WO1999000135A1

WO1999000135A1 - Composition comprising vitamin k and vitamin d, for treating or preventing osteoporosis

Info

Publication number: WO1999000135A1
Application number: PCT/EP1998/004031
Authority: WO
Inventors: Paul Rodney Clayton
Original assignee: The Boots Company Plc
Priority date: 1997-06-28
Filing date: 1998-06-25
Publication date: 1999-01-07
Also published as: GB9713620D0; AU8853998A

Abstract

Compositions for the prevention and treatment of osteoporosis comprise vitamin K (preferably vitamin K1) and vitamin D (preferably vitamin D3) optionally with vitamin B6, vitamin C, vitamin A, diosgenin, and mineral supplements, for example magnesium, calcium, zing, boron and molybdenum.

Description

COMPOSITION COMPRISING VITAMIN K AND VITAMIN D, FOR TREAΗNG OR PREVENΗNG OSTEOPOROSIS

The present invention relates to the prevention and treatment of osteoporosis and to compositions for use in such prevention or treatment.

Compositions for the prevention and treatment of osteoporosis according to the present invention comprise a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D said compositions being characterised in that they contain no diosgenin or, if diosgenin is present, the amount present should be such that the amount to be administered each day is less than 100 mg. Optionally the composition also contains a therapeutically effective amount of vitamin B6 and/or mineral supplements (eg magnesium, calcium, zinc, boron and/or molybdenum) and/or vitamin C and/or vitamin A.

Method of preventing or treating osteoporosis according to the present invention comprises the administration to a subject in need thereof a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D said method being characterised in that either no diosgenin is administered to the patient or, if diosgenin is administered the amount administered to the patient each day is less than 100 mg. Optionally the method of the present invention also comprises the administration of a therapeutically effective amount of vitamin B6 and/or mineral supplements (eg magnesium, calcium, zinc, boron and/or molybdenum) and/or vitamin C and/or vitamin A. The vitamin K, vitamin D and optional vitamin B6, mineral supplements, vitamin C, vitamin A and diosgenin may be administered simultaneously or sequentially. For simultaneous administration the components may be combined into a single dosage form or may be formulated into several dosage forms which are intended to be taken at the same time. The term "Vitamin K" as used herein is intended to cover vitamin K in any of its forms (ie vitamin K1 , vitamin K2, vitamin K3 , vitamin K4, vitamin K5, vitamin K6 and vitamin K7) or any precursor or analogue to any of these vitamins ( such as the naphthaquinones ) which would give rise to vitamin K -like activity after administration. Preferred vitamin K components are provided by vitamin K1 and/or vitamin K2 . The amount of vitamin K to be administered per day is in the range 5 to 5000 μg, preferably 10 to 200 μg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The term "Vitamin D" as used herein is intended to cover vitamin D in any of its forms (ie vitamin D1 ,vitamin D2 vitamin D3 or vitamin D4) or any precursor or analogue to any of these vitamins which would give rise to vitamin D-like activity after administration. The preferred form of vitamin D is vitamin D3. The amount of vitamin D to be administered per day is in the range 5 to 5000 μg preferably 10 to 100 μg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The term "Vitamin B6" as used herein is intended to cover pyridoxine hydrochloride or any other of the vitamins of the B6 complex (ie codecarboxylase, pyridoxal hydrochloride or pyridoxamine dihydrochloride) or any precursors or analogues thereof which would give rise to vitamin B6-like activity. The amount of vitamin B6 to be administered per day is in the range 100 μg to 1000 mg, preferably 5 to 100 mg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The term "mineral supplements" used herein represents supplements containing calcium preferably given as salts (eg the carbonate, gluconate or lactate salts of calcium) and magnesium preferably given as magnesium oxide or as salts (eg the carbonate or chloride salts of magnesium). The amount of calcium (expressed as the amount of elemental calcium) to be administered per day is preferably in the range 100 mg to 10 g, more preferably 500 mg to 5 g, most preferably about 1000 mg. The amount of magnesium (expressed as the amount of elemental magnesium) to be administered per day is preferably in the range 50 mg to 5g, more preferably in the range 50 mg to 5 g, more preferably 100 mg to 1 g, most preferably about 500 mg. In preferred compositions there is a molar excess of calcium over magnesium. The molar ratio of calcium to magnesium is preferably greater than 1 , more preferably greater than 1.5, most preferably about 2. One form of administration of the mineral supplement is as an effervescent tablet which is added to water to provide a solution of the minerals which is ingested by the patients. Such tablets are well known in the art and comprise an effervescent couple which react together in the presence of water to release a gas which causes the effervescence. The effervescent couple may comprise a carbonate or bicarbonate salt such as sodium carbonate or bicarbonate and an acidic component ascorbic or adipic acid or an acid salt such as disodium hydrogen citrate. If the calcium and magnesium salts given as the mineral supplement are in the form of their carbonate salts, these salts may form all or part of the carbonate component of the effervescent couple. The mineral supplements may also contain other elements eg zinc, boron and molybdenum. The amount of zinc (expressed as the amount of elemental zinc) to be administered per day is preferably in the range 1 to 100 mg, more preferably 5 to 20 mg. The zinc is preferably administered in the form of zinc oxide or of salts such as the gluconate or orotate salts. The amount of boron (expressed as the amount of elemental boron) to be administered per day is preferably in the range 1 to 100 μg preferably 5 to 20 μg. The boron is preferably administered in the form of sodium or potassium perborate. The amount of molybdenum (expressed as the amount of elemental molybdenum) to be administered per day is preferably in the range 10 to 1000 μg more preferably 50 to 500 μg. The molybdenum is preferably administered in the form of sodium or potassium molybdate. The mineral supplements may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The term "Vitamin C" as used herein is intended to cover vitamin C in any of its forms (eg salts of ascorbic acid) or any precursor or analogue which would give rise to vitamin C-like activity after administration. The preferred form of vitamin C is ascorbic acid. The amount of vitamin C to be administered per day is in the range 5 to 5000 mg preferably 50 to 200 mg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The term "Vitamin A" as used herein is intended to cover retinol and salts thereof such as the acetate or palmitate salts or any precursors or analogues thereof which would give rise to vitamin A-like activity. The amount of vitamin A to be administered per day is in the range 0.5 to 100 mg, preferably 1 to 10 mg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

Diosgenin [(25R)-spirost-5-en-3β-ol] optionally used in the compositions and method of the present invention may be used in a chemically pure form which may be isolated from natural sources (eg from yams), may be prepared by chemical modification of saponins obtained from natural sources or may be prepared synthetically. Alternatively, an extract obtained from a natural source which is rich in diosgenin or a precursor thereto may be used. A suitable source would be an extract of yam. The amount of diosgenin to be administered per day is in the range 1 to 99 mg preferably 10 to 90 mg most preferably 20 to 50 mg. This amount may be administered in a single dose or in more than one dose which may be taken at different times throughout the day.

The pharmaceutical compositions of the present invention may be administered as oral dosage forms and may be solid dosage forms eg tablets, capsules, lozenges, chewable tablets or capsules or may be liquid dosage forms eg solutions, suspensions, dispersions or syrups. A preferred pharmaceutical composition for the vitamins and optional diosgenin is a soft-gel capsule in which the active ingredients are dissolved or dispersed in a liquid non-aqueous centre. Alternatively, the compositions of the present invention may be formulated so that the active materials are administered transdermally. Examples of suitable transdermal dosage forms are creams and gels containing the active materials or patches which may be adhesively attached to the skin and which contain a reservoir of the active material optionally in combination with a penetration enhancer or other suitable excipients.

These oral and transdermal dosage forms may be prepared by methods which are well-known to those skilled in the art.

The preferred soft gel capsules may be prepared by dissolving or suspending the active ingredients and any excipients or other desirable formulation aids in an oily medium which is then encapsulated in the soft gel capsule .

The efficacy of the compositions of the present invention and the effectiveness of the method of the present invention can be shown by means of clinical trials. In one such trial volunteers are given the compositions of the present invention containing vitamin K (for example 120μ of vitamin K1 ), vitamin D (for example 20μ of vitamin D3), vitamin B6 (for example 10 mg) and optionally diosgenin for a period of 84 days. Analysis of blood and urine samples taken at the start and end of the trial and at the midpoint _^of the trial will enable the bone status and level of metabolic activity to be determined for each subject.

A second such trial is conducted on the double blind placebo controlled principle in which neither the subjects nor the physician are aware of whether the subject is receiving active material or a placebo, and is carried out to CTX standards. Every 24 weeks over a 96 week period, bone mass and the biochemical parameters of bone metabolism are measured in two groups of post menopausal women. One group receives a composition of the present invention and the other group receives placebo. An example of a composition of the invention for use in these trials is detailed below.

Vitamin K1 120 μg

Vitamin D3 20 μg

Vitamin A 2 mg Vitamin B6 10 mg

Calcium 500 mg

Magnesium 200 mg

Zinc 7.5 mg

Boron 20 μg Molybdenum 100 μg

Diosgenin 99 mg

Claims

1. Compositions for the prevention and treatment of osteoporosis comprising a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D said compositions being characterised in that they contain no diosgenin or, if diosgenin is present, the amount present should be such that the amount to be administered each day is less than 100 mg.

2. Compositions as claimed in claim 1 comprising a therapeutically effective amount of vitamin K1 and a therapeutically effective amount of vitamin D3.

3. Compositions as claimed in claim 1 or 2 which also contain a therapeutically effective amount of vitamin B6 and/or mineral supplements and/or vitamin C and/or vitamin A.

4. Compositions as claimed in claim 3 wherein the mineral supplements comprise magnesium, calcium, zinc, boron and/or molybdenum.

5. A method of preventing or treating osteoporosis comprising the administration to a subject in need thereof a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D, said method being characterised in that either no diosgenin is administered to the patient or, if diosgenin is administered, the amount administered to the patient each day is less than 100 mg.

6. The method according to claim 5 comprising the administration to a subject in need thereof a therapeutically effective amount of vitamin K1 and a therapeutically effective amount of vitamin D3.

7. The method according to claim 5 or 6 which also comprises the

administration of a therapeutically effective amount of vitamin B6 and/or mineral supplements and/or vitamin A and/or vitamin C.

8. The method according to claim 7 wherein the mineral supplements comprise magnesium, calcium, zinc, boron and/or molybdenum.