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The possibility of controlling periorbital hyperpigmentation disorders is one of the most important research goals in cosmetic preparations. In the current investigation, 1% vitamin K (Vit K) was incorporated into a Chitosan/alginate hydrogel which aimed to increase the dermal delivery and anti-pigmentation effect. The Vit K-hydrogel was evaluated using several different tests, including volume expansion/contraction analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), ultraviolet (UV) absorbance spectroscopy, and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Vit K hydrogel's drug release profile showed a steady increase over time. Furthermore, the modified Vit K hydrogel formulations showed no harmful effects in an in vitro cytotoxicity study. The Vit K hydrogel was tested for dermal irritation on Wistar rats, and the hydrogel was found to be non-irritating. Furthermore, Vit K-hydrogel inhibited melanin formation (31.76 ± 1.14%) and was remarkably higher than free Vit K. In addition, Vit K-hydrogel inhibited L-dopa auto-oxidation to a greater extent (94.80 ± 2.41%) in comparison with Vit K solution (73.95 ± 1.62%). Vit K-hydrogel enhanced percutaneous transport of Vit K, according to in vitro percutaneous absorption findings, suggesting that this innovative formulation may provide new therapeutic options for periorbital hyperpigmentation. [ABSTRACT FROM AUTHOR]

Transdermal administration of chemo therapeutics into burn healing may be an effective treatment to reduce toxic side effects and improve patient compliance for burns. As a transdermal delivery system, Camelina lipid droplets (CLDs) have received great attention due to their biocompatibility, high drug payload, and rapid absorption. However, the absorbed-related mechanisms of Camelina lipid droplets have not yet been reported. Thus, this paper not only demonstrated that CLD can accelerate skin burn healing through promoting hFGF2 absorption, but also elucidated the mechanism between the skin tissue and keratinocytes using Franz, HE staining, DSC, FTIR spectroscopy, and atomic force microscopy with the presence of CLD-hFGF2 freeze-dried powder. We found that the cumulative release rate of CLD-hFGF2 freeze-dried powder was significantly higher than that of free hFGF2 freeze-dried powder into the skin. At the same time, CLD can change the structure and content of lipids and keratin to increase the permeability of hFGF2 freeze-dried powder in skin tissue. Unlike the free state of hFGF2, the biophysical properties of single cells, including height and adhesion force, were changed under CLD-hFGF2 freeze-dried powder treatment. Meanwhile, CLD-hFGF2 freeze-dried powder was more easily taken up through keratinocytes without damaging cell integrity, which provided a new viewpoint for understanding the absorption mechanism with the CLD system for cellular physiology characteristics. Overall, our findings demonstrated that CLD could break through the stratum corneum (SC) barrier and elucidated the transport mechanism of lipid droplets in skin tissue, which provides a crucial guideline in drug delivery applications for future engineering. [ABSTRACT FROM AUTHOR]

Nanomaterials manufactured of amphiphilically‐altered polysaccharides have sparked a great deal of interest due to their capability to elevate drug transport across the skin. The study presents the fabrication of alkylated chitosan through 2‐tert‐butoxymethyloxirane alteration (alkylation degree 29.7%), that was typified by spectroscopic, chromatographic, and thermal analysis approaches before being constructed into nanomaterials for the analysis of their capability in governing fusidic acid diffusion percutaneously. The nanomaterials were constructed via the ionic interaction of positively charged chitosan and negatively charged cross linker sodium tripolyphosphate, with a loading degree of fusidic acid of ca. 20% reported. Fusidic acid release was slower in nanomaterials constructed of alkylated chitosan than in neat chitosan. Under application‐relevant conditions, in vitro incubation with HaCaT cells exhibited insignificant toxicity. Using Franz diffusion cells, the alkylated chitosan nanomaterials induced fusidic acid to infiltrate the Strat‐M® membrane at a 2‐fold greater rate than the neat chitosan nanomaterials. Based on the agar diffusion test, fusidic acid was shown to have better antimicrobial activity when loaded into alkylated chitosan nanomaterials than when loaded into neat chitosan nanomaterials. Ultimately, the in vitro results revealed that alkylated chitosan nanomaterials offer a great deal of potential for percutaneous delivery, which merits greater analysis. [ABSTRACT FROM AUTHOR]

The local treatment of kojic acid (KA) as a tyrosinase inhibitor results in inadequate skin absorption and a number of side effects. The current study aims to maximize KA skin delivery. To produce KA-hydrogel, 1% KA was injected into a Chitosan/alginate hydrogel. The impacts of biopolymer proportion on the KA-hydrogel preparations were investigated. Swelling analysis, weight loss analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), UV absorption spectroscopy, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy were used to evaluate the KA-hydrogel. The swelling percentages of KA-hydrogel increased significantly after 4 h. After two weeks, up to 60% of the primary mass of the KA- hydrogel has been removed. By alternation in biopolymer proportion, the drug release profile of KA-hydrogel demonstrated a sustained pattern. According to the skin absorption experiment, KA-hydrogel had higher skin deposition (25.630 ± 3.350%) than KA-plain gel (5.170 ± 0.340%). Moreover, an in vitro cytotoxicity analysis for the modified KA-hydrogel preparations revealed no cytotoxic effects on HFF cell line (90%). Moreover, KA hydrogel had inhibitory effect on melanin synthesis and are comparable with KA. Furthermore, KA-hydrogel had higher inhibitory effect on L-dopa auto oxidation (94.84 ± 2.41%) in comparison KA solution (73.95 ± 3.28%). Also, the dermal irritation study on Wistar rat revealed that the hydrogel constituent used did not irritate the skin. These results revealed that the KA-hydrogel might be employed as KA local administration, thus opening up new prospects for the therapies of hyperpigmentation problems. [ABSTRACT FROM AUTHOR]

Background: There has been an increase in demand for cosmetic skin-whitening products with efficacy toward lightening skin tone. β-arbutin is an inhibitor of tyrosinase enzyme activity within the skin's melanocytes, and so has shown considerable promise as a skin-lightening agent. It is, however, both hydrophilic and hygroscopic, which hinders its penetration of the skin to reach these melanocytes. Chitosan (CS) possesses considerable penetration-enhancing properties when utilized in topical delivery formulations. The strong affinity of positively charged chitosan nanoparticles toward negatively charged biological membranes can be exploited to achieve site-specific targeting. Objective: To investigate the use of chitosan nanoparticles (CSNPs) as carrier units to enhance the topical delivery of β-arbutin. Method: CSNPs containing β-arbutin were prepared using an ionic cross-linking method, and entrapment efficiency and loading capacity were evaluated at numerous β-arbutin concentrations. Further characterization involved using FTIR, XRD, TEM, and TGA, and in vitro permeation studies were conducted using in vitro Franz diffusion cells. Results: β-arbutin chitosan nanoparticles were successfully formulated with a size range of 211–289 d.nm, a polydispersity index between 0.2–0.3, and zeta potential in the range 46.9–64.0 mV. The optimum encapsulation efficiency (EE) and loading capacity (LC) of β-arbutin were 68% and 73%, respectively. TEM revealed the nanoparticles to be spherical in shape. FTIR spectra revealed characteristic chitosan-related peaks appearing at 3438.3 cm−1 (-OH stretching) and 3320 cm−1 (-CH stretching), together with 1598.01 cm−1 (-NH2) specific to β-arbutin nanoparticles. XRD analysis revealed an increase in crystallinity and TGA analyses identified increasing thermal stability with increasing β-arbutin concentration. In vitro studies indicated higher permeation and improved penetration of β-arbutin loaded in CSNPs compared to its free form. Conclusion: CSNPs present considerable promise as effective carriers for improved topical delivery of β-arbutin. [ABSTRACT FROM AUTHOR]

Transdermal administration of chemo therapeutics into burn healing may be an effective treatment to reduce toxic side effects and improve patient compliance for burns. As a transdermal delivery system, Camelina lipid droplets (CLDs) have received great attention due to their biocompatibility, high drug payload, and rapid absorption. However, the absorbed-related mechanisms of Camelina lipid droplets have not yet been reported. Thus, this paper not only demonstrated that CLD can accelerate skin burn healing through promoting hFGF2 absorption, but also elucidated the mechanism between the skin tissue and keratinocytes using Franz, HE staining, DSC, FTIR spectroscopy, and atomic force microscopy with the presence of CLD-hFGF2 freeze-dried powder. We found that the cumulative release rate of CLD-hFGF2 freeze-dried powder was significantly higher than that of free hFGF2 freeze-dried powder into the skin. At the same time, CLD can change the structure and content of lipids and keratin to increase the permeability of hFGF2 freeze-dried powder in skin tissue. Unlike the free state of hFGF2, the biophysical properties of single cells, including height and adhesion force, were changed under CLD-hFGF2 freeze-dried powder treatment. Meanwhile, CLD-hFGF2 freeze-dried powder was more easily taken up through keratinocytes without damaging cell integrity, which provided a new viewpoint for understanding the absorption mechanism with the CLD system for cellular physiology characteristics. Overall, our findings demonstrated that CLD could break through the stratum corneum (SC) barrier and elucidated the transport mechanism of lipid droplets in skin tissue, which provides a crucial guideline in drug delivery applications for future engineering.

Psoriasis is a chronic, recurrent, and inflammatory skin disease. Topical agents, which can avoid the adverse effects of systemic treatment, are the first-choice therapy for patients with mild-to-moderate psoriasis. Hederacoside C (HSC) with anti-inflammatory properties has been used to treat some inflammatory diseases. We speculated that HSC might also be effective for psoriasis treatment. However, topical application of HSC for psoriasis treatment is challenging because of its low water solubility and poor skin permeability. Therefore, it is important to effectively deliver HSC percutaneously using certain biomaterials. Here we constructed a hydroxypropyl-β-cyclodextrin-coated liposome gel formulation for the loading and percutaneously delivering of HSC, referred to as HSC-Lipo@gel. The characterization, stability, release properties, and mechanical or transdermal features of the HSC-Lipo@gel were evaluated. Its therapeutic potential was also demonstrated using mouse models of IMQ-induced psoriasis. We found that HSC-Lipo@gel effectively improved the skin permeability of HSC with the property of good stability and sustained release. Importantly, HSC-Lipo@gel showed higher efficacy than HSC@gel without liposomes in alleviating psoriatic skin lesions. It attenuated epidermal hyperplasia and suppressed expression of IL-17A, TNF-α, IL-6, and IL-23 in lesional skin. Interestingly, HSC-Lipo@gel reduced the expression of CC chemokine ligand 17 (CCL17), but not CCL22, in the skin. Especially, HSC-Lipo@gel inhibited CCL17 expression by skin dendritic cells while increasing regulatory T cells (Tregs) in both skin and draining lymph nodes of psoriatic mice. Administration of CCL17 resulted in severe skin lesions and reduced CD4 + FoxP3 + Tregs in psoriatic mice previously treated with HSC-Lipo@gel. Finally, HSC or HSC-Lipo also suppressed the CCL17 production by dendritic cells in vitro . Therefore, HSC-Lipo@gel alleviated psoriasiform skin inflammation by increasing cutaneous Tregs via downregulation of the expression of CCL17, but not CCL22. Thus, HSC-Lipo@gel may be a stable, highly permeable, and effective system for topical treatment of psoriasis.

The study aims to formulate and characterize nanoformulations produced from amphipathically‐modified pectin containing fusidic acid, making clear the importance of nanocarrier amphipathicity in boosting drug permeation through the skin. For this purpose, the amphipathically‐modified pectin (GBE‐PEC) fabrication was achieved following glycidol butyl ether modification via the nucleophilic substitution SN2 reaction, which was then characterized using thermal analysis, spectroscopic, and chromatographic tools. The materials were subsequently converted into spherical nanostructures (NSs) (size 250–290 nm; zeta potential −25 to −34 mV) via a nanoprecipitation in situ cross‐linking approach, demonstrating low viscosity and good colloidal stability under pH 4 conditions. The encapsulated fusidic acid (loading degree 14.9%) was released from GBE‐PEC NSs in a more controlled fashion, with release profiles best characterized by the Higuchi model. Interactions with HaCaT cells in vitro demonstrated no apparent cytotoxicity at application relevant conditions, with efficient cellular absorption as evidenced by flow cytometry analysis. Using Franz diffusion cells, GBE‐PEC NSs had a 2‐fold greater penetration rate through the Strat‐M® membrane than the native pectin NSs. Overall, the study has introduced new insights into the design, fabrication, characterization, and tremendous potential of NSs formulated from GBE‐PEC for percutaneous delivery of poorly penetrating actives, which merit further analysis. [ABSTRACT FROM AUTHOR]

Yun-Chun Zhao,1 Hai-Li Zheng,2 Xiao-Rong Wang,1 Xiao-Ling Zheng,1 Yue Chen,1 Wei-Dong Fei,1 Yong-Quan Zheng,1 Wen-Xi Wang,2 Cai-Hong Zheng1 1Pharmacy Department, Zhejiang University, Women’s Hospital, School of Medicine, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, People’s Republic of ChinaCorrespondence: Cai-Hong ZhengZhejiang University, Women’s Hospital, School of Medicine, 1 Xueshi Road, Hangzhou 310006, People’s Republic of ChinaTel +86-0571-89991730Email chzheng@zju.edu.cnWen-Xi WangCollege of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, People’s Republic of ChinaTel +86-0571-88320320Email yjw@zjut.edu.cnBackground: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100– 120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.Conclusion: These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.Keywords: N N-dimethyl-(N′ N′-di-stearoyl-1-ethyl)1, 3-diaminopropane, methotrexate, micelle, percutaneous delivery

Background: There has been an increase in demand for cosmetic skin-whitening products with efficacy toward lightening skin tone. β-arbutin is an inhibitor of tyrosinase enzyme activity within the skin’s melanocytes, and so has shown considerable promise as a skin-lightening agent. It is, however, both hydrophilic and hygroscopic, which hinders its penetration of the skin to reach these melanocytes. Chitosan (CS) possesses considerable penetration-enhancing properties when utilized in topical delivery formulations. The strong affinity of positively charged chitosan nanoparticles toward negatively charged biological membranes can be exploited to achieve site-specific targeting. Objective: To investigate the use of chitosan nanoparticles (CSNPs) as carrier units to enhance the topical delivery of β-arbutin. Method: CSNPs containing β-arbutin were prepared using an ionic cross-linking method, and entrapment efficiency and loading capacity were evaluated at numerous β-arbutin concentrations. Further characterization involved using FTIR, XRD, TEM, and TGA, and in vitro permeation studies were conducted using in vitro Franz diffusion cells. Results: β-arbutin chitosan nanoparticles were successfully formulated with a size range of 211–289 d.nm, a polydispersity index between 0.2–0.3, and zeta potential in the range 46.9–64.0 mV. The optimum encapsulation efficiency (EE) and loading capacity (LC) of β-arbutin were 68% and 73%, respectively. TEM revealed the nanoparticles to be spherical in shape. FTIR spectra revealed characteristic chitosan-related peaks appearing at 3438.3 cm−1 (-OH stretching) and 3320 cm−1 (-CH stretching), together with 1598.01 cm−1 (-NH2) specific to β-arbutin nanoparticles. XRD analysis revealed an increase in crystallinity and TGA analyses identified increasing thermal stability with increasing β-arbutin concentration. In vitro studies indicated higher permeation and improved penetration of β-arbutin loaded in CSNPs compared to its free form. Conclusion: CSNPs present considerable promise as effective carriers for improved topical delivery of β-arbutin.

Yixuan Wang, Sisi Cao, Kaiyue Yu, Fengdie Yang, Xiuming Yu, Yuanhao Zhai, Chuanbin Wu, Yuehong XuDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of ChinaBackground: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs.Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506.Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1–chloro–2, 4–dinitrobenzene (DNCB)-induced murine AD.Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application.Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence.Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537)Keywords: tacrolimus, microemulsion, menthol, camphor, eutectic, atopic dermatitis, percutaneous delivery

The study focused on formulation of carmellose sodium hydrogels and nonionic microemulsions with 5% and 10% of levetiracetam and investigation of drug concentration influence on their physicochemical characteristics and in-use stability as well as influence of drug concentration and carrier type on in vitro drug release and in vivo antihyperalgesic/antiedematous activity in a rat model of localized (intraplantar) carrageenan-induced inflammation. Hydrogels were pseudoplastic semisolids with thixotropy and pH 7.37–7.58. Microemulsions were low viscous Newtonian nanodispersions of oil droplets (13.11–15.11 nm) in water, with pH 4.01–4.64. Physical stability of the investigated systems was preserved over the 3-month storage under ambient conditions. Levetiracetam release followed zero order and Korsmeyer-Peppas models (R2 ≥ 0.99) reflecting the combined effects of drug concentration and carrier viscosity. All levetiracetam-loaded formulations produced significant reduction of hyperalgesia and paw swelling induced by carrageenan (p < 0.001). Their efficacy in exerting antihyperalgesic activity was significantly higher than that observed with the reference 5% ibuprofen hydrogel preparation (up to 6 h) (p < 0.001), while antiedematous activity was comparable with the reference product. No erythema and visible blood vessels were observed in a rat ear test. The study demonstrated percutaneous delivery of levetiracetam as useful and safe therapeutic option for localized inflammatory pain with potential to overcome the insufficient efficacy of topically applied nonsteroidal anti-inflammatory drugs in the form of a hydrogel. [ABSTRACT FROM AUTHOR]

Kaiyue Yu, Yixuan Wang, Tao Wan, Yuanhao Zhai, Sisi Cao, Wenyi Ruan, Chuanbin Wu, Yuehong Xu School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China Background: Topical application of tacrolimus (FK506) was effective in the treatment of atopic dermatitis (AD); however, adverse effects frequently occurred with the increase of FK506 dose during long–term treatment.Objective: The objective of this project was to develop a hybrid skin targeting system encapsulating FK506 based on nicotinamide (NIC) and chitosan nanoparticles (CS–NPs), ie, FK506–NIC–CS–NPs, which took advantages of both of NIC and CS–NPs to obtain the synergetic effects of percutaneous delivery and treatment efficacy enhancement along with dose reduction.Methods: The formulation of FK506–NIC–CS–NPs was optimized and characterized. In vitro and in vivo skin permeation studies were performed. AD–like skin lesions were constructed with BALB/c mice by 1–chloro–2, 4–dinitrobenzene (DNCB)–induced, and FK506–NIC–CS–NPs containing different dose of FK506 were topically administered to treat AD–like skin lesions in comparison with Protopic.Results: NIC was found to significantly increase the FK506 EE to 92.2% by CS–NPs. In comparison with commercial FK506 ointment (Protopic), in vitro and in vivo skin permeation studies demonstrated that NIC–CS–NPs system significantly enhanced FK506 permeation through and into the skin, and deposited more FK506 into the skin. The treatment efficacy on clinical symptoms, histological analysis, and molecular biology of the AD–mice demonstrated that NIC–CS–NPs with ~1/3 dose of FK506 of Protopic was superior to that of Protopic, and NIC–CS–NPs vehicle exhibited the adjuvant therapy and moderate anti–AD effects.Conclusion: The system of NIC–CS–NPs enhances the permeability of FK506, plays an adjuvant role in anti-AD, reduces the dose of FK506 in treating AD, and is therefore a promising nanoscale system of FK506 for the effective treatment of AD. Keywords: tacrolimus, chitosan, nanoparticles, nicotinamide, atopic dermatitis, percutaneous delivery, reducing dose

Tao Wan,* Wenhui Pan,* Yueming Long, Kaiyue Yu, Sibo Liu, Wenyi Ruan, Jingtong Pan, Mengyao Qin, Chuanbin Wu, Yuehong Xu Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The hybrid system based on nanoparticles (NPs) self-assembled by the conjugations of hyaluronic acid with cholesterol (HA–Chol NPs) combined with nicotinamide (NIC) for tacrolimus (FK506), ie, FK506 NPs–NIC, has been confirmed to exhibit a significant synergistic effect on FK506 permeation through and into intact skin; thus, it may be a promising approach for FK506 to effectively treat skin diseases. The aim of this study was to evaluate its potential for the treatment of psoriasis. In vitro permeation through the psoriatic skin was carried out, and the results revealed that the combination of NPs with NIC exhibited a significant synergistic effect on FK506 deposition within the psoriatic skin (3.40±0.67 µg/cm2) and penetration through the psoriatic skin (30.86±9.66 µg/cm2). The antipsoriatic activity of FK506 NPs–NIC was evaluated through the treatment for imiquimod (IMQ)-induced psoriasis. The psoriasis area and severity index (PASI) score demonstrated that FK506 HA–Chol NPs–NIC exerted the effect on ameliorating the skin lesions comparable to clobetasol propionate (a positive drug for psoriasis) and superior to commercial FK506 ointment (Protopic®), and the histological study showed that it presented a synergistic effect on antipsoriasis after FK506 incorporation into NPs combined with NIC hydrotropic system, which might ultimately increase the therapeutic effect and minimize the systemic side effects by reducing the overall dose of FK506. RAW 264.7 cell uptake presented the enhancement of drugs delivered into cells by HA–Chol NPs–NIC. The antiproliferative activity on HaCaT cells identified that FK506 HA–Chol NPs–NIC exhibited significant inhibiting effects on HaCaT proliferation. The results support that the combination of HA–Chol NPs with NIC is a promising approach for FK506 for the treatment of psoriasis. Keywords: tacrolimus, nanoparticles, nicotinamide, percutaneous delivery, psoriasis, antiproliferation

Gold nanoparticles functionalized with 3-mercapto-1-propansulfonate (AuNPs-3MPS) have been prepared and loaded with Methotrexate (MTX), an immunosuppressive agent used in the systemic treatment of moderate–severe inflammatory diseases. The effects of the AuNPs-3MPS@MTX topically administered in vitro on skin model and in vivo on imiquimod-induced psoriasis-like mice model, have been studied. Clinical response, epidermal thickness, cell proliferation rate and inflammation were tested. AuNPs-3MPS@MTX treated mice showed a decreasing of scaling and erythema score, reduction of epidermal thickness, parakeratosis and hyperkeratosis, compared to AuNPs-3MPS treated mice. Immunohistochemistry analysis staining displayed that Ki67, K6 CD3 and CD8 stainings were reduced in AuNPs-3MPS@MTX treated mice. Blood evaluation showed no differences in blood count and in ALT and AST levels before and after AuNPs-3MPS or AuNPs-3MPS@MTX treatment. Topical AuNPs-3MPS@MTX treatment is able to induce a reduction of keratinocytes hyperproliferation, epidermal thickness and also inflammatory infiltrate in vivo on imiquimod-induced psoriasis like mice model. Topical treatment with functionalized gold nanoparticles loaded with methotrexate was used in vivo on imiquimod-induced psoriasis like mice model. The AuNPs-3MPS@MTX system allowed to reduce keratinocytes hyperproliferation, epidermal thickness and inflammatory infiltrate. Unlabelled Image [ABSTRACT FROM AUTHOR]

Developments in nanotechnology have expanded novel nanoparticles for several applications, including cosmetic topical preparation. The aim of this article was to review recent literature on percutaneous delivery of cosmetics active ingredient by nanoparticles. The main focus here, is on lipid based nanoparticles since they are of great importance in skin cargo delivery and have vast application in current cosmetic formulations. Data were collected via electronic databases using MeSH keywords, including nanoparticles, lipid particles, cosmetic, dermal delivery and combinations of these words. According to literature nanoparticles play a major role in improving the usefulness of cosmetics. They are able to improve the physiochemical stability of the skin based cosmetic products. Based on data, lipid nanostructures can be added to current cosmetic formulations without any significant problem due to their physical stability and compatibility with other ingredients. However, due to their basically risky nature of nanoparticles, their risk assessment should be taken into consideration. [ABSTRACT FROM AUTHOR]

In this study, we demonstrate for the first time the dual roles of Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) based microemulsion (ME) for tacrolimus (TAC) to enhance TAC percutaneous delivery and anti-psoriatic efficacy. The ME formulation was developed and optimized based on pseudo-ternary phase diagrams combined with in vitro permeation. The result of Fourier transform infrared spectroscopy (FTIR) demonstrated that TAC was completely solubilized in the TPGS-ME. In vitro permeation studies showed that TPGS-ME enhanced TAC permeation through and into the skin, and the enhanced deposition of TAC in the normal or psoriatic skin was further confirmed in vivo. The cellular uptake performed with HaCaT cells presented more pronounced uptake of TPGS-ME. Topical TAC-TPGS-ME treated imiquimod-induced psoriasis in mice more efficaciously than the commercial formulation of TAC (Protopic ® ), which is consistent with the enhanced TAC levels by TAC-TPGS-ME in the psoriatic skin. Haematoxylin and Eosin (HE) staining revealed that TAC-TPGS-ME significantly diminished the severity of the psoriasis-like skin inflammation. Moreover, TPGS-ME vehicle exhibited a moderate anti-inflammatory activity, which indicated that TPGS acted as a potential adjuvant in the TAC anti-psoriasis process, and the synergism was identified in anti-proliferation against HaCaT cells. The colloidal nano-carrier combined ME with TPGS is a potential approach for percutaneous delivery of TAC, which exploited both virtues of ME and TPGS to obtain the synergetic effects of enhanced permeability and anti-psoriatic efficacy. [ABSTRACT FROM AUTHOR]

Implantable cardiac pacemakers have seen remarkable progress in the last sixty years and remained as cornerstone therapy for symptomatic bradycardia. Despite this progress the current day traditional transvenous implanted pacemaker systems are limited by the need for a surgically created pocket for the generator, indwelling leads in the vascular system and lastly passage through the tricuspid valve. A majority of the implant and explant related complications are due to the surgical pocket and indwelling leads. Leadless pacemakers represent a major leap in technology and emerged as an alternative to traditional systems promises to eliminate lead and pocket associated complications. As with any disruptive technology, some questions remain unanswered with the leadless pacing systems, specifically longevity and end of life management for the device. Despite the unknowns, as the technology progresses, it is possible that pacing leads will become extinct and pacemakers will miniaturize even further. This review summarizes the available technology, implant and explant details, and long-term safety and efficacy data for leadless pacemakers. [ABSTRACT FROM AUTHOR]

Tamoxifen (TAM) is frequently prescribed for the management breast cancer, but is associated with the challenges like compromised aqueous solubility and poor bioavailability to the target site. It was envisioned to develop phospholipid-based mixed micelles to explore the promises offered by the biocompatible carriers. Various compositions were prepared, employing soya lecithin, polysorbate 80, sodium chloride/dextrose, and water, by self-assembled technique. The formulations were characterized for micromeritics and evaluated for in vitro drug release, hemolysis study, dermatokinetic studies on rodents, and cytotoxicity on MCF-7 cell lines. Cellular uptake of the system was also studied using confocal laser scanning microscopy. The selected composition was of sub-micron range (28.81 ± 2.1 nm), with spherical morphology. During in- vitro studies, the mixed micelles offered controlled drug release than that of conventional gel. Cytotoxicity was significantly enhanced and IC value was reduced that of the naïve drug. The bioavailability in epidermis and dermis skin layers was enhanced approx. fivefold and threefold, respectively. The developed nanosystem not only enhanced the efficacy of the drug but also maintained the integrity of skin, as revealed by histological studies. The developed TAM-nanocarrier possesses potential promises for safe and better delivery of TAM. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease that is difficult to treat. Quercetin (QT) is a dietary flavonoid known for its anti-inflammatory effects and safe use in humans. However, the topical application of quercetin for psoriasis treatment presents a significant challenge due to its poor water solubility and low stability in semisolid preparations, where it tends to recrystallize. This work presents a novel liposome-in-gel formulation for the quercetin-based topical treatment of psoriasis. The quercetin-loading liposomes are stabilized by hydroxypropyl-β-cyclodextrin (HPCD), which interacts with phospholipids via hydrogen bonding to form a layer of an HPCD coating on the liposome interface, thus resulting in improved stability. Various analytical techniques, such as FTIR spectroscopy, Raman spectroscopy, and TEM, were used to characterize the molecular coordination patterns between cyclodextrin and liposomes. The results demonstrated that HPCD assisted the liposomes in interfacing with the matrix lipids and keratins of the stratum corneum, thereby enhancing skin permeability and promoting drug penetration and retention in the skin. The in vivo results showed that the topical QT HPCD-liposome-in-gel improved the treatment efficacy of psoriatic plaque compared to free QT. It alleviated the symptoms of skin thickening and downregulated proinflammatory cytokines, including TNF-α, IL-17A, and IL-1β. The results suggested that the HPCD-coordinated liposome-in-gel system could be a stable carrier for topical QT therapy with good potential in psoriasis treatment.

Prosthetic annuloplasty rings are a common treatment modality for mitral regurgitation, and recently, percutaneous implantation techniques have gained popularity due to their favorable safety profile. Although in common use, biocompatibility of annuloplasty rings has been reported only sparsely in the literature, and none of these reports used the percutaneous technique of implantation. We report on the biocompatibility and the systemic safety of a novel transcatheter mitral valve annuloplasty ring (AMEND™) in 6 minipigs. This device is composed of a nitinol tube surrounded by a braided polyethylene terephthalate fabric tube. The device produced no adverse inflammatory response, showing gradual integration between the metal ring and the fabric by normal host fibrocellular response, leading to complete neoendocardium coverage. There was no evidence for adverse reactions, rejection, or intolerance in the valvular structure. In 2 animals, hemopericardium resulted from the implantation procedure, leading to right-sided cardiac insufficiency with pulmonary edema and liver congestion. The findings reported herein can serve as a case study for the expected healing pathology reactions after implantation of transcatheter mitral valve annuloplasty rings. [ABSTRACT FROM AUTHOR]

A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60–1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage.Ex vivopermeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20 kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30 min. Sonophoresis pre-treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2 h period. MN application increased permeability at a time of 0.5 h for up to ∼17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7 min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3 h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Plaque psoriasis is characterized by an abnormal thickening of the epidermis, which causes great difficulties for traditional topical drug delivery. Microneedles can pierce the thickened epidermis and deliver drugs to the skin for psoriasis treatment. Tacrolimus is a poorly water-soluble immunosuppressant used for the treatment of psoriasis. In this study, tacrolimus (TAC) nanocrystals (NCs) were produced using a bottom-up technique that dispersed TAC into a sodium hyaluronate-based microneedle patch (MNP), and its therapeutic efficacy was evaluated. The average particle size of the TAC NCs was 259.6 ± 2.3 nm. The mechanical strength of the microneedles was 0.41 ± 0.06 N/needle, which was sufficient to penetrate psoriatic skin. Microneedles were detached from the substrate 10 min after insertion into the psoriasis skin with an insertion depth of 258.8 ± 14.4 μm. The intradermal retention of the MNP (8.40 ± 0.33 μg/cm2) was six times that of the commercial ointment (1.40 ± 0.12 μg/cm2). In pharmacodynamic experiments, results indicated improvement in the phenotypic and histopathological features and reduction in the level of TNF-α, IL-17A, and IL-23 of psoriatic skin treated with TAC NCs MNP. Therefore, MNP loaded with TAC NCs may be a promising approach for psoriasis treatment. [ABSTRACT FROM AUTHOR]

Common local anaesthetics such as lidocaine are administered by the hypodermic parenteral route but it causes pain or anxiety to patients. Alternatively, an ointment formulation may be applied which involves a slow drug diffusion process. In addressing these two issues, this paper aims to understand the significance of the 'poke and patch' microneedle (MN) treatment on skin in conjunction to the lidocaine permeation, and in particular, the vertical (depth averaged) and horizontal (e.g. lateral) permeation profiles of the drug in the skin. The instantaneous pharmacokinetics of lidocaine in skin was determined by a skin denaturation technique coupled with Franz diffusion cell measurements of the drug pharmacokinetics. All pharmacokinetic profiles were performed periodically on porcine skin. Three MN insertion forces of 3.9, 7.9 and 15.7 N were applied on the MN to pierce the skin. For the smaller force (3.9 N), post MN-treated skin seems to provide an 'optimum' percutaneous delivery rate. A 10.2-fold increase in lidocaine permeation was observed for a MN insertion force of 3.9 N at 0.25 h and similarly, a 5.4-fold increase in permeation occurred at 0.5 h compared to passive diffusional delivery. It is shown that lidocaine permeates horizontally beyond the area of the MN-treated skin for the smaller MN insertion forces, namely, 3.9 and 7.9 N from 0.25 to 0.75 h, respectively. The lateral diffusion/permeation of lidocaine for larger MN-treated force (namely, 15.7 N in this work) seems to be insignificant at all recorded timings. The MN insertion force of 15.7 N resulted in lidocaine concentrations slightly greater than control (passive diffusion) but significantly less than 3.9 and 7.9 N impact force treatments on skin. We believe this likelihood is due to the skin compression effect that inhibits diffusion until the skin had time to relax at which point lidocaine levels increase. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to develop an optimal microemulsion (ME) formulation as topical nanocarrier of caffeine (CAF) to enhance CAF skin retention and subsequently improve its therapeutic effect on UVB-induced skin carcinogenesis. The pseudo-ternary phase diagram was developed composing of Labrafil M 1944 CS as oil phase, Cremophor EL as surfactant, tetraglycol as cosurfactant, and water. Four ME formulations at water content of 50, 60, 70, and 80% were prepared along the water dilution line of oil to surfactant ratio of 1:3 and characterized in terms of morphology, droplet size, and electric conductivity. A gel at the same drug loads (1%, w/ w) was used as control. Ex vivo skin permeation studies were conducted for ME optimization. The optimized formulation (ME4) was composed of 5% ( w/ w) Labrafil M 1944 CS, 15% ( w/ w) Smix (2/1, Cremophor EL and tetraglycol), and 80% ( w/ w) aqueous phase. The skin location amount of CAF from ME4 was nearly 3-fold higher than control ( P < 0.05) with improved permeated amount through the skin. The skin targeting localization of hydrophilic substance from ME4 was further visualized through fluorescent-labeled ME by a confocal laser scanning microscope. In pharmacodynamics studies, CAF-loaded ME4 was superior in terms of increasing apoptotic sunburn cells ( P < 0.05) as compared with control. Overall results suggested that the ME4 might be a promising vehicle for the topical delivery of CAF. [ABSTRACT FROM AUTHOR]

Percutaneous heart valves provide a promising future for patients refused surgery on the grounds of significant technical challenges or high risk for complications. Since the first human intervention more than 10 years ago, over 50 different types of valves have been developed. The CoreValve and Edwards SAPIEN valves have both experienced clinical trials and the latter has gained FDA approval for implantation in patients considered inoperable. Current complications, such as major vascular bleeding and stroke, prevent these valves from being commonly deployed in patients considered operable in conventional surgery. This review focuses on the past and present achievements of these valves and highlights the design considerations required to progress development further. It is envisaged that, with continued improvement in valve design and with increased clinical and engineering experience, percutaneous heart valve replacement may one day be a viable option for lower-risk operable patients. [ABSTRACT FROM PUBLISHER]

Abstract: This project was carried out to exploit the feasibility of using microemulsion (ME) as an alternative carrier for percutaneous delivery econazole nitrate (ECN) and elucidate the underlying mechanism of permeation enhancement. The ME was developed based on Labrafil M 1944 Cs as oil phase, Solutol HS15 and Span 80 as surfactants, Transcutol P as cosurfactant and water as aqueous phase. The solubility of ECN was firstly determined for screening the ingredients of the system. Pseudo-ternary phase diagrams were constructed to formulate ME and select surfactant and cosurfactant. Central composite design-response surface methodology (CCD-RSM) was utilized to optimize the formulation of ME. The ECN loaded ME was characterized in terms of morphology, particle size and size distribution, pH value, refractive index, viscosity and conductivity, and storage stability of the ECN loaded ME was assayed. Percutaneous permeation of ECN from ME in vitro through rat skin was investigated in comparison with PBS aqueous suspension (1%, w/w), and results showed that ME enhanced drug retention in the skin and permeation through the skin, the enhancement of ME on skin deposition was further visualized through fluorescent-labeled ME by confocal laser scanning microscope (CLSM). The action mechanism of ME on improving percutaneous delivery was studied by performing a pretreatment test. It can speculate that ME does not simply behave as enhancer but it also acts as drug carrier. Furthermore, ME-skin interaction was elucidated through transmission electron microscope (TEM), and attenuated total reflectance fourier-transform infrared (ATR-FTIR). TEM was performed to visualize the micro morphological change of skin. ATR-FTIR was carried out to investigate the molecular vibrations of the components of stratum corneum (SC). The results indicate that the ME system may be a promising vehicle for percutaneous delivery of ECN. [Copyright &y& Elsevier]

Abstract: The barrier properties of the skin pose a significant but not insurmountable obstacle for development of new effective anti-inflammatory therapies. The objective of this study was to design and evaluate therapeutic efficacy of anti-nociception agent Capsaicin (Cap) and anti-TNFα siRNA (siTNFα) encapsulated cyclic cationic head lipid-polymer hybrid nanocarriers (CyLiPns) against chronic skin inflammatory diseases. Physico-chemical characterizations including hydrodynamic size, surface potential and entrapment efficacies of CyLiPns were found to be 163±9nm, 35.14±8.23mV and 92% for Cap, respectively. In vitro skin distribution studies revealed that CyLiPns could effectively deliver FITC-siRNA up to 360μm skin depth. Further, enhanced (p<0.001) Cap permeation from CyLiPns was observed compared to Capsaicin-Solution and Capzasin-HP. Therapeutic efficacies of CyLiPns were assessed using imiquamod-induced psoriatic plaque like model. CyLiPns carrying both Cap and siTNFα showed significant reduced expression of TNFα, NF-κB, IL-17, IL-23 and Ki-67 genes compared to either drugs alone (p<0.05) and were in close comparison with Topgraf®. Collectively these findings support our notion that novel cationic lipid-polymer hybrid nanoparticles can efficiently carry siTNFα and Cap into deeper dermal milieu and Cap with a combination of siTNFα shows synergism in treating skin inflammation. [Copyright &y& Elsevier]

We encapsulated recombinant human epidermal growth factor (rhEGF) into nano-liposomes (NLs) system for topical delivery. The rhEGF-loaded NLs were prepared using a high pressure homogenization method. Morphology and overall particle distribution of NLs were investigated using transmission electron microscopy (TEM) and high resolution microscope (CytoViva™). Particle size, zeta ( ζ) potential and encapsulation efficiency were measured and the percutaneous delivery of NLs was evaluated using Franz diffusion cells and immunofluorescence confocal laser scanning microscopy (CLSM). The mean particle size, zeta potential and encapsulation efficiency of the NLs were 155.57 ± 2.59 nm, −57.92 ± 4.35 mV and 9.00 ± 0.39%%, respectively. TEM and microscopic analysis showed spherical, very even-sized vesicles approximately 150 nm. The skin permeation and localization of rhEGF were enhanced by NLs. CLSM image analysis provided that the NLs enhanced the permeation and localization of rhEGF in rat skin by facilitating entry through pores of skin. [ABSTRACT FROM AUTHOR]

At present, no widely accepted surgical options exist for treating chronic deep venous insufficiency (CDVI). Experimental efforts to improve catheter-based management for CDVI have shown disappointing results, hindering application of these techniques in the clinical arena. A review of the literature focusing on technical aspects of valve stent design was conducted. Eight experimental studies were scrutinized to derive data on (1) stent design and configuration; (2) valve design, composition, and configuration; (3) delivery system; (4) functional outcome; and (5) histology to provide a basis for the design of a new prosthetic venous valve. The analysis of available experimental data found that all prosthetic valve designs currently under development/testing rely on some type of a stent to act as a carrier or frame for valve attachment. Most valve models reviewed were for the most part implanted safely and accurately, with good short-term patency and competency. The most commonly reported adverse event was thrombosis, which limited durability. It is assumed that valve configuration determines long-term results after repair. Hence, the newly proposed valve design consisted of 2 stent rings without barbs to fix the valve in the host vein. Because a little reflux might actually benefit the patency of the valve, the valve cusp in the new design forms a billowing 'sail' that does not completely open or close, which also prevents the valve cusp from sticking to the wall. This technology remains of great interest to the interventionist and all physicians who are involved in the care for patients with advanced chronic venous disease. Valve design remains a challenge, but promising new valve substitutes such as the one outlined here are under evaluation. [ABSTRACT FROM AUTHOR]

Abstract: Insulin delivery relies on subcutaneous or intravascular injection, leading to reduced patient compliance. Transdermal delivery of insulin has been successfully demonstrated but dose accuracy and skin irritation are problematic in addition to the complex basal-bolus delivery profile required by insulin therapy. Here we present a novel intraepidermal delivery technology (delivered site at epidermis layer, <150 μm) by combining skin pretreatment with short microneedles (<150 μm in length) and iontophoresis transdermal patch (enhanced transport via electrical field) that can provide a continuous basal dose and on-demand bolus dosing for mealtime insulin needs. To our knowledge, this is the first demonstration of therapeutic equivalence between fast-acting human regular insulin and long-acting insulin with possibilities for on-demand dose adjustment. This new intraepidermal delivery technology is likely to change the therapy regimen of patients suffering from insulin-dependent diabetes mellitus and provide a way to lower cost in comparison with insulin pumps and improve patient compliance. From the Clinical Editor: The authors present a novel intraepidermal insulin delivery technology by combining skin pretreatment with short microneedles and iontophoresis transdermal patch to provide a continuous basal dose and on-demand bolus dosing. This new method is has the potentials to replace insulin pumps by offering a cost effective alternative with less inconvenience and improved compliance. [Copyright &y& Elsevier]

Abstract: Cyclizine (I) alkyl analogues (II–IV) were synthesized and their skin permeation parameters evaluated in vitro. It was hoped that these compounds would possess physicochemical properties more favourable for percutaneous delivery than (I). The identification and levels of purity for the compounds were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry, and infrared spectrometry (IR) while melting points were determined by an electrothermal digital Bϋchi melting point apparatus. Aqueous solubilities (25°C) and partition coefficients were determined and in vitro permeation studies were performed in buffer (37°C) at pH 7.4 over a period of 24h, using Franz diffusion cells fitted with human epidermal membranes. Generally, the analogues were more lipophilic, but nevertheless possessed higher aqueous solubilities as compared to (I). (II) and (IV) exhibited two- to three-fold increase in aqueous solubility and their melting temperatures dropped by more than 55°C. Compound (III) had similar aqueous solubility to (I), but its melting point dropped by about 35°C. Measured steady-state fluxes indicated that (II) is a far better penetrant (J=6.95μg/cm2/h) of human epidermis than (I). Although fluxes of (III) and (IV) drop off markedly from that of (II), they remained above the flux of (I), which is (0.132μg/cm2/h). In conclusion, (II) was the best skin permeant and also exhibited the highest aqueous solubility and lowest level of crystallinity as compared to (I) and other analogues. (III) and (IV) were more lipophilic. The overall permeation data of this series indicated that the more water-soluble and the lowest melting point compound was the best skin permeant. [Copyright &y& Elsevier]

Advantages associated with the transdermal delivery route are well documented, but in the past scientists have concentrated primarily on means of decreasing the barrier function of the skin for improved permeability. Pro-drugs, which possess more favourable physicochemical properties for improved transdermal permeability may have considerable potential. These have been considered in the past but recent information concerning structure activity relationships in dermal penetration has prompted increased interest. During this study, N-methyl (2), N-ethyl (3) and N-(2-hydroxyethyl) carbamazepine (4) analogues were synthesised for transdermal evaluation. [Copyright &y& Elsevier]

Arthritis is a heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage. Major classes of drugs which are widely used for the treatment of arthritis are Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Development of an efficient means of percutaneous delivery can increase drug concentration in local soft-tissues and joints while reducing the systemic distribution of a drug and its side effects. The present work is aimed at synthesisand evaluation of prodrugs of some NSAIDs for percutaneous drug delivery for the treatment of arthritis.

Purpose. The purpose of this study was to determine the permeation parameters of thalidomide and three of its N-alkyl analogs and to establish a correlation between the physicochemical properties of these compounds and their percutaneous rates of absorption. Methods. In vitro permeation studies were performed from buffer, n-alkanols and various mixed components using vertical Franz diffusion cells fitted with human epidermal membranes. Results. Measured steady-state fluxes indicate that N-methyl thalidomide is a far better penetrant of human skin than the “parent molecule”. However, fluxes through skin drop off markedly from that of the methylated compound when the chain length is extended to propyl and pentyl. However, they remain well above the flux of thalidomide, which is less than 0.025 μg/cm2/h. Conclusions. The best skin permeant of this series was the N-methyl analog, which also exhibited the highest water (buffer) solubility compared to thalidomide, and the N-propyl and N-pentyl analogs. The N-propyl and N-pentyl analogs were more lipid soluble and exhibited higher partition coefficient values than the N-methyl analog. From all the permeability data using buffer, a series of n-alkanols and various combinations of solvents and enhancers as vehicles, the more water-soluble compound and not the more lipid soluble one was the best skin permeant. [ABSTRACT FROM AUTHOR]

Schematic diagram of cerosomes coloading methotrexate (MTX) and nicotinamide (NIC) and its effects on the alleviation of psoriatic skin. Cerosomes deliver MTX and NIC targeting to deeper skin layers to reduce the skin thickness and the expression of proinflammatory cytokines in psoriatic skin. [Display omitted] Psoriasis is an immune-mediated skin disorder that affects populations worldwide. Methotrexate (MTX) is a cytotoxic drug with powerful anti-proliferative and anti-inflammatory effects that has gained prominence in treating inflammatory diseases including psoriasis. However, low solubility and side effects through oral administration hinder its systemic application. In this study, we developed a novel niosomes based on ceramide (cerosomes) to co-deliver MTX and nicotinamide (NIC), i.e., MTX/NIC cerosomes, for topically treating psoriasis with the aim to enhancing the efficacy and reducing the toxicity. NIC significantly solublized MTX by forming hydrogen bonds with MTX. In vitro and in vivo permeation studies showed that the cerosomes significantly promoted drug permeation through and retention in the skin, and the enhancing mechanism was clarified by Fourier transform infrared and Raman spectroscopy. MTX/NIC cerosomes exhibited strong anti-proliferation effect on lipopolysaccharide- irritated HaCaT cells by arresting the cell cycle at S phase and inducing apoptosis. Importantly, compared to MTX oral administration, topical application of MTX/NIC cerosomes on imiquimod (IMQ)-induced psoriatic mouse model exhibited a superior performance in ameliorating skin lesions, reducing spleen index and epidermal thickness, and downregulating the mRNA expression levels of proinflammatory cytokines including TNFα, IL-23, IL-17A, IL-6, IL-1β, and IL-22. Taken together, MTX/NIC cerosomes is a promising approach for psoriasis topical treatment. [ABSTRACT FROM AUTHOR]

Gold nanoparticles functionalized with 3-mercapto-1-propansulfonate (AuNPs-3MPS) have been prepared and loaded with Methotrexate (MTX), an immunosuppressive agent used in the systemic treatment of moderate-severe inflammatory diseases. The effects of the AuNPs-3MPS@MTX topically administered in vitro on skin model and in vivo on imiquimod-induced psoriasis-like mice model, have been studied. Clinical response, epidermal thickness, cell proliferation rate and inflammation were tested. AuNPs-3MPS@MTX treated mice showed a decreasing of scaling and erythema score, reduction of epidermal thickness, parakeratosis and hyperkeratosis, compared to AuNPs-3MPS treated mice. Immunohistochemistry analysis staining displayed that Ki67, K6 CD3 and CD8 stainings were reduced in AuNPs-3MPS@MTX treated mice. Blood evaluation showed no differences in blood count and in ALT and AST levels before and after AuNPs-3MPS or AuNPs-3MPS@MTX treatment. Topical AuNPs-3MPS@MTX treatment is able to induce a reduction of keratinocytes hyperproliferation, epidermal thickness and also inflammatory infiltrate in vivo on imiquimod-induced psoriasis like mice model., (Published by Elsevier Inc.)

Arthritis is a heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage. Major classes of drugs which are widely used for the treatment of arthritis are Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Development of an efficient means of percutaneous delivery can increase drug concentration in local soft-tissues and joints while reducing the systemic distribution of a drug and its side effects. The present work is aimed at synthesisand evaluation of prodrugs of some NSAIDs for percutaneous drug delivery for the treatment of arthritis. [ABSTRACT FROM AUTHOR]