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WO1996017616A1 - Kit for osteoporosis treatment cycle - Google Patents

Kit for osteoporosis treatment cycle Download PDF

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Publication number
WO1996017616A1
WO1996017616A1 PCT/FR1995/001596 FR9501596W WO9617616A1 WO 1996017616 A1 WO1996017616 A1 WO 1996017616A1 FR 9501596 W FR9501596 W FR 9501596W WO 9617616 A1 WO9617616 A1 WO 9617616A1
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WO
WIPO (PCT)
Prior art keywords
tiludronic acid
calcium
pharmaceutically acceptable
kit
acceptable salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/FR1995/001596
Other languages
French (fr)
Inventor
Martine Gazard
Olivier Gros
Jacques Girard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SK685-97A priority Critical patent/SK68597A3/en
Priority to PL95320564A priority patent/PL320564A1/en
Priority to AU43073/96A priority patent/AU4307396A/en
Priority to CZ971753A priority patent/CZ175397A3/en
Priority to FI972383A priority patent/FI972383L/en
Priority to JP8517359A priority patent/JPH10509729A/en
Priority to BR9509961A priority patent/BR9509961A/en
Priority to EP95941761A priority patent/EP0797444A1/en
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of WO1996017616A1 publication Critical patent/WO1996017616A1/en
Priority to MXPA/A/1997/004105A priority patent/MXPA97004105A/en
Priority to NO972558A priority patent/NO972558L/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a kit for use in a therapeutic cycle for the treatment and / or prevention of osteoporosis. More particularly, the invention relates to a kit for use in the therapy of osteoporosis where a bisphosphonate and a nutritional supplement (or a placebo) are administered sequentially.
  • EP-A-0100718 describes new compounds having a structure
  • bisphosphonate including (4-chlorophenyl) - tiomethylenediphosphonic acid, the corresponding INN of which is tiludronic acid. This compound has shown very interesting properties in the treatment of osteoporosis (J.Y. Reginster et al., The Lancet, Dec. 23/30, 1989).
  • EP-A-0162510, BE 902308 and AU 8541619 describe sequential treatments for osteoporosis with kits containing a bone cell activator compound, a phosphonate and a nutritional supplement (or a placebo), to be administered in sequence, for periods defined times.
  • EP-A-210728 describes a kit for use in the treatment of osteoporosis containing a bisphosphonate - to be administered for 1-90 days - and a nutritional supplement (or a placebo) - to be administered for the following 50-120 days.
  • WO 94/00129 describes a method of treating osteoporosis comprising the administration of a "high potency" phosphonate in a treatment cycle of 1 to 30 days, optionally followed by a rest period of at least one day .
  • the above international application lists "high potency” phosphonates which can be used according to the invention; in this patent application, tiludronate is indicated as one of the "low power” phosphonates, which are not suitable for carrying out the invention.
  • the present invention therefore relates to a kit intended for the treatment and / or prevention of osteoporosis comprising the sequential administration of tiludronic acid or one of its salts and / or solvates and a nutritive supplement, said kit being characterized in that it contains:
  • compositions of tiludronic acid include salts with physiologically compatible inorganic and organic bases; pharmaceutically acceptable salts of tiludronic acid are disodium tiludronate, disodium tiludronate hydrated and disodium tiludronate monohydrate (EP-582515), the latter two being preferred.
  • the term "nutritional supplement in the present description indicates one or more substances which normally should be introduced into the organism by the regular food, like for example calcium and vitamin D; when these substances are not taken in sufficient quantity the normal diet runs the risk of jeopardizing the success of therapy with tiludronic acid or one of its salts and / or solvates, which is why therapy with tiludronic acid or one of its salts and / or solvates is associated with the administration of said nutritional supplement, a particularly advantageous nutritional supplement being calcium.
  • the calcium is in salified form with pharmaceutically acceptable inorganic or organic acids.
  • Such calcium salts include carbonate, chloride, chloride hexahydrate, citrate, formate, glucoheptonate, gluconate, gluconolactate, glutamate, glycerophosphate, hydrogenophosphate, lactate, lactobionate, lactophosphate, l ⁇ vulinate, oleate, monobasic or tribasic phosphate, pidolate, sulfate; gluconolactate, carbonate and gluconate are the particularly preferred calcium salts. Therefore, when talking about calcium, we are referring to a calcium salt in an amount corresponding to the desired dose of Ca ++ .
  • the above calcium salts can be administered alone or in combination.
  • the kit according to the invention allows the patient suffering from osteoporosis to carry out therapeutic cycles, based on the sequential administration of tiludronic acid or one of its salts and / or solvates and a nutritive supplement, convenient and safe way.
  • the doses of tiludronic acid or one of its salts and / or solvates and nutritional supplement will be in the form of compositions intended for oral administration.
  • said oral pharmaceutical compositions are solid forms, such as for example tablets, optionally scored, chewable or effervescent, capsules or granules.
  • the main active ingredient tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates
  • a pharmaceutical vehicle such as gelatin, starch , lactose, magnesium stearate, talc, gum arabic, sodium lauryl sulfate, crospovidone, cellulose derivatives or the like.
  • the tablets can be coated with sucrose or other suitable materials, for example for coloring, or they can be treated so that they have a prolonged or delayed activity and that they release continuously a predetermined amount of active ingredient.
  • compositions of this type contain from 1.5% to 6% by weight of sodium lauryl sulfate relative to tiludronic acid (EP-A-336851).
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
  • Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
  • the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
  • compositions based on calcium salts are prepared according to pharmaceutical techniques well known to those skilled in the art; preferably these compositions will be optionally scored tablets or effervescent tablets or chewable tablets.
  • tiludronic acid or one of its salts and / or solvates and the nutritive supplement necessary for a therapy cycle of 28 to 31 days as described above will be contained in the same packaging; the pharmaceutical compositions respectively containing tiludronic acid or one of its salts and / or solvates and the nutritive supplement could possibly be formulated in different colors or numbered, to facilitate the administration of this type of medicament in a long-term therapy.
  • the daily dose of tiludronic acid or one of its salts and / or solvates to be administered varies according to the characteristics of the subject to be treated such as age, weight and severity of the conditions; in general the daily dose is between 10 and 400 g of tiludronic acid, advantageously between 30 and 300 mg, preferably 50, 75, 100, 125, 150, 175 or 200 mg, for example 50 or 200 mg per day.
  • tiludronic acid is advantageously administered in the form of its disodium salt monohydrate or hemihydrate.
  • tiludronic acid refers to tiludronic acid.
  • the amount administered will be that corresponding to the dose of tiludronic acid desired.
  • the daily dose of nutritional supplement depends on the type of substance administered and the patient's diet.
  • the nutritional supplement is calcium
  • the amount can vary between 200 and 2000 mg per day, advantageously 500 or 1000 mg per day, expressed in mg of Ca ++ .
  • the therapy cycle described above must be repeated several times, as part of a long-term treatment, which can range from 6 months to several years.
  • the treatment cycle should be repeated until the desired increase in bone mass is achieved.
  • the present invention relates to a method of treatment and / or prevention of osteoporosis, which comprises the administration of tiludronic acid or one of its salts and / or solvates during a period of 7 days, followed by a rest period of 21-24 days during which a nutritional supplement, including calcium, can be administered.
  • the present invention also relates to a method for the treatment and / or prevention of osteoporosis in mammals, which comprises administering to said mammals an effective amount of tiludronic acid or a salt thereof and / or pharmaceutically acceptable solvates and a nutritional supplement according to the following scheme:
  • EXAMPLE 1 A Tablets are prepared having the following composition disodium tiludronate hemihydrate 58.6 mg (corresponding to 50 mg of tiludronic aci) lactose 10.06 mg sodium lauryl sulfate 1.125 mg crospovidone 3.75 mg methyl hydroxypropyl cellulose 1.3 125 mg 0.15 mg magnesium stearate
  • the granulation is carried out using purified water which is eliminated in the following preparation steps.
  • Tablets having the following composition are prepared: disodium tiludronate hemihydrate 234.5 mg (corresponding to 200 mg of tiludronic acid) lactose 40.15 mg sodium lauryl sulfate 4.5 mg crospovidone 15 mg methyl hydroxypropyl cellulose 5.25 mg magnesium stearate 0.6 mg
  • the granulation is carried out using purified water which is eliminated in the following preparation steps.
  • B. Tablets are prepared having the following composition (total Ca ++ 500 mg): calcium carbonate 1.25 g sucrose 0.85 g sodium chloride 0.02 g sodium saccharin 0.02 g polyethylene glycol 0.2 g bicarbonate sodium 1 g citric acid 1.65 g orange essence 0.02 g

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a kit to be used in a therapeutical cycle based on the sequential administration of tiludronic acid or one of its salts and/or solvates and calcium during 28 to 31 days, for the treatment and/or prevention of osteoporosis.

Description

Trousse pour cvcle de traitement de l'ostéoporose. Kit for osteoporosis treatment cycle.

La présente invention concerne une trousse à utiliser dans un cycle thérapeutique destiné au traitement et/ou à la prévention de l'ostéoporose. Plus particulièrement, l'invention se rapporte à une trousse à utiliser dans la thérapie de l'ostéoporose où un bisphosphonate et un supplément nutritif (ou un placebo) sont administrés de façon séquentielle.The present invention relates to a kit for use in a therapeutic cycle for the treatment and / or prevention of osteoporosis. More particularly, the invention relates to a kit for use in the therapy of osteoporosis where a bisphosphonate and a nutritional supplement (or a placebo) are administered sequentially.

EP-A-0100718 décrit de nouveaux composés ayant une structureEP-A-0100718 describes new compounds having a structure

"bisphosphonate" parmi lesquels l'acide (4-chlorophényl)- tiométhylenediphosphonique dont la DCI correspondante est l'acide tiludronique. Ce composé a montré des propriétés très intéressantes dans le traitement de l'ostéoporose (J.Y. Reginster et al., The Lancet, Dec. 23/30, 1989)."bisphosphonate" including (4-chlorophenyl) - tiomethylenediphosphonic acid, the corresponding INN of which is tiludronic acid. This compound has shown very interesting properties in the treatment of osteoporosis (J.Y. Reginster et al., The Lancet, Dec. 23/30, 1989).

EP-A-0162510, BE 902308 et AU 8541619 décrivent des traitements séquentiels de l'ostéoporose par des trousses contenant un composé activateur des cellules osseuses, un phosphonate et un supplément nutritif (ou un placebo), à administrer en séquence, pendant des périodes de temps définies.EP-A-0162510, BE 902308 and AU 8541619 describe sequential treatments for osteoporosis with kits containing a bone cell activator compound, a phosphonate and a nutritional supplement (or a placebo), to be administered in sequence, for periods defined times.

EP-A-210728 décrit une trousse à utiliser dans le traitement de l'ostéoporose contenant un bisphosphonate - à administrer pendant 1-90 jours - et un supplément nutritif (ou un placebo) - à administrer pendant les 50-120 jours suivants.EP-A-210728 describes a kit for use in the treatment of osteoporosis containing a bisphosphonate - to be administered for 1-90 days - and a nutritional supplement (or a placebo) - to be administered for the following 50-120 days.

WO 94/00129 décrit une méthode de traitement de l'ostéoporose comprenant l'administration d'un phosphonate "à haute puissance" dans un cycle de traitement de 1 à 30 jours, éventuellement suivi par une période de repos d'au moins un jour. La demande internationale ci-dessus dresse une liste de phosphonates "à haute puissance" qui peuvent être utilisés selon l'invention; dans cette demande de brevet, le tiludronate est indiqué comme l'un des phosphonates "à basse puissance", qui ne sont pas aptes à la mise en oeuvre de l'invention. Dans ladite demande de brevet, la subdivision en phosphonates à "haute, moyenne et basse puissance" est effectuée sur la base des doses efficaces minimales ou LED (de l'anglais: least effective dose), cette LED étant plus élevée pour les phosphonates "à basse puissance"; on affirme ensuite que plus la puissance du phosphonate est faible, plus la fréquence d'administration devra être élevée (page 36, lignes 12-14).WO 94/00129 describes a method of treating osteoporosis comprising the administration of a "high potency" phosphonate in a treatment cycle of 1 to 30 days, optionally followed by a rest period of at least one day . The above international application lists "high potency" phosphonates which can be used according to the invention; in this patent application, tiludronate is indicated as one of the "low power" phosphonates, which are not suitable for carrying out the invention. In said patent application, the subdivision into "high, medium and low power" phosphonates is carried out on the basis of minimum effective doses or LEDs (from the English: least effective dose), this LED being higher for phosphonates " at low power "; it is then said that the lower the power of the phosphonate, the higher the frequency of administration should be (page 36, lines 12-14).

Contrairement à ces enseignements, il a été maintenant trouvé que, dans le traitement de l'ostéoporose, l'administration intermittente d'acide tiludronique ou d'un de ses sels et/ou solvates produit le même effet thérapeutique que l'administration continue, en présentant l'avantage d'éliminer les effets secondaires qui se manifestent principalement au niveau gastro-intestinal après quelques semaines de thérapie ininterrompue à base de bisphosphonates. Plus particulièrement, il a été trouvé, de façon surprenante, que l'administration séquentielle d'acide tiludronique ou d'un de ses sels et/ou solvates pendant 7 jours et d'un supplément nutritif pendant 21 à 24 jours, conduit à une considérable amélioration des conditions osseuses des sujets souffrant d'ostéoporose. La présente invention a donc pour objet une trousse destinée au traitement et/ou la prévention de l'ostéoporose comprenant l'administration séquentielle d'acide tiludronique ou d'un de ses sels et/ou solvates et d'un supplément nutritif, ladite trousse étant caractérisée en ce qu'elle contient:Contrary to these teachings, it has now been found that, in the treatment of osteoporosis, the intermittent administration of tiludronic acid or one of its salts and / or solvates produces the same therapeutic effect as continuous administration, with the advantage of eliminating the side effects which are manifested mainly in the gastrointestinal level after a few weeks of uninterrupted therapy based bisphosphonates. More particularly, it has been surprisingly found that the sequential administration of tiludronic acid or one of its salts and / or solvates for 7 days and a nutritional supplement for 21 to 24 days, leads to a considerable improvement in bone conditions in subjects suffering from osteoporosis. The present invention therefore relates to a kit intended for the treatment and / or prevention of osteoporosis comprising the sequential administration of tiludronic acid or one of its salts and / or solvates and a nutritive supplement, said kit being characterized in that it contains:

(a) 7 doses journalières d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables et(a) 7 daily doses of tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates, and

(b) un supplément nutritif réparti en unités de dosage à administrer pendant les 21 à 24 jours suivant (a).(b) a nutritional supplement divided into dosage units to be administered during the 21 to 24 days following (a).

Les sels pharmaceutiquement acceptables de l'acide tiludronique comprennent les sels avec les bases inorganiques et organiques physiologiquement compatibles; des sels d'acide tiludronique pharmaceutiquement acceptables sont le tiludronate disodique, le tiludronate disodique hé ihydraté et le tiludronate disodique monohydraté (EP-582515), les deux derniers étant préférés.Pharmaceutically acceptable salts of tiludronic acid include salts with physiologically compatible inorganic and organic bases; pharmaceutically acceptable salts of tiludronic acid are disodium tiludronate, disodium tiludronate hydrated and disodium tiludronate monohydrate (EP-582515), the latter two being preferred.

Le terme "supplément nutritif dans la présente description, indique une ou plusieurs substances qui normalement devraient être introduites dans l'organisme par l'alimentation régulière, comme par exemple le calcium et la vitamine D; lorsque ces substances ne sont pas prises en quantité suffisante par le régime alimentaire normal, on court le risque de nuire à la bonne réussite de la thérapie à base d'acide tiludronique ou d'un de ses sels et/ou solvates. Cest pour cette raison que la thérapie à base d'acide tiludronique ou d'un de ses sels et/ou solvates est associée à l'administration dudit supplément nutritif, un supplément nutritif particulièrement avantageux étant le calcium.The term "nutritional supplement in the present description indicates one or more substances which normally should be introduced into the organism by the regular food, like for example calcium and vitamin D; when these substances are not taken in sufficient quantity the normal diet runs the risk of jeopardizing the success of therapy with tiludronic acid or one of its salts and / or solvates, which is why therapy with tiludronic acid or one of its salts and / or solvates is associated with the administration of said nutritional supplement, a particularly advantageous nutritional supplement being calcium.

Pour être administré en tant que supplément nutritif selon la présente invention, le calcium est sous forme salifiée avec des acides inorganiques ou organiques pharmaceutiquement acceptables. De tels sels de calcium comprennent le carbonate, le chlorure, le chlorure hexahydraté, le citrate, le formiate, le glucoheptonate, le gluconate, le gluconolactate, le glutamate, le glycérophosphate, l'hydrogénophosphate, le lactate, le lactobionate, le lactophosphate, le lέvulinate, l'oléate, le phosphate monobasique ou tribasique, le pidolate, le sulfate; le gluconolactate, le carbonate et le gluconate sont les sels de calcium particulièrement préférés. Par conséquent, lorsqu'on parle de calcium, on se réfère à un sel de calcium en quantité correspondant à la dose de Ca++ souhaité.To be administered as a nutritional supplement according to the present invention, the calcium is in salified form with pharmaceutically acceptable inorganic or organic acids. Such calcium salts include carbonate, chloride, chloride hexahydrate, citrate, formate, glucoheptonate, gluconate, gluconolactate, glutamate, glycerophosphate, hydrogenophosphate, lactate, lactobionate, lactophosphate, lέvulinate, oleate, monobasic or tribasic phosphate, pidolate, sulfate; gluconolactate, carbonate and gluconate are the particularly preferred calcium salts. Therefore, when talking about calcium, we are referring to a calcium salt in an amount corresponding to the desired dose of Ca ++ .

Les sels de calcium ci-dessus peuvent être administrés seuls ou en association entre eux.The above calcium salts can be administered alone or in combination.

La trousse selon l'invention permet au patient souffrant d'ostéoporose, d'effectuer des cycles thérapeutiques, basés sur l'administration séquentielle d'acide tiludronique ou d'un de ses sels et/ou solvates et d'un supplément nutritif, de façon pratique et sûre. Par mesure de commodité d'utilisation, compte-tenu du caractère à long terme de la thérapie en question, les doses d'acide tiludronique ou d'un de ses sels et/ou solvates et de supplément nutritif seront sous forme de compositions destinées à l'administration orale.The kit according to the invention allows the patient suffering from osteoporosis to carry out therapeutic cycles, based on the sequential administration of tiludronic acid or one of its salts and / or solvates and a nutritive supplement, convenient and safe way. For convenience of use, taking into account the long-term nature of the therapy in question, the doses of tiludronic acid or one of its salts and / or solvates and nutritional supplement will be in the form of compositions intended for oral administration.

Selon un aspect préféré de l'invention, lesdites compositions pharmaceutiques orales sont des formes solides, comme par exemple les comprimés, éventuellement sécables, à croquer ou effervescents, les gélules ou les granules.According to a preferred aspect of the invention, said oral pharmaceutical compositions are solid forms, such as for example tablets, optionally scored, chewable or effervescent, capsules or granules.

Lorsqu'on prépare une composition solide sous forme de comprimés, on mélange l'ingrédient actif principal, l'acide tiludronique ou l'un de ses sels et/ou solvates pharmaceutiquement acceptables, avec un véhicule pharmaceutique tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique, le lauryl sulfate de sodium, la crospovidone, les dérivés de la cellulose ou analogues. On peut enrober les comprimés de saccharose ou d'autres matières appropriées, par exemple pour obtenir une coloration, ou encore on peut les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.When preparing a solid composition in the form of tablets, the main active ingredient, tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates, is mixed with a pharmaceutical vehicle such as gelatin, starch , lactose, magnesium stearate, talc, gum arabic, sodium lauryl sulfate, crospovidone, cellulose derivatives or the like. The tablets can be coated with sucrose or other suitable materials, for example for coloring, or they can be treated so that they have a prolonged or delayed activity and that they release continuously a predetermined amount of active ingredient.

Des compositions préférentielles de ce type contiennent de 1,5 % à 6 % en poids de laurylsulfate de sodium par rapport à l'acide tiludronique (EP-A- 336851).Preferred compositions of this type contain from 1.5% to 6% by weight of sodium lauryl sulfate relative to tiludronic acid (EP-A-336851).

On obtient une préparation en gélules en mélangeant l'ingrédient actif avec un diluant et en versant le mélange obtenu dans des gélules molles ou dures. Les poudres ou les granules dispersibles dans l'eau peuvent contenir l'ingrédient actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinylpyrrolidone, de même qu'avec des édulcorants ou des correcteurs du goût.A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules. Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.

Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports ou additifs.The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

Les compositions orales à base de sels de calcium, éventuellement mélangés entre eux, sont préparées selon les techniques pharmaceutiques bien connues de l'homme du métier; de préférence ces compositions seront des comprimés éventuellement sécables ou des comprimés effervescents ou encore des comprimés à croquer.The oral compositions based on calcium salts, optionally mixed together, are prepared according to pharmaceutical techniques well known to those skilled in the art; preferably these compositions will be optionally scored tablets or effervescent tablets or chewable tablets.

De préférence, l'acide tiludronique ou un de ses sels et/ou solvates et le supplément nutritif nécessaires pour un cycle de thérapie de 28 à 31 jours tel que décrit ci-dessus, seront renfermés dans le même conditionnement; les compositions pharmaceutiques contenant respectivement l'acide tiludronique ou un de ses sels et/ou solvates et le supplément nutritif pourront éventuellement être formulées en couleurs différentes ou bien numérotées, pour faciliter l'administration de ce type de médicament dans une thérapie de longue durée. La dose journalière d'acide tiludronique ou d'un de ses sels et/ou solvates à administrer varie selon les caractéristiques du sujet à traiter telles que l'âge, le poids et la gravité des affections; en général la dose journalière est comprise entre 10 et 400 g d'acide tiludronique, avantageusement entre 30 et 300 mg, de préférence 50, 75, 100, 125, 150, 175 ou 200 mg, par exemple 50 ou 200 mg par jour.Preferably, tiludronic acid or one of its salts and / or solvates and the nutritive supplement necessary for a therapy cycle of 28 to 31 days as described above, will be contained in the same packaging; the pharmaceutical compositions respectively containing tiludronic acid or one of its salts and / or solvates and the nutritive supplement could possibly be formulated in different colors or numbered, to facilitate the administration of this type of medicament in a long-term therapy. The daily dose of tiludronic acid or one of its salts and / or solvates to be administered varies according to the characteristics of the subject to be treated such as age, weight and severity of the conditions; in general the daily dose is between 10 and 400 g of tiludronic acid, advantageously between 30 and 300 mg, preferably 50, 75, 100, 125, 150, 175 or 200 mg, for example 50 or 200 mg per day.

Selon un aspect préféré de la présente invention, l'acide tiludronique est avantageusement administré sous forme de son sel disodique monohydraté ou hémihydraté.According to a preferred aspect of the present invention, tiludronic acid is advantageously administered in the form of its disodium salt monohydrate or hemihydrate.

Ces doses se réfèrent à l'acide tiludronique. Lorsque celui-ci est administré sous forme de l'un de ses sels et/ou solvates pharmaceutiquement acceptables, la quantité administrée sera celle correspondant à la dose d'acide tiludronique souhaitée.These doses refer to tiludronic acid. When the latter is administered in the form of one of its pharmaceutically acceptable salts and / or solvates, the amount administered will be that corresponding to the dose of tiludronic acid desired.

La dose journalière de supplément nutritif dépend du type de la substance administrée et du régime alimentaire du patient. Lorsque le supplément nutritif est du calcium, la quantité peut varier entre 200 et 2000 mg par jour, avantageusement 500 ou 1000 mg par jour, exprimée en mg de Ca++.The daily dose of nutritional supplement depends on the type of substance administered and the patient's diet. When the nutritional supplement is calcium, the amount can vary between 200 and 2000 mg per day, advantageously 500 or 1000 mg per day, expressed in mg of Ca ++ .

Pour obtenir l'effet thérapeutique souhaité, le cycle de thérapie décrit ci- dessus, doit être répété plusieurs fois, dans le cadre d'un traitement au long cours, qui peut aller de 6 mois à plusieurs années.To obtain the desired therapeutic effect, the therapy cycle described above must be repeated several times, as part of a long-term treatment, which can range from 6 months to several years.

En général, le cycle de traitement doit être répété jusqu'à atteindre l'augmentation souhaitée de la masse osseuse.In general, the treatment cycle should be repeated until the desired increase in bone mass is achieved.

Selon un autre de ses aspects, la présente invention concerne une méthode de traitement et/ou de prévention de l'ostéoporose, qui comprend l'administration d'acide tiludronique ou d'un de ses sels et/ou solvates pendant une période de 7 jours, suivie par une période de repos de 21 à 24 jours pendant laquelle on peut administrer un supplément nutritif, notamment du calcium.According to another of its aspects, the present invention relates to a method of treatment and / or prevention of osteoporosis, which comprises the administration of tiludronic acid or one of its salts and / or solvates during a period of 7 days, followed by a rest period of 21-24 days during which a nutritional supplement, including calcium, can be administered.

Ainsi, la présente invention concerne également une méthode pour le traitement et/ou la prévention de l'ostéoporose chez les mammifères, qui comprend l'administration auxdits mammifères d'une quantité efficace d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables et d'un supplément nutritif selon le schéma suivant:Thus, the present invention also relates to a method for the treatment and / or prevention of osteoporosis in mammals, which comprises administering to said mammals an effective amount of tiludronic acid or a salt thereof and / or pharmaceutically acceptable solvates and a nutritional supplement according to the following scheme:

(a) une période de 7 jours pendant laquelle on administre des doses journalières d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables suivie par(a) a period of 7 days during which daily doses of tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates are administered, followed by

(b) une période de 21 à 24 jours pendant laquelle on administre des doses journalières de calcium sous forme d'un de ses sels pharmaceutiquement acceptables;(b) a period of 21 to 24 days during which daily doses of calcium are administered in the form of one of its pharmaceutically acceptable salts;

(c) répétition de (a) et (b) jusqu'à l'obtention de l'augmentation souhaitée de la masse osseuse.(c) repeating (a) and (b) until the desired increase in bone mass is obtained.

Pour cette méthode de traitement, on utilise une trousse telle que définie ci- dessus.For this treatment method, a kit as defined above is used.

Dans des essais cliniques, il a été démontré que l'administration intermittente des principes actifs renfermés dans le kit de la présente invention selon le cycle thérapeutique décrit ci-dessus, conduit au même effet thérapeutique que l'administration continue d'acide tiludronique ou d'un de ses sels et/ou solvates.In clinical trials, it has been demonstrated that the intermittent administration of the active ingredients contained in the kit of the present invention according to the therapeutic cycle described above, leads to the same therapeutic effect as the continuous administration of tiludronic acid or d 'one of its salts and / or solvates.

De plus, ce type de régime thérapeutique, est très bien toléré et réduit considérablement les effets secondaires par rapport à la thérapie traditionnelle à base de bisphosphonates. Les exemples qui suivent illustrent l'invention. EXEMPLE 1 A. On prépare des comprimés ayant la composition suivante tiludronate disodique hémihydraté 58,6 mg (correspondant à 50 mg d'aci tiludronique) lactose 10,06 mg laurylsulfate de sodium 1,125 mg crospovidone 3,75 mg méthylhydroxypropyl cellulose 1,3125 mg stéarate de magnésium 0,15 mgIn addition, this type of therapeutic diet is very well tolerated and considerably reduces side effects compared to traditional bisphosphonate therapy. The following examples illustrate the invention. EXAMPLE 1 A. Tablets are prepared having the following composition disodium tiludronate hemihydrate 58.6 mg (corresponding to 50 mg of tiludronic aci) lactose 10.06 mg sodium lauryl sulfate 1.125 mg crospovidone 3.75 mg methyl hydroxypropyl cellulose 1.3 125 mg 0.15 mg magnesium stearate

La granulation est effectuée à l'aide d'eau purifiée qui est éliminée dans les étapes de préparation suivantes.The granulation is carried out using purified water which is eliminated in the following preparation steps.

B. On prépare des comprimés ayant la composition suivante (Ca++ total 500 mg): gluconolactate de calcium 2,94 g carbonate de calcium 0,30 g saccharose 0,85 g chlorure de sodium 0,02 g saccharine sodique 0,02 g polyéthylèneglycol 0,2 g bicarbonate de sodium acide citrique 1,65 g essence d'orange 0,02 gB. Tablets are prepared having the following composition (total Ca ++ 500 mg): calcium gluconolactate 2.94 g calcium carbonate 0.30 g sucrose 0.85 g sodium chloride 0.02 g sodium saccharin 0.02 g polyethylene glycol 0.2 g sodium bicarbonate citric acid 1.65 g orange essence 0.02 g

C. On dispose les comprimés des points A et B dans un conditionnement adapté à l'administration de médicaments. EXEMPLE 2C. The tablets of points A and B are placed in a packaging suitable for the administration of drugs. EXAMPLE 2

A. On prépare des comprimés ayant la composition suivante: tiludronate disodique hémihydraté 234,5 mg (correspondant à 200 mg d'acide tiludronique) lactose 40,15 mg lauryl sulfate de sodium 4,5 mg crospovidone 15 mg méthylhydroxypropyl cellulose 5,25 mg stéarate de magnésium 0,6 mg La granulation est effectuée à l'aide d'eau purifiée qui est éliminée dans les étapes de préparation suivantes.A. Tablets having the following composition are prepared: disodium tiludronate hemihydrate 234.5 mg (corresponding to 200 mg of tiludronic acid) lactose 40.15 mg sodium lauryl sulfate 4.5 mg crospovidone 15 mg methyl hydroxypropyl cellulose 5.25 mg magnesium stearate 0.6 mg The granulation is carried out using purified water which is eliminated in the following preparation steps.

B. On prépare des comprimés ayant la composition suivante (Ca++ total 500 mg): carbonate de calcium 1,25 g saccharose 0,85 g chlorure de sodium 0,02 g saccharine sodique 0,02 g polyéthylèneglycol 0,2 g bicarbonate de sodium 1 g acide citrique 1,65 g essence d'orange 0,02 gB. Tablets are prepared having the following composition (total Ca ++ 500 mg): calcium carbonate 1.25 g sucrose 0.85 g sodium chloride 0.02 g sodium saccharin 0.02 g polyethylene glycol 0.2 g bicarbonate sodium 1 g citric acid 1.65 g orange essence 0.02 g

C. On dispose les comprimés des points A et B dans un conditionnement adapté à l'administration de médicaments. C. The tablets of points A and B are placed in a packaging suitable for the administration of medicaments.

Claims

REVENDICATIONS 1. Trousse destinée à un régime pour le traitement et/ou la prévention de l'ostéoporose par l'administration séquentielle d'acide tiludronique ou d'un de ses sels et/ou solvates et d'un supplément nutritif, ladite trousse étant caractérisée en ce qu'elle contient:1. Kit intended for a diet for the treatment and / or prevention of osteoporosis by the sequential administration of tiludronic acid or one of its salts and / or solvates and a nutritive supplement, said kit being characterized in that it contains: (a) 7 doses journalières d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables et(a) 7 daily doses of tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates, and (b) un supplément nutritif reparti en unités de dosage à administrer pendant les 21 à 24 jours suivant (a). (b) a nutritional supplement divided into dosage units to be administered during the 21 to 24 days following (a). 2. Trousse selon la revendication 1, caractérisée en ce que les doses journalières d'acide tiludronique sont comprises entre 10 et 400 mg. 2. Kit according to claim 1, characterized in that the daily doses of tiludronic acid are between 10 and 400 mg. 3. Trousse selon la revendication 2, caractérisée en ce que les doses journalières d'acide tiludronique sont choisies parmi 50, 75, 100, 125, 150,3. Kit according to claim 2, characterized in that the daily doses of tiludronic acid are chosen from 50, 75, 100, 125, 150, 175 et 200 mg. 175 and 200 mg. 4 Trousse selon la revendication 2, caractérisée en ce que l'acide tiludronique est sous forme de son sel disodique monohydraté ou disodique hémihydraté.4 Kit according to claim 2, characterized in that the tiludronic acid is in the form of its disodium salt monohydrate or disodium hemihydrate. 5. Trousse selon la revendication 1, caractérisée en ce que le supplément nutritif est du calcium sous forme d'un de ses sels pharmaceutiquement acceptables.5. Kit according to claim 1, characterized in that the nutritive supplement is calcium in the form of one of its pharmaceutically acceptable salts. 6. Trousse selon la revendication 4, caractérisée en ce que la dose journalière de calcium est comprise entre 200 et 2000 mg, de préférence 500 mg ou 1000 mg, exprimée en mg de Ca++.6. Kit according to claim 4, characterized in that the daily dose of calcium is between 200 and 2000 mg, preferably 500 mg or 1000 mg, expressed in mg of Ca ++ . 7. Trousse selon la revendication 1, caractérisée en ce que (a) et (b) sont sous forme de comprimés.7. Kit according to claim 1, characterized in that (a) and (b) are in the form of tablets. 8. Trousse selon la revendication 1, caractérisée en ce qu'elle renferme8. Kit according to claim 1, characterized in that it contains (a) 7 comprimés contenant 50 mg d'acide tiludronique sous forme de tiludronate disodique hémihydraté ou monohydraté et(a) 7 tablets containing 50 mg of tiludronic acid in the form of disodium tiludronate hemihydrate or monohydrate and (b) 21 à 24 comprimés contenant 500 mg de calcium, exprimé en mg de Ca++, en tant que supplément nutritif, sous forme d'un de ses sels pharmaceutiquement acceptables.(b) 21 to 24 tablets containing 500 mg of calcium, expressed in mg of Ca ++ , as a nutritional supplement, in the form of one of its pharmaceutically acceptable salts. 9. Trousse selon la revendication 1, caractérisée en ce qu'elle renferme9. Kit according to claim 1, characterized in that it contains (a) 7 comprimés contenant 50 mg d'acide tiludronique sous forme de tiludronate disodique hémihydraté ou monohydraté et (b) 21 à 24 comprimés contenant 1000 mg de calcium, exprimé en mg de Ca++, en tant que supplément nutritif, sous forme d'un de ses sels pharmaceutiquement acceptables. (a) 7 tablets containing 50 mg of tiludronic acid in the form of disodium tiludronate hemihydrate or monohydrate and (b) 21 to 24 tablets containing 1000 mg of calcium, expressed in mg of Ca ++ , as a nutritional supplement, in the form of one of its pharmaceutically acceptable salts. 10. Trousse selon la revendication 1, caractérisée en ce qu'elle renferme (a) 7 comprimés contenant 200 mg d'acide tiludronique sous forme de tiludronate disodique hémihydraté ou monohydraté et (b) 21 à 24 comprimés contenant 500 mg de calcium, exprimé en mg de Ca++, en tant que supplément nutritif, sous forme d'un de ses sels pharmaceutiquement acceptables. 10. Kit according to claim 1, characterized in that it contains (a) 7 tablets containing 200 mg of tiludronic acid in the form of disodium tiludronate hemihydrate or monohydrate and (b) 21 to 24 tablets containing 500 mg of calcium, expressed in mg of Ca ++ , as a nutritional supplement, in the form of one of its pharmaceutically acceptable salts. 11. Trousse selon la revendication 1, caractérisée en ce qu'elle renferme11. Kit according to claim 1, characterized in that it contains (a) 7 comprimés contenant 200 mg d'acide tiludronique sous forme de tiludronate disodique hémihydraté ou monohydraté et (b)21 à 24 comprimés contenant 1000 mg de calcium, exprimé en mg de Ca++, en tant que supplément nutritif, sous forme d'un de ses sels pharmaceutiquement acceptables.(a) 7 tablets containing 200 mg of tiludronic acid in the form of disodium tiludronate hemihydrate or monohydrate and (b) 21 to 24 tablets containing 1000 mg of calcium, expressed in mg of Ca ++ , as a nutritional supplement, in the form one of its pharmaceutically acceptable salts. 12. Méthode pour le traitement et/ou la prévention de l'ostéoporose chez les mammifères, comprenant l'administration d'acide tiludronique ou d'un de ses sels et/ou solvates pendant une période de 7 jours, suivie par une période de repos de 21 à 24 jours. 12. Method for the treatment and / or prevention of osteoporosis in mammals, comprising administering tiludronic acid or one of its salts and / or solvates for a period of 7 days, followed by a period of rest from 21 to 24 days. 13. Méthode selon la revendication 12, caractérisée en ce qu'on administre un supplément nutritif pendant la période de repos.13. Method according to claim 12, characterized in that a nutritional supplement is administered during the rest period. 14. Méthode selon la revendication 13, caractérisée en ce que le supplément nutritif est du calcium.14. Method according to claim 13, characterized in that the nutritive supplement is calcium. 15. Méthode pour le traitement et/ou la prévention de l'ostéoporose chez les mammifères, comprenant l'administration auxdits mammifères d'une quantité efficace d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables et un supplément nutritif selon le schéma suivant :15. Method for the treatment and / or prevention of osteoporosis in mammals, comprising the administration to said mammals of an effective amount of tiludronic acid or of a pharmaceutically acceptable salt and / or solvate thereof and a supplement nutritious according to the following scheme: (a) une période de 7 jours pendant laquelle on administre des doses journalières d'acide tiludronique ou d'un de ses sels et/ou solvates pharmaceutiquement acceptables suivie par(a) a period of 7 days during which daily doses of tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates are administered, followed by (b) une période de 21 à 24 jours pendant laquelle on administre des doses journalières de calcium sous forme d'un de ses sels pharmaceutiquement acceptables; (c) répétition de (a) et (b) jusqu'à l'obtention de l'augmentation souhaitée de la masse osseuse. (b) a period of 21 to 24 days during which daily doses of calcium are administered in the form of one of its pharmaceutically acceptable salts; (c) repeating (a) and (b) until the desired increase in bone mass is obtained. 16. Méthode selon la revendication 15, caractérisée en ce qu'on utilise une trousse selon l'une quelconque des revendications 1 à 11. 16. Method according to claim 15, characterized in that a kit is used according to any one of claims 1 to 11. 17. Méthode selon la revendication 15, caractérisée en ce que les doses journalières d'acide tiludronique sont comprises entre 10 et 400 mg. 17. Method according to claim 15, characterized in that the daily doses of tiludronic acid are between 10 and 400 mg. 18. Méthode selon la revendication 17, caractérisée en ce que les doses journalières d'acide tiludronique sont choisies parmi 50, 75, 100, 125, 150, 175 et 200 mg. 18. Method according to claim 17, characterized in that the daily doses of tiludronic acid are chosen from 50, 75, 100, 125, 150, 175 and 200 mg. 19. Méthode selon l'une des revendications 12 ou 15, caractérisée en ce que l'acide tiludronique est administré sous forme de tiludronate disodique monohydraté ou de tiludronate disodique hémihydraté. 19. Method according to one of claims 12 or 15, characterized in that tiludronic acid is administered in the form of disodium tiludronate monohydrate or disodium tiludronate hemihydrate. 20. Méthode selon la revendication 15, caractérisée en ce qu'on administre pendant la période (b) des doses journalières de calcium comprises entre 200 et 2000 mg , sous forme d'un de ses sels pharmaceutiquement acceptables. 20. Method according to claim 15, characterized in that one administers during period (b) daily doses of calcium of between 200 and 2000 mg, in the form of one of its pharmaceutically acceptable salts.
PCT/FR1995/001596 1994-12-06 1995-12-05 Kit for osteoporosis treatment cycle Ceased WO1996017616A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP95941761A EP0797444A1 (en) 1994-12-06 1995-12-05 Kit for osteoporosis treatment cycle
PL95320564A PL320564A1 (en) 1994-12-06 1995-12-05 Therapeutic set for treating osteoporosis
AU43073/96A AU4307396A (en) 1994-12-06 1995-12-05 Kit for osteoporosis treatment cycle
CZ971753A CZ175397A3 (en) 1994-12-06 1995-12-05 Kit used for treating or prevention of osteoporosis
FI972383A FI972383L (en) 1994-12-06 1995-12-05 Osteoporosis treatment package
SK685-97A SK68597A3 (en) 1994-12-06 1995-12-05 Kit for osteoporosis treatment cycle
BR9509961A BR9509961A (en) 1994-12-06 1995-12-05 Osteoporosis treatment cycle kit
JP8517359A JPH10509729A (en) 1994-12-06 1995-12-05 Kit for osteoporosis treatment cycle
MXPA/A/1997/004105A MXPA97004105A (en) 1994-12-06 1997-06-03 Set for use in a therapeutic treatment cycle of osteoporo
NO972558A NO972558L (en) 1994-12-06 1997-06-05 Set for osteoporosis treatment cycle

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR94/14630 1994-12-06
FR9414630A FR2727629A1 (en) 1994-12-06 1994-12-06 OSTEOPOROSIS TREATMENT CYCLE KIT

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WO1996017616A1 true WO1996017616A1 (en) 1996-06-13

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JP (1) JPH10509729A (en)
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AR (1) AR002946A1 (en)
AU (1) AU4307396A (en)
BR (1) BR9509961A (en)
CA (1) CA2207028A1 (en)
CZ (1) CZ175397A3 (en)
FI (1) FI972383L (en)
FR (1) FR2727629A1 (en)
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US5994329A (en) * 1997-07-22 1999-11-30 Merck & Co., Inc. Method for inhibiting bone resorption
US6432932B1 (en) 1997-07-22 2002-08-13 Merck & Co., Inc. Method for inhibiting bone resorption
US7192938B2 (en) 2002-05-10 2007-03-20 Hoffmann-La Roche Inc. Method of treatment using bisphosphonic acid
US7923028B2 (en) 2002-12-20 2011-04-12 Hoffman-La Roche Inc. High dose oral formulation of bisphosphonate and a process for making thereof

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EP0210728A2 (en) * 1985-06-06 1987-02-04 The Procter & Gamble Company Kit containing polyphosphonate for treating osteoporosis
EP0381296A1 (en) * 1984-04-30 1990-08-08 THE PROCTER & GAMBLE COMPANY Kit for use in the treatment of osteoporosis
WO1994000129A1 (en) * 1992-06-30 1994-01-06 Procter & Gamble Pharmaceuticals, Inc. Use of phosphonates for the treatment of osteoporosis
EP0582515A1 (en) * 1992-08-05 1994-02-09 Sanofi Monohydrate of the disodium salt of 4-chlorophenylthiomethylene-bisphosphonic acid, its preparation and pharmaceutical compositions containing it

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0381296A1 (en) * 1984-04-30 1990-08-08 THE PROCTER & GAMBLE COMPANY Kit for use in the treatment of osteoporosis
EP0210728A2 (en) * 1985-06-06 1987-02-04 The Procter & Gamble Company Kit containing polyphosphonate for treating osteoporosis
WO1994000129A1 (en) * 1992-06-30 1994-01-06 Procter & Gamble Pharmaceuticals, Inc. Use of phosphonates for the treatment of osteoporosis
EP0582515A1 (en) * 1992-08-05 1994-02-09 Sanofi Monohydrate of the disodium salt of 4-chlorophenylthiomethylene-bisphosphonic acid, its preparation and pharmaceutical compositions containing it

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994329A (en) * 1997-07-22 1999-11-30 Merck & Co., Inc. Method for inhibiting bone resorption
US6225294B1 (en) 1997-07-22 2001-05-01 Merck & Co., Inc. Method for inhibiting bone resorption
US6333316B1 (en) 1997-07-22 2001-12-25 Merck & Co., Inc. Method for inhibiting bone resorption
US6432932B1 (en) 1997-07-22 2002-08-13 Merck & Co., Inc. Method for inhibiting bone resorption
US6465443B2 (en) 1997-07-22 2002-10-15 Merck & Co., Inc. Method for inhibiting bone resorption
US6544967B2 (en) 1997-07-22 2003-04-08 Merck & Co., Inc. Method for inhibiting bone resorption
US7192938B2 (en) 2002-05-10 2007-03-20 Hoffmann-La Roche Inc. Method of treatment using bisphosphonic acid
US7410957B2 (en) 2002-05-10 2008-08-12 Hoffmann-La Roche Inc. Method of treatment using bisphosphonic acid
US7718634B2 (en) 2002-05-10 2010-05-18 Hoffman-La Roche Inc. Method of treatment using bisphosphonic acid
US7923028B2 (en) 2002-12-20 2011-04-12 Hoffman-La Roche Inc. High dose oral formulation of bisphosphonate and a process for making thereof

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FI972383A7 (en) 1997-06-05
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AU4307396A (en) 1996-06-26
MX9704105A (en) 1997-09-30
FI972383A0 (en) 1997-06-05
TR199501530A1 (en) 1996-10-21
NO972558L (en) 1997-08-05
AR002946A1 (en) 1998-05-27
ZA9510184B (en) 1996-06-11
PL320564A1 (en) 1997-10-13
CN1168634A (en) 1997-12-24
CA2207028A1 (en) 1996-06-13
HUT77382A (en) 1998-04-28
NO972558D0 (en) 1997-06-05
JPH10509729A (en) 1998-09-22
FI972383L (en) 1997-06-05
CZ175397A3 (en) 1997-10-15
IL116168A0 (en) 1996-01-31
KR980700083A (en) 1998-03-30
FR2727629A1 (en) 1996-06-07
SK68597A3 (en) 1997-11-05
EP0797444A1 (en) 1997-10-01
BR9509961A (en) 1997-11-25

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