GB2194885A

GB2194885A - Pharmaceutical compositions containing vanadium

Info

Publication number: GB2194885A
Application number: GB08621756A
Authority: GB
Inventors: Ephraim Kaplan
Original assignee: Individual
Current assignee: Individual
Priority date: 1986-09-10
Filing date: 1986-09-10
Publication date: 1988-03-23
Also published as: GB8621756D0

Abstract

Pharmaceutical compositions comprising a vanadyl compound and a thiosulphate, preferably together with a pharmaceutical carrier, in forms for oral, parenteral, rectal or topical administration, have anti- arteriosclerotic and anti-tumour activity. Suitable compositions are aqueous solutions of vanadyl gluconate and magnesium thiosulphate.

Description

SPECIFICATION Pharmaceutical compositions The present invention relates to pharmaceutical compositions for the prevention and treatment of various pathological conditions.

Vanadyl compounds, which contain the VO radical, have been rarely used in pharmacology. The suggestion in U.S. Patent No.

2135111 that vanadyl lactate and possibly other vanadyl carboxylates have antiseptic, and in particular insecticidal and fungicidal properties, does not appear to have led to the widespread use of such compounds for the stated purposes.

Thiosulphates, on the other hand, find pharmacological application e. g. for the treatment of cyanide poisoning, allergic conditions and drug sensitization caused by gold, arsenic, mercury or bismuth preparations. A magnesium thiosulphate preparation in the form of tablets or injectable aqueous solutions is available on the market and is stated to be indicated for shock, medicament intolerance, as well as for anaphylactic conditions due to serums or vaccines.

The present inventor has surprisingly found that the combination of a vanadyl compound and a thiosulfate is effective for the treatment, and so far as can be presently ascertained the prevention, of a variety of pathological conditions, inciuding conditions quite different from those for which thiosulphates alone have been suggested, or for which certain vanadyl compounds alone have been proposed.

The present invention accordingly provides a novel composition of matter which comprises an admixture of a vanadyl compound and a thiosulfate, as well as a pharmaceutical composition which comprises as active ingredients, a vanadyl compound and a thiosulfate, together with an inert carrier, diluent or excipient. In either case, the composition may comprise, for example, 1 part vanadyl compound and from about 100 to about 20, 000 parts thiosulphate, by weight.

The invention also provides processes for preparing the compositions, details of which wil be given infra.

The compositions of the invention are in particular useful for the treatment or prevention of such diverse conditions as arteriosclerosis and malignant tumours in mammals, and mental syndromes in the elderly.

The pharmaceutical compositions of the present invention may be presented in a form suitable for oral, parenteral, rectal or topical administration, and may be in unit dosage form. The compositions may be formulated as e.g. tablets, capsules, powders, syrups, suspensions, orally administrable solutions, injectable solutions (in particular such solutions which are suitable for intramuscular or intravenous injection, including especially aqueous solutions), ointments, suppositories or any other pharmaceutical form.

In general terms, any carrier, diluent or excipient known in pharmacology may be used to formulate the pharmaceutical compositions of the invention. It should be noted that the invention moreover includes compositions containing the two necessary components even in the absence of such adjuvants; such compositions may be used for administration in their own right, but will more generally be used as concentrates, to be made up as required with a carrier, diluent or excipient.

The vanadyl compound used in the compositions of the invention may be selected from vanadyl salts with non-toxic inorganic or organic acids. Water-soluble vanadyl salts are preferred, and more particularly vanadyl salts which are selected from vanadyl lactate, vanadyl tartrate, vanadyl citrate and a vanadyl sugar-derived carboxylate, such as vanadyl gluconate. Inorganic salts such as vanadyl phosphate, are also suitable, however.

The thiosulphate may be, e.g., selected from lithium, sodium, potassium, calcium and magnesium thiosulfates; magnesium thiosulphate is presently the preferred thiosulphate.

The processes available for the preparation of the compositions of the invention are well known to those skilled in the art, and the details of such preparative processes given herein are by way of exemplification only.

For example, the compositions may be made by a process which comprises mixing the dry components. Alternatively, the components maye be mixed in presence of a solvent, followed by removal of the solvent. In yet another alternative, the preparative process may comprise mixing the components, at least one of which is in the form of a solution, followed by removal of the solvent or solvents, where necessary or desired.

It will be appreciated that thiosulphates are acid-sensitive compounds, so that it will be preferable to take care to avoid acid conditions, when preparing the compositions of the invention. One way of avoiding acid conditions, when using a solution of vanadyl compound, is to neutralize such solution, e. g. to a pH of about 7.0 to about 7.5, prior to mixing with the thiosulphate component. Any suitable non-toxic agent may be used for the neutralization step; non-limiting examples are sodium bicarbonate, magnesium oxide and magnesium hydroxycarbonate.

The thus-neutralized solution of vanadyl compound may be, according to one procedure, mixed with a solution of the thiosulphate. According to an alternative procedure, the neutralized solution may be evaporated, and a thiosulphate solution mixed with the residue. The solutions used in these procedures are preferably aqueous solutions.

Following the neutralization step, it will be desirable to clarify the solution of vanadyl compound by removing any insoluble matter, before proceding further, whatever the exact nature of the subsequent step or steps may be.

Thus, a process for preparing the compositions of the invention may comprise neutralizing to a pH of about 7.0 to about 7.5, an aqueous solution of the vanadyl compound, removing any insoluble matter, evaporating the thus-neutralized and clarified solution, maintaining the residue in an inert gas atmosphere for any desired period of time, and then mixing with it an aqueous solution of the thiosulphate, followed by the optional step of removing the aqueous solvent if desired.

The compositions of the invention are useful for treating arteriosclerosis or malignant tumours in mammals, as well as mental syndromes in the elderly. The term "mammals" is intended to convey both humans and nonhuman mammals such as horses and cattle.

The amounts of the active components in the compositions of the invention used to treat the foregoing conditions will normally be such as to provide a daily dosage of from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g. thiosulphate, when administration is by injection. Owing to the lower absorption of vanadyl compound when administered orally, the quantity of vanadium as vanadyl administered by the oral route can be considerably increased, e.g. up to about 40 mg. and the quantity of thiosulphate can be correspondingly increased e.g. up to about 10.0 g. It will be apparent to those skilled in the art how the quantities of active ingredients are adjusted when other forms of administration are used. Such quantities of the active compounds may conveniently be administered in the form of 1 to 6 unit dosages, daily.The Examples, infra, show an advantageous rate of success, when the pathological conditions mentioned above have been treated with the compositions of the invention.

It is presently believed that the compositions of the invention are effective in preventing or delaying the incidence of the pathological conditions mentioned above. This belief is supported by preliminary clinical studies carried out by the inventor. However, it will be appreciated by those skilled in the art that it is considerably more difficult to establish prevention of a disease or condition which has not yet occurred, than it is to show that an existing disease or condition has been cured or at least ameliorated, by treatment.

As is known, the quantities of therapeutic agents useful for prevention are usually a fraction of the quantities useful for treating a condition. It is presently believed that the amounts of the active components in the compositions of the invention which will be useful to prevent the foregoing conditions will normally be such as to provide a daily dosage of from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 g. thiosulphate, when administration is by injection. Owing to the lower absorption of vanadyl compound when administered orally, the quantity of vanadium as vanadyl administered by the oral route can be considerably increased, e.g. up to about 13.3 mg. and the quantity of thiosulphate can be correspondingly increased e.g. up to about 3.3 g.It will be apparent to those skilled in the art how the quantities of active ingredients are adjusted when other forms of administration are used. As with the compositions of the invention to be used for treatment, such quantities of the active compounds may conveniently be administered in the form of 1 to 6 unit dosages, daily.

It will be appreciated by those skilled in the art that the actual daily dosages of the compositions of the invention to be administered to a patient or to a non-human mammal will lie entirely within the discretion of the physician or veterinarian, as the case may be.

Whether the daily dosage for treatment of a condition, or prevention of a condition, will lie within the ranges of quantities stated above, or whether the daily dosage will be above or below such ranges, will depend on such factors as the sex and maturity of the patient or non-human mammal, its weight, and where treatment especially is concerned, the nature and severity of the condition itself.

It will be evident, for example, that taking the ranges of quantities described above as generally including typical daily dosages for an adult human male of average weight (i.e.

about 70 kg.), an adult female or child (or for that matter a non-human mammal of lesser weight than the average human male) is, other factors being equal, likely to require a daily dosage of the active components in the lower part of these ranges, or below the minima of one or both of these ranges, whereas the converse would be expected when dealing with e.g. either humans or non-human mammals which are heavier than the average human male.

Moreover, it will be evident to those skilled in the art that administering these two components separately would in a sense be an obvious equivalent of administering these components as part of the same composition. Nevertheless, besides the convenience of using a single type of dosage unit comprising both active components, it is believed that such separate administration is likely to be relatively inferior.Thus, while the present invention is not to be restricted by any theory of the manner in which the components act in the body, it is possible that one component acts to promote the activity of the other component, or perhaps that the two components act synergistically. (For example, it could be postulated that vanadyl compounds activate aerobic metabolism and in particular respiration, at the cellular level, and that thiosulphate enables the vanadyl compounds to be effective in low and non-toxic levels).

Any such manner of cooperative action would require the two components to be present in the optimum concentration together, whereas a time lag between the administration of the components is likely to act so as to minimize the possibility that such optimum concentration would be obtained and to require higher doses of the active ingredients, which could undesirably approach the toxic limits.

The invention will now be illustrated by the following non-limitative Examples. In all cases the vanadyl gluconate solutions were obtained by reacting together vanadyl sulphate and calcium gluconate solutions, removing the thusformed calcium sulphate by filtration or centrifugation, and recovering the filtrate or supernate containing vanadyl gluconate. The presence of negligible quantities of calcium sulphate and/or glutonate in the filtrate or supernate does not adversely affect the compositions of the invention. The neutralization step is effected using sodium bicarbonate, magnesium oxide or magnesium hydroxycarbonate, followed if necessary by clarification by filtration or centrifugation. The presence of small quantities of sodium or magnesium ions in the thus-obtained filtrate or supernate does not adversely affect the compositions of the invention.

EXAMPLE I Daily injections of 10 ml. 12% magnesium thiosulphate aqueous solution, to which had been added neutralized vanadyl gluconate aqueous solution containing 1.5 mg. vanadium as vanadyl radical, were administered to 10 patients suffering from various forms of arteriosclerosis. In all cases there was observed a marked and steady improvement in their clinical condition after 1-3 months of treatment.

The injections were given intramuscularly in 8 cases and intravenously in 2 cases. No side effects were observed.

EXAMPLE II Daily intramuscular injections of 10 ml. 12% magnesium thiosulphate aqueous solution, to which had been added neutralized vanadyl gluconate aqueous solution containing 3. 0 mg.

vanadium as vanadyl radical, were administered to 7 patients suffering from various forms of malignant tumours (1 breast tumour, 3 prostate tumours, 1 multiple myeloma and 2 bladder tumors, in different patients). All the patients were regarded as terminal or preterminal, and previous treatments were non-beneficial. There was observed a marked improvement in all cases after 2-3 weeks of treatment. Complete clinical recovery was observed in 4 cases after 4 months. No side effects were observed.

EXAMPLE III Daily intramuscular injections of 10 ml. 12% magnesium thiosulphate aqueous solution, to which had been added neutralized vanadyl gluconate aqueous solution containing 5.0 mg.

vanadium as vanadyl radical, were administered to 10 elderly patients suffering from organic geriatric mental syndromes. After one month of treatment, there was observed a marked improvement in 7 cases and a slight improvement in 3 cases. No side effects were observed.

Claims

1. A novel composition of matter which comprises an admixture of a vanadyl compound and a thiosulfate.

2. A composition according to claim 1, which comprises part vanadyl compound and from about 100 to about 20,000 parts thiosulphate, by weight.

3. A pharmaceutical composition which comprises as active ingredients, a vanadyl compound and a thiosulfate, together with an inert carrier, diluent or excipient.

4. A composition according to claim 3, which comprises part vanadyl compound and from about 100 to about 20,000 parts thiosulphate, by weight.

5. A composition according to either claim 3 or claim 4, which is in a form suitable for oral, parenteral, rectal or topical administration.

6. A composition according to claim 5, which is in unit dosage form.

7. A composition according to either claim 6 or claim 7, which is in the form of tablets, capsules, powders, syrups, suspensions, orally administrable solutions, injectable solutions ointments, suppositories or any other pharmaceutical form.

8. A composition according to claim 7, which is in the form of a solution suitable for intramuscular or intravenous injection.

9. A composition according to claim 8, which is an injectabie aqueous solution.

10. A composition according to any of the preceding claims, wherein the vanadyl compound is selected from vanadyl salts with non-toxic inorganic or organic acids.

11. A composition according to claim 10, wherein said vanadyl salts are water-soluble.

12. A composition according to claim 11, wherein said vanadyl salts are selected from the group consisting of vanadyl lactate, vanadyl tartrate, vanadyl citrate and a vanadyl sugarderived carboxylate.

13. A composition according to claim 12, which comprises vanadyl gluconate.

14. A composition according to any of the preceding claims, wherein the thiosulphate is selected from the group consisting of lithium, sodium, potassium, calcium and magnesium thiosulphates.

15. A composition according to claim 14, wherein the thiosulphate is magnesium thiosulphate.

16. A process for preparing the composition of claim 1 or claim 2, which comprises mixing the dry components.

17. A process for preparing the composition of claim 1 or claim 2, which comprises mixing the components in presence of a solvent, followed by removal of the solvent.

18. A process for preparing the composition of claim 1 or claim 2, which comprises mixing the components, at least one of which is in the form of a solution, followed by removal of the solvent or solvents.

19. A process for preparing the composition of any of claims 3 to 15, which comprises mixing the dry components.

20. A process for preparing the composition of any of claims 3 to 15, which comprises mixing the components in presence of a solvent, and if necessary or desired, removing the solvent.

21. A process for preparing the composition of any of claims 3 to 15, which comprises mixing the components, at least one of which is in the form of a solution, and if necessary or desired, removing the solvent or solvents.

22. A process according to claim 21, which comprises neutralizing to a pH of about 7.0 to about 7.5, a solution of the vanadyl compound, and then mixing the thus-neutralized solution with a solution of the thiosulphate.

23. A process according to claim 21, which comprises neutralizing to a pH of about 7.0 to about 7.5, a solution of the vanadyl compound, evaporating the thus-neutralized solution and then mixing with the residue, a solution of the thiosulphate.

24. A process according to any of claims 21 to 23, in which the said solutions are aqueous solutions.

25. A process for preparing the composition of any of claims 3 to 15, which comprises neutralizing to a pH pf about 7.0 to about 7.5, an aqueous solution of the vanadyl compound, removing any insoluble matter, evaporating the thus-neutralized and clarified solution, maintaining the residue in an inert gas atmosphere for any desired period of time, and then mixing it with an aqueous solution of the thiosulphate, followed by the optional step of removing the aqueous solvent if desired.

26. A composition according to any of claims 3 to 15, which is in the form of dosage units containing the active ingredients in amounts such that one to six such units contain from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g. thiosulphate, for administration by injection, the said maxima being increased for oral administration up to about 40 mg. vanadium as vanadyl comound and up to about 10.0 g thiosulphate.

27. A composition according to any of claims 3 to 15, which is in the form of dosage units containing the active ingredients in amounts such that one to six such units contain from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 g. thiosulphate, for administration by injection, the said maxima being increased up to about 13.3 mg. vanadium as vanadyl comound and up to about 3.3 g thiosulphate for oral administration.

28. A composition as defined in either claim 26 or claim 27, which has been prepared by the process according to any of claims 16 to 25.

29. A method for treating arteriosclerosis in mammals, which comprises administering to mammals diagnosed for arteriosclerosis, a composition according to any of claims 3 to 15.

30. A method according to claim 29, wherein the composition and the amount thereof administered is such that per day there are administered from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g.

thiosulphate, per mammal, for administration by injection, the said maxima being increased up to about 40 mg. vanadium as vanadyl comound and up to about 10 g. thiosulphate for oral administration.

31. A method for treating malignant tumours in mammals, which comprises administering to mammals diagnosed for malignant tumors, a composition according to any of claims 3 to 15.

32. A method according to claim 31, wherein the composition and the amount thereof administered is such that per day there are administered from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g.

thiosulphate, per mammal, for administration by injection, the said maxima being increased up to about 40 mg. vanadium as vanadyl compound up to about 10 g. thiosulphate for oral administration.

33. A method for treating mental syndromes in the elderly, which comprises administering to patients falling into this category, a composition according to any of claims 3 to 15.

34. A method according to claim 33, wherein the composition and the amount thereof administered is such that per day there are adminis tered from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g.

thiosulphate, per patient, for administration by injection, the said maxima being increased up to about 40 mg. vanadium as vanadyl comound and up to about 10 g. thiosulphate for oral administration.

35. A method for preventing malignant tumours in mammals, which comprises administ ering thereto, a composition according to any of claims 3 to 15.

36. A method according to claim 35, wherein the composition and the amount thereof administered is such that per day there are administered from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 g.

thiosulphate, per mammal, for administration by injection, the said maxima being increased up to about 13.3 mg. vanadium as vanadyl comound and up to about 3.3 g. thiosulphate for oral administration.

37. A method for preventing arteriosclerosis in mammals, which comprises administering thereto, a composition according to any of claims 3 to 15.

38. A method according to claim 37, wherein the composition and the amount thereof administered is such that per day there are administered from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 g.

39. A method for preventing mental syndromes in the elderly, which comprises administering thereto, a composition according to any of claims 3 to 15.

40. A method according to claim 39, wherein the composition and the amount thereof administered is such that per day there are administered from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 g.

thiosulphate, per patient, for administration by injection, the said maxima being increased up to about 13. 3 mg. vanadium as vanadyl comound and up to about 3.3 g. thiosulphate for oral administration.

41. A method for treating pathological conditions in mammals, which comprises administering to the mammals therapeutically effective amounts of a vanadyl compound and a thiosulphate.

42. A method for the prophylactic treatment of mammals, which comprises administering to the mammals prophylactically effective amounts of a vanadyl compound and a thiosulphate.

43. A method according to claim 41, which comprises administering to the mammals a daily dosage falling within the ranges of from about 0.3 to about 18.0 mg. vanadium as vanadyl compound and from about 0.2 to about 5.0 g. thiosulphate, for administration by injection, the said maxima being increased up to about 40 mg. vanadium as vanadyl comound and up to about 10 g. thiosulphate for oral administration.

44. A method according to claim 42, which comprises administering to the mammals a daily dosage falling within the ranges of from about 0.06 to about 9.0 mg. vanadium as vanadyl compound and from about 0.04 to about 2.5 9. thiosulphate, for administration by injection, the said maxima being increased up to about 13.3 mg. vanadium as vanadyl comound and up to about 3.3 g. thiosulphate for oral administration.

45. A composition according to any of claims 1 to 15, and 26 to 28, substantially as hereinbefore described.

46. A composition according to any of claims 1 to 15, and 26 to 28, substantially as hereinbefore described in any of the Examples.

47. A process according to any of claims 16 to 25, substantially as hereinbefore described.

48. A process according to any of claims 16 to 25, substantially as hereinbefore described in any of the Examples.

49. A method according to any of claims 29 to 44, substantially as hereinbefore described.

50. A method according to any of claims 29 to 44, substantially as hereinbefore described in any of the Examples.