Microencapsulation of water-soluble drugs using coacervation-phase separation method is very challenging, as these drugs partitioned into the aqueous polymeric solution, resulting in poor drug entrapment. For evaluating the effect of ovalbumin on the microencapsulation of drugs with different solubility, pseudoephedrine HCl, verapamil HCl, propranolol HCl, paracetamol, and curcuminoid were used. In addition, drug mixtures comprising of paracetamol and pseudoephedrine HCl were also studied. The morphology, encapsulation efficiency, particle size, and in vitro release profile were investigated. The results showed that the solubility of the drug determined the ratio of ovalbumin to be used for successful microencapsulation. The optimum ratios of drug, ovalbumin, and gelatin for water-soluble (pseudoephedrine HCl, verapamil HCl, and propranolol HCl), sparingly water-soluble (paracetamol), and water-insoluble (curcuminoid) drugs were found to be 1:1:2, 2:3:5, and 1:3:4. As for the drug mixture, the optimum ratio of drug, ovalbumin, and gelatin was 2:3:5. Encapsulated particles prepared at the optimum ratios showed high yield, drug loading, entrapment efficiency, and sustained release profiles. The solubility of drug affected the particle size of the encapsulated particle. Highly soluble drugs resulted in smaller particle size. In conclusion, addition of ovalbumin circumvented the partitioning effect, leading to the successful microencapsulation of water-soluble drugs.
Obesity is one of the most important problems worldwide. Khat (Catha edulis), an evergreen shrub, is thought to reduce body-weight. Its effect is more prominent when khat leaves are chewed. Thus, anti-obesity effects of khat and its associated side effects may depend on the release rate of its active constituents. The present study aimed to investigate the effect of a selected low dose of dried-khat, extracted, formulated as controlled release delivery systems on the body weight (BW), food intake (FI), cholesterol (CS) and triglyceride (TG) levels in rats. Khat extract (KE) was microencapsulated (KE235) and formulated into a parenteral implant (InjKE235). The effects of KE, KE235 and InjKE235 on BW, FI, CS and TG in rats were investigated. The results showed that microcapsules sustained the khat alkaloid release with T50% 1.58 h for KE235 and 14.41 days for InjKE235. KE and KE235 caused maximum reduction in BW, FI, CS and TG during the first to third weeks but rebound gradually thereafter. On the contrary, InjKE235 exhibited a sustained reduction in BW, FI, CS and TG levels for 2 months. The T50% of KE, KE235 and InjKE235 correlated with the reduction in BW, CS and TG but not with FI. In conclusion, the subcutaneous injection and sustained release rate of khat extract play an important role in enhancing the anti-obesity effect in SD rats.:
Khat (Catha edulis) as well as garlic (Allium sativum) has a potential effect on reducing the lipid contents of blood. However, a mechanism by which garlic or khat reduces plasma lipids has not been fully investigated. This study aimed to investigate the direct action of khat and/or garlic (in vitro). The effects of extracted khat and/or garlic on human blood constituents (cholesterol and triglycerides) and on vegetable oil were investigated. The results showed that aqueous garlic extract was able to form an emulsion with oil but not khat extract. Even though, either khat or garlic extract has slight effect on reducing lipid contents of blood; a higher reduction was obtained when the extracts were added in combination. The mechanism of garlic on reducing lipids could be explained by its emulsifying property, while the mechanism of khat is by lipolysis. In conclusion, the synergistic effect of garlic and khat extracts opened an interesting area for further investigation on their roles in combating cardiovascular and obesity disorders.:
Khat (Catha edulis) is an evergreen tree/shrub that is thought to affect sexual motivation or libido. Its positive effect on sexual desire is more frequently observed in females than in males and occurs when khat is chewed. Thus, khat's effects on sexual behavior may depend on the release mode of its active constituent.
Curcumin, the main active constituent of turmeric herb (Curcuma longa L.) have been reported to possess many medicinal values. The application of curcumin in dermatological preparations is limited by their intense yellow color property, which stains the fabric and skin. The objectives of this study were to reduce the color staining effect and enhance the stability of curcumin via microencapsulation using gelatin simple coacervation method. As for curcumin, ethanol and acetone were used as coacervating solvents. Curcumin was dispersed in ethanol while dissolved in acetone. Irrespective of the types of coacervating solvents used, microencapsulation resolved the color-staining problem and enhanced the flow properties and photo-stability of curcumin. Nevertheless, it was found that more spherical curcumin microcapsules with higher yield, higher curcumin loading, and higher entrapment efficiency were obtained with acetone than ethanol. The in vitro release of curcumin after microencapsulation was slightly prolonged. Further evaluation of the effects of solubility of core materials in coacervating solvent or polymeric aqueous solution using six different drug compounds, namely, ketoconazole, ketoprofen, magnesium stearate, pseudoephedrine HCl, diclofenac sodium, and paracetamol, suggested that the solubility of core materials in aqueous polymeric solution determined the successful formation of microcapsules. Microcapsules could only be formed if the core materials were not dissolved in the aqueous polymeric solution while the core materials could either be dissolved or dispersed in the coacervating solvent. In summary, microencapsulation not only circumvents the color-staining problem but also improved the stability and flowability of curcumin. The solubility of core material in aqueous polymeric solution plays a pivotal role in determining the successful formation of microcapsules.
Singapore is a tropical island city-state with a population of 2.4178 million consisting of Chinese (76.7%), Malays (14.7%), Indians (6.4%) and other races (2.2%). A diabetic survey of the adult population, aged 15 years and above, carried out in 1975, shows that the prevalence of diabetes is 1.99%; it is higher in males (2.36%) than in females (1.64%). It occurs mainly in the age group 40 years and above (5.08%) and is uncommon in the age group 15-39 years (0.40%). In males, the highest prevalence of diabetes (7.0%) is in the age group 45-49 years while in females the highest prevalence (7.2%) is in the age group 55-59 years. 43.3% of the diabetics are of normal weight while 44.3% are overweight and 12.4% are underweight. 59.6% of the diabetics are newly diagnosed while 40.4% are known diabetics; 64.3% of the newly diagnosed diabetics have no symptoms. The prevalence of diabetes among the Indians (6.07%) is significantly higher than that in Malays (2.43%) and Chinese (1.55%). Indian diabetics have a slightly higher positive family history of diabetes (12.7%) than Malays (10.9%) and Chinese (6.5%). Obesity is commoner in Malay diabetics (64.7%) than in Chinese (41.6%) and Indians (35.7%). The possible factors leading to the significantly higher prevalence of diabetes among the Indians compared to the other ethnic groups in Singapore are discussed. It is suggested that the Indian gene is susceptible to diabetes (diabetic genotype) and increased food consumption, altered lifestyle and greater obesity leads to the expression of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
A country-wide diabetic survey of the population (age 15 years and above) of Singapore shows that the prevalence of diabetes mellitus in Singapore is 1.99 percent. It is commoner in males (2.36 percent) than in females (1.64 percent). The prevalence of diabetes in the age group 15-39 years is only 0.40 percent and in the age group 40 years and older it is 5.08 percent. The prevalence of diabetes in Indians (6.07 percent) is significantly higher than that in Malays (2.43 percent) and Chinese (1.55 percent). Indian diabetics have an insignifi"cantly higher incidence of positive family of diabetes (12.7 percent) than Malays (10.9 percent) and Chinese (6.5 percent). Obesity was commoner in Malay diabetics (67.4 percent) than in Chinese diabetics (41.6 percent) and Indian diabetics (35.7 percent). The survey shows that 40.4 percent of the diabetics are known while 59.6 percent of the diabetics are newly diagnosed. The majority of the diabetics are treated with oral hypoglycaemic drugs (71.5 percent) and only 4.8 percent are receiving insulin injections. A mong the female diabetics, 63.0 percent have 4 or more pregnancies and large babies at birth are recorded in 12.3 percent. In the newly diagnosed diabetics, 64.3 percent have no symptoms. The complications of the diabetics are hypertension (26.8 percent), nephropathy (9.8 percent), retinopathy (8.5 percent), coronary heart disease (6.1 percent), skin infection (4.6 percent) and neuropathy (3.3 percent). The high prevalence of diabetes among the Indians is likely to be due to a genetic predisposition coupled with an environmental factor (obesity), although this hypothesis is not conclusively demonstrated by the present study.
The potential of using poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer to prepare BDP-loaded micelles with high entrapment efficiency and mass median aerodynamic diameter of less than 5 microm demonstrating sustained release properties was evaluated. The result showed that lyophilized BDP-loaded polymeric micelles with entrapment efficiency of more than 96% could be achieved. Entrapment efficiency was affected by both the drug to polymer molar ratio and the amount of drug used. Investigation using FTIR and DSC confirmed that there was no chemical or physical interaction and the drug was molecularly dispersed within the micelles. TEM images showed that the drug-loaded polymeric micelles were spherical in shape with multivesicular morphology. Further analysis by photon correlation spectroscopy indicated that the particle size of the BDP-loaded micelles was about 22 nm in size. In vitro drug release showed a promising sustained release profile over six days following the Higuchi model. The mass median aerodynamic diameter and fine particle fraction were suitable for pulmonary delivery. Moreover, the small amount of deposited drug in the induction port (throat deposition) suggested possible reduction in incidence of oropharyngeal candidiasis, a side effect normally associated with inhaled corticosteroids therapy. The high encapsulation efficiency, comparable inhalation properties, sustained release behavior together with biocompatibility nature of the polymer support the potential of BDP-loaded polymeric micelles as a versatile delivery system to be used in the treatment of asthma and chronic obstructive pulmonary disease.
Aim: To develop an LC-MS/MS method for simultaneous determination of duloxetine and its metabolite, 4-hydroxy duloxetine glucuronide (4HDG) in human plasma and to investigate the potential back-conversion of 4HDG to duloxetine using stability study. Materials & methods: The LC-MS/MS method was validated according to the EMA and USFDA Bioanalytical Method Validation Guidelines and applied to pilot bioequivalence study. Results & conclusion: The method validation results were within the acceptance limits. The stability study and incurred sample reanalysis results ruled out the occurrence of back-conversion. The study highlighted the conduct of back-conversion test and the advantages of LC-MS/MS method in terms of sensitivity, specificity and low consumption of organic solvents.
To determine the incidence of insulin dependent diabetes mellitus (IDDM) in children 0-12 years of age in Singapore, which has a population of 2.9 million.
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.
The effect of deprotenizing agents on recovery of donepezil hydrochloride in the development of a simple, rapid, selective and sensitive high performance liquid chromatography method for quantification of donepezil hydrochloride in human plasma was described. The deprotenizing agents were comprised of, perchloric acid, methanol, acetonitrile, chloroform and their mixtures. The chromatographic separation was carried out using reversed phase C18 column (Agilent Eclipse Plus C18) with UV detection at 268 nm. The mobile phase was comprised of 0.01 M potassium dihydrogen phosphate buffer, methanol and acetronitrile (50:30:20, v/v) adjusted to pH 2.7 with phosphoric acid (80%). A combination of perchloric acid and methanol gave a cleaner sample with a good recovery of donepezil hydrochloride of above 96%. The method showed intraday precision and accuracy in the range of 6.82% to 1.5% and 3.13% to 1.12% respectively, while interday precision and accuracy ranged between 1.06% to 4.71% and 13.01% to 6.43% respectively. The standard calibration curve was linear from 30ng/mL to 4000ng/mL, with a correlation coefficient of 0.9965±0.0034. The retention time of donepezil was 5.9 min with a run time of 7.0 min. The method can be applied to analyze large batch plasma samples in pharmacokinetic studies.
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.
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.
An easy, fast and validated RV-HPLC method was invented to quantify donepezil hydrochloride in drug solution and orally disintegrating tablet. The separation was carried out using reversed phase C-18 column (Agilent Eclipse Plus C-18) with UV detection at 268 nm. Method optimization was tested using various composition of organic solvent. The mobile phase comprised of phosphate buffer (0.01M), methanol and acetonitrile (50:30:20, v/v) adjusted to pH 2.7 with phosphoric acid (80%) was found as the optimum mobile phase. The method showed intraday precision and accuracy in the range of 0.24% to -1.83% and -1.83% to 1.99% respectively, while interday precision and accuracy ranged between 1.41% to 1.81% and 0.11% to 1.90% respectively. The standard calibration curve was linear from 0.125 μg/mL to 16 μg/mL, with correlation coefficient of 0.9997±0.00016. The drug solution was stable under room temperature at least for 6 hours. System suitability studies were done. The average plate count was > 2000, tailing factor <1, and capacity factor of 3.30. The retention time was 5.6 min. The HPLC method was used to assay donepezil hydrochloride in tablet and dissolution study of in-house manufactured donepezil orally disintegrating tablet and original Aricept.
The aim of this study was to develop a taste-masked oral disintegrating film (ODF) containing donepezil, with fast disintegration time and suitable mechanical strength, for the treatment of Alzheimer's disease. Hydroxypropyl methylcellulose, corn starch, polyethylene glycol, lactose monohydrate and crosspovidone served as the hydrophilic polymeric bases of the ODF. The uniformity, in vitro disintegration time, drug release and the folding endurance of the ODF were examined. The in vitro results showed that 80% of donepezil hydrochloride was released within 5 minutes with mean disintegration time of 44 seconds. The result of the film flexibility test showed that the number of folding time to crack the film was 40 times, an indication of sufficient mechanical property for patient use. A single-dose, fasting, four-period, eight-treatment, double-blind study involving 16 healthy adult volunteers was performed to evaluate the in situ disintegration time and palatability of ODF. Five parameters, namely taste, aftertaste, mouthfeel, ease of handling and acceptance were evaluated. The mean in situ disintegration time of ODF was 49 seconds. ODF containing 7 mg of sucralose were more superior than saccharin and aspartame in terms of taste, aftertaste, mouthfeel and acceptance. Furthermore, the ODF was stable for at least 6 months when stored at 40°C and 75% relative humidity.
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.
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.
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.
The effect of hydroxypropyl methylcellulose (HPMC) concentration on β-cyclodextrin (β-CD) solubilization of norfloxacin was examined. The solubility and dissolution of norfloxacin/β-CD and norfloxacin/β-CD/HPMC inclusion complexes were studied. The presence of β-CD increased significantly the solubility and dissolution of norfloxacin. The addition of HPMC until 5% (w/w) improved the solubilization of norfloxacin but further addition above 5% (w/w), decreased norfloxacin solubilization. Fourier transformed Infra-red (FTIR) showed that norfloxacin was successfully included into β-CD. Differential scanning calorimetry (DSC) showed that the norfloxacin endothermic peak shifted to a lower temperature with reduced intensity indicating the formation of inclusion complex. The addition of HPMC reduced further the intensity of norfloxacin endothermic peak. Most of the sharp and intense peaks of norfloxacin disappeared with the addition of HPMC. In conclusion, the concentration of hydrophilic polymer used to enhance β-CD solubilization of poorly soluble drugs is very critical.