• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.21-26
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• 2000

Bioavailability of ipriflavone (3-phenyl-7-isopropoxy-4H-I-benzopyran-4-one, IP), an antiosteoporotic drug with poor water-solubility, was studied for various types of pharmaceutical preparation in SD rats. The IP preparation types included (1) intact IP, (2) freezer milled IP (FIP), (3) freezer milled IP physically mixed with freezer milled poly-N-vinylpyrrolidone (PVP) (FIP+FPVP) and (4) spray-dried IP with PVP (SIP). Upon oral administration, SIP showed significantly higher absorption and elimination half-lives and the lag time $(t_{lag})$ than those of FIP+FPVP (approximately 2-fold). These results may be due to a sustained releasing effect of IP in the gastrointestinal tract by spray-drying with PVP. The $C_{max}$ of SIP was about 2 and 10 times higher than those of FIP+FPVP and FIP, respectively. The AUC of SIP was about 6 times higher than that of FIP+FPVP and 60 times that of FIP. Scanning electron microscopy (SEM) showed that SIP consisted of the finest particle size and minimal aggregation than other IP preparations. It is concluded that the IP formula prepared by the spray-drying method with PVP is the most effective approach to the improvement of bioavailability of IP.

• Journal of Pharmaceutical Investigation
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• v.30 no.4
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• pp.235-239
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• 2000

Ipriflavone (3-phenyl-7-isopropoxy-4H-1-benzopyran-4-one, IP) is a well-known antiosteoporotic drug with poor bioavailability. In the previous study, we reported that the IP formulation prepared by spray-drying method with polyvinylpyrrolidone (PVP) (SIP) was very effective in improving the bioavailability of IP. In this study, we examined the effects of molecular weight and mixture ratios of PVP to IP on the systemic absorption of IP following oral administration of SIP at a dose of 50 mg/kg to rats. In the effect of molecular weight, the Cmax of spray-dried IP with PVP K30 (SIP-K30) was significantly higher than those of spray-dried IP with PVP 360 (SIP-360), spray-dried IP with PVP K90 (SIP-K90), and spray-dried IP with PVP K17 (SIP-K17) (p<0.05). The AUC of SIP-K30 was about 2, 3, and 5.5 times higher than those of SIP-360, SIP-K90, and SIP-K17, respectively. The AUC value of SIP-K30 was significantly greater than those of SIP-K17 and SIP-K90 (p<0.05) except for SIP-360. In the ratio of PVP K30 to drug, the $C_{max}$ and the AUC value of 3 : 7 IP-PVP solid dispersion were similar to those of 5 : 5 IP-PVP and significantly higher than those of the other solid dispersions (p<0.05). It was concluded that the spray-dried IP with PVP K30 at the ratio of 3:7 (w/w) was the best formulation for improving the bioavailability of IP.

• Polymer(Korea)
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• v.27 no.3
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• pp.226-234
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• 2003

Ipriflavone (IP), a non-hormonal isoflavone derivative, has been shown to interfere with bone remodeling by inhibiting bone resorption and stimulating bone formation. IP consistently increased the amount of Ca incorporated into the cell layer by mesenchymal stem cells (MSCs). In this study, we developed the novel IP loaded poly(L-lactide-co-glycolide) (PLGA) scaffolds for the possibility of the application of the tissue engineered bone. IP/PLGA scaffo1ds were prepared by solvent casting/salt leaching method and were characterized by porosimeter, scanning electron microscopy, determination of residual salt amount, differential scanning calorimetry, and X-ray diffractometer, respectively. IP/PLGA scaffolds were implanted into the back of athymic nude mouse to observe the effect of IP on the osteoinduction compared with control PLGA scaffo1ds. Thin sections were cut from paraffin embedded tissues and histological sections were stained H&E, von Kossa, and immunohistochemical staining for Type I collagen and osteocalcin. It can be observed that the porosity was above 91.7% and the pore size was above 101 $\mu\textrm{m}$. Control scaffo1d and IP/PLGA scaffo1ds of 50% IP were implanted on the back of athymic nude mouse to observe the effect of IP on the induction of cells proliferation for 9 weeks. The evidence of calcification, osteoblast, and osteoid from the undifferentiated stem cells in the subcutaneous sites and other soft connective tissue sites having a preponderance of stem cells has been observed. From these results, it seems that IP plays an important role for bone induction in IP/PLCA scaffolds.

• Polymer(Korea)
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• v.27 no.1
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• pp.9-16
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• 2003

Ipriflavone (IP) stimulates proliferation and differentiation of osteoblast and also enhances calcitonin secretion in the presence of estrogen. Poly(lactide-co-glycolide) (PLCA) due to its controllable biodegradability and relatively good biocompatibility is one of the most significant candidates for the study of drug controlled release system. In this study, IP-loaded PLGA microspheres (MSs) was prepared by using conventional O/W solvent evaporation method. The size of MSs was in the range of 5~200 $mu extrm{m}$. The morphology of MSs was characterized by SEM. And, in vitro release amounts of IP were analyzed by HPLC. The highest encapsulation efficiency were obtained by using gelatin and polyvinyl alcohol (PVA) as emulsifiers. The morphology, size distribution, and in vitro release pattern of MSs were changed by several preparation parameters such as molecular weights (8, 20, 33 and 90 kg/mol), polymer concentrations (2.5, 5, 10 and 20%), emulsifier types (PVA, gelatin and Tween 80), initial drug loading amount (5, 10, 20 and 30%) and stirring speed (250, 500 and 1000 rpm). The release of IP in vitro was more prolonged over 30 days, with close to zero-order pattern by controlling the preparation parameters. The physicochemical properties of IP-loaded PLGA MSs were investigated by XRD and DSC.

• Polymer(Korea)
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• v.33 no.1
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• pp.26-32
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• 2009

The aim of this research was to prepare microparticulate systems based on poly (lactide-co-glycolide)(PLGA) for the local release of ipriflavone in order to reduce bone loss. We developed the IP loaded PLGA microspheres using relatively simple oil-in-water(O/W) solvent evaporation method. HPLC was used to perform the in vitro release test of IP and morphology of cell attached on the micro-spheres was investigated using SEM. Cytotoxicity was assayed by cell counting kit-8 (CCK-8) test. Osteogenic differential cells were analyzed by ALP activity. Through RT-PCR analysis, we observed osteocalcin, ALP, and Type I collagen mRNA expression. The release of IP in vitro was more prolonged over 42 days and IP/PLGA microspheres showed the improvement on the cell proliferation, ALP activity and RT-PCR comparing with control (only PLGA). This initial research will be used to direct future work involved in developing this composite injectable bone tissue engineering system.

• Macromolecular Research
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• v.11 no.4
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• pp.207-223
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• 2003

For last five years, we are developing the novel local drug delivery devices using biodegradable polymers, especially polylactide (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) due to its relatively good biocompatibility, easily controlled biodegradability, good processability and only FDA approved synthetic degradable polymers. The relationship between various kinds of drug [water soluble small molecule drugs: gentamicin sulfate (GS), fentanyl citrate (FC), BCNU, azidothymidine (AZT), pamidronate (ADP), $1,25(OH)_2$ vitamin $D_3$, water insoluble small molecule drugs: fentanyl, ipriflavone (IP) and nifedipine, and water soluble large peptide molecule drug: nerve growth factor (NGF), and Japanese encephalitis virus (JEV)], different types of geometrical devices [microspheres (MSs), microcapsule, nanoparticle, wafers, pellet, beads, multiple-layered beads, implants, fiber, scaffolds, and films], and pharmacological activity are proposed and discussed for the application of pharmaceutics and tissue engineering. Also, local drug delivery devices proposed in this work are introduced in view of preparation method, drug release behavior, biocompatibility, pharmacological effect, and animal studies. In conclusion, we can control the drug release profiles varying with the preparation, formulation and geometrical parameters. Moreover, any types of drug were successfully applicable to achieve linear sustained release from short period ($1{\sim}3$ days) to long period (over 2 months). It is very important to design a suitable formulation for the wanting period of bioactive molecules loaded in biodegradable polymers for the local delivery of drug. The drug release is affected by many factors such as hydrophilicity of drug, electric charge of drug, drug loading amount, polymer molecular weight, the monomer composition, the size of implants, the applied fabrication techniques, and so on. It is well known that the commercialization of new drug needs a lot of cost of money (average: over 10 million US dollar per one drug) and time (average: above 9 years) whereas the development of DDS and high effective generic drug might be need relatively low investment with a short time period. Also, one core technology of DDS can be applicable to many drugs for the market needs. From these reasons, the DDS research on potent generic drugs might be suitable for less risk and high return.