Technical field

The invention relates to a pharmaceutical composi¬ tion, the use of this composition for regenerating living cells and a method for regenerating living cells. More particularly, the invention relates to a pharmaceutical composition comprising zinc, magnesium, phosphorus and potassium in a determined ratio.

Background art

It is known that mineral substances and trace ele¬ ments are of vital importance in the human (generally in living) organism(s) . A great number of publications deal with the effect of the given elements (such as zinc, potassium, magnesium and phosphorus) applied separately.

The idea of the "milieu interieur" created by Claude Bernard in the last century is also known. According to Mr. Bernard the main condition of the free and independent life is the stability in the interior milieu. The mechanism ensuring the permanence in the interior milieu is very important for life. The question of the "milieu interieur" is still under dispute, however, it is admitted by every scientist that the extracellular and intracellular ion concentrations are a part of it.

The second main thermodinamical thesis is a universal rule, so it must be valid in case of living organisms as well.

The living organisms (living cells) seem to be out¬ side the effect of this rule by keeping themselves at an energy level higher than that of their environment. Of course this is just an appearance, the cells are unable to uphold this higher energy level, that is why they get old, sick and die.

Having studied numerous publications I came to the

recognition that in old or sick cells the concentration of adenozine triphosphate (ATP) carrying the biological energy is decreasing, or at least the maximal amount of the ATP which can be formed in a certain time period is lower, thus the maximal efficiency of the cell is de¬ creased. In close connection with this fact the intra- cellular ion concentration of the patient is changed, which can be both cause and effect. The trend of this change in the ion concentration can be predicted in a high probability (surely because of the fact that some ions are kept within the cell and others are kept off the cytoplasm by consuming biological energy, mainly ATP) . The original ion milieu seems to be optimal, any change in it exerts a negative effect on the cellular metabolism, and consequently on the ATP formation as well, which results in a further damage in the ion milieu of the cell, thus a particular self-inducing circle is developed. As a rule this process does not go to the end, i.e. to necrocytosis, but the metabolism and the ion milieu of the cell usually stabilizes at a lower level. This is valid first of all for the actually sick groups, tissues or organs, but it can be followed by secondary and tertiary alterations and the defensive mechanisms of the organism may simultaneously be activated.

I found that in the ill cells the concentration of the following ions tend to increase: sodium, calcium, hydrogen, chlorine, copper. At the same time the concentration of the following ions probably decreases in the ill cells: potassium, magnesium, zinc, monohydro- phosphate, dihydrophosphate.

This whole concept is just a hypothesis, since the existence of ion pumps working with biological energy (ATP) is proved and accepted only in case of three of the above ions (sodium, potassium and calcium) . As to the rest of the ions the data available are few (as to di- and monohydro- phosphate ions) or contradictory (zinc) , or there are no data at all (as to chlorine, hydrogen or Cu ions) , or

support an oppositional view [e.g. in case of magnesium ions suppose an active transport in the opposite direction, see Hoang, N.D.: Magnesium Bulletin, 2=1 , 159-165 (1989)]. However, the reality of my concept is proved by good results of the clinical experiments.

Several works have recently been published regarding the physiological and pathological effect of magnesium and zinc. Rasmussen H.S. [Clin. Cardiol. 1 377-381 (1988)] applied with success magnesium salts in the form of i.v. infusions in a dose above the physiological level for treating acute myocardial infarction. Others have used magnesium salt i.v. in a dose close to the toxical level for treating arrhythmia [Iseri, L.T. et al: Magnesium 8., 299-306 (1989)].

Rasmussen, H.S. et al [Clin. Cardiol. 11 , 377-381 (1988)] have found that the i.v. application of magnesium in large doses has a long-lasting positive effect. This is due to the fact, I think, that magnesium had a normalizing effect on the ill cells, i.e. it promoted re¬ generation. Probably this is also an ion supplementation, however, it could be (partially) achieved only with very large serum doses.

Other researchers consider the use of magnesium in a physiological dose to be favourable, e.g. in case of hypertonia (magnesium aspartate containing 200 mg of magnesium daily) . In this dose the results are moderate or even doubtful. It is generally accepted at the same time, that the majority of the civilized nations is underfed with magnesium, thus the application of magnesium products is not harmful, but definitely desirable also for healthy people.

As regards zinc the experiences are similar. It has been used as dermacological agent for centuries, however, it met real success only after its new discovery [Prasad, A.S. et al: J. Lab. Clin. Med. .61 _/ 537-549 (1963)]. This had been preceeded by the publication of Vallee's standard work about the per os use of zinc for treating liver cirrhosis [Vallee, B.L.: N. Engl. J. Med. 257.

1055-1065 ^' ( 1957) ] .

Although zinc is used nowadays for treating 25 different diseases in a dose exceeding the physiological level 6-8 times, its use is not widespread in medical practice. The more popular it is as a paramedical medi¬ cine e.g. in the United States. The majority of the population is underfed also with zinc [Golden, M.H.N. and Golden, B.E.: British Med. Bull. 3_7, 31-36 (1981)].

The lack of potassium caused by diuretics and other agents is generally known and accepted, just like the fact that this lack must be ceased. The lack of potassium caused by insufficient nourishment is rare, but the increase of the serum (potassium) level occurs more often than in case of the previous two ions and this increase is more dangerous (e.g. in case of renal insufficiency or tissue necrsis) .

In medical literature the lack of phosphate ions is deemed to be very rare. Some monographs [e.g. Knochel J.P.: Arch. Int. Med. 137, 203-220 (1977)] mention more than a hundred articles, which prove the lack of phosphate ion and the importance of hypophosphatemia in connection with completely different diseases. Knochel, J.P. mentions that the lack of magnesium, potassium and phosphate ions occurs in many cases simultaneously. He mentions later, that hypophosphatemia and the deficiency in phosphorus are rare conditions and are even more rare to be cured. [N. Eng. J. Med. Chem. 313. 447-449 (1985)]. Hypophosphatemia differs from phosphorus de- ficiency, there is only a loose correlation between them. One can suffer from intracellular phosphorus deficiency even if one has a normal phosphate level in blood serum.

Practically there are no prior art references concerning intracellular phosphorus deficiency. Therefore it has become a common view among practicioners that the only thing to be mentioned about phosphate ion is that we eat too much of it, thus we can speek about phosphate overfeeding (and not underfeeding) [see Selye M. : Amer. Heart J. : 55., 805-809 (1958) and Proc. Soc. Exp. Biol.

Med. 9_8, 580-583 (1958)]. And this can lead to the breakdown of the ion balance, which may cause diseases (Seeling, M. : Amer. J. Cardiol. 63: 46-216, 1989).

Contrary to what was thought, I have found in my investigations that inspite of the sufficient or excessive phosphate intake the occurance of the intracellular phosphate ion lack is similar to that of the intracellular magnesium and potassium lack. This is probably due to metabolic and energetic reasons. (Consequently, any dose of phosphate ions is (or would be) added, the intracellular stability cannot be restored unless magnesium, potassium and zinc are applied simultaneously as well, thus promoting the improvement of the cellular metabolism and the ATP formation (since this will finally lead to the normalization of the ion con¬ centration) .

The exclusive application of phosphate ions in an overdose damages the organism also because it may bind magnesium and zinc in the intestines by forming hardly soluble precipitates, and thus causing lack of said elements and developing diseases.

The aim of the invention is to produce a pharma¬ ceutical composition comprising a combination of magnesium, zinc, phosphorus and potassium for regenera¬ ting cells. In most cases the effect of this composition on the sick organism is favourable (better than that of using the elements separately) , and there are practically no side effects. The invention is based on the recognition that if the appropriate magnesium, potassium and zinc supply is ensured, than the phosphorus ions do not hinder but promote the effect of these elements. Applying these elements simultaneously the effect is considerably better than applying any of them separately.

Consequently, the effect of a composition comprising Mg, Zn and K ions can be improved considerably by adding a mixture of HPθ ₄ ² ~/H2Pθ4~ salts in an appropriate amount.

The invention is based on the recognition that a pharmaceutical composition containing zinc, magnesium, phosphorus and potassium in a certain ratio is effective for regenerating living cells. It could not be expected from the prior art that such a mixture produces a significant synergistic effect.

Disclosure of the invention

In accordance with the present invention, a novel pharmaceutical composition is provided which comprises zinc, magnesium, phosphorus and potassium, wherein the weight ratio based on zinc, magnesium, phosphorus and potassium atoms is in the range of 1-15:25-300:50-

600:100-1200, optionally in association with a phar a- eutical carrier or excipient or additive.

The above elements (Zn, Mg, P, K) may be in¬ corporated in the composition according to the invention in any form which is not toxic for the organism.

Examples are chemical compounds, such as organic and inorganic compounds, chelates.

The elements may also be included on support such as ion exchanger, vegetable fibre, inert carrier with large specific surface, and the like. These supports are well known in the art.

In case of using a support, said support leaves the gastrointestinal tract without resorption.

Optionally the magnesium and potassium compounds may be selected from the phosphor-containing magnesium and potassium compounds. The zinc, magnesium and potassium compounds may preferably be selected from salts with organic or mineral acids. A mixture of these compounds can also be used. Preferred zinc salts are for example zinc hydrogen aspartate [Zn(AspH)2], zinc glutamate [Zn(GluH)2], zinc hydrogen phosphate (ZnHPθ4) and the like.

Preferred magnesium salts are, among others, magnesium hydrogen aspartate [Mg(AspH)2], magnesium

glutamate [Mg(GluH) ₂ ], magnesium hydrogen phosphate (MgHPθ4) , magnesium hydrogen citrate (MgHCitrate) , magnesium sulfate (MgSθ4) , magnesium oxid (MgO) and the like. Among the potassium salts preferred are potassium dihydrogen phosphate (KH2PO4) , dipotassium hydrogen phosphate (K2HPO4) , potassium hydrogen aspartate (KHAsp) , potassium hydrogen glutamate (KHGlu) , and the like.

The phosphorus is preferably included in the com- position in the form of a zinc, magnesium and/or potassium compound containing phosphorus.

Among the zinc salts the use of a salt with aspartic acid is particularly preferred. Also preferred is the use of such phosphorus compounds which contain phosphate, hydrogen phosphate or dihydrogen phosphate ion.

Among the potassium salts dipotassium hydrogen phosphate and potassium dihydrogen phosphate are parti¬ cularly preferred. In a particularly preferred embodiment of the inven¬ tion the composition comprises

1 % by weight of zinc hydrogen aspartate 25 % by weight of magnesium hydrogen aspartate 25 % by weight of a 1:1 mixture of potassium di- hydrogen phosphate and dipotassium hydrogen phosphate in association with 49 % by weight of a carrier. When preparing the composition, the ingredients are mixed and formulated by methods well known in the art. Another object of the present invention is the use of a composition comprising zinc, magnesium, phosphorus and potassium wherein the weight ratio of zinc, magnesium, phosphorus and potassium atoms is 1-15:25- 300:50-600:100-1200 for regenerating living cells.

Yet a further object of the present invention is a method for regenerating cells in an individual, which comprises administering a therapeutic amount of a com¬ position containing zinc, magnesium, phosphorus and

potassium, wherein the weight ratio of zinc, magnesium, phosphorus and potassium atoms is 1-15:25-300:50-600:100- 1200.

One of the main advantages of the invention is the use of such elements which have substancially no side effects, being the natural constituents of the living organism.

One hypothesis of the mechanism responsible for the advantageous results obtained by the present invention is as follows:

The composition according to the invention acts on the part of the cell metabolism which is common in all cells. The effect is not specific for a certain cell or tissue and not even for a species. The composition according to the invention promotes the restitution of ill cells i.e. is cell regenerating.

It is restoring physiological intracellular and extracellular ion levels thus improving the damaged energy balance of the cells.

Increasing the intracellular ATP concentration increases the intracellular ion concentration and so on; a "reversed circulus vitiosus" is observed. This may explain the often observed prompt improvement in the condition of the patients where the conventional medicaments had no effect.

On the basis of our experiments on ill and healthy people, the composition according to the invention may be considered as a tonic or roborant which decreases the psychical tension, the muscle tonus in state of rest; has a positive effect on the physiological sleep and on the general physical condition.

Administered for prophylactic purposes, the composi¬ tion according to the invention has a protective effect on cells against toxic influence or stress.

The composition according to the invention can be used alone but it is obvious administering it in combina¬ tion with other medicaments. Namely, it reinforces their specific effect as a non specific tonic thus the dose of

the medicaments can be decreased.

Also, the undesired and toxic side effects of certain medicaments can be diminished by the composition according to the invention. It is known namely, that toxic effects often decrease the ATP concentration and modify the intracellular ion concentrations.

The composition according to the invention may act on any cell or tissue, thus one cannot predicte all the diseases on which it is useful. I have found that the best results in case of blood- gas disturbances or a deficiency in serum electrolit con¬ centration, such as hyponatremia, hypocalcemia, respira¬ tory acidosis, metabolic acidosis, alkalosis caused by hyperventilation and metabolic alkalosis. In the latter case I have observed additionally a significant improve¬ ment of the obesity of unknown origin in 3 patients since the composition according to the invention produced a lack of appetite. Besides, I have found a positive effect with my composition in neuropsychiatric diseases, such as panic disorder (although the earlier given sedative had no effect) , neurosis depressiva, stroke, confusion in cerebrosclerosis. The composition acted also positively on the nervous symptoms accompanying the alcohol depriva¬ tion.

In cardiology the composition showed also good results. More closely, atriotachycardia, digitalis intoxication, instabil angina could be cured. Also, I observed that the dyspnoea was decreased independently from its origin (cardiac, pulmonary or neurotic) .

The composition according to the invention can also be used in chest diseases, such as chronic bronchitis, cor pulmonale (this will be demonstrated in the Experimental part of this disclosure) .

When treating diabetic coma or diabetic ketosis with my composition, together with antidiabetic agents, in¬ sulin resistance stopped, acetonemia and acetonuria

improved .

Hepatic disease caused by alcoholism could also be quick1y improved.

Bone pain caused by arthrosis, osteoporosis or trau- matic bone pain can also be relieved by my composition. The amount of the composition administered in accordance with the present invention will, of course be dependent on the subject being treated, the manner of administration and the judgement of the prescribing physician. However, an effective dose of the composition according to the invention, for instance, will be in the range of 0.1-40 gs/day/70 kg, preferably 2-10 gs/day/70 kg. Dosages may be adjusted by monitoring the effects of the amount administered and adjusting subsequent amount as appropriate.

In cases where the compound is administered to prevent diseases, the dose may be adjusted according to lower maintanence levels. Administration of the pharmaceutical composition according to the invention can be via any of the accepted modes of administration such as oral and parenteral (i.v.)

Depending on the intended mode, the compositions according to the invention may be in the form of solid, semi-solid or liquid dosage forms, such, for example, as tablets, capsules, pills, powders, granules, crystals, liquids, suspensions, or the like, preferably in unit- dosage forms suitable for administration of relatively precise dosage. The compositions may include a con¬ ventional pharmaceutical carrier or excipient.

For solid compositions the composition may include any conventional non-toxic solid carrier such as, for example, pharmaceutical grades of mannitol, lactose, starch, talcum, cellulose, glucose, sucrose, and the like.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving the mixture of the active ingredients in a carrier such as, for

example, sterile water, aqueous dextrose, glycerol, and the like, to thereby form a solution or suspension. Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture thereof.

If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as acids to aid solubility, sweeteners and flavouring agents. It is especially advantageous to formulate the com¬ position according to the invention in dosage unit form for ease of administration and uniformity of dosage. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, injectable solutions or suspensions, teespoon- fuls, tablespoonfuls and the like, and segregated multiples thereof.

The compositions according to the invention may be supplied in containers having printed instructions which direct the user to employ the compositions for the purposes described herein. Accordingly, said container having such instruction are considered an aspect of the present invention. The instructions for use may be printed on the container or on a separate sheet which is included with the container.

The following examples are intended to illustrate and not to limit the scope of the present invention. Unless otherwise stated all parts therein are by weight.

Composition examples Example 1: Tablets

1 part of Zn(AspH)2/ 25 part of Mg(AspH)2, 15 part of K2HPO ₄ , 10 part of KH2PO4 and 49 part of lactose are mixed well and compressed into tablets.

Example 2: Tablets

0.5 part of Zn(GluH) ₂ , 32 part of Mg(GluH) ₂ , 20 part

of K ₂ HPθ , 17 part of KH P0 ₄ and 4030.5 part of lactose are mixed well and compressed into tablets.

Example 3: Tablets 1 part of Zn(AspH) ₂ / 44 part of Mg(AspH) ₂ , 3 part of K2HOP4, 2 part of KH2PO4 and 50 part of lactose are mixed well and compressed into tablets.

Example 4: Tablets l part of Zn(AspH)2, 25 part of MgHPθ4, 40 part of KH ₂ PO ₄ and 34 part of lactose are mixed well and compressed into tablets.

Example 5: Powder

3 part of ZnHP0 ₄ , 147 part of MgHP0 ₄ and 50 part of KHAsp are mixed well.

Example 6: Powder 3 part of ZnHP0 ₄ , 147 part of MgHP0 ₄ and 50 part of KHGlu are mixed well.

Example 7: Powder

4 part of ZnHCitrate, 222 part of MgHCitrate, 66 part of KH2PO4, 84 part of K2HPO4 and 24 part of citric acid are mixed well.

Example 8: Granulate

5 part of Zn(AspH)2 355 part of Mg(AspH)2, 66 part of KH ₂ P0 ₄ , 84 part of K ₂ HP0 and 10 part of polyvinyl- pyrrolidone are granulated and if desired compressed into tablets.

Example 9: Oral solution 5 part of Zn(AspH)2, 355 part of Mg(AspH) ₂ / 66 part of KH2PO4, 84 part of K2HPO4, 70 part of citric acid are dissolved in 6000 part of water.

Example 10: Oral solution

5 part of Zn(AspH)2, 355 part of Mg(AspH)2, 66 part of KH2PO4, 84 part of K2HPO ₄ , 100 part of ascorbic acid, 1 part of aspartam (from Nutrasweet) and 1 part of raspberry essece are dissolved in 6000 part of water.

Example 11: Capsules

5 part of Zn(AspH)2/ 355 part of Mg(AspH)2, 66 part of KH2PO4 and 84 part of K ₂ HPO ₄ are vigorously stirred together. The resulting mixture is filled into suitable hardened gelatine capsules.

Biolocial Examples Example 12: Chronic bronchitis 10 patients suffering from chronic bronchitis were administered orally 7 g/day of the composition according to Example 8, during 7 days. 7 subjects showed a positive response, while 3 subjects showed no significant change: In table 1 are listed the main values FEV-jyvc (Forced Ex- piratory Volume during 1 sec, based on the Vital Capacity, in %) .

Table 1

before after treatment treatment

This value is normally between 75 and 90 %.

Example 13: Cor pulmonale 8 patients suffering from Cor pulmonale were administred orally 10 g/day of the composition according to Example 8 during 14 days. 6 of them showed a signi- icant response, the originally high arterious partial CO2 tension, p(C02) returned to the normal level.

The results are shown in Table 2.

Table 2

before after treatment treatment

Pa ^co 2 75 mm mercury 46 mm mercury

The normal value of pC02 is about 40 mmHg.

Example 14: Hyponatremia

This is a deviance of common occuranσe. 15 to 30 % of the patients in a hospital suffer from hyponatremia, i.e. their serum sodium content (SeNa) is < 135 mmole/1. (The normal level is 142±4 mmole/1.) 20 patients suffering from hyponatremia were administered orally 7 g/day of the composition according to Example 8, during 5 to 10 days. 15 patients showed an increase in the SeNa level, while their general condition was also improving. The results are shown in Table 3.

Table 3

before after treatment treatment

SeNa 128±6 mmole/1 135±4 mmole/1