Sontaya Limmatvapirat

Use of spray-dried chitosan acetate and ethylcellulose as compression coats for colonic drug delivery: effect of swelling on triggering in vitro drug release.

Spray-dried chitosan acetate (CSA) and ethylcellulose (EC) were used as new compression coats for 5-aminosalicylic acid tablets. Constrained axial or radial swelling of pure CSA and EC/CSA tablets in 0.1 N HCl (stage I), Tris-HCl, pH 6.8 (stage II), and acetate buffer, pH 5.0 (stage III), was investigated. Factors affecting in vitro drug release, i.e., % weight ratios of coating polymers, dip speeds of dissolution apparatus or pH of medium or colonic enzyme (beta-glucosidase) in stage III, and use of a super disintegrant in core tablets, were evaluated. Swollen CSA gel dissolved at lower pH and became less soluble at higher pH. The mechanism of swelling was Fickian diffusion fitting well into both Higuchis and Korsmeyer-Peppas models. EC:CSA, at 87.5:12.5% weight ratio, provided lag time rendering the tablets to reach stage III (simulated colonic fluid of patients), and the drug was released over 90% within 12 h. The system was a dual time- and pH-control due to the insolubility of EC suppressing water diffusion and the swelling of CSA in the stages I and II. The erosion of CSA gel in the stage III induced the disintegration of the coat resulting in rapid drug release. The lower dip speed and higher pH medium delayed the drug release, while a super disintegrant in the cores enhanced the drug release and no enzyme effect was observed.

Effect of Chitosan Salts and Molecular Weight on a Nanoparticulate Carrier for Therapeutic Protein

The objective of this study was to investigate the potential of chitosan salts as a carrier in the preparation of protein-loaded nanoparticles. Glutamic and aspartic acids were used to prepare chitosan salts of 35, 100, and 800 KDa. Nanoparticles of chitosan base, chitosan glutamate, and chitosan aspartate were produced by ionotropic gelation with sodium tripolyphosphate (TPP). Bovine serum albumin (BSA) was applied as a model protein at loading concentrations ranging from 0.2 to 2 mg/mL. The size of the nanoparticles, as measured by photon correlation spectroscopy, was in the range of 195 to 3450 nm, depending on type and molecular weight of chitosan. Nanoparticles prepared with higher molecular weight chitosan showed larger sizes. The encapsulation was controlled by the competition of BSA in forming ionic cross-linking with chitosan and by the entrapment of BSA during the gelation process. Higher BSA encapsulation efficiency (EE) was obtained for nanoparticles prepared with chitosan salts compared to those prepared with the base. The higher EE was a result of a higher degree of ionization, causing more active sites to interact with BSA. In addition, a higher and faster release of BSA from the nanoparticles into pH 7.4 buffer medium was observed for nanoparticles of the chitosan salts than was observed for nanoparticles of the chitosan base. The higher and faster release was attributed to higher EE and lower entrapment of BSA within the matrix of the nanoparticle during the gelation process. The influence of molecular weight on the property of nanoparticles exhibited different effects. The difference was a result of different organic acids used to prepare nanoparticles leading to the difference in polymer conformation and viscosity of organic acid solution. Therefore, this study showed that the characteristics of chitosan nanoparticles loaded with a protein drug could be readily modulated by changing the salt form or the molecular weight of the chitosan carrier.

Modulation of drug release kinetics of shellac-based matrix tablets by in-situ polymerization through annealing process

A new oral-controlled release matrix tablet based on shellac polymer was designed and developed, using metronidazole (MZ) as a model drug. The shellac-based matrix tablets were prepared by wet granulation using different amounts of shellac and lactose. The effect of annealing temperature and pH of medium on drug release from matrix tablets was investigated. The increased amount of shellac and increased annealing temperature significantly affected the physical properties (i.e., tablet hardness and tablet disintegration) and MZ release from the matrix tablets. The in-situ polymerization played a major role on the changes in shellac properties during annealing process. Though the shellac did not dissolve in acid medium, the MZ release in 0.1N HCl was faster than in pH 7.3 buffer, resulting from a higher solubility of MZ in acid medium. The modulation of MZ release kinetics from shellac-based matrix tablets could be accomplished by varying the amount of shellac or annealing temperature. The release kinetics was shifted from relaxation-controlled release to diffusion-controlled release when the amount of shellac or the annealing temperature was increased.

Structural change and complexation of strictly linear amylose induced by sealed-heating with salicylic acid

Strictly linear amyloses have been heated in a sealed ampoule in the presence of salicylic acid (SA). When using an amylose of molecular weight 1310000 (AS-1310), two types of inclusion complexes, differing in helix structure, were formed, depending on the amount of SA. With 10% SA a complex with 71-helix structure was obtained, with one SA molecule tightly accommodated per helical turn of AS-1310. With 30% SA an 81-helix complex was obtained, in which two SA molecules were assumed to be loosely accommodated per helical turn.

Self-Nanoemulsifying Drug Delivery System of Nifedipine: Impact of Hydrophilic–Lipophilic Balance and Molecular Structure of Mixed Surfactants

A simple but novel mixed surfactant system was designed to fabricate a self-nanoemulsifying drug delivery system (SNEDDS) based on hydrophilic–lipophilic balance (HLB) value. The impacts of HLB and molecular structure of surfactants on the formation of SNEDDS were investigated. After screening various oils and surfactants, nifedipine (NDP)-loaded liquid SNEDDS was formulated with Imwitor® 742 as oil and Tween®/Span® or Cremophor®/Span® as mixed surfactant. Droplet size of the emulsions obtained after dispersing SNEDDS containing Tween®/Span® in aqueous medium was independent of the HLB of a mixed surfactant. The use of the Cremophor®/Span® blend gave nanosized emulsion at higher HLB. The structure of the surfactant was found to influence the emulsion droplet size. Solid SNEDDS was then prepared by adsorbing NDP-loaded liquid SNEDDS comprising Cremophor® RH40/Span® 80 onto Aerosil® 200 or Aerosil® R972 as inert solid carrier. Solid SNEDDS formulations using higher amounts (30–50% w/w) of Aerosil® 200 exhibited good flow properties with smooth surface and preserved the self-emulsifying properties of liquid SNEDDS. Differential scanning calorimetry and X-ray diffraction studies of solid SNEDDS revealed the transformation of the crystalline structure of NDP due to its molecular dispersion state. In vitro dissolution study demonstrated higher dissolution of NDP from solid SNEDDS compared with NDP powder.

Effect of alkali treatment on properties of native shellac and stability of hydrolyzed shellac

The objective of this study was to investigate the effect of alkali treatment on properties of shellac. The native shellac was treated with sodium hydroxide for 15, 30, and 60 min to obtain hydrolyzed shellac. All types of shellac, namely native and hydrolyzed shellac at various times of treatment, were then prepared in films as free acid and ammonium salt forms by using ethanol and ammonium hydroxide solution, respectively. The results showed that alkali treatment caused an increase in acid value and a decrease in ester value. This is due to higher free carboxylic and hydroxyl groups caused by ester bond breaking. The longer the alkali treatment the higher impact of bond breaking, therefore, causing an increase in acid value, solubility at pH 7, strain, a decrease in ester value, water vapor permeability coefficient, and stress. The films were then kept at 40°C, 75% RH for a period of three months. The aging effect led to an esterification of free carboxylic and hydroxyl groups, resulting in the significant change of acid value, ester value, and insoluble solid for both native and hydrolyzed shellac films in acid form. On the other hand, all types of shellac films in ammonium salt form exhibited a reasonable stability in physicochemical and mechanical properties as all films were protected from the esterification due to the formation of ammonium salt at the carboxylic binding site. It could be concluded that alkali treatment could produce hydrolyzed shellac with higher solubility in the intestine, the stability was yet in dilemma unless the shellac was in an ammonium salt form. The result obtained could, thus, provide a guideline in the use of shellac.

Specific complexation of ursodeoxycholic acid with guest compounds induced by co-grinding

Ursodeoxycholic acid (UDCA) was ground with a variety of organic compounds using a vibrational mill. Only when either phenanthrene or anthrone was used did powder X-ray diffraction and thermal analysis data indicate that a specific interaction developed with UDCA in the ground mixture. From fluorescence and infrared spectroscopic data, inclusion complex formation with UDCA was suggested during the co-grinding process. The stoichiometry of the inclusion compounds of UDCA–phenanthrene/anthrone was evaluated as a 1:1 molar ratio. Interestingly, no complexes could be obtained by the coprecipitation method, which was conventionally applied for the preparation of inclusion complex of bile acids. Consequently, except when the co-grinding process was performed with either phenanthrene or anthrone, UDCA did not form an inclusion complex.

Enhanced dissolution and oral bioavailability of nifedipine by spontaneous emulsifying powders: effect of solid carriers and dietary state.

The objective of this study was to prepare spontaneous emulsifying powder (SEP) for improving dissolution and enhancing oral bioavailability of a poorly water-soluble drug, nifedipine (NDP). In order to investigate the effects of solid carrier properties, such as surface area and pore size, and a concurrent food intake on absorption of NDP in rats, different SEP formulations were prepared by adsorbing liquid spontaneous emulsifying formulation (SEF), composing of polyoxyl 35 castor oil, caprylic/capric glyceride and diethylene glycol monoethyl ether at a ratio of 1:1:8, onto various solid carriers (i.e., silica (FS), porous calcium silicate (PCS) and porous silicon dioxide). The solid characterization by scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction revealed the absence of crystalline NDP in the formulations. SEP also demonstrated excellent spontaneous emulsification properties similar to SEF. The droplet size of emulsions formed after dilution was less than 200 nm. The solid carriers (particularly PCS) had significant and positive effect in drug dissolution; the mean dissolution time of SEP containing PCS was considerably improved. SEP also provided a good stability after storage in accelerated and long-term conditions for 6 months. The bioavailability study resulted in enhanced values of C(max) and AUC for SEP formulations, when tested in both fasted and fed rats. Furthermore, comparing the AUC in fasted and fed rats, NDP powder exhibited a significant food effect. The difference in bioavailability of NDP in fed compared to fasted state can be avoided by using SEP.

Application of multiple stepwise spinning disk processing for the synthesis of poly(methyl acrylates) coated chitosan–diclofenac sodium nanoparticles for colonic drug delivery

The production of pharmaceutical nanoparticles by the spinning disk processing (SDP) technique has advantages in terms of its scalability and its capacity to produce readily tunable nanoparticles of narrow size distribution. In this study, we successfully developed a novel multiple stepwise SDP technique to develop aggregates of uniformly sized poly(methyl acrylates)-coated chitosan-diclofenac sodium nanocores (CS-PMA NPs) for colonic drug delivery. The processing conditions were optimized using the Box-Behnken design. SEM and TEM micrographs showed the optimized system to consist of 10 μm-sized agglomerates of CS-PMA NPs, the latter measuring 10nm in diameter. High drug entrapment of 88% was attained. Potential colon-targeted drug release from the CS-PMA NPs was demonstrated, with retardation of drug release in simulated gastrointestinal fluids and over 90% of the drug load released into simulated colonic fluid within 8 h. Drug uptake from CS-PMA NPs into Caco-2 cells was threefold higher than that from a control drug solution, with no apparent cytotoxicity observed at the NP doses administered. The collective data suggest that the SDP is a robust manufacturing method that can potentially be used to scale up the production of composite nanoparticulate colon-targeted drug delivery systems.

Effect of molecular weight and concentration of polyethylene glycol on physicochemical properties and stability of shellac film.

The effects of molecular weight and concentration of plasticizer on physicochemical properties and stability of shellac films were investigated. Type of plasticizer was previously reported to have some effects on the stability of shellac films, and polyethylene glycol (PEG) was the plasticizer of choice for plasticizing shellac films. In this study, different molecular weights of PEG (200, 400 and 4000) were chosen at a concentration of 10% w/w of shellac films. Shellac in alcohol was prepared in a free film. The stability of shellac film was then performed at 75% RH, 40 °C for 3 months. The comparison was made between the film with and without plasticizer. Shellac films were then determined for acid value, insoluble solid, mechanical properties and water vapor permeability coefficient. It was reported that different molecular weights of PEG had some influence on physicochemical properties of the shellac films. Among different molecular weights of PEG, PEG 400 showed a suitable molecular weight that could protect the shellac chain at the carboxylic and hydroxyl groups. Therefore, the molecular weight of plasticizer played a crucial role for the protective ability at active sites. Further study was performed to investigate the effect of concentrations of PEG 400 on the stability. The results demonstrated that PEG 400 at a concentration of 10% (w/w) could prevent the polymerization process for only 4 months and a significant change of all parameters was then reported. However, a higher concentration, 20% (w/w) of PEG 400, could prolong the stability of shellac for 6 months of study. Therefore, the drawback of shellac as a natural polymer in pharmaceutical and food industries could be tackled by the appropriate size and concentration of plasticizer.