Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1996-02-01
1998-02-24
Spear, James M.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424464, 424465, 424489, 514874, 514770, 514784, A61K 908, A61K 916, A61K 920, A61K 946
Patent
active
057209774
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/02465 filed Jul. 26, 1994.
TECHNICAL FIELD
The present invention relates to oral water soluble pharmaceutical compositions containing estrone derivative, useful for the substitutive hormonal therapy (hypoestrogenic) and in the prevention of the bone loss in the cases of senile or post-menopausal osteoporosis.
BACKGROUND ART
Estrone, the metabolite of estradiol, is used alone or in combination with other natural estrogens, in the form of ester (acetate, propionate) or as hydrosoluble conjugate (sodium or piperazine sulphate) in the substitutive hormonal therapy (hypoestrogenic) and in the prevention of the bone loss in the cases of post-menopausal Osteoporosis or in oophorectomized women.
The administration of estrone at therapeutical doses is effected both by oral route (tablets) and parenteral or transdermal route.
Estrogens are usually administered as oral tablets, the most common preparations being conjugated (equine) estrogens, micronized estradiol, and estrone piperazine sulfate (estropipate).
The oral administration of liquid compositions containing estrone presents some difficulties due to the insolubility in water of the compound, as well as of its esters. This problem can be solved by formulating the medicament in solid oral forms, but the problem of the incomplete absorption of the active ingredient at gastric level and of the possible difficulty of administering said forms to patients with poor swallowing capacity still remains.
It is well known that oral water soluble, liquid and optionally effervescent forms promote the absorption of the active ingredient, as for example in the case of aspirin, paracetamol, potassium, and others. Moreover, the liquid effervescent formulations result particularly appreciated to patients in view of their aspect and the possibility to give them good palatability.
For the preparation of liquid forms comprising estrone it is necessary to provide their hydrosoluble compounds. The alkali-conjugate estrone salts (sodium-sulfates) are hydrosoluble, but unstable in aqueous media, with the resulting precipitation of insoluble products.
In the bone-loss preventive therapy it is common practice to provide a calcium supplement to the patient. A large number of calcium preparations are available, including chewable tablets, ordinary oral tablets and even effervescent preparations.
The oral absorption of these available preparations is deemed to be satisfactory, although it can be variable depending on the nature of the calcium salt (carbonate, citrate, gluconate, lactate, phosphate, etc.). An extensive description of available calcium preparations can be found in the 3.sup.rd edition of Martindale, The Extra Pharmacopoeia, London, The Pharmaceutical Press, 1993, page 853 to 856.
If the skilled technician had thought to combine an estrogen derivative with a calcium salt in an oral, liquid composition, he would have faced some critical issues of pharmaceutical technology and pharmacology.
The estrogen component must be freely soluble in aqueous concentrated electrolyte solutions and stable, at neutral or basic pH, if the resulting pH of the liquid preparation is acidic, the estrogen component must be stable in a conjugate form (acid sulfate) even if present as a finely dispersed colloidal form, readily absorbed at intestinal pH.
The calcium preparations must be readily soluble in water giving a solution which should be clear or slightly cloudy but without insoluble residues, which, if formed, will not be completely absorbed.
The combination tablet or sachet must be pharmaceutically stable, particularly concerning the estrogen component and have an acceptable shelf-life.
The tablet or sachet must dissolve in water within a conveniently short time, preferably within a few minutes, to avoid hydrolysis of the estrogen component or precipitation of the calcium salts out of the saturated aqueous solution.
If needed, the effervescence during dissolution of the preparation should be moderate to avoid spraying the saturated solution on the wa
REFERENCES:
patent: 5004651 (1991-04-01), Becker
Ettinger B. et al., "Calcium enhances the bone-sparing effects of low-dosage estrogen in postmenopausal women", Osteoporosis Int. (United Kingdom), 1993, vol. 3, Suppl. 1, pp. 157-158.
Geenant H.K. et al., "Effect of estrone sulfate on postmenopausal bone loss" Obstetric & Gynecology (USA) 1990, vol. 76, No. 4, pp. 579-584.
Harris E.T. et al., "The Effects of Estrone Ogen on Sprinal Bone Density of Postmenopausal Women" Arch Internal Medicine, vol. 151, No. 10, pp. 1980-1984, Oct. 1991.
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