Yie W. Chien

Effect of HPMC and Carbopol on the release and floating properties of Gastric Floating Drug Delivery System using factorial design.

The purpose of this study is to investigate the effect of formulation variables on drug release and floating properties of the delivery system. Hydroxypropyl methylcellulose (HPMC) of different viscosity grades and Carbopol 934P (CP934) were used in formulating the Gastric Floating Drug Delivery System (GFDDS) employing 2 x 3 full factorial design. Main effects and interaction terms of the formulation variables could be evaluated quantitatively by a mathematical model. It was found that both HPMC viscosity, the presence of Carbopol and their interaction had significant impact on the release and floating properties of the delivery system. The decrease in the release rate was observed with an increase in the viscosity of the polymeric system. Polymer with lower viscosity (HPMC K100LV) was shown to be beneficial than higher viscosity polymer (K4M) in improving the floating properties of GFDDS. Incorporation of Carbopol, however, was found to compromise the floating capacity of GFDDS and release rate of calcium. The observed difference in the drug release and the floating properties of GFDDS could be attributed to the difference in the basic properties of three polymers (HPMC K4M, K100LV and CP934) due to their water uptake potential and functional group substitution.

The influence of biodegradable microcapsule formulations on the controlled release of a protein

Abstract Biodegradable microcapsules were prepared from various polymer compositions such as poly- d,l -lactic acid or poly- l -lactic acid and poly- d,l -lactide-co-glycolide for the controlled release of a model protein Bovine Serum Albumin (BSA). ELISA data indicated that the binding activity of BSA toward anti-BSA antibody was not lost during the microencapsulation process and the release from microcapsules. The effect of different microcapsule formulations on release profiles of the protein was investigated. It was found that the polymer composition, total amount of polymers and protein loading were factors involved in the determination of release profiles of BSA. The degradation of various microcapsules was also investigated. Factors such as degrees of the hydrolytic chain scission of ester linkages, water content and internal structures were compared. The microcapsule formulation influenced the porosity and the degree of concentration gradient of BSA. These were related to the initial burst effects and release patterns. All these factors interplayed their roles on the release characteristics of BSA. Depending on the microcapsule formulation, controllable and predictable release profiles of BSA that could be described by either zero- or firstorder kinetics were observed.

Biodegradable microcapsules prepared by a w/o/w technique: effects of shear force to make a primary w/o emulsion on their morphology and protein release

A water-in-oil-in-water (w/o/w) technique, sometimes known as in-water drying method, was used to prepare microcapsules consisting of polylactic acid and poly(lactide-co-glycolide). The influence of shear force to produce an initial water-in-oil (w/o) emulsion on the characteristics of microcapsules and protein release was investigated. Bovine serum albumin (BSA) was used as the model protein drug for encapsulation. The initial w/o emulsion was prepared by a Polytron homogenizer. The shear rate was varied from 11 to 23 krpm to produce w/o emulsions with different shear forces. This study revealed pronounced effects of shear force on the characteristics of microcapsules and release profiles of BSA. Depending on the degree of the shear applied, the inner structure of microcapsules showed very different morphology, which was responsible for different release patterns. A low shear produced microcapsules with a high initial burst release of BSA, whereas microcapsules using a high shear exhibited a controlled release of protein without any initial burst release. Also, at a given shear force, a variation in polymer composition of microcapsules was found to be effective in controlling the release characteristics of protein. Thus, the homogenization technique should be carefully considered in designing microcapsules with desirable release profiles of proteins and an adequate period of protein delivery.

Hydrogel-Based lontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugs

Hydrogels were synthesized as the drug reservoir matrix for peptide-based pharmaceuticals, and the iontophoretic release and transdermal delivery of three model peptides, insulin, calcitonin, and vasopressin, from these hydrogel-based iontotherapeutic devices were investigated. The swelling behavior of polyacrylamide-type hydrogel as a function of its monomer and cross-linker concentration was studied, and a hydrogel with minimal swelling was synthesized. The release of peptides from the hydrogel matrix was found to follow a Q vs t1/2 relationship under passive diffusion conditions, which shifted to a Q vs t relationship under iontophoresis-facilitated transport. The release flux (dQ/dt) of peptides was observed to decline when the electric current was turned off and was resumed when the current was turned on, thus allowing for modulation of drug release by varying the application parameters of iontophoresis-facilitated transport. The permeability coefficients for these peptides across the hairless rat skin were evaluated using the hydrogel formulations prepared from polyacrylamide, p-HEMA, and carbopol. A rank order of vasopressin > calcitonin > insulin was obtained in accordance with the order of molecular size.

Statistical Optimization of Gastric Floating System for Oral Controlled Delivery of Calcium

The development of an optimized gastric floating drug delivery system is described. Statistical experimental design and data analysis using response surface methodology is also illustrated. A central, composite Box-Wilson design for the controlled release of calcium was used with 3 formulation variables: X1 (hydroxypropyl methylcellulose [HPMC] loading), X2 (citric acid loading), and X3 (magnesium stearate loading). Twenty formulations were prepared, and dissolution studies and floating kinetics were performed on these formulations. The dissolution data obtained were then fitted to the Power Law, and floating profiles were analyzed. Diffusion exponents obtained by Power Law were used as targeted response variables, and the constraints were placed on other response variables. All 3 formulation variables were found to be significant for the release properties (P<,05), while only HPMC loading was found to be significant for floating properties. Optimization of the formulations was achieved by applying the constrained optimization. The optimized formulation delivered calcium at the release rate of 40 mg/hr, with predicted n and T50% values at 0.93 and 3.29 hours, respectively. Experimentally, calcium was observed to release from the optimized formulation with n and T50% values of 0.89 (±0.10) and 3.20 (±0.21) hours, which showed an excellent agreement. The quadratic mathematical model developed could be used to further predict formulations with desirable release and floating properties.

Enhancement of the in Vitro Skin Permeability of Azidothymidine (AZT) via Iontophoresis and Chemical Enhancer

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C10MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C10MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C10MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.

Continuous release of proteins from biodegradable microcapsules and in vivo evaluation of their potential as a vaccine adjuvant

Abstract A series of biodegradable microcapsules were prepared from blends of lactic/glycolic acid polymers for the controlled release of model proteins such as bovine serum albumin (BSA), transferrin and trypsin. The influence of microcapsule formulations on its degradability and permeability to proteins was demonstrated by the degree of water uptake, their susceptibility to hydrolysis and in vitro release characteristics of proteins. Microcapsules reported in this research provided continuous release profiles of proteins rather than polyphasic and/or pulsatile release kinetics. In vivo experiments demonstrated that continuous release of a model antigen BSA evoked high-titered immune responses in mice which persisted for more than 142 days. The adjuvanticity of the microcapsules was found to be superior to that of aluminum hydroxide and comparable to that of Freunds incomplete adjuvant. Control experiments substantiated that the mixture of antigen and blank microcapsules did not induce greater immune responses than BSA in saline solution alone, suggesting that blank microcapsules do not possess adjuvanticity and BSA should be encapsulated into and slowly released from microcapsules for its immunopotentiation. In addition, immunization of animals with BSA-containing microcapsules was more effective in stimulating its immunogenicity than that with one prime and two booster injections of BSA in saline solution. Therefore, the microcapsule providing continuous release of antigen can be an effective alternative to multiple injections of antigen and have a potential of use as vaccine adjuvants.

Facilitated transdermal delivery of therapeutic peptides and proteins by iontophoretic delivery devices

Abstract Over the years, extensive research effort has been devoted to the development of noninvasive drug delivery techniques for controlled systemic delivery of therapeutic peptides and proteins through various easily accessible organs/tissues. Iontophoresis has recently been discovered as a potential drug delivery technique for noninvasive, programmed systemic delivery of peptide and protein drugs. Several iontophoretic delivery devices have been developed. In this article, the feasibility of using iontophoretic delivery devices to facilitate the transdermal transport of hydrophilic charged macromolecules of peptides, such as vasopressin and proteins, such as insulin, across the skin (which has the lipophilic stratum corneum as the permeation barrier) is demonstrated. In vitro skin permeation studies and in vivo pharmacokinetic and pharmacodynamic studies in diabetic animals suggested that the systemic bioavailability of peptides and proteins, as well as the pharmacodynamic responses, are dependent upon the electronic variables of the iontophoretic delivery device, e.g. waveform, frequency, on/off ratio and intensity of the current applied, physiochemical parameters, e.g. pH and ionic strength, as well as physiological variables, such as treatment of the stratum corneum. The pharmacokinetics-pharmacodynamics relationship is established and the mechanism of iontophoresis-facilitated transdermal transport of peptide-based macromolecules are analyzed.

Development of a Dynamic Skin Permeation System for Long-Term Permeation Studies

AbstractA dynamic skin permeation system was developed aiming to eliminate the deficiencies observed in the apparatus currently available. It consists of two half-cells in mirror image, each contains a stirring platform to permit a starhead magnet to rotate at a synchronous speed. The solution chamber is equipped with a sampling port, which can be tightly closed with glass stopper. The design characteristics of this new system was calibrated, using the commercially available Franz diffusion cell as the reference. The results clearly suggested that this newly developed skin permeation system shows consistently superior than the Franz diffusion cell in terms of the control of skin surface temperature and the efficiency of solution mixing. To investigate the potential effect of environment, the temperature on the stratum corneum surface was varied, while the dermal solution was maintained at constant body temperature, and its effect on the kinetics of skin permeation was studied. The energy requirements for ...

A mechanistic analysis to characterize oramucosal permeation properties

The hypotheses of this study are that the permeation of ionizable molecules follows the pH-partition theory, that the preferred transport pathway for penetrants depends on their charge status and that transport resistance is related to the membrane-coating granules (MCG). Transcellular resistance is believed to be proportional to the volume of MCG in the intracellular space while paracellular resistance is believed to result from the extrusion of the lipid contents of the MCG into the intercellular space. Nicotine, an ionizable model compound with two pK(a) values (3.4 and 8.2), was chosen as a molecular probe to investigate the pH-partition theory on permeation through porcine oramucosae, to characterize the differences in permeability among various oramucosae, and to explore the preferred transport pathways of each nicotine species through oramucosae. The pH-partition theory was proved from the observations that permeability, partition coefficient and diffusivity of nicotine varied as a function of pH. The keratinized gingiva was found to have greater permeability than the non-keratinized buccal and sublingual mucosae. The neutral nicotine species had a higher permeability than the ionized species due to its higher partition coefficient and diffusivity. A mechanistic analysis (permeability ratio-pH profile) was conducted to determine the preferred transport pathway of each nicotine species. The permeability of neutral nicotine was found to be proportional to the occupied volume of MCG in the intracellular space. This indicates that the preferred transport pathway for neutral nicotine is transcellular. As the solution pH was decreased, and a greater fraction of nicotine became protonated, the transport of hydrophilic, charged nicotine species along the intercellular pathway was preferred.