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US2608510A - N-benzylsulfamyl benzoic acid - Google Patents

N-benzylsulfamyl benzoic acid Download PDF

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US2608510A
US2608510A US168542A US16854250A US2608510A US 2608510 A US2608510 A US 2608510A US 168542 A US168542 A US 168542A US 16854250 A US16854250 A US 16854250A US 2608510 A US2608510 A US 2608510A
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penicillin
adjuvant
benzoic acid
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benzylsulfamyl
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US168542A
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James M Sprague
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Sharp and Dohme Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • This .inventiomv relates to a a, sulfamylbenzoic acid. whichis veffective --as an adjuvant for use in conjunctionwith the aadministrationzof penicillin, tonprovidean increase-in theblood plasmapenicillinzconcentration with, a given dose-of penicillinwthereby- :making 3 possible very high penicillin l blood levels ors permitting the useiof smaller-v. quantities, of -lpenicillin rfor providing a given, blood level; ornpermittingi the. less frequent. adv ministration, of penicillin ,while maintaining a h periicillinebloodfi level adequate for bactericidal on lbacteriostatic purposes.
  • This invention also relatestothe preparation-f various dosage forms? in'xwhich.thistnewtcompoundlis, incorporated for,
  • Penicillin today is ea swells established thera Guideic agentused-in A the treatment: of bacterial,-.
  • Various agents including; diodrast' and hippuric acid,- or derivatives or PIG-z cursors' thereof, have been: proposedaor usedfor this purpose. Such agents do not, however seem.
  • the highly effective adjuvant of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc. to almost zero, so that the actual elimination of penicillin from the blood stream becomes substantially that resulting from glomerular filtration, that is, about onefifth the normal rate (ignoring plasma binding).
  • the adjuvant is eliminated by the glomeruli.
  • the adjuvant can'be administered orally or, when dissolved in an aqueous solution, it can be administered intravenously or intramuscularly.
  • This last method has not yet proven desirable for single injection of the material, because in general, administration of more than 2 cc.-per single injection intramuscularly is inadvisable, and the quantities of adjuvant desirable to use, i.'e., 4 to 16 grams per day, are such as to make injection by this route impractical.
  • the benzylsulfamylbenzoic acid or its salts are well adapted for continuous intramuscular or subcutaneous clysis.
  • oral administration of the adjuvant at the rate of 4 to 1.6 grams per day is adequate to suppress the rate of penicillin excretion to an extent such that the blood level with a givendose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as much as four times the level obtain d without the use of the adjuvant, and will permit either the use of a very much smaller quantity of penicillin to provide a given blood level, for'example, permitting the penicillin doses to beabout one-fourth of those commonly used, or permitting the provision of penicillin blood levels several times as great as those obtainable with the administration of penicillin by the routes ordinarily used today.
  • the adjuvant of the invention or a suitable salt of it can be administered in admixture with the levels of about 4 to 16 grams per day orally and somewhat less than this intravenously.
  • the adjuvant can be prepared in any convenient dosage form, either alone or admixed with penicillin, such as in a compressed tablet, a dry filled capsule or a soft elastic capsule. It is to be. understood, of course, that other ingredients, such as binders, diluents, excipients, antacid substances, or other inert or therapeutically active compounds may be incorporated into any selected dosage form along with the adjuvant or adjuvantplus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin.
  • the adjuvant' and, if desired, the penicillin can be dispersed in an oleaginous base either alone or along with other suitable substances and filled into soft elastic capsules or an aqueous solution may be prepared and filled into ampuls.
  • suitable dosage forms will be readily apparent to those skilledzinthe art, and it is notthe pur-.
  • Para-(benzylsulfamyl)-benzoic acid is preferably prepared by reacting para-cyanobenzenesulfonyl chloride with benzylamine in the-presence of an inert solvent, such as pyridine.
  • the resulting N-benzyl-para-cyanobenzenesulfonamide is converted by the action of hot, anhydrous alcoholic hydrochloric acid to para-(benzylsulfamyD-benzamide.
  • the benzamide is then converted to the corresponding para-(benzylsulfamyl) -benzoic acid in good yield upon refluxing with 10% sodium hydroxide.
  • Example I -Pam (benzylsulfamyl) benzoic acid.19.1 g. of benzylamine were dissolved in cc. dry pyridine and 30 g. of 4-cyanobenzenesulfonylchloride added in portions with shaking. Considerable heat was evolved during the addition and the mixture was finally warmed gently on; a hot plate for 45 minutes.
  • the invention is further illustrated by, but not restricted to, the following various dosage forms of different compositions for administraion by various routes.
  • Example a Compressed tablet.10,000 grams of lactose and 100,000 grams of the adjuvant
  • para-(benzylsulfamyl)-benzoic acid are uniformly mixed and wetted with sufiicient water to permit its ready granulation.
  • 2,000 grams of dried cornstarch, 500'grams of karaya gum powder, 2,500 grams of talc, and 1,000 grams of I calcium stearate are intimately mixed and then mixed together uniformly with the 110,000 grams of the mixture of the granulated adjuvant and lactose.
  • the final mixture is then tableted (u sing inch die standard curvature punches) yield mg 200,000 tablets of 0.58 gram each, and ease containing 0.5 gram of the adjuvant.
  • Example d.-Dry filled capsule with penicillin yielding 200,000 tablets weighing 0.6 gram and each containing 0.5 gram of adjuva)nt and 25,000 units penicillin (plus 10% excess Example d.-Dry filled capsule with penicillin. Under atmosphere controlled as in Example 0, 25 kilos of the adjuvant, para-(benzylsulfamyl) benzoic acid, 850 grams of crystalline penicillin sodium (as used above), and 150 grams of dried cornstarch are intimately and uniformly mixed, and the mixture filled into capsules, yielding 50,- 000 capsules, each holding 0.52 gram of mixture containing 0.5 gram of adjuvant and 25,000 units penicillin (plus 10% excess).
  • compositions containing penicillin it is advisable, in accordance with customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the labelclaimed quantity in accordance with present practice.
  • An excess of penicillin introduces no dinicutly save its cost.
  • the penicillin used may be any of the forms available for use, such as the calcium, sodium, potassium, procaine, and. the like salts of amorphous or crystalline penicillin.
  • the quantity per dose of adjuvant and penicillin will depend upon the blood level and duration of action required for the particular condition encountered in each case.
  • An advantageous ratio of adjuvant to penicillin per tablet or capsule is about one-half gram of the selected adjuvant to 25,000 to 200,000 units of penicillin.
  • compositions of the invention can also include an antacid material, such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for the purpose of neutralizing gastric acidity.
  • an antacid material such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for the purpose of neutralizing gastric acidity.
  • the amount of antacid material is liimted only to that which is desirable to use in connection with penicillin or which can be physically incorporated in a tablet or capsule of suitable size for administration.
  • binders and lubricants used in making the tablets such materials as lactose, corn starch, gum karaya, talc, calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in proportions commonly used in preparing tablets of this nature.
  • compositions are produced in the form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose.
  • Corn oil or other suitable oil is used with advantage.
  • An adjuvant which is a member or: the group consisting of para-(benzylsulfamyl) -benzoic acid having the formula zylsulfamyl) -benzoic acid having the formula 10 I QCHPNH-SOq-OG 0 OH and its non-toxic, Water-soluble salts, the quantity of adjuvant and penicillin in the composi- 15 tion being in the ratio of 0.5 gram of adjuvant to from 25,000 to 200,000 units of penicillin.
  • Soc-H00 "Activity of Penicillin Combined With Other Anti-Streptococcal Agents, Archives Biochemistry, September 1944, pages 99 to 106.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Patented Aug. 26, 1952 N'-'BENZYL SULFAMYL BENZOIC ACID J ames sprague -Drexel Hill, Par, .assignor .to Sharp 8; Dohme Incorporated, Philadelphia; 1 Pan at-zcorporationlof Maryland.
N'o" Drawing." Original application-August '20,
1949;"Sria1No. 111,585. Divided and this ap-- plication June .15.,2'1950, Serial No. 168,542
2 Claims. (01. 167-55) This .inventiomvrelates to a a, sulfamylbenzoic acid. whichis veffective --as an adjuvant for use in conjunctionwith the aadministrationzof penicillin, tonprovidean increase-in theblood plasmapenicillinzconcentration with, a given dose-of penicillinwthereby- :making 3 possible very high penicillin l blood levels ors permitting the useiof smaller-v. quantities, of -lpenicillin rfor providing a given, blood level; ornpermittingi the. less frequent. adv ministration, of penicillin ,while maintaining a h periicillinebloodfi level adequate for bactericidal on lbacteriostatic purposes. This invention .also relatestothe preparation-f various dosage forms? in'xwhich.thistnewtcompoundlis, incorporated for,
administration bygvarioush routes. in
Penicillin today :is ea swells established thera peutic agentused-in A the treatment: of bacterial,-.
in pacticulan coccus infections; For: internal use,
it is commonly administered intravenously, orin-, tramusoularly, or-oral1y.- Where high blood levels are-required intravenousadministration or radministration by continuous venoclysis, is used The major cause ofl-thev-diffioulties :involved in attempting tol-maintain-iadequate orhigh penicilling blood levels, lfollows from the fact that subofy ther-tuhules ati least within plasma concentrations whi'chl have been explored, with the a result. that its r-rate of excretion a from, the blood stream is approximately five times that oft-materials.
which are excreted by glomerular filtration alone,
then-tubular. exoretionaaccounting "for about 80 (c tizens thesglomeruli. about 201 (1,9) 1
Various ,proposals: have'been made to overcome the ,difliculties due :-to-: the rapid-elimination oi longing-the timeaintervalbetween injections; its disadvantage -.is -than the-K penicillin :is still excreted. almost-quantitatively when the blood" passes ithrough the renal system i and, therefore, T does not permit, the:- maintenance of high blood levelslnor. does it permit the use of smaller quantities of penicillin to-obtaina given blood level.
The second proposaltwhich-has been madeto provide for the reductionin the-rate of excretion of penicillin has been totuse ,';in [com unctionwith its a material which -ilihe rpenicillin; i s: selectively .25 stantially alllpfithevzpenicillin inlthe blood=is:re-,- moved in 'asingle circulation. through: the kidneys. Penicillin appears to, be almost quantitatively; excreted fromtthe blood byithe epithelial cells excreted-by the tubulesi; By: havingrthecratio of- 2:1 large; this concept provides for a substantlalqre-w ducti-on-in the rate of excretion ofpenicilliniby-y the tubules andthuslslows down its -removalatoi a substantial extent. Various agents including; diodrast' and hippuric acid,- or derivatives or PIG-z cursors' thereof, have been: proposedaor usedfor this purpose. Such agents do not, however seem. to ;afiord*a solutionrtozthe problem Off value except 111i extreme cases, becauseasthezreductioni in the rate of penicillin excretion. is azreflectiona. of: the degree of overloading of "the tubules with; materials which: they function toremove-Hiram; the blood; it is necessary to maintain a very rhig-hl-sconcentration 01113118 agent -in the blood stream to ,afiord' a favorable partitioni ratio between: the! agent and the penicillin and, in'sadditionybecauset the agents. are themselves rapidly removedimm. the blood stream, it is-necessary to administer: them in large quantitiesto maintain the inecesi-x sar-y ghigh plasma concentrationsiv This :presentsi an" additional problem since in .order' -to main-- tain the high concentration ofthese agents-they must be administered intravenouslyas r-theyl -arei not well absorbed from lthe gastric-intestinal tractor e Thelpresent invention; is-:based upon .thewdisecovery that removal .of. penicillin from.-the .blood;' streamby the kidney tubules can be effectively blocked by the newadjuvant of this invention, carboxyphenylsulfonamidoephenyl-methane,inane;
other name for .it being-para:(benzylsulfamyLl-} benzoic acid, having the generalformulm and its salts; Theinvention also contempl'fites the possibility of- -adding 1 a 'nitro "or" 'an r amino group to-the para-position of -the ben zyl radical of this compound. The benzylsulfamyl benzoio acid of this'inVen-" tion is relatively non-toxic, it is soluble inibloodl plasma and operates, when carried :by the :blood: stream into contact withthe tubules;:ftowpre-e vent their normalraction in removinglpenic'illin from the blood stream. Thevadjuvant itself; not excreted to any substantial extent iby' f th'e'." tubules, andthe available evidence indicatestliat. oncoming into contactswith the"epitheliala:cellse of the tubules, "it operates to:block"*theirsractioni by interference-with the normal func'tioningajof the epithelial cells and does not inhibit the I ex-i cretion of" the penicillin by" competing Jvvithz.v ti within the tubular functional-i capacitw i the iadjuvantis eflective inz'eliminating'r orclv radically?" reducing; tubulan Iexcretiont: ofipeni'ctl'z 3 lin in plasma concentrations around mg. per 100 00., which is about the threshold value for agents such as p-aminohippuric acid or diodrast which inhibit tubular penicillin excretion by competition for the available tubular excretion capacity. The highly effective adjuvant of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc. to almost zero, so that the actual elimination of penicillin from the blood stream becomes substantially that resulting from glomerular filtration, that is, about onefifth the normal rate (ignoring plasma binding). The adjuvant is eliminated by the glomeruli.
The adjuvant can'be administered orally or, when dissolved in an aqueous solution, it can be administered intravenously or intramuscularly. This last method has not yet proven desirable for single injection of the material, because in general, administration of more than 2 cc.-per single injection intramuscularly is inadvisable, and the quantities of adjuvant desirable to use, i.'e., 4 to 16 grams per day, are such as to make injection by this route impractical. However,'the benzylsulfamylbenzoic acid or its salts are well adapted for continuous intramuscular or subcutaneous clysis.
In general, oral administration of the adjuvant at the rate of 4 to 1.6 grams per day is adequate to suppress the rate of penicillin excretion to an extent such that the blood level with a givendose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as much as four times the level obtain d without the use of the adjuvant, and will permit either the use of a very much smaller quantity of penicillin to provide a given blood level, for'example, permitting the penicillin doses to beabout one-fourth of those commonly used, or permitting the provision of penicillin blood levels several times as great as those obtainable with the administration of penicillin by the routes ordinarily used today.
The adjuvant of the invention or a suitable salt of it can be administered in admixture with the levels of about 4 to 16 grams per day orally and somewhat less than this intravenously.
The adjuvant can be prepared in any convenient dosage form, either alone or admixed with penicillin, such as in a compressed tablet, a dry filled capsule or a soft elastic capsule. It is to be. understood, of course, that other ingredients, such as binders, diluents, excipients, antacid substances, or other inert or therapeutically active compounds may be incorporated into any selected dosage form along with the adjuvant or adjuvantplus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin. Similarly, the adjuvant' and, if desired, the penicillin can be dispersed in an oleaginous base either alone or along with other suitable substances and filled into soft elastic capsules or an aqueous solution may be prepared and filled into ampuls. Other suitable dosage forms will be readily apparent to those skilledzinthe art, and it is notthe pur-.
pose of this discussion to limit the mode of packaging or administration to those specifically described herein.
Para-(benzylsulfamyl)-benzoic acid is preferably prepared by reacting para-cyanobenzenesulfonyl chloride with benzylamine in the-presence of an inert solvent, such as pyridine. The resulting N-benzyl-para-cyanobenzenesulfonamide is converted by the action of hot, anhydrous alcoholic hydrochloric acid to para-(benzylsulfamyD-benzamide. The benzamide is then converted to the corresponding para-(benzylsulfamyl) -benzoic acid in good yield upon refluxing with 10% sodium hydroxide.
The preparation of this compound is illustrated by, but not restricted to, the following example:
Example I .-Pam (benzylsulfamyl) benzoic acid.19.1 g. of benzylamine were dissolved in cc. dry pyridine and 30 g. of 4-cyanobenzenesulfonylchloride added in portions with shaking. Considerable heat was evolved during the addition and the mixture was finally warmed gently on; a hot plate for 45 minutes.
filtered, washed and dried. 30 g. of this were suspended in 350 cc. of anhydrous alcohol partially saturated with dry HCl. The mixture was gently refluxed for one hour while a steady stream of' dry HCl was bubbled into the mixture. Solution was complete. The alcohol was removed under reduced pressure and the residue dissolved in 200 cc. 10% sodium hydroxide solution. The solution was treated with charcoal and the product precipitated by acidifying with hydrochloric acid, giving para-(benzylsulfamyl)-benzamide.' .29 g. of this were dissolved in 250 00.40% NaOH and the solution refluxed gently for 1% hours during which time ammonia gas was evolved. The hot solution was treated with charcoal, cooled and acidified with hydrochloric acid, giving para- (benzylsulfamyl) -benzoic acid which was filtered washed and dried. Purification was efiected by precipitation from sodium bicarbonate solution with hydrochloric acid, and 'recrystallizations from 75% and anhydrous alcohol solutions; The thuspurified product melted at 238-239 vC.
The invention is further illustrated by, but not restricted to, the following various dosage forms of different compositions for administraion by various routes.
Example a.Compressed tablet.10,000 grams of lactose and 100,000 grams of the adjuvant,
para-(benzylsulfamyl)-benzoic acid, are uniformly mixed and wetted with sufiicient water to permit its ready granulation. 2,000 grams of dried cornstarch, 500'grams of karaya gum powder, 2,500 grams of talc, and 1,000 grams of I calcium stearate are intimately mixed and then mixed together uniformly with the 110,000 grams of the mixture of the granulated adjuvant and lactose. The final mixture is then tableted (u sing inch die standard curvature punches) yield mg 200,000 tablets of 0.58 gram each, and ease containing 0.5 gram of the adjuvant.
Measured amounts of the composition of ample a, or merely the adjuvant alone, can be filled into hard gelatin, telescopic Capsme e m holding 0.5 gram of adjuvant.
After standing overnight, the mixture was poured into 500 cc. dilute hydrochloric acid and the oily precipitate which formed was worked until it solidified. The N-benzyl-4-cyanobenzenesulfonamide was then aeosgum:
gram of the pendedfingvery nearly lit'er'siot 'distilledlwater. nd l3? 3 r, 2 o Sod hrd xl d a e d ed to"he1p in thedissolution of theadjuvant.' .1390
r W monopotassium phosphate are added andlil tilledflwater added to" makethegvolumeof. some ,up macliters mime assume), 5 The en. fil di ntdampulsforfi cc."liquid hich" are theni flame l efd "and ample 33l 5-"grams oi'sodiumipenicillim(1630 units per mg?) 2625grams' dried "cornstarch? 500 grams karaya gum powder, 2500 grams talc and 1,000 grams calcium stearate are mixed together in an atmosphere controlled at relative humidity at 21 C., and then under the same conditions mixed with the granulation of the adjuvant and the lactose and tableted with the same die as in Example (1. yielding 200,000 tablets weighing 0.6 gram and each containing 0.5 gram of adjuva)nt and 25,000 units penicillin (plus 10% excess Example d.-Dry filled capsule with penicillin. Under atmosphere controlled as in Example 0, 25 kilos of the adjuvant, para-(benzylsulfamyl) benzoic acid, 850 grams of crystalline penicillin sodium (as used above), and 150 grams of dried cornstarch are intimately and uniformly mixed, and the mixture filled into capsules, yielding 50,- 000 capsules, each holding 0.52 gram of mixture containing 0.5 gram of adjuvant and 25,000 units penicillin (plus 10% excess).
Example e.Soft elastic capsule with penicillin-Under atmosphere controlled as in Example 0, 1.69 kilos of the same crystalline penicillin sodium are homogeneously dispersed in 48.31 kilos of corn oil and 50 kilos of the 'adjuvant, para- (benzylsulfarnyl) -benzoic acid, similarly dispersed in the oil, and the resulting composition encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 100,000 capsules, each holding one gram net of the composition and containing 0.5 gram of adjuvant with 25,000 units penicillin (plus 10% excess).
Example f.--FZame-sealed ampul filled with 1761L'L'CZ Zlfl7L.l2.5 kilos of the adjuvant, para- (benzylsulfamyD-benzoic acid, are stirred into very nearly liters of sterile, pyrogen-free, distilled water and 1716.6 grams of sodium hydroxide are added to aid in the dissolution of the ad- .juvant. Then 390 grams of monopotassium phosphate are added and, under atmosphere conditions as in Example 0, 169 grams of the same crystalline penicillin sodium are added and stirred into solution and suilicient water added to bring the total volume of solution to 30 liters.
12 cc. of this solution are then filled into each pounds?p essure ror.-20?minutes the adjuvant,'paraflbenzylsulfamyll benzoic ,acid, and granulated "as in.1Ex-
removedri iro'muthe apparatus andutha extension of the glass neck beyond the topsofiutherstoppersf is fiame-sealed-.- The contents of the flame-sealed ampul-vial is then restoredwith sterile, pyrogenfree, distilled water shortly before the-product is to be used. When'thusrestored'to 2 ll cc. liquid: volume, the-resulting solution is bufiered at pH 7.4 'and contains 100,000 units penicillin (plus. the:
10% excess.) and 25%of the adjuvant;
Example g.-Ampul oil suspension with :peni
sion of the white wax; While this mixtureis still;
suflicientlydiquid; and under atmosphere condi' tions'asjinExamplec, 10 kilos of the ;adjuvant," para-lbenzylsulfamyl)#benzoic acid; and" 1873' grams of-calcium penicillin (734 units/mg.) are added and the mixture stirred to homogeneity. Each cc. of the resulting oil suspension contains 25,000 units of penicillin (plus 10% excess) and 0.2 gram of adiuvant. It is put up in flame-sealed ampuls containing suitable volume of the suspension which is as stable as the ordinary penicillin in peanut oil preparation.
In those compositions containing penicillin, it is advisable, in accordance with customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the labelclaimed quantity in accordance with present practice. An excess of penicillin introduces no dinicutly save its cost. The penicillin used may be any of the forms available for use, such as the calcium, sodium, potassium, procaine, and. the like salts of amorphous or crystalline penicillin.
The quantity per dose of adjuvant and penicillin will depend upon the blood level and duration of action required for the particular condition encountered in each case. An advantageous ratio of adjuvant to penicillin per tablet or capsule is about one-half gram of the selected adjuvant to 25,000 to 200,000 units of penicillin.
The compositions of the invention can also include an antacid material, such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for the purpose of neutralizing gastric acidity. The amount of antacid material is liimted only to that which is desirable to use in connection with penicillin or which can be physically incorporated in a tablet or capsule of suitable size for administration.
As to binders and lubricants used in making the tablets, such materials as lactose, corn starch, gum karaya, talc, calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in proportions commonly used in preparing tablets of this nature.
If the compositions are produced in the form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose. Corn oil or other suitable oil is used with advantage.
This application is a division of my joint application with Charles S. Miller, Serial No. 111,585, filed August 20, 1949, now abandoned; which application in turn was in part a continuation of my then copending joint application with Karl H. Beyer, Jr., Serial No. 695,040, filed September 5, 1946, now abandoned. l
Having now particularly described the invention, what is claimed is:
1. An adjuvant Which is a member or: the group consisting of para-(benzylsulfamyl) -benzoic acid having the formula zylsulfamyl) -benzoic acid having the formula 10 I QCHPNH-SOq-OG 0 OH and its non-toxic, Water-soluble salts, the quantity of adjuvant and penicillin in the composi- 15 tion being in the ratio of 0.5 gram of adjuvant to from 25,000 to 200,000 units of penicillin.
JAMES M.-SPRAGUE.
REFERENCES CITED The following references are of record in the file of this patent:
Reid, "Prolongation of Penicillin Activity With Penicillinase-Inhibiting Compounds," Proc. Soc. Exptl. B101. and Med., November 1946, pages 438 to 443.
Soc-H00, "Activity of Penicillin Combined With Other Anti-Streptococcal Agents, Archives Biochemistry, September 1944, pages 99 to 106.
Meads, Caronamide and Penicillin," J. Am. Med. Assoc., Nov. 20, 1948, pages 8'74 to 877.
Pratt et al., Antibiotics, Lippincott Co., 1949, pages 112 to 116. (Book in Division 43.)
Steinkopf et al., Chem. Abstracts, volume 21, page 3604 (1927).
Gilman et al., J. Am. Chem. 800., volume 69, column 1537-8 (1947). (Copies in Sci. Library.)

Claims (1)

  1. 2. A COMPOSITION SUITABLE FOR THERAPEUTIC USE, COMPRISING PENICILLIN AND AN ADJUVANT WHICH IS A MEMBER OF THE GROUP CONSISTING OF PARA-(BENXYLSULFAMYL)-BENZOIC ACID HAVING THE FORMULA
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2805250A (en) * 1954-07-15 1957-09-03 Cassella Farbwerke Mainkur Ag Nu-nu-dibenzylsulfamyl benzoic acid

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* Cited by examiner, † Cited by third party
Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2805250A (en) * 1954-07-15 1957-09-03 Cassella Farbwerke Mainkur Ag Nu-nu-dibenzylsulfamyl benzoic acid

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