International Journal of Pharmaceutics (v.324, #2)

This paper describes the synthesis of capecitabine-loaded semi-interpenetrating network hydrogel microspheres of chitosan-poly(ethylene oxide-g-acrylamide) by emulsion crosslinking using glutaraldehyde. Poly(ethylene oxide) was grafted with polyacrylamide by free radical polymerization using ceric ammonium nitrate as a redox initiator. Capecitabine, an anticancer drug, was successfully loaded into microspheres by changing experimental variables such as grafting ratio of the graft copolymer, ratio of the graft copolymer to chitosan, amount of crosslinking agent and percentage of drug loading in order to optimize process variables on drug encapsulation efficiency, release rates, size and morphology of the microspheres. A 24 full factorial design was employed to evaluate the combined effect of selected independent variables on percentage of drug release at 5 h (response). Regression models were used for the response and data were compared statistically using the analysis of variance (ANOVA). Grafting, interpenetrating network formation and chemical stability of the capecitabine after encapsulation into microspheres was confirmed by Fourier infrared spectra (FTIR). Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) studies were made on drug-loaded microspheres to investigate the crystalline nature of drug after encapsulation. Results indicated amorphous dispersion of capecitabine in the polymer matrix. Scanning electron microscope (SEM) confirmed spherical shapes and smooth surface morphology of the microspheres. Mean particle size of the microspheres as measured by the laser light scattering technique ranged between 82 and 168 μm. Capecitabine was successfully encapsulated into semi-IPN microspheres and percentage of encapsulation efficiency varied from 79 to 87. In vitro release studies were performed in simulated gastric fluid (pH 1.2) for the initial 2 h, followed by simulated intestinal fluid (pH 7.4) until complete dissolution. The release of capecitabine was continued up to 10 h. Release data were fitted to an empirical relationship to estimate the transport parameters. Dynamic swelling studies were performed in the simulated intestinal fluid and diffusion coefficients were calculated by considering the spherical geometry of the matrices.
Keywords: Chitosan; Poly(ethylene oxide); Capecitabine; Microspheres; Controlled release; Grafting; Interpenetrating polymer network; Factorial design;

An experimental/computational approach for examining unconfined cohesive powder flow by AbdulMobeen Faqih; Bodhisattwa Chaudhuri; Albert W. Alexander; Clive Davies; Fernando J. Muzzio; M. Silvina Tomassone (116-127).
This paper describes a new method to quantitatively measure the flow characteristics of unconfined cohesive powders in a rotating drum. Cohesion plays an important role, affecting flow properties/characteristics, mixing rates, and segregation tendencies. The method relies on measuring the change in center of mass of the powder bed as it avalanches in the vessel, using a load cell that is sampled continuously. Filtering and analysis of the signal is done using Fast-Fourier transform into the frequency domain, where noise is eliminated using signal processing methods. The filtered data is transformed back to the time domain by using an inverse Fast-Fourier transform to give quantitative information on the powder flow characteristics. In order to understand the nature of the forces controlling powder flow behavior, a computational model was developed to estimate the relationship between inter-particle cohesive strength and experimental measurements. A “flow index” generated by the method correlates well with the degree of bed expansion (dynamic dilation) of the cohesive powders. The flow index also predicts the dynamics of flow through hoppers. As the flow index increases it becomes increasingly difficult for the powder to flow through the hoppers.
Keywords: Powder flow; Cohesion; Powder avalanche; Simulations;

The aim of this work was to explore texture analysis for quantitative evaluation of the effect of hydrophilic solvent systems used as capsule fills on the mechanical properties of hard gelatin capsules. For this purpose, a texture analyzer (Stable Micro Systems, model TA.XT Plus) equipped with a capsule separating rod fixture was used. The tests were conducted in a tension mode. Elastic stiffness, tensile force and elongation at break were determined from the experimental stress–strain curve in order to quantitatively describe both brittleness and softening of capsules. In this paper, it has been demonstrated that the effect of various hydrophilic solvent (i.e. propylene glycol (PG), polyethylene glycol 400 (PEG 400), ethanol) mixtures on the mechanical properties of hard gelatin capsules can be easily monitored using texture analysis. Significant counteractive effects between PG and PEG 400 or ethanol on the integrity of capsule shells were discovered in this study. Texture analysis is found to be a convenient tool for studying formulation compatibility. It can be invaluable in early screening studies of liquid filled hard gelatin capsules.
Keywords: Texture analysis; Hard gelatin capsules; Mechanical properties; Hydrophilic solvents; Experimental design;

Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique by Srisagul Sungthongjeen; Ornlaksana Paeratakul; Sontaya Limmatvapirat; Satit Puttipipatkhachorn (136-143).
A multiple-unit floating drug delivery system based on gas formation technique was developed in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form. The system consists of the drug-containing core pellets prepared by extrusion–spheronization processes, which are coated with double layers of an inner effervescent layer (sodium bicarbonate) and an outer gas-entrapped polymeric membrane of an aqueous colloidal polymer dispersion (Eudragit® RL 30D, RS 30D, NE 30D). Only the system using Eudragit® RL 30D as a gas-entrapped polymeric membrane could float. The time to float decreased as amount of the effervescent agent increased and coating level of gas-entrapped polymeric membrane decreased. The optimum system could float completely within 3 min and maintained the buoyancy over a period of 24 h. The drug release was sustained and linear with the square root of time. Increasing coating level of gas-entrapped polymeric membrane decreased the drug release. Both the rapid floating and the sustained release properties were achieved in the multiple-unit floating drug delivery system developed in this present study.
Keywords: Floating drug delivery system; Pellets; Effervescent agent; Polymeric membrane; Sustained release;

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by an emulsion solvent evaporation process using an acetone/liquid paraffin system. The effects of solvent evaporation rate on particle properties and drug release characteristic of the microspheres were evaluated. The solvent evaporation rate was controlled by the rate of increase in temperature of the water bath, ranging 7.5–30 °C/h. Drug release from the microspheres was examined using JPXIV 2nd fluid (pH 6.8) containing 0.1% Tween 80, and was found to be greatly affected by the solvent evaporation rate. The percentage of drug released until 8 h varied; from 28% to 84% for 30 and 7.5 °C, respectively. Differential scanning calorimetry and powder X-ray diffraction studies revealed that TH partially interacted with the polymer and drug crystallinity was maintained intact in the microspheres. According to scanning electron microscopy observations, all microspheres showed a well-formed spherical particle with a solid interior. The appearances of the microspheres were, however, extremely different. Microspheres prepared at 30 °C/h had a very smooth surface, while those prepared at 7.5–15 °C/h had a rough surface with large craters. These findings demonstrated that the surface morphology and drug release characteristic were controlled by the rate of increase of temperature.
Keywords: Microencapsulation; Solvent evaporation; Temperature-increase rate; Controlled release; Hydrophobic dextran derivate; Theophylline;

In vitro controlled release of sodium ferulate from Compritol 888 ATO-based matrix tablets by Feng-Qian Li; Jin-Hong Hu; Jia-Xin Deng; Hua Su; Shu Xu; Ji-Yong Liu (152-157).
A controlled release matrix formulation for freely water-soluble drug of sodium ferulate (SF) was designed and developed to achieve a 24 h release profile. Using Compritol 888 ATO as an inert matrix-forming agent to control the release of SF, formulation granules containing the physical mixtures or solid dispersions were investigated. The matrix tablets for these formulations were prepared by direct compression and their in vitro release tests were carried out. The solid dispersion based tablets were found to be more effective than those compressed from physical mixtures in retarding the release of SF. Drug release from the matrix tablets containing physical mixtures nearly completed within 12 h, while that from the solid dispersion formulations lasted for over 24 h. Images of the tablet surface and cross-section were characterized by scanning electron microscopy to show the formed pores and channels in the matrices. These might provide the release pathway for the inner embedded drugs. Drug released fast from the matrix tablets with the release-enhancer of lactose. The addition of surfactants was also found to increase the release rate of SF effectively. Moreover, the co-mixing of polyethylene glycol 6000 (PEG 6000) in the waxy matrices played a meaningful role in controlling the drug release for 24 h. The drug release from the novel formulation might be attributed to the diffusion-controlled mechanism.
Keywords: Sodium ferulate; Compritol 888 ATO; Solid dispersion; Controlled release matrix tablet; Drug release in vitro;

To develop a new polypeptide delivery system, insulin nano-aggregates with sizes of 100–230 nm were prepared by the salting out method with NaCl and encapsulated via the layer-by-layer (LbL) adsorption to provide the insulin nanoparticles shelled with two oppositely charged polyelectrolytes. Poly(α,β-l-malic acid) (PMA) and water-soluble chitosan (WSC) as the weak polyelectrolytes with good biodegradability and biocompatibility in vivo were chosen to be the encapsulating materials of the LbL adsorption. In the preparation of the insulin nano-aggregates, the NaCl concentration and pH in the medium obviously affected yield and particle size of the insulin nano-aggregates. After eight adsorption cycles of the polyelectrolytes on the insulin nano-aggregates, the insulin–polyelectrolyte nanoparticles with the sizes of 100–250 nm were obtained with about 20% insulin loss. The insulin release from the nanoparticles was mostly pH-dependent owing to sensitivity of the weak polyelectrolytes to pH. Insulin was hardly released from the nanoparticles in a medium at pH 4–5 while it could be released at pH 7.4, corresponding to the pH of the human blood and the body fluid. A burst effect was also observed although it could be reduced via increasing the polyelectrolyte layers of PMA and WSC assembled on insulin nano-aggregates.
Keywords: Nanoparticles; Layer-by-layer adsorption; Insulin; Water-soluble chitosan; Poly(α,β-l-malic acid);

The objective of this study was to identify key variables affecting the initial release (burst) and the encapsulation of leuprolide acetate-containing poly(lactide-co-glycolide) (PLGA) microparticles, which were prepared by the cosolvent evaporation method. Adjusting parameters, which affected the PLGA precipitation kinetics, provided efficient ways to increase the encapsulation efficiency and to control the initial release. Addition of 0.05 M NaCl to the external aqueous phase increased the encapsulation efficiency and the initial release; in contrast, NaCl at high concentration (0.5 M) delayed polymer precipitation and resulted in non-porous microparticles with a low initial release. The presence of ethanol in the external phase led to porous microparticles with an increased initial release but a decreased encapsulation efficiency. The initial release also decreased with decreasing volume of the external phase and homogenization speed, as well as with covering the preparation apparatus; however, these variations had no significant effect on the encapsulation efficiency. Scale-up of the laboratory size by a factor of 5 and 25 showed insignificant influence on the encapsulation efficiency, particle size, and drug release.
Keywords: Burst; Encapsulation efficiency; Initial release; Microencapsulation; Poly(lactide-co-glycolide); Scale-up; Solvent evaporation method;

Preparation of vancomycin microparticles: Importance of preparation parameters by Walid Hachicha; Laurent Kodjikian; Hatem Fessi (176-184).
The aim of the present work was to prepare microparticles containing vancomycin for intraocular injection. The primary objective was to guarantee continuous release and keep an intracameral drug concentration above the minimal inhibitory limit for at least 24 h, needed in endophthalmitis prophylaxis after cataract surgery. Poly(lactide-co-glycolide) microparticles were prepared using the double emulsion (water-in-oil-in-water) solvent extraction/evaporation method. The influence of preparation parameters on the final microparticles properties was explored in an attempt to control particle sizes, stability, encapsulation rate and vancomycin release profile. Satisfying release profile and stability were obtained, independently of the process. Sizes and encapsulation rate were controlled using an experimental design. Final obtained properties demonstrated that the fabricated particles are suitable for the prophylactic intraocular use in cataract surgery. Further in vitro and in vivo experiments will be conducted to assess efficiency of the entrapped antibacterial and then validate its potential usefulness in prophylaxis.
Keywords: Encapsulation; Endophthalmitis; Vancomycin; Experimental design;

Preparation of poly ɛ-caprolactone nanoparticles containing magnetite for magnetic drug carrier by J. Yang; S.-B. Park; Ho-Geun Yoon; Y.-M. Huh; S. Haam (185-190).
Magnetic poly ɛ-caprolactone (PCL) nanoparticles were prepared in a well shaped spherical form by the o/w emulsion method. The influence of some preparative variables on the size and surface property was investigated. Nanoparticles were smooth, well individualized and homogeneous in size. The presence of magnetite and its superparamagnetic characteristic were confirmed by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR) and vibrating sample magnetometer (VSM), respectively. The anti-cancer drug was encapsulated in the magnetic nanoparticle during preparation. A typical release behavior was observed for 30 days. In vitro experiment of magnetic susceptibility under external magnetic field demonstrated that the magnetic PCL nanoparticles have sufficient magnetic susceptibility for a potential magnetic drug carrier for targeted delivery.
Keywords: Poly ɛ-caprolactone; Magnetite; Emulsion; Nanoparticle; Magnetic drug targeting;

Nanoparticles (NPs) of poly(lactide)–Vitamin E TPGS (PLA–TPGS) copolymers were synthesized by a dialysis method in the present study to formulate paclitaxel for oral chemotherapy with Caco-2 cells as an in vitro model of the gastrointestinal (GI) drug barrier. The PLA–TPGS NPs were of size 340 nm in diameter with 5.2% drug loading. The drug release kinetics showed a 31% initial burst in the first day, followed by 80% accumulative drug release after 30 days in the PBS buffer at pH 7.4, and the release rate was found lower in simulated gastric and intestinal conditions. The internalization of fluorescent PLA–TPGS NPs by Caco-2 cells was visualized by confocal laser scanning microscopy (CLSM). PLA–TPGS NPs showed significant increase in the cellular uptake by 1.8- and 1.4-fold in comparison with poly(lactide-co-glycolide) (PLGA) NPs cultured with HT-29 and Caco-2 cells, respectively, and the cellular uptake efficiency was found affected by the incubation time and the particle concentration in the culture medium. Investigation on HT-29 and Caco-2 cytotoxicity showed advantages of the PLA–TPGS NP formulation versus Taxol®. The IC50 of the PLA–TPGS NP formulation with HT-29 cells was found 40% lower than of Taxol® at the same dose of paclitaxel. The results obtained in this research demonstrated feasibility for the PLA–TPGS NPs to be applied for oral delivery of paclitaxel as well as other anticancer drugs.
Keywords: Biodegradable polymers; Cancer; Cancer nanotechnology; GI barrier; Oral drug delivery; Nanomedicine; Taxol®;

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