HK1161130B

HK1161130B - Enteric solid oral dosage form of bisphosphonate containing a chelating agent

Info

Publication number: HK1161130B
Application number: HK12101977.1A
Authority: HK
Inventors: R．J．当塞罗; D．E．小布吉奥
Original assignee: 宝洁公司
Priority date: 2004-05-24
Filing date: 2007-06-29
Publication date: 2014-05-30

Description

Bisphosphonate enteric solid oral dosage form comprising a chelating agent

The patent application of the invention is a divisional application of an invention patent application with an international application number of PCT/US 2005/012537, an international application date of 2005, 4 months and 14 days, and an application number of 200580016087.0 entering the China national phase.

Technical Field

The present invention relates to oral dosage forms of bisphosphonates consisting of a safe and effective amount of a pharmaceutical composition comprising a bisphosphate, a chelating agent for administration of a bisphosphonate active ingredient with food or beverages, a method for affecting the delayed release of the bisphosphonate and chelating agent in the lower gastrointestinal tract, and one or more pharmaceutically acceptable excipients. The oral dosage form of the present invention provides for delivery of the pharmaceutical composition into the lower gastrointestinal tract of a mammalian subject and provides for pharmaceutically effective absorption of the bisphosphonate with or without administration with food or beverages. The invention also relates to methods of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism comprising administering to a human or other mammal in need thereof an oral dosage form as described herein.

Background

Bisphosphonates were first developed to complex calcium in hard water to improve detergent performance. Later, bisphosphonates have been found to be useful in the treatment and prevention of diseases or conditions characterized by abnormal calcium and phosphate metabolism. These disorders can be divided into two broad categories:

1. disorders characterized by abnormal calcium and phosphate migration, resulting in general or specific bone loss or excessive calcium and phosphate levels in body fluids. The above condition is sometimes referred to herein as pathologic hard tissue demineralization.

2. Conditions that cause or result in abnormal calcium and phosphate deposition in the body. These conditions are sometimes referred to herein as pathological calcification.

The first category of disorders includes osteoporosis, a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. A substantial amount of cancellous bone is lost and the space for marrow and bone becomes larger, resulting in a reduction in cancellous bone strength. Bone density also becomes lower and bone also becomes brittle. Osteoporosis can be divided into several subclasses such as senile, drug-induced (e.g., corticoid-induced, as may occur with steroid therapy), disease-induced (e.g., arthritis and tumors), etc., however, its symptoms are similar. Another disorder of the first category is paget's disease (osteitis deformans). In this disease, normal osteolysis occurs and then the normal bone is occasionally replaced by soft, less mineralized tissue, causing bone deformation under load-bearing pressure, especially in the tibia and femur. The first category also includes hyperparathyroidism, hypercalcemia of malignancy, and osteolytic bone metastases.

The second category, relates to conditions that manifest as abnormal calcium and phosphate deposition, including progressive myositis ossificans, systemic calcinosis, and conditions such as arthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions that predispose the involved tissues to calcium phosphate deposition.

Bisphosphonates tend to inhibit bone tissue resorption, which is beneficial for patients suffering from excessive bone loss. However, many of the early bisphosphonates, such as ethane-1, 1-diphosphonic acid (EHDP), propane-3-amino-1-hydroxy-1, 1-diphosphonic Acid (APD) and methylene chloride diphosphonic acid (C12MDP), have a tendency to inhibit bone mineralization when administered at high dosage levels. Although there are more biologically effective bisphosphonates which can be administered at low dosage levels (e.g. 1-hydroxy-2- (3-pyridyl) -ethylidene-1, 1-bisphosphonic acid (risedronate), alendronate, ibandronic acid and zoledronic acid), oral bisphosphonates sometimes cause patients to feel malaise shortly after administration. This physical discomfort is often characterized by heartburn, esophageal burning, pain and/or difficulty in swallowing and/or pain behind and/or in the middle of the sternum in the patient. It is postulated that this irritation is caused by the bisphosphonate tablet adhering to epithelial and mucosal tissues, causing its local irritation. To avoid potential upper gastrointestinal irritation, patients taking bisphosphonates are instructed to take a full glass of water when taking the medication and to remain upright for at least thirty minutes after taking a dose of bisphosphonate.

Oral doses of bisphosphonates are known to be poorly absorbed in the Gastrointestinal (GI) tract (less than 1% of oral doses). See "adv. drug del. rev." 42: 175-95(2000). Several methods have been proposed for enhancing the absorption of oral bisphosphonates in the gastrointestinal tract. These methods include altering the permeability of the intestinal mucosa (e.g., by using absorption enhancers), or altering the physical or chemical properties of the bisphosphonate compounds themselves (e.g., by prodrugs).

While the use of absorption enhancers, such as ethylenediaminetetraacetic acid (EDTA), which increase intestinal permeability at high doses, has been proposed as a means of enhancing oral bisphosphonate absorption, its applicability as an agent in human drug therapy has been considered "impossible" in terms of its effect on mucosal integrity. See "adv. drug del. rev." 42: 185(2000). Others have also concluded that: the amount of ethylenediaminetetraacetic acid required to achieve increased gastrointestinal absorption is high, which excludes it as a candidate agent for oral bisphosphonate therapy. See Janner et al "calcif.tissue int." 49: 280-83(1991).

Although the primary site of bisphosphonate absorption is the small intestine, bisphosphonates such as risedronate have similar absorption throughout the small intestine, independent of where it is delivered. See Mitchell et al, "Pharm Re s." volume 15, phase 2: 228-232(1998). Targeted delivery of the bisphosphonate alone to the small intestine does not increase absorption or efficacy of the bisphosphonate. However, others have attempted to increase bisphosphonate absorption by enhancing the permeability of the intestinal mucosa by delivering microparticles of chelating agents and bisphosphonates to the reported absorption site (BR 2001-006601).

Bisphosphonates such as risedronate and alendronate have been approved by various regulatory agencies for their therapeutic effects in the treatment of various bone disorders. However, the interaction between bisphosphonates and foods and minerals (especially cations such as calcium, magnesium, aluminum and iron containing foods or supplements) allows less bisphosphonate to be absorbed for use. For example, in Mitchell et al, "br.j.clin.pharmacol" 48: 536-542(1999) demonstrated that the amount of risedronate absorbed is reduced by 50% over a 30 minute meal compared to administration in the fasted state. To reduce this food impact, labeling of oral bisphosphonate products instructs patients to take their medication at least thirty minutes prior to the first meal of the day, or sixty minutes prior to taking ibandronic acid, and patients to take calcium supplements at another time of the day, or on a day they do not take oral doses of bisphosphonate. These administration guidelines can be complex and inconvenient for the patient, which can result in poor patient compliance.

There is a continuing need to develop bisphosphonates in an oral dosage form which can be taken with or without food or drink (i.e., have effective absorption of the drug regardless of whether food or drink is taken), depending on the preference of the patient, and which do not produce irritation of the upper gastrointestinal tract.

It has been found that a pharmaceutical composition comprising a bisphosphonate, a sufficient amount of a chelating agent for binding ions and minerals in food, and a method for affecting the delayed release of the bisphosphonate and the chelating agent in the lower gastrointestinal tract, can be used to provide an oral dosage form that provides for delivery of the bisphosphonate into the lower gastrointestinal tract and for pharmaceutically effective absorption of the bisphosphonate, whether administered with food or beverages. The oral dosage form of the present invention may be taken with or without food or beverages, thus simplifying bisphosphonate treatment and allowing increased patient compliance and convenience. In addition, the oral dosage form of the present invention provides for the delayed release of the bisphosphonate and the chelating agent in the lower gastrointestinal tract, which may alleviate upper gastrointestinal irritation experienced when taking other bisphosphonate dosage forms and reduce the need to remain upright for thirty minutes after administration.

Summary of The Invention

The present invention relates to an oral dosage form of a bisphosphonate active ingredient comprising a safe and effective amount of a pharmaceutical composition comprising:

(a) a bisphosphonate;

(b) about 10mg to about 1000mg of a chelating agent; and

(c) a delayed release mechanism for delivery of bisphosphonates and a chelating agent in the lower gastrointestinal tract.

The dosage forms of the present invention provide a method of delivering a bisphosphonate and a chelating agent into the lower gastrointestinal tract of a mammalian subject and provide pharmaceutically effective absorption of a bisphosphonate active ingredient with or without administration with food or beverages.

The present invention substantially mitigates interactions between bisphosphonates and food, which interactions result in reduced absorption of the bisphosphonate active ingredient. The resulting novel oral dosage form can thus be taken with and without food and beverages, which simplifies previously complicated treatment methods and allows increased compliance by patients receiving bisphosphonate treatment and their disease can be better treated if they are compliant. The present invention also alleviates the upper gastrointestinal irritation associated with immediate release oral dosage forms of bisphosphonates by delaying the release of the bisphosphonate active ingredient until the bisphosphonate and chelating agent reach the lower gastrointestinal tract.

The invention also relates to methods of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism comprising administering to a human or other mammal in need thereof an oral dosage form as described herein.

The present invention also relates to a kit comprising one or more oral dosage forms of the invention and a method of promoting compliance of the methods of the invention.

Detailed Description

Definition and use of terms

The term "bolus" as used herein refers to a significant amount of released bisphosphonate and/or chelating agent achieved at the initiation/release site.

The term "sustained" or "continuously" as used herein refers to regular specified intervals. For example, a continuous schedule as described for once-a-week dosing regimen means that the active substance is administered once a week for an unspecified period of time or for a period of time necessary for treatment.

The term "nutrient" as used herein refers to any nutritional or dietary supplement, including, but not limited to, vitamins, minerals, amino acids, herbs or other botanicals, or concentrates, metabolites, components, extracts, or combinations of the same.

The term "pharmaceutical composition" as used herein refers to an oral dosage form comprised of a safe and effective amount of a bisphosphonate active ingredient and one or more pharmaceutically acceptable excipients comprising at least one chelating agent. The pharmaceutical compositions described herein consist of from 0.5% to 75%, preferably from 1% to 40%, of the bisphosphonate active ingredient and from 25% to 99.5%, preferably from 60% to 99%, of a pharmaceutically acceptable excipient comprising at least one chelating agent.

The term "safe and effective amount" as used herein means an amount of a compound or component that is high enough to significantly and positively modify the symptoms and/or conditions being treated, while low enough to avoid serious side effects (reasonable risk/effect ratio), within the scope of sound medical judgment. The safe and effective amount of the active ingredient for use in the methods of the present invention will vary depending upon the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being used, the particular pharmaceutically acceptable excipient being used and other factors within the knowledge and expertise of the attending physician.

The term "sustained release" means that the bisphosphonate and/or chelating agent is not sufficiently released at the starting site but is continuously released all the way from the starting site to the rest of the gastrointestinal tract.

The term "pharmaceutically effective absorption" as used herein means that the amount of chelating compound is high enough to significantly bind metal ions and minerals in food, but low enough not to significantly alter the absorption of the bisphosphonate, i.e. absorption is similar with or without food, compared to absorption in the fasted state. Given the high variability of bisphosphonate absorption, feeding is expected to have drug-efficient absorption with about a 50% fasting.

The term "oral dosage form" as used herein refers to any pharmaceutical composition intended for oral administration to the lower gastrointestinal tract of a human or other mammal via the oral cavity of said human or other mammal. For the purposes of the present invention, the delivery form may be a compressed tablet comprising the bisphosphonate and the chelating agent particles or microparticles, a capsule comprising beads, particles or a suspension of the bisphosphonate and the chelating agent (e.g. soft or hard gelatin consisting of starch or hydroxypropylmethylcellulose), or a dry blend (e.g. a sachet) comprising the bisphosphonate and the chelating agent particles or microparticles, which is used to form a reconstituted suspension in water.

The term "unit dose" or "unit amount" refers to a dosage form containing an amount of a pharmaceutically active or nutraceutical substance suitable for administration as a single dose, in accordance with sound medical experience. The invention is particularly useful for unit dose administration in tablet and capsule form.

The term "gastrointestinal tract" as used herein relates to the digestive tract, i.e., the approximately thirty foot long myo-membranous tube extending from the mouth to the anus. The term "upper gastrointestinal tract" as used herein refers to the oral cavity, pharynx, esophagus and stomach. The term "lower gastrointestinal tract" as used herein refers to the small and large intestines.

The term "small intestine" as used herein refers to the lower gastrointestinal tract portion consisting of the duodenum, jejunum and ileum, i.e., the portion of the intestine immediately distal to the lower duodenal sphincter of the stomach and proximal to the large intestine.

The term "large intestine" as used herein refers to the portion of the lower gastrointestinal tract immediately distal to the small intestine, beginning in the cecum and including the ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.

Bisphosphonate active ingredient

The terms "bisphosphonate" and "diphosphonate" as used herein include acids, salts, esters, hydrates, polymorphs, hemihydrate, solvates, and derivatives thereof. Bisphosphonates of the invention include those preferred compounds containing a nitrogen atom. Non-limiting examples of bisphosphonates useful in the invention include the following: 1-hydroxy-2- (3-pyridyl) -ethylene-1, 1-bisphosphonic acid (risedronate), which is described in U.S. Pat. No. 5,583,122 to Benedict et al, published 12/10 in 1996, U.S. Pat. No. 6,410,520B2 to Cazer et al, published 6/25 in 2002; 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid (alendronate or alendronate) described in U.S. Pat. No. 4,621,077 to Rosini et al, published 11/4/1986, U.S. Pat. No. 6,281,381B1 to Finkelstein et al, published 12/28/1999, U.S. Pat. No. 6,008,207 to Brenner et al, published 12/15/1998, U.S. Pat. No. 5,849,726 to Brenner et al, published 2001 9/13, U.S. Pat. No. 2001/0021705A1 to Brenner et al, published 5/1/1990, U.S. Pat. No. 4,922,007 to Kieczykowski et al, published 5/28/1991, U.S. Pat. No. 5,019,651 to Kieczykowski et al; 3-amino-1-hydroxypropylidene-1, 1-bisphosphonic acid (pamidronic acid), which is described in U.S. patent 4,639,338 to Stahl et al, published 1, 27, 1987; (4-chlorophenyl) thiomethane-1, 1-diphosphonic acid (tiludronic acid), which is described in U.S. patent 4,876,248 issued to Breliere et al at 10/24 1989; 1, 1-dichloromethylene-1, 1-diphosphonic acid (clodronic acid), described in U.S. patent 3,422,021; cycloheptylaminomethylene-1, 1-diphosphonic acid (incadronic acid), described in U.S. patent 4,970,335 to Isomura et al, published 11, 13, 1990; 1-hydroxy-3- (N-methyl-N-pentylamino) propylene-1, 1-bisphosphonic acid (ibandronic acid), described in U.S. patent 4,927,814, published 5-month and 22-days 1990; 1-hydroxy-2- (imidazol-1-yl) ethane-1, 1-bisphosphonic acid (zoledronic acid); and 1- (N-phenylaminothiocarbonyl) methane-1, 1-bisphosphonic acid.

In one embodiment of the invention, the bisphosphonate is selected from risedronic acid, alendronate, pamidronic acid, tiludronic acid, incadronic acid, ibandronic acid, clodronic acid, zoledronic acid, and salts, esters, hydrates, hemihydrate, polymorphs, and solvates thereof, and combinations thereof.

It should be noted that the term "bisphosphonate" as used herein in reference to the therapeutic agents of the present invention also includes bisphosphonates, and diphosphonic acids, as well as salts, esters, hydrates, polymorphs, hemihydrate, solvates and derivatives of these materials.

Non-limiting examples of bisphosphonates which may be used in the present invention include those selected from the group consisting of alkali metal, basic metal, ammonium, and mono-, di-, tri-or tetra-C1-C30-alkyl substituted ammonium salts. Preferred salts are those selected from sodium, potassium and ammonium salts.

The amount of bisphosphonate active ingredient included in the oral dosage form of the present invention will depend on the particular bisphosphonate selected and the continuous dosing schedule according to which the bisphosphonate is administered to a patient. A continuous dosing schedule of daily, weekly, twice-a-month, three times a month, and once a month is a non-limiting example of a dosing regimen suitable for use with the oral dosage forms of the present invention. The term "three times per month" or "three times a month" means that the oral dosage form is administered three times, i.e. three times, in one month. In a three-a-month schedule, the oral dosage form may be administered over three consecutive days, or once every about nine to eleven days. The term "twice a month" or "twice a month" means that the oral dosage form is administered twice a month, i.e. twice. In a twice-a-month approach, the oral dosage form may be administered on consecutive days, or once every approximately fourteen to sixteen days. The term "monthly" or "monthly" means that the oral dosage form is administered once a month, i.e., once, that is, every about 28 to 31 days.

Unless specifically indicated, the specific nomenclature used for the bisphosphonate or bisphosphonates is not intended to limit the scope of the present invention. Currently, one of ordinary skill in the art uses a mixed nomenclature, such as the specific weight or percentage of bisphosphonate active ingredients being based on anhydrous monosodium salt for risedronate and anhydrous free acid for alendronate. For purposes of the present invention, the phrase "about 35mg of a bone resorption inhibiting bisphosphonate selected from risedronate, pharmaceutically acceptable salts thereof, and mixtures thereof, based on anhydrous monosodium salt, means that the amount of bisphosphonate compound selected is calculated based on about 35mg of anhydrous risedronate monosodium salt. The phrase "about 70mg of a bone resorption inhibiting bisphosphonate selected from alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof based on anhydrous acid" means that the amount of the selected bisphosphonate compound is calculated based on about 70mg of anhydrous alendronic acid.

Typically, the oral dosage form of the present invention will comprise about 1mg to about 500mg of the bisphosphonate on an anhydrous weight basis. When the bisphosphonate is administered daily, the oral dosage form comprises about 1mg to about 100mg of the bisphosphonate on an anhydrous weight basis. When the bisphosphonate is administered weekly, the oral dosage form comprises about 10mg to about 200mg of the bisphosphonate on an anhydrous weight basis. When the bisphosphonate is administered twice a month, the oral dosage form comprises about 20mg to about 300mg of the bisphosphonate on an anhydrous weight basis. When the bisphosphonate is administered three times a month, the oral dosage form comprises about 15mg to about 250mg of the bisphosphonate on an anhydrous weight basis. When the bisphosphonate is administered monthly, the oral dosage form comprises about 50mg to about 500mg of the bisphosphonate on an anhydrous weight basis.

When the bisphosphonate active ingredient is risedronate, the daily oral dosage form of the present invention comprises about 1mg to about 10mg risedronate based on risedronate anhydrous monosodium salt. The weekly oral dosage form comprises about 10 to about 50mg risedronate based on risedronate anhydrous monosodium salt. The twice-a-month oral dosage form contains about 20 to about 100mg, preferably about 75mg, of risedronate based on risedronate anhydrous monosodium salt. An oral dosage form administered three times per month contains about 15 to about 75mg, preferably about 50mg, of risedronate based on risedronate anhydrous monosodium salt. The monthly oral dosage form contains about 50 to about 200mg risedronate, preferably about 100 to about 175mg, more preferably about 150mg risedronate, based on risedronate anhydrous monosodium salt.

Chelating agents

The term "chelating agent" as used herein refers to a molecule containing two or more electron coordinating atoms, which is capable of forming a coordinate bond with a single metal ion. The term "chelating agent" is understood to include chelating agents as well as their salts. For example, the term "chelating agent" includes citric acid and its salt forms.

The most common and widely used chelating agents are coordinatively bound to the metal atom through an oxygen or nitrogen coordinating atom, or both. Other less common chelating agents coordinate through sulfur in the form of-SH (thiol or mercapto) groups. After the first coordination bond is formed, each successive binding coordination atom forms a ring containing the metal atom. The chelating agent may be bidentate, tridentate, tetradentate, etc., depending on whether it contains two, three, four or more coordinating atoms capable of binding the metal atom. See "Kirk-Othmer encyclopedia of Chemical Technology" (4 th edition, 2001).

In a homogeneous dilution solution, the equilibrium constant for a solvated metal ion (e.g., calcium) and the fully dissociated form of the chelator to form a complex is referred to as the formation or stability constant, K. The practical significance of the formation constant is that a high log K value means a high ratio of chelated to unchelated (or free) metal ions when equal amounts of metal ions and chelating agent are present. In order to complex almost all metal ions with a chelating agent rather than a bisphosphonate, a higher ratio (or difference, provided K is expressed in logarithmic units) of chelating agent and bisphosphonate complexation constants is preferred. For example, for equimolar amounts of bisphosphonate and chelating agent, the log K of the chelating agent must be at least 4 units higher than the log K of the bisphosphonate-metal ion complex in order to have 99% of the metal ion complexed to the chelating agent. Another technique for promoting the chelating agent-metal ion complex over the bisphosphonate-metal ion complex is to add an excess molar amount of chelating agent, which is based on the rule that mass action promotes the formation of the chelating agent-metal ion complex.

While pH and solution concentration may affect the formation constant, generally the log K of the chelating agent is preferably at least equal to the log K of the bisphosphonate. In other embodiments, the chelating agent has a log K2 to 5 units greater than the log K of the bisphosphonate. In other embodiments, the molar amount of chelating agent is in excess to the molar amount of bisphosphonate. The chelating agent of the above examples is present in a molar ratio to the bisphosphonate of at least 2: 1.

The chelating agent may be soluble or insoluble in the gastrointestinal tract, so long as it readily complexes with metal ions in the food. In one embodiment, a chelating agent that is soluble in the gastrointestinal tract is used because the availability of a poorly soluble chelating agent is too slow to complex most of the calcium ions ingested in concert with food. In other embodiments, the chelating agent should have a solubility equal to or greater than that of the bisphosphonate, such that it is present in its complexed form at a concentration at least equal to that of the bisphosphonate,

a variety of chelating agents are suitable for use in the present invention. Non-limiting examples of these types include polyphosphates (e.g., sodium tripolyphosphate, hexametaphosphate, sodium acid pyrophosphate, sodium pyrophosphate, tetrasodium pyrophosphate, sodium hexametaphosphate, sodium metaphosphate); aminocarboxylic acids (e.g., ethylenediaminetetraacetic acid (EDTA), 1, 2-bis (2-aminophenoxy) ethane-N, N' -tetraacetic acid (EGTA), ethylene glycol bis (2-aminoethyl) tetraacetic acid (BAPTA), N- (hydroxyethyl) -ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), N-dihydroxyethylglycine (2-HxG), ethylenebis (hydroxyphenylglycine) (EHPG), glutamic acid, aspartic acid, glycine, lysine); 1, 3-diketones (e.g., acetylacetone, trifluoroacetylacetone, thenoyltrifluoroacetone, ascorbic acid); hydroxycarboxylic acids (e.g., tartaric acid, citric acid, malic acid, gluconic acid, ferulic acid, lactic acid, glucuronic acid); polyamines (e.g., diethylenetriamine, triethylenetriamine); aminoalcohols (e.g., triethanolamine, N-hydroxyethylethylenediamine, aminoethylethanolamine (AEEA)), phenols (e.g., orthophenylenedisulfonic acid, chromophoric acid), aminophenols (e.g., quinolinesulfonic acid), Schiff bases (e.g., disalicylaldehyde, 1, 2-propyleneimine), tetrapyrroles (e.g., tetraphenylporphyrin, phthalocyanine dyes), silicates (calcium aluminum silicate, calcium silicate, sodium aluminosilicate sodium calcium aluminosilicate (hydrate), tricalcium silicate), sulfur compounds (e.g., potassium ethylsulfonate, sodium diethyldithiocarbamate, diethyldithiophosphoric acid, thiourea, magnesium sulfate), synthetic macrocyclic compounds (e.g., hexamethyl- [14] -4, 11-diene N4, 2.2.2-cryptate), polymers (e.g., polyethyleneimine, polyisomethacryloylacetone, poly (p-vinylbenzylimine diacetic acid)), phosphoric acid (e.g., cyanocyclopropanephosphoric acid, ethylenediamine tetra- (methylenephosphoric acid), hydroxyethylidene diphosphonic acid).

In one embodiment, the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, malic acid, tartaric acid, lactic acid, adipic acid, succinic acid, aspartic acid, glutamic acid, lysine, sodium hexametaphosphate, and combinations thereof. In another embodiment, the chelating agent is ethylenediaminetetraacetic acid, citric acid, or sodium hexametaphosphate.

In another embodiment of the invention, a monodentate chelating agent, typically precipitated as a metal ion complex, is used in place of the multidentate chelating agent. Suitable monodentate complexing agents include, but are not limited to, phosphates (e.g., sodium phosphate, sodium aluminum phosphate, sodium acid phosphate, dipotassium phosphate, disodium phosphate, monobasic) and carboxylic acids (e.g., acetic acid).

The amount of chelating agent contained in the oral dosage form of the present invention will depend on the particular chelating agent or agents (i.e., mixture of chelating agents) selected, the amount of bisphosphonate active ingredient contained in the oral dosage form, and the particular portion of the lower gastrointestinal tract to which the chelating agent and/or bisphosphonate active ingredient is to be delivered. After ingestion of milk, it has been demonstrated in the art that the calcium concentration decreases when passing through the lower gastrointestinal tract, starting in length from the small intestine and up to the end of the large intestine. See, Mahe, J. et al, "tissue diagnostics and electrolyte movement after bovinemilk injection in humans" (am.J. Clin.Nut r.56: pages 410 to 16, 1992). Thus, for example, given the same dose of bisphosphonate active ingredient, a lower concentration of a particular chelating agent may be required to affect delivery of the bisphosphonate to the transverse colon than would be required to affect delivery of the bisphosphonate to the terminal ileum.

Generally, the oral dosage form of the present invention will contain a safe and effective amount of a chelating agent suitable to achieve the desired chelating effect, i.e., to chelate residual metal ions present in the gastrointestinal tract from food at the site of delivery, without significantly affecting bisphosphonate absorption in the absence of food. In one embodiment, the oral dosage form comprises from about 10mg to about 1000mg of the chelating agent per unit dose. In another embodiment, the oral dosage form comprises from about 10mg to about 500mg of the chelating agent per unit dose. When the chelating agent is disodium edetate, a preferred range is from about 55mg to about 500mg, preferably from about 75mg to about 250mg, per unit dose. When the chelating agent is citric acid, a preferred range is from about 100mg to about 1000mg, preferably from about 250mg to about 500mg, per unit dose.

Delayed release in the lower gastrointestinal tract

Humans or other mammals suffering from diseases or disorders of calcium and phosphate metabolism may be successfully treated by delivering a bisphosphonate active ingredient into the lower gastrointestinal tract of the human or other mammal. The novel dosage forms described herein affect delivery to the lower gastrointestinal tract and inhibit the undesirable release of bisphosphonates in the mouth, pharynx, esophagus and/or stomach, thereby inhibiting erosion, ulceration or other similar irritation of the epithelial or mucosal layers of these tissues. In some embodiments, it may be desirable to affect the delivery of the bisphosphonate and the chelating agent to the small intestine or a particular segment of the small intestine (e.g., the terminal ileum). In other embodiments, it may be desirable to affect delivery of the bisphosphonate and chelating agent to the entire lower gastrointestinal tract or to a segment of the gastrointestinal tract, beginning delivery to the small intestine and continuing delivery (if delivery to the large intestine is desired). In another embodiment, it may also be desirable to affect the bolus delivery of the bisphosphonate and the chelating agent to the lower gastrointestinal tract or a particular portion of the lower gastrointestinal tract. In one embodiment of the invention, the delivery of the active substance starting from the small intestine and continuing through the large intestine can be achieved by using sustained release formulations known to the person skilled in the art. The sustained release formulations are designed to be administered orally through the lower gastrointestinal tract to slow the release of the bisphosphonate and chelating agent over a specified period of time. In other embodiments, it may also be desirable to achieve delivery of the bisphosphonate and the chelating agent to the large intestine or a particular segment thereof (e.g., the descending colon). In other embodiments, it may also be desirable to deliver large doses of the chelating agent and bisphosphonate to the large intestine. In other embodiments, it may also be desirable to deliver the chelating agent to one segment of the lower gastrointestinal tract and the bisphosphonate to a different segment of the lower gastrointestinal tract. For example, it may be desirable to deliver a chelating agent to the terminal ileum and a bisphosphonate to the descending colon.

The term "extended release" as used herein refers to delivery of the bisphosphonate active ingredient and the chelating agent closer to the end of the lower gastrointestinal tract by formulating pharmaceutical compositions comprising the bisphosphonate and chelating agent such that they successfully complete release at some generally predictable location in the lower gastrointestinal tract, which should have been successfully completed if there is no change in the delivery of the bisphosphonate and chelating agent.

In another embodiment of the invention, the bisphosphonate and the chelating agent may be administered to a mammalian subject in more than one oral dosage form, each dosage form comprising a method of delivering the contents of the oral dosage forms to the lower gastrointestinal tract. For example, the patient may take a unit dose of the bisphosphonate followed by a separate unit dose containing the chelating agent.

In another embodiment, the chelating agent and bisphosphonate may also be released rapidly and as simultaneously as possible, resulting in a local concentration of chelating agent higher than the metal ions in the food. Higher local concentrations of chelating agent in the environment where the active substance is released can complex the metal in the food more effectively and facilitate absorption of the bisphosphonate. This is conveniently achieved by a separate tablet.

Various methods for targeted release of bisphosphonates and chelators in the lower gastrointestinal tract are suitable for use in the present invention. Non-limiting examples of methods for delivery to the lower gastrointestinal tract include pH triggered delivery systems, drug release dosage forms triggered by bacterial enzyme action, and time dependent delivery systems.

In some embodiments, it may be desirable for the bisphosphonate and chelating agent to begin release primarily in the duodenum and/or jejunum. In other embodiments, it is desirable that the bisphosphonate and chelating agent begin to be released primarily in the middle jejunum and/or terminal ileum. In other embodiments, it may also be desirable for the bisphosphonate and chelating agent to be released continuously primarily during transit through the jejunum and terminal ileum. For primary colonic delivery, it may be desirable for the bisphosphonate and chelating agent to begin release in the ascending and/or transverse colon.

pH triggered delivery system

One embodiment of the present invention involves coating (or otherwise encapsulating) the bisphosphonate and the chelating agent with a substance that is not destroyed by gastrointestinal fluids to release the bisphosphonate and chelating agent until a specific desired location in the intestinal tract is reached. In one embodiment, the extended release of the pharmaceutical composition is accomplished by coating the tablet, capsule, or microparticle, granule or bead of the bisphosphonate and chelating agent with a substance that is pH dependent, i.e., the substance breaks down or dissolves at a pH that is normally present in the lower gastrointestinal tract but not in the upper gastrointestinal tract (i.e., mouth, pharynx, esophagus or stomach).

In some embodiments, it may be desirable for the bisphosphonate and the chelating agent to be released at a specific location in the small or large intestine. In other embodiments, it may be desirable to release the bisphosphonate and the chelating agent independently at different locations in the lower gastrointestinal tract. For example, it may be desirable to release the chelating agent in the ascending colon and the bisphosphonate in the transverse colon. When it is desired to target the bisphosphonate and chelating agent together or separately to a particular location in the lower gastrointestinal tract, the choice of coating material and/or coating method (or in other words the combination of bisphosphonate and chelating agent with the selected coating material or other pharmaceutically acceptable excipients) may be varied, or modified as described herein or by any method known to those skilled in the art.

The skilled artisan can satisfactorily control the final location of delivery and/or the rate of delivery in the lower gastrointestinal tract by controlling any one or several of the following factors:

(a) a suitable active ingredient;

(b) the type and amount of disintegrant;

(c) the type of coating, the type and amount of excipients added to the coating, and the thickness of the attendant desired, as well as the permeability (swelling) of the coating;

(d) time-dependent behavior of the coating itself and/or inside the coated tablet, microparticle, bead or granule;

(e) the particle size of the particulate active ingredient; and

(f) the coating itself and/or the pH dependence inside the coated tablet, microparticle, bead or granule.

In particular, the solubility, acidity and hydrolysis sensitivity of various bisphosphonate active ingredients, such as acid salts, salts with phosphoric acid groups (e.g., alkali metal salts, alkaline earth metal salts, etc.) and esters (e.g., alkyl, alkenyl, aryl, aralkyl groups) can be used as a guide for proper selection. In addition, suitable pH conditions may be established in the coated tablet, particle, granule or bead by adding a suitable buffer to the active ingredient depending on the desired release profile.

In addition to the variations described above to achieve the desired release profile, the excipients may also be different so long as they do not affect the activity of the particular bisphosphonate selected.

One embodiment of the invention is the delivery to the lower gastrointestinal tract using a pH-dependent enteric coating substance made from partially formylated methacrylic acid polymers. Oral dosage forms may be in the form of enteric-coated compressed tablets made of granules or microparticles of the active ingredient, or gelatin capsules containing beads or granules of the active ingredient, which are themselves enteric-coated.

Any enteric coating that is insoluble at pH below 5.5 (i.e., pH typically found in the mouth, pharynx, esophagus, and stomach), but soluble at pH5.5 and higher (i.e., pH found in the small and large intestines) can be used in the practice of the present invention. Thus, any enteric coating that is completely or partially insoluble at a pH below 5.5 and soluble at a pH of 5.5 or higher is suitable when it is desired to affect delivery of the bisphosphonate and chelating agent to the small intestine.

The enteric coating must be applied to the compressed tablet, capsule (e.g., gelatin, starch, or hydroxypropyl methylcellulose) and/or beads, microparticles, or granules of the active ingredient to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below 5.5, but dissolves at a pH of 5.5 or higher. Dissolution or disintegration of the excipient coating does not typically occur until the coated dosage form enters the small intestine.

It is contemplated that any anionic polymer exhibiting the desired pH-dependent solubility characteristics can be used as an enteric coating in the application of the present invention to achieve delivery of the bisphosphonate and chelating agent to the lower gastrointestinal tract. The coating chosen must be compatible with the particular bisphosphonate active ingredient chosen. Preferred polymers for use in the present invention are anionic carboxy polymers. Particularly preferred polymers are acrylic polymers, more preferably partially formylated methacrylic polymers, in which the ratio of free anionic carboxyl groups to ester groups is about 1: 1.

Particularly suitable methacrylic polymers areIn particular EudragitAnd Eudragit LIs manufactured inPharma GmbH and co.kg, Darmstadt, germany. In Eudragit LThe ratio of free carboxyl groups to ester groups is about 1: 1. Furthermore, the copolymers are known to be insoluble in gastrointestinal fluids having a pH below 5.5, typically between 1.5 and 5.5 (i.e. the pH typically present in upper gastrointestinal fluids), but readily soluble in gastrointestinal fluids having a pH above 5.5 (i.e. the pH typically present in lower gastrointestinal fluids).

Other suitable methacrylic copolymers for coating the oral dosage form and/or the granules, microparticles or beads of the active ingredient areAnd EudragitIs manufactured inPharma GmbH and co.kg, Darmstadt, germany, the active ingredients can be used alone or in combination with other coatings in the methods of treatment described herein.Unlike Eudragit L30Only the ratio of free carboxyl groups to ester groups is about 1: 2.Also as Eudragit L30Likewise, it is substantially insoluble at a pH below 5.5, but unlike Eudragit LIn gastrointestinal fluids having a pH of 5.5 to 7.0, for example in small intestine fluids, little dissolution occurs.Soluble at a pH of 7.0 or higher (i.e., a pH typically found in the terminal ileum or colon).

Can also be used alone as a coating to provide delivery of the bisphosphonate active ingredient via a delayed release mechanism primarily starting in the large intestine (more terminal than the terminal ileum). Furthermore, poorly soluble in intestinal fluids below pH7.0Capable of dissolving in intestinal fluids above pH5.5 Eudragit L30Combinations to affect a time-release composition that can be formulated to deliver the active ingredient in different parts of the intestinal tract; eudragit L30 usedThe more, the closer the initial release and delivery, the useThe more, the closer the initial release and delivery is to the end.

The coating can and typically will contain plasticizers, and possibly other coating excipients such as colorants, surfactants, talc and/or magnesium stearate, many of which are well known in the coating art. In particular, the anionic carboxy acrylic polymer will generally comprise from 10% to 25% by weight of a plasticizer, especially triethyl citrate, tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, diethyl phthalate, polyethylene glycol, propylene glycol acetylated monoglycerides and triacetin. The coating is applied using conventional coating techniques such as fluidized bed or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains substantially intact until the desired delivery site in the lower gastrointestinal tract is reached.

The solid oral dosage form may be in the form of a coated compressed tablet comprising microparticles or granules of the bisphosphonate active ingredient and the chelating agent, or in the form of a coated or uncoated soft or hard capsule (e.g. gelatin, starch or hydroxypropylmethylcellulose) comprising beads or granules of the bisphosphonate active ingredient and the chelating agent, which are themselves enteric coated.

Sustained release polymers are required for sustained release of the bisphosphonate and the chelating agent to control the rate of dissolution of the bisphosphonate and chelating agent from the dosage form. If both the bisphosphonate and the chelating agent are soluble (defined as being 33mg/ml or more dissolved in water), then high levels of sustained release polymer are required. Sustained release polymers include, but are not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and carbomer.

A. Enteric coated tablet

In one embodiment of the invention, the oral dosage form comprises an enteric coated compressed tablet. Tablets are prepared by combining, blending or otherwise incorporating the bisphosphonate active ingredient and the chelating agent into suitable pharmaceutical excipients including, but not limited to: sucrose, maltodextrin, lactose, cellulose, microcrystalline cellulose, talc, magnesium stearate, polyvinylpyrrolidone, starch and sodium starch glycolate. This mixture is then compressed into tablets using a variety of methods known to those skilled in the art. The compressed tablets are then coated with an enteric coating material prepared with suitable pharmaceutical excipients including, but not limited to, poly (methacrylic acid, methyl methacrylate 1: 1)Poly (methacrylic acid, ethyl acrylate 1: 1(Eudragit L30)Eudragit LPoly (ethyl acrylate, methyl methacrylate 1: 2)EudragitHydroxypropyl methylcellulose phthalate, acetic acid phthalateCellulose formate, polyvinyl acetate phthalate, shellac, cellulose acetate succinate, cellulose acetate 1, 2, 4-trimellitate, polyethylene glycol 400 to 8000, triacetin, dibutyl phthalate, acetylated monoglyceride, triethyl citrate, talc and iron oxide. The enteric coating material is then applied to the compression tablets using a variety of spray techniques available to those skilled in the art.

The enteric coating of the tablet is insoluble in the fluids of the mouth, pharynx, esophagus or stomach, thus limiting the release of bisphosphonate and edetic acid until the oral dosage form reaches the lower gastrointestinal tract. For the coating methods described herein using methacrylate copolymers, it has been found that a coating thickness of between about 10 and about 500 microns is typically required when the desired site of delivery is the lower gastrointestinal tract. In one embodiment of the invention, the thickness is between about 10 to 30 and about 50 microns. In another embodiment, the thickness is between about 200 and about 350 microns. Another way of expressing the coating is to express the amount of coating in terms of weight gain or coating solids relative to the initial tablet weight. In one embodiment of the invention, the weight gain of the coating solids is from 5% to 50% of the initial tablet weight, in another embodiment the weight gain of the coating solids is from 5% to 15%, in another embodiment it is from 15% to 30%, in another embodiment it is from 30% to 50%

B. Enteric coated beads or granules

Another oral dosage form suitable for use in the present invention consists of a gelatin or starch capsule containing enteric coated beads or granules of the active ingredient. Gelatin and starch capsules may themselves be enteric coated, if desired. The use of capsules containing enteric-coated beads is generally not preferred from the standpoint of manufacturing expense and difficulty. However, some active ingredients that must be administered in higher doses are sometimes difficult to compress into tablets. In addition, when ingested with food, the tablet often remains in the stomach until digestion of the food causes the opening of the pyloric sphincter and advances the tablet into the duodenum. When uncoated gelatin or starch capsules are used, the gelatin or starch will rupture in the stomach, releasing the enteric coated beads. The ability of the beads to pass through the pylorus independent of the presence of food reduces the risk of significant amounts of the active ingredient remaining in direct contact with epithelial and mucosal tissues for any period of time. As used herein, "beads" refers to particles containing an active ingredient prepared by administering a bisphosphonate active ingredient and a chelating agent onto inert matrix spheres or beads, preferably using a polymer film.

Thus, the matrix beads are used as an inert matrix to which the bisphosphonate and chelating agent are applied. The beads may be made of one or a mixture of materials selected from, but not limited to, sucrose, mannitol, lactose, dextrose, sorbitol, cellulose, and starch (preferably sucrose and starch). In one embodiment of the invention, the inert matrix beads have a size in the range of 0.25mm to 7.00mm, preferably in the range of 1.00mm to 4.00 mm. In addition, suitable inert matrix beads may be purchased as preforms, such as blank PG beads manufactured by Penwest (Patterson, N.Y.).

The bisphosphonate active ingredient and the chelating agent are immobilized onto an inert matrix bead. In one embodiment, the active ingredient and the chelating agent are immobilized using a polymer film. Furthermore, if the active ingredient selected is soluble, the polymer film will serve to keep the active substance from gaining moisture. The polymer film may provide some stability if the active ingredient selected is not stable in any way. The polymer film preferably comprises a mixture of hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, and/or hydroxypropyl cellulose; and suitable plasticizers. Suitable plasticizers for use in the film include, but are not limited to: polyethylene glycol, propylene glycol, triacetin, acetylated monoglycerides, phthalates, castor oil, dibutyl sebacate, triethyl citrate, and selected mixtures thereof. In one embodiment, the plasticizer comprises from 5% to 40% of the polymer film, preferably from 10% to 25% of the polymer film.

The polymer film may also contain optional fillers, pigments and dyes as described above.

The polymer or polymer mixture can include any combination that provides protection against moisture pickup and/or oxygen transfer, and it is designed to release the active ingredient immediately via intestinal fluid. The amount of bisphosphonate applied to the inert matrix beads may vary depending on the desired concentration in the finished product. However, the weight gain of the film applied to the base beads is between about 5% to 50%, preferably between 5% to 25%. The term "weight gain" as used herein refers to the weight gain expressed as a percentage of the amount of applied solids to the substrate.

After the inert matrix beads are coated with the active ingredient and the chelating agent, they must be enteric coated. The enteric coating is applied using a variety of spray techniques known to those skilled in the art. The coating is applied to the active ingredient beads at a thickness of about 20 to 350 microns, and in another embodiment about 30 to 100 microns. The amount of coating can be expressed as a weight gain of about 10% to 75%, in other embodiments about 20% to 50% compared to the initial weight of the beads.

It may be desirable to use particles coated with the bisphosphonate active ingredient and the chelating agent instead of spraying the inert matrix beads with the bisphosphonate and chelating agent. As used herein, "granulate" refers to a combination of granules of the active ingredient and the chelating agent with suitable pharmaceutically acceptable excipients as described above. Although encapsulation of the enteric coated particles with starch or gelatin capsules is preferred. For administration in oral dosage forms, the granules may also be compressed into tablets.

Granules can be obtained by extrusion of a moist, mouldable material, followed by micropelletization and drying. Particles having a regular shape are preferred, for example, rod-shaped, cylindrical or spherical particles. In one embodiment, the granules are spherical pellet-type granules having a diameter of between about 0.3 to about 1.5mm, preferably between about 0.5 to about 1.25 mm.

Pharmaceutically acceptable excipients suitable for use in the manufacture of the granules for use in the novel dosage forms described herein include, but are not limited to, lactose, mannitol, cellulose, sucrose and starch.

The prepared granules of active ingredient and chelating agent are then coated with an enteric coating substance prepared from pharmaceutically acceptable excipients using a variety of coating techniques known to those skilled in the art. The coating is applied to the granules to a thickness of about 20 to 350 microns, preferably about 30 to 100 microns. The amount of coating can be expressed as a weight gain of about 10% to 75%, preferably about 20% to 50%, compared to the initial weight of the beads.

Bacterial enzyme-triggered system

In one embodiment of the invention, delivery of the bisphosphonate and chelating agent to the lower gastrointestinal tract is achieved by using a bacterial enzyme-triggered system. Oral dosage forms from which the release of the drug is triggered by the action of bacterial enzymes in the colon are known in the art. Various methods suitable for the bacteria-triggered delivery systems of the present invention include disulfide polymers, glycoside prodrugs, and polysaccharides as matrix/coating agents. See "Drug dev. and indes. pharm." 23(9) "by Watts, Peter J. & Illum, Lisbeth: 893 to page 917 (1997).

Methods suitable for bacterial-triggered delivery systems are disclosed in Katsuma et al, "j.of pharm.sci." 93 (5): 1287 to 99 (2004). In one embodiment of the invention, the colon targeted delivery system CODES^TM(Yamanouchi Pharma technologies, Norman, OK) was used to deliver bisphosphonates and chelating agents to the colon. The system comprises a tablet core containing a bisphosphonate, a chelating agent and a sugar, which tablet core is coated with an acid-soluble substance, for exampleThen applied with an enteric coating, e.g.Enteric coatings protect the dosage form from degradation in the stomach and dissolve in the small intestine immediately after gastric emptying. The acid-soluble coating protects the dosage form from degradation as it passes through the small intestine. When the dosage form reaches the large intestine, the local microflora ferments the sugars in the tablet core to short chain fatty acids, which then dissolve the acid-soluble coating to release the core contents into the colon.

Suitable enteric coating materials include EudragitEudragit L 30EudragitCellulose acetate phthalate, shellac, or any enteric coating substance that dissolves above ph 5.5. The enteric coating is applied using a variety of spray techniques known to those skilled in the art. The enteric coating may also comprise one or more pharmaceutically acceptable excipients including, but not limited to: talc, triethyl citrate, polyethylene glycol, Tween(polyoxyethylene sorbitan monooleate, available from sigma chemical co., st. The enteric coating is applied to the tablet core coated with an acid dissolvable substance to provide a weight gain of 2.5% to 40%.

Suitable acid-soluble coating materials include those that dissolve at a pH below 6.0, including but not limited to EudragitPolyvinyl acetoacetamide and chitosan. The acid is solubleThe uncoated may also comprise one or more pharmaceutically acceptable excipients. Such excipients include, but are not limited to: hydroxypropyl methylcellulose, EudragitEthyl cellulose, hydroxypropyl cellulose, polyethylene oxide, polyvinylpyrrolidone, triacetin, polyethylene glycol 400, triethyl citrate, and tweenAnd castor oil. The acid soluble coating is applied using a variety of spray techniques known to those skilled in the art. The weight gain of the coating applied to the tablet core is from 2.5% to 40%.

The tablet core comprises one or more saccharides in an amount of from 10% to 99.9% by weight of the tablet. The action of intestinal bacteria in the lower gastrointestinal tract causes the degradation of carbohydrates to short chain fatty acids, which then dissolve the acid-soluble coating. Suitable sugars include, but are not limited to, lactulose, raffinose, cellobiose, stachyose, fructooligosaccharides, sucrose, glucose, xylose, fructose, maltose, cellulosic galactose, and combinations thereof.

The tablet core comprises a bisphosphonate active ingredient, a chelating agent, and may comprise one or more pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to: crystalline cellulose, dibasic calcium phosphate, polyvinylpyrrolidone, magnesium stearate, sucrose, starch, magnesium oxide, and sodium lauryl sulfate.

Time-dependent delivery system

In another embodiment of the invention, delivery of the bisphosphonate and chelating agent to the lower gastrointestinal tract is achieved by using a time-dependent delivery system. Assuming that the delivery time following gastric emptying is fixed, the drug and/or the chelating agent can be targeted to be released into various parts of the lower gastrointestinal tract. For example, for targeted delivery of bisphosphonate actives and chelating agents to the colon, delivery is madeShould be delayed until 3 to 4 hours after leaving the stomach. See Watts, Peter J.&"Drug Dev.and Ind.pharm." 23(9) "by Illum, Lisbeth: 893-917(1997). Methods suitable for use with the time-dependent delivery systems of the present invention include, but are not limited to, for example, pulsencap^TM(Scherer DDS, Strathclyde, UK), TimeClock^TM(Zambon Group, Milan, Italy), and SyncroDose^TM(Penwest, Patterson, NY), and various coatings that degrade over time to release tablet contents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, or any suitable hydrogel.

In one embodiment of the invention, the pulsencap is designed time-dependently^TMAre used for targeted delivery of active ingredients and chelating agents into the lower gastrointestinal tract. The active ingredient and other excipients, including chelating agents, are contained in the Pulsincap by a hydrogel plug covered by a water-soluble cap^TMWater insoluble capsules. The entire dosage form is optionally coated with an enteric coating material to protect the dosage form from degradation during transit through the upper gastrointestinal tract. When the patient swallows the Pulsincap^TMIn the dosage form, the water soluble cap dissolves and exposes the hydrogel plug to stomach and/or intestinal fluids. The hydrogel cover then expands, eventually bursting to expose the capsule body, thereby releasing the capsule contents. By varying the properties of the hydrogel plug, the capsule contents can be targeted for release into specific regions of the lower gastrointestinal tract. See Watts, Peter J.&"Drug Dev.and Ind.pharm." 23(9) "by Illum, Lisbeth: 893-917(1997).

In one embodiment of the invention, a time-dependent coating is applied over the compressed tablets, followed by an enteric coating, over the time-dependent coating. This is used to target the delivery of the active ingredient and the chelating agent to the lower gastrointestinal tract. The active ingredient and other excipients, including chelating agents, are contained in the core. The entire dosage form is coated with a time-dependent coating and then with an enteric coating. Enteric coating materials are used to protect the dosage form from degradation during transit through the upper gastrointestinal tract. When the patient swallows the dosage form, the enteric coating dissolves after the dosage form leaves the stomach, and the core then begins to expand. Finally, the time-dependent coating ruptures within a predetermined time and in the lower gastrointestinal fluid and releases the core contents into the lower gastrointestinal tract. By varying the core, the time-dependent coating and/or the enteric coating, the tablet contents can be targeted for release into specific regions of the lower gastrointestinal tract.

Pharmaceutically acceptable excipients

Pharmaceutically acceptable excipients include, but are not limited to: polymers, resins, plasticizers, fillers, lubricants, diluents, binders, disintegrants, solvents, co-solvents, surfactants, buffer systems, preservatives, sweeteners, flavoring agents, pharmaceutical grade dyes or pigments, chelating agents, viscosity agents, and combinations thereof. Pharmaceutically acceptable excipients can be used in any of the components used in the manufacture of oral dosage forms, i.e., the core or the coating.

Those flavors, dyes and pigments useful in the present invention include, but are not limited to, those described in the Pharmaceutical excipients handbook (4 th edition, Pharmaceutical Press 2003).

Suitable co-solvents include, but are not limited to, ethanol, isopropanol, and acetone.

Suitable surfactants include, but are not limited to: polyoxyethylene sorbitan fatty acid ester, polyoxyethylene monoalkyl ether, sucrose monoester, simethicone emulsion, sodium lauryl sulfate, tweenAnd esters and ethers of lanolin.

Suitable preservatives include, but are not limited to: phenol, alkyl parabens, benzoic acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, alkylbenzyldimethylammonium chloride, cetylpyridinium chloride, methyl paraben and propyl paraben.

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

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

Suitable polymers include, but are not limited to: ethyl cellulose, 1, 2, 4-trimellitic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate andL 30-D、L 100-55、F530D andS 100pharma GmbH and co.kg, Darmstadt, germany), andand(Colorcon，Inc.，West Point，Pa.)。

suitable lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc.

Application method

The present invention also relates to methods of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism, comprising administering to a human or other mammal in need thereof a safe and effective amount of a pharmaceutical composition delivered to the human or other mammal via an oral dosage form as described herein.

Diseases characterized by abnormal calcium and phosphate metabolism include, but are not limited to: osteoporosis, paget's disease (osteitis deformans), hyperparathyroidism, hypercalcemia of malignancy, osteolytic bone metastases, progressive myositis ossificans, systemic calcinosis, and conditions such as arthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions that favor the involved tissue for calcium phosphate deposition.

The oral dosage forms of the invention are suitable for administration at successive dosing intervals, which are once daily, once weekly, three times monthly, twice monthly and once monthly.

Sleeve box

The invention also includes kits that are particularly useful for administering the oral dosage forms described herein according to a continuous dosing schedule that is once daily, once weekly, three times monthly, twice monthly, or monthly. These kits comprise one or more oral dosage forms comprising a bisphosphonate, a chelating agent, and methods for facilitating compliance with the methods of the invention. The above kit provides a convenient and effective method for ensuring that the subject being treated takes the appropriate oral dosage form in the correct dosage and in the correct manner. The compliance means of the kit described above includes any means for facilitating the administration of the active agent in accordance with the methods of the present invention. Such compliance means include instructions for use, packaging and dispensing assemblies, and combinations thereof. The kit may also contain components for aiding memory including, but not limited to, a list of days of the week, numbers, instruction charts, arrows, braille, stickers, reminder cards, or other components specifically selected by the patient. Examples of packaging and dispensing assemblies are well known in the art and include those described in U.S. patent 4,761,406 to Flora et al, published 2/8 1988 and U.S. patent 4,812,311 to Uchtman, published 14/3 1989.

Optionally, the kit can comprise at least one oral dosage form comprising a bisphosphonate and a chelating agent, with at least one oral dosage form comprising a concomitant nutritional substance. Preferred nutrients are calcium and/or vitamin D. Oral dosage forms of calcium suitable for use in the present invention include capsules, compressed tablets, chewable tablets, and the like. Typical forms of calcium salts suitable for use in the present invention include, but are not limited to, calcium carbonate, calcium citrate, calcium malate, calcium citrate malate, calcium glubionate, calcium glucoheptonate, calcium gluconate, calcium lactate, calcium hydrogen phosphate and calcium phosphate. In one embodiment, the kit of the present invention may comprise a tablet containing from 400mg to 1500mg calcium.

The term "vitamin D" as used herein refers to any form of vitamin D that can be administered to a mammal as a nutrient. Vitamin D is metabolized in the body to provide what is often referred to as an "activated" form of vitamin D. The term "vitamin D" may include both activated and unactivated forms of vitamin D, as well as precursors and metabolites of these forms. These precursors in activated form include vitamin D2 (calciferol, produced in plants) and vitamin D3 (cholecalciferol, produced in skin, present in animal sources and used to fortify food). Vitamins D2 and D3 have similar biological efficacy in humans. Non-activated metabolites of vitamins D2 and D3 include hydroxylated forms of vitamins D2 and D3. Because activated vitamin D analogs are toxic to mammals, they cannot be administered in large doses over intermittent periods of time. However, non-activated vitamin D2, vitamin D3, and their metabolites, can be administered on an intermittent basis at higher doses than the "activated" form of vitamin D and are not toxic. In one embodiment, a kit of the invention may comprise a tablet containing 100IU to 10,000IU of vitamin D.

In another embodiment, the kit of the present invention may comprise one or more tablets of nutrients comprising calcium and vitamin D. In another embodiment, a unit dose of a nutritional substance comprises about 600mg calcium and about 400IU vitamin D.

The following non-limiting examples illustrate the formulations, methods and uses of the present invention.

Examples

Example I

Enteric coated tablet containing risedronate and ethylenediamine tetraacetic acid

Enteric coated tablets comprising risedronate and ethylenediaminetetraacetic acid are prepared by preparing a coating composition and tableting comprising risedronate and ethylenediaminetetraacetic acid, and then applying the coating composition to the tablets.

An enteric coating composition in the form of a paint was prepared, each tablet containing the following excipients:

A. enteric coating suspension

The enteric coating was prepared by the following method:

the pigment suspension was prepared by adding polysorbate 80, ground iron oxide and talc to about two-thirds of purified water while stirring. The suspension was stirred for at least two hours. 30% of simethicone emulsion and the remaining water were added to the pigment suspension and stirred for at least 45 minutes. The Eudragit L30D-55 solution and triethyl citrate were mixed and stirred for at least 45 minutes. The pigment suspension is then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process. The cores were transferred to a coating pan and pre-heated while shaking irregularly. Tablets are coated using a typical pan coating process until the desired amount of coating solution is applied. The tablets are then allowed to cool and collected in a suitable container.

A coating weight gain of 30% (total solids) was obtained by spray coating the above composition onto tablets containing risedronate and ethylenediaminetetraacetic acid, which tablets were prepared in part B below.

B. Compressed tablets comprising risedronate and ethylenediaminetetraacetic acid

The enteric-coating suspension prepared in part a above was spray coated onto 35mg risedronate tablets, each tablet weighing 240mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

the risedronate sodium, edetate disodium, sodium starch glycolate, and microcrystalline cellulose were passed through a grinder and added to a blender equipped with a reinforcing bar. With the intensifier bar open, the mixture was stirred for about ten minutes. The stearic acid and magnesium stearate were screened and added to the blender. The blend was stirred for about 3 minutes with the intensifier bar closed. The blend is compressed into tablets using a suitable tablet press.

Example II

Enteric coated tablet comprising risedronate and ethylenediaminetetraacetic acid

Enteric coated tablets containing risedronate sodium were prepared according to the following procedure using a procedure similar to that described in example I.

Coating compositions were prepared in the form of paints, each tablet containing the following excipients:

the components:

Acryl-EZE (manufactured by Colorcon, Inc., West Point, Pa.) dry solid 200mg

Purified water 950mg

Tablets containing 150mg risedronate and 75mg ethylenediaminetetraacetic acid were given a coating weight gain of 40% by conventional pan-coating methods, resulting in a final oval tablet weight of 500 mg. The composition of each tablet was as follows:

this amount was calculated based on anhydrous risedronate monosodium salt.

Example III

A. enteric coating suspension

The enteric coating was prepared by the following method:

A 10% (total solids) coating weight gain was obtained by spray coating the above composition onto a compressed tablet containing risedronate and ethylenediaminetetraacetic acid, prepared in part B below.

The enteric-coating suspension prepared in part a above was spray coated onto 35mg risedronate tablets, each tablet weighing 230mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

the risedronate sodium, edetate disodium, hypromellose, and microcrystalline cellulose are passed through a grinder and added to a blender equipped with a reinforcing bar. With the intensifier bar open, the mixture was stirred for about twenty minutes. About 50% of the magnesium stearate is sieved and added to the blender. The blend was stirred for about 3 minutes with the reinforcing bar closed, then rolled and ground. The remaining magnesium stearate was sieved and added to the blend along with the granules. The blend was stirred for about 3 minutes with the intensifier bar closed. The blend is compressed into tablets using a suitable tablet press.

Example IV

A. enteric coating suspension

The enteric coating was prepared by the following method:

talc and black iron oxide were added to a portion of the purified water and stirred until homogeneous. Stirring was continued and triethyl citrate was added. The resulting pigment suspension is then passed through a screen or suitable grinder to break up agglomerates. Screening Eudragit L30Then added to a suitable vessel and diluted with a portion of purified water. The pigment suspension was then added to the diluted Eudragit suspension and stirred until homogeneous.

In a suitable coating pan, a compressed tablet (10kg) containing risedronate and ethylenediaminetetraacetic acid, as described below, is heated to about 30 ℃ to 35 ℃. The enteric coating suspension was sprayed onto the tablets at a rate of about 30 grams per minute. When the spraying process is complete, the temperature is lowered, the tablet is removed and dried at 30 to 35 ℃ for about 1 hour.

A 35% (total solids) coating weight gain was obtained by spray coating the above composition onto a compressed tablet containing risedronate and ethylenediaminetetraacetic acid, prepared in part B below.

The enteric coating suspension prepared in part a above was sprayed onto 5mg risedronate tablets, each tablet weighing 240mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

tablets were prepared by sieving risedronate active ingredient and ethylenediaminetetraacetic acid together with 1/2 microcrystalline cellulose in a double drum mixer. The blend will then be stirred until homogeneous. Then 1/2 of stearic acid was added and the blend was further stirred. The blend was then roller rolled and ground. The remaining microcrystalline cellulose and sodium starch glycolate were added and stirred until uniform. Then, the remaining stearic acid is added and stirred until a sufficient degree of lubrication is obtained. The tablets were then compressed on a rotary tablet press.

Example V

Capsules comprising enteric coated particles

Capsules containing enteric coated particles are prepared by preparing particles of risedronate sodium active ingredient and ethylenediaminetetraacetic acid, which are then encapsulated in gelatin capsules. The particles had the following composition:

this amount was calculated based on anhydrous risedronate monosodium salt.

The mixture of risedronate sodium, ethylenediamine tetraacetic acid, lactose and microcrystalline cellulose was soaked with water and shaped, extruded and pelleted. The dried granules were then coated with an enteric coating material prepared as described in example 13.

The enteric coating had the following composition:

in the coating column, granules having the above composition were coated with the coating mixture having the above composition.

Enteric coatings were prepared using the method described in example 13. The granules were heated to about 25 ℃ in a suitable coating column and the enteric coating solution was applied to the granules by spraying a 20% weight gain coating onto the granules. When the spraying process was complete, the ventilation was turned off and the particles were allowed to cool to room temperature.

The coated granules were powdered together with talc and the powder was encapsulated in capsules using a commercial capsule filling machine (capsule size 0).

Example VI

Bacterial enzyme-triggered tablet comprising risedronate and sodium hexametaphosphate

Bacterial enzyme-triggered tablets comprising risedronate and sodium hexametaphosphate were prepared by preparing a two-layer coating composition and a compressed tablet comprising risedronate and sodium hexametaphosphate, and then applying the coating composition to the compressed tablet.

A first layer (acid soluble coating layer) of coating composition in the form of a paint was prepared, each tablet containing the following excipients:

A. acid soluble coating

The acid soluble coating was prepared by the following method:

the talc suspension was prepared by adding talc to about one third of purified water while stirring. The suspension was stirred for at least two hours. Eudragit E100B and hydroxypropyl methylcellulose were added to the remaining water and ethanol mixture and stirred until dissolved. The talc suspension was then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process.

B. Enteric coating suspension (second layer)

The enteric coating was prepared by the following method:

the pigment suspension was prepared by adding ground iron oxide and talc to about two thirds of purified water while stirring. The suspension was stirred for at least two hours. The Eudragit L30D-55 solution and triethyl citrate were mixed and stirred for at least 45 minutes. The pigment suspension is then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process.

The tablets, as described below, were transferred to a coating pan and pre-heated while shaking on an occasional basis. Using a typical pan coating process, the compressed tablets are coated with an acid soluble coating followed by an enteric coating suspension until the desired amount of coating solution has been applied. The tablets are then allowed to cool and collected in a suitable container.

By spraying the above compositions (a and B) onto tablets containing risedronate and sodium hexametaphosphate prepared in section C below, an acid soluble coating can achieve a coating weight gain of 12% and an enteric coating can achieve a coating weight gain (total solid matter compared to tablet core weight) of 13%.

C. Compressed tablets comprising risedronate and sodium hexametaphosphate

The acid soluble coating and enteric coating suspensions prepared in parts a and B above were spray coated onto 35mg risedronate tablets, each tablet weighing 500mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

the risedronate sodium, sodium hexametaphosphate, lactulose, and stearic acid were passed through a grinder and added to a blender equipped with an intensifier bar. The blend was stirred with the reinforcing bar open for about ten minutes and purified water was added to granulate for 15 minutes. The mixture was dried at 30 ℃ overnight and passed through a grinder. Magnesium stearate was sieved and added to the blender. The blend was stirred for about 3 minutes. The blend is compressed into tablets using a suitable tablet press.

Example VII

Time-dependent enteric coated tablet comprising risedronate and sodium citrate

A time-dependent enteric coated tablet comprising risedronate and sodium citrate is prepared by preparing a two-layer coating composition and a compressed tablet comprising risedronate and sodium citrate, and then applying the coating composition to the compressed tablet.

A first (time-dependent coating) coating composition in the form of a polymer was prepared, each tablet containing the following excipients:

A. acid soluble coating

The acid soluble coating was prepared by the following method:

while stirring, the mixture was purified by adding ethyl cellulose to about two thirds of toluene: ethanol mixture to prepare a solution. The solution was stirred for at least two hours. Dibutyl sebacate was added and stirred for an additional two hours. The resulting coating solution was sieved and mixed during the coating process.

B. Enteric coating suspension

The enteric coating was prepared by the following method:

The tablets were transferred to a coating pan and pre-heated while shaking irregularly. The tablets were coated with a time-dependent coating followed by an enteric coating suspension using a typical pan coating process until the desired amount of coating solution had been applied. The tablets are then allowed to cool and collected in a suitable container.

By spraying the above compositions (a and B) onto the tablets comprising risedronate and sodium citrate prepared in section C below, a time-dependent coating can achieve a 10% coating weight gain and an enteric coating can achieve a 13% coating weight gain (total solid matter compared to tablet core weight).

C. Compressed tablets comprising risedronate and sodium citrate

The acid soluble coating and enteric coating suspensions prepared in parts a and B above were spray coated onto 5mg risedronate tablets, each weighing 500mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

the risedronate sodium, sodium citrate, microcrystalline cellulose, croscarmellose sodium, mannitol, and polyvinylpyrrolidone were passed through a grinder and added to a blender equipped with a reinforcing rod. The blend was stirred with the reinforcing bar open for about ten minutes and purified water was added and granulated for 15 minutes. The mixture was dried at 30 ℃ overnight and passed through a grinder. Magnesium stearate was sieved and added to the blender. The blend was stirred for about 3 minutes with the intensifier bar closed. The blend is compressed into tablets using a suitable tablet press.

Example VIII

Time-dependent delivery tablet comprising risedronate and ethylenediaminetetraacetic acid

A time-dependent delivery tablet comprising risedronate and ethylenediaminetetraacetic acid is prepared by preparing a coating composition and compressing a tablet comprising risedronate and ethylenediaminetetraacetic acid, and then applying the coating composition to the tablet.

A coating composition was prepared, each tablet containing the following excipients:

A. coating suspension

The coating was prepared by the following method:

the carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulose were added to purified water at 60 ℃ and stirred for 3 hours. The resulting coating mixture was sieved and mixed during the coating process. The cores were transferred to a coating pan and pre-heated while shaking irregularly. Tablets are coated using a typical pan coating process until the desired amount of coating solution has been applied (60 ℃). The tablets are then allowed to cool and collected in a suitable container.

A coating weight gain of 30% (total solids) was obtained by spray coating the above composition onto a compressed tablet comprising risedronate and ethylenediaminetetraacetic acid, prepared in part B below.

The coating suspension prepared in part a above was sprayed onto 35mg risedronate tablets, each tablet weighing 500mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Tablets having the composition described above were prepared as follows:

the risedronate sodium, disodium edetate, microcrystalline cellulose, spray-dried lactose, and sodium starch glycolate were passed through a grinder and added to a blender equipped with a reinforcing bar. With the intensifier bar open, the mixture was stirred for about ten minutes. Magnesium stearate was sieved and added to the blender. The blend was stirred for about 3 minutes with the intensifier bar closed. The blend is compressed into tablets using a suitable tablet press.

Example IX

Bacterial enzyme-triggered tablet comprising alendronate and tartaric acid

A bacterial enzyme-triggered tablet comprising alendronate and tartaric acid was prepared by preparing a tablet blend and compressing into a tablet.

A. Compressed tablet comprising alendronate and tartaric acid

70mg of alendronate, each tablet weighing 680mg and each tablet comprising:

this amount was calculated based on the anhydrous alendronate trihydrate.

Tablets having the composition described above were prepared as follows:

the alendronate sodium, guar gum, hydroxypropyl methylcellulose, and tartaric acid were passed through a grinder and added to a blender equipped with an intensifier bar. With the intensifier bar open, the mixture was stirred for about ten minutes. The blend was compressed into tablets in a rotary tablet press. The pieces were passed through a grinder and collected. Stearic acid was added to the blender and stirred for about 3 minutes. The blend is compressed into tablets using a suitable tablet press.

The same coating procedure was used to apply the tableting coating using the layers described in example VI.

Example X

Enteric coated tablet comprising alendronate and ethylenediaminetetraacetic acid

Enteric coated tablets comprising alendronate and ethylenediaminetetraacetic acid are prepared by preparing a coating composition with compressed tablets comprising risedronate and ethylenediaminetetraacetic acid, and then applying the coating composition to the tablets.

A. enteric coating suspension

The enteric coating was prepared by the following method:

talc and red iron oxide were added to a portion of the purified water and stirred until homogeneous. Triethyl citrate and simethicone emulsion were added while stirring was continued. The resulting pigment suspension is then passed through a screen or suitable grinder to break up agglomerates. Screening EudragitThen added to a suitable container and diluted with a portion of purified water. The pigment suspension was then added to the diluted Eudragit suspension and stirred until homogeneous.

In a suitable coating pan, a compressed tablet (10kg) containing alendronate and ethylenediaminetetraacetic acid, as described below, is heated to about 30 ℃ to 35 ℃. The enteric coating suspension was sprayed onto the tablets at a rate of about 30 grams per minute. When the spraying process is complete, the temperature is lowered, the tablet is removed and dried at 30 to 35 ℃ for about 1 hour.

A coating weight gain of 19% (total solids) was obtained by spray coating the above composition onto a compressed tablet containing alendronate and ethylenediaminetetraacetic acid, which was prepared in part B below.

B. Compressed tablet comprising alendronate and ethylenediaminetetraacetic acid

The enteric-coating suspension prepared in section a above was sprayed onto 70mg alendronate tablets, each tablet weighing 300mg and containing:

this amount was calculated based on alendronic acid.

Tablets having the composition described above were prepared as follows:

tablets were prepared by sieving alendronate active ingredient and ethylenediaminetetraacetic acid with 1/2 microcrystalline cellulose in a double drum blender. The blend was then stirred until homogeneous. Thereafter, 1/2 magnesium stearate was added and the blend was further stirred. The blend was then roller rolled and ground. The remaining microcrystalline cellulose and polyvinylpyrrolidone were added and stirred until homogeneous. The remaining magnesium stearate is then added and stirred until sufficient lubricity is obtained. The tablets were then compressed on a rotary tablet press.

Example XI

Enteric coated tablet comprising ibandronic acid and citric acid

Enteric coated tablets comprising ibandronic acid and citric acid are prepared by preparing a coating composition with compressed tablets comprising ibandronic acid and citric acid and then applying the coating composition to the tablets.

A. enteric coating suspension

The enteric coating was prepared by the following method:

talc and titanium dioxide were added to a portion of the purified water and stirred until homogeneous. Triethyl citrate and simethicone emulsion were added while stirring was continued. The resulting pigment suspension is then passed through a screen or suitable grinder to break up agglomerates. Screening Eudragit LThen added to a suitable container and diluted with a portion of purified water. Then will beThe pigment suspension was added to the diluted Eudragit suspension and stirred until homogeneous.

In a suitable coating pan, a compressed tablet (10kg) containing ibandronic acid and citric acid as described below was heated to about 30 ℃ to 35 ℃. The enteric coating suspension was sprayed onto the tablets at a rate of about 30 grams per minute. When the spraying process is complete, the temperature is lowered, the tablet is removed and dried at 30 to 35 ℃ for about 1 hour.

A 17% (total solids) coating weight gain was obtained by spraying the above composition onto a compressed tablet comprising ibandronic acid and citric acid, prepared in part B below.

B. Compressed tablets comprising ibandronic acid and citric acid

The enteric-coated suspension prepared in section a above was sprayed onto 100mg ibandronic acid tablets, each tablet weighing 600mg and containing:

this amount was calculated based on ibandronic acid.

Tablets having the composition described above were prepared as follows:

tablets were prepared by sieving ibandronic acid active ingredient and citric acid with 1/2 microcrystalline cellulose in a double drum blender. The blend was then stirred until homogeneous. Thereafter, 1/2 magnesium stearate was added and the blend was further stirred. The blend was then roller rolled and ground. The remaining microcrystalline cellulose and polyvinylpyrrolidone were added and stirred until homogeneous. The remaining magnesium stearate is then added and stirred until sufficient lubricity is obtained. The tablets were then compressed on a rotary tablet press.

Example XII

A. enteric coating suspension

The enteric coating was prepared by the following method:

purified water, about 80% isopropanol, and eudragit s100 were mixed while stirring to form a solution. After stirring for at least 60 minutes, acetone, dibutyl phthalate and the remaining isopropanol were added while stirring. Stirring was continued during the rest of the preparation. Iron oxide and talc were added to the solution and the resulting suspension was then stirred for at least one hour. The coating solution was stirred for at least one hour prior to preparation. The cores were transferred to a coating pan and pre-heated while shaking irregularly. Tablets are coated using a typical pan coating process until the desired amount of coating solution is applied. The tablets are then allowed to cool and collected in a suitable container.

A coating weight gain of 8.5% (total solids) was obtained by spray coating the above composition onto a compressed tablet comprising risedronate and ethylenediaminetetraacetic acid, prepared in part B below.

The enteric-coating suspension prepared in section A above was spray coated onto 35mg risedronate tablets, prepared according to example IB, weighing 240mg per tablet.

Example XIII

Capsules comprising enteric coated beads

Capsules containing enteric-coated beads were prepared by preparing enteric-coated beads and then encapsulating them with gelatin capsules. The beads consist of inert sugar spheres coated with a polymer film containing risedronate and ethylenediaminetetraacetic acid, and then prepared as described in section a below. Enteric coated beads were then prepared using the method described in section B below.

A. Risedronate and ethylenediaminetetraacetic acid coated beads

Components	mg/capsule
		Risedronate sodium	30％
Ethylenediaminetetraacetic acid disodium salt	100
		Sugar ball, 20 to 25 mesh	115.6
Hydroxypropyl methylcellulose	25
		Polyethylene glycol 3350	2.5
Purified water	700

This amount was calculated based on anhydrous risedronate monosodium salt.

Risedronate and ethylenediaminetetraacetic acid coated beads were prepared as follows:

purified water was heated and hydroxypropyl methylcellulose was added slowly. When the hydroxypropylmethylcellulose was dispersed, polyethylene glycol was added, and the solution was cooled to 30 ℃ or less. The risedronate and ethylenediaminetetraacetic acid are then passed through a mill, if necessary, to break up any agglomerates, and then mixed with the polymer solution until homogeneous.

The sugar spheres were heated to about 35 c in a suitable coating column and the risedronate and ethylenediaminetetraacetic acid coating suspension prepared above was sprayed thereon to obtain a coating weight gain of 136% relative to the beads. When the spray process was complete, the vent was turned off and the beads were allowed to cool to room temperature.

B. Enteric coated beads

Talc and yellow iron oxide were added to a portion of the purified water and stirred until homogeneous. Triethyl citrate and simethicone emulsion were added with constant stirring. The resulting pigment suspension is then passed through a screen or suitable grinder to break up agglomerates. Screening Eudragit LThen added to a suitable container and diluted with a portion of purified water. Then will beThe pigment suspension was added to the diluted Eudragit suspension with constant stirring.

In a suitable coating column, risedronate and ethylenediaminetetraacetic acid-coated beads are heated to a suitable temperature. The enteric coating suspension having the composition as described in part B was sprayed onto the beads. When the spraying process is completed, the ventilation is turned off. The coated beads were stored at 25 ℃ to 30 ℃ for at least 12 hours prior to encapsulation. The beads are encapsulated using a suitable capsule filling machine using hard shell gelatin capsules.

Example XIV

A. enteric coating suspension

The enteric coating was prepared by the following method:

the pigment suspension was prepared by adding polysorbate 80, ground iron oxide and talc to about two-thirds of purified water while stirring. The suspension was stirred for at least two hours. 30% of simethicone emulsion and the remaining water were added to the pigment suspension and stirred for at least 45 minutes. Hybrid Eudragit L30Solution and citric acid triethyl saltEster and stirred for at least 45 minutes. The pigment suspension is then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process. The cores were transferred to a coating pan and pre-heated while shaking irregularly. Tablets are coated using a typical pan coating process until the desired amount of coating solution is applied. The tablets are then allowed to cool and collected in a suitable container.

The enteric-coating suspension prepared in part a above was spray coated onto a 35mg risedronate tablet, 240mg tablet weight prepared as described in example I B.

Example XV

Enteric coated soft gelatin capsule comprising risedronate and disodium edetate

Enteric coated capsules comprising risedronate and ethylenediaminetetraacetic acid are prepared by preparing a coating composition comprising risedronate and ethylenediaminetetraacetic acid and a soft gelatin capsule, and then applying the coating composition to the soft gelatin capsule.

A. enteric coating suspension

The enteric coating was prepared by the following method:

the pigment suspension was prepared by adding polysorbate 80, ground iron oxide and talc to about two-thirds of purified water while stirring. The suspension was stirred for at least two hours. 30% of simethicone emulsion and the remaining water were added to the pigment suspension and stirred for at least 45 minutes. The Eudragit L30D-55 solution and dibutyl phthalate were mixed and stirred for at least 45 minutes. The pigment suspension is then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process. The soft gelatin capsules were transferred to a coating pan and pre-heated while shaking irregularly. Typical pan coating methods are used to coat the soft gelatin capsules until the desired amount of coating solution has been applied. The capsules are then allowed to cool and collected in a suitable container.

A 13% (total solids) coating weight gain was obtained by spraying the above composition onto soft gelatin capsules containing risedronate and ethylenediaminetetraacetic acid, prepared in part B below.

B. Soft gelatin capsule comprising risedronate and ethylenediaminetetraacetic acid

The enteric coating suspension prepared in part a above was sprayed onto 50mg risedronate soft gelatin capsules each weighing 764mg and containing:

this amount was calculated based on anhydrous risedronate monosodium salt.

Soft gelatin capsules having the above composition were prepared as follows:

oleoyl polyglycol-6 glyceride was added to a suspension tank equipped with an overhead stirrer. Risedronate sodium, disodium edetate, colloidal silica were passed through a mill and added to oleoyl macrogol-6 glyceride with constant stirring. The mixture was stirred for about 60 minutes. The blend is then bubbled and ready to fill into capsules. While stirring, glycerol, sorbitol specified and purified water were mixed in a heated vacuum vessel. Heat until the temperature reaches at least 80 ℃, then add gelatin and stir for 75 minutes. The gel mass was examined to completely dissolve the particles. Heating and stirring were continued, if necessary, until no undissolved particles were observed. The gel mass was bubbled through and then titanium dioxide, FD & C red No. 40, and FD & C blue No. 1 were added with constant stirring. The gel mass is discharged to a heated gel storage tank for subsequent processing. The capsules are then filled with the fill material on a soft gelatin capsule filling machine.

Example XVI

Enteric coated tablet for releasing citric acid in the jejunum and risedronate in the ascending colon

Enteric coated layered tablets containing risedronate sodium in one layer and citric acid in the other layer were designed to release citric acid in the jejunum and risedronate in the ascending colon. The tablets were prepared as follows:

this amount was calculated based on anhydrous risedronate monosodium salt.

The mixture of risedronate sodium, hydroxypropyl methylcellulose, starch 1500, and microcrystalline cellulose was wetted with purified water in a high shear mixer and granulated. The particles were then sieved and dried at 30 ℃ for 12 hours. Stearic acid is then added and stirred in a low shear mixer until homogeneous, discharging the particles into a fiber drum.

The mixture of citric acid, lactose, polyvinylpyrrolidone and microcrystalline cellulose was wetted with purified water in a high shear mixer and granulated. The particles were then sieved and dried at 30 ℃ for 12 hours. Stearic acid is then added and stirred in a low shear mixer until homogeneous, discharging the particles into a fiber drum. Tablets of 620mg weight were compressed on a tablet press.

Triethyl citrate was added to the purified water and isopropanol while continuing to stir. While stirring continuously, addingIn a suitable coating pan, a compressed layered tablet (10kg) containing risedronate in one layer and citric acid in the other layer is heated to about 30 ℃ to 35 ℃. The enteric coating suspension was sprayed onto the tablets at a rate of about 50 grams/minute. When the spraying process is complete, the temperature is lowered, the tablet is removed and dried at 30 to 35 ℃ for about 1 hour.

Example XVII

An enteric coated oral dosage form as described in example 1 was prescribed once a week to a 65kg woman diagnosed with postmenopausal osteoporosis, said prescription containing 35mg risedronate and 100mg disodium edetate. The patients took the oral dosage form once a week with breakfast. A biopsy of the iliac crest bone was taken two years later, showing an increase in mean wall thickness in the reconstructed cell compared to her baseline biopsy.

Example XVIII

A 70kg male patient diagnosed with prostate cancer and high bone conversion disease was prescribed an enteric coated oral dosage form as described in example 1, comprising 35mg risedronate and 150mg citric acid, and taken once a week. The oral dosage form is taken by the patient once a week and immediately before bedtime. The patient does not experience upper gastrointestinal irritation or discomfort.

Example XIX

A study of 8 treatment parallel groups of a single dose single center with randomized open labeling was conducted to compare the absorption of fasted oral immediate release risedronate sodium tablets delivered to different locations of the lower gastrointestinal tract with fed and fasted risedronate sodium plus edetic acid. The study consisted of a 72 hour period.

The following treatments were administered to treatment groups a to H:

for fasting administration, subjects fasted overnight and were given one dose in the morning. Subjects continued to fast until the drug was released to the indicated location.

To feed the dosing (treatment groups C, E and G), subjects ate a simple breakfast and the subjects took study medication about 3 hours later. After the study medication passed through the stomach, these subjects ate for breakfast immediately. Subjects continued to fast until 2 hours after the drug was released to the indicated location.

Ratio of fed to fasting urine recovery at different release sites

Releasing position	Ratio of fed/fasted urine recovery (% dose)
		Jejunum	0.959
Ileum	1.131
		Ascending colon	1.560

A ratio close to 1 indicates that the absorption is the same with or without food.

Example XX

Enteric coated tablets containing risedronate were prepared in a similar manner as described in example I. The coated formulation was prepared as follows.

A. Enteric coating suspension

The pigment suspension was prepared by adding polysorbate 80, ground iron oxide and talc to about two thirds of purified water while stirring. The suspension was stirred for at least two hours. 30% of simethicone emulsion and the remaining water were added to the pigment suspension and stirred for at least 45 minutes. The Eudragit FS30D solution and triethyl citrate were mixed and stirred for at least 45 minutes. The pigment suspension is then added to the Eudragit solution and stirred for 30 to 60 minutes. The resulting coating suspension was sieved and mixed during the coating process.

The risedronate tablets described in example I were transferred to a coating pan and preheated while shaking indefinitely. Using a typical pan process, the compressed tablets are coated with an enteric coating suspension until the desired coating has been applied.

All documents cited are, in relevant part, incorporated herein by reference and the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

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

Claims

1. An oral dosage form having effective absorption of a drug, the oral dosage form comprising:

(a) 1mg to 500mg, on an anhydrous weight basis, of an active ingredient selected from risedronic acid, salts and esters thereof;

(b)10mg to 500mg of ethylenediaminetetraacetic acid or a salt thereof; and

(c) a delayed release mechanism for delivering said active ingredient selected from risedronic acid, salts and esters thereof, and said ethylenediaminetetraacetic acid in the lower gastrointestinal tract, wherein said delayed release mechanism is selected from the group consisting of: a pH-triggered delivery system, a bacterial enzyme-triggered delivery system, a time-dependent delivery system, and combinations thereof.

2. The oral dosage form of claim 1, wherein the chelating agent is disodium ethylenediaminetetraacetic acid.

3. The oral dosage form of claim 1, wherein the mechanism for extended release is a pH triggered delivery system.

4. The oral dosage form of claim 3, wherein the pH triggered delivery system comprises an enteric coating.

5. An oral dosage form as claimed in claim 1, which comprises from 10mg to 200mg of the active ingredient selected from risedronic acid, salts and esters thereof.

6. The oral dosage form of claim 5, wherein the ethylenediaminetetraacetic acid or a salt thereof is present in an amount of 75mg to 250mg, wherein the ethylenediaminetetraacetic acid or a salt thereof is disodium ethylenediaminetetraacetate.

7. An oral dosage form having effective absorption of a drug, the oral dosage form comprising:

(a) 1mg to 200mg risedronate based on risedronate anhydrous monosodium salt;

(b)75mg to 250mg of disodium edetate; and

(c) an enteric coating that provides for release of the risedronate sodium and the disodium edetate in the lower gastrointestinal tract of a mammal.

8. The oral dosage form of claim 7 comprising 10mg to 50mg risedronate based on risedronate anhydrous monosodium salt.

9. The oral dosage form of claim 8, comprising 100mg disodium edetate.

10. The oral dosage form of claim 9 comprising 35mg risedronate based on risedronate anhydrous monosodium salt.

11. The oral dosage form of claim 10 wherein the enteric coating is a methacrylic acid copolymer.

12. The oral dosage form of claim 7 comprising 50mg to 200mg risedronate based on risedronate anhydrous monosodium salt.

13. The oral dosage form of claim 12, comprising 100mg disodium edetate.

14. The oral dosage form of claim 13 comprising 150mg risedronate based on risedronate anhydrous monosodium salt.

15. Use of an oral dosage form as claimed in claims 1-14 for the manufacture of a medicament for the treatment or prevention of diseases characterized by abnormal calcium and phosphate metabolism.

16. The use of claim 15, wherein the disease is selected from: osteoporosis, osteitis deformans, hyperparathyroidism, hypercalcemia of malignancy, osteolytic bone metastases, and combinations thereof.

17. The use of claim 16, wherein the disease is osteoporosis.

18. An oral dosage form having effective absorption of a drug, the oral dosage form comprising:

(a) 35mg risedronate based on risedronate anhydrous monosodium salt;

(b)100mg of disodium edetate; and