophobic polymers that are capable of controlling or retarding the release of the drug compound from a solid oral dosage form of the application. Suitable rate controlling polymer materials include, but are not limited to: hydroxyalkyl celluloses such as hydroxypropyl celluloses and hydroxypropyl methylcelluloses; poly(ethylene) oxides; alkyl celluloses such as ethyl cellulose and methyl cellulose; carboxymethyl celluloses; hydrophilic cellulose derivatives; polyethylene glycols; polyvinylpyrrolidones; cellulose acetates; cellulose acetate butyrates; cellulose acetate phthalates; cellulose acetate trimellitates; polyvinyl acetate phthalates; hydroxypropyl methylcellulose phthalates; hydroxypropyl methylcellulose acetate succinates; polyvinyl acetaldiethylamino acetates; and poly(alkylmethacrylate) and polyvinyl acetate). Other suitable hydrophobic polymers include polymers and/or copolymers derived from acrylic or methacrylic acid and their respective esters, zein, waxes, shellac, and hydrogenated vegetable oils.

Particularly useful in the practice of the present application are poly(acrylic acid), polyacrylate, poly(methacrylic acid), and poly(methacrylate) polymers such as those sold as Eudragit.™ products (Evonik Industries, Darmstadt, Germany), specifically Eudragit L, Eudragit S, Eudragit RL, and Eudragit RS coating materials, including mixtures of any two or more thereof. Some of these polymers can be used as delayed release polymers to control the gastrointestinal tract site where the drug is released.

Formulations may be solid oral dosage forms, including tablets, multi-particulates, and capsules. An example of a solid oral dosage form is a delayed release dosage form that minimizes the release of drug and enhancer in the stomach, and hence the dilution of the enhancer concentration therein, and releases the major amount of drug and enhancer in the intestine. A delayed release rapid onset dosage form minimizes the release of drug and enhancer in the stomach, and hence the dilution of the local enhancer concentration therein, but releases the drug and enhancer rapidly once the desired site in the intestine has been reached, maximizing the delivery of the poorly permeable drug by maximizing the local concentration of drug and enhancer at the site of absorption.

As used herein, the term "tablet" includes, but is not limited to, immediate release (IR) tablets, sustained release (SR) tablets, matrix tablets, multilayer tablets, multilayer matrix tablets, extended release tablets, delayed release tablets and pulsed release tablets, any of which may optionally be coated with one or more coating materials, including polymer coating materials, such as enteric coatings, rate-controlling coatings, semi-permeable coatings, and the like. The term "tablet" also includes osmotic delivery systems in which a drug compound is combined with an osmagent (and optionally other excipients) and coated with a semi-permeable membrane, the semi-permeable membrane having an orifice through which the drug compound may be released.

As used herein, the term "capsule" includes immediate release capsules, sustained release capsules, coated immediate release capsules, coated sustained release capsules, delayed release capsules, and coated delayed release capsules. In embodiments, a capsule dosage form is an enteric coated capsule dosage form. In embodiments, a capsule dosage form is an enteric coated rapid onset capsule dosage form.

The term "multi-particulate" as used herein means a plurality of discrete particles, including but not limited to powders, granules, pellets, mini-tablets, and mixtures or combinations thereof. If the oral dosage form is a multi-particulate capsule, hard or soft gelatin capsules can suitably be used to contain the particles.
Alternatively, a sachet can suitably be used to contain the particles. The multi-particulates may be coated with a layer containing a rate controlling polymer material. The multi-particulate oral dosage forms may comprise a blend of two or more populations of particles, pellets, or mini-tablets having different in vitro and/or in vivo release characteristics. For example, a multi-particulate oral dosage form may comprise a blend of an instant release component and a delayed release component, contained in a suitable capsule. In embodiments, a multi-particulate dosage form comprises a capsule containing delayed release rapid onset mini-tablets. In embodiments, a multi-particulate dosage form comprises a delayed release capsule containing immediate release mini-tablets. In embodiments, a multi-particulate dosage form comprises a capsule containing delayed release granules. In embodiments, a multi-particulate dosage form comprises a delayed release capsule containing immediate release granules.

In embodiments, multi-particulates, together with one or more auxiliary excipient materials, may be compressed into tablets such as a single layer or multilayer tablets. Typically, multilayer tablets comprise two or more layers, at least one of which contains an active ingredient. In embodiments, different layers contain the same or different levels of the same active ingredient having the same or different release characteristics. Alternatively, a multilayer tablet may contain different active ingredients in different layers. Such tablets, either single layered or multilayered, can optionally be coated with a controlled release polymer to provide additional controlled release properties.

A number of embodiments will now be described. In each case the drug may be present in any amount which is sufficient to elicit a therapeutic effect. As will be appreciated by those skilled in the art, the actual amount of drug compound used will depend on, among other things, the potency of the drug, the specifics of the patient and the therapeutic purpose for which the drug is being used. The amount of drug compound in a dosage form may suitably be in the range of from about 0.5 µg to about 1000 mg. An enhancer is suitably present in any amount sufficient to allow for uptake of therapeutically effective amounts of the drug via oral administration. In embodiments, the drug and the enhancer are present in weight ratios of from 1:100000 to 10:1 (drug:enhancer). In embodiments, the weight ratio of drug to enhancer is from 1:1000 to 10:1. The actual ratios of drug to enhancer used will depend on, among other things, the potency of the particular drug and the enhancing activity of the particular enhancer.

In embodiments, there are provided multilayer tablets comprising compositions of the present application.

Embodiments of a multilayer tablet may comprise a first layer containing a drug and an enhancer in an instant release form, and a second layer containing a drug and an enhancer in a modified release form.

As used herein, the term "modified release" includes sustained, delayed, or otherwise controlled release of a drug upon administration to a patient. In embodiments, a multilayer tablet may comprise a first layer containing a drug and a second layer containing an enhancer. Each layer may independently comprise further excipients chosen to modify the release of the drug or the enhancer. Thus the drug and the enhancer may be released from the respective first and second layers at rates which are the same or different. Alternatively, each layer of the multilayer tablet may comprise both drug and enhancer in the same or different amounts.

In embodiments, there are provided multi-particulates comprising compositions of the present application. In the multi-particulates, a drug and an enhancer may be contained in the same or different populations of granules, pellets, mini-tablets, etc. making up the multi-particulates. A multi-particulate dosage form may comprise a blend of two or more populations of powders, granules, pellets, and/or mini-tablets having different in vitro and/or in vivo release characteristics. For example, a multi-particulate dosage form may comprise a blend of an immediate release component and a delayed release component, contained in a suitable capsule.

In the case of any of the above-mentioned embodiments, a controlled release coating may be applied to the final dosage forms (capsules, tablets, multilayer tablets, etc.). The controlled release coating typically comprises a rate controlling polymer material as described above. The dissolution characteristics of such a coating material may be pH dependent or independent of pH.

Various embodiments of the solid oral dosage forms of the application may further comprise any number of auxiliary excipient materials such as, for example, diluents, lubricants, disintegrants, plasticizers, anti-tack agents, opacifying agents, pigments, flavorings, and the like. As will be appreciated by those skilled in the art, the exact choice of excipients and their relative amounts will depend to some extent on the desired final dosage form characteristics.

Suitable diluents include, for example, pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include: microcrystalline celluloses such as are sold as Avicel™ products (FMC Corp., Philadelphia, PA) for example Avicel PH101, PH102, and PH112; lactose, including lactose monohydrate, lactose anhydrous and Pharmatose™ DCL21; dibasic calcium phosphate such as Emcompress™ products (JRS Pharma, Patterson, NY); mannitol; starch; sorbitol; sucrose; and glucose.
Suitable lubricants, including agents that improve the flowability of particles to be compressed are, for example, colloidal silicon dioxide such as Aerosil™ 200; talc; stearic acid, magnesium stearate, and calcium stearate.

Suitable disintegrants include, for example, lightly cross-linked polyvinylpyrrolidones, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidones, sodium starch glycolate, and combinations and mixtures thereof.

The compositions and dosage forms of the present application also include the use of enhancers other than medium chain fatty acids and medium chain fatty acid derivatives described above. Such absorption enhancers include substances such as: fatty acids other than medium chain fatty acids; ionic, non-ionic, and lipophilic surfactants; fatty alcohols; bile salts and bile acids; micelles; chelators; and the like. These may be used to increase the drug bioavailability and permit dosing at times other than in the morning upon arising from sleep, or within two hours of consuming food, beverages (other than water), calcium supplements, and/or medications.

Nonionic surfactants include: alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene ethers; polyoxyalkylene alkyl ethers; polyoxyalkylene alkylphenols; polyoxyalkylene alkyl phenol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters; sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbates including polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

Ionic surfactants include: alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides;
lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof, carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; sodium laurylsulfate; and quaternary ammonium compounds.

Lipophilic surfactants include fatty alcohols; glycerol fatty acid esters, such as triglycerides; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.

Bile salts and acids include dihydroxy bile salts such as sodium deoxycholate, trihydroxy bile salts such as sodium cholate, cholic acid, deoxycholic acid, lithocholic acid, chenodeoxycholic acid (also referred to as "chenodiol" or "chenic acid"), ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, glycolithocholic acid, glycochenodeoxycholic acid, and glycoursodeoxycholic acid.

Solubilizers include alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycols, polypropylene glycols, polyvinyl alcohols, hydroxypropyl methylcelluloses and other cellulose derivatives, mono-, di- and tri-glycerides of medium chain fatty acids and derivatives thereof, glycerides, cyclodextrins and cyclodextrin derivatives, ethers of polyethylene glycols having average molecular weights of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether or methoxy PEG, amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, polyvinylpyrrolidones, esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsiion-caprolactone and isomers thereof, delta-valerolactone and isomers thereof, beta-butyrolactone and isomers thereof, and other substances such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

The foregoing listings of excipient materials are not intended to be exhaustive, as many others will be useful; those skilled in the art will be aware of the scope of useful materials from the described classes, and the use of such materials is contemplated in this application.

The following examples are provided to further illustrate specific aspects and embodiments of the application, and are not to be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

Examples 1-6: Oral zoledronic acid tablets.

Process of manufacturing may be by direct compression, dry granulation, wet granulation, or slugging (dry compaction).

Examples 7-12: Oral zoledronic acid tablets.

Process of manufacturing may be by direct compression, dry granulation, wet granulation, or slugging (dry compaction).

Examples 13-18: Oral zoledronic acid tablets.

Process of manufacturing may be by direct compression. Mix zoledronic acid and cyclodextrin thoroughly, and then blend the mixture with the diluent (microcrystalline cellulose or lactose) and propylene glycol and/or Captisol, if present in the formula. This mixture from step 2 is further blended with crospovidone and colloidal silicon dioxide, and then is compressed to form tablets.

We claim:

Claim 1: A pharmaceutical composition for oral administration which is effective in delivering therapeutically effective amounts of a drug and an enhancer to an intestine, said composition comprising zoledronic acid and an enhancer, wherein the enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 or more than 20 carbon atoms, or mixtures
thereof.

Claim 2: A pharmaceutical composition comprising zoledronic acid and an atleast one surfactant wherein the composition further comprises 1 mg to about 25 mg zoledronic acid, and further the surfactant is preferably a lower chain or higher chain.

Claim 3: A pharmaceutical composition comprising a bisphosphonate, an enhancer to promote absorption of the bisphosphonate at the GIT cell lining, wherein the enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 or more 20 carbon atoms, or mixtures thereof.

Claim 4: A pharmaceutical composition for oral administration which is effective in delivering therapeutically effective amounts of a drug and an enhancer to an intestine, said composition consisting of: (A) a therapeutically effective amount of a bisphosphonate drug in the form of crystalline and/or amorphous particles; (B) enhancer is surfactant or cyclodextrin or lower chain or higher chain fatty acids (i) is in particulate form; and (ii) is present in the dosage form in a therapeutically effective amount and such that the ratio of the drug to the one or more absorption enhancers is 1:1,000 to 10:1; and (C) one or more excipients selected from the group consisting of rate-controlling polymeric materials, diluents, lubricants, disintegrants, plasticizers, anti-tack agents, opacifying agents, pigments, and flavorings.

Claim 5: A pharmaceutical composition for oral administration according to claim 4, wherein the enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 or more than 20 carbon atoms, or mixtures thereof and atleast one excipient selected from the group consisting of rate-controlling polymeric materials, diluents, lubricants, disintegrants, plasticizers, anti-tack agents, opacifying agents, pigments, and flavorings.

Claim 6: A pharmaceutical composition for oral administration according to claim 1-4, wherein the enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 or more than 20 carbon atoms, or mixtures thereof and atleast one excipient selected from the group consisting of rate-controlling polymeric materials, diluents, lubricants, disintegrants, plasticizers, anti-tack agents, opacifying agents, pigments, and flavorings.

Claim 7: A pharmaceutical composition for oral administration according to claim 4, wherein the enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 or more than 20 carbon atoms, or mixtures thereof and atleast one excipient selected from the group consisting of rate-controlling polymeric materials, diluents, lubricants, disintegrants, plasticizers, anti-tack agents, opacifying agents, pigments, and flavorings.

Claim 8: A pharmaceutical composition for oral administration according to claim 1-4, wherein the enteric-
coated composition is a tablet or capsule.

Claim 9: A pharmaceutical composition for oral administration according to claim 1-4, wherein the enteric coating comprises a polymer selected from the group consisting of poly (acrylic acid), polyacrylate, poly (methacrylic acid), polymethacrylate, and mixtures thereof and enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 and more than 20 carbon atoms, or mixtures thereof.

Claim 10: A pharmaceutical composition for oral administration which is effective in delivering therapeutically effective amounts of a drug and an enhancer to an intestine, said composition consisting of: (A) a therapeutically effective amount of a bisphosphonate is selected from alendronate, etidronate, zoledronic acid; (B) an enhancer is selected from surfactant, cyclodextrin, amino acid, fatty acids having a carbon chain length of less than 6 and more than 20 carbon atoms, or mixtures thereof.