• Journal of Pharmaceutical Investigation
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• v.29 no.1
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• pp.37-45
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• 1999

ABSTRACT-A self-microemulsifying drug delivery system (SMEDDS) was developed to enhance the solubility and dissolution rate of poorly water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The system was optimized by evaluating the solubility of DDB and the microemulsion existence range after the preparation of microemulsions with varying compositions of triacetin and surfactant-cosurfactant mixtures (Labrasol as surfactant (S) and the combination of Transcutol, Cremophor RH 40 and Plurol oleique as cosurfactant (CoS)). SMEDDS in this study markedly improved the solubility of DDB in water up to 10 mg/ml and the size of the o/w microemulsion droplets measured by dynamic light scattering showed a narrow monodisperse size distribution with an average diameter less than 50 nm. The microemulsion existing range is increased proportional to the ratio of S/CoS, however, it decreased remarkably as the oil content was more than 20%. In vitro dissolution study of SMEDDS showed a significantly increased dissolution rate of DDB in water (> 12 fold over DDB powder), and SMEDDS also had significantly greater permeability of DDB in Caco-2 cell compared to powders.

• YAKHAK HOEJI
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• v.48 no.6
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• pp.379-383
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• 2004

Biphenyl dimethyl dicarboxylate (DDB) has been used for the treatment of chronic viral hepatitis B and drug-induced hepatitis through the inhibition of lipid peroxidation and c ovalent binding of drug metabolites to lipids of microsomes. The bioequivalence of two DDB products was evaluated according to the guidelines of KFDA. The test product was Hepaphil soft capsule(R) made by KMS Pharm. Co. Containing 3 mg DDB and the reference product was Nissel tablet(R) made by Taerim Pharm. Co. Containing 25 mg DDB. Twenty healthy male subjects, 25.4(22~30) years old and 66.7(54~77)kg, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After two tablets or two capsules were orally administered, blood was taken at predetermined time intervals and the concentration of DDB in plasma was determined using a validated HPLC method with UV detector. Two pharmacokinetic parameters, $AUC_t$ and $C_{max}$, were calculated and analyzed statistically for the evaluation of bioequivalence of the two products. Analysis of variance was carried out using logarithmically transformed parameter values. The 90% confidence intervals of $AUC_t$ and $C_{max}$ were log 0.91~log1.00 and log 1.05~log 1.15, respectively. These values were within the acceptable bioequivalence intervals of log 0.8 to log 1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating that Hepaphil soft capsule is bioequivalent to Nissel tablet.

• YAKHAK HOEJI
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• v.44 no.3
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• pp.263-271
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• 2000

In an attempt to develop an injectable form of practically insoluble biphenyl dimethyl dicarboxylate (DDB), the effect of various vehicles, cosolvents and hydrotropic agents was investigated. It was found that polyethylene glycol (PEG) 400 revealed the best solvency toward DDB (17.7 mg/ml at $37^{\circ}C$), and decreasing order of the solubility was as follows: PEG 400>PEG 300>diethylene glycol monoethyl ether (DGME)>PEG-8 glyceryl caprylate/caprate. Among the hydrotropes used, sodium salicylate, sodium benzoate and nicotinamide were effective in increasing the solubility in water. The solubility of DDB in 2 M sodium salicylate, sodium benzoate and nicotinamide solutions was increased 44.3, 23.5 and 44.0 times than that in water, respectively. The addition of sodium salicylate and sodium benzoate to PEG 300-water PEG 400-water and DGME-water cosolvents remarkably increased the solubility of DDB, and significantly retarded precipitate formation when mixed with water Hemolytic properties of DDB injections (2 mg/4~10 ml) in PEG 300-water or DGME-water (60:40 v/v) cosolvents containing sodium benzoate (0.14~0.35 M) were very low. It was concluded from the results that these solutions would be applied to the design of new DDB injections.

• Toxicological Research
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• v.16 no.3
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• pp.239-253
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• 2000

This study was carried out to evaluate the three months subacute intravenous toxicity of water soluble dimethyl dimethoxy biphenylate derivative (DDB-S), a newly formulated therapeutic agent for hepatitis, in Beagle dogs. Groups of 12 male and 12 female dogs were given different dosage of DDB-S, 10 mg/kg/day (high dose group), 5 mg/kg/day (middle dose group), 2.5 mg/kg/day (low dose group) and 0 mg/kg/day (control group) for three months by intravenous route. 1n the three months intravenous toxicity study, there were neither dead animals nor significant changes of body weights during the experimental period. 1n addition to, no significant DDB-S related changes were found in clinical signs, urinalysis and other findings. Statistical changes were observed in hematological. biochemical, partial thromboplastin time (PIT) and organ weight parameters of treated groups. However, these alteration had no relationship with dosage. No histopathological lesions were observed in both control and treated animals. Above data suggest that no observed adverse effect level of test materials in Beagle dogs might be over 10 mg/kg/day in this study.

• Journal of Pharmaceutical Investigation
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• v.27 no.3
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• pp.199-205
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• 1997

In order to formulate biphenyl dimethyl dicarboxylate(DDB) aqueous solutions, the effects of various solubilizing agents such as cosolvents(PG, PEG 400, glycerin, ethanol), surfactants,$(poloxamer\;407,\;Cremophor^{\circledR}\; RH40,\;Solutol^{\circledR},\;Tween\;80,\;sodium\;lauryl\;sulfate)$, complexation agent$(CELDEX^{\circledR}\;CH-20)$ and others(urea, niacinamide, propylene carbonate, HPMC) on the solubility of DDB in water were evaluated. The solubility of DDB in water was about $0.21\;{\mu}g/ml\;at\;20^{\circ}C$, while its solubility in PEG 400 was 5,000 times higher than that in water. 60% PEG 400 aqueous solution was selected as an optimum solvent system, and surfactants or other solubilizing agents were added to prevent DDB from recrystalization. The addition of surfactants in water increased the solubility of DDB from 15- to 34-fold, however, $CELDEX^{\circledR}\;CH-20$ and other agents studied showed negligible effects on the solubility of DDB in water. The 60% PEG 400 aqueous solution containing 5% $Cremophor^{\circledR}$　RH40 was appeared as the formula of choice. It showed acceptable physical stability after stored for 7 days at $4^{\circ}C$.

• Journal of Pharmaceutical Investigation
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• v.29 no.3
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• pp.227-234
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• 1999

Solid dispersions were prepared to increase the dissolution rate of biphenyl dimethyl dicarboxylate (DDB) using water-soluble carriers such as povidone, copolyvidone, $2-hydroxypropyl-{\beta}-cyclodextrin (HPCD)$, sodium salicylate or sodium benzoate by solvent evaporation method. Solid dispersions were characterized by infrared spectrometry, differential scanning calorimetry (DSC) and powder X-ray diffractometry, dissolution and permeation studies. DDB tablets (7.5 mg) were prepared by compressing the powder mixtures composed of solid dispersions, lactose, com starch, crospovidone and magnesium stearate using a single-punch press. DDB capsules (7.5 mg) were also prepared by filling the mixtures in empty hard gelatin capsules (size No.1). From the DSC and powder x-ray diffractometric studies, it was found that DDB was amorphous in the HPCD or copolyvidone solid dispersions. Dissolution rates after 10 min of DDB alone and solid dispersions (1 : 10) in sodium benzoate, sodium salicylate and copolyvidone were 11.8, 23.5, 22.8 and 82.5%, respectively. Dissolution rates of DDB after 30 min from 1 : 10 and 1 : 20 copolyvidone solid dispersions were 80.5 and 95.0%, respectively. For the DDB tablets prepared using solid dispersions (1 : 20), the initial dissolution rate was dependent on carrier material, and was ranked in order, $Kollidon\;30\;{\ll}$ copolyvidone < HPCD. For the HPCD solid dispersion tablets, dissolution rate reached 97.4% after 15 min, but thereafter slowly decreased to 80.7% after 2 hr due to the precipitation of DDB. However, in the case of copolyvidone solid dispersion tablets, dissolution increased linearly and reached 93.4% after 2 hr. Reducing the volume of test medium from 900 to 300 ml markedly decreased the dissolution rate of the tablets containing 1 : 20 HPCD solid dispersions and 1 : 10 copolyvidone solid dispersion. For 1 : 20 copolyvidone solid dispersion tablets, there was no significant change in dissolution rate up to 1 hr with different volumes of test medium. Preparation of the copolyvidone solid dispersion (1 : 20) in capsules markedly delayed the dissolution (31.2 % after 2hr) due to the limited diffusion within capsules. The permeation rate $(13.4\;g/cm^2\;after\;8\;hr)$ of DDB through rabbit duodenal mucosa from copolyvidone solid dispersion (1 : 10) was markedly enhanced, when compared with drug alone or physical mixtures. From overall findings, DDB formulations containing copolyvidone solid dispersions (1 : 20) could be used to remarkably improve the dissolution rate in dosage form of powders and tablets.

• Archives of Pharmacal Research
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• v.26 no.2
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• pp.173-181
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• 2003

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialysis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (＞5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.

• Korean Journal of Clinical Pharmacy
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• v.3 no.1
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• pp.45-53
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• 1993

Biphenyl Dimethyl dicarboxylate(DDB) has been regarded as a safe, effective drug for decreasing serum aminotransferase levels from elevated serum aminotransferase levels, which cause acute or chronic hepatitis and chronic liver diseases. This study was designed to low dose(22.5mg/day) & short-term therapy effectiveness for 4 weeks of DDB in 30 chronic hepatitis patients with elevated serum aminotransferases. The following results were observed. 1. Serum alanine aminotransferase(ALT) levels significantly decresed from 173. $97\pm130.62(U/L)$ of pretreatment level to $32.23\pm19.22(U/L)$ after treatment for 4 weeks(p<0.00l) and normalized patients by $73\%$ 2. Serum aspartate (AST) aminotransferase levels significantly decreased from $94.90\pm49.17(U/L)$ of pretreatment level to $45.30\pm23.25(U/L)4 after treatment(p0<0.01). 3. However, no significant effects in the serum AST & ALT changes by which cause hepatitis and hepatitis duration (p>0.05). 4. No significant adverse effects were observed except for mild epigastric discomfort in one patient during DDB treatment It is suggested that DDB small dosage administration can result effectively decreasing serum aminotransferase levels from chronic hepatitis patients with elevated serum aminotransferase levels.

• Toxicological Research
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• v.16 no.2
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• pp.151-161
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• 2000

The Three months subacute toxicity of water soluble dimethyl dimethoxy biphenylate derivative (DDB-S), newly formulated therapeutic agent for hepatitis, was invesgated in SD rats. The body weight and clinical signs were observed after intravenous injection of DDBs at doses of 57, 75 and 100 mg/kg/day for three months. Decrease in motor activity and tremor were observed above 75mg/kg treated groups. Statistically significant changes at serum biochemical analysis were found in some group, how-ever, those changes were within the normal range and had no relationship with dosage. There was no abnormal morphological and pathological findings in relation to DDB-S treatment. The no observable adverse effect level of DDB-S in rats was estimated to be 57 mg/kg/day in this study.

• Journal of Mechanical Science and Technology
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• v.18 no.7
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• pp.1177-1186
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• 2004

In this paper, the spray atomization characteristics of a gasoline direct-injection injector were investigated experimentally and numerically. To visualize the developing spray process, a laser sheet method with a Nd :YAG laser was utilized. The microscopic atomization characteristics such as the droplet size and velocity distribution were also obtained by using a phase Doppler particle analyzer system at the 5 ㎫ of injection pressure. With the experiments, the calculations of spray atomization were conducted by using the KIVA code with the LISA-DDB breakup model. Based on the agreement with the experimental results, the prediction accuracy of LISA-DDB breakup model was investigated in terms of the spray shapes, spray tip penetration, SMD distribution, and axial mean velocity. The results of this study provides the macroscopic and microscopic characteristics of the spray atomization, and prediction accuracy of the LISA-DDB model.