ME00862B - Use of a bisphosphnate in the manufacture of a medicament for inhibiting bone resorption - Google Patents

Description

OSNOVA PRONALASKA

Various diseases in humans and other mammals involving or associated with abnormal bone resorption. Such diseases include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, and hyperkalemia of malignancy. The most common of these diseases is osteoporosis, which is the most common manifestation in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural loosening of bone tissue, with consequent increase in bone fragility and suspicion of fracture. Since osteoporosis, like other diseases associated with bone loss, are chronic conditions, it is believed that suitable therapies will generally require chronic treatment.

Multinucleated cells called osteoclasts are responsible for causing bone loss through a process known as bone resorption. Bisphosphonates are well known to be selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of various generalized or localized bone diseases caused by or associated with abnormal bone resorption. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2nd ed., Parthenon Publishing (1995).

For now, a large amount of preclinical and clinical data exists for the potent bisphosphonate compound alendronate. Evidence suggests that other bisphosphonates such as risedronate, tiludronate, ibandronate, and zolendronate share many properties with alendronate, including high potency as inhibitors of osteocalcic bone resorption. An older bisphosphonate compound, etidronate, also inhibits bone resorption. However, unlike stronger bisphosphonates, etidronate decreases mineralization at doses used clinically, and can cause osteomalacia, a condition resulting from an undesirable decrease in bone mineralization. See Boyce, B.F. Fogelman, I., Ralston, S. et al. (1984) Lancet 1 (8381), p. 821-824 (1984), and Gibbs, C.J., Aaron, J.E.; Peacock, M. (1986) Br, Med. J. 292, p. 1227-1229 (1986).

Despite their therapeutic benefits, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B.J. Gertz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int, Suppl. 3: S13-16 (1993) and B.J. Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology & Therapeutics, vol 58, number 3, p. 288-298 (September 1996) which are incorporated herein by reference in their entirety. Intravenous administration has been used to overcome this bioavailability problem. However, intravenous administration is expensive and inconvenient, especially when the patient has to be given an intravenous infusion lasting several hours on repeated occasions.

If oral administration of bisphosphonates is desired, relatively high doses must be administered to compensate for low bioavailability from the gastrointestinal tract. To overcome this low bioavailability, it is usually recommended that the patient take the bisphosphonate on an empty stomach and refrain from eating for at least 30 minutes afterwards. However, many patients find this abstinence from eating on a daily basis uncomfortable. In addition, oral administration is associated with adverse gastrointestinal effects, particularly those related to the esophagus (esophagus). See Fleisch, Id. These effects appear to be related to the irritant potential of bisphosphonates in the esophagus, a problem exacerbated by the presence of refluxing stomach acid. For example, the bisphosphonate pamidronate is associated with esophageal ulcers. See E.G, Lufkin et al., Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, 4: 320-322 1994), which is incorporated herein by reference in its entirety. Also, but not as commonly, the use of alendronate has been associated with esophagitis and/or esophageal ulcers. See P. C. De Groen, et al., Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine, vol 335, no. 124, p. 1016-1021 (1996), D. O. Castell Pili Esophagitis — The Case of Alendronate, New England Journal of Medicine, vol 335, No. 124, p. 1058-1059 (1996), and U. A. Liberman et al., Esophacritis and Alendronate, New England Journal of Medicine, vol 335, No. 124, p. 1069-1070), which are incorporated herein by reference in their entirety. It has been shown that the degree of adverse gastrointestinal effects of bisphosphonates increases with increasing dosage. See C. H. Chestnut et al., Alendronate Treatment of Postmenopausal Osteoporotic Women: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine, vol. 99, p. 144-152 (August 1995). Also, these adverse esophageal effects appear to be more prevalent in patients who do not take bisphosphonates with adequate fluids or who lie down shortly after dosing, increasing the chance of esophageal reflux.

Current oral bisphosphonate therapies generally fall into two categories: (1) those therapies that use continuous daily treatment, and (2) those therapies that use a cyclic regimen of treatment and rest periods.

Continuous daily treatment regimens normally involve chronic administration of relatively low doses of the bisphosphonate compound, with the goal of releasing the desired cumulative therapeutic dose over the course of the treatment period. However, continuous daily dosing has the potential disadvantage of causing adverse gastrointestinal effects due to repeated, continuous and additive irritation of the gastrointestinal tract. Also, because bisphosphonates must be taken on an empty stomach and then abstain from food and maintain an upright position for at least 30 minutes, many patients find daily dosing cumbersome. These factors can therefore disturb the patient's consent, and in serious cases even require the discontinuation of treatment.

Cyclic treatment regimens have been developed because some bisphosphonates, such as etidronate, when given daily for more than a few days, have the disadvantage of actually causing a decline in bone mineralization, ie, osteomalacia. U.S. Patent No. 4,761,406 to Flora et al., issued August 2, 1988 describes a cycling regimen developed to minimize bone mineralization decline while still providing a therapeutic antiresorptive effect. Generally, cyclic regimens are characterized as intermittent, as opposed to continuous, treatment regimens, and have both treatment periods during which bisphosphonates are administered and off-treatment periods that allow systemic bisphosphonate levels to return to baseline. However, cyclic regimens, compared to continuous dosing, seem to lead to a decrease in therapeutic anti-resorptive efficacy. The risedronate data suggest that cyclic dosing is actually less effective than continuous daily dosing for maximizing anti-resorptive bone effects. See L. Mortensen et al., Prevention Of Early Postmenopausal Bone Loss By Risedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1 p.m. sl40 (1995). In addition, these cyclic regimens do not eliminate or minimize adverse gastrointestinal effects, because these regimens typically employ periods of multiple daily dosing. Also, cyclic regimens are difficult to apply and have the disadvantages of low patient compliance and compromised therapeutic efficacy. U.S. Patent No. 5,366,965, issued to Strein on November 22, 1994, attempts to address the problem of adverse gastrointestinal effects by administering a polyphosphonate compound, either orally, subcutaneously, or intravenously, according to an intermittent dosing schedule that has both an inhibitory period of bone resorption and a non-treatment rest period. However, the regimen has the disadvantage that it is not continuous and regular, and requires non-treatment periods ranging from 20 to 120 days. PCT Application No. WO 95/30421 to Goodship et al., published November 16, 1995 describes methods for preventing loosening and migration of dentures using various bisphosphonate compounds. The application of a partial dose of bisphosphonate once a week is described. However, the reference specifically omits to show the occurrence of adverse gastrointestinal effects or to describe the administration of higher or multiple doses.

Lunar News, July 1996, Update: Bisphosphonates, 23-24, reveals that “due to problems with oral bisphosphonates, episodic (once a week) or cyclic (one week each month) administration may be preferred. Even oral alendronate can be given at a dose of 40 or 80 mg once a week to avoid dosing problems and reduce costs. Intravenous administration is also possible".

Lunar News, April 1997, Update: Bisphosphonates, 30-32, reveals: ,one way to reduce the relatively high cost and potential side effects of strong oral bisphosphonates may be to dose them only two or three times a week rather than daily...in humans , there is little difference between 5 and 10 mg/day of alendronate, so a 10 mg dose can theoretically only be given 3x a week or a 40 mg dose once a week...If turnover remains low after three months at 3x a week, the dose can be reduced to 2x per week or lower."

Current learning shows that both daily and cyclic treatment regimens have drawbacks, and that there is a need to develop a dosing regimen to overcome these drawbacks.

In the present invention, it has been found that adverse gastrointestinal effects, which may be associated with daily or cyclic dosing regimens, can be minimized by administering bisphosphonates at relatively high unit doses according to a continuous schedule having dosing intervals selected from the group consisting of single- weekly dosage.

In other words, it was found that the use of bisphosphonates at high relative doses at relatively low frequencies causes less adverse gastrointestinal effects, especially esophageal effects, compared to the use of low relative doses at high relative dosing frequencies. This result is surprising in view of the teaching suggesting that adverse gastrointestinal effects can be expected to increase as a function of increasing bisphosphonate dose. Such methods of administration according to the present invention will be particularly effective in treating patients who have been identified as suffering from or susceptible to upper gastrointestinal diseases, e.g., gastrointestinal reflux disease (ie, "GERD") (gastrointestinal reflux disease), esophagitis, dyspepsia (ie, heartburn), ulcers, and other related ailments. In such patients, conventional bisphosphonate therapy can potentially exacerbate or cause such upper gastrointestinal disease.

From a patient's lifestyle point of view, the methods of the present invention will also be more convenient than a daily or cyclic dosing regimen. Patients will be exposed less often to the disadvantages of taking the drug on an empty stomach and having to refrain from food for at least 30 minutes after dosing. Likewise, patients will not need to keep notes on a complex dosing regimen. The methods of the present invention are likely to have the advantage of promoting better patient compliance, which in turn may translate into better

therapeutic efficacy.

The object of the present invention is to provide uses for the manufacture of a medicament for inhibiting bone resorption and conditions associated therewith.

A further aim of the presented invention is to describe procedures which are oral procedures.

The next objective of the presented invention is to describe such procedures in humans.

A further aim of the present invention is to provide such procedures in patients who are found to be suffering from or susceptible to disorders of the upper gastrointestinal system, e.g. gastrointestinal reflux disease (ie, "GERD"), esophagitis, dyspepsia (ie, heartburn), ulcers, and other related disorders.

A further objective of the present invention is to describe such procedures while minimizing the occurrence or potential for adverse side effects.

A further object of the present invention is to describe such procedures comprising a continuous dosing regimen with once-weekly dosing intervals.

It is a further object of the present invention to describe such procedures in which a continuous dosing regimen is maintained until the desired therapeutic effect is achieved.

These and other objectives will become immediately apparent from the detailed description that follows.

SUMMARY OF THE INVENTION

The presented invention relates to the use of alendronate for the treatment of osteoporosis in a person in need of such treatment, where the said drug is administered orally to the said person as a dose unit containing about 70 mg of the alendronate compound, based on the active mass of alendronic acid, according to continuous regimen with a dosing interval of once a week.

In other embodiments, the present invention describes such procedures that are useful in humans who have been determined to have or be susceptible to disorders of the upper gastrointestinal system.

All percentages and proportions used herein, unless otherwise indicated, are by weight. The invention may contain, consist of, or consist mainly of the necessary as well as optional ingredients, components, and processes described herein.

BRIEF DESCRIPTION OF PICTURES

SI. 1 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin-embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate doses of 50 ml of simulated gastric

juice applied in five consecutive days.

SI. 2 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate doses of 50 ml of 0.20 mg/ml alendronate in simulated gastric juice administered on five consecutive days.

SI. 3 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed 24 hours after infusion with a single 50 ml dose of 0.80 mg/ml alendrinate in simulated gastric juice.

SI. 4 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed 7 days after infusion with a single 50 ml dose of 0.80 mg/ml alendronate in simulated gastric juice.

SI. 5 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin-embedded and stained with hematoxylin and eosin) from an animal sacrificed 7 days after infusion of the last of 4 separate doses of 50 ml of 0.80 mg/ml alendronate in simulated gastric juice administered once weekly, ie ., once every 7 days.

SI. 6 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin-embedded and stained with hematoxylin and eosin) from an animal sacrificed 4 days after infusion of the last of 8 separate doses of 50 ml of 0.40 mg/ml alendronate in simulated gastric juice administered twice weekly, ie, once every 3-4 days.

SI. 7 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed after infusion of the last of five separate doses of 50 ml of 0.20 mg/ml risedronate in simulated gastric juice administered on five consecutive days.

SI. 8 is a photomicrograph (total magnification 270X) of canine esophageal tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five 50 ml doses of 4.0 mg/ml tiludronate in simulated gastric juice administered on five consecutive days.

DESCRIPTION OF THE INVENTION

The present invention utilizes higher individual doses of bisphosphonates at each dosing point than has been typically used heretofore, yet due to the selected dosing schedule, the potential for adverse gastrointestinal effects is minimized. In addition, the invention is more convenient since the disadvantages associated with daily dosing are reduced to a minimum.

The methods of applying the methods of the present invention are particularly useful in the application of bisphosphonate therapy to human patients who have been found to suffer from or are susceptible to upper gastrointestinal diseases, eg, GERD, esophagitis, dyspepsia, ulcers, etc. In such patients, conventional bisphosphonate therapy can potentially exacerbate or cause upper gastrointestinal disease.

The term "pharmaceutically effective amount", as used herein, means an amount of a bisphosphonate compound which will produce the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.

The term "minimizing the occurrence or potential for adverse gastrointestinal effects," as used herein, means reducing, preventing, reducing, or reducing the occurrence or potential for causing adverse gastrointestinal effects in the gastrointestinal tract, i.e., the esophagus, stomach, intestines, and rectum, particularly in the upper gastrointestinal tract, ie, esophagus and stomach, non-limiting adverse gastrointestinal effects include, but are not limited to, GERD, esophagitis, dyspepsia, ulcers, esophageal irritation, esophageal perforation, abdominal pain, and constipation.

The term "abnormal bone resorption" as used herein means a degree of bone resorption that exceeds the degree of bone formation, either locally or in the skeleton as a whole. Alternatively, "abnormal bone resorption" may be associated with the formation of bones that have an abnormal structure.

The term "inhibiting bone resorption", as used herein, means treating or preventing bone resorption by directly or indirectly altering osteoclast formation or activity. Inhibiting bone resorption refers to treating or preventing bone loss, particularly inhibiting the removal of existing bone or mineral phase and/or organic matrix phase, by directly or indirectly changing osteoclast formation or activity.

The terms "continuous schedule" or "continuous dosing schedule" as used herein mean that the dosing regimen is repeated until the desired therapeutic effect is achieved. A continuous schedule or continuous dosing schedule is different from a cyclical or intermittent (alternating) dosing schedule.

The term "until the desired therapeutic effect" as used herein means that the bisphosphonate compound is administered continuously, according to the selected dosage schedule, until such time as the clinical or medicinal effect sought for the disease or condition is observed from by doctors or researchers. For the treatment methods of the present invention, the bisphosphonate compound is continuously dosed until the desired change in bone mass or structure is achieved. In such cases, achieving an increase in bone mass or replacing the bone structure with a more normal bone structure are the desired objects. For the prevention methods of the present invention, the bisphosphonate compound is administered continuously for as long as is necessary to prevent the undesired condition. In such cases, maintaining bone density is often an issue. Non-limiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can range from about 2 weeks to the remaining human lifespan, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most suitable from about 1 year to about 10 children.

The methods of the present invention do not have the disadvantages of current treatment methods that may cause or increase the potential for adverse gastrointestinal effects or that require cumbersome, irregular, or complicated dosing regimens.

The present invention encompasses a continuous dosing schedule whereby a unit dose of a bisphosphonate is regularly administered according to a dosing interval.

Weekly dosing means that a unit dose of bisphosphonate is administered once a week, i.e., once during a period of seven days, primarily on the same day each week. In a weekly dosing regimen, a unit dose is generally administered approximately every seven days. A non-limiting example of a once-weekly dosing regimen will require the administration of a unit dose of bisphosphonate every week. Preferably, the unit dose is not administered on consecutive days, but a once-weekly dosing regimen may include a dosing regimen in which the unit doses are administered on two consecutive days falling within two different weekly periods. The term "generalized bone loss" means bone loss at multiple sites on the skeleton or throughout the skeletal system. The term "localized bone loss" means bone loss at one or more specific, specific skeletal sites.

Generalized bone loss is often associated with osteoporosis. Osteoporosis is most common in women after menopause, where estrogen production is significantly reduced. However, osteoporosis can also be steroid-induced and is seen in men due to age. Osteoporosis can be caused by a disease, for example, rheumatoid arthritis, it can be caused by secondary causes, for example, glucocorticoid therapy, or it can occur without any identified cause, i.e., idiopathic osteoporosis. In the present invention, primary methods include treating or preventing abnormal bone resorption in osteoporotic humans.

Localized bone loss is associated with periodontal disease, bone fractures, and periprosthetic osteolysis (in other words, where bone resorption occurs near the prosthetic implant).

Generalized or localized bone loss can occur from disuse, which is often a problem for those who are bedridden or wheelchair bound, or those with immobilized limbs in casts or extensions.

The present invention is useful for the treatment of the following conditions or diseases: osteoporosis, which may include postmenopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, and idiopathic osteoporosis.

The methods of the present invention are intended to specifically exclude methods for treating and/or preventing denture loss and denture migration in mammals, as described in PCT application WO 95/30421, Goodship. et al., published Nov. 16, 1995, which is incorporated by reference herein in its entirety.

Bisphosphonates

The methods and compositions of this invention contain bisphosphonates. The bisphosphonates according to the present invention correspond to the chemical formula

where

A is OH and X is a 3-aminopropyl group, thus the resulting compound is 4-amino-1-hydroxybutylidene-1,1-bisphosphonate, i.e., alendronate.

Pharmaceutically acceptable salts and derivatives of bisphosphonates are also useful herein. Non-limiting examples of salts include those selected from the group consisting of alkali metals, alkaline earth metals, ammonium, and mono-, di-, tri-, or tetra-C -C30 alkyl substituted ammonium salts. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts. Non-limiting examples of derivatives

include those selected from the group consisting of esters, hydrates and amides.

"Pharmaceutically acceptable" as used herein, means that the bisphosphonate salts and derivatives have the same general pharmacological properties as the free acid form from which they are derived and are acceptable from the point of view of toxicity.

It should be noted that the terms "bisphosphonate" and "bisphosphonates" as used herein in reference to the therapeutic agents of this invention are intended to also include diphosphonates, bisphosphonic acids and diphosphonic acids, as well as salts and derivatives of these materials. The use of specific nomenclature in referring to a bisphosphonate or bisphosphonates is not intended to limit the scope of this invention unless specifically indicated. Due to the mixed nomenclature now in use by those skilled in the art or in the art, references to the specific gravity or percentage of a bisphosphonate compound in this invention are based on the active weight of the acid, unless otherwise stated herein. For example, the phrase "about 70 mg of a bisphosphonate that inhibits bone resorption selected from the group consisting of alendronate, its pharmaceutically acceptable salts and mixtures thereof, based on the active weight of alendronic acid" means that the amount of the selected bisphosphonate is calculated on the basis of 70 mg of alendronic acid .

Non-limiting examples of bisphosphonates useful herein include the following:

Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

Alendronate (also known as alendronate sodium or monosodium trihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate.

Alendronic acid and alendronate are described in U.S. Pat. Patents 4,922,007 Kieczykowsk et al., issued May 1, 1990 and 5,019,651, Kieczykowsk, issued May 28, 1991.

Alendronate, its pharmaceutically acceptable salts and mixtures thereof are more suitable.

Alandronate monosodium trihydrate is most suitable.

Pharmaceutical compositions

Compositions useful in the present invention contain a pharmaceutically effective amount of a bisphosphonate. The bisphosphonate is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers, collectively referred to herein as "carriers," suitably selected for oral administration, i.e., tablets, capsules, elixirs, syrups, effervescent compositions, powders, and the like. and consistent with conventional pharmaceutical practice. For example, for oral administration in the form of a tablet, capsule, or powder, the active component can be combined (mixed) with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose.

magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like; for oral administration in liquid form, e.g., elixirs and syrups, effervescent compositions, oral drug components can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerin, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrants, buffers, coating agents and coloring agents may be incorporated. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, powdered lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as gum acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. A particularly suitable tablet formulation for alandronate monosodium trihydrate is that described in U.S. Pat. Patent No. 5.35 8.9 41, Bechard et al., published October 25, 1994. The compounds used in this procedure can also be combined with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxyl-propylmethacrylamide, and the like.

For once weekly dosing, an oral single dose contains about 70 mg of alendronate compound, based on the active weight of alendronic acid. A unit dose useful for the treatment of osteoporosis contains about 70 mg of alendronate compound.

Non-limiting examples of oral compositions containing alendronate as well as other bisphosphonates are illustrated in the Examples, below.

Consecutive administration of a histamine H2 receptor blocker and/or a proton pump inhibitor with bisphosphonates

In further embodiments, the applications and compositions associated with the present invention may also comprise a histamine H2 receptor blocker (ie, an antagonist) and/or a proton pump inhibitor. Histamine H2 receptor blockers and proton pump inhibitors are well-known therapeutic agents for increasing gastric pH. See L.J. Hixson, et al., Current Trends in the Pharmacotherapy for Peptic Ulcer Disease, Arch. Intem. Med., vol. 152, pp. 726-732 (April 1992).

In the presented invention, it was found that sequential oral administration of histamine H2 receptor blockers and/or proton pump inhibitors, followed by bisphosphonates, can help minimize adverse gastrointestinal effects. In these embodiments, the histamine H2 receptor blocker and/or proton pump inhibitor is administered from about 30 minutes to about 24 hours prior to administration of the bisphosphonate. In preferred embodiments, the blocker

histamine H2 receptor and/or proton pump inhibitor is applied from about 30 minutes to about 12 hours before bisphosphonate administration.

The dose of the histamine H2 receptor blocker and/or proton pump inhibitor will depend on the exact compound chosen and factors associated with the mammal to be treated, ie. size, health, etc.

Non-limiting examples of histamine H2 receptor blockers and/or proton pump inhibitors include those selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omprazole and lansoprazole.

Means for treatment

In further embodiments, this invention relates to a means for convenient and efficient performance of procedures in accordance with this invention. Such agents are particularly suitable for administration in solid oral forms such as tablets or capsules. Such a means primarily includes a number of unit doses. Such means may include a program map that has doses oriented toward their intended use. An example of such a means is a blister pack. Blister packs are well known in the packaging industry and are widely used in the packaging of pharmaceutical unit dosage forms. If desired, a memory aid may be provided, for example, in the form of numbers, letters, or other markings or with a calendar attached, marking days in the treatment schedule on which dosing may be administered. Alternatively, placebo doses or calcium or dietary supplements, either in a form similar to or different from the bisphosphonate dose form, may be included to provide a means in which the dose is taken every day. In these embodiments including a histamine H2 receptor and/or proton pump inhibitor, these agents may be included as part of the agent.

EXAMPLES

The following examples further describe and demonstrate embodiments within the scope of the present invention.

EXAMPLES

Esophageal irritation potential

The esophageal irritation potential of bisphosphonates was determined using a dog model.

Experiments show the relative irritant potential of the following dosing regimens: placebo (Group 1), a single high dose concentration of alendronate monosodium trihydrate (Group 2), a low dose concentration of alendronate monosodium trihydrate administered on five consecutive days (Groups 3 and 4), a high concentration of alendronate monosodium trihydrate trihydrate once weekly for four weeks (Group 5), concentration in the mid-dose range of alandronate monosodium trihydrate administered twice weekly for 4 weeks (Group 6), low-dose risedromate sodium administered for 4 consecutive days (Group 7) and low-dose tiludronate administered for five consecutive days (Group 7), and low dose tiludronate disodium administered for five consecutive days (Group 8).

The following solutions were prepared:

(1) simulated gastric juice (pH about 2), i.e., control solution.

(2) simulated gastric juice (pH about 2) containing about 0.20 mg/ml, alendronate monosodium trihydratin active base alendronic acid.

(3) simulated gastric juice (pH about 2) containing about 0.80 mg/ml alendronate monosodium trihydrate on the active base of alendronic acid.

(4) simulated gastric juice (pH about 2) containing about 0.40 mg/ml alendronate monosodium trihydrate on the active base of alendronic acid.

(5) simulated gastric juice (pH about 2) containing about 0.20 mg/ml alendronate sodium on the active base of alendronic acid.

(6) simulated gastric juice (pH about 2) containing about 4.0 mg/ml tiludronate disodium on the active base tiludronic acid.

Simulated gastric juice was prepared by dissolving about 960 mg of pepsin (L-585,228000B003, Fisher Chemical) in about 147 ml of 0.90 (wt%) NaCl (aqueous), adding about 3 ml of 1.0 M HCl (aqueous), and adjusting the volume to about 300 ml with deionized water. The pH of the resulting solution is measured and, if necessary, adjusted to about 2 using 1.0 M HCI (aqueous) or 1.0 M NaOH (aqueous).

The animals used in the experiment were anesthetized and about 50 ml of a suitable solution was administered over a period of about 30 minutes by infusion into the esophagus using an infusion pump and a rubber catheter. The following treatment experiments were performed:

Group 1: This control group contains four animals. Each animal is administered a dose of about 50 ml of simulated gastric juice /solution (1)/ on each of five consecutive days. Animals were sacrificed immediately after the last dose was administered.

Group 2: This group contains four animals. About 50 ml of simulated gastric juice containing about 0.20 mg/ml alendronate /solution (2)/ was administered to each animal.

of five consecutive days. Animals were sacrificed immediately after the last dose was administered.

Group 3: This group contains five animals. In each animal, a dose of about 50 ml of simulated gastric juice containing about 0.80 mg/ml of alendronate /solution (3)/ is administered on a single day of treatment. The animals were sacrificed about 24 hours after the administered dose.

Group 4: This group contains five animals. In each animal, a dose of about 50 ml of simulated gastric juice containing about 0.80 mg/ml of alendronate /solution (3)/ is administered on a single day of treatment. The animals were sacrificed about 7 days after the dose was administered.

Group 5: This group contains six animals. Each animal was administered a dose of about 50 ml of simulated gastric juice containing about 0.80 mg/ml alendronate /solution (3)/ once a week, ie, every seven days, for four weeks. Animals were sacrificed approximately 7 days after the last dose was administered.

Group 6: This group contains six animals. Each animal is administered a dose of about 50 ml of simulated gastric juice containing about 0.40. mg/ml alendronate /solution (4)/ twice a week, ie, every three to four days, during four weeks. Animals were sacrificed approximately four days after the last dose was administered.

Group 7: This group contains eight animals. Each animal was administered a dose of about 50 ml of simulated gastric juice containing about 0.20 mg/ml risedronate /solution (5)/ on each of five consecutive days. Animals were sacrificed immediately after the last dose was administered.

Group 8: This group contains four animals. Each animal was administered a dose of about 50 ml of simulated gastric juice containing about 4.0 mg/ml tiludronate /solution (6)/on each of five consecutive days. Animals were sacrificed immediately after the last dose was administered.

The esophagus from each sacrificed animal is removed and prepared for histopathology using standard techniques by embedding the tissue in paraffin, staining with hematoxylin and eosin. Sections are examined microscopically. Histopathological results are summarized in Table 1.

For group 1 animals (control group), photomicrographs show that the esophagus is normal with intact epithelium and absence of inflammatory cells in the submucosa. SI. 1 is a representative photomicrograph from group 1 animals.

For group 2 animals, photomicrographs show that the esophagus shows long ulcerations of the epithelial surface and marked submucosal inflammation and vacuolation. SI. 2 is a representative photomicrograph from group 2 animals.

For group 3 animals, photomicrographs show that the esophagus has an intact epithelial surface with very little submucosal inflammation and vacuolation. SI. 3 is a representative photomicrograph from group 3 animals.

For group 4 animals, photomicrographs show that the esophagus has an intact epithelium with either minimal inflammation (two of five animals) or no inflammation (three of five animals) and no vacuoleia. SI. 4 is a representative photomicrograph from a group of 4 animals showing minimal inflammation.

For group 5 animals, photomicrographs show that the esophagus is normal with an intact epithelium and the absence of inflammatory cells in the submucosa. SI. 5 is a representative photomicrograph from group 5 animals.

For group 6 animals, photomicrographs show that the esophagus shows deep ulcerations of the epithelial surface and marked submucosal inflammation and vacuolation. SI. 6 is a representative photomicrograph from group 6 animals.

For group 7 animals, photomicrographs show that the esophagus shows deep ulcerations of the epithelial surface and marked submucosal inflammation and vacuolation. SI. 7 is a representative photomicrograph from group 7 animals.

For group 8 animals, photomicrographs show that the esophagus shows mild ulceration of the epithelial surface and mild submucosal inflammation and vacuolation. SI. 8 is a representative photomicrograph from group 8 animals.

These experiments show that significantly less esophageal irritation (compared to control group 1) was observed from the administration of a single high-concentration dose of alendronate (groups 3 and 4) compared to the administration of low-concentration doses on consecutive days. These experiments also show significantly less esophageal irritation with alandronate on a weekly basis (group 5) or twice weekly (group 6) compared to the administration of low-concentration doses on consecutive days (group 2). These experiments also show that when other bisphosphonates such as risedronate (group 7) or tiludronate (group 8) are administered at low doses on consecutive days, the esophageal irritation potential is high.

Table 1

FIRST 2

Once weekly dosing regimen Treatment of osteoporosis.

Alendronate tablets or liquid formulations containing about 70 mg of alendronate, on the active base of alendronic acid, were prepared (see EXAMPLES 7 and 8). Tablets or liquid formulations are administered orally to a human patient once a week, ie, preferably about once every seven days (eg, every Sunday), over a period of at least one year. This application procedure is useful and suitable for treating osteoporosis and for minimizing adverse gastrointestinal effects, especially adverse esophageal effects.

effects. This procedure is also useful for improving patient acceptance and compliance.

Prevention of osteoporosis

Alendronate tablets or liquid formulations containing about 35 mg of alendronate, on the active base of alendronic acid, were prepared (see EXAMPLES 7 18). Tablets or liquid formulations are administered orally to a human patient once a week, ie, preferably about once every seven days (eg, every Sunday) for a period of at least one year. This application procedure is useful and suitable for preventing osteoporosis and minimizing adverse gastrointestinal effects, especially adverse esophageal effects. This procedure is also useful for improving patient acceptance and compliance.

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Bisphosphonate tablets

Tablets containing bisphosphonates are prepared using standard compounding and emulsification techniques as described in U.S. Pat. Patent No. 5,358,941 to Bechard et al., issued October 25, 1994.

Tablets containing about 35 mg of alendronate on the active base of alendronic acid are obtained using the following relative weights of the components.

Similarly, tablets have been prepared containing other relative weights of alendronate, based on the active mass of alendronic acid, eg, about 70 mg per tablet.

Liquid bisphosphonate formulation

Liquid bisfcnate formulations are prepared using standard compounding techniques. A liquid formulation containing about 70 mg of alendronate monosodium trihydrate, on the active base of alendronic acid, per about 75 ml of liquid is obtained using the following relative weights of the components.

Claims (6)

1. Application of alendronate in the production of a drug for the treatment of osteoporosis in a person in need of such treatment, where the said drug was administered orally to the said person as a dose unit containing about 70 mg of the alendronate compound, based on the active mass of alendronic acid, according to continuous regimen with a one-week dosing interval. 2. Use according to claim 1, characterized in that the bisphosphonate is alendronate monosodium trihydrate. 3. Application according to claim 1 or 2, characterized in that the composition is a tablet, capsule or powder. 4. Use according to claim 1 or 2, characterized in that the composition is a tablet or capsule. 5. Application according to claim 1 or 2, characterized in that the composition is a tablet. 6. Application according to claim 1 or 2, characterized in that the composition is a capsule.