WO2010101537A1

WO2010101537A1 - Pharmaceutical composition of alendronate and a calcium salt combined in a single dosage form

Info

Publication number: WO2010101537A1
Application number: PCT/TR2010/000025
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2009-02-05
Filing date: 2010-02-02
Publication date: 2010-09-10
Also published as: TR200900879A2

Abstract

The present invention relates to a pharmaceutical composition comprising a combination of alendronate and a calcium salt in a single dosage form so as to increase patients' compliance and as a result the success of the treatment.

Description

PHARMACEUTICAL COMPOSITION OF ALENDRONATE AND A CALCIUM SALT COMBINED IN A SINGLE DOSAGE FORM

Field of the invention The present invention relates to a pharmaceutical composition wherein the active agents are combined in a single dosage form so as to increase the patients' s compliance to the treatment and thus the success of the treatment. Background of the invention

The present invention provides an effective combination for the prevention and/or treatment and/ or supplement of diseases and conditions associated with the abnormal bone resorption. The effect caused by the combination prepared according to the present invention as named as "desired effect" thoughout this document. The combination of the present invention includes a calcium salt and alendronate or pharmaceutically acceptable salt, derivative or hydrate thereof.

Alendronic acid is a bisphosphonate which has a chemical name of [4-amino-l- hydroxybutylidene)biphosphonic acid (Formula I).

Alendronic acid is firstly disclosed in patent numbered US4705651 A. In this patent, manufacturing processes and the usage of alendronic acid in osteopathy treatment are included. Although alendronate is a second generation diphosphonate, it is also the first drug of its general group which is capable of the reinforcing of the bone as well as inhibiting the bone loss. Alendronate, is a biphosphonate which connects to hydroxyapatite in the bone and inhibits osteoclast (a kind of bone cell which destroys bone tissue by destroying bone matrix) mediated bone resorption. Bone resorption occurs by ruffled edges of osteoclasts in contact with the bone which are capable of making resorption. Alendronate inhibits the resorption by localizing specially under the resorption area of osteoclasts. In time, normal bone tissues which are produced by osteoblasts plank down onto alendronate. The activity of alendronate continues until it sinks inside the matrix where it shows no activity. However, alendronate will be connected to hydroxyapatite for years. Alendronate shoud be used continually to maintain the octeoclast inhibition on newly formed resorption surface. Alendronate decreases the turnover of the bone. It increases the mass of bone wherein the bone formation exceeds the bone resorption. It also decreases the direct resorption of bone in Paget disease which is a progressive and idiopathic disease wherein the bone metabolism is accelarated and re-shaped. After the six months treatment, deformed bone is transformed into the normal bone structure. It sharply increases the bone mineral density in postmenopausal osteoporosis which is characterized with progressive loss of bone causing increase in fragility of bone mass. This increases in bone mass can be seen in spine and hip after three months of treatment. After a year of treament, bones return back to its normal structure by means of both structure and the mineral content. It cause an important decrease in serum calcium and uriner calcium level at malignant hypercalsemia which is believed to be a result of increased bone resorption in patients with metastatic cancer. It inhibits the progress of osteolytic diseases and relieves severe bone pain. In order to obtain optimum efficiency of normal bone production, calcium supplement is needed in treatments.

Calcium is the chemical element with the symbol "Ca". It is the most abundant mineral found in the human body. 99% of body calcium is found in bone tissue. It plays an important role on bone structure and muscle contractions. The blood coagulation, neural transmission and the provision of electrical conduction in the heart depends on calcium. Parathyroid hormone, vitamin D, calcitonin, glucocorticoids can affect the balance of calcium and magnesium.

Calcium and its salts are used for treatment or prophylaxis of calcium deficiency. Calcium can be administered by oral route in carbonate, chloride, citrate, glubionate, gluceptate, gluconate, lactate, or phosphate salt forms; and it can be administered by parenteral route in acetate, chloride, gluceptate, gluconate, and glycerophosphate / lactate salt forms. Minimum daily requirement of calcium in the postmenopausal women is 1500 mg. In the premenopausal women, this amount is 1000 mg. This indicates that in the in the post menopausal period a woman needs at least 500 mg / day of additional calcium supplementation. Various clinical studies have showed that daily calcium intake in men, just like in women, is lower than the recommended dose. This increases the probability of ratio of diseases (osteoporosis, osteomalacia, etc.) originating from calcium deficiency in adults of advanced age. Therefore, attention to dietary factors, as well as the use of various drugs supplements are also recommended.

Dietary calcium plays an important role in preventing osteoporosis. However, using calcium alone is not possible to treat osteoporosis. Recently, it is a common opinion that in the active period of bone loss the use of calcium alone does not prevent bone loss. However, when calcium is combined with some drugs (biphosphonates such as alendronate) it increasingly exhibits a synergistic effect. For example, calcium requirements for the new bone after the use of alendronate should be provided with calcium supplementation.

The synergistic effect of alendronate and calcium in various combinations in treatment of osteoporosis and falling and fractures depending on osteoporosis was demonstrated in various pre-clinical studies.

• Ho A. Kung A. Efficacy and Tolerability of Alendronate Once Weekly in Asian Postmenopausal Osteoporotic Women. The Annals of Pharmacotherapy: Vol. 39, No. 9, pp. 1428-1433

• Silveri E. et al. Alendronate treatment in postmenopausal osteoporosis: One years experience. Osteoporosis International (1996) vol. 6, supplement 1, p. 269

• Ringe J. D. et al. Alendronate Treatment of Established Primary Osteoporosis in Men: Results of a 2- Year Prospective Study. The Journal of Clinical Endocrinology &

Metabolism Vol. 86, No. 11, 5252-5255

When the state of art is examined, the combinations are observed as a solution of providing a synergistic effect. However, the necessity of combining two active agents that show synergistic effect in a single dosage form is more important. The reason for this requirement is disclosed in patent numbered US20050261250 Al as patients receive medication in two separate time periods can not be able to adjust this time periods and therefore they are unable to adapt to the treatment.

According to researchs, only 50% of patients with chronic diseases in developed countries fulfill the treatment requirements. [Sabate, E. "Adherence to Long term Therapies: Evidence for Action". World Health Organization. Geneva, 2003. 212 pp. ISBN 92-4-154599-2]. More generally, it is determined that 40-60% of patients do not take their medication as prescribed and this causes bad consequences [Heneghan CJ, Glasziou P, Perera R The Cochrane Library, ISSN 1464-780X].

Patients usually skip taking their medications with the reasons of forgetfulness, busy life, different time schedules of used drugs, not finding the proper environment to drink in everytime, not understanding the illness and treatment, communication problems with the doctor, the doctor's low ability to control the patient efficiently, patients^* mistrust to the doctors or the treatment, side effects, treatment perspective of the patients to illness and the treatment, depression, cognitive disorders, financial problems and a complicated treatment regimens. A complicated dose regime, especially multiple drug use in several times a day is one of the most significant factor to prevent the patient's complience to treatment. The patient compliance and therefore the success of treatment will be higher if the treatment regimen is much simpler. For example, the combination of the active ingredients in a single dosage form will simplify treatment and increase patient's complience to treatment[Blonde L. Compliance and Persistence With Medication Therapy. Managed Care (2000). Volume 9, Number 9; archives.who.int/icium/icium2004/resources/ppt/AC016.ppt.]. The negative impact of taking multiple drug on patients will also be eliminated by the use of a combined medication in the foπn of a single dosage form.

The present invention is directed to obtain a combination of alendronate (or pharmaceutically acceptable salts, derivatives or hydrates thereof), and a calcium salt in a single dosage form so as to obtain a combination that provides desired effect by increasing patient's complience to the treatment and hence success of the treatment.

The invention is characterized in that alendronate (or pharmaceutically acceptable salts, derivatives or hydrates thereof) and a pharmaceutically acceptable, non-toxic and therapeutic amount of a calcium salt are combined in a single dosage foπn to achieve desired effect by providing a suitable formulation of these active agents.

Summary of the invention

The present invention relates to a pharmaceutical composition for use in the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or used as a supplement characterized in that the pharmaceutical composition comprises therapeutically effective amount of alendronate or pharmaceutically acceptable salt, derivative or hydrate thereof and therapeutically effective amount of a calcium salt are combined in a single dosage form.

Detailed description of the invention The present invention provides a pharmaceutical composition in a single dosage form which comprises alendronate or pharmaceutically acceptable salt, derivative or hydrates thereof and a calcium salt to increase patient compliance and thus the success of treatment and to achieve the desired effect. According to the invention, the formulations comprise a certain proportions of alendronate (or pharmaceutically acceptable salt, derivative or hydrate thereof) and a certain proportions of calcium salts, optionally one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, lubricant, glidant, surface active agent, stabilizing agent, sweetener and flavoring agent in which the formulation is effective for the prophylaxis and/or treatment and/or supplementation of diseases associated with abnormal bone resorption and mentioned formulations increase the compliance of patient to treatment and thus the success of the treatment.

The term of "the use for the prevention and/or treatment and/or supplementation of disease and conditions associated with abnormal bone resorption" in the invention means in osteoporosis treatment; to reduce the risk of fracture in bones including vertebra and hip in the postmenopausal women; to reduce the risk of bone fractures in men in the treatment of osteoporosis; Idiopathis osteoporosis; various diseases caused by osteoporosis, and glucocorticoid and steroid mediated osteoporosis, osteopenia, osteomalacia, osteogenesis imperfecta, osteocondrodysplasia, Sudek's atrophy, rheumatoid arthritis, Paget's disease, malignant tumors of bone metastases, hypercalcaemia, or in the treatment of diseases such as hyperthyroidism; and nutritional supplements especially for woman which are in growth, pregnant or breast-feeding in the period before and after menopause to maintain bone health, but the explained usage areas are not limited with these.

The terms of "a certain proportion" and "optionally"' mean that in order to obtain the desired therapeutic effect, preferred amount of alendronate ( or pharmaceutically acceptable salt, derivative or hydrate thereof) in the range of 0.1 -980 mg, an amount of calcium salt( on the basis of elemental calcium) in the range of 250-5000 mg, one or more pharmaceutically acceptable excipients to be used when necessary which are selected from a group of diluent, binder, disintegrant, lubricant, glidant, surface active agent, sweetener and flavoring agent. The term of " a pharmaceutically acceptable salt, derivative or hydrate of alendronate" implies that salts can be selected from sodium, potassium, calcium, magnesium and ammonium salts; derivatives can be selected from ester and amide derivatives; hydrates can be selected from monohydrates, dihydrates, trihydrates, hemihydrates, ¹A hydrate, ¹A hydrate, ²A hydrate, % hydrate, ⁵Z₄ hydrate, ⁴Zs hydrate, ⁵Z₂ hydrate and V₂ hydrate; preferably alendronate is alendronate monosodium trihydrate. The term of "calcium salt" implies that it can be selected from carbonate, chloride, citrate, glubionat, gluceptate, gluconate, lactate, phosphate, maleate, glycerophosphate, bicarbonate or tartarate salts.

The pharmaceutically acceptable diluents can be selected from a group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, powdered cellulose, dextrose, dextares, dextrin, sucrose, maltose, fructose, mannitol, sorbitol, xylitol. The diluent is present in the formulations preferably in the range of 0-85% by weight and more preferably 0.1-75% by weight.

The pharmaceutically acceptable binder can be selected from a group consisting of starch (potato starch, corn starch, wheat starch, etc.), sugars such as sucrose, glucose, dextrose, lactose, maltόdextrin, natural and synthetic gums (e.g. acacia), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrollidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols ( e.g. sorbitol, xylitol, mannitol) and water. The binder is present in the formulations preferably in the range of 0- 10% by weight and more preferably in the range of 0.1 - 5% by weight.

The pharmaceutically acceptable disintegrants can be selected from a group consisting of starch (corn starch, potato starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (e.g. croscarmellose sodium or microcrystalline cellulose), polyvinylpyrollidone, crospovidone, alginic acid, sodium alginat, clays (e.g. xanthan gum or veegum), ion-exchange resins and effervescent systems (alkali or alkaline earth metal carbonates [e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate]; sodium hydrogen sulfate, potassium hydrogen sulfate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid, water soluble polybasic organic acids or salts thereof. The disintegrant is present in the formulations preferably in the range of 0-85% by weight and more preferably in the range of 0.1-75% by weight.

Pharmaceutically acceptable lubricants can be selected from a group consisting of metallic stearates (magnesium stearate, calcium stearate. aluminum stearate, etc.), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates (sodium lauryl sulfate, magnesium lauryl sulfate, etc.), sodium chloride, sodium benzoate, sodium acetate and talk. The lubricant is present in the formulations preferably in the range of 0-10% by weight and more preferably in the range of 0.1-5% by weight. The pharmaceutical acceptable glidants can be selected from a group consisting of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, calcium phosphate tribasic metallic stearates, calcium silicate and metallic lauryl sulfate. The glidant is found in a range below 1% by weight in the formulations.

The pharmaceutically acceptable surface active agents can be selected from a group consisting of polyoxyethylene-sorbitane-fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearyl fumarate, po Iy oxy ethylene alkyl ethers, sorbitane fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, aminoacids like L-leucine, sugar esters of fatty acids, glycerides of fatty acids. The surface active agent is present in the formulations preferably in the range of 0-10% by weight and more preferably in the range of 0.1-5% by weight. The stabilizing agent and/or agents can be selected from a group consisting of antioxidants, chelating agents, alkaline agents and photo-protectors. The stabilization agent and/or agents is present in the formulations preferably in the range of 0-85% by weight and more preferably in the range of 0.1-75% by weight. The antioxidants can be selected from a group consisting of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, gallates (e.g. propyl gallates), tocopherol, citric acid, malik acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate.

The chelating agents can be selected from a group consisting of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof. The alkalizing agents can be selected from a group consisting of sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, alkali metal salts such as sodium aluminate; calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, earth alkali metal salts like magnesium aluminate and primary, secondary and tertiary amines, cyclic amines, organic compounds such as N-N^*-dibenzylethylenediamine, diethanoleamine, ethylenediamine, meglumine, monosodium , glucamate, polyacryline sodium, sodium alginate. The photo-protector agents can be selected from a group consisting of metal oxides such as titanium oxide, iron oxide or zinc oxide.

The pharmaceutically acceptable sweeteners can be selected from a group consisting of sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erytritol, lactitol, isomalt, corn syrup, saccharin, saccharin salts, acesulphame potassium, aspartam, D-tryptophan, monoammonium glycerrizinate, neohesperidin dihydrochalcone, taumatine, neotam, alitam, steviosite and cyclamates.The sweetener is present in the formulations preferably in the range of 0-5% by weight and more preferably in the range of 0.1-3% by weight.

The pharmaceutically acceptable flavoring agents can be selected from a group consisting of natural, aroma oils (peppermint oil, partridge currant oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil, etc.). menthol, menthan, anetole, methyl salicylate, ocaliptole, cinnamon, 1 -methyl acetate, ogenol, oxanone, alpha-irisone, marjoram, lemon, orange, propenyl guaetol acetyl, sinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-mentane-3-carboxyamide,3,l-methoxy propane 1,2-diol. The flavoring agent is present in the formulations preferably in the range of 0-5% by weight and more preferably in the range of 0.1- 3% by weight.

In addition to these agents, pharmaceutically acceptable other excipients which are selected from resolution modulators, electrolytes, colorants and coating agents may be used in formulations. According to the invention, the dosage form can be in the form of tablets, capsules, soluble tablets, fast dissolving tablets, effervescent tablets, effervescent granules, fast dissolving granules, fast dissolving powder mixtures or dry powder mixture for preparation of syrup.

The formulation examples of the invention are given below. These examples are given only to explain the invention and invention is not limited to these examples.

EXAMPLES

Example 1.

Equivalent to 10 mg Alendronic Acid

** Equivalent to 1000 mg Calcium

Example 2.

* Equivalent to 35 mg Alendronic Acid ** Equivalent to 1200 mg Calcium Example 3.

Equivalent to 70 mg Alendronic Acid

** Equivalent to 1000 mg Calcium

Example 4.

* Equivalent to 10 mg Alendronic Acid ** Equivalent to 500 mg Calcium

Claims

1. A pharmaceutical composition for use in the treatment and/or prophylaxis of diseases and conditions associated with abnormal bone resorption and/or used as a supplement, characterized in that the pharmaceutical composition comprises therapeutically effective amount of alendronate or a pharmaceutically acceptable salt, derivative or hydrate thereof and therapeutically effective amount of a calcium salt combined in a single dosage form.

2. The use of a pharmaceutical composition according to claim 1 characterized in that the pharmaceutical composition comprises,

• Alendronate or a pharmaceutically acceptable salt, derivative or hydrate thereof in the range of 0.1 -980 mg

• A calcium salt (on elemental calcium basis) in the range of 250-5000 mg, and optionally one or more pharmaceutically acceptable excipients selected from a group of comprising diluent, binder, disintegrant, lubricant, glidant, surface active compound, stabilizing agent, sweetener and flavoring agent.

3. The use of a composition according to claim 1 characterized in that the composition provides an effective combination for the prevention and/or treatment and/ or supplement of diseases and conditions associated with the abnormal bone resorption in osteoporosis treatment; to reduce the risk of fracture in bones including vertebra and hip in the postmenopausal women; to reduce the risk of bone fractures in men in the treatment of osteoporosis; Idiopathis osteoporosis; various diseases caused by osteoporosis, and glucocorticoid and steroid mediated osteoporosis, osteopenia, osteomalacia, osteogenesis imperfecta, osteocondrodysplasia, Sudek's atrophy, rheumatoid arthritis, Paget's disease, malignant tumors of bone metastases, hypercalcaemia, or in the treatment of diseases such as hyperthyroidism; and nutritional supplements especially for woman which are in growth, pregnant or breast-feeding in the period before and after menopause to maintain bone health.

4. The use of a composition according to claim 1 or 2 characterized in that a pharmaceutically acceptable salt of alendronate is selected from, salts such as sodium, potassium, calcium, magnesium and ammonium salts; a pharmaceutically acceptable derivative of alendronate is selected from derivatives, such as ester and amide derivatives; a pharmaceutically acceptable hydrate of alendronate is selected from hydrates such as monohydrates, dihydrates, trihydrates, hemihydrates, ¹A hydrate, ¹A hydrate, % hydrate, ³A hydrate, V₄ hydrate, V₃ hydrate, V₂ hydrate and V₂ hydrate.

5. The use of a composition according to claim 4 characterized in that the composition comprises alendronat monosodium trihydrate as a pharmaceutically acceptable salt, derivative or hydrate of alendronate.

6. The use of a compositon according to claim 1 or 2 characterized in that the calcium salt is selected from a group consisting of carbonate, chloride, citrate, glubionate, gluceptate, gluconate, lactate, or phosphate, maleate, glycerophosphate, bicarbonate or tartarate salts

7. The use of a compositon according to claim 1 or 2 characterized in that the diluent is selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol, xylitol

8. The use of a compositon according to claim 7 wherein the diluent is present in a composition preferably in the range of 0-85% by weight and more preferably 0.1-75% by weight

9. The use of a compositon according to claim 1 or 2 characterized in that the binder is selected from starch (potato starch, corn starch, wheat starch, etc.), sugars such as sucrose, glucose, dextrose, lactose, maltodextrin, natural and synthetic gums (e.g. acacia), gelatin, cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrollidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols ( e.g. sorbitol, xylitol, mannitol) and water.

10. The use of a composition according to claim 9 characterized in that the binder is present in a composition preferably in the range of 0-10% by weight and more preferably in the range of 0.1 -5% by weight.

11. The use of a composition according to claim 1 or 2 characterized in that the disintegrant is selected from a group consisting of starch (corn starch, potato starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrollidone, crospovidone, alginic acid, sodium alginat. clays ( such as xanthan gum or veegum), ion-exchange resins and effervescent systems (alkali or alkaline earth metal carbonates [such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate]; sodium hydrogen sulfate, potassium hydrogen sulfate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid, water soluble polybasic organic acids or salts thereof.

12. The use of a composition according to claim 11 characterized in that the disintegrant is present in a composition preferably in the range of 0-85% by weight and more preferably in the range of 0.1 -75% by weight.

13. The use of a composition according to claim 1 or 2 characterized in that the lubricant is selected from a group consisting of metallic stearates (magnesium stearate, calcium stearate, aluminum stearate, etc.), fatty acid esters(such as sodium stearil fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates

(sodium lauryl sulfate, magnesium lauryl sulfate, etc.), sodium chloride, sodium benzoate, sodium acetate and talk.

14. The use of a composition according to claim 13 characterized in that the lubricant is present in a composition preferably in the range of 0-10% by weight and more preferably in the range of 0.1 -5% by weight.

15. The use of a composition according to claim 1 or 2 characterized in that the glidant is selected from a group consisting of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.

16. The use of a composition according to claim 15 characterized in that the glidant is found in a range below 1% by weight.

17. The use of a composition according to claim 1 or 2 characterized in that the surface active agent is selected from a group consisting of polyoxyethylene-sorbitane-fatty acid esters(polysorbates), sodium lauryl sulfate, sodium stearil fumarate. polyoxyethylene alkyl ethers, sorbitane fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, amino acids like L- leucine, sugar esters of fatty acids, glycerides of fatty acids.

18. The use of a composition according to claim 17 characterized in that the surface active agent is present in a composition preferably in the range of 0-10% by weight and more preferably in the range of 0.1 -5% by weight.

19. The use of a composition according to claim 1 or 2 characterized in that the stabilizing agent is selected from a group antioxidants consisting of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxy toluene (BHT), sodium sulfite, gallates (e.g. propyl gallate), tocopherol, citric acid, malik acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate.

20. The use of a composition according to claim I or 2 characterized in that the stabilizing agent is selected from a group of the chelating agents consisting of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof.

21. The use of a composition according to claim 1 or 2 characterized in that the stabilizing agent is selected from a group of the alkalizing agents consisting of sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, alkali metal salts such as sodium aluminate; alkali metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate and primary, secondary and tertiary amines, cyclic amines, organic compounds such as N-N^*- dibenzylethylenediamine, diethanoleamine, ethylenediamine, meglumine, monosodium glucamate. polyacryline sodium, sodium alginate.

22. The use of a composition according to claim 1 or 2 characterized in that the stabilizing agent is selected from a group of the photo-protector agents consisting of metal oxides such as titanium oxide, iron oxide or zinc oxide.

23. The use of a composition according to claims 19 to 22, characterized in that the stabilizing agent is used in an amount of 0-85% by weight and preferably in an amount of 0.1 - 75% by weight.

24. The use of a composition according to claim 1 or 2 characterized in that the sweetener is selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol. isomalt, corn syrup, saccharin, saccharin salts, acesulphame potassium, aspartam, D-tryptophan, monoammonium glycerrizinate, neohespheridin dihydrochalcon, taumatine, neotam, alitam, steviosite and cyclamates.

25. The use of a composition according to claim 24 characterized in that the sweetener is present in a composition preferably in the range of 0-5% by weight and more preferably in the range of 0.1-3% by weight.

26. The use of a composition according to claim 1 or 2 characterized in that the flavoring agent is selected from natural, aroma oils (peppermint oil, partridge currant oil. clove bud oil, parsley oil. eucalyptus oil, lemon oil. orange oil. etc.), menthol, menthan, anetole, methyl salicylate, ocaliptole, cinnamon, 1 -methyl acetate, ogenol, oxanone, alpha-iiϊsone, marjoram, lemon, orange, propenyl guaetol acetyl, sinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-mentane-3-carboxyamide,3,l-methoxy propane 1,2-diol.

27. The use of a composition according to claim 26 characterized in that the flavoring agent is present in a composition preferably in the range of 0-5% by weight and more preferably in the range of 0.1 -3% by weight.

28. The use of a composition according to any of the preceeding claims characterized in that the dosage form is in the form of tablets, capsules, fast dissolving tablets, effervescent tablets, effervescent granules, fast dissolving granules, fast-dissolving powder mixtures or dry powder mixture for preparation of a syrup.

29. The use of a composition according to any preceeding claims characterized in that the composition combines two active agents together in a single dosage form and as a result the composition increases the patient's compliance to the treatment and thus the success of the treatment.

30. The use of a composition according to any of the preceeding claims characterized in that the composition comprises,

Alendronate monosodium trihydrate in the range of 0.1-980 mg

Calcium carbonate in the range of 250- 5000 mg

Citric acid in the range of 0-85% by weight

Sodium hydrogen carbonate in the range of 0-85% by weight Aspartame in the range of 0-5% by weightLemon flavor in the range of 0-5% by weight.