Multi-layered granules were prepared by a fluidized-bed coater and uniformed granules were obtained with a size range between $950{\sim}1000{\mu}m$ in diameter. The granule system was composed of three layers, i.e. seed layer with sugar sphere bead and a water-swellable polymer, middle layer with a drug, solubilizer and polymer, and the top layer of porous membrane with a polymeric binder. The aim of this work is to find out the dependence of a drug dissolution rate on the amount of a water-soluble binder and a solubilizer in the granule system. The results showed that the higher amount of hydrophilic binder in the porous membrane, gave the bigger pore size and porosity and made faster dissolution rate and also the higher amount of solubilizer in drug layer enhanced the dissolution rate of drug.
We fabricated the 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine)-loaded PLGA wafers containing poly(N-vinylpyrrolidone) (PVP) or tedium chloride (NaCl) in order to control the release profile of drug in special shape (3 in diameter, 1 mm in thickness) by direct compression method. In vitro release profiles of BCNU could be controlled by additives contained in the wafers. Initial release amount, release rate and duration of BCNU could be controlled with presence of PVP or NaCl. In vitro antitumor activity accessed using 9L gliosarcoma cell line has been evaluated by assaying the viability of cells treated with BCNU released from the wafers containing additives resulting in continuous growth inhibition of 9L gliosarcoma tumor cells. Specially, the continuous growth inhibition of BCNU-loaded PLGA wafers containing additives was more effective than that of non-additive BCNU-loaded PLGA wafers. The cytotoxic effect of the drug from the wafers containing NaCl as compared to wafers containing PVP was more enhanced.
It is well established that dissolution is freruently the rate limiting step in the gastrointestinal absorpton of a drug from a solid dosage from. The relationship between the dissolution rate and absorption is particularly distinct when considering drugs of low solubility. Consequently, numerous attempts have been made to modify the dissolution characteristics of poorly water soluble drugs. Since dissolution rate is directly proportional to surface area, one may increase the rate by decreasing the particle size of the drug. Levy has considered a number of methods by which a drug may be presented to the GI fludids in finely divided from. The direct method is the utilization of microcrystalline or micronized particles. A second method involves the administration of solutions from which, upon dilution with gastric fluids, the dissolved drug will precipitate in the form of very fine particles. A more unique way of obtaining microcrystalline dispersions of a drug has been ercently suggested by Sekiguchi et al. They have first proposed the formation of a eutectic mixture of a poorly water soruble drug with a physiologically inert, easily soluble carrier. When such systems are exposed to water or GI fluids, the soluble carrier will dissolve rapidly and the finely dispersed drug particles will then be released. It has been suggested by Shefter and Higuchi that the formation of crystalline solvate could be a powerful tool in affecting rapid disslution of highly insoluble substances. Goldberg et al. have noted that the formation of solid solution could reduce the particle size to a minimum and increase the dissolution rate as well as the solubility of the durgs. It has also been shown that the rates of solution of drugs were appreciably increased by coprectipitating the drug with soluble polymers. The increase was found to be sensitive to the method of preparation, the molecular weight of polymer and the particular ratio of drugs to polymer. Although several investigations have demontrated that the solubility and/or dissolution rates of drugs can be increased in this manner, little information is available in the literature related to the in vivo absorption pattern of drugs orally administered as PVP coprecipitates. Recently, however, it was demonstrated that both the rate and extent of absorption of the insoluble drug could be markedly enhanced when orally administered to rats in the form of a coprecipitate with PVP. The purpose of the present investigation was to ascertain the general appility of soluble polymer coprectation technique as a method for enhancing the in vitro dissolution rate of hydrophobic indomethacin. To accomplish this aim, the dissolution characteristics of pure indomethacin, indomethcin-polymer physical mixtures and indomethacin-polymer coprecipitates were quantitatively studied by comparing their relative dissolution rates. The solubility and dissolution behavior of these systems were also examined.
Drug releasing porous poly($\varepsilon$-caprolactone) (PCL)-chitosan matrices were fabricated for bone regenerative therapy. Porous matrices made of biodegradable polymers have been playing a crucial role as bone substitutes and as tissue-engineered scaffolds in bone regenerative therapy. The matrices provided mechanical support for the developing tissue and enhanced tissue formation by releasing active agent in controlled manner. Chitosan was employed to enhance hydrophilicity and biocompatibility of the PCL matrices. PDGF-BB was incorporated into PCL-chitosan matrices to induce enhanced bone regeneration efficacy. PCL-chitosan matrices retained a porous structure with a 100-200 $\mu$m pore diameter that was suitable for cellular migration and osteoid ingrowth. $NaHCO_3$ as a porogen was incorporated 5% ratio to polymer weight to form highly porous scaffolds. PDGF-BB was released from PCL-chitosan matrices maintaining therapeutic concentration for 4 week. High osteoblasts attachment level and proliferation was observed from PCL-chitosan matrices. Scanning electron microscopic examination indicated that cultured osteoblasts showed round form and spread pseudopods after 1 day and showed broad cytoplasmic extension after 14 days. PCL-chitosan matrices promoted bone regeneration and PDGF-BB loaded matrices obtained enhanced bone formation in rat calvarial defect. These results suggested that the PDGF-BB releasing PCL-chitosan porous matrices may be potentially used as tissue engineering scaffolds or bone substitutes with high bone regenerative efficacy.
Journal of the Korea Academia-Industrial cooperation Society
/
v.18
no.1
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pp.506-512
/
2017
The purpose of this study was to improve release rate and bioavailability of nateglinide formulation. Polymorphism selection and particle size control were performed to enhance formulation dissolution rate, and a pH modifier was included in the formulation to overcome pH-dependent solubility of nateglinide. The enhanced dissolution rate was characterized by using a dissolution test. The results showed that H-type raw material had a higher dissolution rate than that of B-type raw material. There was 6.2% difference in dissolution between the two materials at 60 min. With regard to particle size, raw material with a $1.13{\mu}m$ particle size showed a 20% faster release rate than that of raw material with a $2.28{\mu}m$ particle size. Furthermore, fumaric acid was included in formulation as a pH modifier. That addition produced a greater than 50% improvement in dissolution rate. In conclusion, dissolution rate of nateglinide can be enhanced by optimizing its polymorphism and particle size; moreover, a synergistic effect on the enhancement of dissolution rate is obtained by including fumaric acid, a pH modifier, in the formulation.
Both the calcium and collagen in bone powder are hard to be absorbed by the body. Although enzymatic hydrolysis by protease increased the bio-availability of bone powder, it was a meaningful try to further increase $Ca^{2+}$ release, oligopeptide formation and antioxidant activity of the sheep bone hydrolysate (SBH) by lactic acid bacteria (LAB) fermentation. Lactobacillus helveticus was selected as the starter for its highest protease-producing ability among 5 tested LAB strains. The content of liberated $Ca^{2+}$ was measured as the responsive value in the response surface methodology (RSM) for optimizing the fermenting parameters. When SBH (adjusted to pH 6.1) supplemented with 1.0% glucose was inoculated 3.0% L. helveticus and incubated for 29.4 h at $36^{\circ}C$, $Ca^{2+}$ content in the fermented SBH significantly increased (p<0.01), and so did the degree of hydrolysis and the obtaining rate of oligopeptide. The viable counts of L. helveticus reached to $1.1{\times}10^{10}CFU/mL$. Results of Pearson correlation analysis demonstrated that LAB viable counts, $Ca^{2+}$ levels, obtaining rates of oligopeptide and the yield of polypeptide were positively correlated with each other (p<0.01). The abilities of SBH to scavenge the free radicals of DPPH, OH and ABTS were also markedly enhanced after fermentation. In conclusion, L. helveticus fermentation can further boost the release of free $Ca^{2+}$ and oligopeptide, enhance the antioxidant ability of SBH. The L. helveticus fermented SBH can be developed as a novel functional dietary supplement product.
Background: Hydrogels are a class of polymers that can absorb water or biological fluids and swell to several times their dry volume, dependent on changes in the external environment. In recent years, hydrogels and hydrogel nanocomposites have found a variety of biomedical applications, including drug delivery and cancer treatment. The incorporation of nanoparticulates into a hydrogel matrix can result in unique material characteristics such as enhanced mechanical properties, swelling response, and capability of remote controlled actuation. Materials and Methods: In this work, synthesis of hydrogel nanocomposites containing magnetic nanoparticles are studied. At first, magnetic nanoparticles ($Fe_3O_4$) with an average size 10 nm were prepared. At second approach, thermo and pH-sensitive poly (N-isopropylacrylamide -co-methacrylic acid-co-vinyl pyrrolidone) (NIPAAm-MAA-VP) were prepared. Swelling behavior of co-polymer was studied in buffer solutions with different pH values (pH=5.8, pH=7.4) at $37^{\circ}C$. Magnetic iron oxide nanoparticles ($Fe_3O_4$) and doxorubicin were incorporated into copolymer and drug loading was studied. The release of drug, carried out at different pH and temperatures. Finally, chemical composition, magnetic properties and morphology of doxorubicin-loaded magnetic hydrogel nanocomposites were analyzed by FT- IR, vibrating sample magnetometry (VSM), scanning electron microscopy (SEM). Results: The results indicated that drug loading efficiency was increased by increasing the drug ratio to polymer. Doxorubicin was released more at $40^{\circ}C$ and in acidic pH compared to that $37^{\circ}C$ and basic pH. Conclusions: This study suggested that the poly (NIPAAm-MAA-VP) magnetic hydrogel nanocomposite could be an effective carrier for targeting drug delivery systems of anti-cancer drugs due to its temperature sensitive properties.
Heo, Hye Jin;Park, So Youn;Lee, Yi Sle;Shin, Hwa Kyoung;Hong, Ki Whan;Kim, Chi Dae
The Korean Journal of Physiology and Pharmacology
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v.24
no.4
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pp.299-310
/
2020
Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and α7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.
Recent researches demonstrated well promising anticancer activities for antibiotics. Such effects would be significantly increased while nanoparticle based delivery systems were applied. In this study, the goal was aim to improve anticancer and antitoxic effects of Streptomycin by loading on special kind of dendrimer (anionic-linear-globular second generation). In the current study, Size and zeta potential as well as AFM techniques have been used to prove the fact that the loading was performed correctly. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of the drug loaded on dendrimer nanoparticle were determined and compared with both of dendrimer alone and free drug with respect to staphylococcus aureus as the test microorganism. The anticancer activity among three groups including Streptomycin, Streptomycin -G2 dendrimer, and control was measured in vitro. In vitro studies showed that G2 anionic linear-globular polyethylene-glycol-based dendrimer, which loaded on Streptomycin was able to significantly improve the treatment efficacy over clinical Streptomycin alone with respect to proliferation assay. Maximal inhibitory concentration (IC50) was calculated to be $257{\mu}g/mL$ for streptomycin alone and $55{\mu}g/mL$ for Streptomycin -G2 dendrimer. In addition, Streptomycin -G2 dendrimer conjugate prevented the growth of MCF-7 cancerous cells in addition to enhance the number of apoptotic and necrotic cells as demonstrated by an annexin V-fluorescein isothiocyanate assay. Streptomycin -G2 dendrimer conjugate was able to increase Bcl-2/Bax ratio in a large scale compared with the control group and Streptomycin alone. Based on results a new drug formulation based nano-particulate was improved against S. aureus with sustained release and enhanced antibacterial activity as well as anticancer activity shown for functional cancer treatment with low side effects.
Kim, Hee-Jin;Park, Hae-Young;Kim, Jeong-A;Kang, Il-Hyun;Kim, Tae-Sung;Han, Soon-Young;Kang, Tae-Seok;Park, Kui-Lea;Kim, Hyung-Sik
Toxicological Research
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v.22
no.4
/
pp.307-313
/
2006
The development of in vitro assays has been recommended to screening and testing the potential endocrine disruptors (EDs). These assay systems focus only on identifying the estrogenic or antiestrogenic activity of EDs, whereas a few studies have been carried out to screen the thyroid hormone (TH) disruptors. The aim of this study was to evaluate a test system to detect TH disruptors using rat pituitary tumor $GH_3$ cells. The test system is based on the TH-dependent increase in growth rate. As expected, L-3,5,3-triiodothyronine ($(T_3)$ markedly induced a morphological change in $GH_3$ cells from flattened fibroblastic types to rounded or spindle-shaped types. $T_3$ stimulated $GH_3$ cell growth in a dose-dependent manner with the maximum growth-stimulating effect being observed at a concentration $1{\times}10^9M$. In addition, $T_3$ increased the release of growth hormone and prolactin into the medium of the $GH_3$ cells culture. Using this assay system, the TH-disrupting activities of bisphenol A (BPA) and its related compounds were examined. BPA, dimethy/bisphenol A (DMBPA), and TCI-EP significantly enhanced the growth of $GH_3$ cells in the range of $1{\times}10^{-5}M\;to\;1{\times}10^{-6}M$ concentrations. In conclusion, this in vitro assay system might be useful for identifying potential TH disruptors. However, this method will require further evaluation and standardization before it can be used as a broad-based screening tool.
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