3,137,625 United States Patent Office Patented June 16, 1964

1 2 3,137,625 low those which cause disturbing side effects and yet DIURETHI COMBINATIONS €ONTAENHNG A maximum diuresis and electrolyte excretion obtained with TiHAZIDE AND A MERCURlAL out gastro-intestinal irritation. John H. Biel, Milwaukee, Wis, assignor to Lakeside The use of a thiazide diuretic in‘ combination with a Laboratories, Inc, Milwaukee, Wis, a corporation of .mercurial diuretic effects the increased diuresis while Delaware 7 actually reducing potassium excretion, thus greatly in No Drawing. Filed Jan. 9, 1961, Ser. No. 81,244 creasing the safety margin for this type of therapy. The 4 Claims. (Cl. 167-65) mercurial diuretic apparently inhibits the increased potas sium output normally produced by a thiazide diuretic. This invention relates to the treatment of humans. 10 The combination of a thiazide diuretic and a mercurial More particularly, this invention is concerned with a diuretic thus provides safe, maximum diuretic therapy and novel method of inducing diuretic activity in humans, sodium chloride excretion with a minimum of side effects and novel pharmaceutical compositions useful therein. and thus is a major advance in the treatment of congestive There are on the market various diuretics of the heart failure, edema, high blood pressure and glaucoma. “thiazide” type, viz., those containing the 7-sulfamoyl By using the diuretic combination of this invention the 2H-1,2,4-benzothiadiaZine-l,l-dioxide or 7-sulfamoyl greatest reduction in amount of diuretic needed is in the 2H-3,4-dihydro-1,2,4-benzothiadiazine-1, l-dioxide nucleus, mercurial component rather than in the thiazide. The including chlorothiazide, dihydrochlorothiazide, dihydro gastro-intestinal side e?ects incident to the higher mer v?umethiazide, benzydro?umethiazide, methylchlorothiaz curial dosage is thus essentially eleminated. However, ide and trichloromethiazide. Chlorothalidone (Hygroton, 20 the amount of mercurial used in the combination never Ciba), while it contains a nucleus somewhat different than theless suppresses the potassium excretion usually induced that of the thiazides just described is a sulfonamide-con by the thiazide diuretic while simultaneously increasing taining diuretic and for the purpose of this invention is diuresis over that obtainable by use of the thiazide alone. to be considered Within the terminology used when thiaz The combination of a thiazide diuretic with a mer ide diuretics are mentioned. Such compounds, and others 25 curial diuretic is advisably formulated into suitable phar 'of the thiazide type, are orally effective and increase di maceutical unit dosage forms such as tablets and cap uretic activity in humans at daily dosage amounts of from about 4 to 300 mgm. sules. Carriers can be used as desired to achieve a suit able volume to dosage relationship to facilitate ease of Although the thiazide type of diuretic is orally active handlingthe unit dosage form. Such formulating is with— and readily absorbed from the gastrointestinal tract, there 30 in the skill of the pharmaceutical chemist. are three major disadvantages involved with their use. The amount of thiazide diuretic and mercurial di The ?rst is that the thiazide diuretics do not eliminate retic used in the combination will be goverened by the all of the excess fluid and sodium electrolyte but usually activity of the particular drug used since the activity varies leave a 20% excess residue of sodium and water. They from one to the other. The following, however, are par thus do not usually bring a cardiac patient down to “dry 35 ticular dosage combinations which can be used: Weight." This is particularly disturbing in the more severe cardiac patient. Due to the ?at dose-response curve ob Mg. tained with the thiazide type diuretics, not even larger (A) dosages can rid the body of this excess residue. Sec Trichloromethiazide ______1 to 10 Chlormerodrin ______1 to 30 ondly, thiazide diuretics eliminate not only excess sodium 40 ion, which is desirable, but also increased amounts of (B) potassium which in highly undesirable and can lead to Chlorothiazide ______50 to 500 death, in some cases, due to a potassium de?ciency. Chlormerodrin ______1 to 40 Thirdly, prolonged administration of large doses of thiaz (C) ide diuretics can produce a gouty arthritis which necessi 45 Dihydrochlorothiazide ______10 to 100 tates withdrawal of the drug. ' Chlormerodrin ______1 to 40 In addition to the thiazide diuretics, there are presently available on the market various orally effective mercurial (D) diuretics including Chlormerodrin (Neohydrin) and Dihydro?umethiazide ______10 to 200 merbiurelidin (Meterox). Such mercurial diuretics suffer 50 Chlormerodrin ______1 to 40 from relatively low absorption from the gastro-intestinal . . (E) tract and therefore must be administered at a dose level Chlorthalidone ______10 to 300 which produces gastro-intestinal irritation and side effects. Chlormerodrin ______; ______1 to 40 According to the present invention it has been dis ' , . (F) covered that by concomitant, and advisably simultaneous, 55 Benzydro?umethiazide ______1 to 20 oral administration of a thiazide diuretic and a mercurial diuretic to a human there is achived a much greater, but Chlormerodrin ______l to 40 unexpected, diuretic action than could be achieved by ad (G) ministering either of these drugs in the absence of the Methylchlorothiazide ______1 to 20 other. Furthermore, by administering a combination of 60 Chlormerodrin ______1 to 40 a thiazide diuretic and a mercurial diuretic, lower amounts (H) of each drug can be administered to a human than are Trichloromethiazide ______1 to 10 needed when each drug is used separately to obtain an Merbiurelidin ______1 to 40 equal diuretic effect. As a result, the two drugs in com bination can be administered at dosages substantially be 65 A speci?c gelatin capsule could contain 4.0 mg. of trichloromethiazide and 18.5 mg. of chlormerodrin. 3 The diuretic activity of the novel combinations pro surprising when it is considered that the 18.5 in". dose of vided by this invention is illustrated by the results ob chlormerodrin is one-third of the accepted daily dose of tained with six normal human volunteers to Whom 4.0 this drug when administered alone. At such a reduced mg. per day of trichloromethiazide was administered sep dosage, side effects which occur with higher dosages, do arately, and in combination with 118.5 mg. per day of not appear. Furthermore, a daily dose of 18.5 mg. of chlormerodrin. The results of this ?rst test, on an indi-v chlormerodrin alone is recognized to be insu?icient to vidual basis, are as follows with all determinations having signi?cantly increase diuresis and this is shown in the sec been made on 24 hour urine samples: ond test. Thus, essentially no change in urine or sodium output resulted. With respect to potassium, two indi viduals had a signi?cant increase in potassium output. Vol. Percent mEq Percent rnEq Percent 10 (rnL) Vol. Na+ Na+ K“ K“ Compared with the combination of trichloromethiazide Change Change Change and chlormerodrin, the potassium output appeared to be higher with chlormerodrin alone. Thus, chlormerodrin 1.11.13; in non-diuretic doses potentiates the diuretic and natruire Control ______-_ 1,365 ______189 ______70 ______Triehloromethiatide--- 1,585 +16 212 +12 71 +1 15 tic e?ects of trichlorornethiazide, but at the same time Chlormerodrin+ , inhibits potassium excretion. ’ T'érifghloromethiaZide.-- 2,085 +52 323 +70 64 —10 , . Various changes and modi?cations of the invention can Control ______-_ 1,820 ______203 ______o- 77 ______-_ be made and, to the extent that such variations incorpo Trichloromethiazide___ 2,610 +44 283 +40 72 —6 Chlorrnerodrin+ rate the spirit or" this invention, they are intended to be J grghloromethiazide--- 3,140 +72 319 +58 75 0 included Within the scope of the appended claims. , . 20 Control ______2,045 ______204 ______._ 93 ______What is claimed is: Trichloromethiazide___ 2,165 +6 315 +54 110 +18 1. The method of increasing diuresis in a human while Chlormerodrh1+ C'¥i-Iiehl0romethiazide___ 2,730 +35 387 +00 101 +8 reducing potassium excretion caused by administration of a thiazide diuretic alone, and without producing the side Control ______1,165 ______130 ______80 ______._ 'I‘richloromethiazide.-- 1,360 +17 239 +85 120 +50 25 effects caused by administration of an orally effective Ghlormerodrin+ mercurial diuretic alone, which comprises orally admin A’I‘ri]e)hlororuethiazide_._ 1,650 +43 214 +65 89 +11 istering to a human a combination of trichloromethiazide Control ______-_ 1,110 ______150 ______-_ 50 ______Trichloromethiazide___ 1,935 +72 261 +73 70 +40 and chlormerodrin, said combination containing said tri Chlormerodrin+ chloromethiazide in an amount effective to increase di 1jTriq’ohloromethiazide___ 1,720 +55 231 +54 60 +20 uresis and containing the said chlormerodrin in an ‘.1’. .: Control ______3,060 ______196 ______89 ______. amount su?icient to suppress potassium excretion induced Triehloromethiazide.-- 3,125 0 259 +30 116 +30 Ghlormerodrin+ by said trichloromethiazide but in an amount below that Trichloromethiazide_._ 4,305 +33 256‘ +30 106 +17 which causes sufficient adverse side e?ects in the gastro intestinal tract. Subsequently, in a second test, the same six volunteers 35 2. The method of claim 1 wherein the amount of tri were administered the chlormerodrin (18.5 mg.) without chlorometbiazide is 1 to 10 mgs. and the amount of chlor the concomitant administration of trichloromethiazide. merodrin is 1 to 30 mgs. The results are as follows: 3. A pharmaceutical composition in unit-dosage form containing trichloromethiazide in an amount effective to Vol. Percent mEq Percent mEq Percent 40 increase diuresis in a human and chlormerodrin in an (1111.) Vol. Na+ Na+ 11+ K+ amount sufficient to suppress potassium excretion induced Change Change Change by said trichloromethiazide but in an amount below that which causes signi?cant adverse side effects in the gastro

Control ______1,100 120.14 ______.. 74.25 ...... __ intestinal tract, and a pharmaceutical carrier. ' C lormcrodrin_.__ 1,025 156.83 +21 65.50 ~12 a 4. A pharmaceutical composition in unit—dosage form Control.-._ 1, 720 ______98. 73 ______4. 38. 70 ______containing from 1 to 10 mgs. of trichloromethiazide and 1,220 —29 70.03 -—28 46. 24 +2 1 to 30 mgs. of chlormerodrin, and a pharmaceutical

1,440 ______212.83 ______85.39 ______carrier. 1, 365 —5 201.75 —-5 94. 32 +11

1,225 ______100.70 ______73.99 ______References Cited in the ?le of this patent Chlormerodrin.___ 1,225 0 105.47 +5 99. 59 +36 Meyer et al.: “Diuretic Therapy,” October 1958, pp. Control ______-_ 1,590 ______113.37 ______57.72 ______574-586, esp. 583. Chlsormerodrim." 1,330 ~16 129.64 +14 83.66 +45 US. Dispensatory, vol. 2, 1960 ed., pp. 43-46, 77-78 ControL ______3,165 ______._ 178.82 ______75.96 ______and 188. Chlormerodrin____ 3,255 +3 130.20 ~27 78.12 +4 55 Conn: Current Therapy, 1960, page 1318 (Saunders, pub, Phila.). ' The results of the ?rst test show that the combination Cornish: Antibiotic Medicine and Clinical Therapy, of trichloromethiazide and chlormerodrin achieved a VI: 8, pages 443-451 (pages 446—447 relied upon), Au much more marked increase in diuresis in all subjects ex gust 1959. cept one than trichloromethiazide alone, and that the in 60 Clinical Medicine, October 1958, pp. crease was obtained with a decrease in potassium out Hirschleifer : put. In addition, in three of the six subjects there was 1371~1374. also an increase in sodium excretion by use of the combi Keyes et 211.: J.A.M.A., 169: 2, pp. 93-96, Ian. 10, 1959. . nation over trichloromethiazide alone. Drug Trade News, 35: 10, pp. 53 and 71, May 16, 1960. The results obtained from the ?rst test are even more 65.