In vivo evaluation of tablets and capsules containing spray-dried o/w-emulsions for oral delivery of poorly soluble drugs.

It is recognised that poorly soluble drugs may show an increased oral bioavailability when incorporated in o/w-emulsions. Encapsulating the emulsion lipid droplets in hydroxypropyl methylcellulose (HPMC) by spray drying has been demonstrated to preserve an improved bioavailability releasing lipid droplets from the powder in vivo. However, the spray-dried powder is cohesive and bulky requiring additional processing to improve handling. This was resolved in previous work where a directly compressible dry emulsion formulation was described. The purpose of the present study is to investigate the oral bioavailability resulting from administration of a directly compressible dry emulsion as a tablet and compare it with a HPMC dry emulsion powder and a simple lipid solution. Four female Beagle dogs received a single dose of each formulation containing the same amount of medium-chain triglycerides (MCT) and a model drug, Lu 28-179. Cyclodextrin solutions administered orally and intravenously were used as references. The absolute bioavailability decreased in the order cyclodextrin solution (0.14), HPMC dry emulsion (0.11), technically improved dry emulsion (0.10) and MCT solution (0.06). The directly compressible dry emulsion tablets were concluded to be comparable to a HPMC dry emulsion powder in terms of bioavailability. The lack of statistically significant differences relative to a MCT solution was ascribed to a low and variable absolute oral bioavailability of the model drug.

Expression levels and functional aspects of the hyaluronan receptor CD44. Effects of insulin, glucose, IGF-I, or growth hormone on human arterial smooth muscle cells.

An increased amount of hyaluronan (HA) in the arterial wall is a feature of the diabetic macroangiopathy. The functional consequences of accumulated HA are mediated through binding to CD44. The regulation of this receptor by diabetic metabolic and hormonal factors is, however unknown. The objective of this study was to examine the influence of glucose, insulin, insulin-like growth factor I (IGF-I), and human growth hormone (hGH) on the formation and function of the HA receptor CD44 in cultures of human aortic smooth muscle cells (SMCs). Migration of nonproliferating SMCs were determined by estimating the area covered by cells 6 days after removal of a barrier. Cellular content of standard CD44 and its isoforms, CD44v3 and CD44v6, and HA-binding capacity were measured using a modified enzyme-linked immunosorbent assay procedure. The analysis is made either with antibodies against CD44 or with HA as a ligand. The migration assay showed that glucose, insulin, and IGF-I were able to stimulate SMC migration (2 P < .01). Anti-CD44 antibody inhibited the stimulated migration at most concentrations. Insulin increased HA binding at 100 to 1000 micro U/mL insulin (2 P < .03). CD44 expression was only elevated at 1000 micro U/mL insulin (2 P < .03), whereas CD44 content decreased at 2 ng/mL hGH and increased at 16 ng/mL hGH (2 P < .01). Glucose and IGF-I reduced the amount of the variant isoform CD44v3 (2 P < .01) but did not change the amount of total CD44. CD44v6 was not present on human arterial SMCs. In conclusion, the present data obtained with human arterial SMCs in vitro support a role of CD44 and its isoform, CD44v3, in the SMC response to the metabolic and hormonal disorders of diabetes.

Process characteristics and compaction of spray-dried emulsions containing a drug dissolved in lipid.

The objective of the present study is to prepare directly compressible powders, containing a poorly water-soluble drug dissolved in medium-chain triglycerides (MCT), by spray drying o/w-emulsions in a pilot plant spray dryer. In addition to the lipid phase, the emulsions contained a water-soluble carrier (a sugar), a water-insoluble carrier (magnesium alumino metasilicate) and a combined emulsifier and film-forming agent (gelatine). A factorial design was used to investigate the effect of formulation variables on the spray drying process and powder properties. The factors varied were soluble carrier type (trehalose or mannitol), insoluble carrier particle size distribution (granular or fine powder) and amount of lipid phase in the emulsion (low or high). Compressibility and compactibility of the spray-dried emulsions were mainly affected by the content of lipid in the powders and decreased on increasing the amount of lipid. Increasing the particle size of the insoluble carrier decreased spray drying process yield and lipid encapsulation efficiency whereas compactibility and handling properties were improved. Incorporation of a soluble carrier becoming amorphous on spray drying resulted in tablets with an increased mechanical strength compared to powders containing a crystalline soluble carrier.

Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols.

The partitioning of poorly soluble drugs into an aqueous micellar phase was exploited using an in vitro lipid digestion model, simulating the events taking place during digestion of acylglycerols in the duodenum. The aqueous micellar phase was isolated after ultracentrifugation of samples obtained at different degrees of triacylglycerol hydrolysis. Flupentixol, 1'-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4' piperidine] (LU 28-179) and probucol were studied. The effect of the alkyl chain length of the triacylglycerol was studied using a medium-chain triacylglycerol (MCT) and a long-chain triacylglycerol (LCT), respectively. In general, an oil solution was used as the lipid source in the model. Samples were analysed in regard to micellar size, lipid composition and drug concentration. During lipolysis, the content of lipolytic products in the aqueous micellar phase increased. The micellar size (R(H) approximately 3 nm) only increased when long-chain lipolytic products were incorporated in the mixed micelles (R(H) approximately 7.8 nm). Flupentixol was quickly transferred to the mixed micelles due to high solubility in this phase (100% released). A tendency towards higher solubilisation of LU 28-179, when it was administered in the LCT (approximately 24% released) compared to when it was administered in the MCT (approximately 15% released) at 70% hydrolysis, and a lagphase was observed. There was no difference in the solubilisation of probucol using MCT or LCT ( approximately 20% released), respectively. Differences in the physicochemical properties of the drugs resulted in differences in their distribution between the phases arising during lipolysis.