WO1996017616A1

WO1996017616A1 - Kit for osteoporosis treatment cycle

Info

Publication number: WO1996017616A1
Application number: PCT/FR1995/001596
Authority: WO
Inventors: Martine Gazard; Olivier Gros; Jacques Girard
Original assignee: Sanofi
Priority date: 1994-12-06
Filing date: 1995-12-05
Publication date: 1996-06-13
Also published as: CN1168634A; BR9509961A; IL116168A0; EP0797444A1; MA23737A1; JPH10509729A; FR2727629A1; FI972383A0; HUT77382A; FR2727629B1; MX9704105A; AU4307396A; NO972558L; TR199501530A1; CA2207028A1; NO972558D0; SK68597A3; AR002946A1; FI972383A; CZ175397A3

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

Kit for osteoporosis treatment cycle.

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. 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).

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 daily doses of tiludronic acid or one of its pharmaceutically acceptable salts and / or solvates, and

(b) a nutritional supplement divided into dosage units to be administered during the 21 to 24 days following (a).

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.

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.

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 ⁺⁺ .

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. 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.

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.

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.

Preferred 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.

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.

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.

According to a preferred aspect of the present invention, tiludronic acid is advantageously administered in the form of its disodium salt monohydrate or hemihydrate.

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.

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 ⁺⁺ .

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.

In general, the treatment cycle should be repeated until the desired increase in bone mass is achieved.

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.

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) 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) 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.

For this treatment method, a kit as defined above is used.

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.

In 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

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 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. The tablets of points A and B are placed in a packaging suitable for the administration of drugs. EXAMPLE 2

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. 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. The tablets of points A and B are placed in a packaging suitable for the administration of medicaments.

Claims

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:

2. Kit according to claim 1, characterized in that the daily doses of tiludronic acid are between 10 and 400 mg.

3. Kit according to claim 2, characterized in that the daily doses of tiludronic acid are chosen from 50, 75, 100, 125, 150,

175 and 200 mg.

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. Kit according to claim 1, characterized in that the nutritive supplement is calcium in the form of one of its pharmaceutically acceptable salts.

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. Kit according to claim 1, characterized in that (a) and (b) are in the form of tablets.

8. Kit according to claim 1, characterized in that it contains

(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 500 mg of calcium, expressed in mg of Ca ⁺⁺ , as a nutritional supplement, in the form of one of its pharmaceutically acceptable salts.

9. Kit according to claim 1, characterized in that it contains

(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. 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. 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 1000 mg of calcium, expressed in mg of Ca ⁺⁺ , as a nutritional supplement, in the form one of its pharmaceutically acceptable salts.

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. Method according to claim 12, characterized in that a nutritional supplement is administered during the rest period.

14. Method according to claim 13, characterized in that the nutritive supplement is calcium.

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:

(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. Method according to claim 15, characterized in that a kit is used according to any one of claims 1 to 11.

17. Method according to claim 15, characterized in that the daily doses of tiludronic acid are between 10 and 400 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. 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. 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.