Influence of chemical penetration enhancers on skin permeability of ellagic acid-loaded niosomes

This study aimed to develop niosomes of ellagic acid(EA),a potent antioxidant phytochemical substance,for dermal delivery and to investigate the influence of chemical penetration enhancers on the physicochemical properties of EA-loaded niosomes.The EA niosomes were prepared by reverse phase evaporation method using Span 60,Tween 60 and cholesterol as vesicle forming agents and Solulan C24 as a steric stabilizer.Polyethylene glycol 400(PEG)was used as a solubilizer while dimethylsulfoxide(DMSO)or Nmethyl-2-pyrrolidone(NMP)was used as a skin penetration enhancer.It was found that the mean particle sizes of EA-loaded niosomes were in the range of 312e402 nm with PI values of lower than 0.4.The niosomes were determined to be spherical multilamellar vesicles as observed by transmission electron microscope and optical microscopy.All niosomes were stable after 4 months storage at 4
C.In vitro skin permeation through human epidermis revealed that the skin enhancers affected the penetration of EA from the niosomes at 24 h.The DMSO niosomes showed the highest EA amount in epidermis;whereas the NMP niosomes had the highest EA amount in the acceptor medium.Concomitantly,the skin distribution by confocal laser scanning microscopy showed the high fluorescence intensity of the DMSO niosomes and NMP niosomes at a penetration depth of between 30e90 mm(the epidermis layer)and 90e120 mm(the dermis layer)under the skin,respectively.From the results,it can be concluded that the DMSO niosomes are suitable for epidermis delivery of EA while the NMP niosomes can be used for dermis delivery of EA.

Influence of short chain ceramides and lipophilic penetration enhancers on the nano-structure of stratum corneum model membranes studied using neutron diffraction

Oriented stratum corneum model lipid membranes were used to study the influence of the short chain ceramides （CER）[NP] and [AP] as well as the impact of the lipophilic penetration enhancer molecules oleic acid （OA） and isopropyl myristate （IPM） on the lipid nanostrueture. The influence of the enhancer molecules were studied using specifically deuterated OA and IPM and neutron diffraction. 2H NMR spectroscopy was used to study the impact of the ceramides＇ degree of order within the stratum corneum model lipid membranes. It was found that CER[NP] forms two very stable phases with high resistance against temperature increase. Phase B showed unusual hydration behavior as no water uptake of this phase was observed. The 2H NMR spectroscopic measurements showed that CER[NP] based ternary model system had a higher state of lamellar order in comparison to CER[AP] based lipid matrix. The studies confirmed that the short chain ceramides, particularly CER[NP], have a very high impact on the integrity of the Stratum comeum lipid bilayers. The penetration enhancer OA has not influenced the repeat distance of the model membrane based on CER[AP], and was not able to induce a phase separation in the investigated lipid matrix. However, a disorder and a fluidisation of the model membranes were observed when OA was incorporated. IPM showed the same effect but two phases （assigned as phase A and B） appeared, when IPM was used as penetration enhancer and incorporated into the model membrane. Furthermore, two arrangements of IPM were identified in phase A using deuterated IPM. A model of the nanostructure of the Stratum corneum lipid membranes is presented.

Investigating a Vitamin D Delivery Toothpaste Using a Penetration Enhancer Compound

Expanding in the oral care business, being passionately driven by innovative and scientific products, functional toothpaste has recently become more popular for functionality, variety, and efficacy. Many new types of toothpaste are commercially manufactured with diverse fragrances, colors, probiotics, and pharmaceutical ingredients to enhance the functionalities of toothpaste. Our study attempted to create a toothpaste formulation that might facilitate the intraoral delivery of vitamin D3 into the bloodstream. Simply brushing our teeth with toothpaste should be easy to take the essential vitamin regularly. In this study, an emulsion-based toothpaste mixed with an azone compound and sodium dodecyl sulfate as penetration enhancers blended thoroughly with other ingredients and then with vitamin D. Multiple toothpaste characteristic tests were performed, such as abrasiveness, scratchiness, spreadability, pH, foaming, cleaning, and antibacterial strength with our vitamin D toothpaste, and compared with those of other commercial brand toothpaste. To confirm the intraoral delivery of vitamin D through the oral cavity, an earthworm transport study and TEER value test were conducted using L. terrestris skin. Our data demonstrated the high feasibility of intraoral delivery of vitamin D based on those two skin studies with various experimental support;our vitamin D toothpaste had comparable characteristics with other commercial toothpaste for cleaning functionality.

Percutaneous penetration enhancement effect of essential oil of mint (Mentha haplocalyx Briq.) on Chinese herbal components with different lipophilicity

Objective:To investigate the percutaneous penetration effect of essential oil of mint from Mentha haplocalyx Briq.on the complex active components in Chinese herbal external preparations,and assess its toxicity on the skin cells.Methods:The cytotoxicity of mint oil on HaCaT keratinocytes and CCC-ESF-1 fibroblasts was measured using an MTT assay.Five model drugs with a wide range of lipophilicity,namely osthole,tetramethylpyrazine,ferulic acid,puerarin,and geniposide,were tested using in vitro permeation studies to investigate the percutaneous penetration enhancement effect of mint oil.Secondary structure alterations of skin stratum corneum(SC)were measured using Fourier transform infrared spectroscopy(FTIR).Saturation solubilities and SC/vehicle partition coefficients of the five model drugs with and without mint oil were also determined to understand the potential mechanisms of the essential oil.Results:Half maximal inhibitory concentration(IC50)values of mint oil were significantly higher in HaCaT and CCC-ESF-1 cell lines than values in the well-established and standard penetration enhancer Azone.Conclusions:Mint oil at proper concentration could effectively facilitate percutaneous penetration of both lipophilic and hydrophilic drugs,and exhibit higher efficiency for moderate hydrophilic drugs.Mechanisms of penetration enhancement by mint oil could be explained with saturation solubility,SC/vehicle partition coefficient and the secondary structure change of SC.

IMPROVE OPTICAL CLEARING OF SKIN IN VITRO WITH PROPYLENE GLYCOL AS A PENETRATION ENHANCER

In order to enhance the optical clearing effect of topically applied optical clearing agents(OCAs),we evaluated the effect of propylene glycol(PG)as a chemical penetration enhancer(PE)on optical clearing of skin in vitro by observation and measurement of optical-transmittance and diffuse-reflectance spectra.Three OCAs,i.e.,glycerol,D-sorbitol and PEG400,and two other penetration enhancers,Azone and Thiazone,were used in this study.The results indicated that the decrease of reduced scattering coefficient caused by OCA/PG was larger than that by pure OCA,and the change by OCA/water was the least after the same treatment time.There were significant differences for the reduced scattering coefficient at 630 nm after 120 min application of agents between OCA and OCA/PG.The efficacy of optical clearing caused by OCA/PG depended on the OCA itself.When PEG400 was mixed with three different PEs,we found the optical clearing were different.The penetration enhancing ability of PG was much better compared to Azone,and suboptimal to Thiazone.Also,this study provides evidence for the use of PG as a PE in order to improve skin optical clearing.

Transdermal permeation of Zanthoxylum bungeanum essential oil on TCM components with different lipophilicity

Objective:To investigate the percutaneous penetration enhancement effect of essential oil from Zanthoxylum bungeanum Maxim.(Z.bungeanum oil)on active components in externally-applied traditional Chinese medicines.Methods:Five model drugs,geniposide,puerarin,ferulic acid,tetramethylpyrazine,and osthole,were chosen based on their lipophilicity and tested using in vitro transdermal permeation studies consisting of Franz diffusion cells and full thickness rat abdominal skin.Scanning electron microscopy was employed to observe the morphological changes of rat skin tissue after treatment with Z.bungeanum oil.The molecular interactions between the oil and the polar head groups in stratum corneum(SC)lipids were monitored using molecular dynamic simulation,and the SC/vehicle partition coefficients and saturation solubilities of the selected model drugs treated with and without the oil were also determined to ascertain its mechanisms of action.Results:As oil concentration increased,the log ERflow trended toward a negative linear relationship with the lipophilicity of drugs.After treatment with Z.bungeanum oil,a mild lifting up and wrinkle on the SC surface were observed,and appeared to become more pronounced as oil concentration increased.There was no significant difference between the control and the Z.bungeanum oil at different concentrations in terms of saturation solubility of GP,while saturation solubilities of the 4 other drugs gradually increased as oil concentration increased.The oxygen-containing constituents in Z.bungeanum oil,such as terpinen-4-ol and 1,8-cineole,which accounted for 57.95%of total oil,could form stable hydrogen bonds with the polar head group of ceramide 3.Conclusion:Z.bungeanum oil facilitated transdermal permeation of drugs with different lipophilicity,including the extremely hydrophilic and lipophilic drugs,whereas it exhibited greater enhancement activity for strongly hydrophilic drugs.The mechanisms of transdermal permeation enhancement by the oil could be explained with SC/vehicle partition coefficient,saturation solubility,and the interactions with SC lipids.

Ballistic limit and residual velocity of PELE penetrating against metal target

Based on analyzing the conservation of energy of penetrator with enhanced lateral efficiency （PELE） the penetrating against metal target, a theoretical expression predicting the residual velocity of PELE perforating the target is obtained. By modifying De Marre semi-experience formula,the ballistic limit velocities of PELE penetrating into 2024 aluminum alloy and 45# steel targets are also given. The theoretical predictions fit well with experimental or simulative results.

Effect of projectile parameters on opening behavior of PELE penetrating RC target

When a penetrator with enhanced lateral effect(PELE) impacts on a reinforced concrete(RC) target,the target is damaged with a large opening.An understanding of how PELE projectile parameters affect the opening dimension,is essential for effective design of the PELE projectile.In this study,under the condition that the impact velocity and target parameters(strength and thickness) were fixed values,the important influence factors of the PELE(jacket wall thickness B,jacket material strength Y1,filling material strength Y2 and angle of monolithic jacket θ) were determined by a dimensional analysis.Tests and simulations of the PELE penetrating the RC target were conducted to analyze the influence of these factors on opening diameter(D,an equivalent diameter under relative kinetic energy).Based on the test and simulation results,it is found that the influence of these factors B,Y1 and θ on the deformation mode of the jacket shows a similar trend:as values of the three factors decrease,the jacket deforms from small bending deformation to large one,and then to curling deformation.This causes the opening diameter to first increase with the decrease of these three factors,and then decreases.It is well known that the bending resistance of the jacket is related to these factors B,Y1 and θ.Therefore,a plastic limit bending moment(M0) of the jacket was quoted to characterize the influence of these factors on the bending deformation of the jacket and the opening diameter of the target.The influence factor Y2 causes D to first increase with the increase of Y2,and then decreases.A formula was developed to predict the opening diameter,whose influence parameters were considered in a dimensionless way.It has been shown that the dimensionless opening diameter D/d1 is dependent on two dimensionless parameters■ and■,where d1 and fc are the outer diameter of the projectile and the compressive strength of the target,respectively.

Efficacy and mechanism of methyl salicylate in the enhancement of skin delivery of herbal medicines

Objective: To elucidate the molecular mechanism(s) by which methyl salicylate enhances the skin delivery of herbal ingredients with diverse lipophilicity.Methods: The toxicity of methyl salicylate on skin cell lines was evaluated using the MTT assay. The Franz diffusion cell method was used to measure the permeability enhancing activities of methyl salicylate for five herbal ingredients with a range of lipophilicities. The interaction between methyl salicylate and the stratum corneum(SC) was observed by using an infrared spectroscopy technique. Moreover, the solubilities and SC-vehicle partition coefficient were determined to monitor the impact of methyl salicylate on the drug thermodynamic activities and partition into the SC layer, respectively.Results: Compared with azone(1-dodecylazacycloheptan-2-one), methyl salicylate showed lower toxicity to skin cells in terms of the IC50 values. The in vitro skin permeation studies showed that methyl salicylate could greatly improve the cumulative amounts or steady state flux of the selected model drugs with the exception of osthole, which indicated that methyl salicylate was prone to promote the skin delivery of hydrophilic drugs. The Fourier transform infrared spectroscopy studies revealed that methyl salicylate mainly interacted with SC lipids, leading to the disruption of the orderly arrangement of the SC.In addition, methyl salicylate had no obvious effect on the drug thermodynamic activity and partition into the SC.Conclusion: Methyl salicylate could effectively promote the skin delivery of relatively hydrophilic ingredients in externally used traditional Chinese medicines(TCM) without obvious cytotoxicity.

Enzyme-triggered deep tumor penetration of a dual-drug nanomedicine enables an enhanced cancer combination therapy

Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging nanomedicines.However,tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site,and ROS at a low level promote tumor cell growth,thus diminishing the therapeutic effect of these nanomedicines.Herein,we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine(Lap@pOEGMA-b-p(GFLG-Dendron-Ppa),GFLG-DP/Lap NPs)that incorporates a photosensitizer,Pyropheophorbide a(Ppa),for ROS therapy and Lapatinib(Lap)for molecular targeted therapy.Lap,an epidermal growth factor receptor(EGFR)inhibitor that plays a role in inhibiting cell growth and proliferation,is hypothesized to synergize with ROS therapy for effectively killing cancer cells.Our results suggest that the enzyme-sensitive polymeric conjugate,pOEGMA-b-p(GFLG-Dendron-Ppa)(GFLG-DP),releases in response to cathepsin B(CTSB)after entering the tumor tissue.Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes,which promotes efficient penetration and long-term retention.Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity.Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis.Meanwhile,Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions,thus generating a significant synergistic anti-tumor therapeutic effect.This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.

Enhanced penetration strategies for transdermal delivery

Transdermal delivery offers several advantages in drug distribution,including convenience,painless administration,avoidance of first-pass metabolism,and ease of termination.However,the natural protective barriers of the skin,such as the stratum cormeum,the topmost layer of skin,limit the systemic absorption of extermal therapeutics via transdermal delivery.Therefore,extensive application of transdermal delivery in medical treatment has been limited.Over the past few years,many formulation strategies and physical technologies,therefore,have been developed to enhance transdermal delivery.This review summarizes various formulation strategies pro-posed for transdermal delivery and their application in medical treatment.

Nanomedicine-based treatment:An emerging therapeutical strategy for pulmonary hypertension

Pulmonary hypertension(PH)can cause breathing difficulty,a rapid decline of exercise capacity,heart failure,eventually death of the patients.The latest epidemiological study demonstrates that PH has a much higher incidence than previously thought.PH is still a highly fatal disease due to the many disadvantages of the current drugs,such as short half-life,lack of targeting,potent side effects.The PH pathological features offer great opportunities for nanomedicines for PH.Recently,emerging nanomedicines demonstrated great advantages in the therapeutic effect of PH by enhancing the accumulation of drugs in PH lesion,optimizing drug efficacy,minimizing drug side effects.However,this promising field of cross-cutting research is far from being widely explored due to the huge professional barriers.To solve this problem,we provide a comprehensive review for the latest progresses of nanomedicines in the treatment of PH.Firstly,we systematical summarized the PH pathological features and the current clinical drug treatment of PH.The advantages of nanomedicines are also deeply discussed in the treatment of PH.Subsequently,we focused on the research progresses of nanomedicines in PH through three aspects:advanced nano-drug delivery system for traditional drugs and new target drugs,gene therapy-based nanomedicines,other nanomedicines for the treatment of PH.Finally,we also discussed the prospects and challenges for the clinical application of nanomedicines in PH,provided directions for the research and development of nanomedicines for PH treatment in the future.

Bioorthogonal Prodrug–Antibody Conjugates for On-Target and On-Demand Chemotherapy

Current antibody–drug conjugates(ADCs)suffer from low tissue penetration and significant side effects,largely due to the permanent linkage and/or premature release of cytotoxic payloads.Herein,we developed a prodrug–antibody conjugate(ProADC)strategy by conjugating a bioorthogonal-activatable prodrug with an antibody that allowed on-target release and on-demand activation of cytotoxic drugs at a tumor site.The bioorthogonal-caged prodrug exhibited an enhanced permeability into and on-demand activation within cancer cells,while the pH-sensitive ADC linker allowed on-target release of the anticancer agent.Together,the ProADCs showed enhanced tumor penetration and alleviated side effects for use as an on-target and on-demand chemotherapy agents.