Nanomaterial Lipid-Based Carrier for Non-Invasive Capsaicin Delivery; Manufacturing Scale-Up and Human Irritation Assessment

Capsaicin is an active compound in chili peppers (Capsicum chinense) that has been approved for chronic pain treatment. The topical application of high-strength capsaicin has been proven to reduce pain; however, skin irritation is a major drawback. The aim of this study was to investigate an appropriate and scalable technique for preparing nanostructured lipid carriers (NLCs) containing 0.25% capsaicin from capsicum oleoresin (NLC_C) and to evaluate the irritation of human skin by chili-extract-loaded NLCs incorporated in a gel formulation (Gel NLC_C). High-shear homogenization with high intensity (10,000 rpm) was selected to create uniform nanoparticles with a size range from 106 to 156 nm. Both the NLC_C and Gel NLC_C formulations expressed greater physical and chemical stabilities than the free chili formulation. Release and porcine biopsy studies revealed the sustained drug release and significant permeation of the NLCs through the outer skin layer, distributing in the dermis better than the free compounds. Finally, the alleviation of irritation and the decrease in uncomfortable feelings following the application of the Gel NLC_C formulation were compared to the effects from a chili gel and a commercial product in thirty healthy volunteers. The chili-extract-loaded NLCs were shown to be applicable for the transdermal delivery of capsaicin whilst minimizing skin irritation, the major noncompliance cause of patients.     

Thermodynamic behavior of lipid nanoparticles upon delivery of Vitamin E derivatives into the skin: in vitro studies

This article reports the thermodynamic changes of lipid nanoparticles (LN) upon delivery of lipophilic vitamin E derivatives to the skin. Skin penetration of α-tocopherol (α-T) and α-tocopherol acetate (α-Ta) into and across porcine ear skin was investigated in vitro using tape-stripping test in modified Franz diffusion cells. Wide angle X-ray scattering (WAXS) and differential scanning calorimetry (DSC) have been used to characterize the polymorphism of the solid matrix of LN before and after in vitro skin penetration assay. Cetyl palmitate LN with a loading capacity of 20% of vitamin E derivatives (with regard to the lipid matrix) have shown the typical β’ modification of waxes, with a crystallinity index (%CI) between 30 and 40%. Mean particle size and shelf life stability was assessed by static (laser diffractometry, LD) and dynamic (photon correlation spectroscopy, PCS) light scattering techniques. Submicron-sized LN were produced, i.e., 99% of LN showed a size below 600 nm immediately after production. A mean size between 180 and 350 nm (polydispersity index < 0.25) was obtained for LN stored at both 8 and 22 °C, and this size range was kept constant for at least 20 days of shelf life. Quantification of α-T and α-Ta in the skin using tape-stripping provided a 3.4-fold increase in the level of actives within the stratum corneum (SC) and 1.3-fold increase in the viable epidermis (VE). LN increased skin penetration of both actives, following a cumulative release during 8 h in modified Franz diffusion cells. The differences in the distribution levels observed between α-T and α-Ta when delivered via LN was due to the different thermodynamic activity of both actives, i.e., following increased partition coefficient of α-Ta into SC and VE, in comparison to α-T.     

Topical Administration of Terpenes Encapsulated in Nanostructured Lipid-Based Systems

Terpenes are a group of phytocompounds that have been used in medicine for decades owing to their significant role in human health. So far, they have been examined for therapeutic purposes as antibacterial, anti-inflammatory, antitumoral agents, and the clinical potential of this class of compounds has been increasing continuously as a source of pharmacologically interesting agents also in relation to topical administration. Major difficulties in achieving sustained delivery of terpenes to the skin are connected with their low solubility and stability, as well as poor cell penetration. In order to overcome these disadvantages, new delivery technologies based on nanostructures are proposed to improve bioavailability and allow controlled release. This review highlights the potential properties of terpenes loaded in several types of lipid-based nanocarriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers) used to overcome free terpenes’ form limitations and potentiate their therapeutic properties for topical administration.     

Dual-labeled visual tracer system for topical drug delivery by nanoparticle-triggered P-glycoprotein silencing

Using nanoparticle-based drug delivery systems as enhancers is a robust strategy for transdermal delivery; however, the mechanisms by which these systems promote transdermal penetration are still unclear. Here, we fabricated a dual-labeled nano drug delivery system that allows discrete visualization of both the drug and the nanoparticle carrier. To comprehensively examine its potential mechanism, we investigated its effects on human epidermal keratinocyte HaCaT cells, including changes in cell membrane potential, intracellular Ca²⁺ concentration, and Ca²⁺-ATPase activity. P-glycoprotein (P-gp) expression in nanoparticle-treated human dermal microvascular endothelial cells was detected by western blotting and immunofluorescence. Furthermore, the transdermal absorption and biodistribution of the dual-labeled nanoparticles were deeply investigated by skin permeability study in vitro and in vivo using fluorescence microscopy and in vivo imaging, respectively. In addition to reducing membrane potential, increasing the intracellular Ca²⁺ concentration, and decreasing Ca²⁺-ATPase activity, our results indicate that the dual-labeled nanoparticles can downregulate P-gp to promote transdermal absorption. Fluorescence and in vivo imaging visually demonstrated that the nanoparticle delivery system penetrated into the dermis through the stratum corneum. All these results indicate that this dual-labeled nano delivery system provides a new method for future in-depth visual explorations of transdermal drug delivery mechanisms.     

Light-stimulus Dual-drug Responsive Nanoparticles for Photoactivated Therapy Using Mesoporous Silica Nanospheres

Photoactivated therapy is an exciting new method of cancer treatment. A new light-stimulus dual-drug responsive nanoparticles based on mesoporous silica nanoparticles(MSN) were developed to control cellular anticancer drug release. The prepared Curcumin(Cur)-loaded nanoparticles MSN-Pt-PEG@Cur[PEG=poly(ethylene glycol)] could be activated by photostimulation to generate reactive oxygen species(ROS) from Cur and Pt(Ⅱ) from Pt(IV), respectively. Compared with free anti-cancer drugs' chemotherapy and single photoactivated therapy, the prepared MSN-Pt-PEG@Cur displayed increased cytotoxicity. Therefore, the strategy of light-stimulus dual-drug responsive nanoparticles is a promising approach to photoactivated therapy.     

Aggregation of sodium dodecylsulfate in aqueous nitric acid medium

Curcumin (Cur) shows low anticancer activity in vivo due to its reduced systemic bioavailability stemmed from its poor aqueous solubility and instability. Suitably functionalized nanocarriers designed to empty the drug specifically at tumor sites can potentially enhance the antitumor activity of Cur. We devised a simple method for the fabrication of water soluble Cur conjugated gold nanoparticles to target various cancer cell lines. Cur was conjugated to hyaluronic acid (HA) to get a water soluble conjugate (HA-Cur). We generated gold nanoparticles (AuNPs) by reducing chloroauric acid using HA-Cur, which played the dual role of a reducing and stabilizing agent and subsequently anchored folate conjugated PEG. These entities were probed using different analytical techniques, assayed the blood compatibility and cytotoxicity. Their interaction with cancer cell lines (HeLa cells, glyoma cells and Caco 2 cells) was followed by flow cytometry and confocal microscopy. Blood-materials interactions studies showed that the nanoparticles are highly hemocompatible. Flow cytometry and confocal microscopy results showed significant cellular uptake and internalization of the particles by cells. HA-Cur@AuNPs exhibited more cytotoxicity comparing to free Cur. The strategy, we adopted here, resulted the formation blood compatible Cur conjugated AuNPs with enhanced targeting and improved efficacy.     

Dendritic Nanogels Directed Dual-Encapsulation Topical Delivery System of Antimicrobial Peptides Targeting Skin Infections

Antimicrobial peptides (AMPs) are promising antibacterial agents in the fight against multidrug resistant pathogens. However, their application to skin infections is limited by the absence of a realizable topical delivery strategy. Herein, a hybrid hierarchical delivery system for topical delivery of AMPs is accomplished through the incorporation of AMPs into dendritic nanogels (DNGs) and their subsequent embedding into poloxamer gel. The high level of control over the crosslink density and the number of chosen functionalities makes DNGs ideal capsules with tunable loading capacity for DPK-060, a human kininogen-derived AMP. Once embedded into the poloxamer gel, DPK-060 encapsulated in DNGs displays a slower release rate compared to those entrapped directly in the gels. In vitro EpiDerm Skin Irritation Tests show good biocompatibility, while MIC and time-kill curves reveal the potency of the peptide toward Staphylococcus aureus. Anti-infection tests on ex vivo pig skin and in vivo mouse infection models demonstrate that formulations with 0.5% and 1% AMPs significantly inhibit the growth of S. aureus. Similar outcomes are observed for an in vivo mouse surgical site infection model. Importantly, when normalizing the bacteria inhibition to released/free DPK-060 at the wound site, all formulations display superior efficacy compared to DPK-060 in solution.     

Cytoplasmic delivery of quantum dots via microelectrophoresis technique

Nanoparticles with specific properties and functions have been developed for various biomedical research applications, such as in vivo and in vitro sensors, imaging agents and delivery vehicles of therapeutics. The development of an effective delivery method of nanoparticles into the intracellular environment is challenging and success in this endeavor would be beneficial to many biological studies. Here, the well-established microelectrophoresis technique was applied for the first time to deliver nanoparticles into living cells. An optimal protocol was explored to prepare semiconductive quantum dots suspensions having high monodispersity with average hydrodynamic diameter of 13.2–35.0 nm. Micropipettes were fabricated to have inner tip diameters of approximately 200 nm that are larger than quantum dots for ejection but less than 500 nm to minimize damage to the cell membrane. We demonstrated the successful delivery of quantum dots via small electrical currents (–0.2 nA) through micropipettes into the cytoplasm of living human embryonic kidney cells (roughly 20–30 μm in length) using microelectrophoresis technique. This method is promising as a simple and general strategy for delivering a variety of nanoparticles into the cellular environment.     

Development of a Microfluidic Formatted Ultrasound-Controlled Monodisperse Lipid Vesicles' Hydrogel Dressing Combined with Ultrasound for Transdermal Drug Delivery System

Transdermal drug delivery system (TDDS) has attracted much attention in the pharmaceutical technology area. However, the current methods are difficult to ensure penetration efficiency, controllability, and safety in the dermis, so its widespread clinical use has been limited. This work proposes an ultrasound-controlled monodisperse lipid vesicles (U-CMLVs) hydrogel dressing, which combines with ultrasound to form TDDS. Using microfluidic technology, prepare size controllable U-CMLVs with high drug encapsulation efficiency and quantitative encapsulation of ultrasonic response materials, and even uniform mix them with hydrogel to prepare the required thickness of dressings. The high encapsulation efficiency can ensure sufficient dosage of the drugs and further realize the control of ultrasonic response through quantitative encapsulation of ultrasound-responsive materials. Using high frequency (5 MHz, 0.4 W cm⁻²) and low frequency (60 kHz, 1 W cm⁻²) ultrasound to control the movement and rupture of U-CMLVs, the contents not only penetrate the stratum corneum into the epidermis but also break through the bottleneck of penetration efficiency, and deep into the dermis. These findings provide the groundwork for deep, controllable, efficient, and safe drug delivery through TDDS and lay a foundation for further expanding its application.     

Dead Sea Minerals loaded polymeric nanoparticles

Therapeutic properties of Dead Sea Water (DSW) in the treatment of skin diseases such as atopic dermatitis, psoriasis and photo aging UV damaged skin have been well established. DSW is in fact rich in minerals such as calcium, magnesium, sodium, potassium, zinc and strontium which are known to exploit anti-inflammatory effects and to promote skin barrier recovery. In order to develop a Dead Sea Minerals (DSM) based drug delivery system for topical therapy of skin diseases, polymeric nanoparticles based on Poly (maleic anhydride-alt-butyl vinyl ether) 5% grafted with monomethoxy poly(ethyleneglycol) 2000 MW (PEG) and 95% grafted with 2-methoxyethanol (VAM41-PEG) loaded with DSM were prepared by means of a combined miniemulsion/solvent evaporation process. The resulting nanoparticles were characterized in terms of dimension, morphology, biocompatibility, salt content and release. Cytocompatible spherical nanoparticles possessing an average diameter of about 300 nm, a time controlled drug release profile and a high formulation yield were obtained.     

Oral delivery of polyester nanoparticles for brain-targeting: Challenges and opportunities

Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance; and(4) restriction by the BBB. Then the key factors infl...     

Dispersive liquid–liquid microextraction as an effective preanalytical step for the determination of estradiol in human urine

In this work, a fast and effective dispersive liquid–liquid microextraction was developed for the isolation and preconcentration of free 17 β‐estradiol, the main human estrogen, from real human urine samples. To optimize the extraction technique, few important parameters such as type and volume of extraction and dispersive solvents, centrifugation conditions, effect of salt addition, and extraction time were studied. Optimal conditions were obtained when injecting 600 μL mixture of tetrachloromethane as extraction solvent and ethanol as dispersive solvent (1:5, v/v) into 2 mL of urine containing 8% NaCl and following centrifugation at 10 000 rpm, thus reaching enrichment factor 28 and extraction recovery 98% for estradiol. Procedure was evaluated by means of high‐performance liquid chromatography with UV detection (λ = 280 nm) using a C‐18 column and methanol/water (60:40, v/v) as the mobile phase. The method was linear within the concentration range 1.0–250.0 mg/L (r  = 0.9997) and provided a limit of detection of 0.25 mg/L. The proposed method was applied to the determination of free estradiol in real human pregnancy urine.     

Penetration of drugs through skin,a complex rate-controlling membrane

Penetration of molecules and particles inside and through skin has long been well documented but it now merits renewed attention as a result of new areas of concern such as transdermal therapies, safety of cosmetic products, penetration of environmental compounds and skin decontamination.The topic is complex as skin structure is heterogeneous and because there are a number of penetration routes through the stratum corneum barrier: the intercellular, intracellular and follicular pathways. Recent advances in the study of penetration mechanisms deal with the control of the intercellular penetration route by the crystalline state of lipids, and the penetration through skin appendages (the follicular pathway) that appears to contribute much more than was previously thought.Applications dependent on skin penetration that have received special attention include transdermal delivery of nano- and microparticles by hair follicles, targeting of the skin immune system in order to develop new vaccination strategies, and problems relating to the risk assessment of nanoparticles and skin decontamination.     

Development of different temoporfin-loaded invasomes—novel nanocarriers of temoporfin: Characterization, stability and in vitro skin penetration studies

A previous study revealed that the invasome dispersion containing 3.3% (w/v) ethanol and 1% (w/v) of the terpene mixture (cineole:citral:d-limonene = 45:45:10, v/v = standard mixture) could significantly enhance skin penetration of the highly hydrophobic photosensitizer temoporfin (mTHPC). Invasomes enhanced mTHPC-deposition in stratum corneum (SC) compared to liposomes without terpenes and conventional liposomes, and they were efficient in delivering mTHPC to deeper skin layers [J. Control. Release 127 (2008) 271–280]. The aim of this study was to develop new mTHPC-loaded invasomes in order to further enhance the drug penetration. The ratio between d-limonene, citral and cineole was varied in the standard terpene mixture and also single terpenes were used. As a result new mTHPC-loaded invasome dispersions were prepared, characterized and investigated for stability and in vitro penetration of mTHPC into abdominal human skin using Franz diffusion cells.Invasomes were of a small particle size (<150 nm), high homogeneity (<0.3), mostly unilamellar and spherical, but also deformed vesicles were detected. Invasomes containing 1% (w/v) cineole provided the highest skin penetration enhancement of mTHPC, i.e. they provided high amounts of mTHPC in the SC and deeper skin layers, indicating that also incorporation of a single terpene into invasomes could provide efficient nanocarriers of mTHPC. These invasomes could be considered as a promising tool for delivering the photosensitizer mTHPC to the skin.However, in contrast to most invasomes, being effective nanocarriers of mTHPC, there were also formulations less effective than liposomes containing 3.3% (w/v) ethanol and one formulation was less efficient than conventional liposomes.     

Inhibitory effects of silk protein, sericin on UVB-induced acute damage and tumor promotion by reducing oxidative stress in the skin of hairless mouse

This study was conducted to assess protective effect of an antioxidant protein, sericin, on UVB-induced acute damage and tumor promotion in mouse skin. In experiment 1, HR-1 hairless mice were treated with 180 mJ/cm2 of ultraviolet B light (UVB) once daily for 1 and 7 days. The treatment for 7 days caused red sunburn lesions of the skin. The intensity of red color and area of these lesions were inhibited by the topical application of sericin at the dose of 5 mg after UVB treatment. Immunohistochemical analyses showed that the application of sericin significantly suppressed UVB-induced elevations in 4-hydroxynonenal (4-HNE), expression of cyclooxygenase-2 (COX-2) protein, and proliferating cell nuclear antigen (PCNA)-labeling index in the UVB-exposed epidermis. In experiment 2, HR-1 hairless mice were treated with 200 nmol of 7,12-dimethylbenz [alpha] anthracene (DMBA) followed 1 week later by irradiation with 180 mJ/ cm2 of UVB twice weekly for 22 weeks. The protective effect of sericin was evident in terms of significant reduction in tumor incidence and tumor multiplicity at the dose of 5 mg. The results suggest that sericin possesses photoprotective effect against UVB-induced acute damage and tumor promotion by reducing oxidative stress, COX-2 and cell proliferation in mouse skin.     

A Nanomedicine-Enabled Ion-Exchange Strategy for Enhancing Curcumin-Based Rheumatoid Arthritis Therapy

Curcumin (Cur) has been clinically used for rheumatoid arthritis treatment by the means of reactive oxygen species (ROS) scavenging and immune microenvironment regulation. However, this compound has a poor water solubility and moderate antioxidative activity, favoring no further broadened application. Metal complexes of curcumin such as zinc-curcumin (Zn−Cur) features enhanced water solubilities, while copper-curcumin (Cu−Cur) shows a higher antioxidant activity but lower solubility than Zn−Cur. Based on their inherent biological properties, this work proposes a nanomedicine-based ion-exchange strategy to enhance the efficacy of Cur for rheumatoid arthritis treatment. Copper silicate nanoparticles with hollow mesoporous structure were prepared to load water-soluble Zn−Cur for constructing a composite nanomedicine, which can degrade in acidic microenvironment of arthritic region, releasing Cu²⁺ and Zn−Cur. Cu²⁺ then substitute for Zn²⁺ in Zn−Cur to form Cu−Cur with a significantly enhanced antioxidative effect, capable of efficiently scavenging ROS in M1 macrophages, promoting their transition to an anti-inflammatory M2 phenotype. In addition, the silicate released after nanocarrier degradation and the Zn²⁺ released after ion exchange reaction synergistically promote the biomineralization of osteoblasts. This work provides a new approach for enhancing the antiarthritic effect of Cur via an ion-exchange strategy.     

A Novel Methacryloyl Chitosan Hydrogel Microneedles Patch with Sustainable Drug Release Property for Effective Treatment of Psoriasis

Psoriasis is a chronic and recurrent skin disease that often requires long-term treatment, and topical transdermal drug delivery can reduce systemic side effects. However, it is still a challenge in efficient transdermal drug delivery for psoriasis treatment due to low penetration efficiency of most drugs and the abnormal skin conditions of psoriasis patients. Here, a safe and effective methacryloyl chitosan hydrogel microneedles (CSMA hMNs) patch is developed and served as a sustained drug release platform for the treatment of psoriasis. By systematically optimizing the CSMA preparation, CSMA hMNs with excellent morphological characteristics and strong mechanical properties (0.7 N needle⁻¹) are prepared with a concentration of only 3% (w/v) CSMA. As a proof-of-concept, methotrexate (MTX) and nicotinamide (NIC) are loaded into CSMA hMNs patch, which can produce a sustained drug release of 80% within 24 h in vitro. In vivo experiments demonstrated that the CSMA hMNs patch can effectively inhibit the skin thickening and spleen enlargement of psoriatic mice and has a good biosafety profile at sufficient therapeutic doses. This study provides a new idea for the preparation of hMN systems using modified CS or other biocompatible materials and offers an effective therapeutic option for psoriasis treatment.     

Topical application of Scutellaria baicalensis suppresses 2,4-dinitrochlorobenzene-induced contact dermatitis

Allergic contact dermatitis (ACD) is a prototypic T-cell-mediated cutaneous inflammatory response. In the present study we describe the anti-allergic effect of topically applied Scutellaria bacalensis aqueous extract (WSBE) in suppressing 2,4-dinitrochlorobenzene (DNCB)-induced ACD in BALB/c mice. Topically applied WSBE attenuated the epidermal thickness and mast cell infiltration into the skin in DNCB-induced contact dermatitis. Furthermore, WSBE suppressed DNCB-induced production of serum IgE as well as IL-4, IFN-γ, and TNF-α in the skin. Topical application of WSBE also ameliorated the significant decrease in dermal glutathione and superoxide dismutase levels. Moreover, present results demonstrated that the baicalin, bioactive compound of WSBE, was able to penetrate into the skin following topical application, which was confirmed by the HPLC analysis using rat model. Taken together, topical application of WSBE exerts beneficial effects in contact dermatitis model, suggesting that WSBE might be a candidate for the treatment of contact dermatitis.     

Electroporation-mediated topical delivery of vitamin C for cosmetic applications.

It is now medically recognized that sagging skin and other signs of degenerative skin conditions, such as wrinkles and age spots, are caused primarily by oxy-radical damage. Vitamin C (Vit. C), in the form of L-ascorbic acid (Asc), is the one vitamin that can accelerate wound healing, protect fatty tissues from oxidation damage, and play an integral role in collagen synthesis. It is known that the lipid-rich stratum corneum (SC) is a highly resistant barrier to chemical agents penetrating into the skin. This report describes the first feasibility study of electroporation-mediated topical delivery (EMTD) of Asc for potential cosmetic applications. Both a cream formulation (20% Asc) and a crystal suspension (33% Asc) were applied respectively to human cadaver skin and fresh surgical skin. Six exponential pulses at 60 or 100 V and pulse lengths of 2.7-30 ms were selected. EMTD was more effective on fresh human skin than on human cadaver skin. For both skin models, EMTD with cream resulted in a greater enhancement of Vit. C penetration than with suspension. The distribution of electrical fields through the SC, epidermis, and dermis is demonstrated in computer simulation. Assuming that this fresh skin model and certain experimental conditions simulate projected in vivo applications, EMTD of Vit. C may represent an alternative method to ameliorate skin aging.     

Improved Dermal and Transdermal Delivery of Curcumin with SmartFilms and Nanocrystals

Poor aqueous solubility of active compounds is a major issue in today’s drug delivery. In this study the smartFilm-technology was exploited to improve the dermal penetration efficacy of a poorly soluble active compound (curcumin). Results were compared to the dermal penetration efficacy of curcumin from curcumin bulk suspensions and nanocrystals, respectively. The smartFilms enabled an effective dermal and transdermal penetration of curcumin, whereas curcumin bulk- and nanosuspensions were less efficient when the curcumin content was similar to the curcumin content in the smartFilms. Interestingly, it was found that increasing numbers of curcumin particles within the suspensions increased the passive dermal penetration of curcumin. The effect is caused by an aqueous meniscus that is created between particle and skin if the dispersion medium evaporates. The connecting liquid meniscus causes a local swelling of the stratum corneum and maintains a high local concentration gradient between drug particles and skin. Thus, leading to a high local passive dermal penetration of curcumin. The findings suggest a new dermal penetration mechanism for active compounds from nano-particulate drug delivery systems, which can be the base for the development of topical drug products with improved penetration efficacy in the future.