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Azithromycin dosage forms with reduced side effects

A technology of azithromycin and dosage form, applied in the field of azithromycin dosage form with reduced side effects, can solve problems such as low bioavailability

Active Publication Date: 2005-11-16
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many controlled-release dosage forms, especially those explicitly exemplified in that document, were later found to be less bioavailable than their immediate-release equivalents

Method used

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  • Azithromycin dosage forms with reduced side effects
  • Azithromycin dosage forms with reduced side effects
  • Azithromycin dosage forms with reduced side effects

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] Effects of Various Alkalizing Reagents on Gastric pH

[0215] A clinical study was performed to monitor gastric pH (using a pH probe) after administration of six different formulations containing an alkalizing agent. Prior to conducting this clinical study, a titration study was performed on the formulation containing the basifying agent to determine the change in pH upon addition of 0.1 N HCl to the basifying agent.

[0216] The formulations tested included the following alkalizing agents:

[0217] Formulation 1-176 mg TSP anhydrous

[0218] Formulation 2-352 mg TSP anhydrous

[0219] Formulation 3 - 352 mg anhydrous TSP and 500 mg calcium carbonate

[0220] Formulation 4 - 352 mg anhydrous TSP and 250 mg magnesium hydroxide

[0221] Formulation 5-352 mg anhydrous TSP and 500 mg tromethamine (TRIS)

[0222] Formulation 6 - 352 mg anhydrous TSP and 1000 mg tromethamine (TRIS)

[0223] In addition, by mixing a specific alkalizing agent with 19.36g sucrose, 0.067g...

Embodiment 2

[0245] Dosage forms of the same but different amounts of alkalizing reagent

[0246] Comparison of release rates in vitro

[0247] Various azithromycin ER dosage forms containing 2 gA of the same azithromycin multiparticulate (MP1) and different amounts of TSP as alkalizing agent were tested compared to azithromycin dosage forms containing MP1 multiparticulates without TSP and azithromycin immediate release dosage forms containing TSP in vitro release rate. Prepare sustained-release dosage forms as described in Step A below, and perform in vitro release rate studies and measure the results as described in Step B below.

[0248] Step A - Preparation of Azithromycin Sustained Release Dosage Form

[0249] Five sustained-release dosage forms of azithromycin (hereinafter denoted "SR1", "SR2", "SR3", "SR4", "SR5") were prepared by mixing 2000 mgA of azithromycin multiparticulate MP1 with one of six excipient mixtures, The preparation method and five dosage forms are described...

Embodiment 3

[0271] Comparison of In Vitro Release Rates of Dosage Forms with Different Basifying Agents

[0272] The in vitro release rate of azithromycin was determined in 0.01N HCl from various azithromycin extended-release dosage forms, each containing 2gA azithromycin multiparticulate MP1 prepared from one of three excipient mixtures, as described below:

[0273] "SR6" includes 38.7g sucrose and 100mg sodium carbonate weak base,

[0274] "SR7" includes 38.7g sucrose and 50mg magnesium hydroxide, and

[0275] "SR8" consists of 38.7g sucrose and 1.0g Liquid Maalox(R) (smooth cherry (smooth cherry), regular strength, from Novartis), which contains 37.1mg aluminum hydroxide, 37.1mg magnesium hydroxide and 3.7mg simethicone ).

[0276] The release rate of azithromycin from these extended release dosage forms was measured as described in Example 2. The results of these dissolution tests, shown in Table 2 below, show that the addition of various basifying agents slowed the release rate ...

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Abstract

An oral dosage form comprising azithromycin and an effective amount of a basifying agent. Preferably, the oral dosage form comprises an effective amount of a basifying agent and azithromycin multiparticulates, wherein the multiparticulates comprise azithromycin, a mixture of glyceryl monobehenate, glyceryl dibehenate, and glyceryl tribehenate, and porol sham. Typically, such oral dosage forms include any form suitable for oral administration such as powders for oral suspensions, unit dose sachets or sachets, tablets or capsules. Also disclosed is an oral suspension comprising azithromycin, an effective amount of a basifying agent, and a vehicle. Preferably, the azithromycin is in the form of multiparticulates, wherein the multiparticulates comprise azithromycin, a mixture of glyceryl monobehenate, glyceryl dibehenate and glyceryl tribehenate, and a poloxamer. Also disclosed is a method of reducing gastrointestinal side effects associated with administration of azithromycin to a mammal, comprising continuously administering to said mammal azithromycin and an effective amount of an alkalizing agent, wherein the incidence of gastrointestinal side effects is lower than that of an equivalent dose of azithromycin Incidence without administration of the basifying agent. Also disclosed is a method of treating a mammal in need against a bacterial or protozoan infection comprising sequentially administering to said mammal a single oral dosage form, wherein said oral dosage form comprises azithromycin and an effective amount of a basifying agent. Also disclosed are azithromycin multiparticulates comprising azithromycin, a surfactant; and a pharmaceutically acceptable carrier.

Description

Background of the invention [0001] Azithromycin is an antibiotic given orally or intravenously that is used to treat a variety of infections, especially those of the urinary tract, bronchi, lungs, sinuses, and middle ear. [0002] Oral administration of azithromycin can lead to adverse gastrointestinal (GI) side effects such as nausea, cramping, diarrhea and vomiting in a significant number of patients. Such gastrointestinal side effects can also occur in non-human mammals such as dogs. In a clinical combination study of azithromycin involving 3,995 patients (all dose levels studied in the combination), gastrointestinal side effects were reported in 9.6% of patients; the most common side effects were diarrhea (3.6%), nausea (2.6%), and abdominal pain (2.5%), see Hopkins, 91 Am. J. Med. 40S (suppl 3A 1991). [0003] The incidence of these side effects increased with increasing dose levels of azithromycin. For the treatment of adults, given a single dose of 1 gram of oral sus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K38/00
Inventor 蒂莫西·A·哈根斯科特·M·赫比格朱利安·B·洛阿维纳什·G·托布里利厄·E·阿佩尔马歇尔·D·克鲁德韦恩·T·弗里森戴维·K·莱昂斯科特·B·麦克雷詹姆斯·B·韦斯特
Owner PFIZER PRODS ETAT DE CONNECTICUT
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