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Spray-congeal process using an extruder for preparing multiparticulate azithromycin compositions containing preferably a poloxamer and a glyceride

A technology of azithromycin and azithromycin ester, which is applied in the directions of medical preparations containing active ingredients, drug delivery, pharmaceutical formulations, etc., can solve the problems of uneven azithromycin content, uneven shape, and uneven size of formation, and reduce mutual agglomeration. risk, good taste, good content uniformity

Inactive Publication Date: 2007-01-03
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This approach has a number of disadvantages, including the possibility of azithromycin crystals appearing on the surface of multiple particles, thus exposing them to other azithromycin ester-forming excipients in the dosage form; formation of non-uniformly sized and larger particles, resulting in larger Large particle size distribution; non-uniform azithromycin content due to suspended drug settling during the time required to solidify the mixture; drug degradation at elevated temperatures with prolonged exposure to liquid wax; non-uniformly shaped particles; and the risk of particle agglomeration

Method used

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  • Spray-congeal process using an extruder for preparing multiparticulate azithromycin compositions containing preferably a poloxamer and a glyceride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0175] Study the tendency of azithromycin to form esters in the melt at different temperatures and over different time periods. Glyceryl behenate (13 to 21% by weight of monobehenate, 40 to 60% by weight of dibehenate and 21 to 35% by weight of tribehenate) (from Paramus, New Jersey Gattefossé Corporation’s COMPRITOL 888 ATO) was deposited in a glass vial as a 2.5 g sample and melted in a temperature-controlled oil bath at 100°C (Example 1), 90°C (Example 2) and 80°C (Example 3) . Then 2.5 grams of azithromycin dihydrate was added to each of these three melts, thereby forming a suspension of azithromycin in molten COMPRITOL 888 ATO. After stirring the suspension for 15 minutes, take 50 to 100 milligrams of the suspension sample from each molten sample and allow those to coagulate by cooling to room temperature. Each suspension was continuously stirred, and additional samples were collected 30, 60, and 120 minutes after forming the suspension. Store all samples at -20°C until analy...

Embodiment 4-25

[0184] Investigate the tendency of azithromycin to form esters in the melt at different temperatures and over different time periods. Screening Examples 4-25 were prepared as in Examples 1-3, except that various excipients, temperatures and exposure times listed in Table 3 were used. The chemicals composed of the various carriers selected are as follows: MYVAPLEX 600 is glyceryl monostearate; GELUCIRE50 / 13 is mono-, di- and tri-alkyl glycerides and polyethylene glycol mono- and di-glycerides -A mixture of fatty acid esters; carnauba wax is a compound mixture of acid and hydroxy acid esters, oxypolyols, hydrocarbons, resinous substances and water; microcrystalline waxes are linear and optionally branched saturated mixtures obtained from petroleum A petroleum-derived mixture of alkanes; paraffin is a purified mixture of solid saturated hydrocarbons; stearyl alcohol is 1-octadecyl alcohol; stearic acid is octadecanoic acid; PLURONIC F127 is a block of ethylene oxide and propylene oxi...

Embodiment 26

[0189] This example illustrates how the degree of acid / ester substitution can be determined from the saponification number of the excipient. Divide the saponification number of the carrier listed in Pharmaceutical Excipients 2000 by 56.11 to determine the degree of acid / ester substitution of the excipients listed in Table 5 [A].

[0190] Excipient

[0191] *Milli equivalent / g carrier

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Abstract

Azithromycin multiparticulates containing acceptably low concentrations of azithromycin esters are formed by a melt-congeal process using an atomizer and extruder.

Description

Background of the invention [0001] Multiparticulates are well-known dosage forms that contain many particles that collectively represent a dose of a drug desired to be medically useful. In oral administration, the multi-particles are usually freely dispersed in the gastrointestinal tract, and are excreted from the stomach relatively quickly and reproducibly to achieve maximum absorption and minimize side effects. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994) and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989). [0002] It is known to prepare drug particles by melting the drug to form droplets and cooling the droplets to form small drug particles. These methods of preparing multiple particles are usually called "melting and freezing" methods. Refer to US Patent Nos. 4,086,346 and 4,092,089, both of which disclose rapid melting of phenacetin and spray melts in an extruder to form phenacetin particles. [0003] Azithromycin is the generic n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K31/00A61K9/00A61K9/14A61K31/7032A61K31/7052
CPCA61K9/1694A61K31/7032A61K31/7052A61K9/1641A61K9/1617A61K9/145A61K9/0095A61P31/04A61K9/16
Inventor L·E·阿佩尔M·D·克鲁D·T·弗里森S·M·赫比格S·R·莱莫特J·B·罗D·K·莱昂S·B·麦克雷D·D·纽博尔特R·J·雷J·B·韦斯特
Owner PFIZER PRODS ETAT DE CONNECTICUT