FR2620334A1 - COMPOSITION FOR ORAL ADMINISTRATION CONTAINING MAGNESIUM AND POTASSIUM - Google Patents

Abstract

The invention relates to a solid composition, for oral administration, intended in particular for the treatment or prophylaxis of potassium and magnesium deficiencies of the skeletal and cardiac muscle, containing approximately 3 to approximately 50 milliequivalents of bioavailable potassium, approximately 0 , 1 to about 25 milliequivalents of bioavailable magnesium, with a ratio of milliequivalents of potassium to magnesium between about 2/1 and about 14/1, the potassium and optionally magnesium being in a controlled release form.

Description

The present invention relates to a new improved composition for

  oral administration for the treatment or prophylaxis of simultaneous intracellular potassium and magnesium deficiencies of skeletal and cardiac muscle associated with gastrointestinal depletion or renal loss, as well

  that their application to the treatment of patients.

  Many clinical conditions are associated with a simultaneous potassium and magnesium deficiency of the skeletal and cardiac muscle. They generally include gastrointestinal depletion due for example to nutritional deficiencies; malnutrition; malabsorption, such as that caused by other electrolyte disturbances, in particular childhood hypocalcemia; diarrhea; a primary magnesium deficiency; intravenous therapy in the presence of extrarenal losses of magnesium and potassium and the like; and renal losses, in particular such as drug-induced losses, including those caused by so-called "loop" diuretics, gentamicin, cisplatin, ethanol and the like; post-obstructive diuresis; renal tubular acidosis or acute tubular necrosis; a primary loss of magnesium due to intrinsic renal abnormalities of

  reabsorption of magnesium; Bartter's syndrome; hyperaldo-

steronism and the like.

  Clinical evidence of potassium and magnesium intracellular depletion has been established by electrolyte analysis of lymphocytes from patients with congestive heart failure, and intravenous or intramuscular administration of magnesium sulfate has been reported to significantly increase lymphocyte levels magnesium and potassium. The 3 role of magnesium deficiency in the pathogenesis of cardiovascular disease and arrhythmias, including digital arrhythmias, and the use of magnesium for their treatment have

also been mentioned.

  It is known that the extracellular and intracellular levels of sodium, calcium, potassium and magnesium differ greatly and that the concentrations of sodium and calcium are higher in the extracellular compartments, while the concentrations of potassium and magnesium are higher in cells only outside. Skeletal and heart muscle cells require appropriate levels of magnesium to maintain normal levels of cellular potassium. Therefore, a cellular deficiency of magnesium leads to a decrease in cellular potassium, and simultaneous deficiencies of potassium and intracellular magnesium, in the skeletal and cardiac muscle, cause a loss of cellular potassium greater than that which would occur with an isolated potassium deficiency. Therefore, an uncorrected coexisting magnesian cell depletion slows the cellular potassium recharge. For a complete overview of the role of magnesium in potassium cell deficiency, see PK Welton et al., Potassium in Cardiovascular and Renal Medicine, pages 23-35 (1986), Marcell Decker Inc. A goal of the invention is to provide an oral composition in the form of a solid dose for the treatment or prophylaxis of simultaneous intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle, associated with their gastrointestinal depletion or their renal loss, this medicament

  containing per unit dose between about 3 and about 50 milli-

  potassium equivalents in the form of a bioavailable salt suitable for pharmacy, between approximately 0.1 and approximately 25 milliequivalents of magnesium in the form of a bioavailable salt suitable for pharmacy, in a ratio in milliequivalents of potassium to magnesium between approximately 2/1 and about 14/1, the potassium salt being released in such a way that, after oral administration, the bioavailable potassium is released into the gastrointestinal tract at a rate low enough to reduce minimum local gastrointestinal irritation caused by potassium. Another object of the invention is to provide a method of treating or preventing intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle associated with their gastrointestinal depletion or their renal loss in a patient in need of such treatment , by oral administration of an effective refill amount of such a composition. Other objects of the invention will appear on reading the

detailed description which follows.

  One embodiment of the invention consists of a

  oral position, in the form of a solid dose, for the treatment or prophylaxis of simultaneous intracellular deficiencies of potassium and magnesium in the skeletal and cardiac muscle associated with their gastrointestinal depletion or their renal loss, this composition comprising per dose unit a) between about 3 and about 50 milliequivalents of potassium in the form of a bioavailable salt suitable for use in pharmacies; b) between about 0.1 and about 25 milliequivalents of magnesium in the form of a bioavailable salt suitable for use in pharmacies; c) the ratio in milliequivalents of bioavailable potassium to bioavailable magnesium in the composition lying between approximately 2/1 and approximately 14/1; and

  d) the bioavailable potassium being present in the

  positioned in a controlled release form such that, by oral administration, bioavailable potassium is released into the gastrointestinal tract at a rate low enough to minimize the local gastrointestinal irritation caused

by potassium.

  Appropriate bioavailable potassium salts are well known and include conventional organic and inorganic salts of potassium supplemental food intake, such as potassium citrate, potassium acetate, bicarbonate

  potassium and in particular potassium chloride.

  Likewise, the bioavailable magnesium salts are well known and include the conventional organic and inorganic salts of a dietary supplement of magnesium, such as magnesium oxide, magnesium phosphate, magnesium diphosphate, magnesium carbonate, magnesium aspartate, magnesium aspartate hydrochloride, magnesium chloride

and their hydrates and the like.

  Bioavailable potassium is in a sustained release form.

  trôlée from which, after ingestion, potassium is released into the gastrointestinal tract for an extended period of time to essentially avoid local concentration

  important potassium ions in the region of the composition.

  It has been reported that such a large local concentration of potassium ions, upon dissolution of supplemental potassium food intake forms without controlled release, causes gastrointestinal irritation, including damage by stenosis and / or ulceration, hemorrhage or perforation

  gastrointestinal or intestinal obstruction.

  The composition can be in the form of a conventional solid pharmaceutical unit dose, such as a tablet, a capsule or a sachet or the like, containing the potassium and magnesium components in the required ratio, in which at least the potassium component is controlled release form required. For example, potassium may be present in the core of a tablet or the like or as one of the components of a multi-layered tablet in a controlled release form. The potassium salt can thus be present in the core of a tablet, this core being surrounded by a semi-permeable membrane insoluble in water comprising an outlet passage to form an osmotic system. The magnesium compound may be present in the mixture with the potassium compound in the core or, if not, some or preferably all of the magnesium salt may be contained in an outer coating or the like applied to the outer surface of the membrane , so that, after ingestion, the coating containing the magnesium salt disintegrates or dissolves to release the bioavailable magnesium by activating the osmotic system to release potassium in the gastrointestinal tract continuously and gently. Osmotic systems containing an active agent suitable for supplying potassium salts are described, for example, in the US patent.

No. 4,016,880.

  Otherwise, the potassium salt may be present in the nucleus of a tablet or the like, the matrix of this nucleus having been coated with a dialysis film which serves as a membrane to allow the gastrointestinal liquid to reach the matrix of the nucleus and dissolve the potassium salt which is then released so

  continuous and managed by leaching from the nucleus matrix.

  The magnesium salt may be present as a component of the core and thus be leached from the matrix with potassium, or some or preferably all of the magnesium may be contained in an outer coating applied to the outer surface of the membrane, as described in the previous paragraph. Tablet leaching systems suitable for supplying salts of

  potassium are described for example in US Patent 3,538,214.

  Otherwise, the potassium salt may be in the form of compressed granules coated with a semi-permeable membrane which penetrates into the granules to form a honeycomb structure. After ingestion, the gastrointestinal fluid enters the compartments of the honeycomb structure by dialysis, and the compartments of the honeycomb structure burst openly when filled with liquid to release the agent essentially continuously active. Honeycomb core structures for oral administration as well as their preparation are described, for example, in US Patent No. 2,478,182. If desired, so that the magnesium salt is present in the core in a honeycomb, the magnesium salt and the potassium salt are mixed to form the compressed granules which are coated, or part or preferably all of the magnesium salt may be present in an external coating which the it is applied to the surface of the honeycomb core to form a coating containing a magnesium salt which erodes or dissolves after ingestion to allow the gastric liquid to soak the

inner honeycomb core.

  In a preferred embodiment, the potassium salt and optionally at least a portion of the magnesium salt are in the form of a multi-unit controlled release composition containing, per unit dose, a large number, typically more and better at at least 100 individually coated or "microencapsulated" units of potassium salt, so that the individual coated units may be available in the gastrointestinal tract of the human host ingesting the composition, such as a tablet, capsule , a sachet or the like. The release of bioavailable potassium and optionally bioavailable magnesium by such a controlled release multiple unit form is generally controlled either by diffusion through a coating, or by erosion of the coating under the effect of the gastrointestinal fluid, or by a combination of

  these mechanisms. An advantage of the multi-unit form of administration

  The main reason for controlled release is that high local concentrations of the potassium compound in the gastrointestinal tract are avoided, as the units are distributed freely throughout the gastrointestinal tract, generally independent of gastric emptying. Typically, the multi-unit composition may be a capsule or sachet which disintegrates in the stomach to release a large number of individual coated units contained in the capsule or sachet, or a tablet which disintegrates in the stomach to release a large number of coated units initially combined in the

compressed.

  The magnesium salt, as indicated above, can either be present in the composition in the form of multiple units

  additional controlled release, either in a release form

  uncontrolled "instant" or consist of a combination of these forms. In one embodiment, the magnesium and potassium salts can be coated together in the form of crystals or

  of mixed pellets having a diameter of 0.1 to about 2 mm.

  In a preferred secondary embodiment, the bioavailable magnesium salt is released from the composition in an average percentage at least equal to the average percentage release of the potassium salt, relative to the total weight expressed in magnesium and potassium equivalents respectively, in the composition in the form of a unit dose. The equal or faster release of magnesium ensures, during its absorption by the host, an appropriate improvement in cellular potassium recharge by

  following simultaneous cellular magnesium recharge.

  The individual units of the multi-unit composition are prepared by coating the individual units with a coating which is essentially insoluble in water but which allows the diffusion of water, such as a film coating made of a plastic or polymer material allowing the diffusion of water. Examples of such materials include cellulose derivatives, for example ethylcellulose, acrylic polymers, vinyl polymers and other high molecular weight materials, such as cellulose acetate, cellulose propionate,

  cellulose butyrate, cellulose valerate, acetatopropio-

  cellulose nate, polyvinyl acetate, polybutyral

  vinyl, polymethyl methacrylate, polycarbonate, poly-

  styrene, polyester, polybutadiene, ethylene copolymers-

  vinyl acetate and the like. The coating is generally applied to the crystal or to the unitary pellet in the form of a solution or dispersion of the plastic or polymer material in an organic solvent or a mixed aqueous / organic solvent. Suitable organic solvents include, for example, lower alkanols, such as ethanol or isopropanol, lower alkyl ketones, such as acetone, lower alkyl ethers, such as diethyl ether, or mixtures thereof. Hydrophobic adjuvants, to further slow down or modify the release of the unitary active agent, can also be used in the form of a liquid or solid dispersion in the organic solvent containing the coating material. Suitable hydrophobic builders include hydrocarbons and hydrocarbon derivatives, such as waxes, oils, fats and mixtures thereof, devoid of pharmaceutical activity. Preferred waxes include beef tallow, beeswax, solid paraffin, hydrogenated castor oil and higher fatty acids, such as myristic, palmitic, stearic and

  behenic as well as their waxy esters suitable in pharmacy.

  When used, these waxy builders can be present in coatings in proportions of about 1% to about

  %, especially from about 3% to about 20% by weight.

  Preferably, the coated units have an average diameter between about 0, 1 and 2 mm, preferably between about 0.2 and about 1.5 mm. The unit nuclei can be in the form of crystals or pellets. In lozenges, the core can be made from a combination of the potassium salt or a mixture of potassium and magnesium salts and excipient. Suitable excipients include diluents, such as starch, microcrystalline cellulose and the like; binders, such as cellulose derivatives such as methylcellulose or hydroxypropylcellulose or polymeric binders, such as polyethylene glycol, polyvinylpyrrolidone; or agar or gelatin. Generally, these excipients are present in a proportion of about 0.2 to about 25%. If desired, a buffer can also be used to modify the pH of the nucleus so that it is between about 1 and about 7.5, preferably between about 4 and about 6. Suitable buffers include the salts of the phosphoric acid, citric or tartaric acid salts, amino acid salts and the like, in an amount between about 1 and about 30% of the weight of the nucleus. If desired, a plasticizer may also be added to the coating material, for example in an amount of about 0.01 to about 1% by weight, and such a plasticizer includes triacetin, an acetylated monoglyceride, rapeseed oil, olive oil, sesame oil, tributyl acetyl citrate, triethyl acetyl citrate, glycerin, sorbitol, diethyl malate, diethyl tartrate, polyethylene glycol and the like and their mixtures. Fillers, pigments and other inert conventional excipients may also be present in

small proportions.

  Generally, the crystals or the pellets of the nucleus are coated in a fluidized bed or in a turbine and dried to remove the solvent. The proportion of the coating is between approximately 1 and approximately 25% by weight relative to the weight of the

  units, preferably between about 2 and about 20% by weight.

  The units containing the potassium salt in the form of coated crystals or lozenges can then be combined with the magnesium salt, optionally also in the form of coated crystals or lozenges, and placed in capsules or sachets containing a large number of these. units or shaped into tablets that disintegrate in the gastrointestinal tract

  to release many of these units.

  The adjuvants and excipients suitable in pharmacy used in the preparation of disintegrable tablets are those conventionally used for this purpose. Suitable fillers include sugars, such as lactose, sucrose, glucose and the like, calcium sulfate, calcium phosphates, starches, such as rice starch, and microcrystalline cellulose. Useful binders include gum arabic, tragacanth, gelatin, starches, alginates, cellulose derivatives and the like. Disintegrants include starches, clay, microcrystalline cellulose, gums and starch derivatives. Lubricants include stearate

  magnesium, talc, colloidal silicon dioxide and waxes.

  The active ingredient bioavailable magnesium, as indicated above, can be incorporated into the composition in the form of a controlled release ingredient or can be incorporated into the composition in a form whose release is essentially uncontrolled, by simple mixing the bioavailable magnesium salt with the coated potassium salt and the tablet-making excipients and pressing the tablets according to methods known per se. Methods of coating multiple crystals or unit pellets, including potassium chloride units, and converting them to capsules and tablets are described

  for example in US Pat. No. 4,572,838, the description of which is

  incorporated here for reference.

  In a preferred embodiment of the invention, the com-

  solid position for oral administration contains, per unit dose, between 3 and approximately 15 milliequivalents of bioavailable potassium and approximately 1 to approximately 7 milliequivalents of bioavailable magnesium with a ratio of milliequivalents of potassium to magnesium between approximately 2/1 and approximately 14 / 1, preferably between about 2/1 and about 8/1, more preferably still between about

2/1 and about 5/1.

  In the following examples, all parts are by weight unless otherwise indicated. The examples are purely illustrative

  and are in no way intended to limit the scope of the invention.

Example 1

  The following tests are carried out to determine the effects of the variation of the external concentration of magnesium on the conductance for potassium using as models ventricular myocytes isolated from guinea pigs, with various determined concentrations of external potassium. At each level of potassium concentration, the concentration of

  magnesium which maximizes potassium conductance.

  Guinea pig ventricular myocytes are isolated as follows.

  A male guinea pig is sacrificed by breaking the neck and the heart is quickly removed, which is rinsed and perfused with an oxygenated Tyrode solution without calcium. Tyrode's solution consists of 140 mM sodium chloride, 10 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose and 5 mM HEPES, and this solution has a pH of 7.26. Heart cells are dissociated by infusion with an oxygenated and recycled collagenase solution containing 0.02% collagenase (Sigma, type IA), 0.1% bovine albumin and 20 micromoles of calcium chloride in Tyrode's solution without calcium for 40 minutes. The atria are removed and the ventricular myocytes are dispersed in a "KB" solution (70 mM potassium chloride, 3 mM dipotassium monohydrogen phosphate, 5 mM yric acid, 5 mM pyruvic acid, 20 mM taurine, 20 mM-hydroxybutyric, 5 mN pyruvic acid, 20 mM taurine, 20 mM il of glucose, 5 mM magnesium sulfate, 5 mM succinic acid, mM creatine, 0.5 mM EGTA and 5 mM ATP, the solution with a pH of 7.3). Cellular debris is removed by filtration through a 200 micron grid and the myocytes are incubated at room temperature for 1 hour. The cells are then placed in 30 ml of Tyrode solution (140 mM of sodium chloride, 10 mM of potassium chloride, 1 mM of magnesium chloride, 2 mM of calcium chloride, 10 mM of glucose and 5 mM of HEPES having a pH of 7.4) at a temperature of 37C and allowed to stand at 21C for 1 hour. A small number of cells are transferred to 35 mm culture dishes just before each experiment. The myocytes are made to bathe in a Tyrode solution, the potassium of which has been modified so that it is respectively 4 and 7 mM (in potassium chloride) without compensation for the osmolality, to determine the optimal quantity of serum magnesium necessary. to maximize conductance for potassium

  within the expected normal range of serum potassium (4 to 7 mM).

  Using capillary microelectrodes from 1 to MD containing an intracellular solution (125 mM potassium chloride, 4 mM magnesium chloride, 30 mM potassium hydroxide, 10 mM sodium chloride, 10 mM EGTA , 5 mM HEPES and 10 mM glucose at a pH of 7.2) to establish GI type contacts with the cell membrane. An Agar / AgCl agar reference electrode is used to ground the bath. The study is carried out according to the technique of the imposed potential using an amplifier. Two protocols are used for the imposed potential technique: either voltage pulses in steps of 0.8-5 s, or saw teeth at 6 mV / s. There is no difference in the relationship between current and voltage between the

  step or sawtooth protocols.

  For a concentration of serum potassium of 4 mM, the concentration of magnesium expressed in mM necessary to establish the maximum conductance for potassium appears to be 0.9 mM of divalent magnesium. This corresponds to a ratio in milliequivalents of potassium to magnesium of 2/1. For a serum potassium concentration of 7 mM, the concentration of magnesium expressed in mM necessary to cause the maximum potassium conductance turns out to be 0.26 mM of divalent magnesium. This corresponds to a

  ratio in milliequivalents of potassium to magnesium of 14/1.

  So to establish optimal potassium muscle conductance in the normal range of serum potassium levels, magnesium must be present in a milliequivalents ratio of potassium to magnesium between about 2/1 and about 14/1, depending on the

aforementioned model.

  Example 2 According to Example 1 of US Pat. No. 4,572,833, incorporated herein by reference, granules of film-coated potassium chloride having a diameter of approximately 0.4 to 1.2 mm are prepared. These granules contain approximately 93% by weight of potassium chloride and are prepared by film coating of potassium chloride crystals with a film coating mixture containing paraffin, tributyl acetyl citrate,

  ethylcellulose and silicon dioxide in isopropanol.

  Film-coated crystals of magnesium chloride hexahydrate are prepared as follows: About 1.0 kg of magnesium chloride hexahydrate is mixed with 5 mg of magnesium stearate and the

  mix through a sieve with 1.41 mm mesh opening (n '12).

  In 800 g of methylene chloride, 20 g of ethylcellulose and 30 g of polyvinylpyrrolidone are dissolved and the solution is sprayed on magnesium chloride hexahydrate by granulating the mixture in a Hobart mixer. The granules are dried at a temperature of 40 ° C. and passed through a sieve with 1.41 mm of mesh opening (No. 12). The product contains 94.5% by weight

  magnesium chloride hexahydrate.

  In the same way as magnesium chloride hexahydrate, a film coating is applied to magnesium aspartate hydrochloride by simply replacing the mass of 1.0 kg of magnesium chloride hexahydrate indicated in the previous paragraph by 1.0 kg of hydrochloride magnesium aspartate. The film-coated product contains approximately 94.5% by weight of hydrochloride

  magnesium aspartate trihydrate.

Example 3

  A composition in the form of tablets containing 10 milliequivalents of potassium and 2 milliequivalents of magnesium, both in a controlled release form, is prepared as follows: To 214 mg by weight of the film-coated potassium chloride of Example 2, 214 is added, 8 parts by weight of the granules of magnesium chloride hexahydrate coated with Example 2, 175 parts of microcrystalline cellulose, 24 parts of talc and 3.2 parts of magnesium stearate and are mixed and pressed into tablets containing 10 milliequivalents of potassium and

2 milliequivalents of magnesium.

Example 4

  In the same way as in Example 3, three compositions are prepared which are shaped into tablets. In compositions A and B, uncoated magnesium aspartate hydrochloride trihydrate is used and in composition C, granules coated with magnesium aspartate hydrochloride trihydrate prepared according to Example 2 are used to ensure controlled release of magnesium. In the three compositions, the coated potassium hydrochloride granules are those of Example 2.

  Ingredients Weight (mg) per tablet

A B C

  Coated KCl granules 806 806 806 Avicel PH 101 * 100 -

Avicel PH 102 * - 100 -

Talc 50 50 50

Aspartate of Mg.HCl.3H20 259 259 -

  Coated Mg.HCl.3H O20 aspartate - - 259 2 5 Magnesium stearate 5.5 5.5 5.5 Total weight 1,220.5 1,220.5 1,220.5 Tablet thickness 8.3 mm 8.3 mm 8.3 mm Tablet hardness **, N. (SCU) 84 (12) 84 (12) 84 (12) * microcrystalline cellulose ** Strong-Cobb units (1SCU = 6.997 Newton) The above tablets each contain about

  milliequivalents of potassium and 2 milliequivalents of magnesium.

Example 5

  In the same way as in Example 3, tablets are prepared each containing 203 mg of magnesium chloride hexahydrate coated in Example 2, 644.8 mg of potassium chloride coated in Example 2, 175 mg of cellulose microcrystalline Avicel PH 101, 24 mg of talc and 3.2 mg of magnesium stearate. The tablets obtained each contain 8 milliequivalents of potassium and 2 milliequivalents of magnesium and have a hardness between 49 and 56 N (7-8 SCU) and a friability of 0.5% after approximately 4 minutes. We resume the composition, except that we use

  188 mg Avicel PH 101 per tablet and no magnesium stearate.

  The tablets obtained have a hardness of 77 N (11 SCU) and a

  0.9% friability after 12 minutes.

Example 6

  In the same way as in Example 3, tablets are prepared each containing 203 mg of magnesium chloride hexahydrate coated in Example 2, 322.4 mg of potassium chloride coated in Example 2, 100 mg of cellulose microcrystalline Avicel PH 101, 18 mg of talc and 1.8 mg of magnesium stearate. The tablets each contain 4 milliequivalents of potassium and

2 milliequivalents of magnesium.

Claims (18)

  1. Solid composition for oral administration for the treatment or prophylaxis of potassium and magnesium deficiencies of the skeletal and cardiac muscle in a patient, characterized in that it contains as active ingredients, a) approximately 3 to approximately milliequivalents of potassium bioavailable, b) approximately 0.1 to approximately 25 milliequivalents of bioavailable magnesium, c) the ratio in milliequivalents of potassium to magnesium being between approximately 2/1 and approximately 14/1, and d) potassium being in a controlled release form so that, after oral administration, bioavailable potassium is released into the gastrointestinal tract at a rate low enough to minimize local gastrointestinal irritation caused by potassium. 2. Composition according to claim 1, in which potassium and magnesium are both in the form of a salt   bioavailable suitable in pharmacies.   3. Composition according to claim 2, in which the   potassium is in the form of potassium chloride.   4. Composition according to claim 2, in which the magnesium is in the form of a food additive salt   complementary suitable in pharmacy.   5. Composition according to claim 1, which contains per unit dose between 3 and about 15 milliequivalents of bioavailable potassium and about 1 to about 7 milliequivalents of bioavailable magnesium in a ratio of milliequivalents of potassium to   magnesium between about 2/1 and about 14/1.   6. Composition according to claim 5, in the form of a tablet. 7. Composition according to claim 5, in laluelle potassium and magnesium are both in the form of a salt   bioavailable suitable in pharmacies.   8. Composition according to claim 7, in which the   potassium is in the form of potassium chloride.   9. Composition according to claim 8, in the form of a tablet. 10. Solid composition for oral administration according to claim 1, for the treatment or prophylaxis of potassium and magnesium deficiencies of the skeletal and cardiac muscle in a patient, characterized in that it contains, as the only active ingredients, a ) approximately 3 to approximately 50 milliequivalents of bioavailable potassium, b) approximately 0.1 to approximately milliequivalents of bioavailable magnesium, c) the ratio in milliequivalents of potassium to magnesium being between approximately 2/1   and about 14/1, and d) the potassium being in a li-   controlled beration so that, after oral administration, bioavailable potassium is released into the gastrointestinal tract at a rate low enough to minimize local gastrointestinal irritation caused by potassium.   11. The composition of claim 10, wherein the potassium and magnesium are both in the form of a salt   bioavailable suitable in pharmacies.   12. Composition according to claim 10, in which the   potassium is in the form of potassium chloride.   13. Composition according to claim 10, in which the magnesium is in the form of a food additive salt   complementary suitable in pharmacy.   14. Composition according to claim 10, which contains per unit dose between 3 and about 15 milliequivalents of bioavailable potassium and about 1 to about 7 milliequivalents of bioavailable magnesium in a ratio of milliequivalents of potassium to   magnesium between about 2/1 and about 14/1.   15. Composition according to claim 14, in the form of a compressed.   16. The composition of claim 14, wherein the potassium and magnesium are both in the form of a salt   bioavailable suitable in pharmacies.   17. Composition according to claim 16, in which the   potassium is in the form of potassium chloride.   18. Composition according to claim 17, in the form of a tablet.