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The aim of this study was to develop and assess the potential of nanostructured emulsion carriers for resveratrol topical application. Different compositions of resveratrol-loaded nanostructured emulsions were prepared using different types and amounts of surfactants and oily phases (isopropyl myristate and caproyl 90). The produced nanostructured emulsions were within the nanosized range 23.4-422.2nm with low viscosity range 2.15-17.53cps. The transdermal amount and deposition amount in the skin after 24 applications of resveratrol-loaded nanostructured emulsion were significantly increased about 896.2-fold and 10.2-fold respectively, when compared to the drug-saturated solution-treated group. Nanostructured emulsion containing IPM and low amounts of mixed surfactant of Tween80/Span 20 showed highest permeation capacity. In vivo study showed that the plasma concentration of resveratrol could be maintained at high levels for a long time after topical application of drug-loaded nanostructured emulsion. The histological examination demonstrated that the free drug- and drug-loaded nanostructured emulsion demonstrated considerably less irritation than the standard irritation group (0.8% paraformaldehyde-treated). The residual contents of resveratrol in the tested formulations after 3 months of storage at 25°C and 40°C were more than 99.97±3.90%. The results of present work confirm the high potential of nanostructured emulsion as carriers for drug topical application.

Background Transforming growth factor‑β (TGF-β) signaling is a crucial inducer of tissue fibrosis and extracellular matrix accumulation and a vital suppressor of epithelial cell proliferation and cancer metastasis. The nature of this multifunctional cytokine has prompted the development of TGF-β signaling inhibitors as therapeutic agents. Our research group has recently isolated the polyprenylated polycyclic acylphloroglucinol garcimultiflorone K (GMK) from the stems of Garcinia multiflora; GMK exhibits antiangiogenic activity in endothelial cells. Purpose In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Garcimultiflorone K in hepatocellular carcinoma cells. Methods Cell proliferation and viability were evaluated using the MTT assay. The migratory ability of HepG2 cells was measured using wound healing assays. The inhibitory effect of GMK against the nuclear translocation of Smad by TGF-β was assessed through immunofluorescence staining and Western blotting. To investigate TGF-β-dependent gene expression profiles upon GMK stimulation, RNA transcript levels were determined using reverse transcription polymerase chain reaction. The effects of GMK in Smad2-driven transcriptomic activities were studied using a reporter gene assay. Protein levels were detected using Western blotting. Results Our data revealed that GMK inhibited TGF-β-induced cellular responses, including Smad protein phosphorylation, cell migration, and extracellular matrix production, during epithelial–mesenchymal transition (EMT). Mechanistic studies further demonstrated that GMK suppressed TGF-β signaling by downregulating TGF-β receptor II (TβRII). Conclusion These findings elucidate that TβRII expression in hepatic cells can be specifically suppressed by GMK to attenuate metastasis and the disease-promoting effects of EMT, representing a therapeutic approach.

Objective Post–renal transplantation diarrhea is a common complication; however, it is easily ignored. This study aimed to determine the factors influencing graft function for renal transplant recipients with diarrhea. Methods A single-center retrospective study with the use of the Hyperion data warehouse was conducted to search and evaluate for renal transplant recipients who came for medical care for diarrhea at our transplant center from January 2009 to August 2015. The clinical features of patients with diarrhea were compared with the features of recipients without diarrhea. The causes and risk factors of post-transplantation diarrhea were also evaluated. Results For the 67 patients collected for the study, infectious diarrhea (ID) was confirmed in 27 patients (40.3%), and the most common causes were cytomegalovirus and Clostridium difficile infection. A significant difference was found between ID and noninfectious (NID) groups for serum creatinine change (0.31 ± 0.51 vs 0.1 ± 0.27 mg/dL; P = .0319), revealing that the impact of diarrhea on renal function was greater for ID patients. When diarrhea of ≥10 days was used as a cutoff for serum creatinine change, the change of serum creatinine became greater when the diarrhea period was longer ( 14 d: 0.07 ± 0.22 vs 0.55 ± 0.6 mg/mL; P = .0001). Conclusions Infectious diarrhea does more damage to the kidney graft than NID in transplant recipients. If the period of diarrhea is lengthened to >10 days, the renal function of the graft would be impaired and irreversible graft loss would be expected.

Background and aims Hyperglycemia, a major side effect of patients receiving total parenteral nutrition (PN), is associated with higher mortality in critically ill patients. The aim of this study was to determine whether elevated blood glucose levels would be associated with worse outcomes in patients receiving PN. Methods This retrospective study included postoperative patients admitted to our surgical intensive care unit (SICU) from July 2008 to June 2009. Data collected included blood glucose levels, length of stay, and outcome measures. Correlations among daily average, maximum, and minimum blood glucose levels and outcome measures were calculated. Results Sixty-nine patients were enrolled and divided into PN ( n = 40) and non-PN ( n = 29) groups. The initial mean blood glucose levels were 138.4 ± 63.1 mg/dL and 123.2 ± 41.8 mg/dL for the PN and non-PN groups, respectively. The mean blood glucose concentration was significantly increased (ΔBS = 44.8 ± 57.3 mg/dL; p p = 0.004). The blood glucose concentration was significantly increased and consequently, consumption of insulin was increased on the 2 nd day of ICU admission. The risk of mortality increased by a factor of 1.3 (OR = 1.30, 95% CI = 1.07–1.59, p = 0.010) for each 10 mg/dL increase in blood glucose level, when the daily maximum blood glucose level was >250 mg/dL. There were no cases of mortality in the current study when the blood glucose levels were controlled below 180 mg/dL. The mean blood glucose level in patients receiving PN was higher in those with diabetes than in those without diabetes (215.5 ± 42.8 vs. 165.8 ± 42.0 mg/dL, respectively, p = 0.001). Conclusion The blood glucose level was associated with patient outcome and should be intensively monitored in critically ill surgical patients. We suggest that blood glucose levels should be controlled below 180 mg/dL in postoperative critically ill patients.

Gastric cancer is one of the most common malignancies worldwide, and the main cause of cancer-related death in Asia. The present study assessed the anticancer effects of euphol, a triterpene alcohol with anti-inflammatory and antiviral activities on human gastric cancer cells. Euphol showed higher cytotoxicity activity against human gastric CS12 cancer cells than against noncancer CSN cells. In addition, it up-regulated the pro-apoptotic protein BAX and down-regulated the prosurvival protein Bcl-2, causing mitochondrial dysfunction, possibly by caspase-3 activation. The anti-proliferative effects of euphol were associated with the increased p27(kip1) levels and decreased cyclin B1 levels. Inhibition of ERK1/2 activation by PD98059 reversed euphol-induced pro-apoptotic protein expression and cell death. Taken together, these findings suggest that euphol selectively induced gastric cancer cells apoptosis by modulation of ERK signaling, and could thus be of value for cancer therapy.

The objective of the present work was to investigate the specific brain targeting of baicalein by intravenous injection after incorporation into nanostructured lipid carriers (NLCs). The NLC system, composed of tripalmitin, Gelucires, vitamin E, phospholipids, and poloxamer 188 (referred to as tocol NLCs), was characterized in terms of its physicochemical properties, differential scanning calorimetry (DSC), stability, in vivo pharmacokinetics, and brain distribution. The lipid nanoparticles were spherical with an average size of ∼100 nm. The zeta potential of the nanoparticles was about -50 mV. DSC studies suggested that the majority of the inner cores of tocol NLCs had a slightly disordered crystal arrangement. The nanoparticulate dispersions demonstrated good physical stability during storage for 6 days. The incorporation of vitamin E in the formulations greatly reinforced baicalein's stability. The aqueous control and tocol NLCs were intravenously administered to rats. The plasma level of baicalein in NLCs was much higher and the half-life much longer than those in the free control. In the experiment on the brain distribution, NLCs respectively revealed 7.5- and 4.7-fold higher baicalein accumulations compared to the aqueous solution in the cerebral cortex and brain stem. Greater baicalein accumulations with NLCs were also detected in the hippocampus, striatum, thalamus, and olfactory tract. A 2-3-fold increase in baicalein amounts were achieved in these regions. Tocol NLCs improved baicalein's stability and the ability of baicalein to penetrate the brain; thus, this is a promising drug-targeting system for the treatment of central nervous system disorders.

The aim of the current study was to find an optimal estradiol-loaded microemulsion with higher permeation rate and shortened lag time (LT) for transdermal application by using a response surface methodology (RSM) and constrained mixture design. Isopropyl myristate (X1 ), distilled water (X2 ), and ethanol (X3 ) were selected as independent variables, whereas the viscosity of microemulsion and permeation parameters including the cumulative amount at 24 h (Q24h ) and LT of estradiol-loaded microemulsion through skin were set as dependent variables. The result showed that the three independent variables had a remarkable effect (p0.05) on the dependent variables. Moreover, the predicted and observed values of these three dependent variables of the optimal microemulsion formulations, which were produced by the RSM optimization technique, were close, demonstrating that RSM was a useful technique for optimizing pharmaceutical formulations. However, the experimental estradiol-loaded microemulsion with higher permeation rate was expected to provide effective therapeutic concentration in a workable administration area.

The aim of this study was to evaluate the influence of components such as type, level, and hydrophilic-lipophilic balance (HLB) value of surfactant, type and amount of cosurfactant, and drug concentration on the permeability of buspirone hydrochloride microemulsions through rat skin. The cumulative amount at 24 h ranged from 502.2 ± 57.8 to 1754.3 ± 616.6 μg/cm(2), flux ranged from 23.03 ± 1.84 to 83.36 ± 25.08 μg/(cm(2)/h), and lag time ranged from 3.0 to 4.7 h, indicating that the permeation parameters of buspirone from microemulsions were markedly influenced by the composition of microemulsions. In comparison with the effect of composition of microemulsions on the buspirone permeation capacity, it was found that microemulsions containing surfactant with HLB value of 11.16 possessed higher flux. The viscosity of microemulsions increased, flux decreased, and lag time was prolonged when amount of surfactant in microemulsions increased. The various cosurfactants can also influence the microemulsion formation and drug permeability. The microemulsion with ethanol as cosurfactant had higher permeation rate. However, the buspirone microemulsion with higher flux can provide the therapeutic minimum effective concentration, at workable administrated area about 3.3-5.8 cm(2), demonstrating microemulsions could be a promising drug carrier for transdermal delivery systems.

Apomorphine, a dopamine receptor agonist for treating Parkinson's disease, has very poor oral bioavailability (

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.

The purpose of the present study was to design an optimal ketoprofen gel with appropriate penetration rate, shortened lag time and acceptable skin irritation. The combination of different mechanism enhancers including nonivamide, menthol and ethanol were used as multi-enhancers for producing a synergistic enhancement effect and reducing the skin irritation via diminishing the used amount of enhancers. The central composite design was applied to prepare a systemic formulation. The penetration rate (PR), lag time (LT) and skin irritation score (TIS) of a commercial product (Formax plus gel containing 3% ketoprofen) were determined by in vivo study and used as a criterion for designed formulations. The PR, LT and TIS of commercial product were 462.2+/-162.5 microg/h, 0.6+/-0.1 h and 12.7+/-0.6, respectively. Among these designed experimental formulations, four formulations including F07 (code: -1/+1/-1), F11 (code: +1/+1/-1), F13 (code: 0/0/-1.732) and F14 (code: 0/+1.732/0), their PR was not smaller and LT and TIS were not greater than that of commercial product, indicating that these experimental ketoprofen gels could be used in the clinical situation.

The influences of a combination of different mechanisms of penetration enhancers on the penetration absorption properties of meloxicam sodium formulations through rat skin were investigated using response surface methodology. A uniform design was applied to prepare model formulations systematically that were composed of four independent variables: the content of ethanol ( x 1 ), propylene glycol ( x 2 ), menthol ( x 3 ), and azone ( x 4 ). The penetration rate (flux) of meloxicam sodium gel through rat skin was chosen as the response which had to be higher than 400 μg/h cm 2 the required flux of meloxicam gel to maintain a therapeutic concentration. The result showed optimal formulation could be obtained from this response surface methodology. Menthol had the greatest potential influence on the penetration absorption of meloxicam sodium, followed by azone, ethanol and PG, respectively. By in vivo study, meloxicam could be determined 1 h after topical administration and reached steady-state concentration at about 12 h. The bioavailability (%) of the optimal meloxicam sodium gel was about 50.1%.

A sensitive high-performance liquid chromatography method with electrochemical detection was developed for the purpose of determining the concentration of the new anti-tumor agent 1-[4-(furo[2,3-b]-quinolin-4-ylamino)phenyl]ethanone (FQPE) in rats. The plasma samples were spiked with the internal standard diclofenac and extracted using dichloromethane. A C 18 250 mm × 4 mm column was used for the separation of analyte with a mobile phase consisting of 50% acetonitrile and 50% pH 3.0 of sodium 1-pentansulfonate solution at a flow rate of 1.0 mL/min. FQPE was detected by electrochemical detector at 1.0 V and 20 nA. Intra-day and inter-day precision and accuracy were acceptable down to the limit of quantization of 1 ng/mL. The lower limit of detection (LOD) was 0.5 ng/mL. The pharmacokinetic parameters of FQPE in rats after intravenous administration of 2.1 and 4.2 mg/kg were determined. The apparent volume of distribution, half-life of elimination, and clearance showed no significant difference between the two dosages. The area under the plasma concentration time curve increased proportionally with dose. The half-life of FQPE was prolonged about 2.4-fold, compared with amsacrine.

The stability of recombinant human epidermal growth factor (rhEGF) as a function of buffer pH, temperature, burn skin and the effect of various protease inhibitors were investigated by reverse-phase high-performance liquid chromatography. The results showed that the pH of maximum stability of rhEGF in McIlvaine buffer solutions was 7.2. Based on the Arrhenius equation, the half-life of rhEGF at 25 °C was 6.93 h. Burn wound induced activity of acid proteolytic enzymes was the main explanation as the cause for rhEGF rapid degradation in first day post-burn skin homogenate. An aminopeptidase inhibitor (bestatin) had a better stabilizing effect on the degradation of rhEGF in normal skin than other protease inhibitors (aprotinin and leupeptin).

San-Huang-Xie-Xin-Tang (SHXT) is a traditional Chinese medicinal formula containing Coptidis rhizoma, Scutellariae radix and Rhei rhizoma. The present study aimed to determine the preventive effects of standardized SHXT on lipopolysaccharides (LPS)-induced arterial hypotension, protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), cytokines formation and prostaglandin E2 (PGE2) production. LPS-induced activation of iNOS has been recognized to increase cytokines and nitric oxide, some of them play predominant roles in sepsis. Intravenous injection of LPS (10 mg/kg) caused a marked decrease of the mean arterial pressure in normotensive rats. However, the LPS-induced arterial hypotension was inhibited by SHXT (0.01 and 0.03 g/kg), when it was given 30 min before LPS. Moreover, plasma level of cytokines and PGE2 were lowered by SHXT. In RAW 264.7 cells, SHXT (20-200 microg/ml) dose-dependently inhibited LPS (1 microg/ml)-induced iNOS and COX-2 expression, and it also significantly decreased LPS-induced cytokines in a dose-dependent manner. In conclusion, our data suggest that SHXT prevented LPS-induced arterial hypotension, which might be mediated through its inhibition activities on the expression of iNOS and COX-2, cytokines formation and PGE2 production. Therefore, its protection activity against LPS-induced arterial hypotension and inflammatory mediators release might be beneficial in the treatment of endotoxin shock and/or associated inflammation.

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.

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.

Objective The aim of this study was to evaluate directly the utility of Fourier transform infrared microscopy (FTIR-MC) in detecting cervical precancer by comparison with the pathological examination of biopsy tissue. Methods Cervical biopsy specimens were obtained from the outpatient department at Kaohsiung Municipal Ta-Tung Hospital. Freshly isolated tissue was washed in isotonic saline and then frozen for use. Two successive slices were cut with a microtome. One unstained slice was used for reflectance FTIR-MC analysis; the other slice was stained with hematoxylin and eosin and used for position reference by microscopic mapping. Results The spectral region from 950 to 1500 cm −1 is the most critical region in the IR spectrum of the tissue. There were two special peaks that had growth and decline in the IR spectra. The one at 1150 cm −1 disappeared and the other at 1240 cm −1 broadened when the tissue had pathological changes. From the results, we found that the ratio of the areas of the two regions between 1130 to 1180 cm −1 and 1180 to 1260 cm −1 was an exceptionally useful factor in discriminating precancerous tissues from normal tissues. Conclusion We carried out microscopic mapping of the tissues and demonstrated that the color map reflects pathological changes in the cervical tissues.

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.

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium–aluminum–garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.

The influences of different mechanisms of penetration enhancers (such as menthol, azone, ethanol and nonivarnide) regarding the percutaneous absorption and skin irritation of ketoprofen formulations through rat skin were investigated by in vitro and in vivo study. The skin irritation degree at the end of the experiment (10 h) was deterinined by pathologic biopsy and colorimetry methods. In vitro, the menthol showed the most potent enhancing effect. Furthermore, the enhancement effect of a combination of menthol and nonivamide was higher than that of their individual use alone. In vivo the formulation containing 0.05% nonivantide, 5% menthol and 20% ethanol showed a higher penetration rate and an acceptable degree of skin irritation compared to a commercial product (Formax plus gel containing 3% ketoprofen), indicating that it could be used in the clinical situation.

Polymers were used in vehicles to form hydrogel matrices in this study to evaluate the in vitro permeation and in vivo microdialysis of enoxacin. The highest transdermal delivery determined by area under flux-time curve (AUC) and intracutaneous enoxacin concentration were observed in methylcellulose (MC) and polyvinylpyrrolidone (PVP) hydrogels, respectively. To avoid the pH shift in vehicles during iontophoresis, buffer species were added to formulations to increase the buffer capacity. As expected, the permeability of enoxacin of anodal iontophoresis was larger than that of cathodal iontophoresis. Combination of benzalkonium chloride, a cationic surfactant as an enhancer, and iontophoresis exerted an enhancing effect for anionic enoxacin at pH 10.0. However, no effect or a negative effect was detected for cationic enoxacin in deionized water or pH 5.0 buffer, due to the shielding of the negative charge in the skin. The skin residue of enoxacin was slightly increased after the incorporation of Azone in PVP hydrogel. The result of in vivo microdialysis was in accordance with that of in vitro study. The effect of Azone on the intracutaneous enoxacin was more significant for in vivo microdialysis than in the in vitro study indicating the clinical feasibility of Azone for iontophoretic delivery. Microdialysis can be considered as a useful technique to investigate the pharmacokinetics of transdermal iontophoresis in vivo.

The permeation of sodium nonivamide acetate (SNA), a newly designed analogue of capsaicin, from ethanol/pH 4.2 buffer solutions containing antinucleant polymers across rat skin, was investigated. The in vitro release of SNA was determined under an open condition at 25°C and 65% relative humidity. Therefore, the influence of the evaporation of vehicle components on the permeation of SNA was examined. Evaporation of the vehicle led to so drastic compositional changes that supersaturation is attained quickly. However, supersaturated solutions started to crystallize reducing the thermodynamic activity of SNA. Antinucleant polymers were used in the preparation of volatile vehicles in order to maintain the increased activity state of the drug. Methyl cellulose (MC) and hydroxypropyl cellulose (HPC) were both the efficient antinucleant polymers to increase the permeation of SNA. The permeation of SNA determined from volatile vehicles with 2% MC showed the result that the flux of SNA reached maximum at a certain ethanol proportion. A part of ethanol in the vehicle may penetrate into the skin causing the dehydration of stratum corneum and, therefore, the reduction of SNA permeation. The permeation of SNA was increased when ethanol in the volatile vehicle was replaced by n-propanol which could be due to the increased SNA solubility and reduction of diffusional barrier of stratum corneum in the presence of n-propanol.

The patch or semisolid dosage form is more applicable than solution as a transdermal iontophoretic delivery system to be administered clinically. Therefore the effect of iontophoresis for sodium nonivamide acetate (SNA) from various polymer formulations was investigated by using an in vitro permeation study. The cumulative amount–time curves were suitable to fit by a zero-order equation which indicated a steady-state permeation rate or sustained release effect could be achieved from polymer hydrogels. The permeability coefficient of SNA from polyvinylpyrrolidone (PVP) or hydroxypropylcellulose (HPC) were similar and showed the highest penetration capacity among six individual polymers. In order to develop optimal devices for clinical utilization, blends of two polymers as binary system formulations were prepared in order to attain acceptable bioadhesion and viscosity. The binary cellulose–PVP formulations apparently improve the mechanical characteristics of hydrogel. Moreover, the flux of SNA from these binary systems increased in the order of methylcellulose (MC)+PVP

The effect of iontophoresis combined with pretreatment of penetration enhancers such as benzalkonium chloride, cetylpyridinium chloride, sodium laurylsulfate and isopropyl myristate on the transdermal transport of sodium nonivamide acetate (SNA) and histologically structural properties of rat skin was undertaken. Cetylpyridinium chloride and isopropyl myristate showed the highest iontophoretic enhancement factor (E) and iontophoretic flux (J I ) on the transdermal penetration of SNA after pretreatment with skin, respectively. However, because of the severe change on the histological structure of rat skin irritated by isopropyl myristate, its clinical use is limited. The iontophoretic flux of SNA of sodium laurylsulfate pretreatment group was lower than that of control group. The reason for this phenomenon was that iontophoretic transport of SNA would be restricted by the hindrance of sodium laurylsulfate molecules inhibiting entry into pores of the skin. In the study of the different pretreatment duration of penetration enhancer for time ranging from 6 to 24 h, the total enhancement factor over passive diffusion was decreased following the increase of pretreatment duration both in cetylpyridinium chloride- and isopropyl myristatepretreated skin. This illustrated that penetration enhancers could largely influence the passive transport of SNA but only showed a minor effect on the iontophoretic transport of SNA. In the result for anatomical skin structures treated by current density, there was almost no change observed in the structure of skin after iontophoretic treatment as compared with the control group. Accordingly, iontophoretic delivery is a transdermal enhancement method with high safety. A combination of physical iontophoresis with the chemical enhancer may be a potential route for transdermal delivery of drugs as this present study indicates.

Four available skin membranes (mouse, rat, rabbit, pig) and human skin were utilized to evaluate the in vitro penetration of captopril. The flux of captopril increased in the order of human = pig < rabbit < rat < mouse. The penetration rate of captopril through rabbit skin was optimal to evaluate the variation of formulations. Hence, the rabbit skin was picked out as a model membrane for in vitro penetration experiments of captopril. The flux of captopril was increased linearly when the concentration of captopril increased from 1% up to 10% (r = 0.9777). The enhancing effect of penetration enhancers including fatty alcohols (2C–14C), aliphatic esters (2C–10C) and other compounds on captopril penetration through excised rabbit skin were also evaluated. The enhancement of fatty alcohols and aliphatic esters were related to the chain length of enhancers. The C6-C10 of fatty alcohols, butyl acetate and N-dodecyl-γ-lactame showed the most enhancing effect on captopril penetration.

The purpose of this investigation was to design and evaluate the percutaneous absorption of captopril from a hydrophilic cellulose gel base®. The effect of type and concentration of saturated fatty acids, amount of gel base as well as the concentration of drug on percutaneous absorption of captopril gel through rabbit skin were evaluated and selected to obtain some optimal formulations. Then the required flux (1488 μg/h) for captopril transdermal drug delivery system to maintain the therapeutic minimum effective concentration through human skin was used to evaluate the development of the optimal formulations. The results indicated that these formulations containing 3, 5 and 10% captopril with 5% capric acid using 22.89, 6.98 and 4.89 cm 2 of administered area were attained to the therapeutic minimum effective concentration. Therefore these formulations were suitable for possible development of transdermal drug delivery system.

Transdermal iontophoresis is a process which enhances skin permeation of ionized species by an electrical field as driving force. The aim of this present study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide acetate (SNA). Studies of electrical and physicochemical factors acting on the kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal penetration flux of SNA as compared to the passive diffusion in this study. Several application modes which possessed the same electrical energy had been researched. The iontophoretic flux of SNA increased following the decrease of donor buffer pH values. This trend could be due to the physiological property of skin and electro-osmotic flow presented. Comparing the various application modes, the discontinuous on/off cyclic current mode showed higher penetration capacity than did continuous mode which was due to the intensity of effective current which would not decay for on/off cyclic application of iontophoresis. The result of the present study is particularly helpful in the development of a SNA transdermal iontophoretic delivery system.

The effect of pretreatment by 5% cardamom oil in an alcohol-H 2 O vehicle on the percutaneous absorption of piroxicam gel was investigated. The area under the curve of plasma concentration from 0 to 24 h (AUC 0 24 h ) of piroxicam for 30 min pretreatment with cardamom oil was about 67.09-fold higher than that of non-pretreatment and the absolute bioavailability obtained was 83.23% and was similar to that for 60 min pretreatment. On increasing the pretreatment period from 0 to 30 min, the AUC 0–24 h value increased linearly. In addition, a pharmacokinetic model with two consecutive first-order processes was developed and successfully described the plasma level after topical administration of piroxicam by penetration enhancer for pretreatment. A good correlation was observed between the AUC 0–24 h and the absorption rate constant.

The effect of pretreatment by the penetration enhancer, cardamom oil, on the percutaneous penetration of piroxicam from gel through rabbit abdominal skin was investigated using an in vitro technique. The flux and the cumulative amount (at the 48th h) after 1 h pretreatment with 10% cardamom oil in three vehicle systems (alcohol, alcohol/pH 5.8 buffer and alcohol/pH 7.4 buffer) were higher than that of nonpretreatment, and were similar to that of 3 or 6 h pretreatment. A specific correlation between the flux of piroxicam and the pretreatment period was found. Compared to the lag time of skin penetration of piroxicam for nonpretreatment, the lag time for pretreatment was remarkably diminished. The penetration index (PI) of piroxicam after 1 h pretreatment with 10% cardamom oil in alcohol/pH 7.4 buffer (50/40) was about 340.9-fold higher than that of nonpretreatment. In contrast to previous results. 1 h pretreatment with 10% cardamom oil in alcohol had no significant enhancing effect on the percutaneous penetration of piroxicam from gel dosage form. From these results, the alcohol proportion of the vehicle system was the more effective factor for penetration index.

Nonivamide (NVA) and non-pungent sodium nonivamide acetate (SNA) are synthetic derivatives of capsaicin. In this study, in vitro formulation evaluations in pigs and in vivo bioengineering methods in humans were performed to obtain the information on percutaneous absorption for capsaicin, NVA and SNA. After the consideration of penetration capacity, skin irritation and physicochemical properties of the formulations in vitro, 0.6% Carbopol 940® gel form for capsaicin and NVA as well as 3.8% isopropyl myristate-added hydrophilic o/w ointment for SNA were utilized to study the following in vivo test in humans. In the study of in vivo surface recovery techniques, SNA showed an equivalent therapeutic capability to that of NVA after calculation of the antinociceptive index. After the quantification of skin erythema by laser Doppler flowmetry (LDF), capsaicin caused more severe irritation than NVA in humans. In addition, SNA showed no skin irritation, toxicity and pungent sensation. The transepidermal water loss (TEWL) values were determined using an evaporimeter. A comparison of the gel form showed there was significantly higher TEWL AUC values in capsaicin and NVA than in the control group. The AUC value of the hydrophilic ointment control group was significantly higher than that of the gel control group. The reason was that isopropyl myristate and sodium laurylsulfate, two additives incorporated in the hydrophilic base, could cause slight skin irritation resulting in the increase of TEWL. The results of this study suggest that SNA possesses potent antinociceptive activities after transdermal application. Furthermore, SNA can be used extensively in clinical therapy because it avoids any pungent skin sensation and burning pain to improve patients' compliance.

Nonivamide (NVA) and nonpungent sodium nonivamide acetate (SNA) are both synthetic derivatives of capsaicin. In this study, in vivo systemic drug plasma data of capsaicin, NVA and SNA following intravenous and transdermal ointment base administration in rabbits were performed to establish the pharmacokinetic analysis of these analogues. In order to describe the capsaicin, NVA and SNA plasma profiles observed, one-compartment pharmacokinetic open model for capsaicin and NVA, and two-compartment model for SNA was used in the i.v. plasma data. After the percutaneous administration, the plasma profiles between capsaicin and NVA were quite different although these two analogues showed similar physicochemical properties and intravenous pharmacokinetic parameters. The high plasma concentrations of SNA were obtained in the early period after transdermal application. This phenomenon suggested that SNA passes through skin via the intercellular and transappendageal routes. In the study of the in vivo percutaneous effect of NVA — SNA combined ointments, the result indicated that NVA and SNA could often act as the potent penetration enhancer for each other to higher absorption amount and bioavailability than individual NVA or SNA ointment base. The information of the pharmacokinetic analysis of capsaicin and its analogues in rabbits are helpful for the development of capsaicin, NVA and SNA transdermal drug delivery system.

Nonivamide (NVA) and sodium nonivamide acetate (SNA) both are synthetic analogues of capsaicin. In the present study, in vitro penetration experiments through rat skin from ointment bases were performed in order to establish and develop the transdermal drug delivery system of these two capsaicin analogues. This study was also carried out to evaluate the relative skin permeability of capsaicin and its derivatives through different skin types. As regards the in vitro transdermal absorption of ointment bases, o/w emulsion-type bases (hydrophilic and University of California Hospital (UCH) ointment) revealed better percutaneous absorption effects than the others for both NVA and SNA. However, there was a higher accumulative amount for NVA in the gel base but none for SNA. There were no changes observed in the appearance and texture when the aqueous phase of the three ointment bases (hydrophilic, absorption and UCH ointment) was replaced by pH 4.2 buffer. In the steady-state flux of absorption ointment for NVA and UCH, absorption ointment for SNA was significantly higher (P < 0.05) in pH 4.2 buffer-replaced base than in the original. In the comparison of in vitro permeability through various animal skin types, full-thickness human skin showed the poorest permeability for NVA, SNA and capsaicin. The trends of steady-state flux through the various skin types for capsaicin, NVA and SNA were quite different. However, pig skin could be successfully used as a model to study in vitro percutaneous absorption of these three compounds through human skin.

The effect of the penetration enhancer, cardamom oil, on percutaneous absorption was investigated. Three kinds of drugs, indomethacin, piroxicam and diclofenac, which have different solubility in a mixed solvent system (phosphate buffer/alcohol, 50:50, v/v), were selected to evaluate the drug permeation with or without cardamom oil. For all drugs, the flux, lag time, accumulated amount (at 48 h) and penetration parameters were also determined at various pH values by using an in vitro permeation technique through rabbit abdominal skin. The solubility of each of the three drugs in the solvent system containing 1° cardamom oil was similar to that without enhancer. The penetration index of piroxicam was extremely increased by 1% cardamom oil, about 81.9-fold at the pH 5.8 solvent system, compared with that of indomethacin or diclofenac. The shorter lag time of indomethacin and diclofenac was observed in in vitro permeation experiments with 1°, cardamom oil. These results suggest that the enhancing effect of cardamom oil is not due to changing the solubility of the drug in the solvent system and was dependent on the kind of drug, pH value of solvent system and concentration of cardamom oil.

The major part of the FAPG base is a gel-like structure composed of propylene glycol and fatty alcohol with a crystalline network. Stearic acid is used as a penetration enhancer incorporated into FAPG base. Stearic acid's change of nature resulting from process-induced variation was investigated by differential scanning calorimetry, X-ray powder diffraction, infrared spectroscopy and polarized microscopy. Under a slow rate of cooling, the pure C form of stearic acid was obtained through propylene glycol in the presence of 5% w/w 1,2,6-hexanetriol and with increase in cooling rate, a mixture of forms B and C was produced. The polymorphic modifications are affected more strongly by the growth rate than by the stirring rate. When stearic acid is combined with stearyl alcohol, the supersaturation of stearic acid and precipated forms in propylene glycol no longer occurs, since stearic acid readily dissolves in the melting stearyl alcohol. Simultaneous IR and DSC measurements indicated that during the heating and cooling process, the components of the ointment did not chemically interact with one another. However, different manufacturing processes will result in markedly different physical properties, especially with respect to solubility.