HRP20000035A2 - Method for inhibiting bone resorption - Google Patents

Description

References relating to the application

This invention relates to U.S. Pat. application Ser. no. 09/060,419, filed Apr. 15, 1998, and U.S. Pat. temporary application ser. no. 60/053,535 filed Jul. 23, 1997, and 60/053,351, filed Jul. 22, 1997, the contents of which are incorporated herein by reference.

Field of invention

This invention relates to oral methods for inhibiting bone resorption in mammals while minimizing potential adverse effects on the gastrointestinal system.

These methods include oral administration to mammals in need thereof, pharmaceutically effective amounts of bisphosphonates as unit doses according to a continuous schedule of intake; and the dosing interval was selected from the group consisting of weekly dosing, biweekly dosing, biweekly dosing, and bimonthly dosing. This invention also relates to a pharmaceutical composition and accessories for use in carrying out these methods.

Background of the invention

Various disorders in humans and other mammals involve or are related to abnormal bone resorption. These disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. The most common of these disorders is osteoporosis, which is most often manifested in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fractures. Osteoporosis, as well as other disorders related to bone loss, are chronic conditions, and it is believed that adequate therapy generally requires ongoing treatment. Multinucleated cells called osteoclasts are responsible for bone loss through a process called bone resorption. Bisphosphonates are known to be selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of various general or localized bone disorders caused by, or related to, abnormal bone resorption. See H. Fleisch, Biophosphonates In Bone Disease, From the Laboratory to the Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated herein by reference in its entirety.

There is now a large amount of preclinical and clinical data for the effective bisphosphonate compound alendronate. There is evidence that other bisphosphonates such as risedronate, tiludronate, ibandronate and zolendronate have properties similar to alendronate, including high potency as inhibitors of osteoclastic bone resorption. An older bisphosphonate compound, etidronate, also inhibits bone resorption. However, unlike the more effective bisphosphonates, etidrionate inhibits mineralization at clinical doses, and can cause osteomalacia, a condition that results in an unwanted decrease in bone mineralization. See Boyce, B.F., Fogelman, L, 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), both of which are incorporated herein by reference in their entirety.

Despite their therapeutic benefits, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B.J. Getz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int, SuppL 3: S13-16 (1993) and BJ. Gertz and others, Studies of the Oral Bioavailability of Alendronate, Clinical Pharmacology and Therapeutics, vol. 58, no. 3, p. 288-298 (September 1995), which are incorporated herein by reference in their entirety. Intravenous administration has been used to overcome the problem of bioavailability. However, intravenous use is expensive and inconvenient, especially when the patient has to be given an intravenous infusion lasting several hours, on several occasions.

If oral administration of bisphosphonates is desired, relatively high doses may be administered to compensate for poor bioavailability from the gastrointestinal tract. To compensate for this low bioavailability, it is generally recommended that the patient take the bisphosphonate on an empty stomach, and fast for at least 30 minutes afterwards.

However, many patients find daily fasting uncomfortable. Moreover, oral administration is associated with adverse effects on the gastrointestinal tract, especially the esophagus. See Fleisch, Id. These actions appear to be related to the esophageal irritant properties of bisphosphonates, a problem that is exacerbated by the presence of gastric acid reflux. For example, the bisphosphonate pamidronate is associated with esophageal ulceration. See E.G. Lufkin et al., Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, 4: 320-322 (1994), which is hereby incorporated by reference in its entirety. slightly less common, the use of alendronate has been associated with esophagitis and/or esophageal ulceration. See P. C. De Groen, et al. Esophagitis Associated With the Use of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), D.O. Castell, Pill Esophagitis — The Case of Alendronate, New England Journal of Medicine, vol. 335, no. 124, p. 1058-1059 (1996) and U.A. Liberman et al., Esophagitis and Alendronate, New England Journal of Medicine, vol 335, no. 124, pp. 1069-1070 (1996), which are incorporated herein by reference in their entirety. The degree of undesirable gastrointestinal effects of bisphosphonates has been proven to increase with increasing doses. See C.H. Chestnut et al., Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine, vol. 99, p. 144-152, (August 1995), which is incorporated herein by reference in its entirety. 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, thus increasing the likelihood of esophageal reflux.

Contemporary oral bisphosphonate therapies are generally divided into two categories: (1) therapies with continuous daily treatment and (2) therapies with cyclic treatment regimens and rest periods.

Continuous daily treatment regimens normally involve continuous administration of relatively low doses of bisphosphonates, with the aim of providing the desired cumulative therapeutic dose over the course of treatment. However, continuous daily dosing has the potential drawback of possibly causing undesirable gastrointestinal effects caused by repeated, continuous and cumulative irritation of the gastrointestinal tract. Because bisphosphonates should be taken on an empty stomach with fasting, and maintaining an upright body position for at least 30 minutes, daily dosing is difficult for many patients. These factors can hinder the patient's cooperation, and in severe cases cause the discontinuation of therapy.

Cyclic treatment regimens were developed because some bisphosphonates such as etidronate, given daily for several days, cause a decrease in bone mineralization, i.e. osteomalacia. LOUSE. Patent No. 4,761,406, to Flora et al., issued Aug. 2, 1988, which is hereby incorporated by reference in its entirety, describes a cycling regimen developed in an attempt to minimize bone mineralization decline while maintaining therapeutic anti-resorptive effects. In general, cyclic regimens are characterized as intermittent, as opposed to continuous, treatments, and contain periods of treatment, during which bisphosphonates are administered, as well as rest periods that allow systemic bisphosphonate levels to return to baseline. However, cyclic regimens, compared to continuous dosing, appear to result in reduced antiresorptive activity. Risedronate data suggest that cyclical dosing is actually less effective than continuous daily dosing for maximizing bone antiresorptive properties. See L. Mortensen et al., Prevention of Early Postmenopausal Bone Loss By Risedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1, p. 140 (1995), which is incorporated herein by reference in its entirety. Furthermore, these cyclic regimens do not eliminate or minimize adverse gastrointestinal effects because such regimens typically use a multi-day dosing period. Also, cyclic regimens are difficult to apply, and have the disadvantage of low patient cooperation, and thus reduced therapeutic effectiveness. LOUSE. Patent No. 5,366,965, to Strein, issued Nov. 22, 1994, which is hereby incorporated by reference in its entirety, attempts to solve the problem of adverse gastrointestinal effects by administering a polyphosphonate compound, either orally, subcutaneously, or intravenously, on an intermittent dosing schedule, while also having a period of inhibition of bone resorption , and a period of rest without therapy. However, the regimen has the disadvantage that it is not continuous and regular, and requires periods without therapy that vary from 20 to 120 days. PCT Application No. 95/30421, to Goodship et al., issued Nov. 16, 1995, which is hereby incorporated by reference in its entirety, discloses methods for preventing prosthetic loosening and migration using various bisphosphonate compounds. The use of a partial dose of bisphosphonates once a week has been described. However, the reference fails to address the issue of adverse gastrointestinal effects or to describe the use of higher or multiple dosages.

It is evident from modern knowledge that both daily and cyclical regimens of therapy have shortcomings and that there is a need for the development of dosage regimens to eliminate these shortcomings.

In the present invention, it has been found that adverse gastrointestinal effects that may be associated with daily or cyclic dosing regimens can be minimized by administering bisphosphonates in relatively high unit doses on a continuous schedule, having a dosing interval selected from the group consisting of once weekly dosing, dosing twice a week, dosing biweekly and dosing twice a month. In other words, examples of bisphosphonates at relatively high doses at relatively low dosing frequencies have been found to cause less adverse gastrointestinal effects, particularly on the esophagus, compared to the use of relatively low doses at relatively high dosing frequencies. This result is surprising, considering the studies that claim that adverse gastrointestinal effects can be expected exactly proportionally with increasing bisphosphonate dosage. Such methods of application of the present invention may be particularly useful in the treatment of patients found to be suffering from or susceptible to disorders of the upper gastrointestinal tract, e.g., gastrointestinal reflux disease, esophagitis, dyspepsia (ie, heartburn), ulcers, and other similar disorders. In such patients, conventional bisphosphonate therapy may increase or cause such disorders of the upper gastrointestinal tract.

From a patient quality of life point of view, the methods of the present invention are more suitable for daily or cyclic dosing regimens. Patients are less often subjected to the inconvenience of taking the drug on an empty stomach and forced fasting for 30 minutes after dosing. Also, patients do not have to remember a complex dosing regimen. The methods of the present invention are suitable for promoting better patient cooperation, which can further lead to better therapy efficiency.

The object of this invention is to present methods for inhibiting bone resorption and conditions related thereto.

Another object of the present invention is to provide methods of treating abnormal bone resorption and related conditions.

Another object of the present invention is to provide methods of preventing abnormal bone resorption and conditions related thereto.

Another object of this invention is to provide oral methods.

Another object of this invention is to facilitate these methods in humans.

Another object of this invention is to enable these methods in patients diagnosed with, or susceptible to, disorders of the upper gastrointestinal tract, such as gastrointestinal reflux disease, esophagitis, dyspepsia (ie, heartburn), ulcers, and other similar disorders.

Another object of the present invention is to enable these methods while minimizing the occurrence or risk of adverse gastrointestinal events.

Another object of the present invention is to enable these methods to include a continuous dosing regimen, having a dosing interval selected from the group consisting of once weekly dosing, twice weekly dosing, biweekly dosing, and twice monthly dosing.

Another object of the present invention is to enable these methods to include a continuous dosing regimen, having a dosing interval varying from every 3 days to every 16 days.

Another object of the present invention is to enable these methods where a continuous dosing regimen is maintained until the desired therapeutic effect is achieved.

Another object of this invention is the treatment or prevention of abnormal bone resorption in mammals with osteoporosis, particularly in humans with osteoporosis.

Another object of the present invention is to provide pharmaceutical compositions and kits for use in the described methods.

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

Brief description of the invention

This invention relates to methods for inhibiting bone resorption in mammals in need, while minimizing potential adverse effects on the gastrointestinal system, wherein said method consists of oral administration to mammals in need of a pharmaceutically effective amount of bisphosphonates as a unit dose according to continuous intake schedule; and the dosing interval is selected from the group consisting of weekly dosing, biweekly dosing, biweekly dosing, and bimonthly dosing, wherein said continuous schedule is maintained until the desired therapeutic effect is achieved in said mammals.

In other embodiments, the present invention relates to methods comprising a continuous dosing schedule, with a dosing interval varying from once every 3 days to once every 16 days.

In other embodiments, this invention relates to methods of treating abnormal bone resorption in mammals in need of such treatment.

In other embodiments, this invention relates to methods of preventing abnormal bone resorption in need of such prevention.

In other embodiments, this invention relates to the use of these methods in humans.

In other embodiments, this invention relates to methods useful in patients diagnosed with, or susceptible to, disorders of the upper gastrointestinal tract.

In other embodiments, this invention relates to methods for treating or preventing osteoporosis in mammals.

In other embodiments, the present invention relates to methods for treating or preventing osteoporosis in humans.

In other embodiments, this invention relates to the inhibition of bone resorption, or the treatment, or prevention of abnormal bone resorption in humans, wherein said patient is administered from about 8.75 mg to about 140 mg of a bisphosphonate, based on the active alendronic acid, selected from the group, consisting of alendronate, its pharmaceutically acceptable salts and mixtures thereof.

In other embodiments, this invention relates to a pharmaceutical composition consisting of about 8.75 mg to about 140 mg of bisphosphonate, based on active alendronic acid, selected from the group consisting of alendronate, its pharmaceutically acceptable salts and mixtures thereof.

All percentages and ratios used herein are by weight, unless otherwise indicated. This invention may consist of or contain the basic as well as optional ingredients, components and methods described herein.

Short description of the pictures

Figure 1 is a photomicrograph (270x magnification) of canine esophageal tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed immediately after infusion of the last of five consecutive 50 ml doses of simulated gastric juice administered over five consecutive days.

Figure 2 is a photomicrograph (270x magnification) of canine esophageal tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed immediately after infusion of the last of five consecutive doses of 50 ml of 0.20 mg/ml alendronate in simulated gastric juice, administered during five days in a row.

Figure 3 is a photomicrograph (270x magnification) of dog esophagus tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed 24 hours after infusion with a single 50 ml dose of 0.80 mg/ml alendronate in simulated gastric juice.

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

Figure 5 is a photomicrograph (270x magnification) of dog Esophagus tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed 7 days after infusion of the last of four separate doses of 50 ml of 0.80 mg/ml alendronate in simulated gastric juice, administered weekly , i.e. once in 7 days.

Figure 6 is a photomicrograph (270x magnification) of canine esophageal tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed 4 days after infusion of the last of eight separate 50 ml doses of 0.40 mg/ml alendronate in simulated gastric juice, administered twice a week, i.e. once every 3-4 days.

Figure 7 is a photomicrograph (270x magnification) of canine esophageal tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed immediately after infusion of the last of five separate doses of 50 ml of 0.20 mg/ml risedronate in simulated gastric juice, administered during five days in a row.

Figure 8 is a photomicrograph (270x magnification) of canine esophageal tissue (paraffin fixed and stained with hematoxylin and eosin) from an animal killed immediately after infusion of the last of five consecutive 50 ml doses of 4.0 mg/ml tiludronate in simulated gastric juice, administered during five days in a row.

Description of the invention

This invention relates to a method, preferably oral, of inhibiting bone resorption in mammals in need thereof, while minimizing potential adverse effects on the gastrointestinal system. This invention relates to methods of treating or preventing abnormal bone resorption in mammals in need of such treatment or prevention. The methods of the present invention consist of oral administration to mammals of a pharmaceutically effective amount of a bisphosphonate as a unit dose, wherein said dose is administered according to a continuous schedule of intake, and the dosing interval is selected from the group consisting of weekly dosing, biweekly dosing, biweekly dosing week, and dosing twice a month. In other embodiments, the present invention relates to methods comprising a continuous dosing schedule, with a dosing interval varying from once every 3 days to once every 16 days. Typically, such a continuous dosing schedule is maintained until the desired therapeutic effect is achieved in the mammal.

This invention uses multiple unit doses of bisphosphonates at each dosage than has been commonly used up to now, but due to the dosing schedule, the dangers of adverse effects on the gastrointestinal tract are minimized. Moreover, this method is more convenient because the inconveniences related to daily dosing are minimized.

The methods of the present invention are generally applicable to mammals in need of bisphosphonate treatment. Preferably, the mammals in question are humans, particularly patients in need of inhibition of bone resorption, such as patients in need of treatment or prevention of abnormal bone resorption.

The methods of this invention are particularly useful in administering bisphosphonate therapy to humans diagnosed with upper gastrointestinal disorders, esophagitis, dyspepsia, ulcers, etc. In such patients, conventional bisphosphonate therapy may exacerbate or induce upper gastrointestinal disorders.

The term "pharmaceutically effective amount" as used herein refers to an amount of a bisphosphonate compound which will achieve the desired therapeutic effect or response when administered in accordance with the desired treatment regimen. A preferred pharmaceutically effective amount of bisphosphonate is that which inhibits bone resorption.

The term "minimizing the occurrence or potential adverse effects on the gastrointestinal tract" as used herein means the reduction, prevention, reduction and reduction of the occurrence or potential for causing adverse effects on the gastrointestinal tract, i.e. the esophagus, stomach, intestines and stomach, especially the upper gastrointestinal tract, i.e. esophagus and stomach. Harmful effects on the gastrointestinal tract are GERD, esophagitis, dyspepsia, ulcers, esophageal irritation, esophageal perforation, abdominal pain, and constipation, as well as others not mentioned here.

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

The term "inhibition of bone resorption" as used herein refers to the treatment or prevention of bone resorption by directly or indirectly altering osteoclast formation or activity. Inhibition of bone resorption refers to the treatment and prevention of bone loss, especially the inhibition of loss of existing bone either from the mineral phase and/or from the organic matrix phase, through direct or indirect changes in the formation or activity of osteoclasts.

The term "continuous schedule" or "continuous dosing schedule" as used herein means that the dosing regimen is repeated until the desired therapeutic effect is achieved. A continuous schedule or continuous dosing schedule is different from cyclic or intermittent dosing.

The term "until the desired therapeutic effect is achieved", as used herein, means that the bisphosphonate compound is continuously administered, according to the selected dosage schedule, until such time as the desired clinical or medical effect on the disease or condition is observed, by the clinician or researcher. For the treatment methods of the present invention, the bisphosphonate compound is continuously administered until the desired changes in bone mass or structure are demonstrated. In such cases, increasing bone mass or replacing the abnormal bone structure with a more normal structure are the desired goals. For the prevention methods of the present invention, the bisphosphonate compound is continuously administered until the adverse condition is stopped. In such cases, the goal is often to maintain bone density. Examples of administration periods can be from 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can vary from 2 weeks to the remaining lifetime, 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 preferably from about 1 year to about 10 years.

Methods of the present invention

The present invention consists of methods for inhibiting bone resorption in mammals. The present invention also encompasses the treatment of abnormal bone resorption in mammals. The present invention also encompasses methods for preventing abnormal bone resorption in mammals. In the most preferred implementation of the present invention, the mammal in question is a human.

The methods of the present invention do not have the disadvantages of current treatment methods, which may cause or increase the possibility of adverse effects on the gastrointestinal tract, or which require difficult, irregular or complicated dosage regimens.

The present invention comprises a continuous dosing schedule, wherein a unit dose of the bisphosphonate is regularly administered according to a dosing interval selected from the group consisting of weekly dosing, biweekly dosing, biweekly dosing, and bimonthly dosing.

By dosing once a week, it is understood that the unit dose of bisphosphonate is given once a week, i.e. once in a period of seven days, preferably always on the same day of the week. In the once-weekly dosing regimen, a unit dose is given every seven days. An example of a once-weekly dosing regimen would be to administer a unit dose of a bisphosphonate every Sunday. Administration of unit doses on non-consecutive days is preferred, but in a once-weekly dosing regimen, administration of unit doses on consecutive days falling on two different weeks is possible.

Dosing twice a week means that the unit dose of bisphosphonate is given twice a week, ie twice in a period of seven days, preferably always on the same two days of the week. In the twice-weekly dosing regimen, a unit dose is given every three to four days. An example of a twice-weekly dosing regimen would be to administer a unit dose of a bisphosphonate every Sunday and Wednesday.

Administration of unit doses on different and non-consecutive days is preferred, but in a twice-weekly dosing regimen, it is possible to administer unit doses on two consecutive days, falling in the same or two different weeks.

By dosing every two weeks, it is understood that the unit dose of bisphosphonate is given once in a period of two weeks, ie once in a period of fourteen days, preferably always on the same day in each two-week period. In the biweekly dosing regimen, each unit dose is given every fourteen days. An example of a biweekly dosing regimen would be to administer a unit dose of a bisphosphonate every other Sunday. Administration of unit doses on non-consecutive days is preferred, but in a biweekly dosing regimen, it is possible to administer unit doses on two consecutive days that fall within two different two-week periods.

Dosing twice a month means that the unit dose of bisphosphonate is given twice a month, i.e. twice in a calendar month. In a twice-monthly dosing regimen, the unit dose is administered preferably on the same two dates each month. In the twice-monthly dosing regimen, a unit dose is given every fourteen to sixteen days. An example of a twice-monthly dosing regimen would be to administer a unit dose of a bisphosphonate on or around the first of the month and on or around the fourteenth of the month, i.e. in the middle of the month. Administration of unit doses on different and non-consecutive days is preferred, but in the twice-monthly dosing regimen, it is possible to administer unit doses on two consecutive days, which fall in the same or two different months. A twice-monthly dosing regimen is defined herein as distinct from and does not include a biweekly dosing regimen, as the two regimens have different periodicities and result in the administration of a different number of doses over a longer period of time. For example, over a one-year period, a total of 24 doses would be given under a twice-monthly dosing regimen, while a total of 26 doses would be given under a biweekly dosing regimen (since there are 52 weeks in a year).

In further implementations or descriptions of the present invention, a unit dose is administered at a frequency of from every 3 to about every 16 days.

The methods and compositions of the present invention are used to inhibit bone resorption and to treat and prevent abnormal bone resorption and related conditions. Such conditions include both generalized and localized bone loss. Also, bone formation with an abnormal structure, as in Paget's disease, can be associated with abnormal bone resorption. The term "generalized bone loss" means loss of bone mass at multiple sites on the skeleton or throughout the skeletal system. The term "localized bone loss" means loss of bone mass at one or more specific, defined skeletal locations.

General loss of bone mass is often associated with osteoporosis. Osteoporosis is most common in postmenopausal women, when estrogen production decreases. However, osteoporosis can be caused by steroids in men, related to aging. Osteoporosis can be caused by a disease, eg, rheumatoid arthritis, it can be induced by secondary causes, eg, glucocorticoid therapy, or it can be caused by unspecified reasons, ie, idiopathic osteoporosis. In the present invention, preferred methods include treating or preventing abnormal bone resorption in humans with osteoporosis.

Localized bone loss is associated with periodontal disease, bone fractures, and periprosthetic osteolysis (in other words, where bone resorption has occurred near prosthetic implants).

General or localized bone loss can result from disuse, which is a common problem in those who are bedridden or wheelchair bound, or those with an immobilized limb in a cast or cast.

The methods and compositions of this invention are used to treat or prevent the following conditions or diseases: osteoporosis, which may include postmenopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis; Paget's disease; abnormal increase in bone wear; periodontal disease; localized bone loss related to periprosthetic osteolysis; and bone fractures.

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

Bisphosphonates

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

[image]

where

A and X are independently selected from the group consisting of H, OH, halogen, NH 2 , SH, phenyl, C 1 -C 30 alkyl, C 1 -C 30 substituted alkyl, C 1 -C 10 alkyl or dialkyl substituted with NH 2 C 1 -C 10 alkoxy, C 1 - C10 alkyl or phenyl substituted with thio, C1-C10 alkyl substituted with phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl.

In the above chemical formula, alkyl groups can be straight-chain, branched or cyclic, provided that enough atoms are selected for the chemical formula. C1-C30 substituted alkyl may include a wide variety of substituents, such as but not limited to those selected from the group consisting of: phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, C1-C10 alkyl or dialkyl substituted with NH2, OH, SH and C1-C10 alkoxy.

In the above chemical formula, A may include X and X may include A, so that the two moieties may form part of the same cyclic structure.

The above chemical formula also includes complex carbocyclic, aromatic and hetero atom structures for A and/or X substituents, such as but not limited to naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Preferred structures are those in which A is selected from the group consisting of: H, OH, and halogen, and X is selected from the group consisting of: C1-C30 alkyl, C1-C30 substituted alkyl, halogen, and C1- C10 alkyl or phenyl substituted with thio.

Even more preferred structures are those wherein A is selected from the group consisting of: H, OH, and Cl, and X is selected from the group consisting of: C1-C30 alkyl, C1-C30 substituted alkyl, Cl, and chlorophenylthio .

The most preferred structures are those in which A is OH and X is a 3-aminopropyl moiety, so that the resulting compound is 4-amino-1-hydroxybutylidene-1,1-bisphosphonate, i.e. alendronate.

Pharmaceutically acceptable salts and derivatives of bisphosphonates are also used herein. Examples, but not limited to the above, are those selected from the group consisting of: alkali metals, ammonium and mono, di-, tri-, or tetra-Cl-C30-alkyl-substituted ammonium. The most preferred salts are those selected from the group consisting of: sodium, potassium, calcium, magnesium and ammonium salts. Examples, but not limited to, are derivatives including 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 forms from which they are derived and are acceptable with respect to toxicity.

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

Examples of bisphosphonates used herein include, but are not limited to, 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 or alendronate are described in U.S. Pat. Patent 4,922,007 to Kieczykowsky et al., issued May 1, 1990, and 5,019,651 to Kieczykowsky et al., issued May 28, 1991, the contents of which are incorporated herein by reference in their entirety.

Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yamanouchi (cimandronate), as described in U.S. Pat. Patent 4,970,335 to Isomura et al., issued November 13, 1990, the contents of which are incorporated herein by reference in their entirety.

1,1-Dichloromethylene-1,1-diphosphonic acid (clodronic acid) and the disodium salt (Clodronate, Procter and Gamble) are described in Belgian Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), the contents of which are incorporated herein by reference in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid (EB-1053).

1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

1-Hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim (ibandronate), as described in U.S. Pat. Patent 4,927,814 issued May 22, 1990, the contents of which are incorporated herein by reference in their entirety.

6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acids (neridronate).

3-(diethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate).

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).

[2-(2-Pyridinyl)ethylidene]-1,1-bisphosphonic acid (pyridronate) is described in U.S. Pat. Patent 4,761,406, the contents of which are incorporated herein by reference in their entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid (risedronate).

(4-Chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) as described in U.S. Pat. Patent 4,876,248 to Breliere et al., issued October 24, 1989, the contents of which are incorporated herein by reference in their entirety.

1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (zolendronate).

Preferred bisphosphonates are selected from the group consisting of:

alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate and their pharmaceutically acceptable salts and their mixtures.

Even more preferred is alendronate, its pharmaceutically acceptable salts and mixtures thereof.

Alendronate monosodium trihydrate is most preferred.

Pharmaceutical compositions

The compositions useful in the present invention comprise a pharmaceutically effective amount of bisphosphonate. The bisphosphonate is usually administered in admixture with suitable pharmaceutical solvents, excipients or carriers, collectively referred to as "carriers", suitably selected for oral administration, i.e. tablets, capsules, elixirs, syrups, effervescent tablets, powders and the like and in accordance with conventional pharmaceutical practice. For example, for oral administration in the form of tablets, capsules or powders, the active ingredient can be with an oral, non-toxic pharmaceutically acceptable inert carrier such as: lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, sodium caramel , and similar. For oral administration in liquid form, eg elixirs and syrups, effervescent tablets, oral medicinal components can be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, binders, lubricants, disintegrating agents, buffers, glazes, and colors can be incorporated. Suitable binding agents may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free lactose, beta-lactose and corn sweeteners, natural and synthetic gums such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like. The lubricants used in these forms are sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Particularly preferred tablet formulations for alendronate monosodium trihydrate are those described in U.S. Pat. Patent 5,358,941 to Bechard et al., issued October 25, 1994, the contents of which are incorporated herein by reference in their entirety. The compounds used in these methods can also be bound to soluble polymers as drug carriers. Such polymers can be: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl methacrylamide, and the like.

The exact dosages of bisphosphonates will vary with the dosing schedule, the oral action of the bisphosphonate used, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder being treated, and other relevant medical and physical factors. Therefore, exact pharmaceutically effective amounts cannot be specified in advance, and may be determined by the treatment provider or clinician. Appropriate amounts can be determined through routine experimentation in animal models and human clinical studies. In general, appropriate amounts of bisphosphonates are selected to obtain the effect of inhibiting bone resorption, i.e., an amount of bisphosphonate that inhibits bone resorption is administered. For humans, an effective oral dose of a bisphosphonate is usually from about 1.5 to 6000 μg/kg of body weight and preferably from about 10 to about 2000 μg/kg of body weight.

For human oral compositions containing alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dose typically contains from about 8.75 mg to about 140 mg of the alendronate compound, based on the active weight of alendronic acid.

For once-weekly dosing, an oral unit dose contains from about 17.5 mg to about 70 mg of the alendronate compound, based on the active weight of alendronic acid. Examples of weekly oral doses are unit doses that are useful for the prevention of osteoporosis contain about 35 mg of the alendronate compound, and unit doses that are useful for the treatment of osteoporosis contain about 70 mg of the alendronate compound.

For twice weekly dosing, an oral unit dose contains from about 8.75 mg to about 35 mg of the alendronate compound, based on the active weight of alendronic acid. Examples of twice-weekly oral doses are: unit doses useful for the prevention of osteoporosis contain about 17.5 mg of the alendronate compound, and unit doses useful for the treatment of osteoporosis contain about 35 mg of the alendronate compound.

For biweekly or bimonthly dosing, an oral unit dose contains from about 35 mg to about 140 mg of the alendronate compound, based on the active weight of alendronic acid. Examples of weekly oral doses are: unit doses useful for the prevention of osteoporosis contain about 70 mg of the alendronate compound, and unit doses useful for the treatment of osteoporosis contain about 140 mg of the alendronate compound.

Examples, but not limited to, of oral compositions containing alendronate, such as other bisphosphonates are shown in the Examples, which follow.

Sequential use of H2 histamine receptor blockers and/or proton pump inhibitors with bisphosphonates

In further implementations, the methods and compositions of this invention may also contain histamine H2 receptor blockers (ie, antagonists) and/or proton pump inhibitors. 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 Intern. Med., vol. 152, p. 726-732 (April 1992). the contents of which are incorporated herein by reference in their entirety. It has been found in this invention that the sequential oral administration of H2 histamine receptor blockers and/or proton pump inhibitors, followed by bisphosphonate can help to further reduce adverse effects on the gastrointestinal tract. In these implementations, H2 histamine receptor blockers and/or proton pump inhibitors are administered from about 30 minutes to about 24 hours before bisphosphonate administration. In more preferred implementations, H2 histamine receptor blockers and/or proton pump inhibitors are administered from about 30 minutes to about 12 hours prior to bisphosphonate administration.

The dosage of H2 histamine receptor blockers and/or proton pump inhibitors depends on the chosen compound and factors related to the mammal being treated, ie size, health, etc.

Examples of, but not limited to, H2 histamine receptor and/or proton pump inhibitors include those selected from the group consisting of: cimetidine, famotidine, nizatidine, ranitidine, omprazole, and lansoprazole.

Accessories for treatment

In the following implementations, this invention relates to accessories for convenient and effective execution of methods in accordance with the subject invention. Such accessories are particularly suitable for administering solid oral forms such as tablets or capsules. Such kit preferably includes a number of unit doses. Such kits may include a card with dosages oriented in the order of administration. An example of such an accessory is a "blister pack". Blister packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit doses. If desired, reminders can be included, for example in the form of numbers, letters or other symbols, or in the form of a calendar, marking days in the dosing schedule. Placebo doses or calcium or dietary supplements in a form similar to or different from the bisphosphonate dose form may also be included, to form a "kit" in which the dose is taken each day. In these implementations including H2 histamine receptors and/or proton pump inhibitors, these agents can be part of a "kit".

EXAMPLES

The following examples further describe and demonstrate implementations within the scope of the present invention. The examples are given solely as an illustration and should not be understood as a limitation of the subject invention, considering the number of possible variations thereof in the field of the described invention.

EXAMPLE 1

Potential for esophageal irritation

The esophageal irritation potential of bisphosphonates was evaluated in a dog model.

The experiments show the relative irritation potential of the following dosing regimens: placebo (group 1) a single high-concentration dose of alendronate monosodium trihydrate (group 2), low-concentration doses of alendronate monosodium trihydrate administered over five consecutive days (groups 3 and 4), a high-concentration dose of alendronate monosodium trihydrate administered once a week for 4 weeks (group 5), medium-concentration doses of alendronate monosodium trihydrate administered twice weekly for 4 weeks (group 6), low-concentration doses of risedronate sodium administered consecutively for five days (group 7), and one dose low concentrations of tiludronate disodium (group 8) given for five consecutive days.

The following solutions were prepared:

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

(2) simulated gastric juice (pH about 2) with about 0.20 mg/mL alendronate monosodium trihydrate based on active alendronic acid.

(3) simulated gastric juice (pH about 2) with about 0.80 mg/mL alendronate monosodium trihydrate based on active alendronic acid.

(4) simulated gastric juice (pH about 2) with about 0.40 mg/mL alendronate monosodium trihydrate based on active alendronic acid.

(5) simulated gastric juice (pH about 2) with about 0.20 mg/mL risedronate sodium based on active risendronic acid.

(6) simulated gastric juice (pH about 2) with about 4.0 mg/mL tiludronate disodium based on active tiludronic acid.

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

The animals used in the experiments were anesthetized and given about 50 mL of the corresponding solution over 30 minutes by infusion into the esophagus using a pump and a rubber catheter. The following experiments were performed:

Group 1: This control group had 4 animals. Each animal was given a dose of about 50 mL of simulated gastric juice [solution (1)] for five consecutive days. Animals were killed immediately after administration of the last dose.

Group 2: This control group had 4 animals. Each animal was given a dose of about 50 mL of simulated gastric juice with 0.20 mg/mL alendronate [solution (2)] for five consecutive days. Animals were killed immediately after administration of the last dose.

Group 3: This control group had 5 animals. Each animal was given a dose of about 50 mL of simulated gastric juice with about 0.80 mg/mL alendronate [solution (3)] in one day. Animals were killed approximately 24 hours after dosing.

Group 4: This control group had 5 animals. Each animal was given a dose of about 50 mL of simulated gastric juice with about 0.80 mg/mL alendronate [solution (3)] in one day. Animals were killed approximately 7 days after dosing.

Group 5: This control group had 6 animals. Each animal was given a dose of about 50 mL of simulated gastric juice with about 0.80 mg/mL alendronate [solution (3)] once a week, ie every seven days for four weeks. The animals were given a total of four doses. Animals were killed approximately seven days after the last dose.

Group 6: This control group had 6 animals. Each animal was given a dose of about 50 mL of simulated gastric juice with about 0.40 mg/mL alendronate [solution (4)] twice a week, ie every 3 to 4 days for four weeks. A total of eight doses were given to the animals. Animals were killed approximately four days after the last dose.

Group 7: This control group had 8 animals. Each animal was dosed with about 50 mL of simulated gastric juice with about 0.20 mg/mL risedronate [solution (5)] for five consecutive days. Animals were killed immediately after administration of the last dose.

Group 8: This control group had 4 animals. Each animal was dosed with about 50 mL of simulated gastric juice with about 4.0 mg/mL tiludronate [solution (6)] for five consecutive days. Animals were killed immediately after administration of the last dose.

The esophagus of each killed animal was removed and prepared for histopathology using standard techniques, by embedding the tissue in paraffin, staining with hematoxylin and eosin. Sections were examined under a microscope. Histopathology results are shown in Table I.

For animals in Group 1 (control group), photomicrographs show that the esophagus is normal with an intact epithelium and no inflamed cells in the submucosa. FIGURE 1 is a typical photomicrograph for a Group 1 animal.

For animals from Group 2, photomicrographs show deep ulcerations of the epithelial layer of the esophagus and marked inflammation of cells in the submucosa. FIGURE 2 is a typical photomicrograph for an animal from the Group

2.

For animals from Group 3, photomicrographs show that the esophagus is normal with an intact epithelium and very mild inflammation of the cells of the submucosa. FIGURE 3 is a typical photomicrograph for a Group 3 animal.

For Group 4 animals, photomicrographs show that the esophagus is normal with an intact epithelium and either minimal inflammation (two of five animals) or no inflamed cells in the submucosa (three of five animals). FIGURE 4 is a typical photomicrograph for a Group 4 animal, showing minimal inflammation.

For Group 5 animals, photomicrographs show that the esophagus is normal with an intact epithelium and no inflamed cells in the submucosa. FIGURE 5 is a typical photomicrograph for a Group 5 animal.

For Group 6 animals, photomicrographs show an esophagus with deep ulceration of the epithelium and marked inflammation in the submucosa. FIGURE 6 is a typical photomicrograph for a Group 6 animal.

For Group 7 animals, photomicrographs show an esophagus with deep ulceration of the epithelium and marked inflammation in the submucosa. FIGURE 7 is a typical photomicrograph for a Group 7 animal.

For Group 8 animals, photomicrographs show an esophagus with mild ulceration of the epithelial layer and mild inflammation in the submucosa. FIGURE 8 is a typical photomicrograph for a Group 8 animal.

These experiments show that significantly less esophageal irritation (comparable to Group 1) is observed with the administration of a single high dose of alendronate (Groups 3 and 4) than with the administration of low doses over consecutive days (Group 2). These experiments also show that there is significantly less esophageal irritation when a single high dose of alendronate is given once a week (Group 5) or twice a week (Group 6) than when a low dose is given on consecutive days (Group 2). These trials also show that when other bisphosphonates such as risedronate (Group 7) or tiludronate (Group 8) are given in low doses on consecutive days, the risk of esophageal irritation is high.

Table 1 Study of potential esophageal irritation

[image]

EXAMPLE 2

Dosing regimen once a week.

Treatment of osteoporosis.

Alendronate tablets or solutions with about 70 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients once a week, i.e. preferably once every seven days (eg every Sunday), for a year. This method of administration is suitable for the treatment of osteoporosis and the reduction of unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

Prevention of osteoporosis.

Alendronate tablets or solutions with about 35 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients once a week, i.e. preferably once every seven days (eg every Sunday), for a year. This method of administration is suitable for preventing osteoporosis and reducing unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

EXAMPLE 3

Dosing regimen twice a week.

Treatment of osteoporosis.

Alendronate tablets or solutions with about 35 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients twice a week, ie preferably once every three to four days (eg every Sunday and Wednesday), for a period of one year. This method of administration is suitable for the treatment of osteoporosis and the reduction of unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

Prevention of osteoporosis.

Alendronate tablets or solutions with about 17.5 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients twice a week, ie preferably once every three to four days (eg every Sunday and Wednesday), for a period of one year. This method of administration is suitable for preventing osteoporosis and reducing unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

EXAMPLE 4

Biweekly dosing regimen.

Treatment of osteoporosis.

Alendronate tablets or solutions with about 140 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients every two weeks, i.e. preferably once every fourteen days (eg every other Sunday), for a period of one year. This method of administration is suitable for the treatment of osteoporosis and the reduction of unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

Prevention of osteoporosis.

Alendronate tablets or solutions with about 70 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients every two weeks, i.e. preferably once every fourteen days (eg every other Sunday), for a period of one year. This method of administration is suitable for preventing osteoporosis and reducing unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

EXAMPLE 5

Dosing regimen twice a month.

Treatment of osteoporosis.

Alendronate tablets or solutions with about 140 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients twice a month, ie preferably once every fourteen to sixteen days (eg the first and fifteenth of the month), for a period of one year. This method of administration is suitable for the treatment of osteoporosis and the reduction of unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

Prevention of osteoporosis.

Alendronate tablets or solutions with about 70 mg of alendronate, based on active alendronic acid, are prepared (see EXAMPLES 7 and 8). Tablets or solutions are given orally to patients twice a month, i.e. preferably every fourteen to sixteen days (eg every first and fifteenth of the month), for a period of one year. This method of administration is suitable for preventing osteoporosis and reducing unwanted consequences on the gastrointestinal tract, especially on the esophagus. This method is also suitable from the point of view of patient cooperation.

EXAMPLE 6

In further implementations, alendronate tablets or solutions are administered orally, in the desired doses, according to the dosage schedule of EXAMPLES 2 - 5, for the treatment or prevention of other disorders related to abnormal bone resorption.

In further implementations, other bisphosphonate compounds are administered orally, in the desired doses, according to the dosing schedule of EXAMPLES 2 - 5, to treat or prevent other conditions related to abnormal bone resorption.

EXAMPLE 7

Bisphosphonate tablets.

Bisphosphonate tablets are prepared using standard mixing and forming techniques described in U.S. Pat. Patent No. 5,358,941, to Bechard et al., issued Oct. 25, 1994, the contents of which are incorporated herein by reference in their entirety.

Tablets with about 35 mg of alendronate, based on active alendronic acid, are prepared using the following relative weights of the ingredients.

Ingredients per Tablet per 4000 Tablets

alendronate monosodium trihydrate 45.68 mg 182.72 g

anhydrous lactose, NF 71.32 mg 285.28 g

microcrystalline cellulose, NF 80.0 mg 320.0 g

magnesium stearate, NF 1.0 mg 4.0 g

Caramellose sodium, NF 2.0 mg 8.0 g

The resulting tablets are suitable for administration according to the methods of the present invention to inhibit bone resorption.

Accordingly, tablets can be prepared with different relative weights of alendronate, based on the active alendronic acid, eg around 8.75, 17.5, 70 and 140 mg per tablet. Also, tablets with other bisphosphonates with an appropriate level of activity are prepared in a similar way, eg cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and their pharmaceutically acceptable salts. Also, tablets with combinations of bisphosphonates are similarly prepared.

EXAMPLE 8

Liquid bisphosphonate preparation

Bisphosphonate preparations in liquid form are prepared using standard mixing techniques.

A liquid preparation with about 70 mg of alendronate monosodium trihydrate, based on active alendronic acid, for about 75 mL of liquid is prepared using the following relative weights of the ingredients.

Ingredient Weight

alendronate monosodium trihydrate 91.35 mg

sodium propylparaben 22.5 mg

sodium butylparaben 7.5 mg

sodium citrate dihydrate 1500 mg

anhydrous citric acid 56.25 mg

sodium saccharin 7.5 mg

water 75 mL

1 N sodium hydroxide (aqueous) pH 6.75

The resulting liquid preparation is suitable for administration as a unit dose in accordance with the methods of the present invention to inhibit bone resorption.

Accordingly, liquid preparations can be prepared with different relative weights of alendronate, based on active alendronic acid, for example around 8.75, 17.5, 35 and 140 mg per 75 mL vol. Also, liquid preparations with other bisphosphonates with an appropriate level of activity are prepared at similarly, eg, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof. Also, liquid preparations with combinations of bisphosphonates are similarly prepared.

Claims (52)

1. A method for inhibiting bone resorption in mammals, characterized in that a pharmaceutically effective amount of bisphosphonate is orally administered to mammals as a unit dose, according to a continuous dosing schedule, with a dosing interval selected from the group consisting of: dosing once a week, dosing twice weekly, biweekly dosing and twice monthly dosing. 2. The method according to claim 1, characterized in that said bisphosphonate is selected from the group consisting of: alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and their pharmaceutically acceptable salts and their mixtures . 3. The method according to claim 1, characterized in that said bisphosphonate is selected from the group consisting of alendronate and its pharmaceutically acceptable salts and their mixtures. 4. The method according to claim 3, characterized in that the pharmaceutically acceptable salt is alendronate monosodium trihydrate. 5. The method according to claim 4, characterized in that said mammals are humans. 6. A method for treating osteoporosis in mammals in need thereof, characterized in that said method consists of orally administering to mammals a pharmaceutically effective amount of bisphosphonate as a unit dose, according to a continuous dosing schedule, with a dosing interval selected from the group consisting of: dosing once a week, dosing twice a week, biweekly dosing and dosing twice a month. 7. The method according to claim 6, characterized in that said mammals are humans. 8. The method according to claim 7, characterized in that the mentioned dosing interval is once a week and that the mentioned unit dose contains about 70 mg of alendronate monosodium trihydrate, based on active alendronic acid. 9. The method according to claim 7, indicated by the fact that the mentioned dosage interval is twice a week and that the mentioned unit dose contains about 35 mg of alendronate monosodium trihydrate, based on active alendronic acid. 10. The method according to claim 7, characterized in that the mentioned dosage interval is two weeks and that the mentioned unit dose contains about 140 mg of alendronate monosodium trihydrate, based on active alendronic acid. 11. The method according to claim 7, characterized in that the mentioned dosage interval is twice a month and that the mentioned unit dose contains about 140 mg of alendronate monosodium trihydrate, based on active alendronic acid. 12. A method for preventing osteoporosis in mammals in need thereof, characterized in that said method consists of orally administering to mammals a pharmaceutically effective amount of bisphosphonate as a unit dose, according to a continuous dosing schedule, with a dosing interval selected from the group consisting of: dosing once a week, dosing twice a week, biweekly dosing and dosing twice a month. 13. The method according to claim 12, characterized in that said mammals are humans. 14. The method according to claim 13, characterized in that the mentioned dosage interval is once a week and that the mentioned unit dose contains about 35 mg of alendronate monosodium trihydrate, based on active alendronic acid. 15. The method according to claim 13, characterized in that the mentioned dosing interval is twice a week and that the mentioned unit dose contains about 17.5 mg of alendronate monosodium trihydrate, based on active alendronic acid. 16. The method according to claim 13, characterized in that the mentioned dosage interval is two weeks and that the mentioned unit dose contains about 70 mg of alendronate monosodium trihydrate, based on active alendronic acid. 17. The method according to claim 13, characterized in that the mentioned dosage interval is twice a month and that the mentioned unit dose contains about 70 mg of alendronate monosodium trihydrate, based on active alendronic acid. 18. A method for inhibiting bone resorption in mammals, characterized in that a pharmaceutically effective amount of bisphosphonate is orally administered to mammals, as unit doses according to a continuous schedule in periods from about 3 days to about 16 days. 19. A method for the treatment of osteoporosis in mammals, characterized in that a pharmaceutically effective amount of bisphosphonate is administered orally in mammals, as unit doses according to a continuous schedule in periods from about 3 days to about 16 days. 20. A method for the prevention of osteoporosis in mammals, characterized in that a pharmaceutically effective amount of bisphosphonate is administered orally in mammals, as unit doses according to a continuous schedule in periods from about 3 days to about 16 days. 21. The method according to claim 1-20, characterized in that the unit dose contains about 1.5 to about 6000 μg/kg of body weight bisphosphonate. 22. The method according to claim 1-20, characterized in that the unit dose contains about 10 to about 2000 μg/kg of body weight bisphosphonate. 23. A method for inhibiting bone resorption in mammals, characterized in that said method consists of orally administering to mammals a pharmaceutically effective unit dose of a histamine H2 receptor blocker or a proton pump inhibitor, and a unit dose of a bisphosphonate according to a continuous dosing schedule, with a dosing interval of about 3 days to about 16 days. 24. A method for inhibiting bone resorption in mammals, characterized in that said method consists of orally administering to humans a pharmaceutically effective unit dose of a histamine H2 receptor blocker or a proton pump inhibitor, and a unit dose of a bisphosphonate according to a continuous dosing schedule, with a dosing interval selected from the group which consists of: dosing once a week, dosing twice a week, dosing twice a week and dosing twice a month. 25. The method according to claim 24, characterized in that said histamine H2 blockers or proton pump inhibitors are administered from about 30 minutes to about 24 hours before administration of the bisphosphonate. 26. The method according to claim 24, characterized in that said bisphosphonate is selected from the group consisting of: alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and their pharmaceutically acceptable salts and mixtures thereof . 27. The method according to any of claims 23-26, characterized in that said histamine H2 blockers or proton pump inhibitors are selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole. 28. The composition of accessories is indicated by the fact that it consists of: (a) at least one pharmaceutically effective unit dose of bisphosphonate for oral administration, i (b) at least one pharmaceutically effective unit dose of a histamine H2 receptor blocker or proton pump inhibitor. 29. Accessories according to claim 28, characterized in that said bisphosphonate is selected from the group consisting of: alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and their pharmaceutically acceptable salts and mixtures thereof . 30. The method according to claim 29, characterized in that said histamine H2 blockers or proton pump inhibitors are selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole. 31. Use of a bisphosphonate for the manufacture of a medicament for inhibiting bone resorption in mammals, wherein said medicament is adapted for oral administration in unit dose form according to a continuous dosing schedule, with a dosing interval of from about 3 days to about every 16 days. 32. Use of a bisphosphonate for the manufacture of a medicament for inhibiting bone resorption in mammals, characterized in that said medicament is adapted for oral administration in the form of a unit dose according to a continuous dosing schedule with a dosing interval selected from the group consisting of: dosing once a week, dosing twice times a week, biweekly dosing and dosing twice a month. 33. Use of a bisphosphonate according to claim 32, characterized in that said bisphosphonate is selected from the group consisting of: alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and their pharmaceutically acceptable salts and their mixtures. 34. Use of a bisphosphonate according to claim 32, characterized in that said bisphosphonate is selected from the group consisting of alendronate, and its pharmaceutically acceptable salts and mixtures thereof. 35. Use of a bisphosphonate according to claim 34, characterized in that the pharmaceutically acceptable salt is alendronate monosodium trihydrate. 36. Use of a bisphosphonate according to claim 35, characterized in that said mammals are humans. 37. Use of a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis in a mammal in need thereof, wherein said medicament is adapted for oral administration in unit dose form according to a continuous dosing schedule, with a dosing interval of from about 3 days to about every 16 days. 38. Use of a bisphosphonate for the manufacture of a medicament for the treatment of osteoporosis in a mammal in need thereof, wherein said medicament is adapted for oral administration in unit dose form according to a continuous dosing schedule with a dosing interval selected from the group consisting of: once weekly dosing , dosing twice a week, dosing twice a week and dosing twice a month. 39. Use of a bisphosphonate according to claim 38, characterized in that said mammals are humans. 40. Use of bisphosphonates according to claim 39, indicated by the fact that the mentioned dosage interval is once a week, and the mentioned unit dose contains about 70 mg of alendronate monosodium trihydrate, based on active alendronic acid. 41. The use of bisphosphonates according to claim 39, indicated by the fact that the mentioned dosage interval is twice a week, and the mentioned unit dose contains about 35 mg of alendronate monosodium trihydrate, based on active alendronic acid. 42. Use of a bisphosphonate for the manufacture of a medicament for the prevention of osteoporosis in mammals in need thereof, wherein said medicament is adapted for oral administration in unit dose form according to a continuous dosing schedule, with a dosing interval of from about 3 days to about every 16 days. 43. Use of a bisphosphonate for the manufacture of a medicament for the prevention of osteoporosis in a mammal in need thereof, characterized in that said medicament is adapted for oral administration in the form of a unit dose according to a continuous dosing schedule with a dosing interval selected from the group consisting of: dosing once a week , dosing twice a week, dosing twice a week and dosing twice a month. 44. Use of a bisphosphonate according to claim 43, characterized in that said mammals are humans. 45. Use of bisphosphonates according to claim 44, indicated by the fact that the mentioned dosing interval is once a week, and the mentioned unit dose contains about 35 mg of alendronate monosodium trihydrate, based on active alendronic acid. 46. Use of a combination of a bisphosphonate and a histamine H2 blocker or a proton pump inhibitor, characterized in that a drug for inhibiting bone resorption in mammals is produced, which consists of sequential oral administration of an effective amount of a unit dose of a histamine H2 blocker or a proton pump inhibitor and a unit dose of a bisphosphonate according to continuous dosing schedule, with a dosing interval of about 3 days to about 16 days. 47. Use of a combination of a bisphosphonate and a histamine H2 blocker or a proton pump inhibitor, characterized in that a drug for inhibiting bone resorption in mammals is produced, which consists of sequential oral administration of an effective amount of a unit dose of a histamine H2 blocker or a proton pump inhibitor and a unit dose of a bisphosphonate according to continuous dosing schedule, with a dosing interval selected from the group consisting of: once weekly dosing, twice weekly dosing, biweekly dosing, and twice monthly dosing. 48. A pharmaceutical kit used in the inhibition of bone resorption in mammals, characterized in that it contains at least one effective unit dose of a bisphosphonate for oral administration according to a continuous schedule characterized by: (a) said unit dose of bisphosphonate contains about 70 mg, based on active alendronic acid, of a bisphosphonate selected from the group containing alendronate, its pharmaceutically acceptable salts or esters, and their mixtures. (b) said continuous schedule is once a week, and (c) said kit contains a reminder to take said unit dose. 49. Pharmaceutical accessories, according to claim 48, characterized in that the unit doses are arranged according to the order of administration. 50. Pharmaceutical kit, according to claim 49, characterized in that said reminder indicates that the unit dose is taken once a week. 51. Pharmaceutical kit, according to claim 50, characterized in that said reminder indicates that the unit dose is taken every week, every 2 weeks, every 3 weeks, every 4 weeks. 52. Pharmaceutical kit, according to claim 51, characterized in that said reminder indicates that the unit dose is taken once during a period of 7 days