Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder.

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.

Application of surface area measurement for identifying the source of batch-to-batch variation in processability.

The primary goal of this study was to evaluate the use of specific surface area as a measurable physical property of materials for understanding the batch-to-batch variation in the flow behavior. The specific surface area measurements provide information about the nature of the surface making up the solid, which may include defects or void space on the surface. These void spaces are often present in the crystalline material due to varying degrees of disorderness and can be considered as amorphous regions. In the present work, the specific surface area for 10 batches of the same active pharmaceutical ingredient (compound 1) with varying quantity of amorphous content was investigated. Some of these batches showed different flow behavior when processed using roller compaction. The surface area value was found to increase in the presence of low amorphous content, and decrease with high amorphous content as compared to crystalline material. To complement the information obtained from the above study, physical blends of another crystalline active pharmaceutical ingredient (compound 2) and its amorphous form were prepared in known proportions. Similar trend in specific surface area value was found. Tablets prepared from known formulation with varying amorphous content of the active ingredient (compound 3) also exhibited the same trend. A hypothesis to explain the correlation between the amorphous content and specific surface area has been proposed. The results strongly support the use of specific surface area as a measurable tool for investigation of source of batch to batch variation in processability.

Combination antifungal therapy involving amphotericin B, rapamycin and 5-fluorocytosine using PEG-phospholipid micelles.

PURPOSE: Rapamycin and 5-fluorocytosine (5-FC) are antifungal agents with unique mechanisms of activity, with potential for cooperative interaction with AmB. Combination antifungal therapy involving conventional AmB has been restricted by poor physical stability and compatibility with antifungal drugs and vehicles. METHODS: AmB and rapamycin were encapsulated in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy poly(ethylene glycol) (PEG-DSPE) micelles using a solvent evaporation method. The physical stability of micelle encapsulated AmB and rapamycin with 5-FC and saline was evaluated using dynamic light scattering (DLS). In vitro susceptibility of Candida albicans isolates to 5-FC and PEG-DSPE micelle solubilized AmB and rapamycin has been evaluated. Interactive effects have been quantified using a checkerboard layout. RESULTS: In contrast with conventional AmB, PEG-DSPE micelles encapsulating AmB and rapamycin are compatible with saline and 5-FC over 12 h. The solubilized drugs retain high level of potency in vitro. The combination of solubilized AmB and rapamycin was indifferent, as fractional inhibitory concentration (FIC) index and combination index (CI) values were approximately 1. Combinations of solubilized AmB or rapamycin with 5-FC, and the three-drug combination were moderately synergistic since the FIC index and CI values were consistent less than 1. CONCLUSIONS: These results indicate that AmB solubilized in PEG-DSPE micelles is compatible with solubilized rapamycin and 5-FC. The indifferent or moderately synergistic activity of combinations is encouraging and warrants further investigation in appropriate rodent models.

Effect of cholesterol on the release of amphotericin B from PEG-phospholipid micelles.

Micelles formed from PEG-DSPE solubilize high levels of the poorly water-soluble antifungal amphotericin B (AmB). AmB release from PEG-DSPE micelles is slow in buffer but remarkably rapid in the presence of bovine serum albumin (BSA). Sequential changes in the absorbance spectrum of AmB in PEG-DSPE micelles point to a rapid dissociation of incorporated drug in the presence of BSA. In this context, we have studied micelles formed from PEG-DSPE which coincorporate cholesterol (PEG-DSPE|cholesterol). (1)H NMR measurements point to a lower mobility of lipid in PEG-DSPE|cholesterol micelles compared to PEG-DSPE micelles. The absorbance spectrum of AmB incorporated in PEG-DSPE|cholesterol micelles is distinct from that in PEG-DSPE micelles, which may point to differences in the drug-micelle interaction. AmB release from PEG-DSPE|cholesterol micelles is slow in buffer and in the presence of BSA. The absorption spectrum of AmB in PEG-DSPE|cholesterol micelles remained unchanged in BSA, further supporting stable incorporation and the slow release from the carrier.

Poly(ethylene glycol)-b-poly(epsilon-caprolactone) and PEG-phospholipid form stable mixed micelles in aqueous media.

Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG(5000)-b-PCL(x)) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy poly(ethylene glycol) (PEG-DSPE), possess small size and high thermodynamic stability, raising their potential as long circulating carriers in the context of delivery of antineoplastic and antibiotic drugs. Formation of mixed polymeric micelles was confirmed using size exclusion chromatography and 1H NMR NOESY. Steady-state fluorescence measurements revealed depressed critical micellar concentrations indicative of a cooperative interaction between component hydrophobic blocks, which was quantified using the pseudophase model for micellization. Steady-state fluorescence measurements indicated that the mixed polymeric micelle cores possess intermediate micropolarity and high microviscosity. Pulsed field gradient spin-echo measurements were used to characterize micellar diffusion coefficients, which agree well with those obtained using dynamic light scattering. NOE spectra suggested that the hydrophobic polymer segments from individual components are in close proximity, giving evidence for the formation of a relatively homogeneous core. Contrary to one-component PEG(5000)-b-PCL(x) micelles, the mixed polymeric micelles could incorporate clinically relevant levels of the poorly water soluble antibiotic, amphotericin B (AmB). AmB encapsulation and release studies revealed an interesting composition-dependent interaction of the drug with the mixed polymeric micelle core.