US2608509A - Composition containing penicillin and an adjuvant of the general formula r1ch2so2nhr2cooh - Google Patents
Composition containing penicillin and an adjuvant of the general formula r1ch2so2nhr2cooh Download PDFInfo
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- US2608509A US2608509A US168541A US16854150A US2608509A US 2608509 A US2608509 A US 2608509A US 168541 A US168541 A US 168541A US 16854150 A US16854150 A US 16854150A US 2608509 A US2608509 A US 2608509A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/22—Salts with organic bases; Complexes with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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Description
patented Aug. 26, 1952 f coMPosrrmN. QONTAININGLPENIGILLIN AND ANADJUVANT or THE GENERAL. FORMULA nionzsoznnnzcoon James M. Sprague, Drexel HilLandKarlHq Beyer;
Jr.-, Bala Cynwyd, Pa.-, assignors to Sharp 8: Dohme, Incorporated, Philadclphia,.l?a., a corporationofMaryland This invention relates tmnew compositions. which are. valuable for use in theladministration of..'penicillin .to. providean increase in the blood plasma. penicillin concentration with. a given penicillin "dosage level, therebyrpermitting the use-ofjsmaller quantitiesuof penicillin for pro viding a. givenrbloodiilevel; or the. provision of very high penicillin blood levels or permitting the :less frequent administration of penicillin While maintaining. a. penicillin blood level adequate for bactericidal or bacteriostatic purposes.
Penicillin today isa-well established therapeutic agent used in the treatment of various bacterial in .particular coccus infections. For internal; use it'isy. commonly administered intravenously, intramuscularly, orally, t sublingually, subcutaneously, or rectally. Where: high blood levelsiarerrequired, as. in thetreatment of acute infections or. sub-acute bacterial endoearditis, orwhere. it is desired tOBS'ba'bliShI' a high blood levelupromptly, intravenous administration, and at times. administration by;continuous venoclysis is used: Frequently administration is by intramuscularrinieotion, in which case,.to maintain bloodl'levels adequate. for therapeutic. purposes,
injections. are; ordinarily given at 31 110. 4 ,hour intervalsxwhere the menstruum is aqueous, and at less .-frequent. intervals .where the menstruum is oleaginous; Oraladministration is also used to a .considerable extent, but withv oral: administrationadosages .ofrabout four times those required Winn-intramuscularinjection are; required to establish comparable. blood levels and administration isrequired about as frequently, the. cost thus being; substantially greater.
1 The major cause of: the difficulties involved in. attemptingto maintain adequate or high penicillinblood levels follows from the rapid excretion of=penicillinl by thekidneys. Penicillin is removed, in the kidney, from the blood stream, notonlyaby glomerular filtration butalso by selective excretion by the renal tubules, and its removal from th'eblood stream on passage of the blood through the renal system is almost quantitative. tionis necessary .to keep any measurable amount of penicillinin the. blood stream, and where a high. blood level isrequired it is necessary to use enormous dosages, and to administer penicillin by continuous venoclysis. Thus to maintain blood levels of the order of 10 to 20 units'of penis cillin per cc. of plasma may require the administration of over 10,000,000 units per day of penicillin, and even with administration at this rate, it is not possible to obtain blood levelsz as high For this reason; frequent administra- 2 Claims. (01. 16'if.55)
2 as. may lie-desirable in. many instancestwith9ll't. using? accessory agents, to. be. r f r dtm T e. maintenance of highxbloodjlevels of, penicillinis, in many; cases, important I because, while; r tively low concentrations, forexample,.0-.06g un pence, are extremelyhefiective inmany'cases, other; cases. where, for amples the: o anis s: are resistant to penici1lin, -,.muc,h higher. concen trations are .requiredtocombat thel organis v and: the provisionxoi :tha.hish concentration p lli inthe blood stream permits that/re, ment; oizinfeetions. which. are resist nt: G. 1 cillin :inithe. lowgconcentrations, which. are tain'ecll when itis administeredyorallyqor b intra. muscular injection, as, is,thei'casa ithqt... ganism which: causes. sub-acute "bac er a nd. carditisstreptococcus vim'dans.. 5* .1 The; problem .presentedby the rapid elimina tiorroi penicillin has been recognized, andvar: ious proposals. havebeen .made ,to overcome it; One such proposal, involves the administration. of. penicillin in suspensionpin. an oleaginous m terial, forexample, soyaabean oruotherfattyloil, or a mixtureof. such an: oil:withbeeswax they mixture being administered byaintramuscularina jection. Oleaginous material is absorbedgmuchj less. rapidly than. an aqueous; material similarly injected, and-therefore :the. penicillin is. dissemi 4 nated. in theublo'od: stream. more. slowly and. somel penicillin remains inthe. blood. strean'rzioverray longer period ofsztime; than when. anr aquee lszi menstmum. i-SHSCCL. While. thisproposalis .eifecg; tive in prolonging. the" time interval between; jections, .it. is subject; to; the: disadvantage;- that the penicillin is still: excreted: almostuquantitas tively from the. blood which passes throughotheu renal. system; and: therefore doesnot. permit the maintenance of. high blOOdtlBVGIS .nor'dcesiit ipere mit the use of smaller. quantities:offipenicillin: i0 the establishment era giyen blqudlevel, the effec being merely :to. permitthe .injection'goi arv large: quantity of penicillin at one timeand pro vide for: s s o er. a d more rolonsed absq tion-into theibloodstream. "L
Penicillin. .is removed, by; the kidneys: both by. lomenilar fi t ation nd x r on b th .tu=.-. es; a d ppare ly s no r orbed by the W bules. With anormally functioninglqidney,about of a cryst l i such s penici lin 0 of: the. other erystan m materials in the .p 1 water, is removed by the glomerulijfrom the-bloc which flows-through the .renal; system: :Thifii removal. islconsidered to be of thenature-oia filtration, with. the. plasma. water and. itsso being removedpy the glomeruliandn essedm;
the tubules. Most of the water removed by this glomerular filtration and the crystalloids dissolved therein are returned to the blood stream by reabsorption during passage of the filtrate through the lumen of the tubule to maintain the physiological economy of the system, but certain materials, of which penicillin is one, are not so reabsorbed, and therefore whatever penicillin is removed by glomerular filtration is excreted. The epithelial cells of the tubules als serve to remove certain materials from the blood stream as well as to reabsorb selectively substances from the glomerular filtrate and return them to the blood stream. Materials which are so excreted by the tubules are presumably not reabsorbed. The extent to which tubular excretion takes p ace differs with various materials. Penicillin,
appears to be almost quantitatively excreted from th blood by the epithelial cells of the tubules, at least within plasma concentrations which have been explored. The result of this is that the rate of excretion of penicillin from the blood stream is approximately five times the rate of excretion of materials which are excreted by glomerular filtration alone, the tubular excretion account-V 111g for about 80- (81) and the glomeruli about 20 (19) and substantially all of the penicillin in the blood which passes through the renal system is removed in a single circulation through the kidneys. It is for this reason that it is neccretion by the tubules is thought to be a metabolic process, with the epithelial cells of the tubes functioning physiologically to remove the penicillin from the plasma and transport it to the filtrate in the tubule.
' The second proposal which has been made to provide for the reduction in the rate of excretion oi'penicillin has been to use, in conjunction with the penicillin, a material which, like penicillin, is selectively excreted by the tubules, with the thought that by imposing a suificient load on the tubule excretion mechanism, it could not func tion to remove from the blood stream all of the penicillin and all of the added agent, so that the removal of penicillin would be reduced. By having the ratio of the added agent to the penicillin sufficiently large, this concept provides fora subplasma concentrations.
function to remove from the blood, it is necessary tomaintain a very high concentration of the agent in the blood stream to aiforcl a favorable partition rati between the agent and the penicillin and, in addition, because the agents are themselves rapidly removed from the blood stream, it is necessary to administer them in large quantities to maintain the necessary high Thus, while p-aminohippuric acid is efiective to reduce the rate of penicillin excretion, its threshold concentration, where an inhibiting effect can be noted, is something over 10mg. per 100 cc. and substantial inhibition of tubular excretion of penicillin is only obtained at plasma concentrations of to 60 mg. per 100 cc. To maintain such levels, in view of the rapid excretion of the material, it is necessary to use 130 to 250 grams of material per day by intravenous injection. With such materials as the diethanolamine salt of 3,5-diiodo-4- pyridone-N-acetic acid and p-aminohippuric acid the quantity which must be introduced into the blood stream is so large, both because of the high plasma concentrations required and the high rate of excretion involved, that intravenous adminl-.
stration is required, the materials not being well absorbed from the gastro-intestinal tract.
The new compositions of the invention are composite products including penicillin and an adjuvant of the general formula I RiCHzSOzNHRzCOOH aminophenyl, nitrophenyl, halophenyl, and benstantial reduction in the rate of excretion of penicillin by the tubules and thus slows down the removal of penicillin to a substantial extent. Various agents which ar removed by tubular excretion, including the diethanolamine salt of 3,5- diiodo-d-pyridone-N-acetic acid and hippuric acid, or derivatives or precursors thereof, have been proposed or used for this purpose and their use has resulted in a reduction in the rate of penicillin excreted and provided for higher plasma concentrations or longer duration of the action from a given dose of penicillin. Such agents do not, however, seem to afiord a solution to the problem of value except in extreme cases, because as the reduction in the rate of penicillin excretion is a reflection of the degree of overloading of the tubules with materials which they zyl, and R2 is selected from the class consisting of benzene and thiazole. The adjuvant constituent of the composition operates to block the removal of penicillinfrom the bloodstream by the tubules of the kidneys without itself being excreted to any substantial extent by the tubules. The action of the adjuvant appears to involve an interference with the normal functioning of the transport mechanism of the epithelial cells of v the tubules such that they do not function to remove the penicillin from the blood stream. The new compositions are effective in eliminating or radically reducing tubular excretion of penicillin at plasma concentrations of around 10 mg. of adjuvant per cc. of plasma, which is about the threshold value for agents such as p-amino hippuric acid which inhibit tubular penicillin excretion by competition for the available tubular excretion capacity. By the use of the new compositions, the tubular excretion of penicillin is reduced to almost zero, so that the actual elimination of penicillin from the blood stream becomes that substantially which results from glomerular filtration, that is, about onefifth the normal rate (ignoring plasma binding).
In particular, the invention comprises a composite product including penicillin and one of the adjuvants listed below:
fonanilide.
"7. 2 chlorc-V-carboxwphenylmethanesulion emcee. r 8. 'l nitro--4- --cerbethcxyhenylmethiamesulmm anilide. y '9. 1 e-nitro- 4' -carboxy phenylmethanesulfonanilide. 1034 amino#4- earbethcxyphenylmeth'anesul fon'anilide.
11. =4 amino-4-carboity phenylmethanesulfonanili'de. V 3 -nitrc e -carbethoxy-phenylmethanesulfon aniiide. I
3 'ainino"-carbethoxy phenylinethanesul 4' carbethoxytp phenylethanesulfonanillde.
w4' carboxyfiaphenylethanesulfonanillde.
4 amino? cerboxy phenylmethanesulfon 'anil'ide hydrochloride. v
p-carbethoxyl*pentanesulfonanilide.
' pecarnoxy l-pentanesulfonanilide.
p-Carboxyq heptanesuifonanilide. I
3'-carbcxy phenylmethanesulronanilide.
2' carbomethoxy-phenylmethanesulfonani lide.
2 -"phenylmethanesulfonamido 4 carbethoxy thiazole. m
f2 -"phenylmethanesuhonamido' 4 carb'oxythiazole.
-2 ohenylmethanesulronamido-4-methyl 5- carbethoxymethyltlfiazole.
'2 '-phenylmethanesulfonamido-4-methyl5- carboxyinetnylthiazole.
p4" carbomethoxyaphenylmethanesulronarulide.
27.. p-carboxyj-l '-butanesulfonauilide.
28. p ce'rbcry-'2 -methyl i -propanesu1fonanil ide.
29. 'p-Cerbcxy-tb? qm'ethyltl abutanesulfonahilide.
30.p-Calboxyq liexanesulfonanilide. r
31. p Carboxy 2-ethoigy+1 ethanesi1lfohanilide.
TheFpreparatiQn of these effective adfiuvants is described in detail in copending. patent applica tions Serial No. 6953040, .filedgSeptember 5, 1946,
now abandoned, landxSerial No. 7 611153, :filed A J uly i 15, 1947, now U. S. Patent No. 2,531,367.
In general, the, quantity. ofthe .adjuizant which is inoluded with the zpenicillin in the ,composite product is r from about :8 2120 about v24 :grams per day, which is quite comparable to dosages commonly used :with thesulfohamides and is ade quate, to suppress the lrateof jpenicilli-n excretion tolanextentsuch that-the Zblqod levels with a given dosage :of penicillin administered orally or intramuscularly :aqueous. .solution'=will be increased to as :much as rfour times or' more .the
level obtained without the use of anyedjuvant andvwill permit wither the use of a very much smaller quantity of penicillintto :provide a given account shouldbe taken of "the property of the adjuvant-of markedly increasing the amount of penicillin'theblood. stream-when a given quan- .titytof itisladministered.
In any event the quantity-otthe selected ad- =iuvant included should be such 1. as '100 :provlde aa concentration :in the blood stream adequate to block substantially the excretory mechanism of itheitublfles. Most:ohtheadiuvant:exert a. maxli- 6. mum eflect-with blood plasma fddfifltfitl'ohi aboutt tc 15mg. per ce ebral na Me at dosage levels of about 8 to migraine per 'rleiy'orally and somewhat less than this mtmvenously.
When the composite pr' not including the ad: ju'vant and 'pe'nici-lli'r'l intended-for or lean-1 1m ist'ration, tablets containing one or more adjuvants and the penicillin "may be prepared and both materials administered sunuicaneous y; where the product is to be mimmistereu venously, one of the adjuvants and penicillm y lie-included in a. single ampui, ender thet im Of lls'e'diSS'ol'Vd the filnstfiutifil; big. wet" "bl salinepand adminlstered.
The adjuvants of particular importance rmm the "standpoint of combination of effectiveness in "blocking the tubular excretion of penicillin, low toxicity; and adequate abscr ti'on from the'gasi trointestinal tract, are 4'1-"carboXy-nhenylmeth anesul'fonam'lide (also known by the chemical name -N=- benzylsulfonyl ara:- mi nobenzene acid) ,and: its alkali metalsaltaend -car boiry i pentanesulronanillde and its alkal metal salts.
The invention will be further i-llustrated bu't is'not rei'S'tricted to; the 'followin'g com -posite mow ucts including penicillin and i an adjuvant of the type embraced by the above general rormula 'for administration by yaricus routes;
Example ncompre'ssed tower with queme'il line-#100,000 i'g' rams' OI N ibenzylsulfonyl) para aminob'e'nz'bic acid and 16,000-5'13'1'118 f m'tOS are nil-Red and wetted with sufiicient water t'o permit its ready granulation in the ll'sliell @749 grams of crystalline penicillin sodium U330 units pe'r me. 2651 grams or dried cornstarch, 600 grams kal'a'ya gu'rn pcwderfiaaocemmstald and 1200 'grams calciu'm stearate are mixedtw gethe r under atmosphericconditionscontrolledat 10% relative humidity at 21 0. and, underrhe same conditions, mixed with the ,igramilation and tableted with one-half inch die standard curve ture punches, yielding 200,000 tablets of "0165 gram each andeach containing 50,000 units' pen'l cillin '(.plus"10-% excess). I
Example II c'ompre'ssed tablet with penicillin and magnesium trisilicate.100,000 granl's'ofil f- (benzyls'ulfonyl) -para-aminobenzoic acid, '3000 grams magnesium trisilicate and 7000 grams lac tose are mixed and granulated as before "described. Under atmosphere controlled as in l the preceding example 3375 Era-ins ofthe same are talline penicillin-sodium, 2625 grams of dried cornstarch, 5'00 :erams karayagum powuen csoc grams talc, and 1000 grams calcium stearate-a're mixed andzthen mixedwith thegranulation; and this mixture tableted as before ylelding '20m000 tablets of "0.6 gram. each and each containi'rlQ OLS gram of the compound and 25 -000 units iceni cillln (plus 10% excess).
Example III .Dry filled capsule with pencil Iin.-Under atmosphere controlled as in the preceding examples, 25gikllos of Ne'(ben'zylsulfonyl)=-= para-aminobenzoic acid, 850 grams of crystalline penicillin sodium (as used above) andil50xgrams of dried corn starch are intimately anduniforin 1y mixed, and the mixture filled 'into capsules,
same, type and size of capsule, yielding 50,000 capsules, each holding 0.54 gram of mixture containing 0.5 gram of compound and 50,000 units penicillin (plus excess).
' Example V.-Dry filled capsule with magnesium trisilicate anclpenicillin. Under atmosphere controlled as in Example I, kilos of N-(benzylsulfonyl) -para-aminobenzoic acid, 850 rams of the same crystalline penicillin sodium, and 150 grams of magnesium trisilicate are intimately and uniformly mixed and encapsulated in the same size and type of capsule, yielding 50,000 capsules, each holding 0.52 gramof mixture and containing 0.5 gram of the compound and25,000 units penicillin (plus10% excess). l
Example VI.--Dry filled capsule with magnesium 'trisilicate and peniciZlin.--Under atmosphere controlled asin Example I, 25 kilos of N-- (benzylsulfonyl)-para-aminobenzoic acid, 1.69 kilos of the same crystalline penicillin sodium, and 310 rams of magnesium trisilicate are intimately and uniformly mixed and encapsulated in the same size and type of capsule, yielding 50,000 capsules, each holding 0.54 gram of mixture and containing 0.5 gram of the compound and 50,000 .units penicillin (plus 10% excess).
While each of the individual examples has been illustrated with the respectively disclosed adjuvant, the latter ineach of them may be replaced by any other suitable compound falling within the scope of the general formula, for example, any of those compounds specifically named above.
Example VII.-Soft elastic capsule with penidllim-Underatmosphere controlled as in Example-I, 1.69 kilos of the same crystalline penicillin sodium are homogeneously dispersed in 48.31 kilos of corn oil and kilos ofN-(benzylsulfonyl)-para-aminobenzoic 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 gramof the compound with 25,000 units penicillin (plus 10% excess). I i 1 Example VIII.--Soluble elastic capsule with penicillin and magnesium trisilicate-Under atmosphere as controlled in Example I 1687 grams of the same crystalline penicillin sodium, 73 3 grams of magnesium trisilicate, and 50 kilos of N -(benzylsulfonyl) -para-aminobenzoic acid 'are intimately and uniformly mixed and the mixture homogeneously dispersed in 41 kilos of corn oil, and the dispersion encapsulated in the same type of soluble elastic capsules as in the preceding examples,-yielding 100,000 capsules each holding one, gram net of the dispersion and containing 0.5 gram of the compoundxwith 25,000 units penicillin ,(plus 10% excess).-
While in each'of the preceding examples of soluble elastic capsules a respective individual adjuv'ant was included, any other of the adjuvants named above may be similarly included by substituting the same quantity of itin any of .the' particular examples. 7
Example IX.-Flame-sealed ampul fillerlwith penicillin-42.5 kilos of N-(benzylsul fonyD-i para-aminobenzoic acid are stirred into very nearly 30'liters of sterile, pyrogen-free distilled water and 1795 grams of sodium hydroxide are added toaid in its dissolution. Then 390 grams of monopotassium phosphate are added and, under atmosphere conditions as in Example I, 169 grams of the same crystalline penicillin sodium 8f. are added and stirred into solution and sufficient water added to brin the totalvolume of solution to 30 liters. 12 cc. of this-solution are then filled into each of the required. number of 20 cc. total volume ampul-vials. The contents of the vials are then quickly frozen by rotating them in a bath of methyl Cellosolve chilled with Dry-Ice to -70 C., and desiccated under high vacuum for 48 hours by the method, and apparatus as in United, States .Patent No. 2,353,985, and rubber stoppers inserted in the neck of each of the containers while thevacuum is still being maintained. ;The vacuum is then broken and the containers removed from the apparatus and the extension of the glass neck beyond the top of the stoppers is flame-sealed. The contents of the flame-sealed ampul-vial is then restored with sterile, pyrogen free, distilled water shortly before the product is to'be used. When thus restored to20 cc. liquid volume, the resulting solution is buffered at pH 7.4 and contains 100,000 units penicillin (plus the 10% excessland 25% of the compound. Of oourse,-. the product may be prepared in vials similar to those used for penicillin, i. e., rubber stoppered vials, or other containers, if desired.
. Example X.Ampul oil suspension with penicz'llin.3 kilos of USP white wax are mixedinto 35.127 kilos of purified peanut oil heated sufi'iciently to melt and permit homogeneous dispersion of the White wax. While this mixture is still suiiiciently liquid, and under atmosphere conditions as in Example I, 10 kilos of. N-(benzylsulfonyl) -para-aminobenzoic 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 the compound. It is put up in flamesealed ampuls containing suitable Volume of the suspension which is as stable as'the ordinary penicillin in peanut oil preparation. Other types of containers, such as the ,ordinaryampul' vials, or vials such as are used with penicillin, may be used.
While each of the preceding examples of particular ampul preparations contains its respective specific adjuvant, each of them may be prepared with any of the other adjuvants falling within the'scope of the general formula, above.
In the various. Examples I'through X where no particular specifications for individual ingredients are given, it is understood that there is used such quality of the various ingredients as is suitable forincorporation in pharmaceutical preparations.
This application is a division of our. application-Serial Number 695,040, filed September 5, 1946, now abandoned, and Serial Number 761,l53, filed July 15, 1947, now. Patent Number 2,531,367. V 7
What is claimed is: Y
1. A composite product, prepared for a therapeutic use, said product including penicillin and an adjuvant havin the general formula:
momsoznnnzcoon 'of said composition upon administration functioning substantially to block the excretion or penicillin by interfering with the normal functioning of the transport mechanism of the kidney tubules.
2. A composite product prepared for a therapeutic use, said product including penicillin and the adjuvant N-(benzylsulfonyl)-p-aminobenzoic acid, the adjuvant constituent of said composition upon administration functioning substantially to block the excretion of penicillin by interfering with the normal functioning of the transport mechanism of the kidney tubules.
JAMES M. VSPRAGUE. KARL H. BEYER, JR.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 2,531,367 Sprague Nov. 21, 1950 OTHER REFERENCES Soc-H00; Activity of Penicillin Combined with
Claims (1)
1. A COMPOSITE PRODUCT PREPARED FOR A THERAPEUTIC USE, SAID PRODUCT INCLUDING PENICILLIN AND AN ADJUVANT HAVING THE GENERAL FORMULA:
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US69504046A | 1946-09-05 | 1946-09-05 | |
US168541A US2608509A (en) | 1946-09-05 | 1950-06-15 | Composition containing penicillin and an adjuvant of the general formula r1ch2so2nhr2cooh |
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US2531367A (en) * | 1947-07-15 | 1950-11-21 | Sharp & Dohme Inc | N-(substituted sulfonyl)-aminobenzoic acids |
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US2531367A (en) * | 1947-07-15 | 1950-11-21 | Sharp & Dohme Inc | N-(substituted sulfonyl)-aminobenzoic acids |
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