MXPA00000789A - Method for inhibiting bone resorption - Google Patents

Abstract

Disclosed are methods for inhibiting bone resorption in mammals while minimizing the occurrence of or potential for adverse gastrointestinal effects. Also disclosed are pharmaceutical compositions and kits for carrying out the therapeutic methods disclosed herein. The compounds are bisphosphonates selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etridronate, ibandronate, risedronate, piridronate, pamidronate, zolendronate, optionally in combination with a histamine H2 antagonist.

Description

METHOD FOR INHIBITING BONE RESTORATION CROSS REFERENCE TO RELATED REQUESTS The present invention is related to United States Application No. 09 / 060,419 of April 15, 1998 and US Provisional Applications to Serial Nos. 60 / 053,535 on July 23, 1997 and 60 / 053,351 of the July 1997, the contents of which are incorporated herein by reference. 10 FIELD OF THE INVENTION The present invention relates to oral methods for inhibiting bone resorption in a mammal while minimizing the occurrence of or potential for adverse gastrointestinal effects. These methods consist in orally administering to a mammal in need thereof a pharmaceutically effective amount of a bisphosphonate as a unit dose according to a continuous program having a dosage range selected from the group consisting of dosing once a week, Dosage twice a week, dosing every two weeks, and dosing every two months. The present invention also relates to pharmaceutical compositions and equipment useful for carrying out these methods.

BACKGROUND OF THEINVENTION A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, and malignant hypercalcemia. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in post-menopausal women. Osteoporosis is a systemic skeletal disorder characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Because osteoporosis, as well as other disorders associated with bone loss, are chronic conditions, it is believed that adequate therapy will generally require chronic treatment. Multiple-core cells called osteoclasts are responsible for causing bone loss through a procedure known as bone resorption. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of generalized or localized bone disorders caused by or associated with abnormal bone resorption. See H. Fleisch, Bisphosphonates in Bone Disease, From The Laboratory To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated by * * reference to the present in its entirety. Currently, there is a large amount of preclinical and clinical data for the potent bisphosphonate alendronate compound. Evidence suggests that other bisphosphonates such as risedronate, tiludronate, vandronate and zolendronate have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone resorption. An older bisphosphonate compound, etidronate, also inhibits bone resorption. However, unlike the more potent bisphosphonates, etidronate impairs mineralization at doses used clinically, and may give rise to osteomalacia, a disease that results in an undesirable decrease in bone mineralization. See Boyce, B. F., Fogelman, I., Ralston, S. et al. (1984) Lancet 1 (8381), pp. 821-824 (1984), and Gibbs, C.J., Aaron, J. E .; Peacock, M. (1986) Br. Med. J. 292, pp. 1227-1229 (1986), both of which are incorporated by reference to the present in its entirety. Despite its 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, pp. 288-298 (September 1995), which are incorporated by reference to the present in its entirety. Intravenous administration has been used to overcome this problem of bioavailability. However, intravenous administration is expensive and inconvenient, especially when the patient must receive an intravenous infusion lasting several hours during repeated occasions. If oral administration of the bisphosphonate is desired, relatively high doses should be administered to compensate for the low 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 after taking it. However, many patients find that such a need for fasting on a daily basis is inconvenient. Moreover, oral administration has been associated with adverse gastrointestinal effects, especially those related to the esophagus. See Fleisch, Id. These effects appear to be related to the potential irritant of bisphosphonate in the esophagus, a problem that is increased by the presence of gastric acid reflux. For example, bisphosphonate, pamidronate has been associated with ulcers of the esophagus. See E.G. Lufkin et al., Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, 4: 320-322 (1994), which is incorporated by reference herein in its entirety. Although not as common, 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, pp. 1016-1021 (1996), D.O. Castell, Pili Esophagitis - The Case of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 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 by reference herein in their entirety. The degree of adverse gastrointestinal effects of bisphosphonates has been shown to be increased by increasing the 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, pp. 144-152 (August 1995), which is incorporated by reference to the present in its entirety. In addition, these adverse effects on the esophagus appear to be more prevalent in patients who do not take the bisphosphonate with an adequate amount of fluid or who lie shortly after dosing, thereby increasing the chance of reflux in the esophagus. Current oral bisphosphonate therapies generally fall into two categories: 1) those therapies that use continuous daily treatment, and 2) those therapies that utilize a cyclic treatment regimen and rest periods. Continuous daily treatment regimens typically involve the chronic administration of relatively low doses of the bisphosphonate compound, in order to provide the desired cumulative therapeutic dose during the course of the treatment period. However, continuous daily dosing has the potential disadvantage of causing adverse gastrointestinal effects due to repetitive, continuous, and additive irritation to the gastrointestinal tract. In addition, because bisphosphonates should be taken on an empty stomach followed by fasting and maintaining an upright posture for at least 30 minutes, many patients find that daily dosing is annoying. These factors can therefore interfere with compliance on the part of the patient, and in severe cases still require that the treatment cease. Cyclic treatment regimens were developed because some bisphosphonates, as etidronate, when they occur daily for more than several 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, of August 2, 1988, which is hereby incorporated by reference in its entirety, discloses a cyclic regime developed with the intention of minimizing the decline in mineralization of bone while still providing a therapeutic antiresorptive effect. In general, cyclic regimens are characterized as being intermittent, as opposed to continuous treatment regimens and have periods of treatment during which the bisphosphonate is administered and periods without treatment to allow the systemic level of the bisphosphonate to return to the baseline. However, cyclic regimens, in relation to continuous dosing, seem to result in a reduced therapeutic antiresorption effectiveness. The data on risedronate suggest that cyclic dosing is in fact less effective than continuous daily dosing to maximize the antiresorptive effects of bone. See L.

Mortensen, et al., Prevention of Early Ptermenopausal Bone Loss by Risedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1 p. S140 (1995), which is incorporated by reference to the present in its entirety. Additionally, such cyclic regimens do not eliminate or minimize adverse gastrointestinal effects, because such regimens typically use multiple daily dosing periods. In addition, cyclic regimens are annoying to administer and have the disadvantage of poor compliance on the part of the patient and consequently compromise therapeutic efficacy. U.S. Patent No. 5,366,965, to Strein, November 22, 1994, which is incorporated herein by reference in its entirety, attempts to address the problem of adverse gastrointestinal effects by administering a polyphosphonate compound, either orally, subcutaneous, or intravenous, according to an intermittent dosing schedule that has a period of inhibition of bone resorption and a rest period without treatment. However, the regimen has the disadvantage of not being continuous and regular, and requires periods without treatment from 20 to 120 days. PCT Application No. WO 95/30421, to Goodship et al, November 16, 1995, which is incorporated by reference herein in its entirety, discloses methods to prevent prosthetic loss and migration using various bisphosphonate compounds. The administration of a partial dose once a week of the bisphosphonate compound is described. However, the reference fails specifically to address the problem of adverse gastrointestinal effect or to describe the administration of larger or multiple dosages. * It has been observed from the current teachings that cyclical and daily treatment regimens have disadvantages, and that there is a need to develop a dosing regimen to overcome these disadvantages. In the present invention, it is discovered that adverse gastrointestinal effects that may be associated with daily or cyclic dosing regimens can be minimized by administering the diphosphonate at a relatively high unit dose according to a continuous schedule having a dosing range selected from the consistent group of dosing once a week, dosing twice a week, dosing every two weeks, and dosing every two months. In other words, it has been found that administration of a bisphosphonate at a relatively high dosage at a relatively low dosing frequency causes less adverse gastrointestinal effects, particularly effects on the esophagus, compared to the administration of a relatively low dosage at a frequency of relatively high dosage. This result is surprising in view of the teachings that suggest that adverse gastrointestinal effects would be expected to be increased as a function of increasing bisphosphonate dosage. Such methods of administration of the present invention would be especially beneficial for treating patients who have been identified as suffering from or are susceptible to higher gastrointestinal disorders, for example, £ 2 ££ fJ £ X? gastrointestinal reflux disease (ie "GERD"), esophagitis, dyspepsia (ie heartburn), ulcers, and other related disorders. In such patients, conventional bisphosphonate therapy could potentially increase or induce such upper gastrointestinal disorders. From the point of view of the patient's lifestyle, the methods of the present invention would be more convenient than the daily or cyclic dosing regimens. Patients would be less frequently subjected to the inconvenience of having to take the medication with an empty stomach and having to fast for at least 30 minutes after dosing. In addition, patients would not need to stick to a complex dosing regimen. The methods of the present invention are likely to have the advantage of promoting better compliance by the patient, which in turn can translate into better therapeutic efficacy. It is an object of the present invention to provide methods for inhibiting bone resorption and conditions associated therewith. It is another object of the present invention to provide methods for treating abnormal bone resorption and conditions associated therewith. It is another object of the present invention to provide methods for preventing abnormal bone resorption and conditions associated therewith. It is another object of the present invention to provide methods that are oral methods.

It is another object of the present invention to provide such methods in humans. It is another object of the present invention to provide such methods in patients who have been identified as suffering from or are susceptible to upper gastrointestinal disorders, for example gastrointestinal reflux disease (ie "GERD"), esophagitis, dyspepsia (ie heartburn), ulcers, and other related disorders. It is another object of the present invention to provide such methods while minimizing the occurrence of or potential for adverse gastrointestinal effects. It is another object of the present invention to provide such methods comprising a continuous dosing schedule having a dosage range selected from the group consisting of weekly dosing, dosing twice a week, dosing every two weeks, and dosage every two months. It is another object of the present invention to provide such methods comprising a continuous dosing schedule having a dosing frequency in the scale from once every 3 days to approximately once every 16 days. It is another object of the present invention to provide such methods in which the continuous dosing schedule is maintained until the desired therapeutic effect is achieved. It is another object of the present invention to treat or prevent the & sae abnormal bone resorption in an osteoporotic mammal, preferably an osteoporotic human. It is another object of the present invention to provide pharmaceutical compositions and equipment useful in the methods herein. These and other objects will be apparent from the detailed description that follows.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for inhibiting bone resorption in a mammal in need thereof, while minimizing the occurrence of or potential for adverse gastrointestinal effects, said method comprising orally administering to said mammal a pharmaceutically effective amount of a bisphosphonate. as a unit dose according to a continuous program having a dosage range selected from the group consisting of dosing once a week, dosing twice a week, dosing every two weeks, and dosing every two months, wherein Continuous program is maintained until the desired therapeutic effect for said mammal is achieved. In other embodiments, the present invention relates to methods comprising a continuous dosing schedule having a dosing periodicity once every 3 days to once every 16 days.

In another embodiment, the present invention relates to methods of treating abnormal bone resorption in a mammal in need of such treatment. In another embodiment, the present invention relates to methods for preventing the abnormal resorption of bone in a mammal in need of such prevention. In other embodiments, the present invention relates to such methods useful in humans. In other embodiments, the present invention relates to such methods useful in humans identified as having or being susceptible to upper gastrointestinal disorders. In other embodiments, the present invention relates to methods of treating or preventing osteoporosis in a mammal. In other embodiments, the present invention relates to methods of treating or preventing osteoporosis in a human. In other embodiments, the present invention relates to methods of inhibiting bone resorption, or treating or preventing the abnormal bone resorption in a human comprising administering said human from 8.75 mg to 140 mg, on active basis of alendronic acid. , of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof. In other embodiments, the present invention relates to a pharmaceutical composition comprising from 8.75 mg to 140 mg, based on active of alendronic acid, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof. the same. All percentages and relationships used herein, unless otherwise indicated, are by weight. The present invention may comprise, consist of or consist essentially of the essential as well as optional ingredients, components, and methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photomicrograph (total 270 X amplification) of canine esophagus tissue (embedded in paraffin and marked with hematoxylin and eosin) of an animal sacrificed immediately after infusion of at least 5 separate doses of 50 ml of gastric juice simulated administered for 5 consecutive days. Figure 2 is a photomicrograph (total 270X amplification) of canine esophagus tissue (embedded in paraffin and labeled with hemotoxylin and eosin) of an animal sacrificed immediately after infusion of the last of five separate doses of 50 ml of 0.20 mg / ml of alendronate in simulated gastric juice administered for five consecutive days. Figure 3 is a photomicrograph (total amplification 270X) of canine esophagus tissue (embedded in paraffin and marked with hematoxylin and jeos-eosin) of an animal sacrificed 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 (total amplification 270X) of canine esophagus tissue (paraffin embedded and marked with hematoxylin and eosin) of an animal sacrificed 7 days after infusion with a single 50 ml dose of 0.80 mg / ml of alendronate in simulated gastric juice. Figure 5 is a photomicrograph (total amplification 270X) of canine esophagus tissue (embedded in paraffin and marked with hematoxylin and eosin) of an animal sacrificed 7 days after the infusion of the last of 4 separate doses of 50 ml of 0.80 mg / ml of alendronate in simulated gastric juice administered once a week, ie once every 7 days. Figure 6 is a photomicrograph (total amplification 270X) of canine esophagus tissue (embedded in paraffin and marked with hematoxylin and eosin) of an animal sacrificed 4 days after the infusion of the last of 8 doses separately from 50 ml of 0.40 mg / ml of alendronate in simulated gastric juice administered twice a week, ie once every 3-4 days. Figure 7 is a photomicrograph (total 270X amplification) of canine esophagus tissue (paraffin embedded and marked with hematoxylin and eosin) of an animal killed immediately after the infusion of the last of five separate doses of 50 ml of 0.20 mg / ml of risedronate in simulated gastric juice administered for five consecutive days. Figure 8 is a photomicrograph (total amplification 270X) of canine esophagus tissue (paraffin embedded and marked with hematoxylin and eosin) of an animal sacrificed immediately after infusion of the last of five separate doses of 50 ml of 4.0 mg / ml of tiludronate in simulated gastric juice administered for five consecutive days.

DESCRIPTION OF THE INVENTION The present invention relates to a method, preferably an oral method, for inhibiting bone resorption in a mammal in need thereof, while minimizing the occurrence of or potential for adverse gastrointestinal effects. The present invention relates to methods for treating or preventing the abnormal resorption of bone in a mammal in need of such treatment or prevention. The methods of the present invention comprise orally administering to a mammal a pharmaceutically effective amount of a bisphosphonate as a unit dose, wherein said dose is administered according to a continuous schedule having a dosage range selected from the group consisting of dosage once a week, dosage twice a week, dosage every two weeks, and dosage every two months. In other embodiments, the present invention relates to methods comprising a continuous dosing schedule having a dosing periodicity on the scale from once every 3 days to once every 16 days. Typically, the continuous dosing schedule is maintained until the desired therapeutic effect for the mammal is achieved.

The present invention uses higher unit doses of the chosen, the potential for adverse gastrointestinal effects is minimized. Moreover, the method is more convenient because the disadvantages associated with daily dosing are minimized. The methods of the present invention are generally administered to mammals in need of bisphosphonate therapy. Preferably the mammals are human patients, particularly human patients in need of inhibiting bone resorption, such as patients in need of treatment or prevention of abnormal bone resorption. The methods of administration of the present invention are especially useful for administering bisphosphonate therapy to human patients who have been identified as suffering from or are susceptible to upper gastrointestinal disorders, for example GERD, esophagitis, dyspepsia, ulcers, etc. In such patients conventional bisphosphonate therapy could potentially cause or induce such upper gastrointestinal disorders. The term "pharmaceutically effective amount", as used herein, means that amount of the bisphosphonate compound, which will achieve the desired therapeutic effect or response when administered in accordance with the desired treatment regimen. A pharmaceutically effective amount of the bisphosphonate is an amount that inhibits bone resorption. The term "minimize the occurrence of or potential for adverse gastrointestinal effects", such as JJ ln 1a present, means reducing, preventing, decreasing, or attenuating the occurrence of or the potential to incur unwanted side effects in the gastrointestinal tract, is say, the esophagus, stomach, intestines, and rectum, particularly the upper gastrointestinal tract, that is, the 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" can be associated with the formation of bone that has an abnormal structure. The term "inhibition of bone resorption", as used herein, means treating or preventing bone resorption by directly or indirectly altering osteoclast formation or activity. The inhibition of bone resorption refers to the treatment or prevention of bone loss, especially the inhibition of bone removal existing either from the mineral phase and / or the organic matrix phase, through direct or indirect alteration of formation or osteoclast activity. The terms "continuous program" or "continuous dosing schedule", as used, mean that the dosage regimen is repeated until desired therapeutic effect. The continuous program or continuous dosing program is distinguished from cyclic or intermittent administration. The term "until the desired therapeutic effect is achieved", as used herein, means that the bisphosphonate compound is administered continuously, in accordance with the chosen dosage schedule, until such time as the clinical or medical effect. sought for the disease or disorder is observed by the doctor or researcher. For treatment methods of the present invention, the bisphosphonate compound is administered continuously until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass or an abnormal bone structure replacement with more normal bone structure are the desired objectives. For prevention methods of the present invention, the bisphosphonate compound is administered continuously for as long as necessary to avoid unwanted disease. In such instances, maintenance of bone mass density is often the goal. Non-limiting examples of administration periods may be on the scale of 2 weeks to the remaining life period of the mammal. For humans, the administration periods may be in the range of 2 weeks to the remaining life of the human, preferably from 2 weeks to 20 years, more preferably from 1 month to 20 years, more preferably from 6 months to 10 years, and more preferably * ^% from 1 year to 10 years. mw METHODS OF THE PRESENT INVENTION The present invention comprises methods for inhibiting bone resorption in mammals. The present invention also comprises the treatment of abnormal bone resorption in mammals. The present invention also comprises methods for preventing abnormal bone resorption in mammals. In preferred embodiments of the present invention, the mammal in a human. The methods of the present invention do not have the disadvantages of current treatment methods that can cause or increase the potential for adverse gastrointestinal effects, or which require bothersome, irregular, or complicated dosing regimens. The present invention comprises a continuous dosing program in which a unit dose of the bisphosphonate is administered on a regular basis according to a dosage range selected from the group consisting of dosing once a week, dosing twice a week, dosing each two weeks and dosing every two months. By dosing once a week means that a unit dose of the bisphosphonate is administered once a week, i.e. once during a period of seven days, preferably on the same day of each week. In the dosing regimen once a week, the unit dose is generally administered approximately every seven days. A non-limiting example of a two-week regimen once a week would encompass the administration of a unit dose of the bisphosphonate every Sunday. It is preferred that the unit dose is not administered on consecutive days, but the once-a-week dosing regimen may include a dosing regimen in which unit doses are administered on two consecutive days that fall within two different week periods . Dosing twice a week means that a unit dose of the bisphosphonate is administered twice a week, i.e. twice during a period of seven days, preferably on the same two days of each weekly period. In the dosing regimen twice a week, each unit dose is usually administered every three to four days. A non-limiting example of a dosing regimen of twice a week would encompass the administration of a unit dose of bisphosphonate every Sunday and Wednesday. It is preferred that the unit dose is not administered on the same day and or on consecutive days, but the dosing regimen of twice a week may include a dosing regimen in which the unit doses are administered on two consecutive days within a weekly period or different weekly periods. By dosing every two weeks means that a unit dose of the bisphosphonate is administered once during a period of two weeks, i.e. once during a period of 14 days, preferably on the same day during each two week period. In the dosing regimen of two weeks, cads sósís unit is usually administered every fourteen days. A non-limiting example of a dosing regimen every two weeks would encompass the administration of a unit dose of the bisphosphonate every alternate Sunday. It is preferred that the unit dose is not administered on consecutive days, but the dosing regimen of every two weeks may include a dosing regimen in which the unit dose is administered on two consecutive days within two different periods of two weeks. . Dosing twice a month means that a unit dose of the bisphosphonate is administered twice, that is twice, during a monthly calendar period. With the twice-monthly regimen, doses are preferably given on the same dates of each month. In the dosing regimen of twice a month, each unit dose is usually administered every fourteen to sixteen days. A non-limiting example of a dosing regimen every two weeks could encompass dosing on or about the first of the month and on the fifteenth, that is, the midpoint of the month. It is preferred that the unit doses are not administered on the same or consecutive days but the twice-monthly dosing regimen may include a dosage regimen in which the unit doses are administered on two consecutive days within a monthly period, or different monthly periods. The twice-monthly regimen is defined herein as being different from, and not encompassing, the dosing regimen twice a week because the two regimens have a different periodicity and result in the administration of different numbers of dosage for long periods of time. For example, over a period of one year, a total of approximately twenty-four doses would be administered according to the twice-monthly regimen (because there are twelve calendar months in a year), while a total of approximately twenty-six doses would be administered according to the dosage regimen every two weeks (because there are fifty-two weeks in a year). In additional embodiments or descriptions of the present invention, the unit dose is given with a periodicity on the scale from once every three days to once every sixteen days. The methods and compositions of the present invention are useful for inhibiting bone resorption and for treating and preventing abnormal bone resorption and conditions associated therewith. Such conditions include generalized and localized bone loss. In addition, the creation of bone that has an abnormal structure, as in Paget's disease, may be associated with abnormal bone resorption. The term "generalized bone loss" means loss of bone at multiple sites of the skeleton or through the skeletal system. The term "localized bone loss" means loss of bone at one or more specific defined sites of the skeleton. Generalized bone loss is often associated with osteoporosis. Osteoporosis is more common in postmenopausal women, in whom the production of estrogen has been greatly reduced. However, osteoporosis can also be induced by steroids and has been observed in male people due to age. Osteoporosis can be induced by disease, for example rheumatoid arthritis, it can be induced by secondary causes, for example glucocorticoid therapy, or it can come without an identifiable cause, ie idiopathic osteoporosis. In the present invention, preferred methods include the treatment or prevention of abnormal bone resorption in osteoporotic humans. Localized bone loss has been associated with periodontal disease, with bone fractures, and with periprosthetic osteolysis (in other words where bone resorption has occurred close to a prosthetic implant). Generalized or localized bone loss can occur from lack of use, which is often a problem for those confined to a bed or a wheelchair, or for those who have an immobilized cast limb or an orthopedic appliance. The methods and compositions of the present invention are useful for treating and / or preventing the following disease conditions or conditions: osteoporosis, which may include post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, ideopathic osteoporosis , Paget's disease, bone production that increases abnormally, periodontal disease, loss of bone ISel? t? ada associated with periprosthetic cofetolysis; and bone fractures. The methods of the present invention are designed to specifically exclude methods for the treatment and / or prevention of prosthetic loss and prosthetic migration in mammals as described in PCT application WO 95/30421 to Goodship et al., Of 16 November 1995, which is incorporated by reference to the present in its entirety.

Bisphosphonates The methods and compositions of the present invention consist of a bisphosphonate. The bisphosphonates of the present invention correspond to the chemical formula: PO3H2 wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, substituted C1-C30 alkyl, C1-C10 alkyl or dialkyl substituted by NH2, alkoxy of C1-C10, alkyl or C1-C10 phenyl substituted by thio, C1-C10 alkyl substituted by phenyl, pyridyl, furanyl, pyrrolidinyl, imidazoyl, and benzyl. In the above chemical formula, the alkyl groups can be straight, branched, or cyclic, with the proviso that enough atoms are selected for the chemical formula. The substituted C 1 -C 30 alkyl may include a wide variety of substituents, non-limiting examples of which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH 2, alkyl or C 1 -C 10 dialkyl substituted by NH 2 , OH, SH, and C1-C10 alkoxy. In the above chemical formula, A can include X and X can include A in such a way that the two portions can be part of the same cyclic structure. The above chemical formula is also designed to encompass carboxylic complex structures, aromatic structures and heteroatom for substituents A and / or X, non-limiting examples of which include 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 C 1 -C 30 alkyl, substituted C 1 -C 30 alkyl, halogen, and C 1 -C 10 alkyl or phenyl replaced by uncle. The most preferred structures are those in which A is selected from the group consisting of H, OH and Cl and X is selected from the group consisting of C 1 -C 30 alkyl, substituted C 1 -C 30 alkyl, Cl and chlorophenylthio. It is more preferred when A is OH and X is a 3-aminopropyl portion, so that the resulting compound is a 4-amino-1-hydroxybutylidene-1,1-bisphosphonated pyridine. The pharmaceutically acceptable salts and derivatives of the salts include those selected from the group consisting of alkali metal, alkali metal, ammonium and mono-, di, tri-, or tetra-alkyl C1-C30 substituted ammonium. 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 salts and derivatives of the bisphosphonates have the same pharmacological properties in general as the free acid form from which they are derived and are acceptable from a toxicity point of view. It should be noted that the terms "bisphosphonate" and "bisphosphonates", as used herein to refer to the therapeutic agents of the present invention, mean that they also encompass diphosphonates, bisphosphonic acids, and diphosphonic acids, as well as salts and derivatives of those materials. . The use of a specific nomenclature to refer to the bisphosphonate or bisphosphonates does not mean limiting the scope of the present invention, unless specifically indicated. Because the mixed nomenclature currently in use by those of ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is based on weight of acid active, "%" & ' Jr * ». unless otherwise indicated in this letter. For example, the phrase "about 70 mg of a bone resorption inhibiting bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, or a weight basis of alendronic acid active" means that the The amount of the selected bisphosphonate compound is calculated based on 70 mg of alendronic acid. Non-limiting examples of bisphosphonates useful herein include the following: alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. Alendronate (also known as sodium alendronate or monosodium trihydrate), monosodium trihydrate of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. Alendronic acid and alendronate are described in U.S. Patents 4,922,007, Kieczykowski et al., May 1, 1990, and 5,019,651, Kieczykowski, May 28, 1991, both of which are incorporated by reference to the present in its entirety. The cycloheptylaminomethylene-1, 1-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), as described in U.S. Patent 4,970,335, to Isomura et al., November 13, 1990, which is incorporated by reference to the present in totality 1, 1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in the Belgian patent 672,205 (1966) and J. Org. Chem. 32, 4111 (1967), both of which are incorporated by reference herein 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 United States Patent No. 4,927,814, of May 22, 1990, which is incorporated by reference to the present in its entirety. 6-Amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate). 3- (Dimethylamino) -1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate). 3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate). Acid [2- (2-pyridinyl) ethylidene] -1,1-bisphosphonic (pyridronate) is disclosed in U.S. Patent No. 4,761, 406, which is incorporated by reference in its entirety. 1-Hydroxy-2- (3-pyridinyl) -ethylidene-1,1-bisphosphonic acid (risedronate). (4-Chlorophenyl) thiomethane-1,1-disphosphonic acid (tiludronate) acid as described in U.S. Patent 4,876,248, to Breliere et al., Of October 24, 1989, which is incorporated by reference herein. your identity 1-Hydroxy-2- (1 H-imidazol-1-yl) ethylidene-1,1-bisphosphonic acid (zolendronate). Preferred are the phosphonates selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, and mixtures thereof. The most preferred is alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof. The most preferred is monosodium trihydrate of alendronate.

Pharmaceutical Compositions The compositions useful in the present invention consist of a pharmaceutically effective amount of a bisphosphonate. The bisphosphonate is typically administered in admixture with pharmaceutically acceptable diluents, excipients, or carriers, collectively referred to herein as "carrier materials", suitably selected with respect to oral administration, ie, tablets, capsules, elixirs, syrups , effervescent compositions, powders and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet, or capsule, or powder, the active ingredient may be combined with an inert pharmaceutically acceptable, oral, non-toxic carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium, mannitol. , sorbitol, sodium syrup and similar; for oral administration in liquid form, for example, elixirs and syrups, effervescent compositions, the components of the oral drug can be combined with any pharmaceutically acceptable, non-toxic, oral inert carrier, such as ethanol, glycerol, water and the like. Moreover, when desired or needed, binders, lubricants, disintegrating agents, pH regulators, coatings, and suitable coloring agents can also be incorporated. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. A particularly preferred tablet formulation for alendronate monosodium trihydrate is that described in U.S. Patent No. 5,358,941, to Bechard et al, October 25, 1994, which is incorporated by reference herein in its entirety. The compounds used in the present method can also be coupled with soluble polymers as objective drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide, and the like. The precise dosage of the bisfonate will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen for the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. In this way, a precise pharmaceutically effective amount can not be specified in advance and can be easily determined by the caregiver or physician. Adequate amounts can be determined by routine experimentation from animal models and human clinical studies. In general, an appropriate amount of bisphosphonate is chosen to obtain a bone resorption inhibiting effect, i.e. an inhibiting amount of bone reabsorption of the bisphosphonate is administered. For humans an effective oral dose of bisphosphonate is typically from 1.5 to 6000 μg / kg of body weight and preferably from 10 to 2000 μg / kg of body weight. For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dose will typically consist of 8.75 mg to 140 mg of the compound alendronate, based on active weight of alendronic acid. For dosing once a week, an oral unit dose comprises 17.5 mg to 70 mg of the compound alendronate, based on active weight of alendronic acid. Examples of weekly oral dosages include a unit dose that is useful for the prevention of osteoporosis comprising 35 mg of the compound alendronate, and a unit dose that is useful J? >; for treating osteoporosis comprising 70 mg of the compound alendronate. For dosing twice a week, an oral unit dose comprises from 8.75 mg to 35 mg of the compound alendronate, based on active weight of alendronic acid. Exemplary twice-weekly oral dosages include a unit dose that is useful for the prevention of osteoporosis comprising 17.5 mg of the compound alendronate, and a unit dose that is useful for treatment of osteoporosis, comprising 35 mg of the compound alendronate. For dosing twice a week or twice a month, an oral unit dose comprises from 35 mg to 140 mg of the alendrohate compound based on active weight of alendronic acid. Examples of oral doses of twice a week or twice a month include a unit dose which is useful for the prevention of osteoporosis comprising 70 mg of the compound alendronate, and a unit dose which is useful for treatment of osteoporosis, comprising 140 mg of the alendronate compound. Non-limiting examples of oral compositions comprising alendronate, as well as other bisphosphonates, are illustrated in the examples, below.

The administration of histamine H2 receptor blockers and / or proton pump inhibitors with bisphosphonates In further embodiments, the methods and compositions of the present invention may also consist of a histamine H2 receptor blocker (FIG. ie 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. Intern. Med., Vol. 152, pp. 726-732 (April 1992), which is incorporated by reference to the present in its entirety. It has been discovered in the present invention that sequential oral administration of a histamine H2 receptor blocker and / or a proton pump inhibitor, followed by a bisphosphonate can help to further minimize the adverse gastrointestinal effects. In those embodiments, the histamine H2 receptor blocker and / or proton pump inhibitor is administered from 30 minutes to 24 hours before administration of the bisphosphonate. In more preferred embodiments, the histamine H2 receptor blocker and / or proton pump inhibitor is administered from 30 minutes to 12 hours before administration of the bisphosphonate. The dosage of the histamine H2 receptor blocker and / or proton pump inhibitor will depend on the particular compound selected and factors associated with the mammal to be treated, i.e., size, health, etc.

Non-blocking examples of histamine H 2 receptor and / or proton pump inhibitor include those selected from the group consisting of cimetidine, famotidine, α-zatidine, ranitidine, omprazole, and lansoprazole.

Treatment equipment In additional embodiments, the present invention relates to a device for carrying out conveniently and effectively the methods according to the present invention. Such equipment is especially suitable for the supply of solid oral forms such as tablets or capsules. Such equipment preferably includes a number of unit doses. Such equipment may include a card that has the doses oriented for the purpose of its designed use. An example of such equipment is a "bubble pack". Bubble packages are well known in the packaging industry and are widely used to package dosage unit dosage forms. If desired, a memory aid may be provided, for example in the form of numbers, letters, or other marks or with an inserted calendar, which designates the days in the treatment program in which the doses may be administered. Alternatively, dosages of placebo, or calcium or dietary supplements, may be included, either in a manner similar to or different from the bisphosphonate doses, to provide a device in which a dose is taken every day. In those modalities that include a histamine H2 receptor and / or a pump inhibitor 1 > .-r¿íá2 | * ': ¡ís.?! ^, protons, these agents can be included as part of the team.

EXAMPLES The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for purposes of illustration and should not be considered as limitations of the present invention since many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLE 1 Potential irritation of the esophagus The irritation potential of the bisphosphonate esophagus is evaluated using a dog model. The experiments demonstrate the relative irritation potential of the following dosing regimens: placebo (group 1), a single high-dose dosing of alendronate monosodium trihydrate, (group 2) a low-dose dosage of monosodium trihydrate of alendronate administered for five consecutive days (groups 3 and 4), a high-dose dosage of monosodium trihydrate of alendronate administered once a week for four weeks (group 5) , a r-tf ..: dose of half a dose of monosodium trihydrate alendronate administered twice a week for four weeks (group 6), a low dose of risedronate sodium administered for five consecutive days (group 7), and a low dose dosage of disodium tiludronate administered for five consecutive days (group 8). The following solutions are prepared: (1) simulated gastric juice (pH of about 2), ie the control solution. (2) simulated gastric juice (pH of about 2) containing approximately 0.20 mg / mL of alendronate monosodium trihydrate based on active alendronic acid. (3) simulated gastric juice (pH of about 2) containing approximately 0.80 mg / mL of alendronate monosodium trihydrate on alendronic acid active base. (4) simulated gastric juice (pH of about 2) containing approximately 0.40 mg / mL of alendronate monosodium trihydrate based on active alendronic acid. (5) simulated gastric juice (pH of about 2) containing approximately 0.20 mg / mL of risedronate sodium on risedronic acid active base. (6) Simulated gastric juice (pH of about 2) containing about 4.0 mg / mL of disodium tiludronate based on the active ingredient of tiludronic acid.

The gastric juice dissolving 960 mg of pepsin (L-585.228000B003, Fisher Chemicat) in 147 mL of 0.90 (% by weight) NaCl (aqueous), adding 3mL of 1.0 M HCl (aqueous), and adjusting the volume to approximately 300 mL with deionized water. The pH of the resulting solution is measured and if necessary adjusted to 2 using 1.0 M HCl (aqueous) or 1.0 M NaOH (aqueous). The animals used in the experiments are anesthetized and 50 mL of the appropriate solution is administered for 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 approximately 50 mL of simulated gastric juice [solution (1)] on each of five consecutive days. The animals are sacrificed immediately after the last dose is administered. Group 2: this group contains four animals. Each animal is given a dose of 50 mL of simulated gastric juice containing 0.20 mg / mL of alendronate [solution (2)] on each of five consecutive days.

The animals are sacrificed immediately after the last dose is administered. Group 3: this group contains five animals. Each animal is administered a dose of 50 mL of simulated gastric juice containing 0.80 mg / mL of alendronate [solution (3)] in a single day of treatment. The VFS animals are sacrificed 24 hours s fi cte that the dose is administered. Group 4: This group contains five animals. Each animal is administered a dose of 50 ml of simulated gastric juice containing 0.80 mg / ml alendronate [solution (3)] in a single day of treatment. The animals are sacrificed after 7 days of the dose being administered. Group 5: This group contains six animals. Each animal is administered a dose of 50 ml of sham gastric juice containing 0.80 mg / ml alendronate [solution (3)] once a week, ie every seven days, for four weeks. A total of four doses are administered to the animals. The animals are sacrificed 7 days after the last dose is administered. Group 6: This group contains six animals. Each animal is administered a dose of 50 ml of simulated gastric juice containing 0.40 mg / ml alendronate [solution (4)] twice a week, ie every three to four days, for four weeks. A total of eight doses are administered to the animals. The animals are sacrificed four days after the last dose is administered. Group 7: This group contains eight animals. Each animal is administered a dose of 50 ml of simulated gastric juice containing 0.20 mg / ml risedronate [solution (5)] on each day of five consecutive days.

The animals are sacrificed immediately after the last dose is administered. Group 8: This group contains four animals. A dose of 50 ml is administered to each animal | simulated gastric jelly containing 4.0 mg / ml tiludronate [solution (6)] on each of five consecutive days.

The animals are immediately sacrificed after the last dose is administered. The esophagus of each sacrificed animal are removed and prepared for histopathology using standard techniques by incrusting the tissue in paraffin, labeling with hematoxylin and eosin. The sections are examined microscopically. The results of histopathology are summarized in table 1. For animals of group 1 (control group), photomicrographs show that the esophagus is normal with an intact epithelium and absence of inflammatory cells in the submucosa. Figure 1 is a photomicrograph representative of an animal of group 1. For animals of group 2, photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked submucosal inflammation and vacuolation. Figure 2 is a photomicrograph representative of an animal of group 2. For animals of group 3, photomicrographs show that the esophagus has an intact epithelial surface with very light submucosal inflammation and vacuolation. Figure 3 is a photomicrograph representative of an animal of group 3. For animals of group 4, photomicrographs show that the esophagus has an intact epithelium with either minimal inflammation (two of the five animals) or no inflammation (three of the five animals) and without vacuolation. Figure 4 is a photomicrograph representative of a group 4 animal exhibiting minimal inflammation. For animals of group 5, photomicrographs show that the esophagus is normal with an intact epithelium and absence of inflammatory cells in the submucosa. Figure 5 is a photomicrograph representative of an animal of group 5. For animals of group 6, photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked inflammation and submucosal vacuolation. Figure 6 is a photomicrograph representative of an animal of group 6. For animals of group 7, photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked inflammation and submucosal vacuolation. Figure 7 is a photomicrograph representative of an animal of group 7. For animals of group 8, photomicrographs show that the esophagus exhibits a slight ulceration of the epithelial surface and slight inflammation and submucosal vacuolation. Figure 8 is a photomicrograph representative of an animal of group 8. These experiments demonstrate that less severe irritation of the esophagus (comparable to control group 1) is observed from the administration of a single high-dose alendronate (groups 3 and 4) against administration of low concentration doses on consecutive days (group 2). they also show that irritation of the esophagus is observed from the administration of a single high concentration of alendronate on a weekly basis (group 5) or on a two-week basis (group 6) against the administration of doses of low concentration on consecutive days (group 2). These experiments also show that when other bisphosphonates such as risedronate (group 7) or diludronate (group 8) are administered at low concentrations on consecutive days the potential for esophageal irritation is high.

TABLE 1 EXAMPLE 2 Dosing regimen once a week Treatment of osteoporosis Tablets or liquid formulations of alendronate containing 70 mg of alendronate are prepared on the basis of active alendronate (see examples 7 and 8). Tablets or liquid formulations are orally administered to a human patient once a week, preferably preferably once every seven days (eg, every Sunday), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

Prevention of osteoporosis Alendronate tablets or liquid formulations containing approximately 35 mg of alendronate, based on active ingredient alendronate, are prepared (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human patient once a week, ie preferably once every seven days (for example every Sunday), for a period of at least one year. This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

Treatment of osteoporosis Alendronate tablets or liquid formulations containing approximately 35 mg of alendronate, based on active ingredient alendronate, are prepared (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human patient twice a week, preferably once every three or four days (for example every Sunday and Wednesday), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

Prevention of osteoporosis Alendronate liquid tablets or formulations containing approximately 17.5 mg of alendronate are prepared, based on active ingredient alendronate, (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human patient twice a week, preferably once every three or four days (for example every Sunday and Wednesday), for a period of at least one year. This method of administration is useful and convenient to prevent osteoporosis and ^ j "* g f« r .. to minimize particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

EXAMPLE 4 Dosing regimen once every two weeks Treatment of osteoporosis Alendronate tablets or liquid formulations containing approximately 140 mg of alendronate are prepared on the basis of alendronic acid active (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human patient once every two weeks, ie preferably once every fourteen days (eg, on alternate Sundays), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

Prevention of osteoporosis Alendronate liquid tablets or formulations containing approximately 70 mg of alendronate are prepared in an active base of alendronate (see examples 7 and 8). The tablets or liquid formulations are administered orally to a patient every two weeks, ie preferably once every fourteen days (eg, on alternate Sundays), for a period of at least one year. This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

EXAMPLE 5 Dosing regimen twice a month Treatment of osteoporosis Alendronate tablets or liquid formulations containing approximately 140 mg of alendronate are prepared on the basis of alendronic acid active (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human twice a month, ie preferably every fourteen to sixteen days (e.g., the first and fifteenth of each month), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

Sfefe £: Prevention of osteoporosis Tablets are made of liquid formulations of alendronate containing approximately 70 mg of atenonate, on the basis of alendronic acid asset, (see examples 7 and 8). The tablets or liquid formulations are administered orally to a human patient every two weeks, that is once every fourteen to sixteen days (for example, approximately the first and fifteenth of each month), for a period of at least one year. . This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse effects on the esophagus. This method is also useful to improve acceptance and compliance by the patient.

EXAMPLE 6 In additional modalities, tablets or liquid formulations of alendronate are dosed orally, at the desired dosage, according to the dosing schedules of Examples 2-5, to treat or prevent other disorders associated with abnormal bone resorption. In further embodiments, other bisphosphonate compounds are orally administered, at the desired dosage, according to the dosing schedules of Examples 2-5, to treat or prevent osteoporosis and to treat or prevent other disorders associated with abnormal resorption of bone. using mixing and forming techniques as described in U.S. Patent No. 5,358,941 to Bechard et al, October 25, 1994, which is incorporated herein by reference in its entirety. Tablets containing approximately 35 mg of alendronate, on the basis of alendronic acid active, are prepared using the following relative weights of ingredients.

Ingredient Per tablet Per 4000 tablets Trihydrate 45.68 mg 182.72 g monosodium alendronate Lactose anhydrous NF 71.32 mg 285.28 g Cellulose 80.0 mg 320.0 g microcrystalline NF stearate 1.0 mg 4.0 g magnesium NF Croscarmellose 2.0 mg 8.0 g sodium NF The resulting tablets are useful for administration according to the methods of the present invention to inhibit resorption of bone. Similarly, tablets are made consisting of other relative weights of alendronate, on the basis of alendronic acid asset: for example, about 8.75, 17.5, 70, and 140 mg per tablet. In addition, tablets containing other bisphosphonates at suitable levels of active are prepared in a similar manner: for example, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof. In addition, tablets containing bisphosphonate combinations are similarly prepared.

EXAMPLE 8 Liquid bisphosphonate formulation Liquid bisphosphonate formulations are prepared using standard mixing techniques. A liquid formulation containing 70 mg of alendronate monosodium trihydrate, on alendronic acid active basis, for approximately 75 ml of liquid is prepared using the following relative weights of ingredients.

Ingredient Weight Alendronate monosodium trihydrate 91.35 mg Propilparaben sodium 22.5 mg Butylparaben sodium 7.5 mg Sodium citrate dihydrate 1500 mg Anhydrous citric acid 56.25 mg Sodium saccharine 7.5 mg Water cs 75 mL Sodium hydroxide 1 N (aq) cs pH 6.75 The lipid formulation is more useful for administration as a unit dose according to the methods of the present invention for inhibiting bone resorption Similarly, liquid formulations are prepared which consist of other relative weights of alendronate, based on of alendronic acid active, per unit dose: for example 8.75, 17.5, 35, and 140 mg per 75 mL volume.Furthermore, the liquid formulations are prepared to provide other volumes for the unit dosage, for example approximately 135 ml. , liquid formulations are prepared containing other bisphosphonates at appropriate levels of active: for example, cimadronate, clodronate, tiludro nato, etidronate, bandronate, risedronate, pyridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof. In addition, liquid formulations containing bisphosphonate combinations are similarly prepared.

Claims (35)

NOVELTY OF THE INVENTION "• & CLAIMS

1. The use of a bisphosphonate for the manufacture of a medicament for inhibiting bone resorption in a mammal characterized in that said medicament is adapted for oral administration in a unit dose form according to a continuous program having a periodicity of one time each 3 days to once every 16 days.

2. The use of a bisphosphonate for the manufacture of a medicament for inhibiting bone resorption in a mammal wherein said medicament is adapted for oral administration in a unit dosage form according to a continuous program having a dosage range selected from the group consisting of dosing once a week, dosing twice a week, dosing every two weeks, and dosing every two months.

3. The use of a bisphosphonate according to claim 2, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zoledronate, pharmaceutically acceptable salts of the same, and mixtures thereof.

4. The use of a bisphosphonate according to claim 2, wherein the bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

5. The use of a bisphosphonate according to claim 4, wherein said pharmaceutically accepting salt is alendronate monosodium trihydrate.

6. The use of a bisphosphonate according to claim 4, wherein said mammal is a human.

7. The use of a bisphosphonate for the manufacture of a medicament for treating osteoporosis in a mammal in need thereof wherein said medicament is adapted for oral administration in a unit dose form in accordance with a continuous program having a periodicity of once every 3 days to once every 16 days.

8. The use of a bisphosphonate for the manufacture of a medicament for treating osteoporosis in a mammal in need thereof wherein said medicament is adapted for oral administration in a unit dosage form in accordance with a continuous program having a range of dosage selected from the group consisting of dosing once a week, dosing twice a week, dosing every two weeks, and dosing every two months.

9. The use of a bisphosphonate according to claim 8, wherein said mammal is a human.

10. The use of a bisphosphonate according to claim 9, wherein the dosage is once a week and said unit dose consists of 70 mg of alendronic acid active base.

11. The use of a bisphosphonate according to claim 9, wherein said dosage range is twice a week and said unit dose consists of 35 mg of alendronate monosodium trihydrate, on the basis of alendronic acid active.

12. The use of a bisphosphonate according to claim 9, wherein said dosage range is every two weeks and said unit dose comprises 140 mg of alendronate monosodium trihydrate, on alendronic acid active basis.

13. The use according to claim 9, wherein said dosage range is twice a month and said unit dose consists of 140 mg of alendronate monosodium trihydrate, on the basis of alendronic acid active.

14. The use of a bisphosphonate for the manufacture of a medicament for preventing osteoporosis in a mammal in need thereof wherein said medicament is adapted for oral administration in a unit dose form in accordance with a continuous program having a periodicity of once every 3 days to once every 16 days.

15. The use of a bisphosphonate for the manufacture of a medicament for preventing osteoporosis in a mammal in need thereof wherein said medicament is adapted for oral administration in a unit dosage form in accordance with a continuous program having a range of dosage selected from the group consisting of dosing once a week, dosage twice a week, dosage every 2 weeks, and dosage every 2 months.

16. The use of a bisphosphonate according to claim 15, wherein said mammal is a human.

17. The use of a bisphosphonate according to claim 16, wherein said dosage range is once a week and said unit dose consists of 35 mg of monosodium trihydrate of alendronate, on the basis of active alendronic acid.

18. The use of a bisphosphonate according to claim 15, wherein said dosage range is twice a week and said unit dose consists of 17.5 mg of monosodium trihydrate of alendronate, on the basis of active alendronic acid.

19. The use according to claim 15, wherein said dosing interval is every two weeks and said unit dose consists of 70 mg of monosodium trihydrate of alendronate, on the basis of active alendronic acid.

20. The use according to claim 15, wherein said dosing interval is twice a month and said unit dose comprises 70 mg of alendronate monosodium trihydrate, on the basis of alendronic acid active.

21. The use according to any of claims 1-20 wherein said unit dose of bisphosphonate comprises from 1.5 to 6000 mg / kg of body weight.

22. The use according to any of claims 1-20 wherein said unit dose of bisphosphonate comprises from 10 to 2000 mg / kg of body weight.

23. The use of the combination of a bisphosphonate and a histamine H2 receptor blocker or a proton pump inhibitor for the manufacture of a medicament for inhibiting bone resorption in a mammal comprising orally sequentially administering said mammal a pharmaceutically effective amount of a unit dose of a histamine H2 receptor blocker or a proton pump inhibitor and a dosage unit of a bisphosphonate according to a continuous schedule having a dosage range selected from the group consisting of dosage once a week, dosage twice a week, dosage every 2 weeks, and dosage every 2 months.

24. The use of the combination of a bisphosphonate and a histamine H2 receptor blocker or a proton pump inhibitor for the manufacture of a medicament for inhibiting bone resorption in a mammal comprising sequentially administering an effective amount of a unit dose of a histamine H2 receptor blocker or a proton pump inhibitor and a unit dose of a bisphosphonate according to a continuous schedule having a dosage range selected from the group consisting of dosing once a week, dosing 2 times a week, dosage every 2 weeks, and dosage every 2 months.

25. The use according to claim 24 wherein said histamine H2 receptor blocker or proton pump inhibitor is administered from 30 minutes to 24 hours before the administration of said bisphosphonate.

26. The use according to claim 24 wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

27. The use according to any of claims 23-26 wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omerprazole, and lansoprazole.

28. A kit consisting of: (a) at least one pharmaceutically effective oral dosage unit of a bisphosphonate for oral administration, and (b) at least one pharmaceutically effective unit dosage of a histamine H2 receptor blocker or beta-block inhibitor. proton pump.

29. A device according to claim 28, wherein said bisphosphonate is selected from the group consisting of alendronate., cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

30. A device according to any of claims 29, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of: cimetidine, famotidine, nizatidine, ranitidine, omerprazole, and lansoprazole. - A pharmaceutical kit useful for inhibiting bone resorption in a mammal comprising at least one pharmaceutically effective unit dose of a bisphosphonate for oral administration according to a continuous program characterized in that (a) said unit dose of bisphosphonate comprises approximately 70 mg, active base of aledronic acid, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof, (b) said continuous program is once a week, and (c) said equipment it comprises a memory assistant for administering the unit doses. 32. A pharmaceutical equipment according to claim 31, wherein the unit doses are oriented in the pharmaceutical equipment in the order of their designed use. 33. A pharmaceutical equipment according to claim 32 wherein said memory aid indicates that the unit dose is administered once a week. 34. A pharmaceutical equipment according to claim 33, wherein said memory aid indicates that a unit dose is administered in each of the UFHA §É§fel? 2- week 3, and week 4. 35.- A pharmaceutical equipment according to claim 34 wherein the memory aid indicates that said unit dose is administered once during a period of seven days.