ABSTRACT
The main purpose of this study was to investigate the effect of gelatin as interior support on the physical stability of freeze-dried liposomes. Anticancer agent paclitaxel (PTX) was selected as a model drug. Freeze-dried liposomes containing interior gelatin support (GLs) were prepared by thin-film dispersion/freeze-drying method. Several properties of the GLs, including entrapment efficiency, particle size and gelation temperature, were extensively characterized. Encapsulation efficiency of conventional liposomes (CLs) and liposomes containing lyoprotectants as interior support dropped to lower than 20% after reconstitution, while GLs still maintained an entrapment efficiency of over 84%. Scanning electron microscopy revealed well preserved liposomal structure of GLs after reconstitution. Meanwhile, the particle size and entrapment efficiency of GLs were also well preserved after reconstitution. In contrary, deformation of CLs and recrystallization of PTX were observed, as well as significant changes in particle size and entrapment efficiency. Taken together, interior gelatin support obviously enhanced the physical stability of liposomes against the lyophilization stress.
Subject(s)
Gelatin/chemistry , Liposomes/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Drug Compounding , Drug Liberation , Drug Stability , Freeze Drying , Paclitaxel/chemistry , Tubulin Modulators/chemistryABSTRACT
Improved wettability has been ascribed to one of the important mechanisms for enhanced dissolution of solid dispersions. But its relationship with dissolution has not been closely studied to date. In this study, solid dispersion of simvastatin (SV) and polyvinylpyrrolidone (PVP) was prepared without and with sodium dodecyl sulfate (SDS) incorporated, respectively. The dissolution, contact angle and water absorption rate of these solid dispersions were measured to elucidate the relationship between wettability and dissolution. An abrupt increase of dissolution was observed when PVP amount exceeded a critical value. Contact angle was decreased with increasing of PVP amount. And the dissolution efficiency of the solid dispersion was increased with the decreasing of the contact angle, which was divided by a critical angle of 40.8° into two linear parts. The result was validated in the dissolution of SDS incorporated solid dispersions. Contact angle correlated well with water absorption rate. A critical water absorption rate, with value of 0.535 µL/min, was also observed for the transition of dissolution efficiency. In conclusion, both contact angle and water absorption rate are good indicators for dissolution transition of solid dispersion, which show great potential in formula screening of solid dispersion.
Subject(s)
Excipients/chemistry , Povidone/chemistry , Simvastatin/chemistry , Sodium Dodecyl Sulfate/chemistry , Absorption, Physicochemical , Chemistry, Pharmaceutical , Kinetics , Models, Chemical , Reproducibility of Results , Solubility , Water/chemistry , WettabilityABSTRACT
Liposomes containing bile salts (BS-liposomes) significantly enhanced the oral bioavailability of insulin (rhINS). However, the underlying absorption mechanisms have not been well understood yet. In this study, the transiting fate of the liposomes was first investigated using fluorescent imaging tools to confirm the effect of enhanced gastrointestinal stability. In order to obtain evidence of enhanced transcellular permeation, the interaction between BS-liposomes and the biomembrane was investigated in Caco-2 cell lines. BS-liposomes were found to be more stable in the gastrointestinal tract by showing prolonged residence time in comparison with conventional liposomes. BS-liposomes were significantly more effective for cellular uptake and transport of rhINS; and this effect was found to be size- and concentration-dependent. A good linear correlation was observed between the concentration of the liposomes and uptake/transport of rhINS. Confocal laser scanning microscopy visualization further validated the transcellular transit of BS-liposomes. The BS-liposomes showed little effect on cytotoxicity and did not induce apoptosis within 24h investigation. It was concluded that BS-liposomes showed improved in vivo residence time and enhanced permeation across the biomemebranes. Mechanisms of trans-enterocytic internalization could be proposed as an interpretation for enhanced absorption of insulin-loaded liposomes.
Subject(s)
Gastrointestinal Tract/metabolism , Insulin/pharmacokinetics , Recombinant Proteins/pharmacokinetics , Administration, Oral , Animals , Apoptosis/drug effects , Bile Acids and Salts/chemistry , Caco-2 Cells , Cell Survival/drug effects , Humans , Insulin/administration & dosage , Intestinal Absorption , Liposomes , Male , Rats , Rats, Wistar , Recombinant Proteins/administration & dosageABSTRACT
In this study, aripiprazole (APZ), a weak alkaline drug with pH-dependent solubility, was selected as model drug to examine the feasibility of preparing nanosuspensions using nanoprecipitation/homogenization technique based on acid-base neutralization. The related substances in nanosuspensions prepared under optimal conditions were slightly increased as compared with APZ raw material. The resultant APZ nanosuspensions showed a mean particle size of 350 nm with polydispersion index (PI) value of 0.20. Good physical stability was kept for over 40 days. SEM observation showed the morphology of oval crystals with rough surface. Nanosuspensions significantly increased the solubility as well as the dissolution of APZ due to the decreased particle size. Differential scanning calorimetry and powder X-ray diffractometry confirmed the crystallinity of APZ in nanosuspensions. APZ nanosuspensions got maximum absorption rate and extent comparing with APZ commercial tablet and suspensions with relative bioavailability of 123.43 ± 12.98% and 171.41 ± 14.62%, respectively. This technique has the potential to prepare nanosuspensions of insoluble drugs with pH-dependent solubility.
Subject(s)
Antipsychotic Agents/chemistry , Nanoparticles/chemistry , Piperazines/chemistry , Quinolones/chemistry , Administration, Oral , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacokinetics , Aripiprazole , Biological Availability , Calorimetry, Differential Scanning , Chemical Precipitation , Dogs , Drug Stability , Hydrogen-Ion Concentration , Male , Microscopy, Electron, Scanning , Nanoparticles/administration & dosage , Nanoparticles/ultrastructure , Particle Size , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Powder Diffraction , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Solubility , X-Ray DiffractionABSTRACT
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.
Subject(s)
Bile Acids and Salts/administration & dosage , Drug Carriers/administration & dosage , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Insulin/administration & dosage , Insulin/pharmacokinetics , Liposomes/administration & dosage , Administration, Oral , Animals , Bile Acids and Salts/chemistry , Bile Acids and Salts/pharmacokinetics , Biological Availability , Deoxycholic Acid/administration & dosage , Deoxycholic Acid/chemistry , Drug Carriers/chemistry , Glycocholic Acid/administration & dosage , Glycocholic Acid/chemistry , Hypoglycemic Agents/chemistry , Insulin/chemistry , Liposomes/chemistry , Liposomes/pharmacokinetics , Male , Mice , Mice, Inbred ICR , Particle Size , Rats , Rats, Wistar , Taurocholic Acid/administration & dosage , Taurocholic Acid/chemistryABSTRACT
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.
Subject(s)
Drug Carriers , Glycerides/chemistry , Liquid Crystals , Poloxamer/chemistry , Protective Agents/administration & dosage , Protective Agents/pharmacokinetics , Silymarin/administration & dosage , Silymarin/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical , Crystallography, X-Ray , Dogs , Drug Compounding , Male , Microscopy, Polarization , Powder Diffraction , Protective Agents/chemistry , Silymarin/blood , Silymarin/chemistry , Solubility , Technology, Pharmaceutical/methodsABSTRACT
The main purpose of this study was to evaluate liposomes containing a bile salt, sodium deoxycholate (SDC), as oral drug delivery systems to enhance the oral bioavailability of the poorly water-soluble and poorly permeable drug, cyclosporine A (CyA). Liposomes composed of soybean phosphatidylcholine (SPC) and SDC were prepared by a thin-film dispersion method followed by homogenization. Several properties of the liposomes including particle size, polydispersity index, and entrapment efficiency were characterized. The in vitro release of CyA from these liposomes was less than 5% at 12 hours as measured by a dynamic dialysis method. The pharmacokinetic results in rats showed improved absorption of CyA in SPC/SDC liposomes, compared with CyA-loaded conventional SPC/cholesterol (Chol) liposomes and microemulsion-based Sandimmune Neoral(®). The relative oral bioavailability of CyA-loaded SPC/SDC and SPC/Chol liposomes was 120.3% and 98.6%, respectively, with Sandimmun Neoral as the reference. The enhanced bioavailability of CyA was probably due to facilitated absorption by the liposomes containing SDC rather than improved release rate.
