Development of a long-acting tablet with ticagrelor high-loaded nanostructured lipid carriers.

Ticagrelor (TCG), an antiplatelet agent, has low solubility and permeability; thus, there are many trials to apply the pharmaceutical technology for the enhancement of TCG solubility and permeability. Herein, we have developed the TCG high-loaded nanostructured lipid carrier (HL-NLC) and solidified the HL-NLC to develop the oral tablet. The HL-NLC was successfully fabricated and optimized with a particle size of 164.5 nm, a PDI of 0.199, an encapsulation efficiency of 98.5%, and a drug loading of 16.4%. For the solidification of HL-NLC (S-HL-NLC), the adsorbent was determined based on the physical properties of the S-HL-NLC, such as bulk density, tap density, angle of repose, Hausner ratio, Carr's index, and drug content. Florite R was chosen because of its excellent adsorption capacity, excellent physical properties, and solubility of the powder after manufacturing. Using an S-HL-NLC, the S-HL-NLC tablet with HPMC 4 K was prepared, which is showed a released extent of more than 90% at 24 h. Thus, we have developed the sustained release tablet containing the TCG-loaded HL-NLC. Moreover, the formulations have exhibited no cytotoxicity against Caco-2 cells and improved the cellular uptake of TCG. In pharmacokinetic study, compared with raw TCG, the bioavailability of HL-NLC and S-HL-NLC was increased by 293% and 323%, respectively. In conclusion, we successfully developed the TCG high-loaded NLC tablet, that exhibited a sustained release profile and enhanced oral bioavailability.

Comparison of the Pharmacokinetics of a Fixed-Dose Combination of Rosuvastatin/Metformin Sustained-Release (10/1000 mg) and Separate Tablets in Healthy Male Subjects.

Fixed-dose combination (FDC) drugs with various dose combinations for the treatment of type 2 diabetes mellitus and dyslipidemia are currently in demand. We compared the pharmacokinetic (PK) profiles of the rosuvastatin/metformin sustained-release (10/1000 mg) FDC and separate tablets and evaluated the effect of food by randomized, open-label, 3-period, 6-sequence crossover studies conducted in healthy male subjects. Subjects were randomly assigned to one of the following treatments: separate tablets of 10 mg rosuvastatin and 1000 mg metformin sustained release in the fed state and the FDC in the fasted and fed states. PK samples were collected up to 72 hours postdose for rosuvastatin, N-desmethyl rosuvastatin, and metformin. The PK parameters were determined using a noncompartmental method, and the geometric mean ratio (GMR) and the 90% confidence interval (CI) of the treatments were calculated. A total of 35 subjects completed the study. The GMR and 90%CI of the peak concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUClast ) of the FDC and the separate tablets were within the bioequivalence criteria (0.8-1.25) for both rosuvastatin and metformin. The effect of food was statistically significant for both rosuvastatin and metformin but not expected to be of clinical significance.

Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process.

Risperidone-loaded poly (D,L-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24h and minimal release (time-lag) for 7 days. After the lag phase, slow release took a place up to 25 days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24h) followed by the latent phase up to 21 days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients.

Investigation of the factors influencing the release rates of cyclosporin A-loaded micro- and nanoparticles prepared by high-pressure homogenizer.

An oil-in-water solvent evaporation method was used to prepare cyclosporin A (CyA)-loaded particles varying in size (nanoparticles, 'small-sized' microparticles, 'large-sized' microparticles), polymer compositions [poly(D,L-lactide-co-glycolic acid) (PLGA) 50/50, PLGA 85/15, poly(D,L-lactic acid) (PLA)] and additive fatty acid ester (ethyl myristate; EM). The particles were characterized for drug loading and entrapment efficiency by high-performance liquid chromatography, particle size by dynamic light scattering and surface morphology by scanning electron microscopy (SEM). In vitro release kinetics were studied using a modified dialysis method. The results showed drug loadings ranging from 6.48 to 9.01% with high encapsulation efficiency (71.2-98.9%). SEM studies showed discrete and spherical particles with smooth surfaces, whereas rather gross surface defects resulted from the incorporation of EM as an additive. The release profiles of various formulations approximated zero-order release kinetics in the first 3 weeks with a negligible initial burst. In general, the smaller the particle size and the higher the glycolic acid content in the copolymer, the faster the release of CyA. The effect of EM on the release profile appeared to be rather complex since an increased release rate was observed from EM containing PLGA 50/50 particles, whereas the incorporation of EM into the PLGA 85/15 and PLA particles led to a decreased release rate. Further investigation needs to be performed to elucidate the reason why EM influences the CyA release differently depending on the particle size and polymer type.

Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier.

The success of gene therapy is largely dependent on the delivery vector system. Efficient transfection and nontoxicity are two of the most important requirements of an ideal gene delivery vector. To generate both an efficient and nontoxic vector, we rationally constructed polymeric vectors to have simultaneous multiple functions, i.e., controlled degradation, an endosome disruptive function, and positive charges. Remarkably, the transfection efficiency of network poly(amino ester) (n-PAE) synthesized in this manner was comparable to that of polyethylenimine (PEI), one of the most efficient polymeric gene delivery vectors reported to date. However, there was a marked difference in cytotoxicity between the polymers. The majority of PEI-transfected cells were granulated and dead, whereas most of the cells transfected with n-PAE were viable and healthy. Successive events of efficient endosome escape of n-PAE/DNA polyplex and n-PAE biodegradation should result in high transfection efficiency and favorable cell viability response. The n-PAE-mediated transfection was also very efficient in the presence of serum. These data show that the approach we applied is a very appropriate way of making an ideal gene delivery carrier.

Optimal salt concentration of vehicle for plasmid DNA enhances gene transfer mediated by electroporation.

In vivo electroporation has emerged as a leading technology for developing nonviral gene therapies, and the various technical parameters governing electroporation efficiency have been optimized by both theoretical and experimental analysis. However, most electroporation parameters focused on the electric conditions and the preferred vehicle for plasmid DNA injections has been normal saline. We hypothesized that salts in vehicle for plasmid DNA must affect the efficiency of DNA transfer because cations would alter ionic atmosphere, ionic strength, and conductivity of their medium. Here, we show that half saline (71 mM) is an optimal vehicle for in vivo electroporation of naked DNA in skeletal muscle. With various salt concentrations, two reporter genes, luciferase and beta-galactosidase were injected intramuscularly under our optimal electric condition (125 V/cm, 4 pulses x 2 times, 50 ms, 1 Hz). Exact salt concentrations of DNA vehicle were measured by the inductively coupled plasma-atomic emission spectrometer (ICP-AES) and the conductivity change in the tissue induced by the salt in the medium was measured by Low-Frequency (LF) Impedance Analyzer. Luciferase expression increased as cation concentration of vehicle decreased and this result can be visualized by X-Gal staining. However, at lower salt concentration, transfection efficiency was diminished because the hypoosmotic stress and electrical injury by low conductivity induced myofiber damage. At optimal salt concentration (71 mM), we observed a 3-fold average increase in luciferase expression in comparison with the normal saline condition (p < 0.01). These results provide a valuable experimental parameter for in vivo gene therapy mediated by electroporation.