CA1165690A - METHOD OF INCREASING ORAL ABSORPTION OF .beta.-LACTAM ANTIBIOTICS - Google Patents
METHOD OF INCREASING ORAL ABSORPTION OF .beta.-LACTAM ANTIBIOTICSInfo
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- CA1165690A CA1165690A CA000372411A CA372411A CA1165690A CA 1165690 A CA1165690 A CA 1165690A CA 000372411 A CA000372411 A CA 000372411A CA 372411 A CA372411 A CA 372411A CA 1165690 A CA1165690 A CA 1165690A
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- beta
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Abstract
ABSTRACT OF THE DISCLOSURE:
A method and drug form are provided for increas-ing the oral absorption of .beta.-lactam antibiotics such as the penicillins, cephalosporins and related chemical species by the oral aaministration of said .beta.-lactam anti-biotics in a suitable pharmaceutically accepted excipient to which has been added a hydroxy aryl or hydroxy aralkyl acid or salt, amide or ester thereof. The hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester thereof is present in the drug form in quantities sufficient to be effective in enhancing the rate of oral absorption of the .beta.-lactam antibiotic.
A method and drug form are provided for increas-ing the oral absorption of .beta.-lactam antibiotics such as the penicillins, cephalosporins and related chemical species by the oral aaministration of said .beta.-lactam anti-biotics in a suitable pharmaceutically accepted excipient to which has been added a hydroxy aryl or hydroxy aralkyl acid or salt, amide or ester thereof. The hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester thereof is present in the drug form in quantities sufficient to be effective in enhancing the rate of oral absorption of the .beta.-lactam antibiotic.
Description
TITLE OF THE INVENTION
METHOD OF INCREASING ORAL ABSORPTION OF ~-LACTAM
ANTI~IOTICS
BACKGROUND OF THE INVENTION
Field of the Invention The present inventi~n relates to the oral delivery of ~-lactam antibiotics which by this route are poorly absorbed and more especially to the enhancement of this delivery by formulations which contain a hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester thereof.
As employed in this application, the term "~ lactam antibiotics" refers to those antibiotics which contain the ~-lactam moiety and include the penicillins, cephalosporins and related chemical species.
Description of the Prior Art It is well known to this art that the ~-lactam antibiotics which have the common structural feature, a ~-.
6~
METHOD OF INCREASING ORAL ABSORPTION OF ~-LACTAM
ANTI~IOTICS
BACKGROUND OF THE INVENTION
Field of the Invention The present inventi~n relates to the oral delivery of ~-lactam antibiotics which by this route are poorly absorbed and more especially to the enhancement of this delivery by formulations which contain a hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester thereof.
As employed in this application, the term "~ lactam antibiotics" refers to those antibiotics which contain the ~-lactam moiety and include the penicillins, cephalosporins and related chemical species.
Description of the Prior Art It is well known to this art that the ~-lactam antibiotics which have the common structural feature, a ~-.
6~
-2- Rx79A
four-member lactam ring, have been described as the most important class of therapeutic agents to combat gram-positive and gram-negative infections. Inspite of their great popularity, it is also well known that a number of 5 the ~-lactam antibiotics such as the penicillins~
penicillin G, methacillin and carbenicillin, and the cephalosporins, cefa201in, cephapirin, cephaloridine, cephalothin, cephapirin, cephanone, cefamandole, cefaparole, cefoxitin, cephacetrile, cefmetazole, cefuroxime, 10 cefotaxime, T-1551, and the oxacephalosporin, S-6059, show poor oral activity.
The penicillins, which were introduced a number of years ago, suffer from two major disadvantages: poor activity against resistant organisms and lack of oral 15 activity which is due to its inherent instability to gastric acid. The acid instability was partially over-come by the discovery of more acid stable penicillins such as penicillin V, which permit the penicillin to be absorbed with less degradation and hence produce higher blood 20 levels of the active therapeutic agent. However, inspite of these chemical modifications to produce acid stable, orally effective penicillins, many of the penicillins in clinical use, such as penicillin G, methacillin, carbeni-cillin and ticarcillin, cannot be administered by the 25 oral route. Even the newer esters of carbenicillin, carfecillin and carindacillin are only 40~ absorbed and give low blood levels of carbenicillin.
The second ma~or problem with penicillin anti-biotics is their lack of activity against resistant strains 30 of bacteria which produce the degrading enzyme, peni~
Q
_3_ Rx79A
cillinase. The earlier semisynthetic penicillins, such as methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin and nafcillin, were developed to overcome this problem. This class of penicillins were resistant 5 to the penicillinase enzyme and were active against those resistant organisms which produce the enzyme.
However, these compounds were less active than their parents and in particular showed poor activity againat the important gram-negative organisms.
The second class Qf ~-lactam antibiotics, the cephalosporins, were developed because they, unlike the penicillins, were very active against both the penicillinase producing gram-positive bacteria and the ~ram-negative bacteria. However, lack of oral activity, 15 an almost universal characteristic of the cephalosporins, is shared by the parent molecule, cephalosporin C7 and most of the newer semisynthetic analogueg. This lack of oral activity was totally unexpected because the ceph alosporins, unlike the pencillins, are stable in gastr~c 20 acid. Since the molecule is excreted unchanged in the feces, it is apparent that the lack of oral activity is due to poor absorption and is probably caused hy the polar nature of the cephalosporin nucleus. Through chemical modification a number of orally effective ~-25 lactam antibiotics were prepared, such as cephalexin,cephradine, cephaloglycin, cefadioxil and cefaclor, which have been shown to be greater than 80% absorbed. Un-fortunately, they are much less active in vitro than the clinically injectable cephalosporins. It is clear that 30 this chemical modification has produced an orally active 5~
~4_ Rx79A
antibiotic whose antibacterial properties are inferior to those of the currently used injectable cephalosporins.
Thus, there exists a clear and present need for a novel method to enhance the oral absorption of the non-5 orally effective ~-lactam antibiotics. Said method would permit the oral use of the clinically important ~-lactam antibiotics whose use is presently limited to intra-muscular and intravenous administration.
Summary of the Invention:
Accordingly, a major object of this invention is to provide a novel class of agents which enhance the oral absorption of ~-lactam ~ntibiotics.
Another object is to provide a process utiliz-ing said novel class of agents to enhance the oral 15 absorption of ~-lactam antibiotics.
Another object is to provide a stable drug form utilizing said novel class of agents which when administered orally will provide increased blood levels of the therapeutic agent.
Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description of the invention which follows.
All of the ~oregoing objects are readily attained 25 by providing a method and drug form wherein the oral ab~orption of ~-lactam antibiotics is enhanced, the method comprising the steps of preparing a drug form suitable for oral delivery~ and a drug form comprising an effective unit dosage amount of the ~-lactam antibiotic~ a hydroxy-$(~
_5_ Rx79A
aryl or hydroxyaralkyl acid ox salt, amide or ester thereo,the latter adjuvants being present in said drug form in an amount sufficient to be effective in enha~cing the rate of the oral absorption of the antibiotic, and a suitable pharmaceutically accepted excipient.
DETAILED DESCRIPTION OF ~IE INVENTION
The present invention, generally, comprises the steps of preparing a drug form capable of being orally administered, wherein the drug form comprises an effective unit dosage a unt of a ~-lactam antibiotic and hydroxy aryl or hydroxyaralkyl acids or salts, amides or esters thereof, the hydroxy aryl or hydroxy aralkyl acid or salts, amides and esters thereof being present in the drug form in a sufficient quantity to be effective in enhancing the oral absorption rate and administering the drug form to warm-blooded animals. The a unt of ~-lactam antibiotic varies over a wide range, but generally any therapeutically effective unit dosage amount of the selected ~-lactam antibiotic is used.
The hydroxy aryl or hydroxy aralkyl a~ids or their salt, amide and ester forms that are used as the adjuvants in our method and in our drug forms have the following structural formulae including the various isomers possible within the formulae set forth:
I. II.
(R2)y OH (R2) - 6 - ~x79A
wherein Rl is a radical selected from -CO2H, H
~(CH2)n-COOH, -CH = CEI-CO2H, -C- CO2H, ~3 --S03H, X ~ CH2E~, S02NHR4, PO (OH) N (OH) 2 ~ PO (OH) OR4, or a pharmaceutically acceptable salt thereof wherein R2 is a radical selected from OH, H, a lower alkoxy radical having 1-10 carbon atoms, a lower alkyl radical having 1-10 carbon atoms, a lower alkenyl radical having 2-5 carbon atoms, a lower alkanoyl radical having 1-5 carbon atoms, a lower alkanoyloxy radical having 1-5 carbon atoms, a carboxy radical, a carbo-lower alkoxy radical having 1-5 carbon atoms, a halo radical, a mono-, di-, or tri-halo lower alkyl radical having 1-5 carbon atoms, an amino radical, a mono- or di-lower alkyl amino radical having 1-5 carbon atoms, a carbamyl radical, a lower mono- or di-alkyl carbamyl radical wherein the alkyl group has 1-5 carbon atoms, a thio radical, a lower alkyl thio radical wherein the alkyl group has 1-5 carbon atoms, a cyano radical, a lower alkyl sulfone radical wherein the alkyl group has 1-5 carbon atoms, a lower alkyl sulfoxide radical wherein the alkyl group has 1-5 carbon atoms, a nitro radical, N(CN2)2, C(CN)3, an alkynyl radical having 2-6 carbon atoms, a cycloalkyl radical having 3-10 caxbon atoms, a cycloalkenyl xadical having 3-10 carbon atoms, an aryl radical including phenyl, a hetroaryl radical including thiophenyl and imadazoalyl, or a heterocycloalkyl radical including morphilinyl and piperdinyl, wherein R3 is a straight or branched alkyl radical having 1-6 carbon atoms or a hydroxy radical, wherein R4 is H or a lower alkyl radical having 1-5 carbon atoms, wherein X is 0 or S, - 7 - ~x7gA
wherein n is an integer of 0-5, wherein y is l or 2, and when y is 2, both the R2 radicals, taken together, can form a ring containing O, N or S.
More preferred adjuvants are those having the formula:
~Rl (R2)y H
wherein Rl is a radical selected from H
-CO2H, -(CH2) -COOH, CH=CH-CO2H, -C-CO2H, -SO3H, -CH2SO3H, OH
O(CH2) CO2H or a pharmaceutically acceptable salt thereof wherein R2 is selected from OH, H, a lower alkoxy radical having l-10 carbon atoms, a lower alkyl radical having l-10 carbon atoms, a halo radical, a mono-, di-, or tri-halo lower alkyl radical wherein the alkyl group has 1-5 carbon atoms, a lower alkyl thio radical where.in the alkyl radical has 1-5 carbon atoms, a cyloalkyl radical having 3-10 carbon atoms, or a cycloalkenyl radical having
four-member lactam ring, have been described as the most important class of therapeutic agents to combat gram-positive and gram-negative infections. Inspite of their great popularity, it is also well known that a number of 5 the ~-lactam antibiotics such as the penicillins~
penicillin G, methacillin and carbenicillin, and the cephalosporins, cefa201in, cephapirin, cephaloridine, cephalothin, cephapirin, cephanone, cefamandole, cefaparole, cefoxitin, cephacetrile, cefmetazole, cefuroxime, 10 cefotaxime, T-1551, and the oxacephalosporin, S-6059, show poor oral activity.
The penicillins, which were introduced a number of years ago, suffer from two major disadvantages: poor activity against resistant organisms and lack of oral 15 activity which is due to its inherent instability to gastric acid. The acid instability was partially over-come by the discovery of more acid stable penicillins such as penicillin V, which permit the penicillin to be absorbed with less degradation and hence produce higher blood 20 levels of the active therapeutic agent. However, inspite of these chemical modifications to produce acid stable, orally effective penicillins, many of the penicillins in clinical use, such as penicillin G, methacillin, carbeni-cillin and ticarcillin, cannot be administered by the 25 oral route. Even the newer esters of carbenicillin, carfecillin and carindacillin are only 40~ absorbed and give low blood levels of carbenicillin.
The second ma~or problem with penicillin anti-biotics is their lack of activity against resistant strains 30 of bacteria which produce the degrading enzyme, peni~
Q
_3_ Rx79A
cillinase. The earlier semisynthetic penicillins, such as methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin and nafcillin, were developed to overcome this problem. This class of penicillins were resistant 5 to the penicillinase enzyme and were active against those resistant organisms which produce the enzyme.
However, these compounds were less active than their parents and in particular showed poor activity againat the important gram-negative organisms.
The second class Qf ~-lactam antibiotics, the cephalosporins, were developed because they, unlike the penicillins, were very active against both the penicillinase producing gram-positive bacteria and the ~ram-negative bacteria. However, lack of oral activity, 15 an almost universal characteristic of the cephalosporins, is shared by the parent molecule, cephalosporin C7 and most of the newer semisynthetic analogueg. This lack of oral activity was totally unexpected because the ceph alosporins, unlike the pencillins, are stable in gastr~c 20 acid. Since the molecule is excreted unchanged in the feces, it is apparent that the lack of oral activity is due to poor absorption and is probably caused hy the polar nature of the cephalosporin nucleus. Through chemical modification a number of orally effective ~-25 lactam antibiotics were prepared, such as cephalexin,cephradine, cephaloglycin, cefadioxil and cefaclor, which have been shown to be greater than 80% absorbed. Un-fortunately, they are much less active in vitro than the clinically injectable cephalosporins. It is clear that 30 this chemical modification has produced an orally active 5~
~4_ Rx79A
antibiotic whose antibacterial properties are inferior to those of the currently used injectable cephalosporins.
Thus, there exists a clear and present need for a novel method to enhance the oral absorption of the non-5 orally effective ~-lactam antibiotics. Said method would permit the oral use of the clinically important ~-lactam antibiotics whose use is presently limited to intra-muscular and intravenous administration.
Summary of the Invention:
Accordingly, a major object of this invention is to provide a novel class of agents which enhance the oral absorption of ~-lactam ~ntibiotics.
Another object is to provide a process utiliz-ing said novel class of agents to enhance the oral 15 absorption of ~-lactam antibiotics.
Another object is to provide a stable drug form utilizing said novel class of agents which when administered orally will provide increased blood levels of the therapeutic agent.
Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description of the invention which follows.
All of the ~oregoing objects are readily attained 25 by providing a method and drug form wherein the oral ab~orption of ~-lactam antibiotics is enhanced, the method comprising the steps of preparing a drug form suitable for oral delivery~ and a drug form comprising an effective unit dosage amount of the ~-lactam antibiotic~ a hydroxy-$(~
_5_ Rx79A
aryl or hydroxyaralkyl acid ox salt, amide or ester thereo,the latter adjuvants being present in said drug form in an amount sufficient to be effective in enha~cing the rate of the oral absorption of the antibiotic, and a suitable pharmaceutically accepted excipient.
DETAILED DESCRIPTION OF ~IE INVENTION
The present invention, generally, comprises the steps of preparing a drug form capable of being orally administered, wherein the drug form comprises an effective unit dosage a unt of a ~-lactam antibiotic and hydroxy aryl or hydroxyaralkyl acids or salts, amides or esters thereof, the hydroxy aryl or hydroxy aralkyl acid or salts, amides and esters thereof being present in the drug form in a sufficient quantity to be effective in enhancing the oral absorption rate and administering the drug form to warm-blooded animals. The a unt of ~-lactam antibiotic varies over a wide range, but generally any therapeutically effective unit dosage amount of the selected ~-lactam antibiotic is used.
The hydroxy aryl or hydroxy aralkyl a~ids or their salt, amide and ester forms that are used as the adjuvants in our method and in our drug forms have the following structural formulae including the various isomers possible within the formulae set forth:
I. II.
(R2)y OH (R2) - 6 - ~x79A
wherein Rl is a radical selected from -CO2H, H
~(CH2)n-COOH, -CH = CEI-CO2H, -C- CO2H, ~3 --S03H, X ~ CH2E~, S02NHR4, PO (OH) N (OH) 2 ~ PO (OH) OR4, or a pharmaceutically acceptable salt thereof wherein R2 is a radical selected from OH, H, a lower alkoxy radical having 1-10 carbon atoms, a lower alkyl radical having 1-10 carbon atoms, a lower alkenyl radical having 2-5 carbon atoms, a lower alkanoyl radical having 1-5 carbon atoms, a lower alkanoyloxy radical having 1-5 carbon atoms, a carboxy radical, a carbo-lower alkoxy radical having 1-5 carbon atoms, a halo radical, a mono-, di-, or tri-halo lower alkyl radical having 1-5 carbon atoms, an amino radical, a mono- or di-lower alkyl amino radical having 1-5 carbon atoms, a carbamyl radical, a lower mono- or di-alkyl carbamyl radical wherein the alkyl group has 1-5 carbon atoms, a thio radical, a lower alkyl thio radical wherein the alkyl group has 1-5 carbon atoms, a cyano radical, a lower alkyl sulfone radical wherein the alkyl group has 1-5 carbon atoms, a lower alkyl sulfoxide radical wherein the alkyl group has 1-5 carbon atoms, a nitro radical, N(CN2)2, C(CN)3, an alkynyl radical having 2-6 carbon atoms, a cycloalkyl radical having 3-10 caxbon atoms, a cycloalkenyl xadical having 3-10 carbon atoms, an aryl radical including phenyl, a hetroaryl radical including thiophenyl and imadazoalyl, or a heterocycloalkyl radical including morphilinyl and piperdinyl, wherein R3 is a straight or branched alkyl radical having 1-6 carbon atoms or a hydroxy radical, wherein R4 is H or a lower alkyl radical having 1-5 carbon atoms, wherein X is 0 or S, - 7 - ~x7gA
wherein n is an integer of 0-5, wherein y is l or 2, and when y is 2, both the R2 radicals, taken together, can form a ring containing O, N or S.
More preferred adjuvants are those having the formula:
~Rl (R2)y H
wherein Rl is a radical selected from H
-CO2H, -(CH2) -COOH, CH=CH-CO2H, -C-CO2H, -SO3H, -CH2SO3H, OH
O(CH2) CO2H or a pharmaceutically acceptable salt thereof wherein R2 is selected from OH, H, a lower alkoxy radical having l-10 carbon atoms, a lower alkyl radical having l-10 carbon atoms, a halo radical, a mono-, di-, or tri-halo lower alkyl radical wherein the alkyl group has 1-5 carbon atoms, a lower alkyl thio radical where.in the alkyl radical has 1-5 carbon atoms, a cyloalkyl radical having 3-10 carbon atoms, or a cycloalkenyl radical having
3-10 carbon atoms and wherein y is an integer of l or 2.
Highly preferred adjuvants are khose having the formula:
R
o ~X :
'R2)Y OH
-8- Rx79A
wherein Rl is CO2H,-(CH2)~COOH, -C-CO2H, SO3H, OH
or a pharmaceutically acceptable salt thereof wherein R2 is OH, H, a lower alkoxy radical, including methoxy, ethoxy, butoxy, or octyloxy, a lower alkyl radical including methyl, isopropyl, ethyl, t-butyl, n-butyl, or t-octyl, a halo radical, or a tri-halo lower alkyl radical including trifluoromethyl, and wherein y is an integer of 1 or 2.
Specific adjuvants useful in our method and drug forms for enhancing oral absorption of ~-lacam antibiotics include salicylic acid, resorcylic acid, and gentisic acid. Other hydroxyaryl acids, such as l-hydroxy~2-naphthoic acid, naphthoresorcylic acid, ferulic acid, caffeic acid, and homovanillic acid, have similar use~ul ad~uvant activity in our process. Such adjuvants are not considered novel per _ and may be prepared by techniques known to those skilled in the art.
The amount of hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester derivatives thereof used in our method and drug forms may vary over a wide range in general, the identity and the amount of the hydroxy-aryl or hydroxyaralkyl acids or salt, amide or es~er thereof i5 used in connection with the drug in order to be e~fective in enhancing the absorption rate of the drug from the gastroint~stinal compartment into the bloodstream.
The effectiveness of the hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester derivatives thereof becomes significant at local concentration exceeding 0.01% at the absorption site. Their use at a dosage whereby their con-centration at the absorption site exceeds 5% is notrecommended because of the local irritating effect on ~he tissue.
. ~
- 9 - ~x79A
The ~-lactam antibiotics whose enhanced oral delivery is a subject of the present invention encompass both the penicillins, penicillin G, methacillin, carbeni-cillin and ticaricillin, and the cephalosporinS, cephalo-sporin C, cefazolin, cephapirin, cephaloridine, cephalothin,cephapirin, cephanone, cefamandole, cefaparole, cefoxitin, cephacetrile, cefmetazole, cefoxitin, cefuroxime, cefotaxime, T-1551, and the oxacephalosporin, S-6059. T:he quantity of ~-lactam antibiotic necessary for preparing the drug form could vary over a wide range but would normally be regulated by that quantity necessary to comprise the therapeutically effec~ive unit dosage.
~16~
-10- Rx79A
.__ The sodium salt of cefmetazole (50 mg/kg~ and sodium salicylate (200 mg/kg) dissolved in water were given to mice by ga~age. As a control, mice were given an equal dose of the sodium salt o~ cefmetazole in water without the added sodium salicylate. The mice were placed in individual metabolism cages and their urines collected after 24 hours.
The urine samples were acidified to pH 2.0 with lN phosphoric acid. Acidified samples were applied to 100-200 mesh XAD.2 columns (1.5 ml), and the column washed with H2O. Cefmetazole was eluted wi~h 2 ml methanol and measured by high pressure liquid chxomatography which was carried out using an Altex liquid chromatograph equipped with a dual wavelength recorder (254 nm and 280 nm). The column was a LiChrosorb 10 RP-18 (length = 25 cm., internal diameter - 4.6 mm) obtained from Chrompack, Whittier, CA.
All assays were done at ambient temperatures. A 3 cm guard column of RP-18 column material (Rheodyne, Inc., Berkeley, CA) was also used. The mobile phase consisted of 30% tetrahydxofuran, 7.5~10 4 M tetra-n-hexyl ammonium perchlorate, and 70% H20. The flow rate was 2 ml/
min and the pressure less than 2003 psi. Concentrations of cefmetazole were determined by measuring peak height at 254 nm and evaluating on the basis of standard curves run under identical conditions. The results are shown in Table I.
o Rx7 gA
TAsLE I
Urine Levels o:E Cefmetazole NumberPercent of Dose of Micein Urine Cefmetazole 50 mg/kg 2270.8 + 11.9 + sodium salicylate 200 mg/kg Cefmetazole 50 mg/kg 89.1 ~ 7.5 ~standard deviation In like manner the following combinations of other ~-lactams and hydroxyaryl acids were also found to enhance the oral absorption of the corresponding anti-biotic.
Example ~-lactam Antihiotic Hydroxyaromatic Acid 2 penicillin G. salicylic acid 15 3 methacillin sodium salicylate
Highly preferred adjuvants are khose having the formula:
R
o ~X :
'R2)Y OH
-8- Rx79A
wherein Rl is CO2H,-(CH2)~COOH, -C-CO2H, SO3H, OH
or a pharmaceutically acceptable salt thereof wherein R2 is OH, H, a lower alkoxy radical, including methoxy, ethoxy, butoxy, or octyloxy, a lower alkyl radical including methyl, isopropyl, ethyl, t-butyl, n-butyl, or t-octyl, a halo radical, or a tri-halo lower alkyl radical including trifluoromethyl, and wherein y is an integer of 1 or 2.
Specific adjuvants useful in our method and drug forms for enhancing oral absorption of ~-lacam antibiotics include salicylic acid, resorcylic acid, and gentisic acid. Other hydroxyaryl acids, such as l-hydroxy~2-naphthoic acid, naphthoresorcylic acid, ferulic acid, caffeic acid, and homovanillic acid, have similar use~ul ad~uvant activity in our process. Such adjuvants are not considered novel per _ and may be prepared by techniques known to those skilled in the art.
The amount of hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester derivatives thereof used in our method and drug forms may vary over a wide range in general, the identity and the amount of the hydroxy-aryl or hydroxyaralkyl acids or salt, amide or es~er thereof i5 used in connection with the drug in order to be e~fective in enhancing the absorption rate of the drug from the gastroint~stinal compartment into the bloodstream.
The effectiveness of the hydroxyaryl or hydroxyaralkyl acid or salt, amide or ester derivatives thereof becomes significant at local concentration exceeding 0.01% at the absorption site. Their use at a dosage whereby their con-centration at the absorption site exceeds 5% is notrecommended because of the local irritating effect on ~he tissue.
. ~
- 9 - ~x79A
The ~-lactam antibiotics whose enhanced oral delivery is a subject of the present invention encompass both the penicillins, penicillin G, methacillin, carbeni-cillin and ticaricillin, and the cephalosporinS, cephalo-sporin C, cefazolin, cephapirin, cephaloridine, cephalothin,cephapirin, cephanone, cefamandole, cefaparole, cefoxitin, cephacetrile, cefmetazole, cefoxitin, cefuroxime, cefotaxime, T-1551, and the oxacephalosporin, S-6059. T:he quantity of ~-lactam antibiotic necessary for preparing the drug form could vary over a wide range but would normally be regulated by that quantity necessary to comprise the therapeutically effec~ive unit dosage.
~16~
-10- Rx79A
.__ The sodium salt of cefmetazole (50 mg/kg~ and sodium salicylate (200 mg/kg) dissolved in water were given to mice by ga~age. As a control, mice were given an equal dose of the sodium salt o~ cefmetazole in water without the added sodium salicylate. The mice were placed in individual metabolism cages and their urines collected after 24 hours.
The urine samples were acidified to pH 2.0 with lN phosphoric acid. Acidified samples were applied to 100-200 mesh XAD.2 columns (1.5 ml), and the column washed with H2O. Cefmetazole was eluted wi~h 2 ml methanol and measured by high pressure liquid chxomatography which was carried out using an Altex liquid chromatograph equipped with a dual wavelength recorder (254 nm and 280 nm). The column was a LiChrosorb 10 RP-18 (length = 25 cm., internal diameter - 4.6 mm) obtained from Chrompack, Whittier, CA.
All assays were done at ambient temperatures. A 3 cm guard column of RP-18 column material (Rheodyne, Inc., Berkeley, CA) was also used. The mobile phase consisted of 30% tetrahydxofuran, 7.5~10 4 M tetra-n-hexyl ammonium perchlorate, and 70% H20. The flow rate was 2 ml/
min and the pressure less than 2003 psi. Concentrations of cefmetazole were determined by measuring peak height at 254 nm and evaluating on the basis of standard curves run under identical conditions. The results are shown in Table I.
o Rx7 gA
TAsLE I
Urine Levels o:E Cefmetazole NumberPercent of Dose of Micein Urine Cefmetazole 50 mg/kg 2270.8 + 11.9 + sodium salicylate 200 mg/kg Cefmetazole 50 mg/kg 89.1 ~ 7.5 ~standard deviation In like manner the following combinations of other ~-lactams and hydroxyaryl acids were also found to enhance the oral absorption of the corresponding anti-biotic.
Example ~-lactam Antihiotic Hydroxyaromatic Acid 2 penicillin G. salicylic acid 15 3 methacillin sodium salicylate
4 carbenicillin gentisic acid ticaricillin ferulic acid 6 methacillin naphthoresorcyclic acid 7 ticaricillin caffeic acid 20 8 carbenicillin sodium salicylate 9 penicillin G hydroxy-2~naphthoic acid carbenicillin resorcyclic acid 11 cephalosporin ~ sallcylic acid 12 cefazolin sodiu~ salicylate 2513 cefuroxine gentisic acid 14 cephaprin homo~anellic acid cephaloridine sodium salicylate 16 cephmetazole ~ homovanillic acid 17 cephapirin ferulic acid 3018 cephanone salicylic ac~id -12- Rx79A
19 cefmetazole salicylic acid cefaparole sodium salicylate 21 cefoxitin naphthoresorcyclic acid 22 cephacetrile gentisic acid 23 cefmetazole caffeic acid 24 cefoxitin resorcyclic acid cefuroxime sodium salicylate 26 cefotaxime: ferulic acid 27 T-1551 homovanillic acid 28 S-6059 caffeic acid 29 cefmetazole 1-hydroxy-2-naphthoic acid cefamandole gentisic acid 31 cephalothin salicylic acid The drug forms of this inv~ntion are suitably administered in oral dosage form, such as by tablet or capsule, by combining the ~-lactam antibiotic in a therapeutic amount and the hydroxyaromatic acid or salt thereof in sufficient quantity to be effective to enhance oral delivery with any oral pharmaceutically acceptahle inert carrier, such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, Xaolin, mannitol and powdered sugar. In order to reduce the irritation in the stomach, the preferred dose form of the hydroxyaromatic acid should be a pharmaceutically acceptable salt and the drug form should be designed to release the ~ lactam antibiotic and the hydroxyaromatic acid salt beyond the pylorus. In addition, when required, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added~ Typical binders include, without limitation, starch, gelatinl sugars such as sucrose, molasses, and lactose, natural and synthetic gums, such as acacia, sodium alginate, extract of Irish moss, carboxy-methylcellulose, methylcellulose, and polyvinylpyrrolidone, ~L~'6'~
- 13 - Rx7gA
polyethylene glycol, ethylcellulose and waxes. Typical lubricants for use in these dosage forms can include, without limitation, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol.
Suitable disintegrators can include, without limitation, starch, methylcellulose, agar, bentonite, cellulose and wood products, alginic acid, guar gum, citris pulp, carboxy-methylcellulose, and sodium lauryl sulfate. Op~ionally, if desired, a conventionally, pharmaceutically acceptable dye can be incorporated into the oral dosage unit form, e.g~, any of the standard FD&C dyes.
Preparation of Sodium 2 hydroxy-5-methoxy benzenesulfonate p-Methoxyphenol (12.4 g) was dissolved in chloro-form (100 ml) and cooled in ice. Chlorosulfonic acidtll.6 g) was added dropwise to the stirred reaction mixture.
The cooling bath was removed after the addit.ion and stirring continued for 24 hours at room temperature. The chloroform was then evaporated off and the residue was vacuum dried to a hygroscopic light brown solid weighing 20.5 g which was 2-hydroxy-5-methoxy-benzenesulfonic acid.
NMR (CDC13~ 3.73 (3~, s, OCH3), 6.8~7.2 (3H, m, aromatic H), and 9.86 (2H, broad s, OH and SO3H). IR (film) 3500-2900, 1512, 1470, 1229, 1198, 996, 938 cm 1.
The above sulfonic acid (10 g) was dissolved in water (10 ml) and poured into 75 ml of saturaied sodium chloride solution. A white so~id separated immediately.
It was filtered and dried. Crystallization from water gave the pure sodium salt of 2-hydroxy-5-methoxybenzene-sulfonic acid (6.6 g).
NMR (D20~ 3.83 (3H, s, OCH3), 7.05 and 7.33 (3H, multi-plets, aromatic). IR (KBr) 3260, 1518, 1440, 1300, 1280, 1240, 1210, 1905, 1045 cm 1.
- 14 - Rx79A
. _ .. _~
Typical preparation of enteric-coated tablets containing adjuvant.
300 mg Cefoxitin Tablets Ingredient Amount per Tablet Cefoxitin (sodium salt~300 mg Sodium 5-methoxysalicylate 300 mg Microcrystalline cellulose 70 mg Magnesium stearate ~
Total 700 mg The cefoxitin sodium salt was ground, passed through a 40 mesh scxeen, mixed wi h the sodium 5-methoxysalicylate, 1/2 the magnesium stearate and slugged with 1/2" flat punches. The slugs were broken up and passed through a 40 mesh screen, mixed with microcrystalline cellulose and the remaining magnesium stearate. The material was tableted using 7/16" deep concave punches to give tablets of 10 Kg hardness.
Coating:
The tablets were coated with 15 mg pre-coat and 34 mg enteric coat according to the coating procedure described below.
Enterlc Coatinq Procedure Tablets or capsules were placed in a aoating pan containing baffles to provide adequate tumbling. A small amount of the coating solution was applied using an air sprayer and the solvents evaporated with a warm air supply directed into the coating pan. This procedure was repeated until the desired amount of coating material was applied.
The amount of coating material was determined from the weight gain of a representative group of tablets.
Coating Solutions:
Pre-coat: A film of hydroxypropylmethylcellulose was applied to the tablets followed by an enteric coating.
V
- l5 ~ Rx7gA
Enteric coat: A film of hydroxypropylmethyl-cellulosephthalate was applied.
Solutions- A 5~ by weight solution of hydroxy-propylmethylcellulose and a 10% by weight solution of hydroxypropylmethylcellulosephthalate in ethanol:
methylene chloride ~l:l by weight) were used as the coat-ing solutions.
. _ Following the procedure of Example III for the preparation of enteric coated ~ablets and using equivalent quantites of ingredients~ the following compounds can be substituted for cefoxitin which is (6R-cis)-3-[[~amino-carbonyl)oxy]methyl]-7-methoxy-8-oxo-7[(2-thienylacetyl)-amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
l) Cephamandole which i5 7-[(hydroxyphenylacetyl)-amino~-3-[E(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8
19 cefmetazole salicylic acid cefaparole sodium salicylate 21 cefoxitin naphthoresorcyclic acid 22 cephacetrile gentisic acid 23 cefmetazole caffeic acid 24 cefoxitin resorcyclic acid cefuroxime sodium salicylate 26 cefotaxime: ferulic acid 27 T-1551 homovanillic acid 28 S-6059 caffeic acid 29 cefmetazole 1-hydroxy-2-naphthoic acid cefamandole gentisic acid 31 cephalothin salicylic acid The drug forms of this inv~ntion are suitably administered in oral dosage form, such as by tablet or capsule, by combining the ~-lactam antibiotic in a therapeutic amount and the hydroxyaromatic acid or salt thereof in sufficient quantity to be effective to enhance oral delivery with any oral pharmaceutically acceptahle inert carrier, such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, Xaolin, mannitol and powdered sugar. In order to reduce the irritation in the stomach, the preferred dose form of the hydroxyaromatic acid should be a pharmaceutically acceptable salt and the drug form should be designed to release the ~ lactam antibiotic and the hydroxyaromatic acid salt beyond the pylorus. In addition, when required, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added~ Typical binders include, without limitation, starch, gelatinl sugars such as sucrose, molasses, and lactose, natural and synthetic gums, such as acacia, sodium alginate, extract of Irish moss, carboxy-methylcellulose, methylcellulose, and polyvinylpyrrolidone, ~L~'6'~
- 13 - Rx7gA
polyethylene glycol, ethylcellulose and waxes. Typical lubricants for use in these dosage forms can include, without limitation, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol.
Suitable disintegrators can include, without limitation, starch, methylcellulose, agar, bentonite, cellulose and wood products, alginic acid, guar gum, citris pulp, carboxy-methylcellulose, and sodium lauryl sulfate. Op~ionally, if desired, a conventionally, pharmaceutically acceptable dye can be incorporated into the oral dosage unit form, e.g~, any of the standard FD&C dyes.
Preparation of Sodium 2 hydroxy-5-methoxy benzenesulfonate p-Methoxyphenol (12.4 g) was dissolved in chloro-form (100 ml) and cooled in ice. Chlorosulfonic acidtll.6 g) was added dropwise to the stirred reaction mixture.
The cooling bath was removed after the addit.ion and stirring continued for 24 hours at room temperature. The chloroform was then evaporated off and the residue was vacuum dried to a hygroscopic light brown solid weighing 20.5 g which was 2-hydroxy-5-methoxy-benzenesulfonic acid.
NMR (CDC13~ 3.73 (3~, s, OCH3), 6.8~7.2 (3H, m, aromatic H), and 9.86 (2H, broad s, OH and SO3H). IR (film) 3500-2900, 1512, 1470, 1229, 1198, 996, 938 cm 1.
The above sulfonic acid (10 g) was dissolved in water (10 ml) and poured into 75 ml of saturaied sodium chloride solution. A white so~id separated immediately.
It was filtered and dried. Crystallization from water gave the pure sodium salt of 2-hydroxy-5-methoxybenzene-sulfonic acid (6.6 g).
NMR (D20~ 3.83 (3H, s, OCH3), 7.05 and 7.33 (3H, multi-plets, aromatic). IR (KBr) 3260, 1518, 1440, 1300, 1280, 1240, 1210, 1905, 1045 cm 1.
- 14 - Rx79A
. _ .. _~
Typical preparation of enteric-coated tablets containing adjuvant.
300 mg Cefoxitin Tablets Ingredient Amount per Tablet Cefoxitin (sodium salt~300 mg Sodium 5-methoxysalicylate 300 mg Microcrystalline cellulose 70 mg Magnesium stearate ~
Total 700 mg The cefoxitin sodium salt was ground, passed through a 40 mesh scxeen, mixed wi h the sodium 5-methoxysalicylate, 1/2 the magnesium stearate and slugged with 1/2" flat punches. The slugs were broken up and passed through a 40 mesh screen, mixed with microcrystalline cellulose and the remaining magnesium stearate. The material was tableted using 7/16" deep concave punches to give tablets of 10 Kg hardness.
Coating:
The tablets were coated with 15 mg pre-coat and 34 mg enteric coat according to the coating procedure described below.
Enterlc Coatinq Procedure Tablets or capsules were placed in a aoating pan containing baffles to provide adequate tumbling. A small amount of the coating solution was applied using an air sprayer and the solvents evaporated with a warm air supply directed into the coating pan. This procedure was repeated until the desired amount of coating material was applied.
The amount of coating material was determined from the weight gain of a representative group of tablets.
Coating Solutions:
Pre-coat: A film of hydroxypropylmethylcellulose was applied to the tablets followed by an enteric coating.
V
- l5 ~ Rx7gA
Enteric coat: A film of hydroxypropylmethyl-cellulosephthalate was applied.
Solutions- A 5~ by weight solution of hydroxy-propylmethylcellulose and a 10% by weight solution of hydroxypropylmethylcellulosephthalate in ethanol:
methylene chloride ~l:l by weight) were used as the coat-ing solutions.
. _ Following the procedure of Example III for the preparation of enteric coated ~ablets and using equivalent quantites of ingredients~ the following compounds can be substituted for cefoxitin which is (6R-cis)-3-[[~amino-carbonyl)oxy]methyl]-7-methoxy-8-oxo-7[(2-thienylacetyl)-amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
l) Cephamandole which i5 7-[(hydroxyphenylacetyl)-amino~-3-[E(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8
5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2) Amoxicillin which is 6-[[amino(4-hydroxyphenyl)-acetyl]amino~-3,3-dimethyl-7-oxo-4-thia-l-azahicyclo-13.2.0]heptane-2-carboxylic acid 3) N-formimidoyl thienamycin monohydrate.
Also the following adjuvants may be used in combination with any of the drugs or compounds shown in Examples l, 3 or 4 in appropriate ratios.
-16- Rx79A
The adjuvants may be chosen from the following salts or the corresponding acids:
Sodium 5-methoxysalicylate Sodium salicylate Sodium homovanilate Sodium 2,5-aihydroxybenzoate Sodium 2,4-dichydroxybenzoate Sodium 3,4-dihydroxymandelate Sodium 3-methoxy-4-hydroxymandelate Sodium 3-methoxy-4-hydroxycinnamate Sodium 5-methoxy-2-hydroxyphenylsulfonate Sodium 3-methylsalicylate Sodium 5-methylsalicylate Sodium 5-tert-octylsalicylate Sodium 3-tert-butyl-6-methylsalicylate Sodium 3,5-diisopropylsalicylate Sodium 3-ter~-butyl-5-methylsalicylate Sodium guaicolsulfonate Sodium 5-bromosalicylate Sodium 3,5-dibromosalicylate Sodium 5-iodosalicylate Sodium 3,5-diiodosalicylate Sodium 2-hydroxyphenylacetate Sodium 3-hydroxy-2~naphthoate Sodium mandelate Sodium phenyllactate Sodium 2-hydroxyphenylmethanesulfonate Sodium 5-trifluoromethyl-2 hydroxybenzoate Sodium 4-hydroxy-3-hydroxyphenylmethanesulfonate Sodium 3-methoxy~alicylate Sodium 5-octyloxysalicylate Sodium 5-butoxysalicylate 3~
- 17 - Rx79A
Sodium p-hyclroxyphenoxyacetate Sodium 3,4-dihydroxyphenylacetate Sodium 5 chlorosalicylate Sodium 3,4-dihydroxycinnamate Sodium 3,5-dihydroxybenzoate Sodium 2-hydroxy-3-methoxybenzoate Sodium l-hydroxy-2-naphthoate Sodium salicylurate Any skilled artisan concerned with the subject matter of this invention, can prepare these oral dosage forms by simply referring to the oral dosage form preparatory procedure outlined in REMINGTON'S P~ARMACEUTICAL
SCIENCES, Fifteenth Edition (1975), pages 1576 through 1617 inclusive.
From the foregoing description, one of ordinary skill in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. As such, such changes and modifica-tions are properly equitably, and intended to be, within the full range o e~uivalence of the following claims.
Also the following adjuvants may be used in combination with any of the drugs or compounds shown in Examples l, 3 or 4 in appropriate ratios.
-16- Rx79A
The adjuvants may be chosen from the following salts or the corresponding acids:
Sodium 5-methoxysalicylate Sodium salicylate Sodium homovanilate Sodium 2,5-aihydroxybenzoate Sodium 2,4-dichydroxybenzoate Sodium 3,4-dihydroxymandelate Sodium 3-methoxy-4-hydroxymandelate Sodium 3-methoxy-4-hydroxycinnamate Sodium 5-methoxy-2-hydroxyphenylsulfonate Sodium 3-methylsalicylate Sodium 5-methylsalicylate Sodium 5-tert-octylsalicylate Sodium 3-tert-butyl-6-methylsalicylate Sodium 3,5-diisopropylsalicylate Sodium 3-ter~-butyl-5-methylsalicylate Sodium guaicolsulfonate Sodium 5-bromosalicylate Sodium 3,5-dibromosalicylate Sodium 5-iodosalicylate Sodium 3,5-diiodosalicylate Sodium 2-hydroxyphenylacetate Sodium 3-hydroxy-2~naphthoate Sodium mandelate Sodium phenyllactate Sodium 2-hydroxyphenylmethanesulfonate Sodium 5-trifluoromethyl-2 hydroxybenzoate Sodium 4-hydroxy-3-hydroxyphenylmethanesulfonate Sodium 3-methoxy~alicylate Sodium 5-octyloxysalicylate Sodium 5-butoxysalicylate 3~
- 17 - Rx79A
Sodium p-hyclroxyphenoxyacetate Sodium 3,4-dihydroxyphenylacetate Sodium 5 chlorosalicylate Sodium 3,4-dihydroxycinnamate Sodium 3,5-dihydroxybenzoate Sodium 2-hydroxy-3-methoxybenzoate Sodium l-hydroxy-2-naphthoate Sodium salicylurate Any skilled artisan concerned with the subject matter of this invention, can prepare these oral dosage forms by simply referring to the oral dosage form preparatory procedure outlined in REMINGTON'S P~ARMACEUTICAL
SCIENCES, Fifteenth Edition (1975), pages 1576 through 1617 inclusive.
From the foregoing description, one of ordinary skill in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. As such, such changes and modifica-tions are properly equitably, and intended to be, within the full range o e~uivalence of the following claims.
Claims (8)
1. An orally administered drug form com-prising a therapeutically effective amount of .beta.-lactam antibiotic and an adjuvant of the formula:
wherein R1 is CO2H, (CH2)-COOH, , SO3H, or a pharmaceutically acceptable salt thereof wherein R2 is OH, H, lower alkoxy radical, a lower alkyl radical, a halo radical, or a tri-halo lower alkyl radical, and wherein y is an integer of 1 or 2, or salt ester or amide derivative thereof, said adjuvant being present in said drug form in sufficient amount to be effective in enhancing the oral absorption rate of said .beta.-lactam antibiotic.
wherein R1 is CO2H, (CH2)-COOH, , SO3H, or a pharmaceutically acceptable salt thereof wherein R2 is OH, H, lower alkoxy radical, a lower alkyl radical, a halo radical, or a tri-halo lower alkyl radical, and wherein y is an integer of 1 or 2, or salt ester or amide derivative thereof, said adjuvant being present in said drug form in sufficient amount to be effective in enhancing the oral absorption rate of said .beta.-lactam antibiotic.
2. The drug form of Claim 1, wherein said .beta.-lactam antibiotic is a penicillin, a cephalosporin or thienamycin.
3. The drug form of Claim 2, wherein said penicillin is penicillin G, methacillin, carbenicillin, ticaricillin or amoxicillin.
4. The drug form of Claim 2, wherein said cephalosporin is cephalosporin C, cefazolin, cephapirin, cephaloridine, cephalothin, cephapirin, cephanone, cefamandole, cefaparole, cefoxitin, cephacetrile, cefmetazole, cofuroxime, cefotamine, T-1551 or S-6059.
5. The drug form of Claim 2, wherein said .beta.-lactam antibiotic is N-formimidoyl thienamycin mono-hydrate.
6. The drug form of Claim 1, wherein the said .beta.-lactam antibiotic is cefoxitin.
7. The drug form of Claim 1, wherein said adjuvant is 5-methoxysalicylic acid, salicylic acid, homovanillic acid; 2,5-dihydroxybenzoic acid; 2,4-dihydroxybenzoic acid; 3,4-dihydroxymandelic acid;
3-methoxy-4-hydroxycinnamic acid; 5-methoxy-2-hydroxy-phenylsulfonic acid; 3-methylsalicylic acid; 5-methyl-salicylic acid; 5-tert-octylsalicylic acid, 3-tert-butyl-6-methylsalicylic acid, 3,5-diisopropylsalicylic acid; 3 tert-butyl-5-methylsalicylic acid; guaicol-sulfonic acid; 5-bromosalicylic acid; 3,5-dibromo-salicylic acid; 5-iodosalicylic acid, 3,5-diiodo-salicylic acid; 3,5-diiodosalicylic acid; 2-hydroxy-phenylacetic acid; 3-hydroxy-2-naphthoic acid; mandelic acid; phenyllactic acid, 2-hydroxyphenylmethanesulfonic acid; 5-trifluoromethyl-2-hydroxybenzoic acid; 4-hydroxy-3-hydroxyphenylmethanesulfonic acid; 3-methoxysalicylic acid; 5-octyloxysalicylic acid; 5-butoxysalicylic acid;
p-hydroxyphenoxyacetic acid; 3,4-dihydroxyphenylacetic acid; 5-chlorosalicylic acid; 3,4-dihydroxycinnamic acid; 3,5-dihydroxybenzoic acid; 2-hydroxy-3-methoxy-benzoic acid; 1-hydroxy-2-naphthoic acid; salicyluric acid; or the sodium salts thereof.
3-methoxy-4-hydroxycinnamic acid; 5-methoxy-2-hydroxy-phenylsulfonic acid; 3-methylsalicylic acid; 5-methyl-salicylic acid; 5-tert-octylsalicylic acid, 3-tert-butyl-6-methylsalicylic acid, 3,5-diisopropylsalicylic acid; 3 tert-butyl-5-methylsalicylic acid; guaicol-sulfonic acid; 5-bromosalicylic acid; 3,5-dibromo-salicylic acid; 5-iodosalicylic acid, 3,5-diiodo-salicylic acid; 3,5-diiodosalicylic acid; 2-hydroxy-phenylacetic acid; 3-hydroxy-2-naphthoic acid; mandelic acid; phenyllactic acid, 2-hydroxyphenylmethanesulfonic acid; 5-trifluoromethyl-2-hydroxybenzoic acid; 4-hydroxy-3-hydroxyphenylmethanesulfonic acid; 3-methoxysalicylic acid; 5-octyloxysalicylic acid; 5-butoxysalicylic acid;
p-hydroxyphenoxyacetic acid; 3,4-dihydroxyphenylacetic acid; 5-chlorosalicylic acid; 3,4-dihydroxycinnamic acid; 3,5-dihydroxybenzoic acid; 2-hydroxy-3-methoxy-benzoic acid; 1-hydroxy-2-naphthoic acid; salicyluric acid; or the sodium salts thereof.
8. The drug form of Claim 1, wherein the adjuvant is salicylic acid or sodium salicylate.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12809980A | 1980-03-07 | 1980-03-07 | |
| US128,099 | 1980-03-07 | ||
| US21312280A | 1980-12-05 | 1980-12-05 | |
| US213,122 | 1980-12-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1165690A true CA1165690A (en) | 1984-04-17 |
Family
ID=26826260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000372411A Expired CA1165690A (en) | 1980-03-07 | 1981-03-05 | METHOD OF INCREASING ORAL ABSORPTION OF .beta.-LACTAM ANTIBIOTICS |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1165690A (en) |
-
1981
- 1981-03-05 CA CA000372411A patent/CA1165690A/en not_active Expired
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