8-Oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine concentrations in various human body fluids: implications for their measurement and interpretation.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is the most investigated product of oxidatively damaged DNA lesion that has been associated with the development of aging, cancer and some degenerative diseases. Here, we present the first liquid chromatography-tandem mass spectrometry method that enables the simultaneous measurement of its repair products in plasma and saliva, namely 8-oxo-7,8-dihydroguanine (8-oxoGua) and 8-oxodGuo. Using this method, we investigated the underlying transport mechanism of the repair products of oxidatively damaged DNA between cellular compartments and biological matrices. Plasma, saliva and urine samples were collected concurrently from 57 healthy subjects. Various deproteinization methods were evaluated, and the precipitants acetonitrile and sodium hydroxide-methanol were, respectively, selected for plasma and saliva samples due to their effect on recovery efficiencies and chromatography. The mean baseline concentrations of 8-oxoGua and 8-oxodGuo in plasma were demonstrated to be 0.21 and 0.016 ng/mL, respectively, while in saliva they were 0.85 and 0.010 ng/mL, respectively. A relatively high concentration of 8-oxoGua was found in saliva with a concentration factor (CF, concentration ratio of saliva to plasma) of 4 as compared to that of 8-oxodGuo (CF: 0.6), implying that 8-oxoGua in plasma may be actively transported to saliva, whereas 8-oxodGuo was most dependent on a passive diffusion. Good correlations between urine and plasma concentrations were observed for 8-oxoGua and 8-oxodGuo, suggesting that blood was a suitable matrix in addition to urine. Significant correlation between 8-oxoGua and 8-oxodGuo in urine was only observed when the concentrations were not corrected for urinary creatinine, raising the issue of applicability of urinary creatinine to adjust 8-oxoGua concentrations.

The effect of component of microemulsion for transdermal delivery of nicardipine hydrochloride.

PURPOSE: Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study. METHODS: Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study. RESULTS: The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content. CONCLUSIONS: The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53 ± 1.87 µg/cm2/h and was expected to develop a transdermal delivery system.

Comparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapy.

Topical photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for many non-melanoma skin cancers. The major limitation of this therapy, however, is the low permeability of ALA through the stratum corneum (SC) of the skin. The objective of the present work was to characterize ethosomes containing ALA and to enhance the skin production of protoporphyrin IX (PpIX), compared to traditional liposomes. Results showed that the average particle sizes of the ethosomes were less than those of liposomes. Moreover, the entrapment efficiency of ALA in the ethosome formulations was 8-66% depending on the surfactant added. The particle size of the ethosomes was still approximately <200 nm after 32 days of storage. An in vivo animal study observed the presence of PpIX in the skin by confocal laser scanning microscopy (CLSM). The results indicated that the penetration ability of ethosomes was greater than that of liposomes. The enhancements of all the formulations were ranging from 11- to 15-fold in contrast to that of control (ALA in an aqueous solution) in terms of PpIX intensity. In addition, colorimetry detected no erythema in the irradiated skin. The results demonstrated that the enhancement ratio of ethosome formulations did not significantly differ between the non-irradiated and irradiated groups except for PE/CH/SS, which may have been due to a photobleaching effect of the PDT-irradiation process.

Physicochemical and safety evaluation of 5-aminolevulinic acid in novel liposomes as carrier for skin delivery.

In this study we successfully entrapped 5-aminolevulinic acid (ALA) in liposome, although it exists as a zwitter ion. A molar ratio of 2:1:2.5 phosphatidyle-thanolamine (PE)/cholesterol/sodium stearate represented the best condition to achieve high entrapment efficiency (29.37 +/- 1.21%), and the average vehicle size was 133.6 +/- 2.8 nm. After 32 days of storage, the vehicle sizes of formulations with PE series were still approximately less than 200 nm. The safety of liposomes was tested and ensured both with regard to cellular cytotoxicity and erythrocyte hemolysis. Safety studies showed that liposome formulations did not affect cell viability except when both potassium stearate and sodium oleate were added. Moreover, PE and PE/cholesterol did not damage human erythrocytes in this study. The range of the hemolytic effect caused by liposomes was 5 to 37% and the effect was dependent on the amount of sodium stearate added to the formulation. According to the release rates and skin penetration of ALA liposomes in vitro, PE/cholesterol/sodium stearate liposomes might increase skin penetration, and it was shown that penetration across the stratum-corneum (sc) layer was the rate-limiting process. Images from confocal laser scanning microscopy (CLSM) confirmed the great potency of liposomes for delivering ALA into skin.

Development of pH-Sensitive Cationic PEGylated Solid Lipid Nanoparticles for Selective Cancer-Targeted Therapy.

Solid lipid nanoparticles (SLNs) are suitable candidates for the delivery of various anti-cancer drugs. However, currently insufficient tumor-permeability and non-specific uptake by the reticuloendothelial system limits the application of SLNs. Here, we developed novel pH-sensitive cationic polyoxyethylene (PEGylated) SLNs (PEG-SLNs+) that could accumulate long-term at various tumor sites to enhance the therapeutic efficiency of camptothecin (CPT). These CPT-loaded PEG-SLNs+ (CPT-PEG-SLNs+) were spherical nanoparticles, with small size (∼52.3±1.7 nm), positive charge (∼34.3±3.5 mV) and high entrapment efficiency (∼99.4±1.7%). Drug release profile indicated the overall released amount of CPT from CPT-PEG-SLNs+ at pH 5.5 was 20.2% more than at pH 7.4, suggesting CPT-PEG-SLNs+ were a pH-sensitive SLNs. This PEG-SLNs+ could be efficiently uptaken into cells to inhibit the proliferation of CL1-5 cells (IC50 = 0.37 ±0.21 ug/ml) or HCC36 cells (IC50 = 0.16±0.43 ug/ml). In living animal, our PEG-SLNs+ could accumulate long-term (for more than 120 hours) in various types of tumor, including human lung carcinoma (NCI-H358, CRL5802, CL1-5), human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HCC36), and CPT-PEG-SLNs+ could efficiently enhance the therapeutic efficiency of CPT to suppress the growth of the HCC36 or CL1-5 tumors. Therefore, Successful development of these pH-sensitive PEGylated cationic SLNs may provide a selective and efficient drug delivery system for cancer therapy.

Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology.

The purpose of this study was to optimize the pH-dependent release of nicardipine hydrochloride extended release formulations by using simultaneously combination two hydrophilic polymers: hydroxypropylmethylcellulose (HPMC) and sodium alginate as retardant and avicel as additive. The constrained mixture experimental design was used to prepare systematic model formulations which were composed of three formulation variables: the content of HPMC (X1), avicel (X2), and sodium alginate (X3). The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals and to quantify the effect of each formulation variables. The drug release percent at 3, 6 and 12 h were the target responses and were restricted to 10-30% (Y3h), 40-65% (Y6h) and not less than 80% (Y12h), respectively. The results showed that the effect of combination of HPMC and sodium alginate was the most influence factor on the drug release from extended-release matrix tablets. The observed results of Y3h, Y6h and Y12h coincided well with the predictions in the RSM optimization technique, indicating it was quite useful for optimizing pharmaceutical formulation. The mechanism of drug release from extended-release matrix tablets was dependent on the added amount of alginate. The release kinetic of drug from HPMC matrix tablets with alginate was followed the zero-order release pattern.

Chitin/PLGA blend microspheres as a biodegradable drug-delivery system: phase-separation, degradation and release behavior.

A novel chitin-based microsphere was developed for anti-cancer drug-delivery purpose in the present study. These biodegradable microspheres were prepared by directly blending chitin with different contents of poly(D,L-lactide-co-glycolide 50:50) (PLGA 50/50) in dimethylacetamide-lithium chloride solution, and following it by coagulating in water via wet phase inversion. Scanning electron microscopy (SEM) micrography of the blend microsphere showed that there are numerous PLGA particulates homogeneously dispersed in chitin matrix, suggesting the occurrence of obvious phase separation from the blended chitin and PLGA 50/50 phase due to their thermodynamic incompatibility. Degradation of the chitin/PLGA 50/50 blend microsphere depends on the surface erosion of chitin phase and bulk hydrolysis of PLGA phase, according to the examinations of SEM and differential scanning calorimetry studies. Weight loss of the chitin/PLGA 50/50 blend microsphere increases with the increase of chitin content in the microsphere. A two-phase drug-release model is observed from the release of chlorambucil from chitin/PLGA 50/50 blend microspheres. The initial stage of drug-release rate increases with the increased chitin content due to the hydration and surface erosion of hydrophilic chitin phase; however, the following stage of slow release is sustained for several days, mainly contributed by the bulk hydrolysis of hydrophobic PLGA phase. In conclusion, such a chitin/PLGA 50/50 blend microsphere is novel and interesting, and may be used as a special drug-delivery system.

Chitin/PLGA blend microspheres as a biodegradable drug delivery system: a new delivery system for protein.

Novel chitin/PLGAs and chitin/PLA based microspheres were developed for the delivery of protein. These biodegradable microspheres were prepared by polymers blending and wet phase-inversion methods. The parameters such as selected non-solvents, temperature of water and ratio of polylactide to polyglycolide were adjusted to improve thermodynamic compatibility of individual polymer (chitin and PLGAs or chitin/PLA), which affects the hydration and degradation properties of the blend microspheres. Triphasic pattern of drug release model is observed from the release of protein from the chitin/PLGAs and chitin/PLA microspheres: the initially fast release (the first phase), the following slow release (the second phase) and the second burst release (the third phase). Formulations of the blends, which are based on the balance among the hydration rate of the chitin phase and degradation of chitin/PLA and PLGA phase, can lead to a controllable release of bovine serum albumin (BSA). In conclusion, such a chitin/PLGA 50/50 microsphere is novel and interesting, and may be used as a protein delivery system.

Once-daily propranolol extended-release tablet dosage form: formulation design and in vitro/in vivo investigation.

The purpose of this study was to develop and optimize the propranolol once-daily extended release formulations containing HPMC, Microcrystalline cellulose (MCC) and lactose. In vitro studies, the response surface methodology and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals. The constrained mixture experimental design was used to prepare systematic model formulations, which were composed of three formulation variables: the content of HPMC (X(1)) MCC (X(2)) and lactose (X(3)). The drug release percent at 1.5, 4, 8, 14 and 24 h were the target responses and were restricted to 15-30, 35-55, 55-75, 75-90 and 90-110%, respectively. The results showed that the optimized formulation provided a dissolution pattern equivalent to the predicted curve, which indicated that the optimal formulation could be obtained using response surface methodology. The mechanism of drug release from HMPC matrix tablets followed non-Fickian diffusion. In the vivo study, the MRT was prolonged for matrix tablets when compared with commercial immediate release tablets. Furthermore, a linear relationship between in vitro dissolution and in vivo absorption was observed in the beagle dogs.

Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit.

The aim of the present work was to prepare and evaluate the sustained release of potassium chloride formulations. Eudragit RS and/or RL loaded with potassium chloride microspheres were prepared by a solvent evaporation method. The effect of sustained release of Eudragit microspheres was evaluated by an in vitro dissolution test and in vivo oral absorption study, and the results were compared to a commercial product (Slow-K). The results showed that Eudragit microspheres loaded with potassium chloride can be easily prepared and satisfactory results obtained considering the size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-90% and 27%, respectively. Moreover, the Eudragit RS (30-45 mesh) and Eudragit RS/RL (20-30 mesh) microspheres showed a similar sustained release effect of commercial product via in vitro dissolution and in vivo oral absorption study.

In vitro and in vivo evaluation of potassium chloride sustained release formulation prepared with saturated polyglycolyed glycerides matrices.

The aim of the present work was to evaluate the effect of sustained release of potassium chloride semi-solid matrices prepared with different kinds and added amounts of Gelucires by the in vitro dissolution test and in vivo oral absorption study, and compared with a commercial product (slow-K). The results indicating that the release rates of potassium from experimental formulations were dependent on the type of semi-solid matrices (Gelucires). The higher the melting point of the Gelucires was incorporated, the slower release rate of the active substance was observed. Moreover, the values of similarity factor of Formulae F05 and F09 versus the reference in three kinds of dissolution medium (f(2)) were higher than 50, indicating that these experimental formulations had similar sustained release effects to the reference (slow-K) in dissolution test. In vivo study, the cumulative amount (mEq) of potassium excreted curve and the excretion rate curve of F05 and F09 were found to be similar to that of slow-K, and there were no significant differences (P > 0.05) in the maximum excretion rate and the mean time to reach the maximum rate between formulations and slow-K, indicating that the potassium chloride sustained release dosage form could be prepared using the Gelucires as lipid excipients.

The characterization and biodistribution of cefoxitin-loaded liposomes.

To conquer the clinical restriction of relative short half-life and poor tissue retaining activities, liposomes containing cefoxitin were prepared using three methods in this study. The physicochemical properties including cefoxitin encapsulation percentage, vesicle size, stability, as well as the in vivo biodistribution were studied. The highest entrapment percentage was observed by using reverse phase evaporation method, and the molar ratio of cefoxitin to phospholipids was 1:3, DMPC to cholesterol was 2:1, respectively. From the result of stability, the freeze-drying powder and then stored in the frozen condition of cefoxitin-loaded liposome was an ideal storage state. Accordingly, the formulation by reverse-phase evaporation method was selected to investigate the biodistribution of cefoxitin-loaded liposome and compared to free cefoxitin in rats. It was observed that the cefoxitin levels and the duration retained in the liver, spleen, and pancreas of liposome-injected animals were higher and longer than that of free cefoxitin-injected animals. The drug concentrations of bile after post-injection of liposomal cefoxitin at 0.5, 1 and 2 h were all approximately 2.7 times higher than that of free cefoxitin injection group.

Preparation and evaluation of sustained release microspheres of potassium chloride prepared with ethylcellulose.

The water-insoluble polymer ethylcellulose is used as a retardant to prepare the sustained release of potassium chloride microspheres by drying in a liquid process. The effect of sustained release of potassium from ethylcellulose microspheres was evaluated by the in vitro dissolution test, and was compared to a commercial product (Slow-K). The results showed that ethylcellulose microspheres loaded with potassium chloride could be easily prepared and satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-93 and 36%, respectively. However, the potassium/ethylcellulose 2/2 (30-45 mesh) microspheres showed the similar sustained release effect of commercial product.

Effect of microemulsions on transdermal delivery of citalopram: optimization studies using mixture design and response surface methodology.

The aim of this study was to evaluate the potential of microemulsions as a drug vehicle for transdermal delivery of citalopram. A computerized statistical technique of response surface methodology with mixture design was used to investigate and optimize the influence of the formulation compositions including a mixture of Brij 30/Brij 35 surfactants (at a ratio of 4:1, 20%-30%), isopropyl alcohol (20%-30%), and distilled water (40%-50%) on the properties of the drug-loaded microemulsions, including permeation rate (flux) and lag time. When microemulsions were used as a vehicle, the drug permeation rate increased significantly and the lag time shortened significantly when compared with the aqueous control of 40% isopropyl alcohol solution containing 3% citalopram, demonstrating that microemulsions are a promising vehicle for transdermal application. With regard to the pharmacokinetic parameters of citalopram, the flux required for the transdermal delivery system was about 1280 µg per hour. The microemulsions loaded with citalopram 3% and 10% showed respective flux rates of 179.6 µg/cm(2) and 513.8 µg/cm(2) per hour, indicating that the study formulation could provide effective therapeutic concentrations over a practical application area. The animal study showed that the optimized formulation (F15) containing 3% citalopram with an application area of 3.46 cm(2) is able to reach a minimum effective therapeutic concentration with no erythematous reaction.

Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery.

BACKGROUND: The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. AIMS: To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. RESULTS: The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%-64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs with PEG was found in the lung and spine. CONCLUSION: Sufficient amounts of PK-L4 were entrapped in the SLNs, and the pharmacokinetic behavior of PK-L4-loaded SLNs was established. This formulation successfully resolved the delivery problem, and the drug was localized in particular organs.

Characterization of the pattern of ischemic stroke induced by artificial particle embolization in the rat brain.

Embolism is responsible for half of cerebral infarctions, yet few animal models were developed due to the unpredictability of the embolus-induced infarcts. We manufactured artificial embolic particles by blending chitin and poly(D,L-Lactide-co-glycolide) (chitin/PLGA) for their good biocompatibility and rapid hydration expansion property. We subdivided the chitin/PLGA microparticles into 10 size groups (from 38-45 µm to 255-350 µm) and injected them through the external carotid artery toward the bifurcation of the common carotid artery in the rat. Reduced blood flow of the ipsilateral hemisphere was evident immediately after the injection of particles. The spherical appearance of the particle was critical in occluding the cerebral vessels. Particle(212-250 µm) produced the greatest diffuse infarction in the ipsilateral hemisphere, including the cortex, hippocampus, basal ganglion, thalamus, midbrain and cerebellum. Particle(75-90 µm) induced single or sparse isolated infarcts mainly located in the subcortical region, resembling lacunar stroke observed in humans. Particle(38-45 µm) frequently crossed to the contralateral hemisphere and induced diffuse infarctions in both hemispheres. The cortex infarct volumes were positively correlated to neurologic score and seizure incidence. In conclusion, we have established embolic stroke animal models, including a novel model that mainly expresses lacunar infarction, by intravenous injection of chitin/PLGA microparticles.

Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations.

Apomorphine, a dopamine receptor agonist for treating Parkinson's disease, has very poor oral bioavailability (<2%) due to the first-pass effect. The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of apomorphine could be improved by utilizing solid lipid nanoparticles (SLNs). Glyceryl monostearate (GMS) and polyethylene glycol monostearate (PMS) were individually incorporated into SLNs as emulsifiers. It was found that variations in the emulsifiers had profound effects on the physicochemical characteristics. Mean diameters of the GMS and PMS systems were 155 and 63 nm, respectively. More than 90% of the apomorphine was entrapped in the SLNs. The interfacial film was the likely location for most of apomorphine molecules. The PMS system, when incubated in simulated intestinal medium, was found to be more stable in terms of particle size and encapsulation efficiency than the GMS system. Using the GMS and PMS systems to orally administer apomorphine (26 mg/kg) equally enhanced the bioavailability in rats. SLNs showed 12- to 13-fold higher bioavailability than the reference solution. The drug distribution in the striatum, the predominant site of therapeutic action, also increased when using the SLNs. The anti-Parkinsonian activity of apomorphine was evaluated in rats with 6-hydroxydopamine-induced lesions, a model of Parkinson's disease. The contralateral rotation behavior was examined after oral apomorphine delivery. The total number of rotations increased from 20 to 94 and from 20 to 115 when the drug was administered from SLNs containing GMS and PMS, respectively. The experimental results suggest that SLNs may offer a promising strategy for apomorphine delivery via oral ingestion.

Elastic liposomes as carriers for oral delivery and the brain distribution of (+)-catechin.

The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of (+)-catechin could be improved by utilizing elastic liposomes. Liposomes containing soy phosphatidylcholine, cholesterol, and Tween 80 in the presence of 15% ethanol were prepared by a thin-film method and subsequent sonication and extrusion. The size, zeta potential, and stability of the liposomes in simulated gastrointestinal (GI) media were characterized. The mean size of liposomes was 35-70 nm, which decreased with an increase in the Tween 80 concentration. The zeta potential of the system was about-15 mV. More than 80% of the (+)-catechin was entrapped in the aqueous core of liposomes produced with 1% Tween 80. Liposomes entrapping (+)-catechin remained stable in the presence of GI fluids, especially in simulated intestinal fluid. The liposomes showed suppressed and sustained release of (+)-catechin compared with that from an aqueous solution. The aqueous control and liposomes were orally administered to rats. The blood level of liposomal (+)-catechin was enhanced at a later stage after administration compared with the free control. In the experiment on the brain distribution, liposomes with elastic properties showed 2.9- and 2.7-fold higher (+)-catechin accumulations compared with the aqueous solution in the cerebral cortex and hippocampus, respectively. Greater compound accumulations with liposomes were also detected in the striatum and thalamus. The experimental results suggest that elastic liposomes may offer a promising strategy for improving (+)-catechin delivery via oral ingestion.

Topical delivery of 5-aminolevulinic acid-encapsulated ethosomes in a hyperproliferative skin animal model using the CLSM technique to evaluate the penetration behavior.

Psoriasis, an inflammatory skin disease, exhibits recurring itching, soreness, and cracked and bleeding skin. Currently, the topical delivery of 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) is an optional treatment for psoriasis which provides long-term therapeutic effects, is non-toxic and enjoys better compliance with patients. However, the precursor of ALA is hydrophilic, and thus its ability to penetrate the skin is limited. Also, little research has provided a platform to investigate the penetration behavior in disordered skin. We employed a highly potent ethosomal carrier (phosphatidylethanolamine; PE) to investigate the penetration behavior of ALA and the recovery of skin in a hyperproliferative murine model. We found that the application of ethosomes produced a significant increase in cumulative amounts of 5-26-fold in normal and hyperproliferative murine skin samples when compared to an ALA aqueous solution; and the ALA aqueous solution appeared less precise in terms of the penetration mode in hyperproliferative murine skin. After the ethosomes had been applied, the protoporphyrin IX (PpIX) intensity increased about 3.64-fold compared with that of the ALA aqueous solution, and the penetration depth reached 30-80 microm. The results demonstrated that the ethosomal carrier significantly improved the delivery of ALA and the formation of PpIX in both normal and hyperproliferative murine skin samples, and the expression level of tumor necrosis factor (TNF)-alpha was reduced after the ALA-ethosomes were applied to treat hyperproliferative murine skin. Furthermore, the results of present study encourage more investigations on the mechanism of the interaction with ethosomes and hyperproliferative murine skin.

Electrically-assisted skin permeation of two synthetic capsaicin derivatives, sodium nonivamide acetate and sodium nonivamide propionate, via rate-controlling polyethylene membranes.

The objective of this study was to examine the transdermal delivery of sodium nonivamide acetate (SNA) using iontophoresis and electroporation with ultra high molecular weight polyethylene membranes (Solupor) to achieve controlled transdermal drug delivery. A derivative of SNA, sodium nonivamide propionate (SNP), was also used as a model drug in this investigation. Iontophoresis increased the transdermal permeation of SNA as compared to passive diffusion. Most Solupor membranes were rate-limiting for the iontophoretic permeation of SNA except for Solupor 8P07, which showed negligible resistance to SNA delivery. The tortuosity (Gurley number), pore size, and the current density-induced attachments on the surface of the Solupor membranes may have been important for their rate-controlling effect. The trends for inhibiting or controlling SNA permeation were similar for both iontophoretic and electroporation applications. The higher molecular size and lower hydrophilicity of SNP compared to SNA resulted in lower permeation of SNP using electrically-assisted methods. Moreover, the various types of Solupor membranes showed similar trends for both SNA and SNP. This present study indicates that Solupor membranes act as rate-limiting membranes for controlling the release and skin permeation of both SNA and SNP by electrically-assisted methods.