کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10162455 | 1114330 | 2014 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Intramuscular Administration of Paliperidone Palmitate Extended-Release Injectable Microsuspension Induces a Subclinical Inflammatory Reaction Modulating the Pharmacokinetics in Rats
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کلمات کلیدی
tmaxPBPKs.c.CmaxPPPAPIpaliperidone palmitateOROPLMAUC - AUCCL/F - CL / Ft1/2 - t1 / 2Sustained release - آزادی پایدارinflammation - التهاب( توروم) Tem - این استLong-Acting Injectable - تزریق طولانی مدتOil red O - روغن قرمز Osubcutaneously - زیر جلدیBiocompatibility - زیست سازگاریLAI - شبیهIntramuscular - عضلانیMuscle - عضلهPharmacokinetics - فارماکوکینتیکPhysiologically based pharmacokinetic - فارماکوکینتیک مبتنی بر فیزیولوژیSEM - مدل معادلات ساختاری / میکروسکوپ الکترونی روبشیi.m. - من هستم.Active Pharmaceutical Ingredient - مواد اولیه دارویی فعالScanning electron microscopy - میکروسکوپ الکترونی روبشیTransmission electron microscopy - میکروسکوپ الکترونی عبوریPolarized light microscopy - میکروسکوپ نور پلاریزهNanoparticles - نانوذراتhaematoxylin and eosin - هماتوکسیلین و ائوزینHistopathology - هیستوپاتولوژیDisposition - وضعPaliperidone - پالپیریدونLaser diffraction - پراش لیزریPolystyrene - پلیاستایرن Prodrugs - پیش دارو
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The present study aims at elucidating the intricate nature of the drug release and absorption following intramuscular (i.m.) injection of sustained-release prodrug nanocrystals/microcrystals. A paliperidone palmitate (PPP) long-acting suspension was characterized with regard to particle size (Dv,50 = 1.09 μm) and morphology prior to i.m. injection in rats. The local disposition was rigorously investigated by means of (immuno)histochemistry and transmission electron microscopy while the concurrent multiphasic pharmacokinetics was linked to the microanatomy. A transient (24 h) trauma-induced inflammation promptly evolved into a subclinical but chronic granulomatous inflammatory reaction initiated by the presence of solid material. The dense inflammatory envelope (CD68+ macrophages) led to particle agglomeration with subsequent drop in dissolution rate beyond 24 h postinjection. This was associated with a decrease in apparent paliperidone (PP) absorption (near-zero order) until 96 h and a delayed time of occurrence of observed maximum drug plasma concentration (168 h). The infiltrating macrophages phagocytosed large fractions of the depot, thereby influencing the (pro)drug release. Radial angiogenesis (CD31+) was observed throughout the inflammatory rim from 72 h onwards and presumably contributed to the sustained systemic PP concentrations by maintaining a sufficient absorptive capacity. No solid-state transitions of the retrieved formulation were recorded with X-ray diffraction analysis. In summary, the initial formulation-driven prodrug (PPP) dissolution and drug (PP) absorption were followed by a complex phase determined by the relative contribution of formulation factors and dynamic physiological variables.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 103, Issue 7, July 2014, Pages 2072-2087
Journal: Journal of Pharmaceutical Sciences - Volume 103, Issue 7, July 2014, Pages 2072-2087
نویسندگان
Nicolas Darville, Marjolein van Heerden, An Vynckier, Marc De Meulder, Patrick Sterkens, Pieter Annaert, Guy Van den Mooter,