Kai Bin Liew

Effect of polymer, plasticizer and filler on orally disintegrating film

Abstract Context: Difficulty in swallowing tablets or capsules has been identified as one of the contributing factors to non-compliance of geriatric patients. Although orally disintegrating tablet was designed for fast disintegration in mouth, the fear of taking solid tablets and the risk of choking for certain patient populations still exist. Objective: The objective of this study was to develop and characterize orally disintegrating film (ODF), which was prepared using different combinations of polymers, plasticizers and fillers. Materials and methods: Effects of hydroxypropyl methylcellulose (HPMC), polyethylene glycol 400 (PEG 400), glycerin, polyvinyl pyrrolidone (PVP), mannitol and microcrystalline cellulose (MCC) on physical property of ODF formed were studied. The ODF was prepared using the solvent casting method. Results: Increase in HPMC concentration formed ODF with greater tensile strength. Incorporation of plasticizer (PEG 400 and glycerin) reduced tensile strength but increased elasticity of the ODF formed. PVP increased both tensile strength and elasticity of the ODF. Increase in MCC:mannitol ratio reduced the tensile strength and elasticity of the ODF. Disintegration time of film decreased corresponding to decrease in tensile strength of the film. Formulation R with the optimum tensile strength (13.10 N/mm2), bending flexibility (40 times) and disintegration time (41.50 s) was chosen as final formulation. A total of 80% of the drug was released within five minutes and the ODF was stable at least for one year actual condition. Conclusion: An ODF containing donepezil HCl was developed and characterized. The donepezil HCl ODF has the potential to improve the compliance of Alzheimer disease patients.

Simultaneous quantification of sildenafil and N-desmethyl sildenafil in human plasma by UFLC coupled with ESI-MS/MS and pharmacokinetic and bioequivalence studies in Malay population

A simple, rapid, specific and reliable UFLC coupled with ESI-MSMS assay method to simultaneously quantify sildenafil and N-desmethyl sildenafil, with loperamide as internal standard, was developed. Chromatographic separation was performed on a Thermo Scientific Accucore C18 column with an isocratic mobile phase composed of 0.1% v/v formic acid in purified water-methanol (20:80, v/v), at a flow rate of 0.3 mL/min. Sildenafil, N-desmethyl sildenafil and loperamide were detected with proton adducts at m/z 475.4 > 58.2, 461.3 > 85.2 and 477.0 > 266.1 in multiple reaction monitoring positive mode, respectively. Both analytes and internal standard were extracted by diethyl ether. The method was validated over a linear concentration range of 10-800 ng/mL for sildenafil and 10-600 ng/mL for N-desmethyl sildenafil with correlation coefficient (r(2) ) ≥0.9976 for sildenafil and (r(2) ) ≥0.9992 for N-desmethyl sildenafil. The method was precise, accurate and stable. The proposed method was applied to study the bioequivalence between a 100 mg dose of two pharmaceutical products: Viagra (original) and Edyfil (generic) products. AUC0-t , Cmax and Tmax were 2285.79 ng h/mL, 726.10 ng/mL and 0.94 h for Viagra and 2363.25 ng h/mL, 713.91 ng/mL and 0.83 hour for Edyfil. The 90% confidence interval of these parameters of this study fall within the regulatory range of 80-125%, hence they are considered as bioequivalent.

Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer’s disease patients

Abstract Context: Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. Objective: The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer’s disease patient. Methods and materials: The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. Results and discussion: Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. Conclusion: The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer’s disease patients.

Application of freeze-drying technology in manufacturing orally disintegrating films

Abstract Freeze drying technology has not been maximized and reported in manufacturing orally disintegrating films. The aim of this study was to explore the freeze drying technology in the formulation of sildenafil orally disintegrating films and compare the physical properties with heat-dried orally disintegrating film. Central composite design was used to investigate the effects of three factors, namely concentration of carbopol, wheat starch and polyethylene glycol 400 on the tensile strength and disintegration time of the film. Heat-dried films had higher tensile strength than films prepared using freeze-dried method. For folding endurance, freeze-dried films showed improved endurance than heat-dried films. Moreover, films prepared using freeze-dried methods were thicker and had faster disintegration time. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. Scanning electron microscopy showed that the freeze-dried films had more porous structure compared to the heat-dried film as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. The sildenafil film was palatable. The dissolution profiles of freeze-dried and heat-dried films were similar to Viagra® with f2 of 51.04 and 65.98, respectively.

Three-ways crossover bioequivalence study of cephalexin in healthy Malay volunteers

Abstract Context: Although the general pharmacokinetics of cephalexin is quite established up-to-date, however, no population-based study on Cephalexin pharmacokinetics profile in Malay population has been reported yet in the literature. Objective: The objective of this study was to investigate the pharmacokinetics and to compare the bioavailability of three cephalexin products, Ospexin® versus MPI Cephalexin® tablet and MPI Cephalexin® capsule, in healthy Malay ethnic male volunteers in Malaysia. Material and method: A single dose, randomized, fasting, three-period, three-treatment, three-sequence crossover, open label bioequivalence study was conducted in 24 healthy Malay adult male volunteers, with 1 week washout period. The drug concentration in the sample was analyzed using high performance liquid chromatography. Result: The mean (SD) pharmacokinetic parameter results of Ospexin® were Cmax, 17.39 (4.15) μg/mL; AUC0–6, 28.90 (5.70) µg/mL * h; AUC0–∞, 30.07 (5.94) µg/mL * h; while, those of MPI Cephalexin® tablet were Cmax, 18.29 (3.01) μg/mL; AUC0–6, 30.02 (4.80) µg/mL * h; AUC00–∞, 31.33 (5.18) µg/mL * h and MPI Cephalexin® capsule were Cmax, 18.25 (3.92) μg/mL; AUC0–6, 30.04 (5.13) µg/mL * h; AUC0–∞, 31.22 (5.29) µg/mL * h. Conclusion: The 90% confidence intervals for the logarithmic transformed Cmax, AUC0–6 and AUC0–∞, of Ospexin® versus MPI Cephalexin® tablet and Ospexin® versus MPI Cephalexin® capsule were between 0.80 and 1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. The pharmacokinetic profile of cephalexin in Malay population does not vary much from other world population.

Improved protein deproteinization method for the determination of meloxicam in human plasma and application in pharmacokinetic study.

A simple, rapid, specific and reliable high-performance liquid chromatographic assay of meloxicam in human plasma has been developed using a C18 reversed-phase analytical column. Reversed-phase chromatography was conducted using a mobile phase of 0.02 potassium dihydrogen phosphate (adjusted to pH 2.7 with phosphoric acid)-acetonitrile-triethylamine (35:65:0.05, v/v) with UV detection at 354 nm. The drug in human plasma was deproteinized using a combination of methanol and chloroform. This method is simple, rapid and consistent with a high recovery of meloxicam in human plasma ranging from 93.29 to 111.09%. Regression analysis for the calibration plot for plasma standards obtained for the drug concentrations between (25-4000) ng/mL indicated excellent linearity (r ≥ 0.9997). The proposed method was applied to study the bioequivalence between Mobic (original) and Melocam (generic) products. The study was conducted on using two tablets (4 × 7.5 mg) of each of the commercial product and the reference standard in a two-way open randomized crossover design involving 20 volunteers. Area under the concentration-time curve, peak concentration (C(max)) and time to reach C(max) were 72,868.61 ng h/mL, 2133.93 ng/mL and 4.06 h for Mobic, and 78,352.52 ng h/mL, 2525.18 ng/mL and 3.61 h for Melocam. Two C(max) were discovered in the pharmacokinetic profiles which confirm enterohepatic recirculation.

Randomized two‐way cross‐over bioequivalence study of two amoxicillin formulations and inter‐ethnicity pharmacokinetic variation in healthy Malay volunteers

The objectives of this study were to develop a new deproteinization method to extract amoxicillin from human plasma and evaluate the inter-ethnic variation of amoxicillin pharmacokinetics in healthy Malay volunteers. A single-dose, randomized, fasting, two-period, two-treatment, two-sequence crossover, open-label bioequivalence study was conducted in 18 healthy Malay adult male volunteers, with one week washout period. The drug concentration in the sample was analyzed using high-performance liquid chromatography (UV-vis HPLC). The mean (standard deviation) pharmacokinetic parameter results of Moxilen® were: peak concentration (Cmax ), 6.72 (1.56) µg/mL; area under the concentration-time graph (AUC0-8 ), 17.79 (4.29) µg/mL h; AUC0-∞ , 18.84 (4.62) µg/mL h. Those of YSP Amoxicillin® capsule were: Cmax , 6.69 (1.44) µg/mL; AUC0-8 , 18.69 (3.78) µg/mL h; AUC00-∞ , 19.95 (3.81) µg/mL h. The 90% confidence intervals for the logarithmic transformed Cmax , AUC0-8 and AUC0-∞ of Moxilen® vs YSP Amoxicillin® capsule was between 0.80 and 1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. Both formulations were well tolerated. The results showed significant inter-ethnicity variation in pharmacokinetics of amoxicillin. The Cmax and AUC of amoxicillin in Malay population were slightly lower compared with other populations.