Development of a tadalafil transdermal formulation and evaluation of its ability to in vitro transdermal permeate using Strat-M® membrane.

Tadalafil (TDF) has low water solubility, high intestinal permeability and belongs to the Biopharmaceutics Classification System (BCS) Class II. Due to high intestinal permeability, only oral administration (tablets) and oral thin film formulations have been developed. Therefore, it is necessary to develop various formulations, such as external formulations and transdermal absorption formulations requested by patients. The purpose of this study is to improve the solubility and skin permeability of TDF, and to develop a novel transdermal formulation with secured stability over time. The research strategy is to determine solvents that will improve TDF solubility and to screen substances that will enhance TDF permeability. Skin penetration tests were simulated by using a Strat-M® membrane in Franz diffusion cell systems. The optimal formulation (F1, consisting of TDF/HDTMA-Br at a ratio of 1:10 [weight/weight] in DPG) observed the highest permeability compared to all formulations in PBS (pH 7.4). Changes in thermal property of F1 formulation was observed and maintained its stability over 12 months including drug content (µg/mL), appearance, pH, and permeation (µg/cm2). In conclusion, DPG played a supported role in improving both TDF solubilization and permeability, whereas HDTMA-Br played a key role in enhancing permeability. It is thought that these results will be supplemented in the future to conduct research and experiments on humans.

Febuxostat solubilization and stabilization approach using solid dispersion method: Synergistic effect of dicalcium phosphate dehydrate and chitosan.

Drug solubilization studies are continuously being conducted. Febuxostat (FBX) has a low solubility in water. This study aims to develop a stable FBX-solid dispersion (SD) formulation using a solvent evaporation method. The solubilization strategy of FBX is to develope an optimal FBX-SD formulation by selecting a solubilizer and carrier through the screening method. The final selected solubilizer, macrogol 15 hydroxystearate and polyoxyl 15 hydroxystearate (Kolliphor® HS-15), is widely used in the pharmaceutical industry as a nonionic solubilizing and emulsifying agent and has low toxicity. Especially when commonly used in developing lipophilic drug formulations, it dissolves well in water and ethyl alcohol. The optimal composition ratio of the formulation (SD4) was FBX:HS-15®:granular dicalcium phosphate dehydrate (DCP-D): A synthetic magnesium aluminometasilicate (Neusilin®UFL2):chitosan = 1:3:3:1:1 (w/w) and showed 3.0-, 2.3-, and 1.1-fold higher dissolution (%) of FBX compared to that of the Feburic tab® in pH 1.2 media, distilled water (DW), and pH 6.8 buffer, respectively. Also, in vitro release and in vitro permeability in SD4 formulation showed higher than that of Feburic tab®. Based on its stability over 6 months, it was confirmed that chitosan acted as a stabilizer. Moreover, due to weak intermolecular interactions, FBX in the SD4 formulation was considered to exist in a mixed state of amorphous and crystalline FBX. In conclusion, the improved dissolution (%) and stability of FBX in SD4 formulation were secured through the synergistic effect of excipients.

Development and evaluation of febuxostat solid dispersion through screening method.

Febuxostat (Febux) is a BCS II drug and has a very low solubility. In order to overcome this shortcoming, the purpose of study is to increase the in vitro dissolution (%) and drug release (%) of Febux by using a screening method. The Febux-SD formulation was prepared by screening solubilizers, pH agents, and carriers using with a solvent evaporation method. The novel Febux SD formulation was successfully developed. The dissolution (%) of Febux of optimal formulation (SD3) was higher than that of Feburic® tab in pH 1.2, distilled water (DW), and pH 6.8 buffer by 6.3-, 2.6-, and 1.1-fold, respectively, at 60 min. The in vitro drug release (%) and permeability (µg/cm2) of SD3 formulation were improved compared to those of Feburic® tab in the pH shifting method and PBS (7.4), respectively. The SD3 formulation was well maintained the stability for 6 months, and that of physicochemical properties were altered. In conclusion, the Febux solubilization study with meglumine was first attempted and successfully performed. Through the improved dissolution (%) of Febux, high bioavailability of SD3 formulation is expected in animal and human studies.

Development and evaluation of niacinamide transdermal formulation by artificial membrane permeability.

Despite many efforts to improve the transdermal permeability of drugs, most of them are blocked by the skin barrier. Niacinamide (NAC) is a Biopharmaceutics Classification System class I drug with high aqueous solubility and intestinal permeability. Due to the high solubility and intestinal permeability of NAC, the development of new formulations is insufficient as transdermal, injection etc. Thus, this study aimed to develop the novel NAC formulation with improved skin permeability and secured stability. The NAC formulation approach is to first select a solvent that improves skin permeability, and then select a second penetration enhancer to determine the final formulation. All formulations were evaluated for skin permeability using an artificial membrane (Strat-M®). The optimal formulation (non-ionic formulations (NF1) consisted of NAC/Tween®80 = 1:1 wt ratio in dipropylene glycol [DPG]) showed the highest permeability in all formulations in PBS buffer (pH 7.4). The thermal properties of NF1 were altered. Moreover, NF1 maintained a stable drug content, appearance, and pH value for 12 months. In conclusion, DPG had an excellent effect in increasing the NAC permeation, and Tween®80 played a boosting role. Through this study, an innovative NAC formulation was developed, and good results are expected for human transdermal research.

Development and evaluation of pseudoephedrine hydrochloride abuse-deterrent formulations using thermal modified rice starch.

There is a continued global effort to prevent the spread of prescription drug abuse. In particular, chemical structure of pseudoephedrine hydrochloride (PSE), an over-the-counter medication, is very similar to that of methamphetamine (MET). The aim of this study was to develop abuse-deterrent formulations (ADF) of PSE by using thermal modified starch (TMR). PSE is a water-soluble drug, but it is intended to inhibit extraction from the extraction medium in excess tablets. Starch-based formulations were successfully developed using cross-linking agent and lipid. The extraction (%) of PSE from TMR7-L5 formulation (equivalent to 5 tablets) were 75.3% in DW, 2.7% in ethyl alcohol, and 63.0% in 40% ethyl alcohol (v/v) at 60 °C for 30 min. Moreover, TMR7-L5 formulation delayed drug release compared to the commercial product in in vitro release. In conclusion, the development of ADFs using a starch-based formulation shows novelty and has potential to prevent drug abuse.

Development of a naftopidil-chitosan-based fumaric acid solid dispersion to improve the dissolution rate and stability of naftopidil.

Naftopidil (NAF), an α1-adrenoceptor antagonist, is administered as a treatment for benign prostatic hyperplasia; however, according to the Biopharmaceutical Classification System (BCS IV), it is a poorly-soluble drug that exhibits poor permeability. We aimed to increase the dissolution (%) of NAF by adding chitosan to a polymer-free formulation. Compared to the formulation prepared using Flivas®, at 60 min, the solid dispersion (SD) formulation containing NAF, fumaric acid, chitosan, and US2® in a 1:1:2:1 weight ratio improved the dissolution (%) of NAF in distilled water, pH 1.2 media, pH 4.0 and pH 6.8 buffers by 27.2-, 1.2-, 1.1- and 6.5-fold, respectively. The physicochemical properties of the SD1 formulation were also found to be altered, including its thermal properties, crystal intensity, and chemical interaction. As a result, the hydrogen bonding that occurs between NAF and fumaric acid was identified as a major factor in the increase in NAF dissolution (%). Further, chitosan was observed to contribute to the stability of NAF and SD1, which was assessed over a 3-month period. To our knowledge, this is the first study to employ a polymer-free system to improve the solubilization of NAF.

Solubilization of tadalafil using a tartaric acid and chitosan-based multi-system.

Solubilization studies of tadalafil (TDF) have recently improved the dissolution (%) using weak acids and bases in our group. However, the weak acid formulations have a low dissolution (%) of TDF as limitation. Thus, the purpose of this study was to improve the dissolution (%) of TDF over 90% in distilled water (DW) by weak acid-chitosan based multi-system. The SD formulation (SD11: TDF, tartaric acid, chitosan, Aerosil®200, and PVP/VA S-630 in a 1:2:1:1:2 weight ratio) showed higher dissolution (%) of TDF by 5.0-, 6.0-, and 5.8-fold at 60 min than that of Cialis® in DW and pH 1.2 and pH 6.8 buffers, respectively. The physical properties of the SD11 formulation were changed. Moreover, the SD11 formulation maintained stability for 3 months. In conclusion, the solubilization of TDF using chitosan was successfully performed for the first time.

Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals.

To overcome the toxicity of excipient or blank nanoparticles for drug delivery nano-system, the surface modified paclitaxel nanocrystals (PTX-NC) have been developed. PTX-NCs were prepared by nano-precipitation method. The surface of PTX-NCs were modified by grafting with apo-transferrin (Tf) or hyaluronic acid (HA). The physical properties of PTX-NCs were evaluated by field emission scanning electron microscope (FE-SEM), zeta-sizer, zeta-potential, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectrometry. In vitro drug release study was performed in phosphate buffered saline (PBS) with or without 0.5% (w/v) Tween 80 for 24h. Cellular uptake was studied at time intervals of 0.5, 1, and 2h in MCF-7 cells, and cell growth inhibition study was performed for 24h using MCF-7 cells (cancer cells), and HaCaT cells (normal cells). Three different types of PTX-NCs with a mean size of 236.0±100.6nm (PTX-NC), 302.0±152.0nm (Tf-PTX-NC) and 339±180.6nm (HA-PTX-NC) were successfully prepared. The drug release profiles showed 29.1%/6.9% (PTX (pure)), 40.7%/23.9% (PTX-NC), 50.5%/25.1% (Tf-PTX-NC) and 46.8/24.8% (HA-PTX-NC) in PBS with/without 0.5% (w/v) Tween 80 for 24h, respectively. As per the results, the drug release of PTX-NCs showed the faster release as compared to that of PTX (pure). Surface modified PTX-NCs exhibited higher values for cell permeability than unmodified PTX-NC in the cellular uptake study. Surface modified PTX-NCs inhibited the cell growth approximately to 60% in MCF-7 cells, however effect of surface modified PTX-NCs on normal cell line was lower than the PTX-NC and PTX (pure). In conclusion, biological macromolecules (Tf or HA) surface modified PTX-NC enhanced the cellular uptake and the cell growth inhibition.

Biomimetic adhesive materials containing cyanoacryl group for medical application.

For underwater adhesives with biocompatible and more flexible bonds using biomimetic adhesive groups, DOPA-like adhesive molecules were modified with cyanoacrylates to obtain different repeating units and chain length copolymers. The goal of this work is to copy the mechanisms of underwater bonding to create synthetic water-borne underwater medical adhesives through blending of the modified DOPA and a triblock copolymer (PEO-PPO-PEO) for practical application to repair wet living tissues and bones, and in turn, to use the synthetic adhesives to test mechanistic hypotheses about the natural adhesive. The highest values in stress and modulus of the biomimetic adhesives prepared in wet state were 165 kPa and 33 MPa, respectively.

DNA-templated preparation of gold nanoparticles.

DNA-mediated gold nanoparticles were prepared by chemical reduction of DNA-Au(III) complex. The DNA-Au(III) was first formed by reacting DNA with HAuCl4 at a pH of 5.6. The complex in solution was reacted with hydrazine reducing Au(III) to Au. The reduced Au formed nanodimensional aggregates. The particle distributions were obtained by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). This method resulted in a rather uniform dispersion of Au nanoparticles of near-spherical shape and 45~80 nm in diameter. Gold nanoparticles were embedded and stabilized by DNA.

Synthesis and characterization of a fluorescent water-soluble paclitaxel prodrug.

A fluorescence susceptible water-soluble paclitaxel was synthesized by a condensation reaction between PEGylated paclitaxel (namely, PP7) and 1-pyrene butyric acid (PBA) in order to obtain a better understanding of the mechanism of action of paclitaxel as well as of the environment of the paclitaxel-binding site. The reaction was performed successfully and the resulting paclitaxel was characterized by FT-NMR, analytical-HPLC, UV spectro photometry, and fluorescence spectrometry. The synthesized paclitaxel analogue showed a high susceptibility to fluorescence in both excitation and emission spectra. And we have investigated the time-resolved fluorescence behavior of them in different solvents and at different excitation wavelengths.

Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs.

A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.