Title:  Complexes to improve oral absorption of poorly absorbable antibiotics

United States Patent:  6,248,360

Assignee:  International Health Management Associates, Inc. (Rolling Meadows, IL)

Filed:  June 21, 2000

The present invention provides compositions and methods for increasing absorption of poorly absorbable antibiotics, particularly third generation cephalosporin antibiotics, in oral dosage solid and/or suspension forms. Specifically, the composition is comprised of a biopolymer that is preferably swellable and/or mucoadhesive, a poorly absorbable antibiotic, and a cationic binding agent contained within the biopolymer such that the binding agent is tonically bound or complexed to at least one member selected from the group consisting of the biopolymer and the antibiotic.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein, as such process steps and materials may vary to some degree. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting as the scope of the present invention will be limited only by the appended claims and equivalents thereof.

As used herein the following terms shall have the assigned meanings:

It must be noted that, as used in this specification and the appended claims, singular forms of "a," "an, " and "the" include plural referents unless the content clearly dictates otherwise.

"Biocompatible" shall mean any substance that is not toxic to the body.

"Biodegradable" shall mean that the biopolymer used can break down or degrade within the body to non-toxic components before, after, or while an antibiotic is released.

"Poorly absorbable antibiotic" shall mean any antibiotic that exhibits low bioavailability in oral or other non-parenteral dosage form, typically due to relatively high hydrophilicity and/or ionization properties of the antibiotic. Though not required, the preferred antibiotics for use with the present invention are typically poorly absorbable due to the presence of an ionic electrical charge under physiological conditions. The antibiotic can be positively charged, negatively charged, or amphiphilic. Examples of typical poorly absorbable antibiotics that are charged include third generation cephalosporins, though other poorly absorbable antibiotics are also functional with the present invention. The charge on the antibiotic creates difficulty for the antibiotic to cross the mucosal membrane of the intestines alone. Thus, the ability for the antibiotic to cross the mucosal membrane is significantly enhanced when present as part of a composition of the present invention.

"Oral absorption" is used in the context of how the compositions of the present invention are delivered and absorbed into the blood. Typically, the composition is administered orally and the antibiotic of the composition then crosses a mucosal membrane of the gastro-intestinal tract, preferably in the intestines. However, other methods of contacting the compositions of the present invention with the mucosal membrane of the gastro-intestinal tract may be used.

"Metal ion" or "metal cation" shall mean any positively charged metal ion that is functional for use with the present invention. Essentially, the metal cation binds to the antibiotic and/or the biopolymer in accordance with the present invention. In the case of the poorly absorbable antibiotic, the metal cation may be complexed, chelated, or ionically bound to the antibiotic. Exemplary metal cations include, but are not limited to calcium, potassium, magnesium, iron, copper, zinc, aluminum, manganese, chromium, cobalt, nickel, sodium, and combinations thereof.

"Cationic molecule" shall mean any molecule with one or more positively charged moieties that act to ionically bind to the antibiotic and/or the biopolymer. Negatively charged moieties can also be present, though this is not required. Exemplary cationic molecules include cationic polymers, basic amino acids, quaternary ammonium salts, and combinations thereof.

"Cationic binding agent" is intended to include both metal cations and cationic molecules.

"Swellable" shall mean that the biopolymers and/or compositions of the present invention have the ability to swell or enlarge, such as when hydrated.

"Mucoadhesive" shall mean any biopolymer that is capable of adhering to a mucosal membrane, particularly when hydrated.

The absorption of poorly absorbable antibiotics in the small intestines is significantly enhanced by the compositions and methods of the present invention. Essentially, by ionically binding or complexing poorly absorbable antibiotics with a biopolymer (which is preferably mucoadhesive as a swollen hydrogel) and/or a binding agent, the stability of the antibiotic is significantly enhanced and the ionic charge can be partially neutralized facilitating mucosal absorption through the intestinal wall. The intestinal absorption of these otherwise poorly absorbable antibiotics may be enhanced for both solid and suspension dosage forms.

With this in mind, a first embodiment of 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. Such compositions can be prepared for oral dosage in solid or suspension forms.

Alternatively, a second embodiment of a pharmaceutical composition for oral delivery is also 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 tonically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic. Such a composition can be prepared for oral dosage in solid form.

Additionally, a method of delivering a poorly absorbable antibiotic to the blood stream of an animal is disclosed which comprises the steps of (a) orally administering to the animal a composition comprising a biopolymer, an effective amount of a poorly absorbable antibiotic contained within or ionically bound to the biopolymer, and a cationic binding agent ionically bound to at least one member selected from the group consisting of the biopolymer and the antibiotic; (b) causing the biopolymer to swell and adhere to a mucosal membrane lining of an intestinal wall of the animal; and (c) delivering the antibiotic from the composition to the mucosal membrane lining such that the antibiotic, and optionally the binding agent, cross the intestinal wall and enter the bloodstream.

With each of these compositions and methods, the poorly absorbable antibiotic and binding agent can be present within a specific preferred molar ratio, though these ratios are not intended to cover all effective compositions. For example, if a metal cation is used as the binding agent, then the poorly absorbable antibiotic to metal cation molar ratio can be from about 10:1 to 1:5, preferably about 5:1. Additionally, the poorly absorbable antibiotic to biopolymer molar ratio can be from about 5:1 to 1:5, preferably about 2:1. Alternatively, if a cationic molecule is used as the binding agent, then the poorly absorbable antibiotic to cationic molecule molar ratio can be from about 1:4 to 1:1, preferably from about 1:2 to 1:1, e.g., 1:2 for antibiotic:amino acid embodiments and 1:1 for antibiotic:cetyl pyridinium embodiments. Additionally, in this embodiment, the poorly absorbable antibiotic to biopolymer molar ratio can be from about 5:1 to 1:5, preferably about 2:1.

In the above compositions and methods, the biopolymer for use may be any biopolymer that is functional with the present invention. However, when in the form of a hydrogel, mucoadhesive and/or swellable biopolymers are the most preferred. Exemplary biopolymers include, but are not limited to carrageenan, pectin, chondroitin sulfate, sodium alginate, and/or poly(methacrylic acid).

Poorly absorbable antibiotics can include any antibiotic that, in the absence of being part of a composition of the present invention, is substantially inhibited from crossing the mucosal membrane of the intestines. However, poorly absorbable antibiotics with which the technology of the present invention is particularly useful include many charged cephalosporins, charged peptide and polypeptide antibiotics, and/or charged aminoglycosides.

If a charged cephalosporin is used, third generation cephalosporins are included among exemplary poorly absorbable antibiotics that may be used. Specific examples of functional cephalosporins for use with the present invention include, but are not limited to, ceftiofur, cefepime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, and/or moxalactam. If an aminoglycoside is used, functional drugs include amikacin and/or tobramycin. If a peptide or polypeptide antibiotic is used, then vancomycin, daptomycin, polymixin-B, and/or bacitracin can also be functional.

In accordance with the first embodiment, if a metal cation is used as the binding agent, calcium, potassium, magnesium, iron, copper, zinc, aluminum, manganese, chromium, cobalt, nickel, and/or sodium may be used. These cations are preferred because each of these metal cations are biocompatible. However, cations such as zinc, and particularly, calcium are most preferred.

The metal cation can be arranged in relation to the biopolymer and the poorly absorbable antibiotic in one of three preferred manners. First, the metal cation can be bound to the biopolymer forming a cation-biopolymer combination such that the antibiotic is entrained within the cationic-biopolymer ionic combination. Second, the metal cation can be complexed to the antibiotic and the cation-antibiotic complex can then be entrained within the biopolymer. Third, the metal cation can be complexed to the antibiotic and further bound to the biopolymer forming an antibiotic-cation-biopolymer bridge. When using the metal cation as the binding agent, the compositions of the present invention may be prepared in both solid form (e.g., tablets, capsules, etc.) and suspension form.

If a cationic molecule is used as the binding agent (rather than the metal cation), then there are three preferred molecule types that may be used. First, cationic polymers including, but not limited to, poly(allylamine), poly-(l-lysine), poly(arginine), dodecyl trimethyl ammonium bromide, and/or polyethylenimines (primary, secondary, and tertiary) may be used. Additionally, basic amino acids may be used as the cationic molecule. Exemplary basic amino acids include the use of one or more of the naturally occurring amino acids such as arginine, lysine, and/or histidine. Further, the cationic molecule may be a quaternary ammonium salt including, but not limited to, benzalkonium derivatives, cetyl pyridinium derivatives such as chlorides or bromides, dodecyl-trimethyl ammonium salt derivatives, tetradecyl-trimethyl ammonium salt derivatives, and/or cetyl-trimethyl ammonium salt derivatives.

No matter which cationic molecule is used, the cationic molecule can be arranged in relation to the biopolymer and the poorly absorbable antibiotic in one of two preferred manners. First, the cationic molecule can be bound to the biopolymer forming a cationic molecule-biopolymer combination and the antibiotic can be entrained within the cationic molecule-biopolymer combination. Second, the cationic molecule can be bound to the antibiotic forming a cationic molecule-antibiotic combination and the cationic molecule-antibiotic combination can be entrained within the biopolymer.

The compositions of the present invention may be administered orally in a solid state such as in a capsule or tablet or may be delivered orally as a suspension, depending on the formulation used. In either case, the composition is designed such that the antibiotic may be transmucosally delivered into the bloodstream, preferably through the walls of the small intestines.

Claim 1 of 60 Claims

What is claimed is:

1. A pharmaceutical composition for oral delivery comprising:

a) a biopolymer;

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.

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