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*Corresponding Author:
Prof. Kenjiro Koga
Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa, Japan
E-mail:
[email protected]

Abstract

Thalassemia is the name of a group of genetic, inherited disorders of the blood. More speciô€ically, it is a disorder of the hemoglobin molecule inside the red blood cells. According to World health Organization (WHO), there are about 3% beta-thalassemia carrier and about 4% Hb E/beta-thalassemia carrier in Bangladesh. Our objective is to identify the prevalence of beta-thalassemia in our adolescent populations and to review risk factors that would most easily identify a subset of adolescent patients at greatest risk for the development of beta-thalassemia. We also made a study of clinical proô€ile of 53 thalassemic patients, observing the relationship between the patients with their verity ages and sex. The cases are taken on the basis of their age (2-30 years), beta-thalassemia major, clinical jaundice with history of chronic blood transfusion. The cases excluded those who had jaundice due to viral hepatitis or hepatitis due to heavy metal poisoning (Arsenic) and those with spleenectomy. Liver function test has been evaluated in 53 patients. That were recorded with some relevant demographical data such as age, sex, blood group where median age was of 16 years and mean (±SD) age 15.4151 ± 7.90918. Among them were 21 (39.6%) female and 32 (60.4%) male. With an average 15.1% (8 in no.) beta-thalassemia, 7.5% (4 in no.) beta-thalassemia major and 77.4% (41 in no.) E-beta-thalassemia cases have been found in the study. Mean (±SD) TSB in total 53 subjects with age group 2-10 years and 21-30 years is signiô€icant. The study revealed that in thalassemic patients when the age is more, the disease progresses with their complication. Hepatic complication is mainly due to being hepatocellular in nature than that of obstructive one.

Keywords

Generic drug, glycyrrhetinic acid, glycyrrhizae radix, glycyrrhizin, quality evaluation

Introduction

Glycyrrhizin (glycyrrhizin monoammonium; GZ) is a therapeutic drug for eczema, dermatitis, liver function improvement in the chronic hepatitis, which was approved in Japan in 1948. The GZ is a nature ingredient extracted from Glycyrrhiza glabra L. and is the glucoside that glucuronic acid of 2 molecules made ether binding with glycyrrhetinic acid (GA). Except for the injections, oral formulations are marketed as the ethical drugs; however, the absorption of GZ from gastrointestinal tract is very poor. [1-3] Therefore, therapeutic effect of intravenous administration of GZ is very beneficial compared with that of oral administration. The ingredient of bland-name drug of this injection is glycyrrhizin monoammonium 2.65 mg per 1 ml (2 mg as glycyrrhizic acid), glycine (Gly) 20 mg, and L-cysteine hydrochloride hydrate 1.1145 mg (1 mg as L-cysteine hydrochloride (CysH)), and this formulation was gotten the production approval as the combination agent of GZ and amino acids. Recently, 21-kind generic drugs are marketed as same ingredients in Japan. On the other hand, the GZ formulation in foreign countries is commercially available in China, Korea, Taiwan, Mongolia, etc., and spreads as therapeutic drug with high safety and efficacy for chronic hepatitis patients. Especially, in China, several products of GZ are available as compound glycyrrhizin injections. Moreover, optical isomer of GZ, 18alfa-GZ, and glycyrrhizin diammonium are available as single ingredient without amino acid.

In such situation, Stronger Neo-Minophagen C® injection (SNMC, Minophagen Pharmaceutical Co. Ltd., Tokyo, Japan) was recognized as a bland-name drug among GZ formulations marketed in China in 2012. The quality evaluation among the bland-name drug and generic drugs are not investigated officially. For quality evaluation of GZ products in Japan, the differences of physicochemical properties and ingredient contents such as glycirrhizic acid, Gly, and CysH were reported, [4] indicating that these contents in several kind generic drugs were less than that of SNMC. And a remarkable difference was accepted by the content of impurities such as GA, 3-monoglucuronylglycyrrhetinic acid (MGGA), and L-cystine (CysS). Namely, the quality evaluation as the differences between bland-name drug and generic drugs is needed for GZ products marketed in China. In this paper, pH, osmolarity ratio, contents of ingredients (GZ, Gly, and CysH), and contents of impurities (GA, MGGA, and CysS) were determined. Absolutely, this work will contribute to enhance the product quality of GZ injections.

Experimental

Chemical and reagents

Glycyrrhizic acid (GLY0605, 18beta type, purify 100%) was purchased from National Institute of Health Sciences (Tokyo, Japan). Glycyrrhizic acid (18alfa type, purify 96.2%) was a gift from Amato Pharmaceutical Co. Ltd. (Fukuchiyama, Japan). Glycyrrhetinic acid (purify 100%), 3-monoglucuronyl glycyrrhetinic acid (purify 100%), glycine (purify 100%), L-cysteine hydrochloride (purify 99.0%), L-cystine (purify 100%) were purchased from Wako Pure Chemical Industries Co. (Osaka, Japan). Saline was purchased from Otsuka Pharmaceutical Co. Ltd. (Tokyo, Japan). Other chemicals were of HPLC or reagent grade.

GZ Pharmaceutical products

Used commercial products of compound glycyrrhizin injections are shown in Table 1. The bland-name drug is SNMC (No.1). No. 2, 4, 5, 6, 7, 9 products have same ingredients as SNMC, however, No.3 and 8 products are compound glycyrrhizin injection having different composition, the ingredients of No. 3 and 8 products are glycyrrhizin diammonium and glycyrrhizin magnesium, respectively. These products were kept at 20-25°C in a dark room. All products were changed to a screw vial right before analyzing. Freeze-drying products, No. 5, 6, and 9 were dissolved with saline, then were adjusted to 10, 50, and 20 ml, respectively, using flasks of 10, 50, and 20 ml.

Product Lot number Volume (ml) GZ (mg) L-Cys.HCl (mg) Gly (mg)
SNMC G1321 20 40 20 400
  G1331 20 40 20 400
  G1341 20 40 20 400
AI GAN BAO 100503 20 40 20 400
  110701 20 40 20 400
  110703 20 40 20 400
GAN LI XIN 1109171 10 501) 0 0
  111017104 10 501) 0 0
GAN YU 100801 20 40 20 400
  110402 20 40 20 400
  20110606 20 40 20 400
LONG DI TAI 11021901 freeze-drying 20 10 200
  11070301 freeze-drying 20 10 200
  11081902 freeze-drying 20 10 200
OU LI KANG 201012292 freeze-drying 80 40 800
  201106101 freeze-drying 80 40 800
  201109031 freeze-drying 80 40 800
PAI GAN NENG 101203 20 40 20 400
  110314 20 40 20 400
  110708 20 40 20 400
TIAN QING GAN MEI 1107132 10 502) 0 0
  1107181 10 502) 0 0
  1108242 10 502) 0 0
WEI YI XING 110103D1 freeze-drying 40 20 400
  110103D2 freeze-drying 40 20 400
  110501A1 freeze-drying 40 20 400

Table 1: Compound glycyrrhizin injections

pH assay

The pH values of all products were measured three times for each batch sample using a pH meter (HM-7E, DKK-TOA Corporation, Tokyo). The calibration was carried out using pH6.80 and pH4.01 standard solutions.

Osmolarity assay

The osmolarity values of all products were measured three times for each batch sample using a Semi-micro Osmometer (K-7400, Herbert Knauer GmbH, Germany). The calibration was carried out using 0 and 400 mOsm standard solutions. The osmolarity of product No.6 was corrected by 1.25-fold for determination value, because No.6 had to dissolve with 40 ml, but there was not a 40-ml flask. The data were indicated as osmolarity ratio (300 mOsm = 1.0).

GZ (18alfa-GZ and 18beta-GZ) determination

GZ has both optical isomer as 18alfa-GZ (α-GZ) and 18beta-GZ (β-GZ) by direction of hydrogen connected to 18-position carbon in structure. It is written in product information sheets that GZ of product No.1, 2, 4, 5, 6, 7, and 9 are β-GZ and GZ of No.8 is 18α-GZ. The determination of both GZ by HPLC was carried out by the modification of previous report. [5] Product No.1, 2, 4, 5, 6, 7, 9 were diluted 1000-fold with 100 mM phosphate buffered solution (pH7.4), and product No.3, 8 were diluted 2000-fold with 100 mM phosphate buffered solution (pH7.4). Each solution (10 μl) was injected to HPLC system. The HPLC system was a semimicro type; it was equipped with a LC-10ADvp pump, SIL-20A autosampler, DGU-20As degassing apparatus, SPD-20A UV detector, CR7A-plus data processor (Shimadzu, Kyoto, Japan). Briefly, a Capcell Pak 5C18 UG column (1.5- mm inner diameter, 150-mm length, Shiseido, Tokyo, Japan) and a Capcell Pak 5C18 UG120 (1.5-mm inner diameter, 10-mm length, Shiseido) as the guard column was used 40°C during separation. Detection was performed at a UV wavelength of 254 nm. Acetonitrile/0.6% perchloric acid solution adjusted to pH8.0 with 25% ammonia solution (2:8, v/v) was used as the mobile phase; the flow rate was 0.08 ml/min. The detection limit was 200 ng/ml.

GA determination

All products were diluted 2-fold with 100 mM phosphate-buffered solution (pH7.4). Each solution (10 μl) was injected to HPLC system. The HPLC system was the same as GZ determination except for mobile phase. Methanol/0.6% perchloric acid solution adjusted to pH8.0 with 25% ammonia solution (8:2, v/v) was used as the mobile phase.

MGGA determination

All products were diluted 2-fold with 100 mM phosphatebuffered solution (pH7.4). Each solution (10 μl) was injected to HPLC system. The HPLC system was the same as GZ determination except for detection and mobile phase. The detection was performed at a UV wavelength of 251 nm, and methanol/0.6% perchloric acid solution adjusted to pH2.5 with 25% ammonia solution (78:22, v/v) was used as the mobile phase.

Gly determination

All products (0.5 ml) were put in a 50-ml flask and were adjusted with 0.2 M NaOH (sample solutions). Gly was dissolved with 0.2 M NaOH as the standard solution (0.2 mg/ml as the concentration of Gly). The standard or sample solution (80 μl), 0.2 M NaOH (0.7 ml), and 3% phenyl isothiocyanate dissolved with 1-propanol (0.6 ml) were mixed, and then were incubated at 50°C for 30 min. After cooling the mixture solution, the mixture solution and benzene (0.2 ml) were mixed, and were shaken at 500 rpm for 5 min using a Vortex Shaker (VR-36D, Taitec, Saitama, Japan). After the mixture solution was centrifuged at 2500 × g for 5 min, the supernatant was removed using a glass pipette. The lower layer (0.4 ml) and 8 M HCl (0.4 ml) were put in a 10-ml glass-stoppered centrifuge tube, and the mixture solution was incubated at 50°C for 60 min. After cooling the mixture solution, the mixture solution and ethyl acetate (4 ml) were mixed in the centrifuge glass tube, and then was shaken at 500 rpm for 15 min. After centrifuging the mixture solution at 2500 × g for 5 min, the supernatant (0.5 ml) was transferred to a 10-ml glass tube, and was evaporated to dryness under a continuous stream of nitrogen gas and on a block heater set to 80°C. After cooling the glass tube, 1.0 ml of methanol/20 mM sodium acetate (8:17, v/v) was added to the glass tube, and then was shaken for 1 min using a vortex mixer. The final solution was filtered with a Millipore membrane (LCR13-LH, pore size: 0.22 μm, Japan Millipore, Tokyo, Japan). An aliquot (10 μl) of the filtered solution was injected to HPLC system.

The HPLC system was the same as GZ determination except for mobile phase and flow rate. Methanol/20 mM sodium acetate (8:17, v/v) was used as the mobile phase, and the flow rate was set to 0.07 ml/min.

L-Cysteine and L-Cystine determination

CysH standard solution (2 μg/ml as the concentration of L-cysteine hydrochloride) and CysS standard solution (2 μg/ml as the concentration of L-cystine) were prepared by dissolving with mobile phase, acetonitrile/0.1% phosphoric acid with 3.5 mM sodium 1-heptanesulfonate (9:95, v/v). Each product solution was diluted 500-fold with the mobile phase. The HPLC system was the same as GZ determination except for detection, and mobile phase. The detection wavelength was set to 210 nm.

Statistical analysis

Statistical analysis using Dunnett multiple comparison test was performed for data of GZ, GA, MGGA, CysH, and Gly. The controlled group was set to bland-name drug (SNMC). A P value < 0.05 was considered to be statistically significant.

Results and Discussion

Physicochemical properties

Table 2 shows the pH values and osmolarity ratios in 9-kind products of glycyrrhizin compound injections containing bland-name drug (SNMC) and generic drugs. The pH values of SNMC were at the range of 6.05-6.19 (6.12 ± 0.06) in three batches. The pH values of products from GE-A to GE-F with same ingredients were at the range of 5.15-7.10 as the mean, indicating that the pH level was varied by products. Although the standard deviation (SD) of GE-A, GE-B, GE-C, GE-E, GEF, and GE-H were bigger than that of SNMC, the values were all within the defined range. Namely, the variation indicate s the retainment of quality management for batch-to-batch reproducibility.

Product pH Osmolarity ratio
SNMC 6.12 ± 0.06 1.50 ± 0.01
GE-A 7.10 ± 0.24 1.41 ± 0.06
GE-B 7.06 ± 0.17 1.49 ± 0.01
GE-C 6.49 ± 0.12 0.96 ± 0.00
GE-D 6.16 ± 0.03 2.04 ± 0.12
GE-E 5.15 ± 0.07 1.94 ± 0.04
GE-F 5.29 ± 0.10 1.77 ± 0.02
GE-G 6.98 ± 0.03 0.96 ± 0.02
GE-H 7.41 ± 0.11 0.94 ± 0.01

Table 2: pH values and osmolarity ratios in nine products

Osmolarity ratios in 9-kind products were divided to three groups. Namely, the value was approximately 1.0, 1.5 or 2.0. The SD value in GE-D was big compared to those of other products. In similar to pH value, all osmolarity ratios were within the defined range in spite of the variability in batch-to-batch was observed.

On the whole, it is suggested that the physicochemical properties such as pH and osmolarity are managed within the value of standard every products.

Glycyrrhizic acid concentration in products

Although β-GZ is ingredient in SNMC and generic drugs with same composition, a very small amount of α type GZ is included in GZ bulk. Therefore, concomitant determination of both isomers was carried out. Table 3 shows the concentrations of α-GZ and β-GZ in all products. In product information sheet, TIAN QING GAN MEI (No.8 in Table 1) only indicates that α-GZ is contained as the ingredient. The content of β-GZ in SNMC was 101.2-102.0% (101.6 ± 0.3%) in three batches. The content of β-GZ in GE-D was similar to that of SNMC; however, the β-GZ contents in other products were less than 100%. Especially, the β-GZ contents in GE-A, GEB, GE-H were lower than 95%, and GZ content in GE-B was significantly low. The α-GZ content in GE-G was over 100%. The sum of α-GZ and β-GZ in GE-H was 98.4%, indicating that GE-H was distinguishing formulation in comparison with other products. Moreover, the SD values in GE-B, GE-C, GE-D, GE-E, GE-F, and GE-H were remarkably larger than that of SNMC (0.3%). These results suggested that the lack of GZ content and the variation of SD value might be affected by the purity of GZ included in the bulk and a difference of the method for measurement of GZ in the quality of the products. In generic drugs, it is an important problem for product management that the content of GZ is clearly less than 100% in a comparison every batch. For the luck of GZ content, β-GZ content in extract from Glycyrrhiza glabra L. is approximately 75% (detailed experiments are not shown). Namely, many minor constituents are obtained in GZ bulk powder. Interestingly, it was reported that detection as abnormal high peak area in HPLC determination of GZ was observed. [6] As the cause, monomethyl glycyrrhizic acid which is a minor constituent of GZ containing the bulk powder was decomposed to GZ by hydrolysis. In this way, it is predictable that minor constituents (similar compound of GZ) during manufacturing process or after preparation may affect the content of final GZ in products. Therefore, the degree of purify of GZ (approximately 75%) is an important factor for the GZ content. Although normal manufacturing variations are expected, remarkable variation in batch-to-batch levels can indicate that the manufacturing process of the generic drugs was not adequately controlled and was not validated.

Product α-GZ (%) β-GZ (%)
SNMC 0 101.6 ± 0.3
GE-A 0 91.8 ± 0.3*
GE-B 0 94.2 ± 4.5
GE-C 0 97.3 ± 2.9
GE-D 0 100.9 ± 3.5
GE-E 0 96.5 ± 2.1
GE-F 0 95.4 ± 3.1
GE-G 111.4 ± 1.1* 0
GE-H 82.7 ± 5.6 15.7 ± 0

Table 3: α-GZ and β-GZ contents in nine products

Glycyrrhetinic acid concentration in products

Glycyrrhetinic acid (GA) has the structure that 2 glucuronic acids dissociate from GZ. GA is originally contained in the extract from Glycyrrhiza glabra L., is one of main impurities. Interestingly, GA has pharmacological action as similar to GZ such as anti-inflammatory. [7,8] Therefore, the GA content in product may affect therapeutic efficiency by GZ. Table 4 shows GA content and the rate of GA content for GZ content in all products. The GA content in SNMC was 0.52 ± 0.01 μg/ml, and the GA rate for GZ content was 0.026%. This result suggested that GA content in SNMC was very small. Therefore, the GA content is not a level to have an influence on the therapeutic effect of GZ. Among the generic drugs, GA contents in GE-A and GE-B products were approximately 4-fold high compared with that in SNMC (significant high level; P < 0.05 vs. SNMC). On the other hand, GA contents from GE-C to GE-H were similar or lower level as compared to that in SNMC. Interestingly enough, GA content in GE-G was zero. In any case, the GA rate for GZ content was too small (<0.15%). Meanwhile it was reported that pseudo-aldosteronism was occurred by the large amount administration of GZ. Furthermore, it was reported that GA may strongly relate to the pseudo-aldosteronism as one of the factors to induce the adverse effect. [9-11] Therefore, when a small amount of GA included in the GZ products is administered consecutively, the pharmaceutical attention is necessary for patients as the symptom in pseudoaldosteronism.

Product GA (μg/ml) (%) MGGA (μg/ml) (%)
SNMC 0.52 ± 0.01 0.026 0.38 ± 0.04 0.019
GE-A 1.97 ± 0.32* 0.107 0.21 ± 0.04 0.011
GE-B 2.19 ± 1.29* 0.120 0.05 ± 0.04* 0.003
GE-C 0.30 ± 0.12 0.016 0.22 ± 0.01 0.011
GE-D 0.88 ± 0.27 0.043 0.22 ± 0.00 0.011
GE-E 0.22 ± 0.15 0.011 0.61 ± 0.16 0.031
GE-F 0.12 ± 0.10 0.007 0.48 ± 0.15 0.025
GE-G 0.00 0.000 0.00* 0.000
GE-H 0.15 ± 0.03 0.003 0.00* 0.000

Table 4: GA and MGGA contents in nine products

3-monoglucuronyl-glycyrrhetinic acid concentration in products

3-Monoglucuronyl-glycyrrhetinic acid (MGGA) has the structure that one glucuronic acid dissociate from GZ contained two molecule glucuronic acids. As similar to the GA, MGGA is originally contained in the extract from Glycyrrhiza glabra L. Moreover, it was reported that MGGA is metabolized from GA in liver. [12] Intriguingly, there are some reports that MGGA may cause pseudoaldosteronism for chronic hepatitis patients. [13,14] Therefore, the determination of MGGA is important for pharmaceutical quality in products. MGGA contents in products are shown in Table 4. MGGA contents in SNMC were the range of 0.34- 0.43 μg/ml (0.38 ± 0.04 μg/ml), and the ratios for GZ content were 0.019%. This level did not have remarkable difference compared to GA content (%) for GZ content in SNMC. The MGGA contents in other products also had low level for GZ content. Particularly, MGGA content in GE-B among generic drugs with same ingredient was significantly low (P < 0.05 vs. SNMC). Because MGGA content does not have a predominant high level among all products, it is thought that the difference of the product will not be reflected to the incidence of adverse effect such as pseudo-aldosteronism. In addition, GE-G and GE-H among the generic drugs did not contain MGGA, suggesting that the extraction process from Glycyrrhiza glabra L. or refinement process of GZ is superior.

L-Cysteine, L-Cystine, and glycine contents in products

L-Cysteine hydrochloride (CysH) and glycine (Gly) are ingredients in SNMC and generic drugs (GE-A to GE-F). L-Cysteine is easily oxidized in aqueous solution, and is changed to L-cystine (CysS). Therefore, the determination of CysS was also carried out. Table 5 shows these contents in products. For CysH and Gly, the contents were represented as percentage for the content indicated in product sheet.

Product CysH (%) CysS (mg/ml) Gly (%)
SNMC 102.8 ± 5.2 0.0 100.2 ± 0.5
GE-A 90.3 ± 5.2 0.140 ± 0.031 94.6 ± 6.8
GE-B 89.2 ± 2.4 0.138 ± 0.006 96.7 ± 3.1
GE-C 91.3 ± 3.0 0.088 ± 0.047 98.2 ± 4.0
GE-D 91.1 ± 7.2 0.149 ± 0.046 97.9 ± 10.4
GE-E 100.4 ± 6.6 0.051 ± 0.072 105.0 ± 5.2
GE-F 79.9 ± 4.2* 0.006 ± 0.009 97.7 ± 6.7

Table 5: Cystein.HCl, Cystine, and Glycine contents in seven products

The content of CysH in SNMC was 102.8 ± 5.2%. On the other hand, the CysH contents in generic drugs were the range of 79.9-100.4%. Especially, the content in GE-F was significantly low compared to that in SNMC. The result indicated that CysH contents were not satisfied depending on a product. As the reason that determined CysH content was less than defined amount of CysH, two factors are considered. Namely, i) lack of content of CysH in the initial preparation process and ii) degradation of CysH after the preparation. As the latter factor, the measurement of CysS which is a decomposition product of CysH will contribute to the possibility definitely. In fact, the concentration of CysS in SNMC was zero, supporting that CysH in SNMC was filled as defined content (1 mg/ml as the concentration of L-cysteine hydrochloride), and did not decompose to CysS. On the other hand, all generic drugs (GE-A to GE-F) contained CysS. Especially, the CysS concentrations in GE-A, GE-B, and GE-D were high (0.138-0.149 mg/ml). Contrastingly, those in GE-E and GE-F were low, i.e., 0.051 and 0.006 mg/ml, respectively. From these results, it was guessed that the difference in quantity of CysS in generic drugs depended on the decomposition rate from CysH to CysS in the period from manufacture process to storage. Sodium sulfite is added to all products as an antioxidant in order to inhibit the decomposition of CysH. However, the different in antioxidant effect on CysH was observed. As the predicted factors, the temperature condition in manufacture process of each product and final pH of each product solution were assumed. Notably, the mechanism which CysH is easily changed to CysS by small amount of metal ion in neutral or alkaline solution may be tightly correlated with the latter predicted factor. In fact, the pH values of GE-A and GE-B were approximately 7, that is, high values compared to that of SNMC (pH6.12). Therefore, it is thought that high CysS contents in GE-A and GE-B depended on the pH in both products. Whereas, the pH values in GE-E and GE-F were 5.15 and 5.29, respectively. Namely, both pH values were low compared to that in SNMC. The results that CysS contents were low in GE-E and GE-F were identified as the low pH values. Therefore, it is logical to consider that CysS content was affected by the pH level in product. As the other factors, sterilization temperature in manufacture process, dissolved oxygen in product solution, etc. were also considered, however, the detail information was not obtained.

The relationship between pH and stability of CysH is a very important problem. Generally, many generic drugs are produced by condition coordinated with the physicochemical properties of bland-name drug. [15] Therefore, the quality of generic drugs is secured. However, in generic drugs of GZ, there are the products which set a pH level in the acidic or basic direction than SNMC. The difference in pH level supply a characteristic property, however, the recognition of the problem for the stability may be necessary. Furthermore, in all generic drugs of GZ, it is thought that antioxidant provision is necessary as well as setting of this pH based on CysS having been detected.

Gly concentration in SNMC was 100.2%. On the other hand, Gly concentrations in generic drugs were the range of 94.6- 105.0%. Moreover, the variation (standard deviation; SD) in Gly concentration among batches in each product was also remarkably high compared to that in SNMC. Especially, the SD in GE-D was 10.4%. The results that SD levels in generic drugs were more than 3% will submit as an important quality control.

Conclusions

The physicochemical properties (pH and osmolarity), ingredient contents (GZ, CysH, and Gly), and impurity (GA, MGGA, and CysS) in a bland-name drug (SNMC), 6 kind generic drugs with same ingredients, and 2 kind generic drugs with optical isomer of GZ were investigated. For the physicochemical properties, the pH and osmolarity ratio depending on each product were different, however, these values were within the defined values. And the differences in variation (SD) of pH and osmolarity among the batches in each product were observed with acceptable level. Therefore, it was judged that there were not problems for the physicochemical properties. On the other hand, some characteristic differences were observed for the comparison with bland-name drug in ingredient and impurity assay. First, the GZ contents in three batches of SNMC were at the range of 101.2-102.0% (101.6 ± 0.3%). This precision in SNMC was superior to other products conspicuously. Especially, the products which was under 95% in GZ content is recognized, and the products which the variation between the batches has a big are also recognized. Second, an interesting result was provided in the content of the CysH. Although sulfite sodium as an antioxidant was included in all products, the product which CysH content was maintained 100 ± 5% was only SNMC. In generic drugs, CysS content was affected by the pH level of the products, indicating that products with high CysS content were set to high pH level. Third, variation (SD) of Gly content in generic drugs was high compared with that of SNMC.

In conclusion, it was assumed that management during the process of manufacture, the purity of the ingredient, the fixed-quantity of the ingredient after the product preparation, and the way of the quality control of the batch unit will be needed to consider.

References