• Journal of Pharmaceutical Investigation
• /
• 제34권6호
• /
• pp.529-540
• /
• 2004

After new medical system of separation of dispensary from medical practice was started in 2000 in Korea, to expand bioequivalence-proven drug products and to ensure the credibility of the therapeutic equivalence of generic drugs are hot issues in Korea. It will be obligatory to submit bioequivalence reports for getting licenses of all generic prescription drugs in the near future. Like other countries such as US and Japan, the KFDA also has a plan to re-evaluate the already approved drugs by bioequivalence studies. Therefore, it becomes more necessary to develop bioequivalence-demonstrating methods for specific preparations such as topical drug products among already approved drug products. There are some differences between US and Japanese guidances of bioequivalence studies of generic drug products for topical use. The information on Japanese guidance and the guidance's Q&As is already provided in our previous paper. In this paper, we examined the US guideline published in 1995 and compared with the Japanese guideline, which will give a useful information to make a guidance on bioequivalence studies of topical drug products in Korea.

• 대한본초학회지
• /
• 제33권1호
• /
• pp.71-76
• /
• 2018

Objectives : This study was performed to investigate the single oral toxicity of HBX-6 in Sprague-Dawley (SD) rats. Methods : Twenty SD rats were randomly assigned to four groups of 5 rats each and were administrated singly to female and male SD rats, as an oral dose of 2000 mg/kg. HBX-6 is a newly combined Korean herbal medicine formula 30 % Ethanol extract derived from The Dongui Bogam. Now we are developing the prescription for the aim of improving benign prostatic hyperplasia (BPH) without undesirable side effects. HBX-6 is composed of nine medicinal herbs: Aconiti Lateralis Radix Preparata, Corni Fructus, Cistanchis Herba, Psoraleae Semen, Dendrobii Herba, Morindae Radix, Cuscutae Semen, Trigonellae Semen, Foeniculi Fructus. Animals were monitored for the mortality and changes in the body weight, clinical signs, gross observation and necropsy findings for the 14 days according to "Standard for Toxicity Study of Pharmaceuticals" of Korea Food and Drug Administration (KFDA) guideline and "Acute Oral Toxicity - Fixed Dose Procedure" of OECD Test Guideline. Results : We could not find any mortality. Compared with the control group, significant weight change was not observed in the experimental group. After administration, the more common symptoms were not observed. There were no gross abnormalities in all cases. Conclusions : Taken together, these results suggest that the approximate lethal dose of HBX-6 in both female and male SD rats were considered as over 2000 mg/kg.

• 한국환경성돌연변이발암원학회지
• /
• 제22권4호
• /
• pp.296-302
• /
• 2002

In recent years, the safety of sunscreens have been challenged based on the reports of its adverse effects on users; dermatitis, allergic contact dermatitis, photoallergic contact dermatitis. In the toxicological aspect, the need to investigate the safety of sunscreens is steadily increasing. However, there were few studies on the correlation between sun protection factor (SPF) and the safety of sunscreens. The objective of this study was to assess whether there was a correlation between SPF and the skin irritation index of sunscreens. Octyl methoxycinnamate (OMC) was selected, which was the most frequently used (about 92% in korea and about 90% in the world) in sunscreens. In vitro SPF test was performed using the standard samples recommended by KFDA guideline. We examined primary and cumulative skin irritation and eye irritation of OMC standard sample as well as homosalate. As in vitro SPF was increased, skin irritation index was increased in primary skin irritation test ($r^2$=0.986) and cumulative skin irritation test ($r^2$=0.939). In addition, OMC was non-irritating and non-sensitizing. In this results, there was a good correlation between SPF index and skin irritation index.

• 약학회지
• /
• 제44권4호
• /
• pp.308-314
• /
• 2000

Logarithmic transformation of pharmacokinetic parameters is routinely used in bioequivalence studies based on pharmacokinetic and statistical grounds by the United States Food and Drug Administration (FDA), European Committee for Proprietary Medicinal Products (CPMP), and Japanese National Institute of Health and Science (NIHS). Although it has not yet been recommended by the Korea Food and Drug Administration (KFDA), its use is becoming increasingly necessary in order to harmonize with international standards. In the present study, statistical procedures for the analysis of a bioequivalence based on the log transformation and a related SAS procedure were demonstrated in order to aid the understanding and application. The AUC parameters used in this demonstration were taken from the previous bioequivalence study for two aceclofenac tablets, which were performed in a single-dose crossover design. Analysis of variance (ANOVA), statistical power to detect 20% difference between the tablets, minimum detectable difference and confidence intervals were all assessed following log-transformation of the data. Bioequivalence of two aceclofenac tablets was then estimated based on the guideline of FDA. Considering the international effort for harmaonization of guidelines for bioequivalence tests, this approach may require a further evaluation for a future adaptation in the Korea Guidelines of Bioequivalence Tests (KGBT).

• 생명과학회지
• /
• 제22권11호
• /
• pp.1456-1462
• /
• 2012

소라페닙은 멀티카이네즈 억제제로서 신세포암, 전이성 간세포암 환자의 치료에 효과가 입증된 경구용 항암제이다. 이 연구의 목적은 고속액체크로마토그래피 텐덤질량분석기법(LC/MS/MS)을 이용하여 사람 혈장 내 소라페닙의 농도를 측정하는 효율적인 방법을 개발하고 한국식품의약품안전청(KFDA) 기준에 따라 분석법을 검정하는 것이다. 혈장시료($100{\mu}l$)에 내부표준물질인 chlorantraniliprole을 첨가한 후 이소프로필알콜과 에틸아세테이트로 구성(1:4, v/v)된 0.1% 포름산 함유 추출용액을 혼합하였다. 원심분리 후 상층액을 취하여 원심감압농축하였다. 잔사를 이동상에 재용해하고 Waters사의 역상 XTerra$^{TM}$ C18 칼럼(입자크기 $3.5{\mu}m$)을 장착한 고속액체크로마토그래피 장치에 주입하였다. 액체크로마토그래피는 0.1% 포름산과 10 mM 암모늄 포메이트를 함유한 버퍼용액과 메탄올, 아세토나이트릴을 각각 1:6:3으로 혼합한 용액을 이동상으로 사용하였으며 5분 내에 측정을 완료하였다. 분석대상 물질들은 텐덤질량분석기에서 electrospray 양이온 이온화($ES^+$) 검출방식으로 확인하였으며 소라페닙은 'm/z 465.2 ${\rightarrow}$ 252.5', chlorantraniliprole은 'm/z 484.4 ${\rightarrow}$ 286.2'으로 구성한 multiple reaction monitoring 방법을 사용하였다. 검정 결과, 2-5,000 ng/ml의 농도 구간에서 양호한 직선성($r^2$ > 0.99)과 정확도(90.7-103.9%), 정밀도(10% 이하)를 나타내었다. 새롭게 개발된 LC/MS/MS을 이용한 사람 혈장 내 소라페닙의 농도 측정법은 KFDA 기준을 만족하였으며, 기존의 방법에 비해 민감도가 높은 방법이었다.

• 한국임상약학회지
• /
• 제16권2호
• /
• pp.101-106
• /
• 2006

The aim of the present study was to evaluate the bioequivalence of two talniflumate preparations. We used Somalgen tablet (Kun Wha Pharmaceutical Co., Korea.) as a reference drug for bioequivalence of Crimain tablet (Samjini Pharmaceutical Ind. Co., Korea), and performed this whole study according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty four healthy male volunteers, $22.8{\pm}2.2$ years in age and $64.6{\pm}5.3\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 370 mg of talniflumate was orally administered, blood was taken at predetermined time intervals and the concentrations of talniflumate in plasma were determined using HPLC method with UV-detector. The analysis system was validated in specificity, accuracy, precision and linearity. These items of the analysis condition in this study conform to the guideline of KFDA. The pharmacokinetic parameters such as $AUC_t\;and\;C_{max}$ were calculated using the analysis condition we established and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$ and Cmax. $Mean{\pm}SD$ of reference drug and test drug in $AUC_t\;and\;C_{max}$ value were $1.27{\pm}0.58\;({\mu}g/ml{\cdot}hr)\;and\;0.27{\pm}0.13\;({\mu}g/ml)$ and $1.14{\pm}0.46\;({\mu}g/ml{\cdot}hr)\;and\;0.26{\pm}0.10\;({\mu}g/ml)$ respectively. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log (1.25) for $AUC_t\;and\;C_{max}$, respectively. These results indicate that Samjin talniflumate tablet is bioequivalent to reference drug, Somalgen tablet.

• 대한한방내과학회지
• /
• 제27권1호
• /
• pp.102-113
• /
• 2006

Objectives & Methods : To obtain the 50% lethal dose(LD50), approximated lethal dose(ALD) and approximated target organs of 'Mahwangyounpae-tang' for further study into such things as repeated dose toxicity, genotoxicity and reproductive toxicity, single dose toxicity was tested in male SD rats according to KFDA Guideline 1999-61[KFDA, 1999] at dosage levels of 2,000, 1,000, 500, 250 and 125 mg/kg/$10m{\ell}$. In this study, mortalities, clinical signs, body weight changes and body weight gains, gross findings and weight of principal organs were detected during and/or after 14 days of single dosing. Results & Conclusions : After 2 or 3 days of dosing, 1 or 2 animals in 2,000 mg/kg-dosing groups died. Excitation and leaping response were observed as test article-treatment related clinical signs. These abnormal signs were restricted to 2,000 and 1,000 mg/kg-dosing groups and survivors recovered to normal within 3 or 4 days after dosing. Significant decrease in body weight were observed in some periods of observation in 2,000 and 1,000 mg/kg-dosing group, from 1 days after dosing compared to those of vehicle control group. Significantly diminished body weight gains were observed in observation periods in 2,000 and 1,000 mg/kg-dosing group compared to those of vehicle control group. Hypertrophy and hemorrhage of heart and decoloration of kidney were observed as test article-treatment related gross findings. These abnormal findings were restricted to 2,000 and 1,000 mg/kg-dosing groups. A significant increase of absolute and relative heart and kidney weight were demonstrated in 2,000 mg/kg-dosing groups. The value for LD50 found in this study was 2,218.57 mg/kg. ALD in this study was 2,000 mg/kg, and the target organs are considered to be the heart and the kidney.

• Journal of Pharmaceutical Investigation
• /
• 제35권1호
• /
• pp.39-44
• /
• 2005

The purpose of the present study was to evaluate the bioequivalence of two cefaclor capsules, Ceclor (Lilly Korea Co., Ltd.) and Kyongbocefaclor (Kyongbo Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of cefaclor from the two cefaclor formulations in vitro was tested using KP VIII Apparatus II method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty four healthy male subjects, $22.96{\pm}1.52$ years in age and $67.03{\pm}7.90$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ crossover study was employed. After one capsule containing 250 mg of cefaclor was orally administered, blood was taken at predetermined time intervals and the concentrations of cefaclor in serum were determined using HPLC method with UV detector. The dissolution profiles of two formulations were similar at all dissolution media. In addition, the pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated and ANOVA test was 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, Ceclor, were -1.90%, 2.68% and -7.60% 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 $(e.g.,\;log0.91{\sim}log\;1.06\;and\;log0.92{\sim}log\;1.18\;for\;AUC_t\;and\;C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Kyongbocefaclor capsule was bioequivalent to Ceclor capsule.

• Journal of Pharmaceutical Investigation
• /
• 제36권3호
• /
• pp.201-207
• /
• 2006

Acetaminophen (paracetamol), a para-aminophenol derivative, has analgesic and antipyretic properties and weak anti-inflammatory activity. The purpose of the present study was to evaluate the bioequivalence of two acetaminophen tablets, $Tylenol^{\circledR}$ ER (Janssen Korea Ltd.) and Tylicol ER (Hana Pharmaceutical Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of acetaminophen from the two acetaminophen formulations in vitro was tested using KP VIll Apparatus II method with pH 1.2 buffer solution. Twenty six healthy male subjects, $22.8{\pm}1.99$ years in age and $65.6{\pm}8.03$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single tablet containing 650 mg as acetaminophen was orally administered, blood samples were taken at predetermined time intervals and the concentrations of acetaminophen in serum were determined using HPLC with UV detector. The dissolution profiles of two formulations were similar in pH 1.2 buffer solution. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated and ANOVA test was 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, $Tylenol^{\circledR}$ ER, were 2.84, 1.89 and -1.36% 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 $0.987{\sim}log$ 1.08 and log $0.944{\sim}log$ 1.17 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Tylicol ER tablet was bioequivalent to $Tylenol^{\circledR}$ ER tablet.

• Journal of Pharmaceutical Investigation
• /
• 제34권5호
• /
• pp.419-425
• /
• 2004

The purpose of the present study was to evaluate the bioequivalence of two propiverine hydrochloride tablets, BUP-4 (Jeil Pharm. Co., Ltd.) and Kuhnil Propiverine Hydrochloride (Kuhnil Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The propiverine release from the two propiverine hydrochloride formulations in vitro was tested using KP VIII Apparatus II method with a variety of dissolution media (pH 1.2, 4.0, 6.8 buffer solutions, water and blend of polysorbate 80 into pH 6.8). Twenty six healthy male subjects, $23.73{\pm}2.79$ years in age and $67.04{\pm}7.93\;kg$ in body weight, were divided into two groups and a randomized $2\;{\times}\;2$ cross-over study was employed. After one tablet containing 20 mg as propiverine hydrochloride was orally administered, blood was taken at predetermined time intervals and the concentrations of propiverine in serum were determined using HPLC method with UV detector. The dissolution profiles of two formulations were similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was 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 BUP-4 were 0.17%, 7.98% and 4.55% 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) $(e.g.,\;log(0.88){\sim}log(1.l2)\;and\;log(0.90){\sim}log(1.l5)\;for\;AUC_t\;and\;C_{max},\;respectively)$. Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Kuhnil Propiverine Hydrochloride tablet was bioequivalent to BUP-4 tablet.