US 2611730 A
Description (OCR text may contain errors)
Patented Sept. 23, 1952 .MEDICAL PREPARATION FOR REDUCING, V
THE BODY LEVEL OF SODIUM Arthur E. Homing, Lafayette Hill, Pa., assignor to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application September 2, 1950,
Serial No. 183,101
3 Claims. 1
This invention relates to a medical preparation for the control of the assimilation of mineral cations by the body. It is well recognized, byway of example, that restriction of sodium intake as a therapeutic measure has great medical value in the treatment of certain clinical conditions. The value of a diet low in salt content has long been recognized in the treatment of many kinds of conditions, particularly those in which edema is a characteristic, such as, for example, congestive cardiac failure, cirrhosis of the liver, the obesity of pregnancy, and many others, as well as in the treatment of hypertension. Realization, however, of a dietary regimen in; which the salt content is sufliciently low to significantly decrease the patients dietary sodium intake is usually accompanied with many difilculties, not the least of which is lack of acceptability to the patient of a diet so very bland that it is unpalatable.
This invention provides the art with a new, safe, andhighly eifective therapeutic means by which a patient may be placed, for example, in a very low,.or-'even negative, sodium balance. The degree of sodium restriction is readily controlled by the amount of preparation administered. Further, this invention has utility in correcting a cation deficiency.
The use of ion-exchange resins for restriction of mineral cation intake has been very recently "described in the art, but it has been demonstrated that their use in this manner gives rise to certain very undesirable results which have heretofore prevented the adoption of this therapeutic measure to widespread clinical practice. Here again we can, by way of example, consider the removal of sodium ions. It has been observed that the oral administration of ion-exchange resins. has resulted in lowered blood levels of cationic minerals other than sodium. Thus, for example, blood levels of calcium and potassium have been, observed. to. have been dangerously c depleted below those levels known to be physioor acombinationof such resins combined with 2. two or more types of cations. One of thesetypes of cations will be the mineral type.
Preferably, the resin will also be combined with ammonium ions or an amino acid, such as lysine, arginine and histidine, or with any combination of ammonium ions and amino acids. The ammonium ions and the, amino acids have a minor physiological efiect. Thus, their inclusion in the resin results in insignificant physiological effects in the body While at the same time prevents undesired, and in many cases dangerous, physiological effects which would frequently result, incident to excessively high levels of mineral cations, if only physiologically significant mineral cations were used to charge the resin. This" is particularly useful where repeated dosages are required over a protracted period of time.
It will be understood that the particularnovelty of this invention is the successful depletion of selected mineral ions such as sodium ions from the body While at the same time there is a replacement of other mineral ions in the body which are depleted by the ion-exchange resins, thus preventing the lowering of body levels of those'essential ions. Further, a large depletion of a particular mineral cation can be accomplished withceived in the stomach which has a low pH. The
high concentration of hydrogen ions presentin gastric fluids results inthe replacing of the cations with which the resin is charged byhydrogen ions, thus converting the resin to its acid form. Thus-the ammonium cations are released to the stomach fluids and may for all practical purposes be disregarded. The replacement mineral cations are similarly released to the gastro-intestinal tract to be absorbed therein, and thereby increase the concentrations of these physiologically significant mineral cations in the body.
The resin in its acid form proceeds into the intestines, an area of very low acidity or of a pH of approaching 7. Here,.the hydrogen ions of the resin are exchanged for mineral cations depending upon the afiinity of the resin, for these cations and the concentrations of the cations present. Of course, sodium ions will beextra ct ed and,, since no replacement sodium ions were: in the resin, the level of sodium ions in the-body will be reduced. The replacement ionszprevious- 1y released in the stomach will replenish the amounts of the other mineral cations which are depleted by the resin in the intestines. Thus, the body levels of these cations will be maintained.
The resin, being insoluble and physiologically and chemically inert, is not susceptible to assimilation by the body. Thus, it passes through the gastro-intestinal tract unaffected by the process of digestion, except for the exchange of cations.
This invention further has the advantage of eliminating the necessity for subsequent, prior, or coadministration of certain supplementary substances, such as, for example, mineral supplements or gastric buffers, in conjunction with ion-exchange resin therapy. It will be further appreciated to have the advantage of minimizing the danger of incurring acidosis usually encountered in the administration of mineral supplements due to the heretfore unavoidable necessity of simultaneous administration, along with the desired mineral cation, of a corresponding, exogenous union. the presence of which latter may give rise to undesirable acidosis.
The ion-exchange resin oi the preparation according to this invention will, generally speaking, be a synthetic cationic resin exhibiting high capacity for mineral cations and particularly for sodium ions. Although the resin will preferably be of a carboxylic type, it may be desirable under certain conditions to utilize a sulfonic resin or even a mixture of carboxylic and sulfonic exchange resins in order to blend the respective affinities and characteristics of those resins in the combining properties of the preparation.
More particularly the ion-exchange resin of i this preparation will be a synthetic carboxylic resin with a capacity of greater than 3 meq. per I gram of resin. Such a resin, for example, may be prepared by the polymerization of a vinylcontaining carboxylic acid, such as, for example,
, a. derivative of acrylic acid. Such a resin may be copolymerized in various ratios, as may be determined to be necessary to obtain the required characteristics of hardness and permeability of the resulting resin with a molecule containing more than one vinyl group having the ability of participating in the linear polymerization of more than one polymer chain. Such an agent serves to provide cross linkage of the polymer chains in 3 dimensions and serves to provide to the final, I polymerized resin its necessary physical characpolymerization to form a carboxylic ion-exchange resin may be mentioned such substances as acrylic acid, methacrylic acid, methyl acrylate,
i ethyl acrylate, methyl methacrylate or in general, derivatives of acrylic acid and lower alkyl esters thereof. In this connection it is to be noted that where an ester of the carboxylic acid is used to form the polymer, the esterifying group must be I hydrolyzed oif in the preparation of the resin to provide the carboxylic groups in the resin necessary for purposes of cation exchange. The resin as prepared will then be in its hydrogen, or acid,
As further illustrative of a high capacity, synthetic, carboxylic ion-exchange resin suitable for utilization in the preparation of this invention is a resin prepared by copolymerization, using techwhere n is an indeterminate number, with monomeric units occurring at random frequency but in an overall molar ratio of 10:1.
The mineral cations with which the resin or resins according to this invention will be combined will be selected, generally, from the group consisting of mono-, diand trivalent mineral cations occurring naturally in physiological media. Thus, for example, specific mineral cations, with which the resin or resins of this preparation may be combined, will be potassium, calcium, magnesium, iron, cobalt, zinc and manganese. Hydrogen cations can also be used to charge the selected resin in accordance with this invention. It should be noted that the ammonium ion is occasionally considered to be a mineral cation rather than, as is more correct, a
. non-mineral inorganic ion. It is, therefore, de-
claims, is not intended to include ammonium ions.
Where an amino acid is used, it will have a molecular ratio of ammonium groups to carboxylic groups which is always greater than one.
The number of cations with which the resin or resins of the preparation will be combined is determined by the number of physiological cationic substances which the resin itself deletes from physiological media and by the clinical condition which it is desired to treat. Thus, for example, if the afiinity of the resin for ions of sodium, potassium and calcium is found to be sufiicient to delete amounts which are physiologically significant, and if it is desired to place a patient with stomach ulcers in a low sodium balance, it might be desirable to charge the resin or resins with some proportion of cations of potassium, calcium and lysine. The amounts of mineral cations with which the resin will be combined will be such that the levels of those particular cations deleted by the resin in physiologically significant amounts will be replenished and maintained. Thus, upon administration of the preparation, the cations with which the resin is combined would be eluted off from the resin matrix, the mineral cations being in sufficient concentration to replace and maintain the minimum required body levels of those elements; the
appropriate proportions. will be prepared; lay-treating that portion of the resin, as received in its hydrogenform, with a solution of that particular cation in the" form of agentin "the stomach to avoid an undue increase in acidity.
Generally spealiz-ingz;the:multiple cationic ionexchange resin preparation of this invention will be prepared by either oftwomethods. The ionexchange resin" as manufactured may be treated withso-lutions'ofthe various ions with which it is desired to combine the resin, in concentrations such that thoseionswi-ll' ice-absorbed inand on the'resin in" ouantitiesappropriate to 'the'desi-red cationic constitution of the preparation; Thus,
for example, were itdesired to obtain we; preparation containing ammonium and potassium cationssin a particular'ion-excha-nge resinin the ratio of 2:1, the'resin would be treated with a solution containing those two ions in thatsame ratio of concentrations. The concentrations oi the ions in the solution with which the resin is treated should be sufficiently great to cause the resin to become --completel-y saturated with those two ions; i. e., to charge it with those ions to the extent of its capacity. Thus, in theexample mentioned above, ii theresin has a capacity of B-nieq. per gram, each gram of-resin should contain, after being-treated with the charged solution, two meq; of ammonium ion and 1 meq. of potassium ion.
o Alternately, the preparation containing multiple cations in combinationwith the ion-exchange resin'may be preparedby" physically mixing two or more portions-oi resin, each of which-is sat urated with respect to'one particularcation, in Each of the portions a'solub-le compound.
The resulting resin or combination of'resins containing multiplecationsas prepared by either of the two methods above may then desirably be i subjected to micropulverization in order to render the preparation more pharma'ceutically"acceptable for purposes of" oral ingestion, although this is not necessary to the effectiveope-ration of the preparation. It may further be found desirable for" the purposes of administration under certain conditions to reaggregate the finely divided resin with such substanceswas acacia and methyl-cellulose into largergranules; Such granules, for example, may" readily be administered orally in a slurrywith fruit juices; water, chocolate milk, and the like. I
The pulverization of the resin to a finely divided powder will be readily" accomplished l2ipounds of: carboxylic cation-exchange. resin .inits hydrogen .form, prepared from .polymeriza-- tionof metha'crylio :acid:.and di-vinykbenzeneaand exhibiting an available capacity of from 4.5 to V 6.0 meq. per gram in neutral media-was'weighed into a large'hattery jar. Having amoisture content of 46%, this was equivalent-W625 pounds of;
the dried resin. Distiiled water was added to the jar. in suffloient. amount to thoroughlmsqalg; the resin... and the. resinwaatransierred,1 usi ,su1tans wash. techniques, into. .a fi-gallon'bottle.
150.0 m1. concentrated (151i) ammonium. hydroxide-.was. added to the-bottle in :portionaof 50.0. mines-e11.- Followingeachaddition; the-lbottle Buc-hneriunnel, .followedby a.successi-ve;seri es oi washings using approximatelytflitersioi .waten After the-resin was sucked :dry itwas'transterred inglargev wooden. trays. and-dried ini an-ioven at 168-- F. Analysis of the. resin so prepared determined thatv itcontained 5. .0." meq. of ammonia pergram ofdry resin.
12.5 pounds or the acid formtof the-same-oar- ,boxylicresin was-weighed into a S-ga-llon bottle.
The'moisturecontent of: this resin being 485%, this amounted to 6.425 pounds of dry resin. Sufficient water wa added tothe: bottle to cover the resinwtowa-depth 0f'35 andj2310Ygrams of crystalline-KCl-was added'to the slurryin-the bottle, followed by thorough shaking. -A- solutionor 1730 grams of KOH lBJQJlJJBIS/Of water was added to the 5-gallonbottle containing the resin and the KCI solution, following which the bottle was stopperedl"andirotated on its side for 5 minutes. The bottle was then allowed to stand for several hours, interrupted only for periodic shaking. l he supernatant lfquid'was then d'ecanted from the resin in the bottle and the'r'esin was rinsed several-successive times until'all the coloring material" had been removed from the resin. Following" this the -resin: was transferred to large Buchner funnel, washed repeatedly until the rinsings became'neutral', i; e;, until one dropof 1%" phenolphthaleinsolution, upon addition' to 100 m1. of'the washings, was-'deco loi 'i zed by one drop of 0.1 N The resinwa s fthen transferred toporcelain pans, dried overnight in'an oven at 129 *C: and was determined 'to-oohtain 5.88 meq. of potassium per gram of" resin.
The ammonium and" potassium resins prepared asabove, of aparticle size of i'rom ito' -B' meSh, were separatelysubj'ecte'd'topulverization techni'ques such that their -'particl"e size was reduced to '80 mesh or less. 2545 grams of powdered potassium resin and 7-955 grams of'the powdered ammonium resin and" 525' grams of powdered acacia, U. S. P.were all placed in aStokesmiXer and thoroughly mixed for from 3'to S-mihutes. An aqueous solution of"0 .2'% methyl cellulose was prepared .by adding sufficientwater to obtain a final volume of 23 liters of solution to 46 grams of methyl cellulose; heating'to7 5 C." and cooling the resultant mixture back 'tdroom' temperature. The resulting viscousso'lutiorr was; added to the mix. in 3liter' portions initially" and after: 18 liters. had-been added, in smaller amounts. until a doughy-consistency obtained. Thecm'aterial. was thenosoooped-out of the-mixer, forced through a 1=6-mesh screen: onto largewooden trays anddried in an oven-- for 20 hours atl25 "F. The driedparticles were thBHfOliCBd through a 30-mesh screen to obtain the: desired granule partielesize.
The granules. of. ion-exchangeresin; so. prepared. were. determinedto; contain-1.331. meq. :per gram of. potassium. and; 3.33) meq,, per. gram. of ammonium. v
' stantstirring. ammonium hydroxide was then added to the Example 2 wet polyacrylic acid ion-ex- Inasmuch as the resin had a moisture content of 40%, this was equivalent to 270 grams of dry resin. 000 ml. of water was added to the resin and a solution of 40.5 grams of potassium chloride dissolved in 200 ml. of water was added with con- 150 ml. of concentrated (15 N) beaker with constant stirring, after which the beaker and its contents were set aside for two days, interrupted by occasional stirring. The
resin in the beaker was allowed to settle and the 'supernatant liquid was decanted from the resin.
The resin was then rinsed several successive times with distilled water, transferred to a Buchner funnel and washed several times with distilled 'water'. The resin was then sucked dry, trans- Example 3 3000 grams of polyacrylic acid ion-exchange resin was weighed into a 5-gallon bottle and enough water was added to cover the resin to a depth of one inch. A solution of 6 pounds of cacnrno in 3 liters of water was added to the bottle, followed by intermittent shaking over a period of 2 hours. The supernatant solution was decanted from the resin and the resin was rinsed and decanted several successive times with distilled water. A solution of 3 pounds of anhydrous CaClz dissolved in 2 liters of water was then added to the resin followed by the addition of another 5 liters of water. The bottle was stoppered, shaken intermittently for a period of 2 hours and allowed to stand overnight. After decanting the solution from the resin in the bottle, the resin was rinsed several successive times with the distilled water and was transferred onto a Buchner tunnel. After successive washings with distilled water, the resin was filtered, dried, transferred to pans and dried in an oven overnight at 105 C. The resin so prepared was determined to contain 5.0 meq. of calcium per gram of resin.
The calcium resin prepared as above was then micropulverized to a particle size of 60-80 mesh which was then mixed together with powdered ammonium resin prepared in a manner identical with that described in Example 1, which contained 4.4 meq. of ammonium per gram of resin and with a powdered potassium resin prepared in a manner identical with that described in Example 1, which contained 6.5 meq. of potassium per gram of resin in such a manner that 45 grams of homogeneous resin mixture contained meq. of Ca, 100 meq. K and 121 meq. NH4.
In the preparation of 1125 grams of a finely divided ion-exchange resin preparation according to the above specifications, 50 grams of Ca resin prepared above and micropulverized. 387.5 grams of the finely divided potassium resin and 687.5 grams of the finely divided ammonium resin were weighed into a large bottle and thoroughly mixed by prolonged rotation and thorough shaking o the container.
" Example '4 A polyacrylic acid cation-exchange resin preparation containing 0.22 meq. of calcium per gram of resin, 2.22 meq. of potassium per gram of resin, and 2.70 meq. of ammonium per gram of resin, was prepared by treating the resin in its free acid form with a solution of CaCh, KOH, and NH4OH in a manner similar to the preparation of the double salt of the resin described in Example 2 above. The triple salt of the ion-exchange resin so prepared was then dried, pulverized and granulated according to the procedure described in Example 1 above.
Example 5 0.552 g. oi a polyacrylic acid ion-exchange resin having a moisture content of 50%, was treated with a solution of 0.552 g. of lysine in 5.5 ml. of water whose pH was 9.9 according to the techniques described in Example 1 above. The resin so prepared was determined to contain 2.74 millimoles (5.48 meq.) of lysine per gram of resin. The lysine resin was dried, pulverized and granulated according to procedures described above in Example 1.
0.276 g. of the lysine resin was mixed with 0.071 gram of potassium resin, prepared in Example 1 above to contain 5.88 meq. of potassium per gram, to form an ion-exchange resin preparation containing 1.22 meq. of potassium and 2.17 millimoles (4.35 meq.) of lysine per gram of resin preparation. The amino acid capacity of the resin in milliequivalents was calculated on the basis of the molecule containing two active cationic groups.
Example 6 1.004 g. of a polyacryllc ion-exchange resin of a moisture content of 50%, was treated with a solution of 1.004 g. of arginine in 10 ml. of water in a manner identical with that described in Ex ample 5, to yield the arginine resin containing 3.04 millimoles (6.08 meq.) of arginine per gram. This resin was then dried and finely divided.
0.502 g. of the arginine resin was intimately mixed with 0.139 g. pulverized potassium resin prepared in Example 1, and 0.031 g. pulverized calcium resin prepared in Example 3 to yield a homogeneous powdered mixture of resin which was determined to contain 2.27 millimoles (4.54 meq.) arginine, 1.22 meq. of potassium and 0.22 meq. of calcium per gram of the resin powder preparation. The amino acid capacity of the resin in milliequivalents was calculated on the basis of the molecule containing two active cationic groups.
What is claimed is:
l. A medical preparation for reducing the body level of sodium comprising an ion-exchange resin selected from the group consisting of carboxylic and sulfonic ion-exchange resins, said resin being charged with ammonium ions and additionally being charged with potassium ions to maintain the normal body level of potassium, said medical preparation being substantially sodium free.
2. A medical preparation for reducing the body level of sodium comprising a carboxylic ion-exchange resin, said resin being charged with ammonium ions and additionally being charged with potassium ions to maintain the normal body level of potassium, said medical preparation being substantially sodium free.
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UNITED STATES PATENTS Number Name Date 2,409,861 Hunter Oct. 22, 1946 FOREIGN PATENTS Number Country Date 67,658 Norway Apr. 3, 1944 10 OTHER REFERENCES McChesney. American Journal of Physiology, volume 160, February 1, 1950, pages 264 to 276.
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Amberlite IRC-50, April, 1948 (9 pages).
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Kunin (l) Analytical Chemistry, January 1949, pages 87 to 96.
Kunin (2), Industrial and Engineering Chemistry, June 1949, pages 1265 to 1272.
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Dock, Transaction of the Assoc. Amer. Physicians, volume 59, pages 282 to 285 (1946).
Irwin, Jour. Clinical Investigation, volume 28, November 1949, pages 1403 to 1411.
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