Carboxymethyl cellulose-based rotigotine nanocrystals-loaded hydrogel for increased transdermal delivery with alleviated skin irritation.

Transdermal rotigotine (RTG) therapy is prescribed to manage Parkinson's disease (Neupro® patch). However, its use is suffered from application site reactions. Herein, drug nanocrystalline suspension (NS)-loaded hydrogel (NS-HG) employing polysaccharides simultaneously as suspending agent and hydrogel matrix was constructed for transdermal delivery, with alleviated skin irritation. RTG-loaded NS-HG was prepared using a bead-milling technique, employing sodium carboxylmethyl cellulose (Na.CMC) as nano-suspending agent (molecular weight 90,000 g/mol) and hydrogel matrix (700,000 g/mol), respectively. NS-HG was embodied as follows: drug loading: ≤100 mg/mL; shape: rectangular crystalline; crystal size: <286.7 nm; zeta potential: -61 mV; viscosity: <2.16 Pa·s; and dissolution rate: >90 % within 15 min. Nuclear magnetic resonance analysis revealed that the anionic polymers bind to RTG nanocrystals via charge interaction, affording uniform dispersion in the matrix. Rodent transdermal absorption of RTG from NS-HG was comparable to that from microemulsions, and proportional to drug loading. Moreover, NS-HG was skin-friendly; erythema and epidermal swelling were absent after repeated application. Further, NS-HG was chemically stable; >95 % of the drug was preserved up to 4 weeks under long term (25 °C/RH60%), accelerated (40 °C/RH75%), and stress (50 °C) storage conditions. Therefore, this novel cellulose derivative-based nanoformulation presents a promising approach for effective transdermal RTG delivery with improved tolerability.

Evaluation of the Ejection Pressure for Tracking Internal Cracks during Compaction in Bilayer Tablet Formulations Using Experimental and Finite Element Methods.

This study aimed to evaluate the ejection pressure and the correlation of the findings with the occurrence of internal cracks within bilayer tablets (BLTs) consisting of metformin HCl (MF) and evogliptin tartrate (EG). Then, the mechanism of tablet failure was provided by the finite element method (FEM). The ejection pressure and the difference in diameter depending on MAIN-P were evaluated to understand the correlation between ejection pressure and change in the BLT internal structure. The ejection pressure and the difference in diameter increased as the MAIN-P increased, then steeply decreased from 350 MPa to 375 MPa of MAIN-P, despite there being no pattern in compaction breaking force and porosity. The mechanical integrity at the BLT interface was weakened by internal cracks, reducing ejection pressure. The stress distribution analysis during the compression revealed that crack formation caused by entrapped air located at the center of the BLT interface may not propagate due to concentrated stress, which promotes a tight bond at the edge of the BLT. Furthermore, complete delamination can occur in the ejection process due to localized and intensive shear stresses at the BLT interface. These findings indicate that the mechanisms of internal cracking and delamination were successfully confirmed by FEM simulation. Moreover, measuring ejection pressure before BLT manufacturing can prevent invisible tablet cracks without damaging the tablets.

Design of High-Payload Ascorbyl Palmitate Nanosuspensions for Enhanced Skin Delivery.

A high-payload ascorbyl palmitate (AP) nanosuspension (NS) was designed to improve skin delivery following topical application. The AP-loaded NS systems were prepared using the bead-milling technique, and softly thickened into NS-loaded gel (NS-G) using hydrophilic polymers. The optimized NS-G system consisted of up to 75 mg/mL of AP, 0.5% w/v of polyoxyl-40 hydrogenated castor oil (Kolliphor® RH40) as the suspending agent, and 1.0% w/v of sodium carboxymethyl cellulose (Na.CMC 700 K) as the thickening agent, in citrate buffer (pH 4.5). The NS-G system was embodied as follows: long and flaky nanocrystals, 493.2 nm in size, -48.7 mV in zeta potential, and 2.3 cP of viscosity with a shear rate of 100 s-1. Both NS and NS-G provided rapid dissolution of the poorly water-soluble antioxidant, which was comparable to that of the microemulsion gel (ME-G) containing AP in solubilized form. In an ex vivo skin absorption study using the Franz diffusion cell mounted on porcine skin, NS-G exhibited faster absorption in skin, providing approximately 4, 3, and 1.4 times larger accumulation than that of ME-G at 3, 6, and 12 h, respectively. Therefore, the high-payload NS makes it a promising platform for skin delivery of the lipid derivative of ascorbic acid.

Novel bioequivalent oral disintegrating tablet of aripiprazole prepared by direct compression technique with shortened disintegration time.

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1-5.2 kp hardness exhibited rapid disintegration (14.1-17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306-11051 and 0.9448-1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence.

The Effect of Compression Pressure on the First Layer Surface Roughness and Delamination of Metformin and Evogliptin Bilayer and Trilayer Tablets.

The objectives of this study were to evaluate the delamination of convex-shaped metformin HCl (MF) and evogliptin tartrate (EG) multi-layer tablets depending on the pre-compression and main compression pressures and simultaneously correlate these results with those of a surface roughness analysis. Free-flowing MF and EG (median diameters of 38.3 and 44.7 µm, respectively) granules prepared using the wet granulation method were pre-compressed and subsequently compressed into bilayer and trilayer tablets using a universal testing machine. The compaction force required to break the tablets increased linearly as the main compression pressure increased (30-150 MPa). Conversely, the interfacial strength and compaction breaking force decreased as the pre-compression pressure increased (10-110 MPa). A surface roughness analysis employing a profilometer revealed that the first layer (MF) roughness drastically decreased from 5.89 to 0.51 µm (Ra, arithmetic average of profile height deviations from the mean line) as the pre-compression pressure increased from 10 to 150 MPa in the bilayer tablet. Accordingly, the decrease in the roughness of the first layer reduced the inter-penetration at the interface, as observed via energy dispersive spectrometer (EDS)-equipped scanning electron microscopy, decreasing the interfacial bonding strength and causing delamination of the MF/EG multi-layer tablets. These findings indicate the significance of roughness control in the actual preparation of multi-layer tablets and the usefulness of profilometer- and EDS-based surface analyses for interpreting the delamination of multi-layer tablets.

Novel Bioequivalent Tablet of Solifenacin Succinate Prepared Using Direct Compression Technique for Improved Chemical Stability.

We designed a bioequivalent tablet form of solifenacin succinate (SOL) with an improved storage stability using a direct compression (DC) technique. An optimal direct compressed tablet (DCT) containing an active substance (10 mg), lactose monohydrate, and silicified microcrystalline cellulose as diluents, crospovidone as a disintegrant, and hydrophilic fumed silica as an anti-coning agent was constructed by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The physicochemical and mechanical properties of the DCT were as follows: drug content 100.1 ± 0.7%, disintegration time of 6.7 min, over 95% release within 30 min in dissolution media (pH 1.2, 4.0, 6.8, and distilled water), hardness > 107.8 N, and friability ~0.11%. The SOL-loaded tablet fabricated via DC showed an improved stability at 40 °C and RH 75%, exhibiting markedly reduced degradation products compared to those fabricated using ethanol or water-based wet granulation or a marketed product (Vesicare®, Astellas Pharma). Moreover, in a bioequivalence study in healthy subjects (n = 24), the optimized DCT offered a pharmacokinetic profile comparable to that of the marketed product, with no statistical differences in the pharmacokinetic parameters. The 90% CIs for the geometric mean ratios of the test to the reference formulation for the area under the curve and the maximum drug concentration in plasma were 0.98-1.05 and 0.98-1.07, respectively, and satisfied the FDA regulatory criteria for bioequivalence. Thus, we conclude that DCT is a beneficial oral dosage form of SOL with an improved chemical stability.

Functionalized Lipid Nanocarriers for Simultaneous Delivery of Docetaxel and Tariquidar to Chemoresistant Cancer Cells.

The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC) functionalized with PEG and RIPL peptide (PRN) (D^T-PRN) was compared with that of a physically mixed dual-carrier system of DTX-loaded PRN (D-PRN) and TRQ-loaded PRN (T-PRN) to overcome DTX mono-administration-induced multidrug resistance. NLC samples were prepared using the solvent emulsification evaporation technique and showed homogeneous spherical morphology, with nano-sized dispersion (<220 nm) and zeta potential values of -15 to -7 mV. DTX and/or TRQ was successfully encapsulated in NLC samples (>95% encapsulation efficiency and 73-78 µg/mg drug loading). In vitro cytotoxicity was concentration-dependent; D^T-PRN exhibited the highest MDR reversal efficiency, with the lowest combination index value, and increased the cytotoxicity and apoptosis in MCF7/ADR cells by inducing cell-cycle arrest in the G2/M phase. A competitive cellular uptake assay using fluorescent probes showed that, compared to the dual nanocarrier system, the single nanocarrier system exhibited better intracellular delivery efficiency of multiple probes to target cells. In the MCF7/ADR-xenografted mouse models, simultaneous DTX and TRQ delivery using D^T-PRN significantly suppressed tumor growth as compared to other treatments. A single co-loaded system for PRN-based co-delivery of DTX/TRQ (1:1, w/w) constitutes a promising therapeutic strategy for drug-resistant breast cancer cells.

Neutral Oil-Incorporated Liposomal Nanocarrier for Increased Skin Delivery of Ascorbic Acid.

In this study, a neutral oil-incorporated liposomal system (lipo-oil-some, LOS) was designed to improve the skin absorption of ascorbic acid (Vit C), and the effects of an edge activator and neutral oil on the skin absorption of Vit C were evaluated. As components of the LOS system, sodium deoxycholate, polysorbate 80, and cholesterol were screened as edge activators, and camellia oil, tricaprylin, and grapeseed oil were employed as neutral oils. The LOS systems prepared by the ethanol injection method were spherical in shape, 130-350 nm in size, and had 4-27% Vit C loading efficiency (%). In a skin absorption study using a Franz diffusion cell mounted with porcine skin, the LOS system prepared with sodium deoxycholate (10 w/w% of phospholipid) exhibited 1.2-and 2.9-fold higher absorption than those prepared with polysorbate 80 and cholesterol, respectively. Moreover, the type of neutral oil had a marked effect on the absorption of Vit C; the liposomal system containing camellia oil provided 1.3 to 1.8 times higher flux (45.4 µg/cm2∙h) than vesicles with tricaprylin or grapeseed oil, respectively. The optimized lipid nanocarrier is expected to be a promising tool for promoting the skin absorption of Vit C and improving its dermatological functions.

Design of Novel Tricaprylin-Incorporated Multi-Layered Liposomal System for Skin Delivery of Ascorbic Acid with Improved Chemical Stability.

L-ascorbic acid (Vit C) possesses a variety of dermatological functions in maintaining skin health and anti-aging properties. However, its topical application is challenging owing to its liability to light, oxygen, or heat. Therefore, in this study, a novel liposomal system, including a lipophilic neutral oil named a lipo-oil-some (LOS), was designed to improve the chemical stability and aid the skin absorption of Vit C. The vesicular systems were prepared using the ethanol injection method, employing phosphatidylcholine, cholesterol, dipalmitoyl-sn-glycerol-3-phosphoglycerol, and tricaprylin as neutral oil. The optimized LOS was characterized as follows: shape, multi-layered sphere; size, 981 nm; zeta potential, -58 mV; and Vit C encapsulation efficiency, 35%. The encapsulation of the labile compound into the novel system markedly enhanced photostability, providing over 10% higher Vit C remaining compared to Vit C solution or Vit C-loaded conventional liposome under a light intensity of 20,000 lx. On the other hand, the ex vivo skin permeation and accumulation of Vit C with the LOS system were comparable to those of smaller conventional liposomes (198 nm) in a Franz diffusion cell model mounted with porcine skin. Based on these findings, we concluded that the novel liposomal system could be utilized for skin delivery of Vit C with enhanced chemical stability.

Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.

To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.

Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection.

Rotigotine (RTG) is prescribed as a once-daily transdermal patch for managing early Parkinson's disease (PD), which presents issues such as skin irritation and poor patient adherence. Therefore, the aims of the present study were to formulate aqueous and oily vehicle-based RTG crystalline suspensions for prolonged delivery and to compare their pharmacokinetic profiles and the local behaviors of RTG crystals. RTG-loaded aqueous (AS) and oil suspensions (OS) were fabricated using bead-milling technology (100 mg/mL as RTG), employing carboxymethyl cellulose and sesame oil as suspending agent and oily vehicle, respectively. RTG AS and OS exhibited comparable physical properties in terms of particle size (about 800−900 nm), crystallinity, and dissolution profile, despite higher drug solubility in OS than AS (19.6 and 0.07 mg/mL, respectively). However, AS and OS exhibited markedly distinctive local distribution and inflammatory responses at the injection site, which further promoted different pharmacokinetic patterns following subcutaneous injection in rats. With OS, no drug aggregates were observed with prolonged persistence of the Sudan III-stained oily vehicle at the injection site. In contrast, with AS injection, drug clusters > 7 mm were formed, followed by an enclosure with macrophages and a fibroblastic band. Accordingly, AS exhibited a protracted pharmacokinetic profile over 3 weeks, with prolonged elimination half-life. The local inflammatory response caused by AS injection was almost alleviated after 3 weeks post-dosing. Based on these findings, we conclude that RTG AS system can be a platform to design sophisticated long-acting delivery systems with extended dosing intervals to manage PD.

Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery.

Background: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer's disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency. Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration. Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats. Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 µm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 µm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks. Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer's disease with extended dose intervals.

Local retention efficacy of steroid-loaded PLGA microspheres in epidural injection.

Long-term effects of epidural steroid injections for pain management require novel drug formulations that increase tissue retention time. Present study aimed to investigate the local retention of steroid-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in epidural injection using a rabbit model. Twenty rabbits were randomly assigned to a PLGA group (n = 10) and a triamcinolone acetonide (TA) group (n = 10). Each animal was injected with either TA-loaded PLGA microspheres or conventional TA suspension into the lumbar epidural space. The lumbar segments were then harvested from the sacrificed rabbits on day 1, week 1, 2, and 4 after the injection. On day 1, the residual steroid concentration (RSC) was lower in the PLGA group than in the TA group (5.03 ppm vs. 13.01 ppm). However, after a week, more steroids remained in the PLGA group (3.29 ppm vs. 0.58 ppm). After 2 weeks, fewer steroids remained in the PLGA group than in the TA group, although both contained less than 10% of the initial retention dose. This study shows that steroid-loaded PLGA tended to have higher steroid retention in tissue than the steroid itself at the first week after epidural injection. However, most of the steroids disappeared after 2 weeks in both groups.

Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system.

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.

Effect of particle size on in vivo performances of long-acting injectable drug suspension.

Herein, entecavir-3-palmitate (EV-P), an ester prodrug of entecavir (EV), was employed as a model drug, and the effect of drug particle size on in vivo pharmacokinetic profiles and local inflammatory responses, and those associations were evaluated following intramuscular (IM) injection. EV-P crystals with different median diameters (0.8, 2.3, 6.3, 15.3 and 22.6 µm) were prepared using the anti-solvent crystallization method, with analogous surface charges (-10.7 ~ -4.7 mV), and crystallinity (melting point, 160-170 °C). EV-P particles showed size-dependent in vitro dissolution profiles under sink conditions, exhibiting a high correlation between the median diameter and Hixon-Crowell's release rate constant (r2 = 0.94). Following IM injection in rats (1.44 mg/kg as EV), the pharmacokinetic profile of EV exhibited marked size-dependency; 0.8 µm-sized EV-P particles about 1.6-, 3.6-, and 5.6-folds higher systemic exposure, compared to 6.3, 15.3, and 22.6 µm-sized particles, respectively. This pharmacokinetic pattern, depending on particle size, was also highly associated with histopathological responses in the injected tissue. The smaller EV-P particles (0.8 or 2.3 µm) imparted the larger inflammatory lesion after 3 days, lower infiltration of inflammatory cells, and thinner fibroblastic bands around depots after 4 weeks. Conversely, severe fibrous isolation with increasing particle size augmented the drug remaining at injection site over 4 weeks, impeding the dissolution and systemic exposure. These findings regarding the effects of formulation variable on the in vivo behaviors of long-acting injectable suspension, provide constructive knowledge toward the improved design in poorly water-soluble compounds.

High-Payload Nanosuspension of Centella asiatica Extract for Improved Skin Delivery with No Irritation.

BACKGROUND: The titrated extract of Centella asiatica (CA) has received much attention as a cosmeceutical ingredient owing to its anti-wrinkle effect. However, due to the low solubility and high molecular weight of pharmacologically active constituents, including asiatic acid (AA), madecassic acid (MA), and asiaticoside (AS), it is challenging to fabricate high-payload topical preparations of CA with satisfactory skin absorption profiles. PURPOSE: This study aimed to design a high-payload topical preparation of CA using nanocrystallization technique and to evaluate its skin absorption profile and local tolerability. METHODS: High-payload nanocrystal suspensions (NSs) were prepared using lab-scale bead-milling technology, by adjusting the type and amount of suspending agent, CA content, type of vehicle, and milling speed. CA-loaded NSs were characterized in terms of morphology, particle size, crystallinity, and in vitro dissolution pattern. Skin absorption of CA nanocrystals was evaluated using a vertical Franz diffusion cell mounted with porcine skin. In vivo skin irritation following topical application of high-payload NS was assessed in normal rats. RESULTS: The optimized NS system, composed of 10% (w/v) CA, 0.5% polyvinylpyrrolidone (PVP) K30 as steric stabilizer, and 89.5% of distilled water, was characterized as follows: spherical or elliptical in shape, 200 nm in size, with low crystallinity. The in vitro dissolution of AA or MA from NSs was markedly faster compared to raw material, under sink condition. Penetration of AA, MA, and AS in the porcine skin was markedly elevated using the high-payload NS formula, providing 5-, 4-, and 4.5-fold higher accumulation in skin layer, compared to that of the marketed cream formula (CA 1%, Madeca cream). Moreover, topical application of high-payload NS was tolerable, showing neither erythema nor oedema in normal rats. CONCLUSION: The novel NS system is expected to be a virtuous approach for offering a better skin absorption of CA, without using an excess quantity of solubilizers.

Montelukast microsuspension with hypromellose for improved stability and oral absorption.

Oral montelukast (MTK) is prescribed to treat asthma or rhinitis, and is clinically investigated as new medication in the treatment of Alzheimer's dementia. Herein, in order to better patient's compliance, microsuspensions (MSs)-based oral liquid preparations of montelukast (MTK) were formulated with polymeric suspending agents including hypromellose (HPMC), and those drug-polymer interaction, physicochemical stability, dissolution, and in vivo pharmacokinetic profile was evaluated. When amorphous MTK particle was suspended in aqueous vehicle, it was readily converted into crystalline form and grown into aggregates, drastically lowering dissolution rate. However, the addition of HPMC polymer markedly suppressed the crystal growth, providing both improved drug stability and profound dissolution profile. Raman spectrometry denoted the inter-molecular hydrogen boding between MTK particle and HPMC polymer. The crystal growth or dissolution profile of MSs was markedly affected by pharmaceutical additives (sucrose or simethicone) in the preparations or storage temperature. The optimized HPMC-based MS exhibited over 80% higher bioavailability, compared to marketed granule (Singulair®) in rats. Therefore, novel MTK-loaded MS can be a promising liquid preparation, bettering oral absorption and patient's compliance.

Effect of Penetration Enhancers on Toenail Delivery of Efinaconazole from Hydroalcoholic Preparations.

The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-ß-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 °C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.

Current status of the development of intravesical drug delivery systems for the treatment of bladder cancer.

INTRODUCTION: Intravesical instillation is preferred over the systemic route of administration, as an efficient route of drug administration to treat bladder cancer. However, the periodic voiding of urine washes out the instilled drugs, eventually resulting in reduced drug exposure. Moreover, the presence of the bladder permeability barrier limits drug permeation into tumor tissues. It is therefore important to develop a novel delivery system that not only promotes prolonged retention of drugs in the bladder but also enables drugs to penetrate the barrier. AREAS COVERED: This review addresses the limitations of conventional therapeutic regimens and reports the use of polymeric hydrogels and nano/microcarriers for enhanced intravesical drug delivery in bladder cancer. Strategies to prolong residence time in the bladder and enhance cell penetration and target-cell specificity are discussed. EXPERT OPINION: Although promising results have been obtained in the field of intravesical drug delivery, numerous questions remain unanswered in terms of therapeutic efficacy. Specialized function covering extended drug exposure and/or enhanced drug uptake should be considered. Assessment protocols that adequately mimic the human bladder environment in vitro and in vivo experiments are needed to expedite formulation development.

Enhanced docetaxel delivery using sterically stabilized RIPL peptide-conjugated nanostructured lipid carriers: In vitro and in vivo antitumor efficacy against SKOV3 ovarian cancer cells.

Docetaxel (DTX) has poor solubility, low specificity, and severe side effects. For efficient targeting of DTX to hepsin-overexpressing SKOV3 ovarian cancer cells, PEGylated and RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (PEG-RIPL-NLCs) were examined for in vitro and in vivo antitumor efficacy. DTX-loaded plain NLCs (DTX-pNLCs), RIPL-NLCs (DTX-RIPL-NLCs), and PEG-RIPL-NLCs (DTX-PEG-RIPL-NLCs) were prepared using a solvent emulsification-evaporation technique. DTX was successfully loaded with high encapsulation efficiency (>93%), and all NLCs showed homogeneous dispersion with zeta potentials varying from -17 to 15 mV. Drug release was biphasic: initial rapid release, then gradual release. In vitro cytotoxicity was time- and dose-dependent: DTX-RIPL-NLCs and DTX-PEG-RIPL-NLCs exhibited greater cytotoxicity, enhanced cell apoptosis owing to the cell cycle arrest in the G2/M phase, and increased activation of the mitochondria-related intrinsic apoptosis pathway compared to DTX-pNLCs. Pharmacokinetic experiments in male Sprague-Dawley rats revealed that DTX-PEG-RIPL-NLCs increased the mean residence time of DTX but reduced total body clearance and volume of distribution. In a SKOV3-bearing xenograft Balb/c athymic mouse model, DTX-PEG-RIPL-NLCs suppressed tumors, evidenced by tumor volume change and histopathological examination. Thus, we conclude that PEG-RIPL-NLCs have an advantage of high payload of poorly water-soluble drugs and are a good candidate for drug targeting to SKOV3-derived ovarian cancer.