Three months extended-release microspheres prepared by multi-microchannel microfluidics in beagle dog models.

To evaluate in vivo drug release profiles in beagle dogs, finasteride-loaded PLGA microspheres were prepared using a novel method of IVL-PPF Microsphere® microfluidic device. Briefly, the dispersed phase (PLGA and finasteride in dichloromethane) was mixed with the continuous phase (0.25% w/v PVA aqueous solution) in the parallelized microchannels. After lyophilization, the diameter of the microspheres was around 40 µm (PLGA 7502A or 5002A) and around 30 µm (PLGA/PLA02A mixture). Their CV and span values suggested a narrow size distribution in repeated batch preparations. The in vivo drug release from the PLGA microspheres exhibited three substantial phases: an initial burst, a moderate release, and then a plateau. The microspheres based on PLGA 7502A (75:25 co-polymer) demonstrated extended drug release for around 1 month with a minimized initial burst release compared to PLGA 5002A (50:50 co-polymer). Moreover, the in vivo drug release profile in beagle dogs was proportionally related to the amount of drug loading. Furthermore, the addition of PLA02A into the fabrication of the microsphere synergistically extended the drug release up to 3 months. These results demonstrated the value of this method to achieve uniform microspheres and extend the drug release properties with interpretative in vivo PK profiles.

Pharmacokinetic-pharmacodynamic modeling approach for dose prediction of the optimal long-acting injectable formulation of finasteride.

A controlled drug release formulation based on the subcutaneous injection of poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with finasteride was prepared and evaluated for monthly delivery. After selection of biodegradable polymer and polymer-to-finasteride ratio, the formulation was characterized. Scanning electron microscopy (SEM) and laser-light particle size analysis were used to examine the morphology, surface structure, and particle size. High­performance liquid chromatography (HPLC) was used to determine the drug loading, while liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to analyze plasma finasteride concentrations. Results showed that the PLGA microspheres were spherical and of an appropriate size. The formulation stably releases the drug from the microspheres and the release sustained for a month without burst release, which was the desired duration. In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies were conducted in beagle dogs through the administration of PROPECIA® (as a reference drug) per oral and subcutaneous injection of the long-acting injectable microsphere formulation (LAIF) loaded with five different doses of finasteride. From the acquired plasma data, PK-PD models for both PROPECIA®-administered group and LAIFs-injected groups were developed and validated. PK-PD profiles of both groups were predicted for up to one month. The predicted PK-PD profile of all LAIFs showed the achievability of monthly delivery and pharmacological effects without burst release, compared to the simulated PK-PD profile of PROPECIA®. According to the predicted PK-PD profiles, the formulation loaded with 16.8 mg of finasteride was determined to be the optimal dose. The data obtained from the PK-PD model could be used as the basis for the estimation of a first-in-human dose of the formulation.

Development of finasteride polymer microspheres for systemic application in androgenic alopecia.

The use of finasteride for alleviating hair loss has been investigated, and it has been applied as an oral dose medication. However, due to the inconvenience of daily drug administration over long period of time, novel controllable finasteride delivery has been actively investigated. As a novel method of finasteride delivery, the development of finasteride­loaded microspheres for subcutaneous administration is becoming increasingly pharmaceutically important. Therefore, the present study aimed to use finasteride­loaded microspheres in a controlled manner in an attempt to overcome the limitations of the oral administration of finasteride and to cause fewer adverse effects. Finasteride­loaded microspheres containing poly(lactic­co­glycolic acid) and finasteride at a ratio of 4:1 were prepared, and a testosterone­induced androgenic alopecia mouse model was used. Following observation for 10 weeks, the percentage hair growth was 86.7% (total hair growth 60%, partial hair growth 26.7%) in the orally­applied finasteride­treated group as a positive control, and 93.3% (total hair growth 60%, partial hair growth 33.3%) in the finasteride­loaded microspheres­treated group. Serum dihydrotestosterone levels began to decrease at week 6 in the orally­applied finasteride­ and finasteride­loaded microsphere­treated groups. In addition, the finasteride­loaded microspheres­treated group exhibited similar follicular number, follicular length, anagen/telogen ratio and hair bulb diameter values to those of the orally­applied finasteride­treated group. Furthermore, the finasteride­loaded microspheres increased the activities of phosphoinositide 3­kinase/protein kinase B and Wnt/ß­catenin in relation to hair follicle cell growth signaling in mouse skin, and suppressed the apoptosis of hair follicle cells by reducing the expression of transforming growth factor­ß2 and caspase­3, which are indicators of apoptosis. In conclusion, the administration of a single injection of finasteride­loaded microspheres was effective in treating testosterone­induced alopecia. Furthermore, it led to equivalent hair growth effects when compared with orally­applied finasteride, thus revealing the possibility of effective treatment via different routes of administration.

Micro-/nano-sized delivery systems of ginsenosides for improved systemic bioavailability.

Ginsenosides, dammarane-type triterpene saponins obtained from ginseng, have been used as a natural medicine for many years in the Orient due to their various pharmacological activities. However, the therapeutic potential of ginsenosides has been largely limited by the low bioavailability of the natural products caused mainly by low aqueous solubility, poor biomembrane permeability, instability in the gastrointestinal tract, and extensive metabolism in the body. To enhance the bioavailability of ginsenosides, diverse micro-/nano-sized delivery systems such as emulsions, polymeric particles, and vesicular systems have been investigated. The delivery systems improved the bioavailability of ginsenosides by enhancing solubility, permeability, and stability of the natural products. This mini-review aims to provide comprehensive information on the micro-/nano-sized delivery systems for increasing the bioavailability of ginsenosides, which may be helpful for designing better delivery systems to maximize the versatile therapeutic potential of ginsenosides.