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Drug release from microparticle-based topical gels may affect their bioavailability, safety and efficacy. This work sought to elucidate spatial distribution of the drug within the microparticle matrix and how this impacts the product's critical performance attributes. The purpose of this research was to inform the development of in vitro characterization approaches to support a demonstration of bioequivalence. Drug-free microparticles were loaded with tretinoin or drug-loaded microparticles were separated from purchased Retin-A Micro® (tretinoin) topical gel drug products. The resultant microparticles were analyzed for tretinoin content, drug loading efficiency, morphology, surface topography, surface pore size distribution, particle size distribution and tretinoin release. The solid-state characteristics and chemical interaction of tretinoin with the microparticles were also investigated. Microparticles loaded with tretinoin made in-house and those separated from Retin-A Micro® (tretinoin) topical gel were spherical, polydisperse and free of aggregates. The surface porosity of the microparticles was ∼19.8% with an average pore size of ∼327 nm. Microparticles loaded with tretinoin in-house were smaller in size and exhibited faster drug release than those separated from Retin-A Micro® (tretinoin) topical gel. Tretinoin release was found to increase with an increase in the drug loading. Based on XRD and DSC data, tretinoin was present in an amorphous state. The FTIR spectra indicated a disappearance of carbonyl band of microparticles and shifting of the hydroxyl band of tretinoin due to hydrogen bonding. The extent of drug loading and the solid-state interaction of tretinoin with the microparticles may be critical for drug release. Additional characterization of the drug products is necessary to understand the effect of the factors examined in this work on the bioavailability and efficacy of tretinoin gels., (Published by Elsevier B.V.)

Rapid drug release at the specific site of action is still a challenge for antitumor therapy. Development of stimuli-responsive hybrid nanocarriers provides a promising strategy to enhance therapeutic effects by combining the unique features of each component. The present study explored the use of drug-gold nanoparticle conjugates incorporated into liposomes to enhance antitumor efficiency. A model drug, vincristine sulfate, was physically conjugated with gold nanoparticles and verified by UV-visible and fourier transform infrared spectroscopy, and differential scanning calorimetry. The conjugates were incorporated into liposomes by film dispersion to yield nanoparticles (113.4 nm) with light-responsive release properties, as shown by in vitro release studies. Intracellular uptake and distribution was studied in HeLa cells using transmission electron microscopy and confocal laser scanning microscopy. This demonstrated liposome internalization and localization in endosomal-lysosomal vesicles. Fluorescence intensity increased in cells exposed to UV light, indicating that this stimulated intracellular drug release; this finding was confirmed by quantitative analyses using flow cytometry. Antitumor efficacy was evaluated in HeLa cells, both in culture and in implants in vivo in nude mice. HeLa cell viability assays showed that light exposure enhanced liposome cytotoxicity and induction of apoptosis. Furthermore, treatment with the prepared liposomes coupled with UV light exposure produced greater antitumor effects in nude mice and reduced side effects, as compared with free vincristine sulfate.

Oral delivery of protein or polypeptide drugs remains a challenge due to gastric and enzymatic degradation as well as poor permeation across the intestinal epithelia. In this study, liposomes containing bile salts were developed as a new oral insulin delivery system. The primary goal was to investigate the effect of cholate type, particle size and dosage of the liposomes on the hypoglycemic activity and oral bioavailability. Liposomes containing sodium glycocholate (SGC), sodium taurocholate (STC) or sodium deoxycholate (SDC) were prepared by a reversed-phase evaporation method. After oral administration, all liposomes elicited a certain degree of hypoglycemic effect in parallel with an increase in blood insulin level. The highest oral bioavailability of approximately 8.5% and 11.0% could be observed with subcutaneous insulin as reference for SGC-liposomes in non-diabetic and diabetic rats, respectively. Insulin-loaded liposomes showed slower and sustained action over a period of over 20 h with peak time around 8-12h. SGC-liposomes showed higher oral bioavailability than liposomes containing STC or SDC and conventional liposomes. The hypoglycemic effect was size-dependent with the highest at 150 nm or 400 nm and was proportionally correlated to the administered dose. The results supported the hypothesis of insulin absorption as intact liposomes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Silymarin, a mixture of flavonolignans extracted from the seeds of milk thistle, is used clinically as a hepatoprotector to treat liver injuries and chronic hepatitis. However, its therapeutic effect is compromised by its poor oral bioavailability due to the poor solubility and low permeability across intestinal epithelia. The main purpose of this study was to prepare silymarin glyceryl monooleate/poloxamer 407 liquid crystalline matrices (GMO/P407 LCM) to improve the oral bioavailability of silymarin. GMO/P407 LCMs were prepared by a melting/congealing method. The isotropic phenomenon observed under polarized light microscope confirmed the liquid crystalline structure at the junction of LCM and water. Both differential scanning calorimetry and X-ray diffraction analysis confirmed disappearance of silymarin crystallinity after incorporation into the LCMs. In vitro release of silymarin from LCMs was limited, whereas LCMs were readily degraded by lipase and released silymarin quickly and completely. Pharmacokinetic study in beagle dogs showed significantly increased peak concentration for silymarin GMO/P407 LCM, and, most importantly, a 3.46-fold increase in oral bioavailability as compared with Legalon®, a commercial silymarin formulation.

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90-99%. Spray-dried microspheres had a D(50) value of 3.3-4.9 microm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.

Objective Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. Methods The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. Results The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. Conclusion Nanostructured lipid carriers and microemulsions improved luteolin’s oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and higher bioavailability. [ABSTRACT FROM AUTHOR]