Skin Penetration Experiments Research Articles

Mechanics of dissolving microneedles insertion into the skin: Finite element and experimental analyses

AbstractTransdermal drug delivery using dissolving microneedles (DMNs) is promising due to increased patient compliance and safety. This article presents a comprehensive simulation and experimental analysis of DMNs with varying tip and base diameters and polymers. The objective of the simulation study is to identify the optimal tip and base diameter of DMNs, as well as the most suitable polymer, for achieving maximum penetration depth. The simulation results showed that the compound consisting of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) in a ratio of 2:1, with a tip radius of 17.5 μm and a base radius of 150 μm, achieved the deepest penetration among the different types of polymers investigated (including PVA, hyaluronic acid (HA), and PVA/PVP in ratios of 1:1 and 1:2). In addition, mechanical and skin penetration experiments were performed on PVA/PVP 2:1 DMNs with varying concentrations of 4, 7, 10, and 15% w/w to determine the optimal polymer concentration. The results of this study indicated that the optimal composition, considering the viscosity of the polymer solution and the simplicity of filling the silicone negative molds, is a PVA/PVP 2:1 with a concentration of 7% w/w.

A Compound Essential Oil Alters Stratum Corneum Structure, Potentially Promoting the Transdermal Permeation of Hydrophobic and Hydrophilic Ingredients.

The stratum corneum (SC) is the main barrier of the skin, and cosmeceuticals are different from ordinary cosmetics in that they need to deliver active ingredients targeting specific skin problems through the SC into the deeper layers of the skin. Thus, we designed a compound essential oil (CEO) extracted from Salvia miltiorrhiza Bge and Cinnamomum cassia Presl, supplemented with borneol to deliver active ingredients through the SC. The CEO was prepared by flash extraction combined with the microwave method. Moreover, the main components of the CEO were determined using gas chromatography-mass spectrometry (GCMS). Visualization techniques, such as scanning electron microscopy (SEM), haematoxylin-eosin (HE) staining, and confocal laser scanning microscopy (CLSM), were used to study the permeationpromoting mechanism of the CEO on the skin. Furthermore, the permeation-promoting effects of the CEO on both hydrophobic and hydrophilic ingredients were tested via in vitro skin penetration experiments and in vivo microdialysis experiments. The results indicated the ability of the CEO to alter the structure of the SC, leading to enhanced transdermal permeation of hydrophobic and hydrophilic ingredients. The 1.5% CEO group demonstrated the best permeation-promoting effect compared to the other CEO groups and blank groups (P<0.05). Furthermore, the CEO displayed an expedited permeability-promoting effect on hydrophobic ingredients compared to hydrophilic ingredients. It is concluded that the prepared CEO can promote the transdermal permeation of hydrophobic and hydrophilic ingredients. This study will provide a reference for the application of the prepared CEO in the development of cosmeceuticals with natural efficacy.

Study of the skin-penetration promoting effect and mechanism of combined system of curcumin liposomes prepared by microfluidic chip and skin penetrating peptides TD-1 for topical treatment of primary melanoma

The transdermal drug delivery system (TDDS) is an effective strategy for the treatment of melanoma with fewer side effects and good biocompatible, but the skin penetration of drugs should be further promoted. Here, we proposed a new system that combined curcumin liposomes (Cur-Lips) with skin-penetrating peptides to promote skin penetration ability. However, the preparation of Cur-Lips has drawbacks of instability and low entrapment efficiency by the traditional methods. We thus innovatively designed and applied a microfluidic chip to optimize the preparation of Cur-Lips. Cur-Lips exhibited a particle size of 106.22 ± 4.94 nm with a low polydispersity index (＜0.3) and high entrapment efficiency of 99.33 ± 1.05 %, which were prepared by the microfluidic chip. The Cur-Lips increased the skin penetration capability of Cur by 2.76 times compared to its solution in vitro skin penetration experiment. With the help of skin-penetrating peptide TD-1, the combined system further promoted the skin penetration capability by 4.48 times. The (TD-1 + Cur-Lips) system also exhibited a superior inhibition effect of the tumor to B16F10 in vitro. Furthermore, the topical application of (TD-1 + Cur-Lips) gel suppressed melanoma growth in vivo, and induced tumor cell apoptosis in tumor tissues. The skin-penetration promotion mechanism of the system was investigated. It was proved that the system could interact with the lipids and keratin on the stratum corneum to promote the Cur distribute into the stratum corneum through hair follicles and sweat glands. We proved that the microfluidic chips had unique advantages for the preparation of liposomes. The innovative combined system of liposomes and biological transdermal enhancers can effectively promote the skin penetration effect of drugs and have great potential for the prevention and treatment of melanoma.

A matrine-based supramolecular ionic salt that enhances the water solubility, transdermal delivery, and bioactivity of salicylic acid

Salicylic acid (H[Sal]) is an attractive bionic acid that is widely used in cosmetics and drugs for the treatment of skin diseases, owing to its excellent anti-acne, anti-inflammatory, antibacterial, oil-control, stratum-corneum-conditioning, and anti-photoaging abilities. However, H[Sal] is a relatively strong irritant and cannot be used on sensitive skin, and its poor water solubility limits the amounts that can be included in formulas, resulting in poor transdermal efficiency and bioavailability. In this study, we develop matrinium salicylate ([Mat][Sal]), a supramolecular ionic salt that is less cytotoxic and irritates the skin less than H[Sal], while exhibiting enhanced water-solubility, transdermal-delivery, and bioactivity properties. The anticancer, antioxidant, anti-inflammatory, and antibacterial properties of [Mat][Sal] are found to be superior or comparable to those of H[Sal]. The molecular structure of [Mat][Sal] is thoroughly investigated, including through single-crystal structure refinement, to gain an in-depth understanding of its properties. Moreover, in-vitro skin penetration experiments show that forming a salt with matrine increase the transdermal efficiency of H[Sal] while not damaging the skin barrier. The transdermal mechanisms of H[Sal] and [Mat][Sal] are studied both experimentally and using molecular dynamics simulations, which show that, compared to H[Sal], [Mat][Sal] reacts more strongly with the skin, and [Sal]− diffuses more rapidly in the skin owing to its higher water solubility and the ion-pair effect. Furthermore, [Mat][Sal] exhibits satisfactory anti-acne capabilities in a clinical-efficacy trial, highlighting its great potential for use in biomedical and cosmetics applications.

Biodegradable Polymeric Pharmaceutical Nanoemulgel Coloaded with Eucalyptol‐Lornoxicam: Fabrication and Characterizations for Possible Better Pain Management

Nanoemulgels are considered as potential and ideal drug delivery systems for the transdermal administration of poorly soluble drugs like lornoxicam. Their intrinsic characteristics, such as small globule size as well as excipient type, make transdermal passage of the drug easier. The current study was aimed at developing nanoemulgel based formulation of lornoxicam coloaded with eucalyptol to enhance drug skin permeation and bioavailability in order to promote therapeutic outcome in appropriate time. High shear homogenization technique was utilized to develop optimized lornoxicam encapsulated nanoemulsion followed by its conversion into nanoemulgel formulation by the addition of 1% Carbopol 940 as gelling agent. Different characterization tests were performed on optimized formulation such as surface charge, particle size and size distribution, viscosity, spreadability, pH, drug content determination, drug entrapment efficiency, in vitro drug release, and drug permeation analysis. The optimized formulation had globule size of 143.7 ± 2.18 nm. The results of drug entrapment efficiency, in vitro drug release, and skin penetration experiments were found satisfactory. Based on the formulation type, permeability parameters such as permeability constant (Kp), enhancement ratio (Er), and steady state flux (Jss) revealed greater values and satisfactory outcomes. When compared to other formulations (LRX nanoemulgel and EU nanoemulgel), the LRX‐EU nanoemulgel formulation produced improved skin permeation profile (flux, 189.63 ± 7.68 μg/cm2/h; permeability coefficient, 2.09 ± 0.067 cm/h; and ER, 4.274). This work clearly proved that lornoxicam coloaded with eucalyptol nanoemulgel formulations could be developed to generate stable drug delivery systems. Thus, LRX‐EU NEG formulation seems promising in terms of physicochemical properties, enhanced bioavailability, and high skin penetration profile as compared to LRX NEG formulation.

The anti-aging activity of Lycium barbarum polysaccharide extracted by yeast fermentation: In vivo and in vitro studies

Lycium barbarum polysaccharide (LBP) is an important active substance in Lycium barbarum. In this study, LBP was extracted by the hot water method and yeast fermentation method to obtain products called LBP-W and LBP-Y, respectively. Both LBPs have a strong ability to scavenge DPPH, hydroxyl, and superoxide anion free radicals and have a total antioxidant capacity. Both LBPs prolong the lifespan of C. elegans under normal conditions, oxidative stress and heat stress and do not affect fertility, LBPs could prolong the lifespan of C. elegans by upregulating the expression of daf-16, sod-3 and hsp-16.2 genes, and LBP-Y is more efficacious. The molecular weight of the LBPs was characterized by gel permeation chromatography (GPC), and the results showed that LBP-Y is smaller and more uniform than LBP-W. The skin penetration experiment showed that the absorption effect of LBP-Y is better than that of LBP-W. These lines of evidence suggest that the yeast fermentation extraction of LBP produces better antioxidant and anti-aging effects than those obtained with the traditional hot water extraction, which is more suitable for obtaining raw materials with anti-aging functions that can potentially be used in the food and cosmetic industries.

Interactions of hydrophobically modified hyaluronan carrier with bovine serum albumin

The interactions of carrier systems with serum proteins complicate their performance in medical applications. Although interactions of proteins with native hyaluronan (HA) have been investigated, there is little known about the interactions of its derivatives. The interactions of the oleyl derivative of HA (oleyl-HA) with bovine serum albumin (BSA) were investigated using various physicochemical techniques to understand processes and structural changes at the molecular level. The response of used techniques could be divided into three regimes according to an interplay of hydrogen bonding, electrostatic, and hydrophobic interactions at certain BSA to oleyl-HA molar ratios. The hydrophobic interactions led to the incorporation of BSA into the carriers' structure resulting the formation of hybrid BSA-oleyl-HA nanostructures with increased curcumin loading. The structural changes were correlated with skin penetration experiments, which showed decreased penetration efficiency due to altered interfacial behavior of the hybrid nanostructures. The oleyl-HA carriers' ability to carry significant amounts of a hydrophobic active compound was preserved at both low and high amounts of BSA. The results provided important information about the complex behavior of hydrophobically modified HA derivatives in a biological environment. Acquired findings could accelerate the implementation of HA derivatives as drug delivery systems.

Follicular-targeted delivery of spironolactone provided by polymeric nanoparticles

This study proposes developing a topical formulation based on poly-ε-caprolactone (PCL) or methacrylic acid/methyl methacrylate copolymer (EL100) nanoparticles to enable a safer and more effective therapy of alopecia and acne with spironolactone. The effect of the size of the nanoparticle on follicular-targeted drug delivery is also verified. Compatibility studies based on thermal analyses and complementary techniques showed a small interaction of the drug with excipients, which may not compromise the drug stability. PCL nanoparticles of 180.0 ± 1.6 and 126.8 ± 1.0 nm, and EL100 nanoparticles of 102.7 ± 7.1 nm were then prepared. All nanoparticles entrapped more than 75 % of spironolactone, were physically stable, and stabilized the drug for at least 90 days. They were also non-irritant according to HET-CAM tests. Drug release from the nanoparticles was reduced in aqueous buffer media but fast when in contact with oil. Finally, in vitro skin penetration experiments revealed the largest nanoparticles (of 180 nm) targeted drug delivery to the hair follicles 5-fold (p < 0.05) more than the control solution, 2.1-fold (p < 0.05) more than nanoparticles produced with the same polymer (PCL) but with smaller size (123 nm), and 4.9-fold (p < 0.05) more than the 102-nm E100 nanoparticles. In conclusion, follicular targeting can be adjusted according to nanoparticle size, and this work succeeded in obtaining polymeric nanoparticles adequate to enable topical treatment of acne and alopecia with spironolactone.

PLGA based film forming systems for superficial fungal infections treatment

As proven in clinical trials, superficial fungal infections can be effectively treated by single topical application of terbinafine hydrochloride (Ter-HCl) in a film forming system (FFS). Poly(lactic-co-glycolic acid) (PLGA) derivatives, originally synthesized with intention to get carriers with optimized properties for drug delivery, and multifunctional plasticizers - ethyl pyruvate, methyl salicylate, or triacetin - were used for formulation of Ter-HCl loaded FFSs. After spraying, a biodegradable, transparent, adhesive, and occlusive thin layer is formed on the skin, representing drug depot. In situ formed films were characterized by thermal, structural, viscoelastic, and antifungal properties as well as drug release and skin penetration. DSC and SEM showed fully amorphous films with Ter-HCl dissolved in PLGA in high concentration (up to 15%). FFSs are viscoelastic fluids with viscosity which can be easily adjusted by the type of plasticizer used and its concentration. The formulations showed excellent bioadhesion properties, thus ensuring persistence on the skin. In situ film based on branched PLGA/A plasticized with 10% of ethyl pyruvate allowed prolonged release of Ter-HCl by linear kinetics for the first 6 days with a total time of almost 14 days. During ex vivo human skin penetration experiment, Ter-HCl was found to be located only in its target layer, the epidermis. According to our results, plasticized branched PLGA derivatives loaded by Ter-HCl are suitable for the development of FFSs for superficial fungal infections treatment.

Formulation of Liposomes Containing Royal Jelly and Their Quality Assessment.

Royal jelly, a gelatinuous consistency bee product produced and secreted by the hypopharyngeal and mandibular glands of worker honeybees, is beneficial in the treatment of dermatological conditions, likely through its content of the fatty acid 10-hydroxy-2-decenoic acid (10-HDA). However, 10-HAD poorly penetrates into skin. Thus, in this work, we produced royal jelly incorporated liposomes with the aim of increasing skin penetration of 10-HDA. Lipid nanocarriers were prepared by the thin lipid-film hydration method. Size and polydispersity index of the nanocarrier particles, and their stability over 30 days were measured. The effects of royal jelly and 10-HDA liposomal formulations on the viability of immortalized human keratinocyte cells were tested with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The skin penetration of 10-HDA from liposomal formulations and royal jelly solution was studied in vitro with Franz type vertical diffusion cells using porcine skin as limiting membrane. As result, small liposomes were achieved, and the efficacy of the obtained nanoformulations was examined by means of in vitro cell assays with a HaCaT immortalized human keratinocyte cell culture line. Finally, the skin penetration experiments showed that liposomal incorporation greatly increased 10-HDA penetration into skin layers.

Dissolving microneedles for transdermal delivery of huperzine A for the treatment of Alzheimer's disease

Increasingly attention has been paid to the transdermal drug delivery systems with microneedles owing to their excellent compliance, high efficiency, and controllable drug release, therefore, become promising alternative with tremendous advantages for delivering specific drugs such as huperzine A (Hup A) for treatment of Alzheimer’s disease (AD) yet with low oral bioavailability. The purpose of the present study is to design, prepare, and evaluate a dissolving microneedle patch (DMNP) as a transdermal delivery system for the Hup A, investigating its in vitro drug release profiles and in vivo pharmacokinetics as well as pharmacodynamics treating of AD. Skin penetration experiments and intradermal dissolution tests showed that the blank DMNP could successfully penetrate the skin with an adequate depth and could be quickly dissolved within 5 min. In vitro transdermal release tests exhibited that more than 80% of the Hup A was accumulatively permeated from DMNP through the skin within three days, indicating a sustained release profile. In vivo pharmacokinetic analysis demonstrated that the DMNP group resulted in longer T max (twofold), longer t 1/2 (fivefold), lower C max (3:4), and larger AUC(0–∞) (twofold), compared with the oral group at the same dose of Hup A. Pharmacodynamic research showed a significant improvement in cognitive function in AD rats treated with DMNP-Hup A and Oral-Hup A, as compared to the model group without treatment. Those results demonstrated that this predesigned DMNP is a promising alternative to deliver Hup A transdermally for the treatment of AD.

Use of a Simple in vitro Test to Assess Loss of Chemical due to Volatility during an in vitro Human Skin Absorption Study

Background: We tested the cutaneous distribution of 50 chemicals in frozen human skin. The mass balance (MB) values for 48% of the chemicals were < 90%, possibly due to evaporation. Methods: We confirmed the reduction in MB was due to evaporation for two chemicals tested in skin penetration experiments using a carbon filter above the skin to trap airborne chemical. An in vitro assay was used to predict the reduction in MB due to evaporation by comparing the recovery of chemicals after 4 h of incubation at room temperature in open and closed vials. Results: Evaporative losses in vitro correlated well with measured MBs (i.e., < 90%) in skin penetration experiments (R² = 0.81). There was a correlation of the MB with the vapour pressure (VP) which could be used to group chemicals according to their likelihood to evaporate during the course of a skin penetration study. There was also a correlation of MB with Henry’s law constants, melting and boiling points. Conclusion: Our data support the use of a quick and simple test for volatility to account for the loss of MB in skin penetration experiment due to volatility. The best parameter to indicate the potential of a chemical to evaporate is the VP.

Core–shell‐type polymer–lipid nanoparticles for the transdermal delivery of daidzein

Daidzein (DZ) is an ideal Chinese herb for treating cardiocerebrovascular disease. Despite its poor water solubility and limited application, DZ was successfully loaded, along with penetration enhancer azone, onto core–shell-type polymer–lipid nanoparticles through a two-step preparation method. The mean particle diameter, encapsulation efficiency, and drug-loading rate of DZ–polymer-azone–lipid nanoparticles (D-P-Azone-LNs) were 77.59 ± 2.26 nm, 79.91% ± 1.46%, and 1.50% ± 0.02%, respectively. In skin penetration experiment, the cumulative amount of DZ from D-P-Azone-LN reached 14.91 μg·cm−2 at 72 h. This amount was 1.44 and 6.01 times higher than those of DZ–polymer–lipid nanoparticles (D-P-LNs) and DZ solution, respectively. Confocal laser scanning microscopy was used to conduct a qualitative analysis. In vivo study, D-P-Azone-LN achieved better skin retention than those of D-P-LN and DZ. Furthermore, no significant irritation was observed in the skin irritation experiment. These results suggested that the core–shell polymer–lipid nanoparticles, which combined the properties of polymer and lipid nanoparticles, can offer a useful formulation for enhancing the skin permeation of drug for transdermal delivery.

Fatty acids penetration into human skin ex vivo: A TOF-SIMS analysis approach.

Linoleic, oleic, palmitoleic, palmitic, and stearic fatty acids (FAs) are commonly used in dermatological formulations. They differ by their structure, presence in the skin, and mode of application in pharmaceuticals and cosmetics compounding. These FAs are also known as chemical penetration enhancers, but their mechanisms of penetration enhancement and effect on barrier characteristics of the skin require additional study. In this study, the authors conducted an ex vivo analysis of the distribution of lipid components in the epidermis and dermis of human skin after applying individual FAs. The goal was to elucidate possible mechanisms of penetration enhancement and FA effects on barrier characteristics of the skin. FA penetration studies were conducted ex vivo on human skin and time-of-flight secondary ion mass spectrometry (TOF-SIMS) bioimaging analysis was performed to visualize and analyze distribution of FAs in skin sections. The current study demonstrated that TOF-SIMS imaging was effective in visualizing the distribution of linoleic, oleic, palmitoleic, palmitic, and stearic acid in the human skin ex vivo after the skin penetration experiment of individual FAs. The integration of the obtained TOF-SIMS images allowed a semiquantitative comparison of the effects induced by individual FA applications on the human skin ex vivo. FAs showed varying abilities to penetrate the skin and disorder the FAs within the skin, based on their structures and physicochemical properties. Linoleic acid penetrated the skin and changed the distribution of all the analyzed FAs. Skin treatment with palmitoleic or oleic acid increased the amounts of singular FAs in the skin. Penetration of saturated FAs was low, but it increased the detected amounts of linoleic acid in both skin layers. The results indicate that application of FAs on the skin surface induce redistribution of native FAs not only in the stratum corneum layer of epidermis but also in the lipid content of full epidermis and dermis layers. The results indicate that topically applied pharmaceutical products should be evaluated for potential chemical penetration enhancement and lipid component redistribution effects during formulation.

Topical Delivery of Protein and Peptide Using Novel Cell Penetrating Peptide IMT-P8.

Skin, being the largest organ of the body, is an important site for drug administration. However, most of the drugs have poor permeability and thus drug delivery through the skin is very challenging. In this study, we examined the transdermal delivery capability of IMT-P8, a novel cell-penetrating peptide. We generated IMT-P8-GFP and IMT-P8-KLA fusion constructs and evaluated their internalization into mouse skin after topical application. Our results demonstrate that IMT-P8 is capable of transporting green fluorescent protein (GFP) and proapoptotic peptide, KLA into the skin and also in different cell lines. Interestingly, uptake of IMT-P8-GFP was considerably higher than TAT-GFP in HeLa cells. After internalization, IMT-P8-KLA got localized to the mitochondria and caused significant cell death in HeLa cells signifying an intact biological activity. Further in vivo skin penetration experiments revealed that after topical application, IMT-P8 penetrated the stratum corneum, entered into the viable epidermis and accumulated inside the hair follicles. In addition, both IMT-P8-KLA and IMT-P8-GFP internalized into the hair follicles and dermal tissue of the skin following topical application. These results suggested that IMT-P8 could be a potential candidate to be used as a topical delivery vehicle for various cosmetic and skin disease applications.

Penetration of titanium dioxide nanoparticles through slightly damaged skin in vitro and in vivo.

Titanium dioxide nanoparticles (TiO2-NPs) have been widely developed for versatile use, but the potential risk form their skin exposure is still unclear. To evaluate this risk, the skin penetration of TiO2-NPs is necessary to be understood first. The aims of this study are to investigated the penetration of TiO2-NPs through slightly damaged skin and intact skin in vitro and in vivo. TiO2-NPs with a diameter of 20 nm was labeled with 125I.The skin of rat was treated with 2% SLS solution and obtained as slightly damaged skin. The 125I labeled TiO2-NPs (125I-TiO2-NPs)solution and 0.9% PS solution were added into the donor chamber and receptor chamber of static diffusion cells which clamped the skin at the middle of two half-cells, respectively. During 24 hours, samples were extracted from the receptor chamber and counted for 1 min using γ-counter to detect the radioactivity. The skin penetration of TiO2-NPs in vitro was expressed as the percentage of radioactivity of receptor chamber solution compared with total radioactivity in the donor chamber. Thereafter, the 125I-TiO2-NPs was exposed to the rats. After 1 day and 3 days, the blood and tissues of rats were harvested, weighed and counted for 1 min using γ-counter to detect the tissue radioactivity. The skin penetration of TiO2-NPs in vivo was expressed as the percentage dose per gram tissue (% dose/g). In the skin penetration experiment in vitro, the radioactivity of receptor chamber solution through damaged skin was higher than that of through intact skin and was about 2% radioactivity of donor chamber on 24 h. In the skin penetration experiment in vivo, the radioactivity of blood and tissues of rats after exposing to 125I-TiO2-NPs solution though damaged skin or intact skin were less than 0.05% dose/g on 1 d and quickly declined on 3 d. The skin penetration rates of TiO2-NPs through slightly damaged skin and intact skin in vitro and vivo were lower than the rate of free 125I in the TiO2-NPs solution. The TiO2-NPs could not penetrate through the damaged skin or intact skin both in vitro and in vivo. It suggested that the TiO2-NPs should be safe when it was applied and contacted with skin.

A strategy for in-silico prediction of skin absorption in man

For some time, in-silico models to address substance transport into and through the skin are gaining more and more importance in different fields of science and industry. In particular, the mathematical prediction of in-vivo skin absorption is of great interest to overcome ethical and economical issues. The presented work outlines a strategy to address this problem and in particular, investigates in-vitro and in-vivo skin penetration experiments of the model compound flufenamic acid solved in an ointment by means of a mathematical model. Experimental stratum corneum concentration–depth profiles (SC–CDP) for various time intervals using two different in-vitro systems (Franz diffusion cell, Saarbruecken penetration model) were examined and simulated with the help of a highly optimized three compartment numerical diffusion model and compared to the findings of SC–CDPs of the in-vivo scenario. Fitted model input parameters (diffusion coefficient and partition coefficient with respect to the stratum corneum) for the in-vitro infinite dose case could be used to predict the in-use conditions in-vitro. Despite apparent differences in calculated partition coefficients between in-vivo and in-vitro studies, prediction of in-vivo scenarios from input parameters calculated from the in-vitro case yielded reasonable results.

Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules

Genetic skin diseases caused by mutations resulting in diminished protein synthesis could benefit from local substitution of the missing protein. Proteins, however, are excluded from topical applications due to their physicochemical properties. We prepared protein-loaded thermoresponsive poly(N-isopropylacrylamide)-polyglycerol-based nanogels exhibiting a thermal trigger point at 35°C, which is favorable for cutaneous applications due to the native thermal gradient of human skin. At≥35°C, the particle size (~200nm) was instantly reduced by 20% and 93% of the protein was released; no alterations of protein structure or activity were detected. Skin penetration experiments demonstrated efficient intraepidermal protein delivery particularly in barrier deficient skin, penetration of the nanogels themselves was not detected. The proof of concept was provided by transglutaminase 1-loaded nanogels which efficiently delivered the protein into transglutaminase 1-deficient skin models resulting in a restoration of skin barrier function. In conclusion, thermoresponsive nanogels are promising topical delivery systems for biomacromolecules. From the Clinical EditorMany skin disorders are characterized by an absence of a specific protein due to underlying gene mutation. In this article, the authors described the use of a thermoresponsive PNIPAM-dPG nanogel for cutaneous protein delivery in a gene knock-down model of human skin. The results may have implication for nano-based local delivery of therapeutic agents in skin.

Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles.

We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KETnano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KETnano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (Jc) and penetration coefficient through the skin (Kp) values of the KETnano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KETmicro gel ointment; mean particle size 7.7 µm). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (ka) and the areas under the KET concentration-time curve values in the skin of rats receiving the KETnano gel ointment were significantly higher than those of rats receiving the KETmicro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KETnano gel ointment were also significantly higher than those of rats receiving the KETmicro gel ointment. In addition, the application of the KETnano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KETmicro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers of Celecoxib for Topical Application – Preparation, Characterization and Drug Penetration Through Rat Skin

Lipid nanoparticles have been paid growing interest for topical application of non-steroidal anti-inflammatory drugs to increase skin penetration and to reduce side effects. Solid lipid nanoparticles and nanostructured lipid carriers of celecoxib were prepared by high-pressure homogenization technique. Transmission electron microscopy, fourier transform infrared spectroscopy, differential scanning calorimetry, photon correlation spectroscopy and laser diffraction were used for characterization of nanoparticles. Their physical stability was investigated for 6 months of storage at the room temperature, 4oC and 40oC. Nanoemulsions were also prepared at the same conditions for comparison with the aim of pyhsico-chemical characterization of nanoparticles. Spherical nanoparticles with high drug payload were obtained below 250 nm when similar particle sizes were observed for 3 months of storage at all temperatures. Low microparticle content was detected in formulations after 6 months when d(0.5) values were below 270 nm at room temperature and 4oC. 40oC was not detected as a suitable storage condition for formulations. Nanoparticles were observed to provide controlled drug release. Their release profiles fitted Korsmeyer-Peppas model indicating Fickian diffusion release (case I diffusional) as the dominant mechanism. In ex-vivo skin penetration experiments through abdominal rat skins, solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsion significantly increased drug penetration rate 1.4-2.2 times higher compared to a traditional gel formulation containing celecoxib (p0.05). Nanoemulsion displayed the highest drug penetration rate among nano-formulations. Lipid nanoparticles and nanoemulsion were found as good canditates in order to transport celecoxib through deeper skin layers increasing drug penetration.