GB2299992A

GB2299992A - Complexes of magnesium and calcium

Info

Publication number: GB2299992A
Application number: GB9508014A
Authority: GB
Inventors: Willem Jacob Serfontein
Original assignee: Individual
Current assignee: Individual
Priority date: 1995-04-20
Filing date: 1995-04-20
Publication date: 1996-10-23
Also published as: ZA963121B; GB9508014D0

Abstract

A solid, water soluble complex containing magnesium, citrate, calcium and malate producible by the reaction of magnesium citrate and calcium malate as well as pharmaceutical or dietary preparations containing such a complex is useful in the treatment or prevention of osteoporosis and/or systemic alkalinisation in a patient. Also a solid, soluble complex of calcium and magnesium is produced by the addition of the mineral carbonates to at least one acid containing at least one or more carboxylic acid groups and at least one hydroxyl group or amino group.

Description

The present invention relates to a soluble, calcium containing complex for improving the bioavailability of minerals in a patient, a process for its manufacture and to a pharmaceutical or dietary preparation containing such a complex for use in the treatment or prevention of osteoporosis in a patient and/or systemic alkalinisation in a patient.

Osteoporosis is defined as the progressive loss of bone ultimately resulting in critically low bone mass with increased fracture risk. It remains a serious problem in the Western World. The majority of the elderly have clinical evidence of the disease and in these patients mortality may be as high as 12 to 20%. Nutrition plays an extremely important role in the etiology of the disease. Typically the incidence is much lower in Third World countries although dietary calcium intake may be lower in these countries. This has focused attention on the fact that many other minerals apart from calcium are involved in bone formation and are therefore likely to be involved in the development of osteoporosis.

Recent studies have drawn specific attention to the importance of magnesium and it may be that magnesium is at least as important as calcium in the formation and maintenance of bone. At least one study has shown that administration of magnesium alone (without calcium or other minerals) in post menopausal women results in up to 11% bone density increases over a two year period (Magn. Res 1993, h: 155). Because of the high consumption of dairy products, calcium deficiency is not such a serious problem in the Western World and many studies have failed to demonstrate any real advantage of calcium supplementation per se (see for example BMT 1991, :453 and Can Med Assoc J 1991, 144:889).Since there can be no question concerning the importance of calcium in bone formation and structure, the negative outcome of such studies must be assumed to indicate that in some of the population studies, calcium must have been at least marginally adequate, or that calcium absorption may have been a problem. All studies to date involving magnesium adininistration, have yielded positive results.

This focuses attention on the very important interrelationship of calcium and magnesium and to problems surrounding the bioavailability of both minerals.

Previous claims that co-administration of calcium and magnesium might lead to suppressed calcium absorption appear to be unfounded. A recent study has shown that intestinal calcium absorption did not change during high magnesium intakes (J Ann Coll. Nutr. 1993, 12:6001, abstract 77). Conversely it is known that a low magnesium status may inhibit calcium absorption. On a low magnesium intake (below Smg/kg), the magnesium balance and the calcium balance remained negative regardless of the level of calcium intake. It is surmised that this failure of some clinical trials (see above) to demonstrate any advantage of calcium supplementation may have been due to a concomitant sub-clinical magnesium deficiency which, in the Western World, is very common.

Apart from these considerations, there are two other advantages associated with the co-administration of the two minerals. Firstly, magnesium regulates the delicate balance between panthyroid hormone and calcitonin thus preventing soft tissue calcification which usually accompanies administration of high levels of calcium without magnesium (J. Nutr. Med. 1991, 2:165). Secondly, the sparing action of calcium deposits by magnesium has been known for a long time. (Calcif. Tiss. Res.

1972, 1Q:269).

For optimum supplementation of both minerals, two further factors need to be considered: stomach acidity and systemic acidosis. Adequate stomach acidity is required for normal mineral absorption. Therefore these minerals should not be given in a form that will effectively reduce gastric acidity such as carbonates or oxides. In this regard, the mineral citrates (or generally mineral salts of suitable organic fruit acids) are to be preferred (New Engl. J. Med. 1985, :70).

Defective mineral absorption in the presence of low stomach acidity has frequently been reported (see J. Clin. Invest. 1984, 73:640).

Systemic acidosis on the other hand (resulting, for example, from a high dietary protein intake) is an important factor in bone loss which has been known for a long time. Unexpectedly large benefits resulting from effective buffering of systemic pH have recently been demonstrated (New Engl. J. Med 1994, 330: 1776).

Finally biological availability of the different forms of calcium and magnesium is another important factor to be considered. It is known that calcium citrate is more biologically available than the carbonate (J. Clin. Endocr. Metab. 1985, 61:391) and the citrate-malate complex salt of calcium appears to have further advantages in this regard (New Engl. J. Med 1990, =:878).

Calcium citrate malate (CCM) is a complex which is currently favoured as a readily bioavailable source of calcium.

Calcium citrate malate and the methods for making the complex have been described inter alia, in the following documents: Japanese patent specification SHO56-97248, Tanaka published in 1981; US patent no 4,722,847 issued to Hecket, published February 2, 1988 US patent no 5,186,965, issued to Fox et al, February 16, 1993.

Japanese patent specification No SHO56-97248 discloses a CCM salt of increased solubility having a molar ratio of calcium:citrate:malate of 5:2:2.

US patent no 4,722,847 discloses CCM in beverages and the preparation of material in a beverage format.

US patent no 5,186,965 describes a metastable complex of calcium, citrate and malate in a bioavailable form which is soluble in both neutral and acid solutions.

The complex is prepared by the reaction of calcium carbonate, calcium hydroxide or calcium oxide with citric and malic acids in aqueous solution.

US patent no 5,151,274 discloses nutritional mineral supplements comprising CCM and salts of manganese, copper and zinc. In particular there is disclosed a tablet comprising CCM and magnesium stearate as a tabletting agent. However, no complex of CCM and magnesium is contemplated or described.

The complex of CCM however, does have a major disadvantage in its lack of solubility, which although improving on previously known sources of calcium, for example, calcium citrate and calcium malate, leaves nevertheless much to be desired.

Patent no GB 1221633 contemplates a pharmaceutical composition including an organic acid, calcium and one or more citrates or gluconates of magnesium and iron.

EP patent no 0587972A1 discloses a sports drink which includes sodium and potassium and at least either magnesium or calcium, preferably both. In particular, the specification provides for inter alia, magnesium citrate and calcium malate as suitable sources of calcium and magnesium. However, the fact that calcium malate and magnesium citrate may react with one another to form a new soluble complex is not disclosed or described.

The co-administration of calcium and magnesium together in a vitamin supplement or pharmaceutical composition is accordingly not new as such. However, in none of these prior publications was the specific reaction of magnesium and calcium salts to produce new complexes described.

A need exists, however, for a complex containing calcium and magnesium, the complex being highly soluble and having a good bioavailability of the calcium.

A further need exists to induce mild systemic alkalosis (similar to the effect of potassium citrate) which further benefits calcium absorption and retards bone dissolution. Applicant has surprisingly found that the addition of magnesium to calcium under the correct conditions and in a solution of organic acids, for example citric and malic acid, substantially increases both the solubility of the complex formed and the stability of the product in dry form.

This represents a substantial deviation from the prior art in that the addition of magnesium has a three fold purpose: 1) It increases the solubility and stability of the calcium complex including the magnesium, 2) It improves the bioavailability of both the calcium in the complex and 3) It has an allcrlising effect on the systemic pH of the patient.

According to a first aspect of the present invention there is provided a solid water soluble complex of magnesium, citrate, calcium and malate producible by the reaction of magnesium citrate and calcium malate in solution. The invention also extends to such a water soluble complex whenever produced by the reaction of magnesium citrate and calcium malate in solution.

Alternatively, the water soluble complex may be produced by mixing magnesium carbonate, calcium carbonate, malic acid and citric acid. Preferably during the formation of the complex the citric acid is present in excess.

The ratio of calcium to magnesium in the complex may be from 10:1 to 1:10, preferably 7:1 to 1:3, more preferably 3:1 to 1:1 for example 2:1.

According to a second aspect of the present invention there is provided a process for the manufacture of a solid, water soluble complex of magnesium, citrate, calcium and malate the process including the steps of: mixing a solution of magnesium citrate and calcium malate and - removing the resultant soluble product from solution.

The process may include the additional step of drying the resultant soluble product.

Preferably the calcium malate is freshly prepared before adding to magnesium citrate.

According to a third aspect of the present invention there is provided a process for the manufacture of a solid, water soluble complex of magnesium, citrate, calcium and malate, the process including the steps of: - adding calcium carbonate and magnesium carbonate to citric and malic acid and - removing the resultant soluble product from solution.

The process may include the additional step of pre-mixing the citric and malic acid to form a solution to which the calcium carbonate and magnesium carbonate are added. The citric acid and malic acids may be mixed together in a pre-selected molar ratio and preferably the citric acid is present in excess.

The process may include the additional step of drying the resultant product.

The drying step as outlined in either of the above processes may be effected by means of spray drying or freeze drying.

According to a fourth aspect of the present invention there is provided a process for the production of the soluble complex of magnesium and calcium, the process including the step of mixing the carbonates of the two minerals with at least one acid containing at least one or more carboxylic acid groups and at least one hydroxyl group or amino group. Preferably at least one acid is organic.

The acids mentioned above may be selected from the group consisting of citric, malic, isocitric, lactic and aconitic acid and combinations of two or more of these.

In one embodiment of the invention at least one of the acids used is an amino acid, preferably the natural L-form of the amino acid being used.

The invention also extends to a solid soluble complex of calcium and magnesium produced by the addition of the mineral carbonates to at least one acid containing at least one or more carboxylic acid groups and at least one hydroxyl group or amino group.

According to a fifth aspect of the present invention there is provided a pharmaceutical or dietary preparation for the treatment and/or prevention of osteoporosis the preparation including a complex as hereinbefore described. The preparation preferably includes an effective concentration of the complexes hereinbefore described as well as a suitable diluent, excipient or auxiliary.

Preferably included with the preparation is an effervescent agent. In addition, the preparation may also contain salts of other minerals known to be of importance in bone formation (e.g. manganese, zinc, copper, boron and silicon).

The invention also extends to the use of a complex as hereinbefore described for the manufacture of a pharmaceutical or dietary preparation for the treatment and/or prevention of osteoporosis. The treatment or prevention of osteoporosis may include the administration of a pharmaceutically or dietetically effective amount of the complex to the patient in potable form.

The invention also extends to the use of the complex as hereinbefore described in the treatment and/or prevention of osteoporosis, this use including administering to the patient a pharmaceutically or dietetically effective amount of the complex in potable form.

The use of the complex as hereinbefore described as a source of minerals in the treatment of osteoporosis has distinct advantages over the use of a simple mixture of two different soluble magnesium and calcium salts or of the complex of CCM. The advantages may be summarised as follows: - There is a better mineral absorption due to the presence of the magnesium and also that of the citrate; - The use of the complex hereinbefore described allows the preparation of readily soluble compounds of calcium in the presence of citrate, calcium citrate as such being largely insoluble; - Mild systemic allralosis is induced which further benefits bone retention and curbs bone dissolution; - In this form magnesium has a pleasant taste as opposed to the taste of many other magnesium compounds.It also does not cause nausea; - There is a saving of bulk; the volume of the complex as hereinbefore described necessary to supply 500mg of calcium and 300mg of magnesium is less than that of a combination of many other calcium and magnesium compounds. This is advantageous from the point of view of tablet manufacturing; - The complex as hereinbefore described lends itself readily and very conveniently to the manufacture of effervescent powders or tablets since it already contains the necessary acids required for the generation of effervescence.

According to a sixth aspect of the present invention there is provided a pharmaceutical or dietary preparation for systemic alkalinisation of a patient, the preparation including a complex as hereinbefore described. The complex preferably includes an effective concentration of the complexes hereinbefore described together with a suitable diluent excipient or auxiliary. The preparation preferably also includes an effervescent agent.

The invention also relates to the use of a complex as hereinbefore described for the manufacture of a pharmaceutical or dietary preparation for systemic alkalinisation of a patient the systemic alkalinisation preferably including the administration of a pharmaceutically dietetically effective amount of the complex to a patient in potable form.

The invention also relates to the use of a complex as hereinbefore described in systemic alkalinisation of a patient, said use including administering to the patient a pharmaceutically or dietetically effective amount of the complex in potable form.

The preparation of the complexes as hereinbefore described will be illustrated with reference to the following non-limiting examples.

Example This is a preferred process for the manufacture of the complex as hereinbefore described.

i) Preparation of magnesium citrate: 800 g citric acid monohydrate is dissolved in 2 litres of H2O. 444.4 g of magnesium carbonate (MgCO3) is added to the solution. The solution is mixed until no further bubbles are formed.

ii) Preparation of calcium malate: 655.5 g of malic acid is dissolved in 2 litres of H2O. 444.4 g of calcium carbonate (CaCO3) is added to the solution. The solution is mixed until a milky suspension is formed.

iii) Preparation of the complex: The freshly prepared calcium malate solution is added to the magnesium citrate solution. It is important that the calcium malate solution be freshly prepared because upon standing an insoluble salt is formed in the calcium malate solution which precipitates out. The two solutions are mixed until the resultant solution becomes clear. The solution is spray-dried, preferably within 2 hours.

iv) Calculated composition of the spray ied product: The produced complex can be expected to contain the following: Elemental calcium (Ca) 178,2 g 10,21% Elementalmagnesium(Mg) 111,2 g 6,37% Citrate 800,0 g 45,85% Malate 655,5 g 37,57% TOTAL: 1744,9 g 100,0% It can be calculated that 4,9 g of the prepared complex salt will contain 500 mg of elemental calcium and 312 mg of elemental magnesium.

v) The complex as prepared above is white in appearance and when mixed with KHCO3 in the ratio 10:1, it dissolves rapidly in H2O to yield a clear solution with a pH approximately equal to 5,0.

Example 2 In an alternative process for the production of a complex as hereinbefore described the following quantities of reagents were used: Magnesium carbonate 453,2 g Calcium carbonate 444,4 g Citric acid 1206,5 g Malic acid 657,7 g The malic and citric acids were dissolved in 4 litres of H2O.

The magnesium and calcium carbonate were mixed and the mixed powder added gradually over a period of 15 minutes to the stirred aqueous solution of citric and malic acids. Strong effervescence occurred initially which gradually subsided after 2 to 3 hours at room temperature, the reaction being complete and all solids dissolved after this time. The resulting solution which was slightly turbid was immediately spray dried (solution temperature 25"C nozzle temperature 1700C).

Analysis of the complex prepared according to this example indicated that it contained the following quantities of acids and minerals per 6,81 g of the complex (or one daily dose): Elemental Calcium 500 mg Elemental Magnesium 312 mg Citric acid 766 mg Malic acid 512 mg The magnesium to calcium ratio of 312:500 (1:1,6) was selected in this example on clinical grounds on the basis of anticipated daily patient requirements. It is possible to prepare the complex with a wide range of magnesium to calcium ratios.

Similarly, the ratio of the minerals to the acids may also be varied considerably, but an excess of organic acids (especially citric acid) must be present.

In the manufacture of this soluble complex the following relative quantities of reagents were used per 6,81 g of soluble complex: Calcium carbonate 1249 mg (500 mg calcium) Magnesium carbonate 1300 mg (312 mg magnesium) Citric acid 2975 mg Malic acid 1622 mg In this example, 2975 mg of citric acid and 1622 mg of malic acid (4597 mg of total organic acids), were used per 500 mg of calcium since this reflected an adequate excess of organic acids (especially citric acid) to ensure stability of the resulting complexes. However, some variation (per 500 mg of calcium) of both total organic acids as well as the malic acid : citric acid ratio is possible. In the above example, a 7596 excess of citric acid was used over and above that which is necessary to dissolve the minerals (1700 mg).Useful complexes can be prepared in which this excess varies from 30% excess (2210 mg) to more than 100% excess (3400 mg). The preferred quantity of citric acid is 50 to 75 excess (2266 to 2975 mg). Complexes prepared in this manner appear to be the most suitable for purposes of spray drying.

Total organic acids used may vary (per 500 mg calcium and 312 mg magnesium) from approximately 3000 mg to 6000 mg. The preferred quantity, however, is 4597 mg. In the above example, the malic acid, citric acid ratio is 1:1,83. This represents the preferred ratio. It is possible, however, to vary this ratio considerably, for example from 1:1 to 1:5.

Example3 In a further alternate process for the preparation of the complex as hereinbefore described the following quantities of reagents were used: Citric acid 465 g Malic acid 296g Calcium carbonate 200 g Magnesium carbonate 205 g The citric and malic acid were dissolved in 1800 ml H20. The two carbonates were mixed and added stepwise to the aqueous acid solution. The mixture was left at room temperature with occasional shaking. After 6 hours the reaction was complete. The solution was viscous, light yellow and somewhat turbid in appearance. After standing overnight there was a white precipitate which was filtered off. The solution was used for freeze drying which was complete after 48 hours. The freeze dried material was ground to a fine powder which was readily soluble in water or in a sodium bicarbonate solution.

Analysis of components of complex 106,4 mg of the complex salt was dissolved in 100 ml of H2O and the resulting solution analysed for calcium and magnesium with the following result: Elemental Calcium : 9,08% Elemental Magnesium : 4,90%

Claims

CLAM 1. A solid, water soluble complex of magnesium, citrate, calcium and malate producible by the reaction of magnesium citrate and calcium malate in solution.
2. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in claim 1 produced by the reaction of magnesium citrate and calcium malate.
3. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in claim 1, produced by mixing magnesium carbonate, calcium carbonate, malic acid and citric acid.
4. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in any one of claims 1 to 3 during formation of which citric acid is present in excess.
5. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in any one of claims 1 to 4 wherein the ratio of calcium to magnesium in the complex is from 10:1 to 1:10.
6. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in claim 5 wherein the ratio of calcium to magnesium is 7:1 to 1:3.
7. A solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in either one of claims 5 and 6 wherein the ratio of calcium to magnesium is 3: 1 to 1:1, for example 2:1.
8. A process for the manufacture of a solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in any one of claims 1, 2 and 5 to 7 including the steps of: - mixing a solution of magnesium citrate and calcium malate and - removing the resultant soluble product from solution
9. A process as claimed in claim 8 including the additional step of drying the resultant soluble product.
10. A process as claimed in either one of claims 8 and 9 wherein the calcium malate is freshly prepared.
11. A process for the manufacture of a solid, water soluble complex of magnesium, citrate, calcium and malate as claimed in any one of claims 1 and 3 to 7, the process including the steps of: - adding calcium carbonate and magnesium carbonate to citric and malic acid and - removing the resultant soluble product from solution.
12. A process as claimed in claim 11 including the additional step of pre-mixing the citric and malic acid to form a solution to which the calcium carbonate and magnesium carbonate are added.
13. A process as claimed in claim 12 wherein the citric acid and malic acid are mixed together in a pre-selected molar ratio.
14. A process as claimed in any one of claims 11 to 13 wherein the citric acid is present in excess.
15. A process as claimed in any one of claims 11 to 14 including the additional step of drying the resultant soluble product.
16. A process as claimed in either one of claims 9 and 15 wherein the drying is effected by means of spray drying or freeze drying.
17. A process for the production of a soluble complex of magnesium and calcium, the process including the step of mixing the carbonates of the two minerals with at least one acid containing at least one or more carboxylic acid groups and at least one hydroxyl group or amino group.
18. A process as claimed in claim 17 wherein at least one acid is organic.
19. A process as claimed in either one of claims 17 and 18 wherein the acids are selected from the group consisting of citric, malic, isocitric, lactic and aconitic acid and combinations of two or more of these.
20. A process as claimed in any one of claims 17 to 19 wherein at least one acid is an amino acid.
21. A process as claimed in claim 20 wherein the amino acids used are the natural L-forms of the acids.
22. A solid, soluble complex of calcium and magnesium produced by the addition of the mineral carbonates to at least one acid containing at least one or more carboxylic acid groups and at least one hydroxyl group or amino group.
23. A pharmaceutical or dietary preparation for the treatment and/or prevention of osteoporosis, the preparation including a complex as claimed in any one of claims 1 to 7 or 22.
24. A pharmaceutical or dietary preparation as claimed in claim 23 including an effective concentration of a complex as claimed in any one of claims 1 to 7 or 22 together with a suitable diluent, excipient or auxiliary.
25. A preparation as claimed in claim 24 including an effervescent agent.
26. Use of a complex as claimed in any one of claims 1 to 7 or 22 for the manufacture of a pharmaceutical or dietary preparation for the treatment and/or prevention of osteoporosis.
27. Use as claimed in claim 26 wherein the osteoporosis treatment or prevention includes the administration of a pharmaceutically or dietetically effective amount of the complex to a patient in potable form.
28. Use of a complex as claimed in any of claims 1 to 7 or 22 in the treatment and/or prevention of osteoporosis, said use including administering to the patient a pharmaceutically or dietetically effective amount of the complex in potable form.
29. A pharmaceutical or dietary preparation for systemic alkalinisation of a patient, the preparation including a complex as claimed in any one of claims 1 to 7 or22.
30. A pharmaceutical or dietary preparation as claimed in claim 29 including an effective concentration of a complex as claimed in any one of claims 1 to 7 or 22 together with a suitable diluent, excipient or auxiliary.
31. A preparation as claimed in claim 30 including an effervescent agent.
32. Use of a complex as claimed in any one of claims 1 to 7 or 22 for the manufacture of a pharmaceutical or dietary preparation for systemic alkainisation of a patient.
33. Use as claimed in claim 32 wherein the systemic alkalinisation includes the administration of a pharmaceutically or dietetically effective amount of the complex to a patient in potable form.
34. Use of a complex as claimed in any of claims 1 to 7 or 22 in systemic alkalinisation of a patient, said use including administering to the patient a pharmaceutically or dietetically effective amount of the complex in potable form.