TW200300092A - Pharmaceutical composition 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.

Description

200300092 A7 B7 V. Description of the invention (i) The invention relates to US application Serial No. 09 / 060,419, application date April 15, 1998, and US provisional applications Serial Nos. 60 / 053,535, application date July 23, 1997, and 60 / 053,351, application date July 22, 1997, the contents of which are incorporated herein by reference. Scope of the invention The present invention relates to an oral method that inhibits the bone resorption of mammals and reduces the occurrence of potential gastrointestinal side effects to a minimum. Such methods include using a pharmaceutically effective amount of bisphosphonate as a unit dose, and mammals required for oral treatment. According to the continuous treatment process, the administration interval is selected from the group consisting of: once a week, twice a week, and two weeks Dosing once, twice a month. The invention also relates to pharmaceutical compositions and kits for performing such methods. BACKGROUND OF THE INVENTION A variety of conditions in humans and other mammals include abnormal bone aspiration. This condition includes, but is not limited to, osteoporosis, paget's disease, bone loss or osteolysis, and malignant hypercalcemia. The most common such condition is osteoporosis, which most often occurs in 7 menopause women. Osteoporosis is a skeletal disease of the whole body, which is characterized by low skeletal mass and a, and microstructural deterioration, resulting in increased bone fragility and fracture feasibility. Because osteoporosis and other conditions are related to bone loss and are chronic conditions, appropriate chronic treatment is generally required. The process of bone loss caused by multinucleated osteoclasts is called osteoabsorption. Bisphosphonate 疋 is a selective inhibitor of osteoclast inhibition by osteoclasts. These compounds are used to treat or prevent abnormal bone resorption Related, important therapeutics that cause various-like or local osteopathic disorders. This paper standard applies to towels gg * standard (CNS) M specifications (other) <297 public love) ----------- 200300092 A7 B7 V. Description of the invention (2). Reagents. See Η Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated herein by reference in its entirety. Currently, there is a lot of preclinical and clinical data suggesting the potent bisphosphonate compound alendronate. According to the note, other bisphosphonates, such as: risedronate, tiludronate, ibandronate, and zollendronate, and subliminate Polyacid (alendronate) has the same properties and is a highly effective inhibitor of osteoclasts' bone resorption. Older bisphosphonate compounds (etidronate) can also inhibit bone resorption. However, unlike the more potent bisphosphonates, clinical doses of etidronate destroy mineralization and cause chondrosis, leading to a decrease in the mineralization of unfavorable bones. See Boyce, B.F., Fogelman, I., Ralston, S. et al. (1984) Lancet 1 (8381), pp. 821-824 (1984), and Gibbs, C. J., Aaron, JE; Peacock, M. (1986) Br. Med. J. 292, pp. 1227-1229 (1986), both of which are incorporated herein by reference in their entirety. In addition to its therapeutic advantages, the absorption of bisphosphonates in the gastrointestinal pathway is not efficient. See BJ Gertz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl. 3: S13-16 (1993) and BJ Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology &amp; Therapeutics, vol. 58, number 3, pp. 288-298 (September 1995), which is hereby incorporated by reference in its entirety. Intravenous injections can be used to overcome problems with bioavailability. However, intravenous injection is expensive and inconvenient, especially when the patient must repeat the number -5 -_ This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 200300092 A7 B7 V. Description of invention (3) hours When given intravenous perfusion. If oral bisphosphonate treatment is required, a relatively high dose must be taken to compensate for the low bioavailability of the gastrointestinal route. To offset the low bioavailability, patients are generally advised to take bisphosphonates on an empty stomach and fast for at least 30 minutes. However, many patients find this fasting regimen inconvenient. In addition, oral treatment is associated with gastrointestinal side effects, especially with regard to esophageal side effects. See Fleisch, Id. Such effects are related to the potential irritation of the esophagus by bisphosphonates, and in particular the problem of gastric acid reflux makes the problem worse. For example: bisphosphonates, pamidronate are associated with ulcers in the esophagus. 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. Although the use of alendronate (alendronate) causes esophagitis and / or ulcers are not common. See PC De Groen, et al. 5 Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), DO Castell, Pill Esophagitis .-- The Case of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1058-1059 (1996), and UA Liberman et al., Espophagitis and Alendronate, New England Journal of Medicine, vol. 335, no. 124 pp. 1069-1070 (1996), which is hereby incorporated by reference in its entirety. However, the degree of gastrointestinal side effects of bisphosphonates increased with increasing dose. See CH Chestnut et al., Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American ___- 6 -_ This paper size applies to China National Standard (CNS) A4 (210 x 297 male) %)

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J〇 Urnal of Medicine, ν〇 1.99, pp 144 152, (August 1995), the entire text of which is incorporated herein by reference. The side effect on the esophagus is related to the fact that it does not take up the amount of fluid when taking bitenate or bisalt; thus increasing the chance of reflux in the esophagus. At present, oral bisphosphonates are used for treatment-generally divided into two ways: ⑴ daily continuous,% treatment, and (2) the cycle of treatment and rest cycle treatment. The daily continuous treatment regimen involves a relatively low dose of a bisphosphonate compound for therapeutic treatment, with the aim of delivering an appropriate cumulative therapeutic dose during the treatment period. However, the potential disadvantages of continuous daily administration are repeated, sustained, and irritating gastrointestinal effects, which can cause gastrointestinal side effects. At the same time, because of the diphenanthrene phthalate must be taken in the two stomachs, followed by fasting and maintaining the status quo for at least 30 minutes, many patients are very troubled by continuous administration every day. This factor interferes with the patient's co-operation and the need to stop treatment in severe cases. As a result, a cyclic treatment process has been developed, because some bisphosphonates, such as etidronate, which are administered daily for more than a few days, can cause the disadvantage of reduced bone mineralization, which is cartilage. us Patent No. 4,761, 4〇6, t〇 Flora et al, issued August 2, 1988, which is incorporated herein by reference in its entirety, describes a cyclic process that attempts to reduce bone mineralization, but still has therapeutic anti-absorption In addition to the effect. In general, the characteristics of the cyclical regimen are intermittent, as opposed to the continuous regimen. The bisphosphonate treatment period is used for treatment and the non-treatment period is for the systemic bisphosphonate content to return to baseline. However, the cyclic process reduces the effectiveness of therapeutic anti-absorption compared to continuous administration. Data from risedronate indicate that cyclic administration is less effective than continuous reed administration in anti-absorption. See L. Mortensen, et al., This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200300092 A7 B7 V. Description of invention (5)

Prevention Of Early Postmenopausal Bone Loss By Risedronate, Journal of Bone and Mineral Research, vol. 10, supp. 1, p. Sl40 (1995), which is hereby incorporated by reference in its entirety. In addition, such a cyclical procedure cannot rule out or mitigate gastrointestinal side effects, as this procedure uses multiple daily dosing cycles. This circulation process is difficult to treat and the patient cooperation is low, thus reducing the effectiveness of the treatment. US Patent No. 5,366,965, the applicant is Strein, published in November 22, 1994, the entire text of which is incorporated herein by reference, in an attempt to improve the gastrointestinal side effects of oral, subcutaneous or intravenous polyphosphonate compounds, this method is used The intermittent dosing procedure includes a period of osteoporosis inhibition and a non-treatment rest period. However, the disadvantages of this procedure are the discontinuity and irregularity, and the non-treatment period can be as long as 20 to 120 days. PCT Application No. WO 95/30421, the applicant is Goodship et al ', published in November 16, 1995, which is incorporated herein by reference in its entirety, and discloses various methods of using bisphosphonate compounds to prevent loosening and displacement of the prosthesis. Partial doses of bisphosphonates once weekly have been revealed. However, it is still not possible to solve the problem of gastrointestinal side effects with larger or multiple doses. However, these two modern techniques seem to have shortcomings in daily and cyclic treatment processes', so it is necessary to develop new dosing procedures to overcome this shortcoming. It is found in the present invention that a relatively high unit dose of bisphosphonates can be administered daily or in a cyclic administration schedule to reduce side effects on the gastrointestinal tract. The administration interval of the continuous course is selected from the group consisting of once-weekly administration and twice-weekly administration. , Once every two weeks, and twice a month. In other words, relatively high unit doses of bisphosphonates and relatively low dosing frequency are used for treatment and relative -------- 一 —___- 8 _ This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) 200300092 A7 B7 V. Description of the invention (low unit dose of bisphosphonate and relatively high dosing frequency compared to reduce _ gastrointestinal side effects, especially side effects on the esophagus. This result is in the arts and crafts ^^ This is surprising because increasing the bisphosphonate dose is expected to increase gastrointestinal side effects. Therefore, the treatment method of the present invention is useful for confirming that I will experience a bowel disorder (eg, gastrointestinal reflux disease, ie, GERD). Esophageal fire, indigestion, ie heartburn, ulcers, and other related conditions) patients who are susceptible are particularly advantageous in treatment. In this patient, traditional bisphosphonate treatment has worsened or caused this gastrointestinal disorder From the perspective of the patient's life style, the method of the present invention is also more convenient than the daily or daily dosing procedure. The frequency of patients taking the drug on an empty stomach (fasting or at least 30 minutes after administration) Reduced. And the patient does not need to maintain a complicated drug administration process. The method of the present invention is beneficial to improve the patient's coordination and therefore has a better treatment efficiency. Another object of the present invention is to provide a method to inhibit the bone resorption effect and the related conditions. The other object of the present invention is to provide a method for treating abnormal bone resorption and related conditions. | The other object of the present invention is to provide a method for preventing abnormal bone resorption and related conditions. Others of the invention The goal of the invention is to provide an oral method. The other goal of the invention is to provide the method to humans. The other goal of the invention is to provide the method to a patient who is identified as suffering from or is susceptible to gastrointestinal disorders such as gastrointestinal reflux disease That is, GERD '), esophagitis, indigestion (ie, heartburn), ulcers, and other paper standards applicable to the Chinese National Standard (CNS) A4 (210X297) ------

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Related disorders. Another object of the present invention is to provide this and reduce the occurrence or potential of gastrointestinal side effects. &amp; Other objects of the present invention are to provide this method, including: · continuous dosing process whose dosing interval is selected from the group consisting of: once a week, twice a week, twice a week, and twice a month. It is a further object of the present invention to provide such a method, including a continuous dosing process &apos; whose dosing interval is approximately once every 3 days to approximately once every 6 days. It is a further object of the present invention to provide such a method in which the dosing process is continued until a suitable therapeutic effect is achieved. Another object of the present invention is to treat or prevent abnormal osteoporosis of osteoporotic mammals, preferably humans with osteoporosis. It is another object of the present invention to provide pharmaceutical ingredients and kits of the method. These and other objectives can be seen in the detailed description below. SUMMARY OF THE INVENTION The present invention relates to a method for inhibiting bone resorption in a mammal on demand, and at the same time reducing its potential side effects on the gastrointestinal tract. The method includes taking a pharmaceutically effective amount of bisphosphonate as a unit The dose, based on the continuous dosing interval, is selected from: weekly administration, twice weekly administration, bi-weekly administration, and twice-monthly administration, where the continuous process is to achieve the mammalian treatment The present invention relates to a method including a continuous dosing process, and the dosing cycle is about once every 3 days to about once every 6 days. _______ Scale 10 _ This paper size applies to China National Standard (CNS) A4 regulations; ^ 〇 x 297 system ------ 200300092 A7

In other embodiments, the present invention relates to a method for breastfeeding therapy on demand. 'In other embodiments φ, ± 1 β Jr The present invention relates to a method for preventing bone aspiration in breastfeeding on demand.

In other embodiments, the present invention relates to methods for use on humans. In other embodiments, the present invention relates to a method for use in humans, who are susceptible to gastrointestinal lesions. In other specific embodiments, the present invention relates to methods for treating or preventing osteoporosis in mammals. In other embodiments, the invention relates to methods for treating or preventing osteoporosis in humans. '' In other specific embodiments, the present invention relates to a method for inhibiting human bone resorption, or treating or preventing abnormal bone resorption, including treating humans from about 8.75 mg to about 140 mg (as aendoic acid ( alendronic acid), which is a bisphosphonate, the salt is selected from the group consisting of alendronate, pharmaceutically acceptable salts, and mixtures thereof. In other specific embodiments, the present invention relates to a pharmaceutical composition comprising about 8.5 mg to about 140 mg (based on the activity of alendronic acid) of a bisphosphonate, the salt being selected from the group consisting of : Alendronate, and its pharmaceutically acceptable salts, and mixtures thereof 0 All percentages and ratios used herein, unless otherwise specified, are based on weight I. The composition, essential components and selected components, and methods of the present invention are described herein. _____- 11-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

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200300092 A7 B7 V. Description of the invention (9) Brief description of the figure Figure 1 is a micrograph of the dog's esophagus tissue with a total magnification of 270X (stone sacrifice and hematoxylin and eosin staining). 50 ml of simulated gastric fluid treatment at each dose was sacrificed immediately after the last perfusion. Figure 2 is a micrograph of the dog's esophagus tissue at a total magnification of 270X (stone sacrifice and hematoxylin and eosin staining). The animal used five separate doses of 50 mL of 0.20 mg / mL subtotal for five consecutive days. Alendronate mimics gastric juice treatment, sacrificed immediately after the last perfusion. Figure 3 is a micrograph of the total magnification of the dog's esophagus at 270X (stone sacrificial embedding and hematoxylin and eosin staining). Animals used a single dose of 50ml L of 0.80mg / mL Alendo Alendronate mimics gastric juice treatment, sacrificed 24 hours after perfusion. Figure 4 is a micrograph of a total magnification of 27.0X in canine esophagus tissue (stone worm embedding and hematoxylin and eosin staining). Animals used a single dose of 50ml L of 0.80mg / mL Yaren Alendronate mimics gastric juice treatment, sacrificed 7 days after perfusion. Figure 5 is a micrograph of the dog's esophagus tissue at a total magnification of 270X (stone sacrifice and hematoxylin and eosin staining). The animal was treated with four separate doses of 50 mL of 0.80 mg / mL alendoic acid for four consecutive weeks. Alendronate mimics gastric juice treatment (ie once a week), sacrificed 7 days after the last perfusion. Figure 6 is a micrograph of the total magnification of the dog's esophagus at 2700x (Shikan embedding and hematoxylin and eosin staining). The animals were treated with eight separate doses of 50 mL of 0.40 mg / mL subweek for four consecutive weeks. Alendronate mimics gastric juice treatment (ie, once every 3-4 days), sacrificed 4 days after the last perfusion. -12-___ This paper size applies the Zhongguan Family Standard (CNS) A4 specification (21G X 297 public love) --- ~ 200300092 V. Description of the invention (Figure 7 is the total magnification of canine esophagus tissue 2 7 〇χ Micrographs (paraffin-embedded and hematoxylin and eosin staining), the animals were treated for five consecutive days with five separate doses of 50 mL of 0.20 mg / mL lysostronate (risedrOnate) imitated gastric juice, Sacrifice immediately after the last perfusion. Figure 8 is a micrograph of the dog's esophagus tissue at a total magnification of 27 × (paraffin-embedded and hematoxylin and eosin staining). The animals were treated with five separate doses for five consecutive days. 50mL of 4.0mg / mL tiiudronat imitated gastric juice treatment, sacrificed immediately after the last perfusion. Description of the invention The present invention relates to a method of oral administration, preferably oral administration; A mammalian bone aspiration as required, while reducing the potential for gastrointestinal side effects. The present invention is a method for treating or preventing the bone aspiration of mammalian abnormalities that need to be prevented or prevented. The method of the invention includes oral medicine Academically effective amount of bisphosphonate It is a unit-dose treatment of mammals, in which the treatment of doses is based on a continuous process, the administration interval of this process is selected from the group of once-weekly administration, twice-weekly administration, bi-weekly administration, and every two months In other specific embodiments, the present invention, regarding the method of continuous dosing process, the dosing cycle is about twice every 3 days and about once every 16 days. The standard continuous dosing process continues until the therapeutic effect of mammals is achieved B. The standard treatment of the present invention uses a higher unit dose of bisphosphonate at each administration point 'because of the selected dosing schedule' to minimize potential gastrointestinal side effects. In addition, this method is more convenient because it does not require daily administration The method of the present invention generally treats mammals in need with bisphosphonates. 200300092 A7 B7 V. Description of the invention (The preferred mammal is a human patient ', especially a human patient who needs to inhibit bone resorption, for example: need treatment Or prevent patients with abnormal bone aspiration. This month's bisphosphonate treatment method is especially suitable for treating patients with gastrointestinal symptoms Conditions, such as: GERD, esophagitis, indigestion: ulcers, etc. Human patients. Such patients treated with traditional bisphosphonates may exacerbate or cause gastrointestinal disorders. "Pharmaceutically effective amounts herein, , Refers to the content of bisphosphonate compounds, when

According to the appropriate treatment process, the content has an appropriate therapeutic effect or response. A preferred pharmaceutically effective amount of the bisphosphonate is an amount that inhibits bone absorption. "Reducing the occurrence or potential of gastrointestinal side effects" refers to reducing, preventing, reducing, or mitigating the occurrence or potential of gastrointestinal (esophagus, stomach, intestine, and rectum, especially upper gastrointestinal, ie, esophagus and stomach) side effects Non-limiting gastrointestinal side effects include, but are not limited to, GERD, esophagitis, indigestion, ulcers, irritation of the esophagus, perforation of the esophagus, abdominal pain, and constipation. Herein, the term “bone, aspiration” refers to The bone aspiration of the earth or all bones exceeds the extent of bone formation. In addition, "abnormal bone resorption" may be the formation of abnormally structured bones. As used herein, "inhibition of bone resorption" refers to directly or indirectly altering osteoclast formation or activity in order to treat or prevent bone resorption. Inhibition of skeletal aspiration refers to the treatment or prevention of bone loss, especially by directly or indirectly altering osteoclast formation or activity to remove existing bone mineral phases and / or having ___— ____-14-This paper standard applies China National Standard (CNS) Α4 Specification (210 X297 Public Love 1 ------- 200300092 A7 B7 V. Description of the Invention (Inhibition of Organic Matrix Phase. The "continuous process" or "continuous administration process" , Refers to repeated administration of drugs until the therapeutic effect is achieved. Continuous or continuous administration is different from cyclic or intermittent treatment. In this context, "until the therapeutic effect is achieved" refers to the continuous selection. The process of drug administration is continuously treated with bisphosphonate compounds until the physician or the researcher observes that the disease or condition has achieved clinical or medical effects. In the treatment method of the present invention, the bisphosphonate compounds are continuously treated Until the bone or structure changes that are important to the eyebrow are observed. The purpose in this example is to achieve an increase in bone mass or a positive bone structure to replace the abnormal bone structure. Prevention of the invention As long as the method is necessary to avoid the disease, continuous treatment with bisphosphonate compounds is required. The purpose in this case is to maintain bone density. The non-limiting example of the treatment cycle is about 2 weeks to the death of mammals. The treatment cycle of humans Between the age of 2 weeks and the death of human beings, preferably about 2 weeks to about 20 years, more preferably about 1 month to about 20 years, and most preferably about 6 months to about 10 years' Particularly preferred is about one year to about ten years. Methods of the invention The method of the present invention includes inhibiting mammalian bone aspiration. The present invention also includes the treatment of mammalian abnormal bone aspiration. The method of the present invention also includes preventing mammalian abnormal bone aspiration. In addition, in the preferred embodiment of the present invention, the mammals are humans. The present method does not have the danger or cumbersome, annoying, or complicated administration procedures that increase the potential for gastrointestinal side effects in current treatment methods. The present invention includes continuous The flow of administration, which is based on the administration interval, 200300092 A7 B7 V. Description of the invention (13) Administration once a week, administration twice a week, two Dosing once a week, and twice a month, with regular treatment with a unit dose of bisphosphonate. Weekly administration means treating once a week with a unit dose of bisphosphonate, that is, once every seven days, The preferred is the same day of the week. In the weekly dosing schedule, unit dose treatment is generally performed every seven days. In the non-limiting example of the weekly dosing schedule, a unit dose of bisphosphonate is given every Sunday for treatment. The preferred unit dose is not treated on subsequent days, but the once-weekly dosing process can include two consecutive days of unit-dose therapy dosing processes at different cycles. The twice-weekly dosing refers to the unit dose of bisphosphonate treatment per Twice weekly, ie twice in seven days, preferably the same two days in a week. In the twice weekly dosing process, each unit dose is treated approximately once every three to four days. In a non-limiting example of a biweekly dosing schedule, a unit dose of bisphosphonate is administered every Sunday and Wednesday for treatment. The preferred unit dose treatment is different days or not two consecutive days, but the twice-weekly dosing procedure can also include the same cycle or two consecutive days during different week periods. Bi-weekly administration refers to a unit dose of bisphosphonate treatment once every two weeks, ie once every fourteen days, preferably on the same day every two weeks. In the twice-weekly dosing schedule, each unit dose is treated approximately every fourteen days. In a bi-weekly non-limiting example of a dosing schedule, a unit dose of bisphosphonate is administered on a two-week Sunday and Sunday basis. The preferred unit dose treatment is not two consecutive days, but a bi-weekly dosing process can also include a two-day dosing process in different weeks. Dosing twice a month refers to the unit dose of bisphosphonate treatment every two months _-16-_ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 200300092 A7 B7 V. Description of the invention (Times, that is, twice per calendar month. In the course of twice a month, it is preferred that the dose be given on the same two days each month. In this twice-monthly administration process, each unit The dosage is generally about fourteen to sixteen days. In the non-limiting example of the biweekly dosing process, the dosage is about the first day of each month and about the fifteenth day, which is the middle of each month. The unit dose is best treated Do not use it on the same day or two consecutive days, but the twice-monthly dosing process can include the dosing of unit-dose treatment for two consecutive days within a month or different months. The weekly dosing procedure is different because the bi-weekly schedule has no periodicity and long-term administration of different numbers of doses of I. For example, a one-year period, depending on the treatment schedule, a total of about twenty-four doses are given twice a month. (Because every year Two months), and the once-weekly dosing schedule gives about twenty-six doses (because about fifty-two weeks per year). In a further specific embodiment or description of the present invention, the dosing cycle for a unit dose is about every three days to About once every 16 days. The methods and ingredients of the present invention can be used to inhibit bone resorption and to treat and prevent related abnormal bone resorption and conditions. This condition includes: general and local bone loss At the same time, abnormal structures of bones (such as Paget's disease) are associated with abnormal bone aspiration. ,, "General bone loss" refers to multiple bone sites or bone loss through the skeletal system. "Local "Bone loss" refers to bone loss at one or a specific skeletal site. General bone loss is associated with osteoporosis. Osteoporosis most commonly occurs in women with U spoons, because of its substantial reduction in estrogen production. But similar solid

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200300092 A7 B7 V. Description of the invention (P03H2

I

A-C-X

I PO3H2 where A and X are each selected from the group consisting of: Η, 0Η, halogen, NH2, SH, phenyl, C i -C 3 0 alkyl, C i-C 3 0 substituted alkyl, C!-C i 〇 Alkyl or dialkyl substituted NH2, CrCiG alkoxy, CpCw alkyl or phenyl substituted thio, Ci-Ci i substituted phenyl, pyridyl, furyl, or Than slightly crystalline, imidazonyl, and nodular. In the chemical formula of the above formula, the alkyl group may be a linear, branched, or cyclic chemical formula. Ci-Cw substituted alkyls may include various substituents, non-limiting examples include selected from: phenyl, p-pyridyl, cynanyl, 17-pyridyl, imidazolyl, NH2, Ci-Cio Alkyl or dialkyl substituted NH2, OH, SH, and 匚 ^^ "alkoxy. In the above formula, A may include X and X may include A, so these two parts can form the same ring structure The chemical formula of the above formula also includes complex carbocyclic and aromatic groups; and A and / or X substituents of heteroatomic structures. Non-limiting examples include fluorenyl, p-chalinyl, isofluorinyl, and adamantane. And chlorophenylthio. Preferred structures of A are selected from the group consisting of: fluorene, OH, and halogen, and X is selected from the group consisting of: Cl · C3o alkyl, C1-C3o substituted alkyl, halogen, And thio substituted by ci-c-alkyl or phenyl. More preferably, A is selected from: H, OH, and C1, and X is selected from: c

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200300092 A7 B7 V. Description of the invention (17) C30 alkyl, Ci-Cw substituted alkyl, chloro, and chlorophenylthio. The best structure is A is OH and X is the 3-aminopropyl moiety, so the compound produced is 4-amino-1, -hydroxybutylidene-1,1-bisphosphonic acid, which is an alend acid. (Alendronate). Also used herein are bisphosphonates pharmaceutically acceptable salts and derivatives. Non-limiting examples of salts include selected from the group consisting of: alkali metals, basic metals, ammonium, and mono-, bis-, ginseng, or -C1-C30-alkyl substituted ammonium. Preferred salts are selected from the group consisting of: sodium, potassium, calcium, magnesium, and ammonium salts. Non-limiting examples of derivatives include selected from the group consisting of: esters, hydrates, and amidines. Pharmaceutically acceptable π herein refers to salts and derivatives of bisphosphonates, which are derived from free acids which are generally of the same pharmacological properties and are non-toxic and acceptable. It is worth mentioning that `` bisphosphonate π and πbisphosphonate s π '' herein means that the therapeutic agent of the present invention includes: bisphosphonate, bisphosphonic acid, and bisphosphonic acid, and their salts and derivative. The use of specific names of bisphosphonates or bisphosphonates, unless otherwise specified, is not intended to limit the scope of the invention. Because the names are currently confusing, the compounds of the present invention are expressed in terms of specific weights or percentages of bisphosphonates based on the weight of acid activity unless otherwise specified. For example: `` A bisphosphonate with an inhibitory effect of about 70 mg of osteomyelin is selected from the group consisting of: alendronate, and pharmaceutically acceptable salts and mixtures thereof (as Based on the active weight of alendronic acid, the amount of bisphosphonate compound selected is 70 mg based on the weight of alendronic acid. The non-limiting examples of bisphosphonates herein include: Polyacid (alendronic acid), 4-amino-1-butylidene-1,1 -_- 20-_ This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 200300092 A7 B7 5. Description of the invention (18). Bisphosphonic acid.

Alendronate (like alendronate or monosodium trihydrate), 4-amino1-hydroxybutylene-1,1-bisphosphonic acid monosodium trihydrate. Alendronic acid and alendronate are described in US · Patent 4,922,007, the applicant is Kieczykowski et al., Published on May 1, 1990, and 5,019,651, the applicant is Kieczykowski, published on May 28, In 1991, the two documents were incorporated herein by reference in their entirety. Cyclopeptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), is described in US Patent 4,970,335, and the applicant is Isomura et al., Published in November 13, 1990, the entire text is incorporated herein by reference. 1,1-chloromethylene-1,1-bisphosphonic acid (clodronic acid), and ethylenediaminetetraacetic acid (clodronate), Procter and Gamble), described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are incorporated herein by reference in their entirety. 1-Hydroxy-3- (1-pyrrolidinyl) -propylene-1,1-bisphosphonic acid (EB-1053) (Etidronic acid)). 1-Hydroxy-3 (n-methyl-n-propylamino) propylene-1,1-bisamitic acid, also known as BM-210955, Boehringer Mannheim (-this polyacid salt, ibandronate), description Published in US Patent No. 4,927,814, published on May 22, 1990, the entire text of which is incorporated herein by reference. 6-Amino 1-hydroxyhexylene-1,1-bisphosphonic acid (neridronate) ° __ _-21 -_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) 200300092 A7 B7 V. Description of the invention (19) 3- (dimethylamino) -1 · hydroxypropylidene-1,1-bisphosphonic acid (olpadronate) 03-amino group 1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate). [2- (2-pyridyl) ethylene] -1,1-bisphosphonic acid (piridronate) is described in U.S. Patent No. 4,761,406, which is incorporated herein by reference in its entirety. 1-Hydroxy-2- (3-pyridyl) -ethylene-1,1-bisphosphonic acid (risedronate) 〇 (4-chlorophenyl) thiomethyl-1,1- Bisphosphonic acid (tiludronate) is described in US Patent 4,876,248, the applicant is Breliere et al., Published in October 24, 1989, which is incorporated herein by reference in its entirety. 1- # to 2-2- (1Η-imidyl-1-yl) ethylene-1,1-bisquatic acid (such as zollendronate). Preferred bisphosphonates are selected from the group consisting of: alendronate, cimadronate, clodronate, tiludronate, and tiludronate ( etidronate, ibandronate, risedronate, piridonate, pamidronate, zolendronate, and Pharmaceutically acceptable salts and mixtures thereof. More preferred are alendronate, and pharmaceutically acceptable salts thereof, and mixtures thereof. 1 __22 · __ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200300092 A7 B7 V. Description of the invention (2G) The best is Alendronate single steel Trihydrate. Pharmaceutical Compositions Useful ingredients of the present invention include a pharmaceutically effective amount of a bisphosphonate. This bisphosphonate is used in the treatment with an appropriate pharmaceutical diluent, excipient, or carrier. The "carrier substance" here is selected from the group suitable for oral treatment, that is, lozenges, capsules, wine, syrup , Bubbling ingredients, powders, etc., and containing traditional medical prescriptions. For example: tablets, capsules, or powders for oral treatment. Active ingredients can be used with oral, non-toxic, pharmaceutically acceptable inert carriers such as: lactose, starch, sucrose, glucose, cellulose methyl ether, stearin Mixtures of magnesium acid, mannitol, sorbitol, croscarmellose, etc .; liquids for oral treatment, such as: wine and syrup, effervescent ingredients, oral pharmaceutical ingredients can be used with any oral, nontoxic 2. A pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. In addition, appropriate binders, lubricants, disintegrating agents, buffering agents, coating agents, and coloring agents may be added as necessary. Suitable binders include: starch, gelatin, natural sugars, such as glucose, anhydrous lactose, free lactose, / 3-lactose, and corn sweeteners, natural and synthetic resins, such as acacia, Guanhua bean gum , Tragacons gum or sodium alginate, carboxymethyl fiber, polyethylene glycol, paraffin. The lubricants used in this dosage form include: sodium oleate, stearate steel, stearate, residual benzoic acid, sodium acetate, chlorinated steel, and the like. Particularly preferred alendronate monosteel trihydrate lozenges are described in U.S. Patent No. 5,358,941, applicant Bechard et al, published in October 25, 1994, which is incorporated herein by reference in its entirety. The compound used in this method can also be used as a calibrable drug with soluble polymers. _-23-_ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200300092 A7 B7 V. Description of the invention (21) Object-carrier coupling. This polymer includes: polyvinylpyrrolidone, ran copolymer, polyacrylpropylmethylpropionamine, and the like. The exact dose of bisphosphonate depends on the dosing process, the oral efficacy of the particular bisphosphonate chosen, aging, weight, sex and mammalian or human condition, the nature and severity of the condition being treated, and other related medicines and and Depending on physical factors. Therefore, the precise medically effective amount cannot be determined in advance and must be determined by the physician. The appropriate amount can be determined by routine animal models and human clinical studies. In general, an appropriate amount of bisphosphonate has an inhibitory effect on bone resorption, that is, treatment with an amount of bisphosphonate that inhibits bone resorption. For humans, an effective oral dose of bisphosphonate is about 1.5 to about 6000 # g / kg body weight and preferably about 10 to about 2000 # g / kg body weight. Human oral ingredients include alendronate, and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof. Typical unit dosages include about 8.75 mg to about 140. mg of alendronate compound (based on active weight of alendronic acid). For weekly administration, oral unit doses include about 17.5 mg to about 70 mg of an alendronate compound (based on the active weight of alendronic acid). Examples of weekly oral doses include unit doses for the prevention of osteoporosis, including approximately 35 mg of alendronate compounds, and unit doses for the treatment of osteoporosis, including approximately 70 mg Alendronate compounds. _-24-_ This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 200300092 A7 B7 V. Description of the invention (22) For administration twice a week, the oral unit dose includes approximately 8.75 mg to Approximately 35 mg of alendronate compound (based on active weight of alendronic acid). Examples of twice-a-week oral doses include a unit dose for the prevention of osteoporosis, approximately 17.5 mg of an alendronate compound, and a unit dose for the treatment of osteoporosis, including approximately 35 mg Alendronate compounds. For bi-weekly or bi-monthly administration, oral unit doses include from about 35 mg to about 140 mg of the alendronate compound (based on the active weight of alendronic acid). Examples of bi-weekly or twice-monthly oral doses include unit doses for the prevention of osteoporosis, approximately 70 mg of alendronate compounds, and unit doses for the treatment of osteoporosis Including about 140 mg of alendronate compounds. Non-limiting examples of oral ingredients include alendronate and other bisphosphonates, as described in the following examples. Sequential therapy with bisphosphonates and histamine H2 receptor inhibitors and / or proton pump inhibitors In a further specific embodiment, the methods and components of the present invention also include histamine H2 receptor inhibitors (ie, antagonists Agents) and / or proton pump inhibitors. Histamine H2 receptor inhibitors and proton pump inhibitors are known therapeutic agents that increase the pH of the stomach. See LJ Hixson, et al., Current Trends in the Pharmacotherapy for Peptic Ulcer Disease, Arch. Intern. Med., Vol. 152,. Pp. 726-732 (April 1992), which is hereby incorporated by reference in its entirety ________- 25 -__ This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 200300092 A7 B7 V. Description of Invention (23). Taking bisphosphonates after sequential oral administration of histamine H2 receptor inhibitors and / or proton pump inhibitors can further reduce gastrointestinal side effects. In such specific embodiments, the bisphosphonate treatment is performed from about 30 minutes to about 24 hours after the histamine H2 receptor inhibitor and / or proton pump inhibitor treatment. In a more preferred embodiment, the bisphosphonate treatment is performed from about 30 minutes to about 12 hours after treatment with a histamine H2 receptor inhibitor and / or a proton pump inhibitor. The dosage of the histamine H2 receptor inhibitor and / or proton pump inhibitor will depend on the particular compound selected and the factors used to treat the mammal, i.e. weight, health, etc. Non-limiting examples of histamine H2 receptor inhibitors and / or proton pump inhibitors are selected from the group consisting of: cimetidine, famotidine, nizatidine, ranitidine (Ranitidine), omprazole, and lansoprazole. In a further specific embodiment, the present invention relates to a 'set that is effective and convenient for performing the method of the present invention. This kit is particularly suitable for delivering solid oral forms, such as lozenges or capsules. The preferred set includes a number of unit doses. The kit includes a card indicating the dosage to be used. An example of this kit is "foam packaging". Foam packaging is very well known in the packaging industry and is used in a large number of unit dosage forms for packaging medicine and pharmacy. Memory assistance is provided as needed, such as numbers, words, or other marked or inserted calendars, and the days specified in the treatment schedule for the treatment dose. In addition, placebo doses similar to or different from bisphosphonate doses, or calcium or food additives, can also be included in the daily dose set. Such specific examples include histamine H2 receptors and / or substances _-26-_ This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200300092 A7 ____ B7 V. Description of the invention (~ ^ Sub-pump inhibitors, such reagents may be part of a kit. Examples The following examples further describe and illustrate specific examples of the scope of the invention. The examples are for illustration only and are not limiting of the invention, and many of its modifications may The spirit and scope of the present invention is deprived. Example 1 Potential of esophageal irritation caused by bisphosphonates of esophagus can be evaluated by dog model. Experiments show the potential of relative irritation of the following dosing procedure: placebo (experimental group 1) ), A single high-concentration dose of alendronate single-steel trihydrate (experimental group 2), a low-concentration dose of alendronate monosodium trihydrate (experimental group) 3 and 4), high-concentration doses of alendronate monosodium trihydrate are treated once a week for four weeks (experimental group 5), medium-range concentrations of alendronate Sodium trihydrate was treated twice a week for four weeks (Experimental Group 6), low-dose risedronate sodium for five consecutive days (Experimental Group 7), and low-dose Tironate double-dinadium (Tiludronate disodium) for five consecutive days (Experimental group 8). Preparation of the following solutions: (1) Simulated gastric juice (pH about 2), that is, the control group solution. (2) Simulated gastric juice (pH about 2) contains about 0. .20mg / mL of alendronate monosodium trihydrate (based on the activity of alendronic acid). (3) Simulated gastric juice (pH about 2) contains about 0.8 〇mg / mL of alendoic acid ________ -27 -__ This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 200300092 A7 B7 5. Description of the invention (alendronate monosodium trihydrate (Based on the activity of alendronic acid.) (4) The simulated gastric juice (pΗabout 2) contains about 0.40 mg / mL of alendronate monosteel trihydrate (based on (The activity of alendronic acid is subject to change.) (5) The mimic gastric juice (pH about 2) contains about 0.2 mg / mL of risedronate sodium (based on the activity of risedronic acid). (6) Simulated gastric juice (pH about 2) contains about 4.0 mg / mL of Tularacid Tiludronate disodium (based on the activity of tiludronic acid). To simulate the preparation of gastric juice, approximately 960 mg of gastrin (1 -585, 228000B003, Fisher Chemical) was dissolved in approximately 147 mL of 0.90 (wt%) NaCl (aqueous solution), and approximately 3 mL of 1.0 M HC1 (aqueous solution) was added, and The volume was adjusted to approximately 300 mL with deionized water. Measure the p Η of the solution, if necessary, adjust with 1.0M HC1 (aqueous solution) or 1.0M NaOH (aqueous solution) to about 2 0. Anesthetize the experimental animals and infuse about 5 OmL of the appropriate solution into the esophagus with a perfusion pump and rubber catheter. 30 minutes. The following treatment experiments were performed: Test group 1: This is an experimental control group containing four animals. For five consecutive days, each animal was treated with simulated gastric fluid [solution (1)] at a dose of approximately 50 mL. Animals were sacrificed immediately after the last dose. Experimental group 2: This experiment contains four animals. For five consecutive days, each animal uses approximately-; ____ 228-_ This paper size applies to Chinese National Standard (CNS) A4 (21 × 297 mm) 200300092 A7 B7 V. Description of the invention (26) 5 OmL dose of simulated gastric fluid Contains about 0.20 mg / mL of alendronate [solution (2)] treatment. Animals were sacrificed immediately after the last dose. Experimental group 3: This experiment contains five animals. On each treatment day, each animal was treated with approximately 50 mL of a simulated gastric fluid containing approximately 0.80 mg / mL of alendronate [solution (3)]. Animals were sacrificed approximately 24 hours after dose treatment. Experimental group 4: This experiment contains five animals. On each treatment day, each animal was treated with approximately 50 mL of a simulated gastric fluid containing approximately 0.80 mg / mL of alendronate E solution (3)]. Animals were sacrificed approximately 7 days after dose treatment. Experimental group 5: This experiment contains six animals. Once a week, that is, once every seven days for four weeks, each animal was treated with approximately 0.80 mg / mL of alendronate [solution (3)] in a simulated gastric fluid at a dose of approximately .50 mL. Animals were treated with a total of four doses. Animals were sacrificed approximately 7 days after the final dose treatment. Experiment group 6: This experiment contains six animals. Two times a week, ie once every three to four days for four weeks, each animal was treated with approximately 50 mL dose of simulated gastric fluid containing approximately 0.40 mg / mL of alendronate [solution (4)] . Animals were treated with a total of eight doses. Animals were sacrificed approximately 4 days after the final dose treatment. Experiment group 7: This experiment contains eight animals. For five consecutive days, each animal was treated with a simulated gastric fluid at a dose of approximately 50 ml, containing approximately 0.20 mg / mL risedronate [solution (5)]. Immediately after the final dose treatment _-29-_ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200300092

Thing. Experiment group 8: This experiment contains four animals. For five consecutive days, each animal was treated with approximately 50 mL of a simulated gastric fluid containing approximately 40 mg / mL of tiludronate [solution (6)]. The animal was sacrificed immediately after the last dose. The esophagus was removed from each sacrificed animal and tissues were embedded in paraffin with histopathology using standard techniques and stained with hematoxylin and eosin. Examine the section with a microscope. The results of histopathology are shown in Table 1. In the animals of the control group 1 (control experiment group), the microscopy showed that the esophagus was normal and the epithelium was trimmed and there were no inflammatory cells in the submucosa. Figure 1. In the animals of the control group 2, the microscopic examination revealed deep ulcers on the surface of the esophagus and obvious inflammation and vacuolation of the submucosa. See Figure 2. Animal's microscopic examination results in experimental group 3 showed that the esophageal epithelial surface was intact, and the submucosa was slightly inflamed and vacuolated. See Figure 3. In the animals of the experimental group 4, the microscopic examination showed that the esophagus epithelium was intact, slightly inflamed (two of the five animals) or non-inflamed (three of the five animals), and without S-foaming. Figure 4 shows that the four animals in the experiment were only slightly inflamed. In the animals of experimental group 5, the microscopic examination showed that the esophagus was normal, the epithelium was intact and the mucosa: there were no inflammatory cells in the lower layer. See Figure 5. The animal 'microscopic examination of the test group 6 showed that there was a deep ulcer on the surface of the esophagus and there was obvious inflammation and vacuolation in the submucosa. See Figure 6. In the animal of the experimental group 7, the microscopic examination results showed that there was a deep ulcer on the surface of the esophagus and there was obvious inflammation and vacuolation in the submucosa. See Figure 7. In the animal of the experimental group 8, the microscopic examination results showed that the surface of the esophagus epithelium had a slight _ -30- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 200300092 A7 __B7 I. Description of the invention (~~~ — ~ &Quot; ~ Ulcers with slight inflammation and vacuolation in the submucosa. See Figure 8. This type of routine examination showed a single two-dose alendronate treatment (Experimental groups 3 and 4) as a control Treatment at low concentration for five consecutive days (Experimental Group 2), the former has lower esophageal irritation (compared with Controlled Experimental Group 1). Such experiments also show that lower esophageal irritation is a single high concentration of alendoic acid Salt (alendronate) was treated once a week (Experimental Group 5), instead of twice weekly (Experimental Group 6) and low-dose treatment for five consecutive days (Experimental Group 2). Such experiments also show that when other Bisphosphonates, such as dsedate (Experimental Group 7) or tiludronate (Experimental Group 8), treatment at low concentrations for five consecutive days, potential for esophageal irritation Sexual orientation. Table 1 Activity of esophageal irritation potential in experimental group Sacrifice time of reagent mg / mL Histopathology l (n = 4) 0 Sacrifice normal once a day for five days immediately after the last administration. Intact epithelium and submucosa have no inflammatory cells. 2 (n = 4) sub Lentoate 0.20 is administered once a day for five days immediately after the last administration. The deep submucosal layer of the ulcer on the surface of the epithelium is significantly irritated and vacuolated. 3 (n = 5) Alendoate 0.80 IX Sacrifice the complete The submucosa of the epithelial surface is slightly inflamed and vacuolated. 4 (n = 5) Alendoate 0.80 IX Sacrifice intact epithelium after 7 days of administration. Very little inflammation (two of five animals) or no inflammation (five animals). Three of them) and no vacuolation. 5 (n = 6) Alendoate 0.80 once a day for four weeks after the last administration. Intact epithelium is non-inflammation and no vacuolation. 6 (n = 6) Asian Lentoate 0.40 once a day for four weeks immediately after the last administration. Severe inflammation and vacuolation of the deep submucosal layer of the ulcer on the epithelial surface was noticeable. 7 (n = 8) Lesoate 0.20 once a day for 5 days after the last administration Sacrificed immediately Deep surface ulcers (four out of eight animals) markedly inflamed and vacuolated in the submucosa. 8 (n = 4) Tirudoate 4.0 once a day for 5 days. Deep ulcers on the surface of the epithelium 24 hours after the last administration (Three of the four animals, one of which has only mild ulcers.) One — _________ 31-This paper size applies to the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200300092 A7 B7 V. Description of the invention (29 ) Example 2 A weekly dosing schedule for treating osteoporosis alendronate lozenges or liquid formulations containing about 70 mg of alendronate (as alendronate ( alendronic acid) (see Examples 7 and 8). Oral or liquid formulations are administered orally to humans once a week, which is preferably about once every seven days (eg, on Sunday) for at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially the side effects of the esophagus. This method can also effectively improve patient acceptance and cooperation. Osteoporosis prevention alendronate lozenges or liquid formulations contain approximately 35 mg of alendronate (based on the activity of alendronic acid) (see Examples 7 and 8). Formulations of tablets or liquids Oral treatment of human patients once a week, preferably about once every seven days (eg on Sunday) for at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially the side effects of the esophagus. This method can also effectively improve patient acceptance and coordination. Example 3 A twice-weekly dosing schedule for the treatment of osteoporosis. Alendronate lozenges or liquid formulations contain approximately 35 mg of alendronate (as suberic acid ( alendronic acid) _-32-_ This paper size applies to the Chinese National Standard (CNS) A4 (210 x 297 mm) 200300092 A7 B7 V. Description of the invention (the activity shall prevail) (see Examples 7 and 8). Ingot Or liquid formulations for oral treatment of humans twice a week, preferably about once every three or four days (for example: on Sunday and Wednesday) for at least one year. This method can effectively and conveniently treat osteoporosis And reduce gastrointestinal side effects, especially the side effects of the esophagus. This method can also effectively improve the patient's acceptance and compatibility. Prevention of osteoporosis Alendronate tablets or liquid formulations contain about 17.5mg Alendronate (based on the activity of alendronic acid) (see Examples 7 and 8). Tablets or liquid formulations are orally administered to human patients twice a week, which is the better about Once every three or four days (for example: on Sundays and Wednesdays) for a period of at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially esophageal side effects. This method can also effectively improve Patient acceptance and compatibility. Example 4 A bi-weekly dosing schedule for the treatment of osteoporosis with a le ndr nate bond or a liquid formulation containing approximately 140 mg of arsenate (Aiendronate) (see Examples 7 and 8 based on the activity of alendronic acid). Tablets or liquid formulations are used to treat humans orally once every two weeks, which is preferably about once every fourteen days (For example: on alternate Sundays) for a period of at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially esophageal side effects. This method can also effectively improve patient acceptance and cooperation L. _____- 33- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 200300092 A7 B7 V. Description of the invention (31) Prevention of osteoporosis Alendronate lozenges or liquid formulations contain approximately 70 mg ainendronate (based on the activity of alendronic acid) (see Example 7 And 8). Tablets or liquid formulations are used to treat human patients orally once every two weeks, preferably once every fourteen days (for example, on alternate Sundays) for at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially the side effects of the esophagus. This method can also effectively improve patient acceptance and coordination. Example 5 A dosing procedure twice a month. Alendronate bond or liquid formulation for treating osteoporosis contains approximately MO mg of aendronate (based on the activity of alendronic acid) (see Implementation Examples 7 and 8). Tablets or liquid formulations are used for oral treatment of humans twice a month, which is preferably about once every fourteen to sixteen days (for example, about the first and fifteenth days of each month) for at least one year . This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially the side effects of the esophagus. This method can also effectively improve patient acceptance and cooperation.

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Alendronate ammonium or liquid formulations contain approximately 70 mg of alendronate (based on the activity of alendronic acid) (see examples 7 and 8). Tablets or liquid formulations are used for oral treatment of human patients twice a month, that is, once every fourteen to sixteen days. 200300092 A7 B7 5. Description of the invention (32) For example: about the first day and fifteenth day of each month, for a period of at least one year. This method can effectively and conveniently treat osteoporosis and reduce gastrointestinal side effects, especially It is a side effect of the esophagus. This method can also effectively improve the patient's acceptance and coordination. Example 6 In a further specific embodiment, the 'alendjronate lozenge or liquid formula is an oral dose of an appropriate dose According to the dosing procedure of Examples 2 to 5, treat or prevent other conditions related to abnormal bone resorption. In another specific embodiment, other bisphosphonate compounds are oral doses of appropriate doses, according to the examples 2-5 dosing procedures to treat or prevent other conditions related to abnormal bone resorption. Example 7 Preparation of Bisphosphonate Lozenges Bisphosphonate lozenges can be prepared using standard blends. And molding techniques are incorporated in US Patent No. 5,358,941, belonging to Bechard et al., Serving October 25, 1994, which is incorporated herein by reference in its entirety. The tablet contains approximately 35 mg of alendronate (Based on the activity of alendronic acid), the following relative weight ingredients are used to prepare 0 component alendronate mono-nano-trihydrate

Anhydrous lactose, NF

Microcrystalline cellulose, NF

Magnesium stearate, NF

Made of croscarmellose, NF 45.68 mg 71.32 mg 80.0 mg 1.0 mg 2.0 mg 182.72 285.28 320.0 per 4000 per bond

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This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200300092 A7 B7 V. Description of the invention (33) The tablets produced according to the method of the present invention are used for the treatment of inhibiting bone resorption. Similar 'lozenge formulations include other relative weights of alendronate (based on the activity of aiendronic acid): for example, each lozenge contains approximately 8.75, 17.5, 70 And 140 mg. At the same time, the tablet preparation contains other appropriate active amounts of bisphosphonates, such as: cimadronate, ciodoronate, tiludronate, and polyacid Etidronate, ibandronate, riseronate, piridronate, pamidronate, zolen dr on at e), and its pharmaceutically acceptable salts. At the same time, the bisphosphonates of the simply prepared combination are contained in the lozenge preparation. Example 8 Liquid bisphosphonate formulation The liquid bisphosphonate formulation is prepared using standard mixing techniques. About 75 ml of liquid, its liquid formula contains about 70mg of alendronate monosodium trihydrate (based on the activity of alendronic acid), Prepared with the following relative weight ingredients. ----- Sub-weight-alendronate army salamander dihydrate 91.35 mg propyl sinobanjo sodium 22,5 mg butyl samban sodium 7.5 mg sodium citrate dihydrate 1500 mg citric acid Anhydrous 56.25 mg 7.5 mg water qs 75 mL sodium (aq) — qs pH6.75 L ______- 36- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

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Line 200300092 A7 _B7 V. Description of the invention (^ ~) ~ ^ ^ The liquid formula produced according to the method of the present invention is used to inhibit the effect of bone resorption, a unit dose of treatment. Similarly, liquid unit formulations include other relative weights of alendronate (based on the activity of alendronic ac id) per unit dose: for example, approximately 8.75 per 75 mL volume, 17.5, 35, and 140 mg. At the same time, other volume unit doses are provided in liquid formulations, for example: approximately 1 3 5 mL. At the same time, the liquid formulation contains other appropriate active amounts of bisphosphonates, such as: cimadronate, clodronate, tiludronate, and citrate (etidronate), ibandronate, risedronate, piridronate, pamidronate, zollendronate, and Its pharmaceutically acceptable salts. At the same time, the liquid formulation contains a simply prepared combination of bisphosphonates. ___ -37- This paper size is applicable to China National Standard (CNS) A4 (21〇 X 297mm)

Claims (1)

200300092 A8 B8 C8 D8 6. Scope of patent application1. A pharmaceutical composition for inhibiting bone resorption in humans, which includes a pharmaceutically effective unit dose of bisphosphonate for oral administration. It is administered in a continuous process once a day to about once every 16 days, wherein the bisphosphonate is selected from the group consisting of cimadronate, clodronate, and tiludronate. , Etidronate, ibandronate, dsedronate, piridronate, pamidronate, etc. A group of zoledronate, pharmaceutically acceptable salts or esters, and mixtures thereof. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the continuous process has a dosing interval selected from the group consisting of: once a week, twice a week, once every two weeks, and twice a month. 3. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the unit dose of the bisphosphonate comprises about 1.5 to about 6000 micrograms / kg body weight. 4. The pharmaceutical composition according to item 1 of the scope of the patent application, wherein the unit dose of the bisphosphonate comprises from about 10 to about 2000 micrograms per kilogram of body weight. 5. The pharmaceutical composition according to any one of the claims 1-4, which is used for treating human osteoporosis. 6. The pharmaceutical composition according to any one of claims 1-4 in the scope of patent application, which is used to prevent human osteoporosis. 7. The pharmaceutical composition according to any one of claims 1 to 4 of the scope of patent application, wherein the human is suffering from or is susceptible to gastrointestinal diseases. 8. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the human is Binding -38- 200300092 6. Scope of patent application Suffering from or prone to gastrointestinal diseases. 9. The pharmaceutical composition according to item 6 of the scope of patent application, wherein the human is suffering from or is susceptible to gastrointestinal diseases. 10. The pharmaceutical composition according to any one of claims 1 to 4 of the scope of patent application, wherein the use can minimize the occurrence or possibility of adverse gastrointestinal effects. 1 1 · The pharmaceutical composition according to item 5 of the scope of patent application, wherein the use can minimize the occurrence or possibility of adverse gastrointestinal effects. 12. The pharmaceutical composition according to item 6 of the scope of patent application, wherein the use can minimize the occurrence or possibility of adverse gastrointestinal effects. 1 3-A kit for inhibiting bone resorption in humans, comprising at least one pharmaceutically effective unit dose of a bisphosphonate for oral administration, based on from about every 3 days to about every 16 Dosing in a continuous process once a day, wherein the bisphosphonate is selected from the group consisting of cimadronate, ciodoronate, tiludironate, and polyacidification Etidronate, ibandronate, riseronate, piridronate, pamidronate, zoledronate, A group of pharmaceutically acceptable salts or esters, and mixtures thereof. 14 · The set according to item 13 of the scope of patent application, wherein the continuous process has a dosing interval selected from the following: once a week, twice a week, once every two weeks, and twice a month. 1 5 · The set according to item 13 of the scope of patent application, where the bisphosphonate -39- This paper size is applicable to TG Standard (CNS) A4 specification (210 X 297 mm)-200300092 A BCD 6. The unit dosage range of the patent application ranges from about 1.5 to about 6000 micrograms / kg of body weight. 16. The kit according to item 13 of the scope of the patent application, wherein the unit dose of the bisphosphonate comprises about 10 to about 2000 micrograms per kilogram of body weight. 1 7. The set according to any one of claims 1 to 16 of the scope of the patent application, which further includes # 5 supplement. 1 8. —A pharmaceutical composition for inhibiting human bone aspiration, comprising a pharmaceutically effective unit dose of a histamine H2 receptor blocker or a proton pump inhibitor and a pharmaceutically effective unit dose of bisphosphine Acidification, the oral administration is based on a continuous process from about once every 3 days to about every 16 days, wherein the bisphosphonate is selected from the group consisting of cimadronate, copolyacid ( clodronate), tiludronate, etidronate, ibandronate, riseronate, piridronate, palmitate A group consisting of pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. 19. The pharmaceutical composition according to item 18 of the scope of patent application, wherein the continuous process has a dosing interval selected from the group consisting of: once a week, twice a week, once every two weeks, and twice a month . 20. The pharmaceutical composition according to item 18 of the scope of patent application, wherein the histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, and nisatin Nizatidine, ranitidine, Ober Smell-40- This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 200300092 A8 B8 C8 _D8 6. Scope of patent application ( omeprazole) and lansoprazole. 21. The pharmaceutical composition according to any one of claims 18-20, wherein the human is suffering from or is susceptible to gastrointestinal diseases. 2 2. The pharmaceutical composition according to any one of claims 18-20 of the scope of the patent application, wherein the use can minimize the occurrence or possibility of adverse gastrointestinal effects. 23. A kit comprising: (a) at least one pharmaceutically effective unit dose of a bisphosphonate, wherein the bisphosphonate is selected from the group consisting of cimadronate, polyacidifiable (Clodronate), ti ludronate, etidronate, ibandronate, riseronate, piridronate A group consisting of pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof, and (b) at least one pharmaceutically effective dose of tissue Amine H2 receptor blocker or proton pump inhibitor. 24. The set according to item 23 of the scope of patent application, wherein the histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, and nisatidine (nizatidine), ranitidine, omeprazole, and lansoprazole. -41-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)