Chia Lang Fang

Nanostructured lipid carriers (NLCs) for drug delivery and targeting

Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated.

Transdermal delivery of selegiline from alginate–Pluronic composite thermogels

The present work was carried out to design a practical, controlled-release transdermal system for selegiline using thermosensitive hydrogels. The copolymers of alginate and Pluronic F127 (PF127) were used to design thermogels by either physical blending (A+P) or chemical grafting (AP). The thermogels were characterized in terms of the sol-gel temperature, scanning electron microscopy (SEM), degradation ratio, and skin permeation behavior. The chemical grafting of alginate to PF127 could delay the sol-gel temperature from 24.1 to 30.4°C, which is near the temperature of the skin surface. The gelling temperature of the physical mixture of alginate and PF127 (A+P) did not significantly differ. The porosity of the A+P structure was greater compared to that of the AP structure. AP thermogels were regularly degraded, with 60% of the gel matrix remaining after a 48-h incubation. PF127 and A+P hydrogels showed almost no degradation. The results of skin permeation across porcine skin and nude mouse skin suggested that the thermogels could produce sustained selegiline release, with AP showing the most-sustained permeation. AP hydrogels exhibited linear permeation properties for the transdermal delivery of selegiline. Inter-subject variations in skin permeation were reduced by incorporation of the thermogel. Such a thermosensitive hydrogel can be advantageous as a topical therapeutic formulation for selegiline.

Evaluation of drug and sunscreen permeation via skin irradiated with UVA and UVB: Comparisons of normal skin and chronologically aged skin

BACKGROUNDnUltraviolet (UV) exposure is the predominant cause of skin aging. A systematic evaluation of drug skin permeation via photoaged skin is lacking.nnnOBJECTIVESnThe aim of this work was to investigate whether UVA and UVB affect absorption by the skin of drugs and sunscreens, including tetracycline, quercetin, and oxybenzone.nnnMETHODSnThe dorsal skin of nude mice was subjected to UVA (24 and 39 J/cm(2)) or UVB (150, 200, and 250 mJ/cm(2)) irradiation. Levels of skin water loss, erythema, and sebum were evaluated, and histological examinations of COX-2 and claudin-1 expressions were carried out. Permeation of the permeants into and through the skin was determined in vitro using a Franz cell. In vivo skin uptake was also evaluated. Senescent skin (24 weeks old) was used for comparison.nnnRESULTSnWrinkling and scaling were significant signs of skin treated with UVA and UVB, respectively. The level of claudin-1, an indicator of tight junctions (TJs), was reduced by UVA and UVB irradiation. UVA enhanced tetracycline and quercetin skin deposition by 11- and 2-fold, respectively. A similar enhancement was shown for flux profiles. Surprisingly, a lower UVA dose revealed greater enhancement compared to the higher dose. The skin deposition and flux of tetracycline both decreased with UVB exposure. UVB also significantly reduced quercetin flux. The skin absorption behavior of chronologically aged skin approximated that of the UVA group, with photoaged skin showing higher enhancement. UV generally exhibited a negligible effect on modulating oxybenzone permeation.nnnCONCLUSIONSnSkin disruption produced by UV does not necessarily result in enhanced skin absorption. It depends on the UV wavelength, irradiated energy, and physicochemical properties of the permeant. To the best of our knowledge, this is the first report establishing drug permeation profiles for UV-irradiated skin.

Delivery and targeting of nanoparticles into hair follicles

It has been demonstrated that nanoparticles used for follicular delivery provide some advantages over conventional pathways, including improved skin bioavailability, enhanced penetration depth, prolonged residence duration, fast transport into the skin and tissue targeting. This review describes recent developments using nanotechnology approaches for drug delivery into the follicles. Different types of nanosystems may be employed for management of follicular permeation, such as polymeric nanoparticles, metallic nanocrystals, liposomes, and lipid nanoparticles. This review systematically introduces the mechanisms of follicles for nanoparticulate penetration, highlighting the therapeutic potential of drug-loaded nanoparticles for treating skin diseases. Special attention is paid to the use of nanoparticles in treating appendage-related disorders, in particular, nanomedical strategies for treating alopecia, acne, and transcutaneous immunization.

Systematic evaluations of skin damage irradiated by an erbium:YAG laser: histopathologic analysis, proteomic profiles, and cellular response.

BACKGROUNDnThe erbium:yttrium-aluminum-garnet (Er:YAG) laser is used for surgical resurfacing. It has ablative properties with water as its main chromophore.nnnOBJECTIVEnThis study attempted to establish the cutaneous effect and cellular response to Er:YAG laser irradiation using different fluences (7.5 and 15 J/cm(2)).nnnMETHODSnFemale nude mouse was used as the animal model in the study. Physiological parameters were examined and histology was evaluated at 4, 24 and 96 h after laser exposure. A proteomic analysis and immunoblotting were also used to determine the mechanisms of the lasers effect on the skin.nnnRESULTSnBoth fluences were associated with a significant increase in transepidermal water loss (TEWL), erythema (a*), and the skin pH at 4 and 24h. In contrast, at 96 h, the levels of these parameters had generally decreased to the baseline. The histology examined by light microscopy and transmission electron microscopy (TEM) showed vacuolization, hydropic degeneration and epidermal necrosis of laser-irradiated skin. The higher fluence (15 J/cm(2)) exhibited more-severe disruption of the skin. Bulous and scarring were observed in skin treated with the higher fluence during the recovery period. p53 and p21 proteins were significantly activated in skin following exposure to the laser. However, proliferating cell nuclear antigen and cytokeratin expressions were downregulated by the low fluence (7.5 J/cm(2)).nnnCONCLUSIONnBoth proliferation and apoptosis occurred when the laser-irradiated the skin.

The co-drug of conjugated hydroquinone and azelaic acid to enhance topical skin targeting and decrease penetration through the skin

A co-drug of hydroquinone (HQ) and azelaic acid (AA), bis(4-hydroxyphenyl)nonanedioate (BHN), was synthesized and investigated as a topical prodrug with the aim of improving the dermal delivery of the parent drugs. Physicochemical parameters were ascertained, and the enzymatic hydrolysis was examined. Skin permeation of HQ, AA, and BHN was studied by determining the skin deposition and flux across nude mouse skin under equivalent doses with the same thermodynamic activity. The partition coefficient (log P) of the co-drug increased by up to 5.0 with HQ and AA conjugation, which had respective log P values of 0.5 and 1.4. In the skin absorption experiment, BHN in ethanol/pH 7 buffer resulted in a 2-fold enhancement of skin deposition compared to both HQ and AA. With permeation using polyethylene glycol 400/pH 7 buffer as the vehicle, the co-drug, respectively, exhibited 8.1- and 1.4-fold enhancements of skin uptake compared to HQ and AA alone. The transdermal flux from BHN was negligible compared to those with HQ and AA treatments. The results of a preliminary safety evaluation showed no signs of stratum corneum disruption or erythema by BHN application within 24h. The co-drug approach provides a viable option for the treatment of skin hyperpigmentation of HQ and AA.

Activated human neutrophil response to perfluorocarbon nanobubbles: oxygen-dependent and -independent cytotoxic responses.

Nanobubbles, a type of nanoparticles with acoustically active properties, are being utilized as diagnostic and therapeutic nanoparticles to better understand, detect, and treat human diseases. The objective of this work was to prepare different nanobubble formulations and investigate their physicochemical characteristics and toxic responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP)-activated human neutrophils. The nanobubbles were prepared using perfluoropentane and coconut oil as the respective core and shell, with soybean phosphatidylcholine (SPC) and/or cationic surfactants as the interfacial layers. The cytotoxic effect of the nanobubbles on neutrophils was determined by extracellular O₂(.)⁻ release, intracellular reactive oxygen species (ROS), lactate dehydrogenase (LDH), and elastase release. Particle sizes of the nanobubbles with different percentages of perfluorocarbon, oil, and surfactants in ranged 186-432 nm. The nanobubbles were demonstrated to inhibit the generation of superoxide and intracellular ROS. The cytotoxicity of nanobubbles may be mainly associated with membrane damage, as indicated by the high LDH leakage. Systems with Forestall (FE), a cationic surfactant, or higher SPC contents exhibited the greatest LDH release by 3-fold compared to the control. The further addition of an oil component reduced the cytotoxicity induced by the nanobubbles. Exposure to most of the nanobubble formulations upregulated elastase release by activated neutrophils. Contrary to this result, stearylamine (SA)-containing systems slightly but significantly suppressed elastase release. FE and SA in a free form caused stronger responses by neutrophils than when they were incorporated into nanobubbles. In summary, exposure to nanobubbles resulted in a formulation-dependent toxicity toward human neutrophils that was associated with both oxygen-dependent and -independent pathways. Clinicians should therefore exercise caution when using nanobubbles in patients for diagnostic and drug targeting aims.

Hydroquinone-salicylic acid conjugates as novel anti-melasma actives show superior skin targeting compared to the parent drugs

BACKGROUNDnHydroquinone (HQ) and salicylic acid (SA) are drugs for treating melasma through the mechanisms of tyrosinase inhibition and chemical peeling, respectively. Their high frequency of causing skin irritation has led to limited use of both drugs.nnnOBJECTIVESnWe designed the new conjugates obtained by joining HQ and SA by the co-drug concept for evaluating cutaneous absorption capability.nnnMETHODSnMonoester (4-hydroxyphenyl 2-hydroxybenzoate, HPH) and diester (1,4-phenylene bis(2-hydroxybenzoate), PBH) forms of the conjugates were synthesized and physicochemically characterized. The enzymatic hydrolysis to the parent drugs was examined. Both an equimolar dose and a saturated solubility were utilized as the applied dose for testing cutaneous absorption via pig and nude mouse skins.nnnRESULTSnThe conjugates had higher lipophilicity, less aqueous solubility, and a lower melting point/crystallinity than the parent drugs. Both conjugates showed a quick conversion into the parent drugs in esterases and skin homogenates, with PBH showing the greater hydrolysis. The hydrolysis level in skin after topical application was less as compared to that in esterases and homogenates. The tyrosinase inhibition (%) and molecular docking demonstrated that the conjugates possessed skin-lightening capability (3% for HPH and 7% for PBH) although this activity was lower than that of HQ (23%). The conjugates showed an increased skin deposition compared to the respective parent drugs. Total absorption of HPH and PBH led to a 13- and 19-fold enhancement in cutaneous retention compared to HQ alone. A similar increment of skin deposition was shown for the conjugates when compared to SA. Contrary to skin reservoir retention, transdermal transport across the skin was decreased by the conjugates, especially for PBH. This indicates the maximization of cutaneous targeting by the conjugates.nnnCONCLUSIONSnTopically applied HPH and PBH can be the new candidates for treating melasma due to efficient skin absorption and acceptable skin tolerance.

Risk assessment of excess drug and sunscreen absorption via skin with ablative fractional laser resurfacing: Optimization of the applied dose for postoperative care

The ablative fractional laser is a new modality used for surgical resurfacing. It is expected that laser treatment can generally deliver drugs into and across the skin, which is toxicologically relevant. The aim of this study was to establish skin absorption characteristics of antibiotics, sunscreens, and macromolecules via laser-treated skin and during postoperative periods. Nude mice were employed as the animal model. The skin received a single irradiation of a fractional CO2 laser, using fluences of 4–10xa0mJ with spot densities of 100–400 spots/cm2. In vitro skin permeation using Franz cells was performed. Levels of skin water loss and erythema were evaluated, and histological examinations with staining by hematoxylin and eosin, cyclooxygenase-2, and claudin-1 were carried out. Significant signs of erythema, edema, and scaling of the skin treated with the fractional laser were evident. Inflammatory infiltration and a reduction in tight junctions were also observed. Laser treatment at 6xa0mJ increased tetracycline and tretinoin fluxes by 70- and 9-fold, respectively. A higher fluence resulted in a greater tetracycline flux, but lower skin deposition. On the other hand, tretinoin skin deposition increased following an increase in the laser fluence. The fractional laser exhibited a negligible effect on modulating oxybenzone absorption. Dextrans with molecular weights of 4 and 10xa0kDa showed increased fluxes from 0.05 to 11.05 and 38.54xa0μg/cm2/h, respectively. The optimized drug dose for skin treated with the fractional laser was 1/70–1/60 of the regular dose. The skin histology and drug absorption had recovered to a normal status within 2–3xa0days. Our findings provide the first report on risk assessment of excessive skin absorption after fractional laser resurfacing.

In vitro and in vivo percutaneous absorption of seleno- L -methionine, an antioxidant agent, and other selenium species

Aim:To investigate the in vitro and in vivo percutaneous absorption of seleno-L-methionine (Se-L-M), an ultraviolet (UV)-protecting agent, from aqueous solutions.Methods:Aqueous solutions of Se-L-M were prepared in pH 4, 8, and 10.8 buffers. The pH 8 buffer contained 30% glycerol, propylene glycol (PG) and polyethylene glycol (PEG) 400. The in vitro skin permeation of Se-L-M via porcine skin and nude mouse skin was measured and compared using Franz diffusion cells. The in vivo skin tolerance study was performed, which examined transepidermal water loss (TEWL), skin pH and erythema.Results:In the excised porcine skin, the flux was 0.1, 11.4 and 8.2 μg·cm−2·h−1 for the pH 4, 8, and 10.8 buffers, respectively. A linear correlation between the flux and skin deposition was determined. According to permeation across skin with different treatments (stripping, delipidation, and ethanol treatments), it was determined that the intracellular route comprised the predominant pathway for Se-L-M permeation from pH 8 buffer. Aqueous solutions of seleno-DL-methionine (Se-DL-M), selenium sulfide and selenium-containing quantum dot nanoparticles were also used as donor systems. The DL form showed a lower flux (7.0 vs 11.4 μg·cm−2·h−1) and skin uptake (23.4 vs 47.3 μg/g) as compared to the L form, indicating stereoselective permeation of this compound. There was no or only negligible permeation of selenium sulfide and quantum dots into and across the skin. With in vivo topical application for 4 and 8 h, the skin deposition of Se-L-M was about 7 μg/g, and values were comparable to each other. The topical application of Se-L-M for up to 5 d did not caused apparent skin irritation. However, slight inflammation of the dermis was noted according to the histopathological examination.Conclusion:Se-L-M was readily absorbed by the skin in both the in vitro and in vivo experiments. The established profiles of Se-L-M skin absorption will be helpful in developing topical products of this compound.