Comparative Evaluation of Physical Characteristics and Preclinical Data of a Novel Monodisperse Polycaprolactone Microspheres Filler.

BACKGROUND: Demand for dermal fillers has been increasing gradually over the past decade. Polycaprolactone (PCL) fillers, a biodegradable polymer, not only naturally maintain the volume of the skin, but also stimulate collagen production by microsphere. However, inflammation can be caused by several factors such as large diameters, non-uniformity, uneven surfaces and non-spherical shapes of microspheres in use. Thus, a filler using microspheres with a uniform diameter of more than 20 µm and spherical shape was developed. OBJECTIVE: The main purpose of this study was to evaluate the efficacy and safety of newly monodisperse polycaprolactone microspheres fillers, IVL-F001 with smaller microsphere size and better morphology against a conventional commercial PCL filler. MATERIALS AND METHODS: The morphology and diameters of microsphere included in IVL-F001 and the PCL filler were analyzed, and the viscoelasticity and inject ability of both fillers were examined. After intradermal injection to hairless mice, the durability and efficacy of both fillers were evaluated through PRIMOSLITE and Folliscope for 24 weeks. Histology was performed to assess the biocompatibility, inflammation, and collagen synthesis. RESULTS: Microspheres of IVL-F001 demonstrated a narrow size distribution with average diameter of 34.16 µm and distribution of 4.11. The level of injection force was low and the elasticity (G') was high compared to the licensed PCL filler. In the histopathological evaluation, IVL-F001 had significantly lower inflammatory reactions and higher collagen synthesis compared to the licensed PCL filler. CONCLUSION: These data indicated that IVL-F001 has lower inflammatory reaction and improved persistence compared with commercial PCL filler. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Long-acting injectable donepezil microspheres: Formulation development and evaluation.

Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.

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.

Comparative Evaluation of Safety and Efficacy of a Novel Hyaluronic Acid-polynucleotide/Poly-L-lactic Acid Composite Dermal Filler.

BACKGROUND: Poly-L-lactic acid (PLLA) is widely used in tissue engineering. The natural polymer hyaluronic acid (HA) shows excellent biocompatibility and affects cell signaling, proliferation, and differentiation. In addition, a polynucleotide (PN) induces cell growth of human skin fibroblasts and osteoblasts. OBJECTIVE: In this study, we evaluated the properties, safety, and efficacy of a novel composite filler consisting of cross-linked HA with PN in combination with monodisperse PLLA microspheres manufactured using Inventage Lab Precision Particle Fabrication method. MATERIALS AND METHODS: The composition of the filler and characteristics of the microspheres were examined via scanning electron microscopy, particle size analysis, gel permeation chromatography, and rheology and osmolality measurement. Additionally, safety and efficacy of HA-PN/PLLA composite filler were conducted in in vitro and in vivo. RESULTS: Analysis of PLLA microspheres revealed spherical surfaces and a narrower particle size distribution than that in PLLA filler. HA-PN/PLLA composite filler had higher viscosity and elasticity values and similar osmolality as compared to those of HA and PN fillers. The nontoxicity in in vitro and in vivo tests reflected that the composite filler may be safe for human use. In addition, the composite filler maintained a more stable volume than did HA filler for 24 weeks after administration in HWY/Slc hairless rats. Furthermore, the results support the effect of HA-PN/PLLA in restoring skin structure. CONCLUSION: Altogether, these data suggest that the novel composite filler might be a safe and effective option in terms of tissue integration, clinical management during delivery and high esthetic durability. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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.

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1.

This study estimated the population pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, according to genetic polymorphisms in the metabolizing enzyme (CYP2D6) and transporter (ABCB1) genes in healthy subjects. Eighty healthy subjects who received a single oral dose of 2 mg risperidone participated in this study. However, eight subjects with rare genotype variants in CYP2D6 alleles were excluded from the final model built in this study. We conducted the population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T) on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone. A two-compartment model with a first-order absorption and lag time fitted well to serum concentration-time curve for risperidone. 9-hydroxyrisperidone was well described by a one-compartment model as an extension of the parent drug (risperidone) model with first-order elimination and absorption partially from the depot. Significant covariates for risperidone clearance were genetic polymorphisms of CYP2D6*10, including CYP2D6*1/*10 (27.5 % decrease) and CYP2D6*10/*10 (63.8 % decrease). There was significant difference in the absorption rate constant (k ( a )) of risperidone among the CYP2D6*10 genotype groups. In addition, combined ABCB1 3435C>T and CYP2D6*10 genotypes had a significant (P < 0.01) effect on the fraction of metabolite absorbed from the depot. The population pharmacokinetic model of risperidone and 9-hydroxyrisperidone including the genetic polymorphisms of CYP2D6*10 and ABCB1 3435C>T as covariates was successfully constructed. The estimated contribution of genetic polymorphisms in CYP2D6*10 and ABCB1 3435C>T to population pharmacokinetics of risperidone and 9-hydroxyrisperidone suggests the interplay of CYP2D6 and ABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.

Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10.

BACKGROUND AND PURPOSE: The objective of this study was to investigate the combined influence of genetic polymorphisms in ABCB1 and CYP2D6 genes on risperidone pharmacokinetics. EXPERIMENTAL APPROACH: Seventy-two healthy Korean volunteers receiving a single oral dose of 2 mg risperidone were included in this study. KEY RESULTS: Significant differences were observed between the ABCB1 3435C>T genotypes for the pharmacokinetic parameters (peak serum concentration) of risperidone and the active moiety (risperidone and its main metabolite, 9-hydroxyrisperidone). There were no significant differences in the area under the serum concentration-time curves of risperidone and the active moiety among the ABCB1 2677G>T/A and 3435C>T genotypes. However, the peak serum concentration and area under the serum concentration-time curves were significantly different among the ABCB1 3435C>T genotypes in CYP2D6*10/*10. CONCLUSIONS AND IMPLICATIONS: These findings indicate that polymorphisms of ABCB1 3435C>T in individuals with CYP2D6*10/*10, which has low metabolic activity, could play an important role in the potential adverse effects or toxicity of risperidone.