Complexes to improve oral absorption of poorly absorbable...

Details Complexes to improve oral absorption of poorly absorbable... Complexes to improve oral absorption of poorly absorbable...

2000-06-21

2001-06-19

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S484000, C424S488000, C424S485000, C424S464000

Reexamination Certificate

active

06248360

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to compositions and methods for improving or promoting the intestinal absorption of poorly absorbable antibiotics, particularly third generation cephalosporin antibiotics, in oral dosage forms such that the antibiotics may be more readily absorbed through the mucosal membrane of the gastro-intestinal (GI) tract.
BACKGROUND OF THE INVENTION
Antibiotics have been used for several years to successfully fight pathogenic organisms such as bacteria. As technology has advanced and the understanding of pathogens has grown, anti-infective agents have become more effective. Cephalosporins are a prime example of the advance of antibiotic technology.
Cephalosporin is the general term for a group of antibiotic derivatives of cephalosporin C, which is obtained from the fungus
Cephalosporium Acremonium
. First generation cephalosporins and most second generation cephalosporins are functional in oral dosage forms, though they may be ineffective against many forms of bacteria such as those found in typical hospital infections. However, many third generation cephalosporins, such as ceftiofur, cefixime, cefepime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, and moxalactam, due to their broad spectrum of activity, are effective against some bacteria strains that are resistant to many first and second generation cephalosporins.
The GI tract, particularly the small intestines, is the primary site for the absorption of nutrients and most bioactive agents. To accommodate the amount of absorption that must take place in the small intestines, the surface area is enlarged due to the presence of villi and microvilli. However, before a bioactive compound is transferred from the intestinal lumen to the blood, the compound may have to withstand degradation or deactivation by the various components of the luminal contents. Moreover, the compound may be required to pass through several absorption barriers, such as the mucous layer and the intestinal brush-border membrane. Many compounds pass these barriers easily, but there are many nutrients and bioactive agents to which these barriers are a serious obstruction.
Third generation cephalosporins, though effective against some of the more resistant bacteria, are normally poorly absorbed through the mucosal membrane of the intestines and thus, have difficulty reaching the bloodstream systemically. Therefore, these cephalosporins have been less effective when administered by routes other than parenteral to treat systemic bacterial infections. Specifically, administration of third generation cephalosporins is sometimes accomplished by infusion, but more typically by intravenous (i.v.) or intramuscular (i.m.) injections.
Some injectable antibiotics, such as ceftriaxone, can be administered as infrequently as once a day. However, other injectable bioactive agents should be given more frequently than once daily to achieve the greatest amount of effectiveness. In either case, the necessity of obtaining treatment through i.v. or i.m. injections is inconvenient, as such treatments often requires the services of doctors, nurses, or other trained technicians. Additionally, injections can be painful and cause undue physical and psychological stress to many patients.
There are several contributing factors why third generation cephalosporins and other poorly absorbable antibiotics have low absorption in the intestines after oral administration. First, these antibiotics have high ionization properties that do not allow them to readily penetrate the intestinal mucosal membrane. Second, due to relatively high hydrophilic properties, these antibiotics are generally unstable in an aqueous environment such as in gastric juices and small intestine fluids.
As third generation cephalosporins, such as ceftriaxone, and other poorly absorbable antibiotics are poorly absorbed through the mucosal membrane of the intestines, many efforts have been made to find improved compositions and methods for delivering small intestine absorbable third generation cephalosporins or other poorly absorbable antibiotics in the form of capsules, tablets, and/or suspensions that are not harmful to the body. Though ionic surfactants, such as sodium lauryl sulfate, or chelating agents such as EDTA, have been found to enhance intestinal absorption of such large molecules, these substances are known to be harmful to the mucosal membrane.
Some technologies have shown some promise in providing compositions and methods of delivering third generation cephalosporins orally with increased intestinal absorption. In U.S. Pat. No. 4,525,339, &bgr;-lactam antibiotics were shown to penetrate the mucosal membrane of the intestines by co-administering C
2
-C
12
fatty acid mono-, di- , or triglycerides as an absorption enhancer. In U.S. Pat. No. 5,190,748, absorption of antibiotics (such as ceftriaxone) through oral and rectal routes was enhanced by utilizing a two-component absorption enhancing system. This system is comprised of an ether of a C6-C
18
alcohol and a polyoxyethylene glycol together with a second component selected from the group consisting of polyoxyethylene glycol C
6
to C
18
glyceride esters, C
6
to C
18
carboxylic acids or salts thereof, and esters of two or more C
6
to C
18
carboxylic acids, glycerol, and a polyoxyethylene glycol. Additionally, in U.S. Pat. No. 5,318,781, absorption of antibiotics (such as ceftriaxone) through oral and rectal routes was enhanced by utilizing a two-component absorption enhancing system comprised of Laureth-12, a second component salt of capric acid and caprylic acids, and a carrier. For optimum absorption, the antibiotic containing two component enhancer system disclosed therein may include Miglyol-812, which is a capryllic/capric triglyceride. In U.S. Pat. No. 4,722,941, the permucosal absorption of various therapeutics, including antibiotics, is reported to be enhanced by the use of fatty acids and saturated or unsaturated fatty acid glycerides.
Though each of these systems described and others are somewhat effective in delivering poorly absorbable antibiotics through the mucosal membrane after oral delivery, each have drawbacks that prevent their widespread use. Some of the compositions and/or methods do not provide significant enough drug delivery concentrations through the mucosal membrane such that commercial use is practical. Additionally, other compositions and/or methods of mucosal delivery are too costly. As the benefits of third generation cephalosporins and other poorly absorbable antibiotics have become apparent, it would be desirable to provide compositions and methods for administering these poorly absorbable antibiotics orally, and thus, provide an administration route that is more convenient and cost effective to the patient, and enhances the amount of poorly absorbable antibiotic that may be absorbed by the mucosal membrane of the intestines.
SUMMARY OF THE INVENTION
Essentially, the present invention discloses compositions and methods wherein third generation cephalosporins and other poorly absorbable antibiotics may be more readily absorbed in the small intestines, even after oral delivery. Specifically, a pharmaceutical composition for oral delivery is disclosed comprising (a) a biopolymer which is preferably swellable and/or mucoadhesive when hydrated; (b) a poorly absorbable antibiotic contained within or ionically bound to the biopolymer; and (c) a metal cation ionically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic.
Alternatively, a pharmaceutical composition for oral delivery is disclosed comprising (a) a biopolymer which is preferably swellable and/or mucoadhesive when hydrated; (b) a poorly absorbable antibiotic contained within or ionically bound to the biopolymer; and (c) a cationic molecule selected from the group consisting of cationic polymers, basic amino acids, quaternary ammonium salts, and combinations thereof, wherein the cationic molecule is ionically bound to at least one member sel

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