April 2001 Biol. Pharm. Bull. 24(4) 409—413 (2001) 409 Changes in the Dissolution of Tolbutamide by a Traditional Chinese Medicine, Sho-saiko-to (Xiao Chaihu Tang) Nobuhiro NISHIMURA, Kohji NAORA, Hidenari HIRANO, and Kikuo IWAMOTO* Department of Pharmacy, Shimane Medical University Hospital, 89–1 Enya-cho, Izumo, Shimane 693–8501, Japan. Received October 30, 2000; accepted January 5, 2001 Dissolution rate is considered an important factor affecting absorption and efficacy after the oral adminis- tration of tolbutamide. Since in many cases traditional Chinese medicines, including Sho-saiko-to (TJ-9, Xiao Chaihu Tang), are taken with other drugs, it is likely that the dissolution and absorption of concomitant drugs in the gastrointestinal tract are influenced by the presence of traditional Chinese medicines. In this study, the effects of TJ-9 on the in vitro dissolution of tolbutamide were examined. We carried out the dissolution test of tolbutamide in the absence or presence of traditional Chinese medi- cines (Kakkon-to, TJ-1; Hachimi-jio-gan, TJ-7; Chorei-to, TJ-40; Shakuyaku-kanzo-to, TJ-68; TJ-9; Gly- cyrrhizae Radix, GR; glycyrrhizin, GL) by using a pH 1.2 dissolution medium. Tolbutamide was determined by HPLC assay. The moment parameters, i.e., mean dissolution time (MDT), and the dissolution rate constant up to 20 min (kd) were estimated from the dissolution profiles on the basis of the first-order kinetics. Preparations containing GR, namely TJ-1, TJ-9 and TJ-68, significantly reduced the kd and increased the MDT of tolbutamide, while TJ-7 and TJ-40 had no effect on the early dissolution profile of tolbutamide. The ex- tent of decrease in the kd in the presence of TJ-1, TJ-9 and TJ-68 was dependent on their GR contents. Similar inhibitory effects on the dissolution rate of tolbutamide were observed when GR alone was added to the test medium. In addition, GL, a major constituent of GR, induced a 50% increase in MDT and a 30% decrease in kd. The above results indicate that Chinese traditional preparations containing GR have an inhibitory effect on the in vitro dissolution of tolbutamide, which is derived from GL in the preparations. Key words Sho-saiko-to; tolbutamide; dissolution; glycyrrhizin; Chinese medicine Tolbutamide is classified into sulfonylureas prescribed for preparations. The effects of TJ-9 and its constituents on the the treatment of diabetic patients. The sulfonylureas have a in vitro dissolution of tolbutamide were examined. potent hypoglycemic effect and sometimes show delayed and erratic absorption, leading to unexpected hypoglycemia.1—3) MATERIALS AND METHODS Simons et al. reported that absorption patterns of tolbu- tamide were well correlated to the dissolution rate from the Materials The reagent of tolbutamide was obtained tablet.4) Although the rate of drug absorption is often not im- from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Tolbu- portant in chronic therapy, some studies have suggested that tamide tablets (Rastinon®) and five traditional Chinese prepa- the absorption kinetics of tolbutamide may determine its hy- rations, Kakkon-to (TJ-1), Hachimi-jio-gan (TJ-7), Sho- poglycemic efficacy. Kivistö and Neuvonen demonstrated an saiko-to (TJ-9), Chorei-to (TJ-40), Shakuyaku-kanzo-to (TJ- increased absorption of tolbutamide with an enhancement of 68), were purchased from Aventis Pharma, Ltd. (Tokyo, blood glucose-lowering effects, presumably due to the im- Japan) and Tsumura & Co., Ltd. (Tokyo, Japan), respectively. proved dissolution of this sulfonylurea by the increase in gas- The TJ-9 extract, which was an extract from the mixture of tric pH.5) Additionally, it was reported that an increase in the herbal medicines composing TJ-9, and Glycyrrhizae Radix in vitro dissolution rate of tolbutamide tablets induced an in- (GR) extract, which includes Glycyrrhizic acid (glycyrrhizin, crease in absorption rates of tolbutamide and a decline in GL), were kindly gifted from Tsumura & Co., Ltd. The con- blood sugar levels in the early period after drug administra- tent of GL in GR was 12.4% (determined by Tsumura & Co., tion.6) Thus, the dissolution rate is considered an important Ltd.). The traditional Chinese preparations of TJ-1, TJ-7, TJ- factor affecting absorption and efficacy after the oral admin- 9, TJ-40 and TJ-68 were oral dosage preparations which in- istration of tolbutamide. cluded additives prescribed for therapeutic use. Herbal com- As the therapeutic use of traditional Chinese medicines positions of these five preparations are summarized in Table combined with other synthetic or biotechnological drugs has 1. GL was obtained from Tokyo Kasei Kogyo Co., Ltd. been increasing in Japan, serious adverse effects or drug in- (Tokyo, Japan). All other reagents and solvents were of ana- teractions caused by them have recently been reported.7—9) lytical grade. Sho-saiko-to (TJ-9; Xiao Chaihu Tang) is a major traditional Dissolution Test Dissolution tests of tolbutamide were Chinese medicine consisting of seven herbals, a mixture of performed in accordance with the Japanese Pharmacopoeia several crude drugs containing many natural substances. (JP) XIII dissolution test with paddle methods (100 rpm) for Since in many cases traditional Chinese medicines are taken tolbutamide tablet, with minor modifications. The JP XIII with other drugs, it is likely that the dissolution and absorp- disintegration medium No. 1 (pH 1.2) was used as the disso- tion of concomitant drugs in the gastrointestinal tract is influ- lution medium maintained at 37 °C in a water bath incubator. enced by the presence of traditional Chinese medicines. In the test using the tolbutamide reagent, tolbutamide was In this study, we employed TJ-9 as a traditional Chinese suspended at a concentration of 50 mg/ml in a 1% potato- medicine, since TJ-9 is one of the most commonly prescribed starch/0.9% NaCl solution. The test medium was pre-incu- ∗ To whom correspondence should be addressed. e-mail: [email protected] © 2001 Pharmaceutical Society of Japan 410 Vol. 24, No. 4 Table 1. Herbal Composition of Chinese Traditional Preparations represented as the Cs. In a preliminary study, we confirmed a) that tolbutamide concentrations in the medium with or with- Content (%) out TJ-9 did not change at all during 5 to 12 h after the be- Components TJ-1 TJ-7 TJ-9 TJ-40 TJ-68 ginning of the incubation, so that Cs was defined as the con- centration of tolbutamide at 5 h. Aconiti Tuber 1.1 Measurement of Surface Tension After incubation of Alismatis Rhizoma 7.4 6.7 tolbutamide reagent (25 mg) with or without TJ-9 prepara- Asini Corii Collas 6.7 Bupleuri Radix 17.5 tion (125 mg) or GL (5.0 mg) in test medium (45 ml) for 30 Cinnamoni Cortex 5.6 2.6 min at 37 °C, the surface tension of each medium was mea- Corni Fructus 7.4 sured by the ring method using a Du Noüy tensiometer (DN; Dioscoreae Rhizoma 7.4 Shimadzu, Kyoto, Japan). Ephedrae Herba 8.3 Data Analysis The concentration of tolbutamide at infi- Glycyrrhizae Radix 5.6 5.0 16.7 Ginseng Radix 7.5 nite time (C∞) and the mean in vitro dissolution time (MDT) Hoelen 7.4 6.7 were defined as follows: Moutan Cortex 5.8 ∞ dC Paeoniae Radix 5.6 16.7 5 t C∞ ∫ dt (1) Pinelliae Tuber 12.5 0 dt Polyporus 6.7 Puerariae Radix 11.1 ∞ dC Rehmanniae Radix 14.4 5 t MDT ∫ t dt/ C∞ (2) Scutellariae Radix 7.5 0 dt Talcum Crystallinum 6.7 Zingiberis Rhizoma 5.6 2.5 where Ct is the concentration of tolbutamide dissolved in the Zizyphi Fructus 8.3 7.5 test medium at time t and dC /dt is the velocity of the tolbu- Additives 50.0 46.6 40.0 66.7 66.7 t tamide dissolution. The MDT was defined as the first mo- 10,11) a) Each value represents the blend ratio (% of the Chinese preparation) estimated ment of the dissolution rate-time curves of tolbutamide. from the labeled data (represented by Tsumura & Co., Ltd.). These moment parameters were calculated by trapezoidal in- tegration using a computer program (Maikon Ni Yoru bated with the TJ-9 preparation (1.67 g) or extract (0.1—1.0 Yakubutsu Sokudoron Nyumon; Nanzando, Tokyo, Japan). g) for 30 min. Five milliliters of the tolbutamide suspension The dissolution rate constant for tolbutamide, kd, was cal- were transferred into 500 ml of the dissolution medium to culated from C∞ and first-order kinetics of the dissolution start the dissolution test. In the tablet test, a tolbutamide profile of tolbutamide up to 20 min after the beginning of the tablet (500 mg) was placed into 900 ml of the dissolution test by the following equation: medium, which was pre-incubated with or without traditional dCt 52kC()∞ C (3) Chinese preparations (2.5 g) or GR (0.05—0.25 g) or GL dt d t (0.01, 0.05 g) for 30 min. In both tests, 1 ml of dissolution medium was collected periodically after the beginning of the Assay Tolbutamide concentrations in the medium were test. Collected medium was immediately filtered through a determined by a HPLC method in accordance with our previ- 0.45 mm membrane (Chromatodisk: Kurabo Industries, Ltd., ous report.12) Briefly, filtered dissolution medium (50 ml) was Osaka, Japan), and then the filtrate was used for the determi- added to 100 ml of the internal standard solution (50 mg/ml of nation of tolbutamide. Additionally, the pH of the medium chlorpropamide) and 350 ml of an acetonitrile–water mixture was determined periodically using a compact pH meter with (1 : 1), and then shaken for 1 min.