Note: Descriptions are shown in the official language in which they were submitted.
- 1 - IX079Y
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~
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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
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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~
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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-
$(~
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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)
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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,
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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
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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.
. ~
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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~
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EXAMPLE 1
.__
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
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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.
EXAMPLE 2
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.
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EXAMPLE 3
. _ .. _~
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.
EXAMPLE 4
. _
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.
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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~
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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.
