Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-06-10
2004-04-06
Criares, Theodore J (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S479000, C424S480000, C424S488000, C424S677000, C424S687000, C514S167000
Reexamination Certificate
active
06716454
ABSTRACT:
The present invention relates to a novel therapeutic combination of vitamin and calcium, to a method of obtaining it, and to the use thereof.
Numerous combinations of vitamin and calcium are known for treating various diseases.
The therapeutic effects associated with simultaneous administration of calcium and of vitamin D are well known, as described, for example, in articles by Marie C. Chapuy et al. “Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women”, British Medical Journal, 308, pp. 1081-1082 (Apr. 23, 1994); Marie C. Chapuy et al. “Vitamin D3 and calcium to prevent hip fractures in elderly women”, New England Journal of Medicine, 327, pp. 1637-1642 (Dec. 3, 1992); and in the article entitled “Supplementation with vitamin D3 and calcium prevents hip fractures in elderly women”, Nutrition Reviews, Vol. 51, 6, pp. 183-185.
Those articles also show up the variability of the therapeutic effects of the combination as a function of calcium dosage and of vitamin D dosage, with an optimum daily dose lying around 1000 mg to 1200 mg of elemental calcium and 800 IU of vitamin D3 for the purpose of preventing and treating osteoporosis.
Calcium and vitamin D are generally administered to the patient simultaneously, but in distinct forms, e.g. tablets of a calcium salt and drops of vitamin D.
Both vitamin D and the salts of calcium that are acceptable from the pharmacological point of view present characteristics that are highly specific from the galenic point of view (see in particular EP-A-0 413 828 which relates to a stabilized preparation of vitamin D3 for potentializing the stability of the active ingredient), which leads to them being packaged in separate forms.
However that makes it difficult to ensure that absolute and relative dosages of calcium and of vitamin D are complied with, and thus that the treatment is carried out correctly, particularly if it takes place over a long period.
Proposals have already been made to associate calcium and vitamin D in the same form, e.g. in WO-A-94 06435 (a gynecological treatment method using, in particular, a combination of vitamin D and calcium), in WO-A-92 19251 (a combination of vitamin D with calcium for treating osteoporosis, in particular in drinkable form), in EP-A-0 197 514 (a pharmaceutical composition comprising a parathyroid hormone or a physiologically active fragment thereof in combination with hydroxylated vitamin D or a non-toxic calcium salt for increasing bone mass), or indeed in DE-A-42 12 122 (a low calorie element based on proteins, a calcium salt, and vitamin D).
However, in those known forms, the proportions of calcium and of vitamin D are generally rather far from the desirable optimal proportions as indicated in particular in the above-specified literature.
Those known forms also often correspond more to vitamin and calcium supplements (food supplements or “OTC” specialities sold without medical prescription) than to real pharmaceutical specialities for therapeutic purposes intended to prevent or treat diseases such as osteoporosis with precise dosage.
At present there exists a need to be able to dispose of an combination of vitamin and of calcium including in a single form an optimal relative dose of calcium and of vitamin D, most particularly for preventing and treating osteoporosis.
However, because of the nature of the available calcium salts that are acceptable from the pharmaceutical point of view, it is relatively difficult to associate calcium in elemental form with vitamin D in certain specific dosages. This is particularly true if it is desired to obtain tablets by a direct compression manufacturing method. The constraints on the active ingredients, in particular the calcium in elemental form and the form of the vitamin D, then prevent direct implementation.
The present invention solves the above-mentioned problems by proposing a therapeutic combination of vitamin and calcium in unitary galenic tablet form, comprising as associated active ingredients, at least one vitamin D and calcium in elemental form, the combination being characterized in that it further includes at least one dry and moist binder combined in synergistic quantity with at least one diluant, at least one binder, and at least one lubricant, at least one of said diluant and said binder being a sweetening agent.
The present invention also provides a method of obtaining a therapeutic combination of vitamin and calcium in unitary galenic tablet form comprising as associated active ingredients calcium in elemental form and at least one vitamin D, the method being characterized in that it consists:
a) in granulating the calcium in elemental form with a dry and moist binder;
b) premixing the vitamin D with a sweetening binder in a separate step;
c) mixing in another separate step a sweetening diluant, an additional sweetening binder, and flavoring with the products of steps a) and b), while also adding a lubricant; and
d) optionally compressing the mixture in a rotary press.
The invention also relates to the use of the novel therapeutic combination of vitamin and calcium for treating osteoporosis.
The invention also relates to the following characteristics:
the ratio of calcium in elemental form to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, lies in the range 1 to 1.5, and preferably in the range 1.2 to 1.3;
the calcium in elemental form comes from a calcium salt selected from calcium carbonate, calcium pidolate, calcium lactate, calcium citrate, calcium gluconate, calcium chloride, calcium glucoheptonate, calcium glycerophosphate, and calcium phosphate;
the vitamin D is selected from vitamin D2 or ergocalciferol, vitamin D3 or cholecalciferol, or a mixture thereof;
the tablet belongs to the group comprising tablets for biting, cleavable tablets, chewable tablets, dispersible tablets, and tablets for a drinkable suspension;
at least one of said diluant and said sweetening binder is a flavoring agent suitable for improving the taste characteristics of the combination, advantageously a polyol, in particular selected from mannitol, sorbitol, xylitol, and maltitol;
the dry and moist binder is selected from a cellulose, maltodextrin, and polyvinylpyrrolidone;
the lubricant is selected from magnesium stearate, steric acid, hydrogenated castor oil, hydrogenated cotton oil, and glycerol behenate;
the combination also includes a flavoring agent and/or an acidifying agent and/or an additional sweetening agent selected from sodium saccharinate, sodium cyclamate, and aspartame; and
the combination of vitamin and calcium complies with the following general formula:
Calcium (carbonate)
1250
mg
(Corresponding to elemental calcium
500
mg)
Cholecalciferol
4
mg*
Xylitol
661
mg
Sorbitol
500
mg
Polyvinylpyrrolidone
45
mg
Flavoring (lemon, orange, etc.)
20
mg
Magnesium stearate
20
mg
(*Vitamin D3 dosed at 100,000 IU/g)
Said formula corresponding to a finished
2500
mg
tablet weighing
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patent: 5502224 (1996-03-01), Eugster et al.
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Ivey. M; “Nutritional Supplement Minera and Vitamin Products”; Handbook of Nonprescription Drugs; Fifth Edition; pp 134-162, 1977.*
Aloia et al.; Calcitriol in the Treatment of Postmenopausal Osteoporosis; Amer. J. Of Med., vol. 84 pp. 401-408 (1988).*
Garr et al., “Direct compression characteristics of xylitol”, International Journal of Pharmaceutics,64 (1990), p. 223-226.
Dills, Jr., “Sugar Alcohols as Bulk Sweeteners”, Department of Chemistry, Southeastern Massachusetts University, North Darmouth, Mass., Annu. Rev. Nutr.,9, 1989, 161-86.
Mosk, Med. Inst.,61, 1968, 128-32 (English Language Abstract).
Physicians' Desk Reference For Nonprescription Drugs,1993, item “SO-CAL 500+D Tablets”.
Physicians' Desk Reference For Nonprescription Drugs,
Meignant Catherine
Stenger Eric
Criares Theodore J
Jacobson & Holman PLLC
Laboratorie Innothera, Société Anonyme
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