Acne, a common skin disease in teenagers, is caused by Propionibacterium acnes (P. acnes). Isotretinoin (ITR) is though reported to have immense antiacne potential, yet there are hardly any reports vouching its antimicrobial activity. The present study, therefore, was undertaken to study the antimicrobial activity of ITR and evaluate the effect of its encasement in nanocarriers on its minimum inhibitory concentration (MIC). The nanocarriers were also evaluated for the skin transport characteristics. MICs of pure drug and entrapped drug in nanolipid carriers (ITR-NLCs) and in solid lipid nanoparticles (ITR-SLNs) were determined by broth dilution method against clindamycin phosphate as the reference antibiotic. It was observed that ITR possessed marked antimicrobial activity against anaerobic pathogen, P. acnes. Nanocarriers loaded with ITR, that is, SLNs and NLCs, enhanced the antimicrobial activity even at lower concentrations vis-à-vis the drug alone and improved drug transport potential vis-à-vis the commercial gel. The unique findings could be the result of effective adhesion of ITR-loaded nanocarriers to the bacterial membranes and release of drug directly to the target. Besides establishing ITR as an antimicrobial agent against acne-causing bacteria, the current work ratifies immense potential of nanocolloidal carriers like SLNs and NLCs to treat acne in a more efficient manner.
The objectives of present studies were to develop the systematically optimized multiple-unit gastroretentive microballoons, i.e. hollow microspheres of itopride hydrochloride (ITH) employing quality by design (QbD)-based approach. Initially, the patient-centric QTPP and CQAs were earmarked, and preliminary studies were conducted to screen the suitable polymer, solvent, solvent ratio, pH and temperature conditions. Microspheres were prepared by non-aqueous solvent evaporation method employing Eudragit S-100. Risk assessment studies carried out by constructing Ishikawa cause-effect fish-bone diagram, and techniques like risk estimation matrix (REM) and failure mode effect analysis (FMEA) facilitated the selection of plausible factors affecting the drug product CQAs, i.e. percent yield, entrapment efficiency (EE) and percent buoyancy. A 3(3) Box-Behnken design (BBD) was employed for optimizing CMAs and CPPs selected during factor screening studies employing Taguchi design, i.e. drug-polymer ratio (X1), stirring temperature (X2) and stirring speed (X3). The hollow microspheres, as per BBD, were evaluated for EE, particle size and drug release characteristics. The optimum formulation was embarked upon using numerical desirability function yielding excellent floatation characteristics along with adequate drug release control. Drug-excipient compatibility studies employing FT-IR, DSC and powder XRD revealed absence of significant interaction among the formulation excipients. The SEM studies on the optimized formulation showed hollow and spherical nature of the prepared microspheres. In vivo X-ray imaging studies in rabbits confirmed the buoyant nature of the hollow microspheres for 8 h in the upper GI tract. In a nutshell, the current investigations report the successful development of gastroretentive floating microspheres for once-a-day administration of ITH.
Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics.
Abstract. The current studies entail systematic quality by design (QbD)-based development of stimuliresponsive gastroretentive drug delivery systems (GRDDS) of acyclovir using polysaccharide blends for attaining controlled drug release profile and improved patient compliance. The patient-centric quality target product profile was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through Ishikawa fish bone diagram and failure mode, effect, and criticality analysis, helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. A face-centered cubic design was employed for systematic development and optimization of the concentration of sodium alginate (X 1 ) and gellan (X 2 ) as the critical material attributes (CMAs) in the stimuli-responsive formulations, which were evaluated for CQAs viz. viscosity, gel strength, onset of floatation, and drug release characteristics. Mathematical modeling was carried out for generation of design space, and optimum formulation was embarked upon, exhibiting formulation characteristics marked by excellent floatation and bioadhesion characteristics along with promising drug release control up to 24 h. Drug-excipient compatibility studies through FTIR and DSC revealed absence of any interaction(s) among the formulation excipients. In vivo pharmacokinetic studies in Wistar rats corroborated extension in the drug absorption profile from the optimized stimuli-responsive GR formulations vis-à-vis the marketed suspension (ZOVIRAX®). Establishment of in vitro/in vivo correlation (IVIVC) revealed a high degree of correlation between the in vitro and in vivo data. In a nutshell, the present investigations report the successful development of stimuli-responsive GRDDS of acyclovir, which can be applicable as a platform approach for other drugs too.
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