In our previous work on levodopa delivery at pH 2.5 using iontophoresis, we found that cathodal delivery showed higher permeation than anodal delivery and electroosmosis plays more dominant role than electrorepulsion. In this work, we studied the transdermal transport of levodopa at very low pH (pH=1.0) where all levodopa molecules are cations, and evaluated some factors which affect the transdermal transport. The transport study at pH 2.5 was also conducted for comparison. The contribution of electrorepulsion and electroosmosis on flux was also evaluated. Using stable aqueous solution, the effect of electrode polarity, current density, current type and drug concentration on transport through skin were studied and the results were compared. We also investigated the iontophoretic flux from hydroxypropyl cellulose (HPC) hydrogel containing levodopa. In vitro flux study was performed at , using side-by-side diffusion cell. Full thickness hairless mouse skin were used. Current densities applied were 0.2, 0.4 or . Contrary to the pH 2.5 result, anodal delivery showed higher flux, indicating that electrorepulsion is the dominant force for the transport, overcoming the electroosmotic flow which is acting against the direction of electrorepulsion. Cumulative amount of levodopa transported was increased as the current density or drug concentration was increased. When amount of current dose was constant, continuous current was more beneficial than pulsed current in promoting levodopa permeation. Similar transport results were obtained when hydrogel was used as the donor phase. These results indicate that iontophoretic delivery of zwitterion such as levodopa is much complicated than that can be expected from small ionic molecules. The results also indicate that, only at very low pH like pH 1.0, electrorepulsion can be the dominant force over the electroosmosis in the levodopa transport.
Solid lipid nanoparticles (SLNs) were freeze-dried to obtain a stable solid dosage form with the aid of various cryoprotectants such as trehalose, sucrose, glucose, fructose, and glycerol. Tricaprin(TC) and trilaurin(TL) were used as lipid matrices for SLNs and stabilizers were egg phosphatidylcholine and pegylated phospholipid. All cryoprotectants tested did not cause changes in mean particle size of SLNs when mixed with SLNs before freeze-drying. However, the mean particle sizes of reconstituted SLNs after freeze-drying were significantly different from those of the un-lyophilized original SLN dispersions depending on the types and concentration of cryoprotectants. Although the freeze-dried SLNs without any cryoprotectants were easily reconstituted by hand-shaking, the mean particle size drastically increased (> for TC SLNs and around for TL SLNs) compared to that of un-lyophilized original dispersion (97 nm for TC SLNs and 164 nm for TL SLNs). Trehalose and sucrose were the most effective additives to protect the SLNs during lyophilization. The reconstituted SLNs were physically stable for 24 hours when lyophilized with 12.5% trehalose, sucrose, glucose, fructose or glycerol.
The Guidance Document for Bioequivalence Study was revised for adding to bioequivalence studies of controlled-release products after meal(Korea Food & Drug Administration Notification #2008-22, 2008.5.7). The bioequivalence study design for controlled-release products is crossover under fast and fed condition in respect. For studies of controlled-release products under fed study, the same high-fat diet should be taken within 20 minutes in at least a 10-hour fasting state. The drug products should be administered 30 minutes after the meal started. A high-fat(more than 35 percent of total caloric content of the meal) and high-calorie(over 900 calories) meal is recommended as a test meal for fed BE studies.
Lacidipine used for the treatment of hypertension has low water solubility and is classified as BCS Class II category. Gelucire-based solid dispersions (SD) containing lacidipine were prepared by solvent evaporation method to enhance drug dissolution. The powdered forms of SD showed irregularly spherical shape. Thermal behaviors of SD from differential scanning calorimetry indicated that distinct endothermic peak of lacidipine () was shifted to lower region (). Drug was present in a crystalline form. NMR spectra also showed some molecular interaction between drug and Gelucire. There was no significant difference in DSC and NMR behaviors between Gelucire 44/14 and Gelucire 50/13. The initial dissolution rate of SD-loaded tablet linearly increased both in water and in water containing 1% tween 20, and much higher than the commercial tablet, . When the amount of SD was increased, the release rate was greater. The Gelucire 50/13 showed higher dissolution than the Gelucire 44/14. The produced solid dispersion with various kinds of excipients and making tablets, it was found that solid dispersions can increase the solubility in artificial gastric juice and finally increases dissolution rate.
Sibutramine is an orally administered centrally-acting antiobesity agent and inhibits both noradrenaline(norephinephirine) and serotonin(5-HT) reuptake. These effects are contributed by its active metabolites, M1 and M2. However, as the free base form of sibutramine is an oil form in room temperature, it had the problem of handling and stability. Thus, this drug should be used in the form of acid salt form in the pharmaceutical application. Unfortunately, anhydrous sibutramine hydrochloride is highly hygroscopic and unstable. In order to solve the hygroscopicity of the anhydrous salt form, another sibutramine acid salt form must be developed as a hydrate form. In this study. to overcome these problems, various of sibutramine acid salt forms were prepared with the pharmaceutically available salts such as maleate, esylate, mandelate, camsylate, besylate, salicylate, tartrate, isethionate and malate forms, and their physicochemical properties were investigated. Sibutramine malate was selected for excellent solubility and stability among the listed salt forms above. Its pharmacokinetic parameters were evaluated in rats comparing with sibutramine HCl, resulting in similar parameters. In vitro dissolution study of sibutramine malate-loaded capsule was performed comparison with commercial product () in pH 1.2, pH 4.0, pH 6.8 and water medium. Our results indicated that there were no significant differences in their dissolution profiles were similar in all tested medium. Thus, sibutramine malate-loaded capsule should be a potential candiate due to its excellent solubility, good stability and biosimilar absorption.
Unlike human, with some exceptions, animals do not heal with excessive scar. The lack of suitable animal model has hindered the development of effective scar therapy. We previously reported that partial thickness rabbit ear wound model resembles human wound heal process. This study was designed to prepare a hypertropic scar wound model which can be employed for testing anti-scar therapy. Four wounds were created down to the bare cartilage on the anterior side of each rabbit ear using 8-mm dermal biopsy punch and histology analysis at post operation day (POD) 5, 28 and 48 were performed. As the outcome of scar formation is largely determined by the early inflammatory response to the wounding and the degree and the duration of occlusion, cephalodin(50 mg/kg) was injected daily and medical occlusive dressings were applied. Five micro wound and scar sections were stained with hematoxylin and eosin for quantification of epidermal regeneration and scar hypertrophy. Sections were also stained using Masson's trichrome and Sirius red to evaluate collagen organization and rete ridge formation. Wound closure process was assessed to 7wks post wounding. Complete removal of the epidermis, dermis and perichondrial layer caused delayed epithelialization, which results in hypertropic scarring. The inability of the wounds to contract and the delay in epithelialization in rabbit ear was likely due to cartilage and it created scar elevation. The results suggest that full thickness surgical punch wound model in rabbit ear could be employed as a reliable and reproducible scar wound model for testing anti-scar therapy.
Losartan potassium, 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol mono-potassium salt, is a new class of antihypertensive agents, and is an antagonist in angiotensin receptor. The purpose of the present study was to evaluate the bioequivalence of two Losartan potassium tablets, Cozaar tablet (MSD Pharmaceutical Co., Ltd.) and Losata tablet (Kyung Dong Pharmaceutical Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of losartan from the two losartan potassium formulations in vitro was tested using KP VIII Apparatus II method with various dissolution media. Twenty eight healthy male subjects, years in age and in body weight, were divided into two groups and a randomized cross-over study was employed. After a single tablet containing 50 mg as losartan potassium was orally administered, blood samples were taken at predetermined time intervals, and the concentrations of losartan in serum were determined using HPLC with fluorescence detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as , and were calculated, and Equiv Test/K-BE Test 2002 was utilized for the statistical analysis of the parameters using logarithmically transformed , and untransformed . The results showed that the differences between two formulations based on the reference drug, Cozaar, were -2.70%, 1.45% and 2.31% for , and , respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8852~log 1.0655 and log 0.8319~log 1.2342 for and , respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Losata tablet was bioequivalent to Cozaar tablet.
This study was carried out to establish standard analytical method of Hippocastani Semen extract. Each standard analytical methods were covered for exact and efficient analytical method. Consequently, analytical method of Deutsches Arzneibuch has been adopted for Hippocastani Semen extract. Analytical methods established in this study could be applied to a reasonable and unified quality control of Hippocastani Semen extract.
K- is a well known program for bioequivalence test using a design. Lee et al.(1998) and Park et al.(1999) suggested a and design, and also discussed their benefits. We developed a computer program, called BioEquiv, which can analyze some complex experimental designs such as, design and design including a standard design. This program is a user-friendly one and overcomes the disadvantages of K-. The detailed statistical formula and structure of BioEquiv are presented with some examples. The comparison between K- and BioEquiv are given with actual data analysis. BioEquiv is able to present a table of ANOVA test over some complex experimental designs. Moreover K- and BioEquiv draw the same result when data consists of design.
Sibutramine is a serotonin-norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The oral administration of sibutramine is followed by its dose-related side effects. In this study, sibutramine was formulated into drug in adhesive (DIA) patches in an attempt to overcome these problems. The effects of different formulation variables including pressure-sensitive adhesive (PSA), loading amount of drug, thickness of matrix and enhancer on the skin permeation of the drug were evaluated using excised hairless mouse skin. In the acrylic adhesive with carboxyl functional group, low release of sibutramine was observed due to the strong interaction between carboxyl group of adhesive and amine group of sibutramine. The acrylic adhesive without functional group provided good adhesion force and allowed high drug loading. Changing drug load as well as thickness of the matrix was found to alter permeation rate. PK40 and A40, were found to be effective enhancers for sibutramine. The optimized patch contained 20% sibutramine, and 5% A40 as permeation enhancer, in thick Duro- 87-9301 matrix.
【This study was carried out to establish standard analytical method of Hippocastani Semen extract. Each standard analytical methods were covered for exact and efficient analytical method. Consequently, analytical method of Deutsches Arzneibuch has been adopted for Hippocastani Semen extract. Analytical methods established in this study could be applied to a reasonable and unified quality control of Hippocastani Semen extract.】
【Ibudilast, 3-isobutyryl-2-isopropyrazolo[1,5-a]pyridine, is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It preferentially inhibits PDE 3A, PDE4, PDE10 and PDE11 as well as a number of the other PDE families, albeit to a lesser extent. Ibudilast is used clinically to treat bronchial asthma and cerebrovascular disorders. Thes e clinical uses are based on the ability of ibudilast to inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The purpose of the present study was to evaluate the bioequivalence of two ibudilast capsules, Ketas capsule (Handok Pharmaceuticals Co., Ltd.) and Pinatos capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The in vitro release of ibudilast from the two ibudilast formulations was tested using KP Apparatus method with various dissolution media. Twenty six healthy male subjects, 23.31 ${\pm}$ 1.09 years in age and 70.45 ${\pm}$ 8.51 kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single capsule containing 10 mg as ibudilast was orally administered, blood samples were taken at predetermined time intervals and the concentrations of ibudilast in serum were determined using HPLC/UV detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$ , $C_{max}$ and $T_{max}$ were calculated, and computer programs (Equiv Test and K-BE Test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$ , $C_{max}$ and untransformed $T_{max}$ . The results showed that the differences between two formulations based on the reference drug, Ketas, were 6.99%, -2.48% and 9.93% for $AUC_t$ , $C_{max}$ and $T_{max}$ , respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8791~log 1.1861 and log 0.8347~log 1.1199 for $AUC_t$ and $C_{max}$ , respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Pinatos capsule was bioequivalent to Ketas capsule.】
We previously showed that the water extracts of rice wine-baked Scutellaria baicalensis Georgi (RWBS) ameliorated colonic inflammation more than crude Scutellaria baicalensis (CS) after oral administration. The aim of this study is to compare the effect of rectal and oral administration of RWBS in the experimental colitis. Experimental colitis was induced in mice by daily treatment with 5% dextran sulfate sodium (DSS) in the drinking water for 7 days. Water was used as vehicle of oral administration, while Carbopol/PEG mucoadhesive gel was used as vehicle of rectal administration. RWBS and RWBS gel (RWBSG) were administered once per day for 7 days. RWBS and RWBSG significantly attenuated the disease activity index (DAI) calculated as the sum of scores of body weight loss, stool consistency and rectal bleeding. Furthermore, RWBS and RWBSG reduced the mucosal myeloperoxidase activity and COX-2 (cyclooxygenase-2) expression in colon tissue. Anti-inflammatory effect of CS on colonic inflammation was increased by baking with rice wine in both oral and rectal administration. Moreover, anti-inflammatory effects of oral administration on colonic inflammation was greater than those of rectal administration. Further study would be required for the development of intra-rectal formulation.
An enzyme immunoassay (EIA) was validated for quantitation of cacitriol in human plasma. Calcitriol was immunoextracted with immunocapsules, which contain monoclonal antibodies to calcitriol linked to solid phase particles in suspension with a vitamin D binding protein inhibitor. Calcitrol was eluated and the eluates were evaporated under a gentle stream of nitrogen gas. The absorbance of analytes was determined using a microplate reader (reference wavelength 650 nm; measurement wavelength 450 nm). The method was specific and sensitive enough to detect as low as 6.5 pmol/L of calcitriol. Linear calibration range was 6.5-491 pmol/L with correlation coefficient greater than 0.99. The overall accuracy was in the range of 83.8 to 111.2% and precision C.V. (%) 0.99 to 8.47%. The recovery was approximately 100% and stability was confirmed during storage and sample preparation. The pharmacokinetic parameters were calculated by baseline subtraction because calcitriol is an endogenous material. Following oral dose of calcitriol, the mean AUC was 1038539 pmol/Lhr and C of 12863.1 pmol/L was reached at 3.501.07 hr. The mean t of calcitriol was 5.132.10 hr. The present EIA method was successfully applied to study bioavailability after oral administration of 2 g of calcitriol in healthy Korean subjects.
Two crystal forms of ziprasidone have been isolated by recrystallization from different organic solvents and characterized by differential scanning calorimetry, powder X-ray diffractometry and thermogravimetric analysis. It was confirmed that Form 2 has the same crystal structure as Form 1.
-h3, is a TGF--induced gene product, extracellular matrix protein with 68 kDa MW(683 amino acids) and has been known for its possible roles in cell adhesion, spreading, migration and proliferation. To minimize a proteolytic degradation of -h3, -h3 incorporated chitosan sponge was prepared and its effects on fibroblast adhesion and migration were investigated. And its wound healing efficacy was evaluated in deep 2nd degree burn rabbit ear wound model. -h3 enhanced fibroblast adhesion and proliferation. In histological observation, a significant over-proliferation of epidermal regeneration was observed in -h3/chitosan dressing applied wound while epidermal regeneration was not proceeded yet in chitosan only treated wound. -h3/sponge dressing could enhance epidermal regeneration.
Docetaxel is an anticancer agent with low aqueous solubility. More extensive clinical use of this drug is somewhat delayed due to lack of appropriate delivery vehicles. An attempt was made to adopt an o/w emulsion as the drug carrier which incorporated docetaxel in the propyleneglycerol stabilized by a mixed-emulsifier system. A suitable formulation was found in this study: 10 mg/mL docetaxel, 10% (w/v) oil blend, 4% (w/v) PG, 3% (w/v) Solutol HS 15 in 2.25% (w/v) glycerol solution. The formulated emulsion has very good stability when stored at , and the docetaxel containment efficiency can be maintained above 95% and the mean emulsion diameter around for at least 3 months. The formulated emulsion is a promising carrier for docetaxel and other lipophilic drugs.
We aimed to optimize the formulation of porcine placental extract (PPE)-loaded liposomes for intramuscular administration and to investigate the effect of surface charges on the muscular retention in mice. PPE-loaded liposomes were formulated to have neutral, anionic, or cationic surface charges. The in vitro release profiles were studied by spectrofluorometry. In vivo distribution patterns at mice were studied using molecular imaging technology. Among the three types of liposomes, 1,2-dioleoyl-3-trimethylammonium-propane and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-based cationic liposomes showed the most prolonged in vitro release profile. Consistent with the in vitro results, the in vivo distribution study revealed that the cationic liposomes were retained at the site of administration for the longest period. Our results suggest the potential of cationic PPE-loaded liposomes for sustained release of the components after intramuscular administration.
The aim of this study was to investigate the frequency of the SNPs on PEPT1 exon 5 and 16 and to analyze haplotype frequency on PEPT1 exon 5 and 16 in Korean population. A total of 519 healthy subjects was genotyped for PEPT1, using pyrosequencing analysis and polymerase chain reaction-based diagnostic tests. Haplotype was statistically inferred using an algorithm based on the expectation-maximization (EM). PEPT1 exon 5 G381A genotyping revealed that the frequency for homozygous wild-type (G/G), heterozygous (G/A) and homozygous mutant-type (A/A) was 30.4, 53.4 and 16.2%, respectively. PEPT1 exon 16 G1287C genotyping revealed that the frequency for homozygous G/G, heterozygous G/C and homozygous C/C type was 88.8, 10.0 and 1.2%, respectively. Based on these genotype data, haplotype analysis between PEPT1 exon 5 G381A and exon 16 G1287C using HapAnalyzer and PL-EM has proceeded. The result has revealed that linkage disequilibrium between alleles is not obvious (|D'|=0.3667).
To develop a topical bioadhesive formulation of clotrimazole for enhanced transdermal delivery, hydroxypropyl methylcellulose gel containing permeation enhancer was formulated and permeation studies were carried out. The release characteristics of the drug from the gel formulation were examined according to the receptor medium, drug concentration, and temperature. The rate of drug release from the gel increased with increasing drug concentration and temperature. The activation energy (Ea) of drug permeation, which was calculated from the slope of log P versus 1/T plots, was 14.41kcal/mol for a 1%(w/w) loading dose. The enhancer, such as saturated, unsaturated fatty acids, pyrrolidones, propylene glycol derivatives, glycerides, and non-ionic surfactants, were incorporated onto the gels to increase the amount of drug permeation into the skin. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the highest level of enhancement. These results show that clotrimazole gels containing polyoxyethylene 2-oleyl ether could be used for the enhanced transdermal delivery of clotrimazole.
