Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1996-11-04
2000-05-30
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424489, 424464, 424484, 424465, A61K 916, A61K 950
Patent
active
060688599
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a controlled-release dosage form of azithromycin having an improved side effect profile, to a process for preparing the dosage form, and to a method of treating a microbial infection, comprising administering azithromycin in such a controlled-release dosage form to a mammal, including a human patient, in need of such treatment.
BACKGROUND OF THE INVENTION
Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A. Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359. These patents disclose that azithromycin and certain derivatives thereof possess antimicrobial properties and are accordingly useful as antibiotics.
It is widely known that oral dosing of azithromycin can result in the occurrence, in some patients, of adverse gastrointestinal (GI) side effects, such as cramping, diarrhea, nausea, and vomiting. In combined clinical studies of azithromycin involving 3,995 patients (all dose levels combined), 9.6% of patients reported gastrointestinal side effects. The most frequent of these side effects were diarrhea (3.6%), nausea (2.6%), and abdominal pain (2.5%) (Hopkins, Am. J. Med. 91(suppl 3A) (1991) 40S-45S).
The incidence of gastrointestinal side effects is higher at higher doses than at lower doses. For example, a common 5 day course of azithromycin therapy consists of 500 mg on day 1 followed by 250 mg on days 2, 3, 4, and 5. For this course of therapy, the reported incidence of various gastrointestinal side effects was 5% diarrhea/loose stools, 3% abdominal pain, and 3% nausea (Zithromax (Trademark of Pfizer Inc.) capsule package insert). After a single 1 g oral dose, the reported incidence of various gastrointestinal side effects was 7% diarrhea/loose stools, 5% nausea, and 2% vomiting (Zithromax capsule package insert).
It is also known that azithromycin can cause gastrointestinal side-effects in non-human mammals, e.g. dogs.
An improved dosage form of azithromycin which permitted oral dosing of high doses of azithromycin (e.g., 2 g) with relatively reduced side effects would permit wider application of single dose azithromycin therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Likewise, an improved dosage form which lowered the incidence of gastrointestinal side-effects at lower doses would also be of significant value.
SUMMARY OF THE INVENTION
This invention provides a controlled release dosage form of azithromycin which decreases, relative to currently marketed instant release azithromycin capsule dosage forms which deliver an equivalent dose, the incidence and/or severity of gastrointestinal side effects. The dosage form can operate by effecting the release of azithromycin at a rate sufficiently slow to ameliorate side effects. The dosage form can also operate by releasing the bulk of the azithromycin contained therein in the portion of the GI tract distal to the duodenum. Specific embodiments can be in the form of a sustained release oral dosage form or, alternatively, in the form of a delayed release oral dosage form, or, alternatively, in the form of an oral dosage form which exhibits a combination of sustained release and delayed release characteristics. The term "controlled" is generic to "sustained" and "delayed". Dosage forms which release more than 70% of their contained azithromycin within one half hour or less are not "controlled release", and form no part of this invention.
In a specific aspect this invention provides a sustained release dosage form comprising azithromycin and a pharmaceutically acceptable carrier which, following ingestion by a mammal in need of such treatment, releases azithromycin to said mammal's gastrointestinal tract at a rate such that the total amount of azithromycin released therein is: first 15 minutes after ingestion, first hour after ingestion, first 2 hours after ingestion, firs
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Curatolo William J.
Friedman Hylar L.
Korsmeyer Richard W.
LeMott Steven R.
Benson Gregg C.
Benston, Jr. William E.
Jones James T.
Page Thurman K.
Pfizer Inc.
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