Luk Chiu Li

Polyanhydride implant for antibiotic delivery--from the bench to the clinic.

A polyanhydride implant (Septacin) containing gentamicin sulfate was developed for sustained local delivery of the drug to the site of infection in the treatment of osteomyelitis. Laboratory-scale injection molding equipment was utilized to fabricate the implant for in vitro characterization. Molding conditions were optimized to produce implants with a skin-core structure which was found to be critical in preventing the initial cracking of the implant during in vitro drug release test in water. A manufacturing process consisting of twin-screw extrusion, pelletizing, and injection molding was developed. Polymer-drug pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The implants were terminally sterilized by gamma-radiation which was found to cause increase in copolymer molecular weight as a result of polymer chain extension. The stability of Septacin was evaluated as a function of storage temperature and time. A marked decline in copolymer molecular weight occurred in samples stored above freezing temperatures and significantly slower drug-release profiles were also exhibited by these samples. In vivo drug release from Septacin in rats showed that the gentamicin plasma levels were extremely low, indicating the low systemic exposure to gentamicin. Furthermore, Septacin samples have demonstrated efficacy in the rat skin-abscess and horse-joint infection models. Results from a human in vivo study also showed high local drug concentrations at implantation sites while systemic exposure to the drug was minimal.

Investigation of the in vitro release of gentamicin from a polyanhydride matrix.

Septacin¿trade mark omitted¿ is a sustained release formulation consisting of gentamicin sulfate dispersed in a biodegradable polyanhydride matrix. The polyanhydride matrix is a copolymer of erucic acid dimer (EAD) and sebacic acid in a 1:1 weight ratio. In vitro drug release was performed in both water and pH 7.4 phosphate buffer. The drug release in water was faster than that in the buffer, which was the opposite of what would be expected based upon a faster polymer hydrolysis rate in the buffer. Theoretical treatment of the data using the Peppas model revealed that release in water was anomalous, while the release in pH 7.4 phosphate buffer was diffusion-controlled. Profound bead morphology differences were observed between beads in these two in vitro release media. Cracking was observed in beads in water and swelling with no apparent cracking was seen in beads in buffer. Concurrent monitoring of drug and sebacic acid release indicated that drug release is not via surface erosion. Osmotic effects were found to play little role in the in vitro drug release. There was no spectroscopic evidence of amide formation between the drug and copolymer. Sulfate release was monitored along with drug release and the results indicate that there is ion-exchange occurring during the pH 7.4 in vitro release. It was subsequently demonstrated that gentamicin can form an insoluble salt with EAD. This salt formation explains the slower drug release in pH 7.4 phosphate buffer.

Nanonization of Itraconazole by High Pressure Homogenization: Stabilizer Optimization and Effect of Particle Size on Oral Absorption

This study was performed to optimize stabilizer systems used in itraconazole (ITZ) nanosuspensions to achieve the greatest extent of size reduction and investigate the effect of particle size on the in vitro dissolution and oral absorption of ITZ. The nanosuspensions were prepared by high pressure homogenization and characterized for particle size, zeta potential, and surface morphology. A central composite method was applied to identify a multiple stabilizer system of Lutrol F127 and sodium lauryl sulfate for optimal particle size reduction. By using the optimized system, an ITZ nanosuspension was prepared that showed the particle size results in good agreement with the values predicted by the model. The nanosuspension was physically stable at 25°C for 1 week. The crystalline form of ITZ was not altered. The ITZ dissolution rate is directly correlated to its particle size, and a smaller particle size yields a faster dissolution rate. Pharmacokinetics study was performed using four ITZ suspensions with various particle sizes in rats (n = 3). A significant increase in both maximal plasma concentration of drug and area under the drug concentration-time curve (AUC) was shown when the particle size was reduced from micrometer to nanometer. However, the AUC was not significantly affected by further reduction of the particle size within the nano-size range.

The effect of moisture content on the compression properties of maltodextrins.

Abstract— The effect of moisture content on the compression properties of maltodextrin powders obtained by different degrees of hydrolysis (depolymerization) of corn starch has been studied using the yield pressure determined from the Heckel plot and the compact tensile strength measured by the diametrical compression method. An increase in the moisture content of the powder reduced the yield pressure and improved the densification for all five maltodextrins evaluated. At the same moisture level, the extent of densification which occurred during compaction was greater for maltodextrins with a lower degree of polymerization. Compacts produced by maltodextrins with a lower degree of polymerization also exhibited a greater tensile strength for a given pressure at a moisture content below 8 0%. However, further increase in moisture content resulted in a decrease in compact tensile strength for maltodextrins having a lower degree of polymerization. Despite the significant difference in compression behaviour, the five maltodextrins did not show noticeable differences in crystallinity as revealed by their x‐ray powder diffraction pattern.

In Vitro Characterization of Polyorthoester Microparticles Containing Bupivacaine

Laboratory-scale spray-congealing equipment was utilized to fabricate injectable microparticles consisting of polyorthoester and bupivacaine. Operating conditions for the spray-congealing process were optimized to produce microparticles with the desired shape and particle size to yield acceptable syringeability and injectability. Characterizations were performed to determine the chemico-physical properties of polyorthoester before and after microparticle fabrication. Microparticles with different drug loadings and comparable particle sizes were produced, and their in vitro drug-release profiles were determined. The in vitro drug release of microparticles with a high drug loading was markedly faster than those with a low drug loading. This is partially attributed to a more significant initial burst–drug release of the microparticles with a high drug loading. The microparticles have demonstrated the potential to be used for long-acting postsurgery pain management by local injection.

The Effect of Agglomeration Methods on the Micromeritic Properties of a Maltodextrin Product, Maltrin 150™

AbstractMaltrin M150 is a fine powder of maltodextrin which is a carbohydrate product made by controlled hydrolysis of corn starch. Agglomerated Maltrin was prepared using a fluidized bed granulation process and a roller compaction method, respectively. The micromeritic properties of these two granular products were compared. Three different sizes of granules (20/30, 40/50 and 80/100 mesh size) were used in the evaluation. Granules produced by the fluidized bed method showed a relatively low bulk density as compared to the roller compacted granules. As the granule size was reduced, the roller compacted granules showed a decrease in bulk density while an increase in bulk density was seen in the fluidized bed granulated product. A better flowability of the roller compacted granules was demonstrated by a higher flow rate and a lower compressibility index. For a given compression pressure, roller compacted granules produced compacts with a lower tensile strength. A significant work-hardening effect was exhibi...

Water Based Silicone Elastomer Controlled Release Tablet Film Coating II - Formulation Considerations and Coating Evaluation

AbstractThe silicone elastomer latex in corporated with polyethylene glycol and colloidal silica produced controlled release film coating on potassium chloride tablets. The release pattern of potassium chloride from coated tablets was dictated by the composition of the coating. Significant formulation variables included the loading level of polyethylene glycol, the molecular weight of the polyethylene glycol used, and the silicone to silica weight ratio in the coating. Non-formulation variables such as coating weight, drying temperature, dissolution medium pH and aging were shown to alter there leaser ate of the active ingredient from coated tablets.

A statistical experimental approach to cosolvent formulation of a water-insoluble drug.

19-Nor-1 alpha, 25-dihydroxyvitamin D2, an analog of vitamin D2, is a nonpolar compound with limited solubility in water. An injectable solution was formulated using a cosolvent system consisting of water, ethanol, and propylene glycol. A statistical response surface approach was used to evaluate the effect of these three solvents on the solubility of the drug (25 degrees C) in the ternary cosolvent system. The data generated from five selected formulations were used to develop a multiple linear regression model that quantitatively defines the solubility of the drug as a function of the cosolvent composition. Close agreement was found between the experimental data and data calculated using the model. The capability of this model to predict drug solubility in cosolvent systems with various combinations of the three solvents was also verified.

Preparation and solidification of redispersible nanosuspensions.

To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility.

Water Based Silicone Elastomer Controlled Release Tablet Film Coating III - Drug Release Mechanisms

AbstractThe release of potassium chloride from polyethylene glycol-silicone elastomer coated tablets was achieved by the diffusion through water-filled pores formed in the hydrated coating and the osmotic pumping generated by the saturated salt solution. The relative contribution of these two mechanisms to the overall drug release rate was shown to be a function of the polyethylene glycol loading in the coating. As the polyethylene glycol loading level increased, the transpore diffusion became the predominant release mechanism. The capability of the polyethylene glycol-silicone elastomer coatings to provide controlled release for therapeutic agents of different water solubilities and dose levels was also demonstrated. Both the rate and extent of release of the active ingredients could be altered by the type of diluent used in the tablet matrix