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The aim of this study was to evaluate the transdermal delivery of two meloxicam salts, meloxicam sodium and meloxicam potassium, enhanced by iontophoresis and/or electroporation in vitro with Wistar rat dorsal skin and human epidermal membrane (HEM) as barriers and in vivo with Wistar rat as the animal model. Iontophoresis and its combination with electroporation could significantly enhance the in vitro permeation of both salts, and two protocols had the same enhancement to each salt. Furthermore, the combination protocol had more enhancement to potassium salt than sodium salt. Interspecies difference was found in some electrical protocols. Electroporation might depress the transdermal delivery of meloxicam sodium while it might enhance that of meloxicam potassium. Iontophoresis, electroporation and their combination could increase the delivery of the two salts and result in significantly higher AUC of drug concentration to time in vivo. It was concluded that the in vitro and in vivo transdermal delivery of meloxicam potassium was more facilitated by the combination protocol than meloxicam sodium.

The purpose of this study was to investigate the sustained release of nicardipine/polymer solid dispersions prepared by solvent evaporation method. The release pattern of drug from solid dispersions was evaluated by the dissolution test in both dissolution medium of phosphate buffer pH 6.8 or gastric acid fluid pH 1.2, and was compared with a commercial long acting product Perdipine(superscript ®). The results showed that the formulations with lower ratio of Nicardipine/Eudragit RS (N/RS) (below 1/5) had sustained release effect in gastric acid fluid (pH 1.2). The release rate of formulation of N/RS=1/5 was slightly faster than that of Perdipine(superscript ®) in gastric acid fluid in the early stage. On the contrary, the release rate was lower than that of Perdipine(superscript ®) in phosphate buffer (pH 6.8). The enteric polymers such as HPMCAS-LF grade (HPMCAS) and hydroxypropyl methylcellulose phthalate, HP-55 grade (HPMCP) were incorporated into the formulation of NC/ERS=1/5 solid dispersion to improve the drug release in both dissolution medium. It was found that the dissolution efficiencies of drug were increased 2.35-21.08 folds with the addition of 20-40% of enteric polymer in pH 6.8 media. Among these formulations of N/RS/HPMCP=1/3.5/1.5 had similar dissolution pattern with Perdipine(superscript ®) in either medium of phosphate buffer or gastric acid fluid (f2 values were above 50), showing that the sustained release dosage form of nicardipine solid dispersions could be developed by using the combination of Eudragit RS and enteric polymer.

The aim of this study was to demonstrate the potential application of electrically-assisted methods, including iontophorcsis and electroporation, on the transdermal delivery of buspirone hydrochloride from a submicron emulsion-based system. The results showed that by applied iontophoresis at 0.5 mA/cm^2 for 3 h or electroporation at 1 pulse, 300 V, 200 ms, 0.5 min spacing for 10 min. increased the cumulative amount of buspirone at 10 h by 2.4 and 2.1 folds, respectively compared to passive diffusion. The combination of iontophoresis and electroporation did not show synergistic effects. For long-time application of iontophoresis, the enhancement effect decreased in the later stage due to skin polarization. The duty cycle or current applied was found to increase iontophoretic efficiency. When compared to passive diffusion, the lag time of buspirone-loaded submicron emulsion permeated through skill was shortened from 3 h to 0.5 h with the use of both electrically-assisted methods, indicating that more rapid onset of buspirone could be obtained by using electrically-assisted methods.

The influences of combination of different mechanisms of penetration enhancers (such as azone, sodium lauryl sulfate and menthol) on the percutaneous absorption of meloxicam formulations through rat skin were investigated using uniform deign and response surface methodology. The uniform design was applied to prepare systematic model formulations which were composed of three formulation factors: azone (x1), sodium lauryl sulfate (x2), and menthol (x3). The result showed that azone had the highest potential influence on the penetration absorption of meloxicam, followed by sodium lauryl sulfate and menthol. With zero-order delivery, the required flux of meloxicam gel to maintain a therapeutic concentration was about 400 μg/hr/cm^2. The result showed that the optimal addition concentration of azone at 4% to 6% could be obtained at high penetration rate and short lag time of meloxicam gel. It was shown that as the concentration of sodium lauryl sulfate increased from 0% to 12% the flux and cumulative amount at 48 hr increased and lag time decreased. On the other hand, menthol had the effect of a shorter lag time. To validate the predictive ability of the hypothesized model, the predicted formulations were prepared and penetration experiments were performed. The predicted formulations were developed for the transdermal drug delivery system.

Morphine is the most effective drugs for attenuating various types of severe pain, but morphine abuse carries a high risk of systemic fibrosis. Our previous have indicated that systemic administration of morphine hinders angiogenesis and delays wound healing. Here we have explained the pathological mechanism underlying the effect of morphine on wound healing. To determine how morphine affects wound healing, we first created a wound in mice treated them with a combination of a low doses (5 mg/kg/day) and high doses (20 or 30 mg/kg/day) of morphine. An In vivo study revealed that high-dose morphine-induced abnormal myofibroblasts persist after the end of wound healing because of connexin 43 (Cx43) upregulation. High-dose morphine-induced Cx43 increased the expression levels of focal adhesion molecules, namely fibronectin and alpha-smooth muscle actin (α-SMA) through the activation of transforming growth factor (TGF)-β1 signaling. In addition, we found that Cx43 contributed to TGF-βRII/ Smad2/3 signaling for regulating the differentiation of fibroblasts into myofibroblasts during high-dose morphine exposure. In conclusion, the abnormal regulation of Cx43 by morphine may induce systemic fibrosis because of abnormal myofibroblast function.

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.

Yi-Ping Fang,1,2 Pei-Yu Hu,1 Yaw-Bin Huang1,3 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 2Department of Medical Research, Kaohsiung Medical University Hospital, 3Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan Introduction: Mitomycin C is an anticancer antibiotic agent that has the potential for broad-spectrum use against several cancers, including mammary cancers. Because its half-life is 17 min after a 30 mg intravenous bolus administration, the suitability of mitomycin C for wide use in the clinical setting is limited. Based on tumor pathophysiology, pH-sensitive liposomes could provide better tumor-targeted effects. The aim of this study was to investigate the possibility of diminishing the side effect of mitomycin C by using pH-sensitive liposomes.Materials and methods: pH-sensitive liposomes was employed to deliver mitomycin C and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay.Results: The results demonstrated that mitomycin C-loaded pH-sensitive liposomes had a particle diameter of 144.5±2.8 nm and an entrapment efficiency of 66.5%. The in vitro release study showed that the pH-sensitive liposome release percentages at pH 7.4 and pH 5.5 were approximately 47% and 93%, respectively. The cell viability of MCF-7 cells showed that both the solution and liposome group exhibited a concentration-dependent effect on cell viability. The MCF-7 cell uptake of pH-sensitive liposomes with a folate modification was higher which was indicated by an increased fluorescence intensity compared to that without a folate modification. The area under the concentration–time curve of mitomycin C-loaded pH-sensitive liposomes (18.82±0.51 µg·h/L) was significantly higher than that of the mitomycin C solution group (10.07±0.31 µg·h/L). The mean residence times of the mitomycin C-loaded and mitomycin C solution groups were 1.53±0.16 and 0.05 h, respectively. In addition, there was no significant difference in terms of Vss (p>0.05). Moreover, the half-life of pH-sensitive liposomes and the mitomycin C solution was 1.35±0.15 and 1.60±0.04 h, respectively. In terms of safety, mitomycin C-loaded pH-sensitive liposomes did not affect the platelet count and the levels of blood urea nitrogen and aspartate aminotransferase.Conclusion: The positive results of pH-sensitive liposomes demonstrated maintained the cytotoxicity and decrease the side effect. Keywords: mitomycin C, liposomes, pH-triggered release, pharmacokinetics, side effect

Reorganization of the actin cytoskeleton is essential for cell motility and chemotaxis. Actin-binding proteins (ABPs) and membrane lipids, especially phosphoinositides PI(4,5)P2 and PI(3,4,5)P3 are involved in the regulation of this reorganization. At least 15 ABPs have been reported to interact with, or regulated by phosphoinositides (PIPs) whose synthesis is regulated by extracellular signals. Recent studies have uncovered several parallel intracellular signalling pathways that crosstalk in chemotaxing cells. Here, we review the roles of ABPs and phosphoinositides in chemotaxis and cell migration. Linked Articles This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24

Objectives To evaluate the anti-oxidant activity of the flavonoid compound, kaempferol, and to examine its role in the suppression of oxidative stress and attenuation of bladder hyperactivity in a rat model of bladder injury. Methods The anti-oxidative activity of kaempferol was examined in lipopolysaccharide-treated RAW264.7 macrophages by using flow cytometry. For in vivo studies, rats were pretreated with kaempferol or vehicle for 24 h. The rat urothelium was injured by the administration of protamine sulfate for 1.5 h and irritated by the subsequent infusion of potassium chloride for 4 h. Oxidative stress in the bladder tissue was assessed using chemiluminescence assay, and the bladder pressure was determination by cystomertrogram. Results Kaempferol significantly suppressed lipopolysaccharide-induced reactive oxygen species production in RAW264.7 rat macrophages. Exposure of the rat bladder to sequential infusion of protamine sulfate and potassium chloride induced bladder hyperactivity. Pretreatment with kaempferol, prevented the formation of reactive oxygen species and prolonged the intercontraction interval. Conclusion Kaempferol suppresses oxidative stress and attenuates bladder hyperactivity caused by potassium chloride after protamine sulfate-induced bladder injury.

Objectives The aim of this study was to determine the pharmacokinetic profile, biodistribution and toxicity of ethyl 2-(2-fluorobenzamido)benzoate (EFB-1) and methyl 2-(2-fluorobenzamido)benzoate (DSM-RX 78), two phosphodiesterase IV inhibitors, which potently attenuate haemorrhagic shock-induced lung injury in rat. Methods Quantification of DSM-RX78, EFB-1 and 2-(2-fluorobenzamido)benzoate (SMP-3) in plasma was carried out by HPLC. Furthermore, the pharmacokinetics and biodistribution of intravenously (1.0 and 3.0 mg/kg) and orally (40.0 mg/kg) administered DSM-RX78, EFB-1, and SMP-3 were determined in Sprague–Dawley rats. Toxicity and histological analyses were also evaluated herein. Key findings A liquid chromatography method has been developed for the quanification of EFB-1, DSM-RX78 and SMP-3 in rat plasma. The method was sensitive with good linearity (r2 = 0.9990) over a range of 1.56–0.0975 μg/ml. The mean kinetic parameters of DSM-RX 78 and EFB-1 following intravenous administration were as follows: elimination half-life (t½) 8.98 and 8.77 min; clearance (Cl) 24.57 and 22.31 ml/min/kg; AUC0-∞ 41.76 and 48.03 min mg/l. Conclusions The pharmacokinetics, toxicity and biodistribution of DSM-RX78 and EFB-1 were determined for the first time. The results showed that the pharmacokinetic profiles of DSM-RX78 and EFB-1 were similar, and that EFB-1 had a better safety profile than DSM-RX78. Therefore, EFB-1 was suitable as a lead compound for the development of new agents in the treatment of neutrophilic inflammatory diseases.

OBJECTIVE Computer-prescriber order entry (CPOE) systems that lack clinical decision components actually increase errors and cause harm rather than the opposite. Recent studies have also demonstrated that dosing errors, typing errors, or miscommunication with other systems are the most common CPOE errors. Our objective was to develop an antibiotic dosing calculator and implement it in the CPOE system while integrating the role of the clinical pharmacist in the CPOE in order to minimize dosing errors in the prescription of antibiotics. METHODS A database was prepared using dosage information for 13 renal function-related antibiotics. The dosages in the database ranged from the standard to the maximum dosage based on various creatinine clearance (CL(cr) levels. The antibiotic dosage monitoring system was developed to screen the entire inpatient database for inappropriate antibiotic dosage regimens and record the results as an Excel document. MAIN OUTCOME MEASURE We tracked the frequency of calculator utilization by physicians, the acceptance rate of recommendations from the calculator and pharmacists, the inappropriate antibiotic dosage regimen prescriptions, and the antibiotic-related renal function deterioration. The relative risk (RR) with 95% confidence intervals (CI) was used to calculate the risk of inappropriate antibiotic dosage prescription, the deterioration in renal function when antibiotics were used. RESULTS From 2005 to 2008, 38,647 antibiotic prescriptions were recorded in the CPOE system. The instances of inappropriate antibiotic dosage prescriptions were decreased by ~ 80% after the calculator was implemented (RR, 0.18 – 0.23; p < 0.001), and the incidence rates of renal function deterioration were lowered from 12.39% to 9.47%. The frequency of antibiotic calculator utilization by physicians (from 239 times/ year in 2005 to 3,480 times/year in 2008) and the acceptance rate of the calculator’s dosage recommendations (from 68.2% in 2005 to 94.7% in 2008) both increased during the study period. The average acceptance rates of pharmacist recommendations by physicians were 97.65%. CONCLUSIONS Integration of the CPOE decision-supporting system and the clinical pharmacist monitoring practice can help physicians provide appropriate antibiotic dosage regimens and decrease the incidence of dosing errors that could be decreased concerned patients with impaired renal function.

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

Purpose A possible interaction between valproic acid and ertapenem resulting in reduced serum valproic acid levels in two patients is reported. Summary In the first case, a 47-year-old woman was brought to the emergency department (ED) with fever, pain, redness, swelling, and local heat in the tissue around her tracheostomy tube and left foot. One month prior she was hospitalized with pneumonia and had a generalized tonic–clonic seizure. She was given teicoplanin and amoxicillin–clavulanate potassium as empirical therapy for cellulitis. On day 3, the patient developed a fever. Amoxicillin–clavulanate potassium was discontinued and replaced by i.v. ertapenem. On day 5, due to a suspected drug-induced fever, carbamazepine was discontinued, and oral valproate sodium was initiated. On day 16, the patient was afebrile, so ertapenem was discontinued. Her serum valproic acid concentration was

The aim of this study was to optimize hesperetin cream formulations by in vitro permeation study and evaluate topical whitening active effect and skin irritation by in vivo study. The results showed that the solubility of lipophilic compound of hesperetin was increased by short-chain alcohol including ethanol, glycerin, propylene glycol and polyethylene glycols 400 (PEG 400). PEG 400 showed strongest solubilized effect by increased 3400-fold. With the addition of 5% enhancers, it was found that menthol showed the most potent enhancing effect, followed by azone and depigmentation agents (linoleic acid and lecithin). Moreover, enhancers could shorten the lag time from 3.7 to 1 h. Combination of menthol, linoleic acid and lecithin of 2.5% had a higher permeation rate of 9.8 microg/cm(2)/h and lower lag time 1 h, therefore the formulation was selected to process the skin whitening and irritation test. The results showed that a significantly topical photoprotective effect with acceptable skin irritation was obtained after hesperetin cream topical application when compared with that of the non-treatment group, indicating that the hesperetin cream may be used as an effective whitening agent.

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%.

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 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.

The purpose of this study was to develop propranolol extended release formulations containing hydroxypropylmethylcellulose (HPMC). The results indicate that the drug release from the tablet form containing a high amount of HPMC was incomplete, and avicel addition could increase the release percent at a later stage. In order to readily obtain an optimal formulation, response surface methodology and multiple response optimization utilizing a quadratic polynomial equation was used. The model formulations were prepared according to a factorial design. The effects of causal factors including the HPMC/drug ratio (X1) and avicel level (X2), on drug release were also measured. The drug release percentage at 1.5, 4, 8, 14 and 24 h were the target response and were restricted to not more than 25%, 35-50%, 55-70%, 75-90%, and 95-110%, 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 matrices tablets followed quasi-Fickian diffusion.

Blood glucose levels are routinely obtained by invasive and painful methods using glucose meters and test strips. The development of less invasive or non invasive techniques would be beneficial for diabetes patients. In this study, a noninvasive method was evaluated using the back diffusion of glucose across skin with or without permeation enhancement methods. An in vitro model was utilized. The stratum corneum (SC) was the predominant barrier for both back and forward diffusion of glucose across skin. Surfactants with various charges and essential oils (cyclic monoterpenes) were used as chemical enhancers to promote the back diffusion of glucose. A cationic surfactant (benzalkonium chloride) showed the highest enhancement, followed by anionic and nonionic surfactants. d-Limonene and 1,8-cineole dispersed in appropriate proportions of ethanol could enhance the glucose diffusion after pretreatment of the skin surface. Electroporation, defined as a physical method, significantly increased the amount of glucose that diffused back. The percentages of diffused glucose by 300 V (volts) and 500 V high voltage pulses on skin for 10 min were found to be 45 and 75 times greater than the control group, respectively.

The purpose of the present study was to investigate the effect of nanoemulsions as a carrier vehicle of hydrophilic drug for transdermal delivery. The response surface methodology with a mixture design was used to evaluate the effect of ingredient levels of nanoemulsion formulations including cosurfactant (isopropyl alcohol, 20 ∼ 30%), surfactant (mixed of Brij 30 and Brij 35, 20 ∼ 30%), and distilled-water (34.5 ∼ 50.0%) on properties of the drug-loaded nanoemulsions including physicochemical characters and drug permeability through rat skin. The result showed that the hydrophilic drug in aqueous solution with or without penetration enhancer could not transport across rat skin after 12 h of application. Used nanoemulsions as carrier vehicle, the permeation rate of drug was significantly increased from 0 to 63.23 µg/cm2/h and the lag time was shortened from more than 12 h to about 2.7 ∼ 4.0 h. Moreover, the drug-loaded nanoemulsion formulation also showed physicochemical stability after 3 month storage at 25°C and 40°C.

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.

The in vitro permeation of three diclofenac salts--diclofenac sodium (DFS), diclofenac potassium (DFP) and diclofenac diethylammonium (DFD)-across skin by both passive and iontophoretic transport were investigated. Various skin types were used as the barriers to elucidate the mechanism controlling transdermal delivery of diclofenac salts. The importance of the intercellular (paracellular) route for both DFS and DFP in passive permeation was elucidated. The transfollicular route constitutes an important permeation pathway for DFS but not for DFP. The route and mechanism for transdermal iontophoresis of DFD across the skin was somewhat different to that of the other salts. Hair follicles may be a more important pathway for DFD than for DFS and DFP under iontophoresis, while the intercellular lipid pathway showed the opposite result. Combination of iontophoresis and a penetration enhancer, cardamom oil, did not show a synergistic effect on diclofenac salt permeation. The results of this investigation suggest that the transdermal mechanism and the route of diclofenac salt uptake via passive and iontophoretic transport can be affected by their counterions.

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.

By using an intradermal microdialysis technique 22 h after the transdermal iontophoretic delivery of sodium nonivamide acetate (SNA), a synthetic derivative of capsaicin, the amount of SNA in the extracellular space was measured. Transdermal iontophoresis is a process that enhances skin permeation of ionized species by using an electric field as a driving force. Iontophoresis increased the amount of SNA in dialysate compared with passive diffusion in this study. By using various polymers incorporated in formulations, indicated hydrogels showed higher capacity for SNA delivery than solution formulations. This result was possibly attributable to the antinucleant ability of polymers resulting in the increase of thermodynamic activity of SNA in formulations. Pretreatment with isopropyl myristate, a lipophilic penetration enhancer, on rat skin enhanced transdermal delivery of SNA both for passive and iontophoretic penetration, indicating the possibility of reducing the surface area of the administrations site in clinical use. Microscopic examination revealed no or slight changes in the skin after iontophoretic treatment compared with penetration enhancer pretreatment. The histologic results also suggested iontophoretic treatment with 0.5 mA/cm2 current density of not more than 7-h application duration may be acceptable clinically. Drug Dev. Res. 46:87–95, 1999. © 1999 Wiley-Liss, Inc.

The in vitro and in vivo effect of pretreatment by cardamom oil, a crude drug extract, in ethanol/water vehicles on the transdermal delivery of indomethacin was investigated. The cyclic monoterpene components in cardamom oil were also determined and quantified in this study. The permeation of indomethacin was significantly enhanced after pretreatment of cardamom oil both in the in vitro and in vivo studies. The result of various pre-treatment periods showed that the indomethacin flux decreased as the length of the pretreatment increased. Both natural cardamom oil and a cyclic monoterpene mixture composed of the components of the oil showed similar enhancement on indomethacin permeation, indicating cyclic monoterpenes are the predominant components altering the barrier property of stratum corneum. The results also showed that three minor components in cardamom oil (alpha-pinene, 6.5%; beta-pinene, 4.8%; alpha-terpineol, 0.4%) had a synergistic effect with 1,8-cineole (59.3%) and d-limonene (29.0%) to enhance the permeation of indomethacin.

The aim of this study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide propionate (SNP). The iontophoretic permeation of SNP from various pH buffers increased following the decrease of pH values. This trend was consistent with that of sodium nonivamide acetate (SNA) which is another synthetic analogue of capsaicin. However, the iontophoretic permeability of SNP was much lower than that of SNA. SNP was also delivered iontophoretically from hydrogel formulations. It is suggested that ionizable polymers should be avoided for iontophoretic delivery to maintain good penetration capacity of drugs. Both nonionic cellulose polymers of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) showed higher iontophoretic flux for SNP than the others did. Furthermore, the flux of SNP leveled off with an increase in the amount of polymers in hydrogel, indicating that the viscosity of vehicles plays an important role in the permeation of SNP. Comparing the various iontophoretic application modes, the discontinuous on/off cyclic mode showed higher penetration capacity than did the continuous mode although they possessed the same electrical energy. Moreover, the desorption time of SNP from skin was approximately 20 min which was longer than that of SNA.

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.

Nonivamide (NVA) and sodium nonivamide acetate (SNA) are synthetic derivatives of capsaicin. In this study, the cationic surfactant benzalkonium chloride was incorporated into the Carbopol 940® gel bases of capsaicin and its synthetic derivatives to evaluate the in vitro percutaneous absorption capacity. Afterwards, the optimal gel formulation selected from the in vitro study was used in a series of in vivo non-invasive bioengineering methods. To quantify the skin erythema and irritation caused by capsaicin, NVA, and SNA, laser Doppler flowmetry (LDF), transepidermal water loss (TEWL), and colorimetry were utilized for determining the cutaneous blood flow and skin barrier impairment to assess the level of irritant reaction. In the in vitro transdermal study, the gel base with 0.05% benzalkonium chloride possessed the highest penetration capacity: this was chosen for the in vivo study. After quantification of skin erythema by LDF, capsaicin developed more severe irritation than NVA, and SNA showed no skin irritation or pungent sensation in volunteers. The result of the TEWL experiment suggested that 0.05% benzalkonium chloride did not cause any skin impairment. Moreover, the Carbopol 940® gel base itself offered a moderate penetration capacity for drugs and avoided any skin irritation. The result of colorimetry confirmed that both Δa* and ΔE* parameters correlated well with the data of LDF and that they are good indicators of skin erythema response. After a series of in vivo applications, SNA was shown to be a potent analogue of capsaicin with a marked pharmacological effect and moderate percutaneous capacity and reduced skin erythema and painful sensation. Drug Dev. Res. 40:56–67, 1997. © 1997 Wiley-Liss, Inc.

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.

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.

Yi-Ping Fang,1 Chih-Hung Chuang,2 Pao-Chu Wu,1 Yaw-Bin Huang,1 Cherng-Chyi Tzeng,3 Yeh-Long Chen,3 Ya-Ting Liu,1 Yi-Hung Tsai,1 Ming-Jun Tsai4–6 1School of Pharmacy, College of Pharmacy, 2Department of Biomedical and Environment Biology, College of Life Science, 3School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 4Department of Neurology, China Medical University Hospital, 5School of Medicine, Medical College, China Medical University, Taichung, 6Department of Neurology, China Medical University An-Nan Hospital, Tainan, Taiwan Abstract: Amsacrine analog is a novel chemotherapeutic agent that provides potentially broad antitumor activity when compared to traditional amsacrine. However, the major limitation of amsacrine analog is that it is highly lipophilic, making it nonconductive to intravenous administration. The aim of this study was to utilize solid lipid nanoparticles (SLN) to resolve the delivery problem and to investigate the biodistribution of amsacrine analog-loaded SLN. Physicochemical characterizations of SLN, including particle size, zeta potential, entrapment efficiency, and stability, were evaluated. In vitro release behavior was also measured by the dialysis method. In vivo pharmacokinetics and biodistribution behavior of amsacrine analog were investigated and incorporated with a non invasion in vivo imaging system to confirm the localization of SLN. The results showed that amsacrine analog-loaded SLN was 36.7 nm in particle size, 0.37 in polydispersity index, and 34.5±0.047 mV in zeta potential. More than 99% of amsacrine analog was successfully entrapped in the SLN. There were no significant differences in the physicochemical properties after storage at room temperature (25°C) for 1 month. Amsacrine analog-loaded SLN maintained good stability. An in vitro release study showed that amsacrine analog-loaded SLN sustained a release pattern and followed the zero equation. An in vivo pharmacokinetics study showed that amsacrine analog was rapidly distributed from the central compartment to the tissue compartments after intravenous delivery of amsacrine analog-loaded SLN. The biodistribution behavior demonstrated that amsacrine analog mainly accumulated in the lungs. Noninvasion in vivo imaging system images also confirmed that the drug distribution was predominantly localized in the lungs when IR-780-loaded SLN was used. Keywords: amsacrine analog, solid lipid nanoparticle, pharmacokinetics, biodistribution, water insolubility

The effects of the administration for a commercial keto-profen gel on the percutaneous absorption of ketoprofen (through rabbit abdominal skin) were investigated. The AUC (area under the curve) value of absorbed ketoprofen for single topical administration of 6 g of ketoprofen gel applied with ODT (occlusive dressing technique) was found to be about 6 -fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied with ODT at 6 h interval in a day. It was about 14-fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied without ODT at 6 h interval in a day. The experiment of volatilation of ketoprofen gels and the in vitro release test of ketoprofen gel applied with ODT and without ODT had been, in addition, respectively approached. The volatilation of solvent in the gel, as a result of this, may clearly be the primary factor for inducing a sharp descending of the plasma ketoprofen level following the Cmax (maximun concentration) in the in vivo per...

Oleic acid (OA) or / and saturated fatty acid (i.e. lauric lyristic, palmitic and stearic acid) decreased the release of piroxican from FAPG (fatty alcohol-propylene glycol) base. The reason would be due to the increase in lipophilicity of the base. The released piroxicam was found to be inversely proportional to the apparent viscosity of the ointments containing OA and saturated fatty acid. However, OA or / and the saturated fatty acids enhanced the in vitro skin permeation and the in vivo percutaneous absorption of piroxican, the enhancing effect was decreased linearly with increasing carbon number of saturated fatty acid from 12 to 18. A useful parameter has been obtained for estimating the properties of the exudation or “bleeding” of the FAPG base. A number of piroxicam FAPG ointments have been selected as an optimal product for less bleeding and more percutaneous absorption of piroxicam than those of controls (containing no oleic acid and saturated fatty acid).

Nonivamide (NVA), sodium nonivamide acetate (SNA) and sodium nonivamide propionate (SNP) are analogues of Capsaicin (CAP). The structure and pungent property of NVA are similar to CAP. The solubilities of SNA in different pH value buffer solution were higher than that of NVA and CAP. For the NVA and SNA, the n-octanol/buffer partition coefficients decreased with increasing pH value. The fluxes of CAP and its analogues were determined using excised rat skin and the effect of pH was also investigated. The flux of NVA and SNA mixture was higher than individually NVA or SNA, and the ratio of 70:30 was a better choice. Sodium lauryl sulfate (SLS), an anionic surfactant, had significant effect on SNA skin permeation.

The objective of this work was to develop a safe and effective delivery vehicle for topical treatment of gemcitabine. The physicochemical properties, drug release rate, drug level in plasma and bladder, and histological changes of tissue after drug administration were investigated. The electrical conductivity, mean size, and viscosity of drug-loaded microemulsions were 0.8—102.0 μS/cm, 116.8—322.5 nm, and 42.9—105.0 cps×103, respectively. Gemcitabine loaded microemulsions showed a slower and sustained release. After intravesical administration of aqueous control and microemulsions treated, the drug concentrations in plasma were 15.11 μg/ml and 2.81—12.82 μg/ml, respectively, and the accumulation in bladder were 18.27 μg and 9.12—64.16 μg, respectively. Microemulsions slightly decreased the systemic absorption and significantly enhanced the accumulation in bladder tissue. Moreover, the preliminary toxicity studies revealed no overt adverse histological changes or tissue irritation by the microemulsion application. Therefore, the microemulsions were suggested to be a promising drug carrier for intravesical chemotherapy.

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.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.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.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.

In this study, we compared the irritation inhibition of various types of anti-irritants such as antihistamines (cyprohetadine, diphenhydramine, and promethazine), alpha-hydroxy acids (gluconolactone and gluco-delta-lactone), corticosteroids (betamethasone and clobetasol), and ion channel modulating agents (amiloride, ethacrynic acid, nifedipine, and verapamil) on the adverse dermatological reaction caused by captopril gel using noninvasive bioengineering methods including measuring the transepidermal water loss (TEWL) and the color change of skin surface [such as change chroma (delta C) and difference in color (delta E) between the gel-treated site and the untreated site]. In addition, the influence of these anti-irritants on the penetration capacity of captopril through the rabbit skin was also investigated. The results showed that the TEWL, change chroma (delta C), and difference in color (delta E) of skin were significantly reduced via incorporating diphenhydramine and clobetasol, indicating that both substances had potent irritation inhibition activity. Moreover, these substances had no effect on the percutaneous absorption of captopril gel. However, flux of the captopril with anti-irritants was about 480 microg/cm2/h and the required minimum administration area to obtain the minimum effective concentration was about 15 cm2, indicating that this formulation could possibly be developed for a transdermal drug delivery system.

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.

Sodium nonivamide acetate (SNA) is a newly synthetic analogue of capsaicin which produces no overt pungent sensation or irritation. In this present study, the effects and roles of penetration enhancers for SNA through rat skin were investigated by in vitro skin penetration experiment and differential scanning calorimeter (DSC) determination. The penetration fluxes of SNA after the incorporation of enhancers increased in the order of Polysorbate 20sodium laurylsulfateor = benzalkonium chloride. This result was consistent with that of DSC profiles which indicated the disruptive effects of surfactants on the rat stratum corneum increased in the order of Polysorbate 20sodium laurylsulfatebenzalkonium chloride. The information gained is particularly helpful in the development of SNA transdermal drug delivery system.

The effects of antioxidants and chelating agent on the stability of captopril in aqueous and semisolid were determined in this study. Then the influence of the combination of additives including antioxidants, anti-irritants and penetration enhancer on stability, skin irritation and penetration capacity of captopril in semisolid dosage form was investigated. In the stability study, the degradation of captopril followed the first-order kinetic. The chelating agent EDTA showed a potent stability effect and obviously increased the shelf-life up to 14-fold that of control gel. The anti-irritants such as clobetasol and diphenhydramine had potent inhibition irritation activity and the effect was not retarded by the addition of EDTA. Moreover, the captopril gel containing penetration enhancer, anti-irritants and chelating agent had a higher penetration capacity and the minimum therapeutic concentration could be obtained by applying about 13.24 cm 2 of administered area, indicating that the formulation can possibly be developed for a transdermal drug delivery system.

The aim of this present study was to investigate the in vitro transdermal iontophoretic delivery of three diclofenac salts-diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD). A series of physicochemical and electrical variables which might affect iontophoretic permeation of diclofenac salts was studied. Application of 0.3 mA/cm 2 current density significantly increased the transdermal flux of diclofenac salts as compared to passive transport. The iontophoretic enhancement increased in the order of DFS>DFP>DFD. The permeability coefficient of diclofenac salts all decreased with increasing donor concentration during iontophoresis. The addition of buffer ions and salt ions such as NaCI, KCI, and C 4 H 12 CIN reduced the permeation of diclofenac salts due to competition. However, this effect was lesser for DFD than for DFS and DFP. Comparing the various application modes of iontophoresis, the discontinuous on/off mode showed lower but more constant flux than the continuous mode.

The objective of this study was to evaluate the influence of a rate-controlling membrane and adhesive on the in vitro permeation of nicotine. The physicochemical properties of the adhesive, including adhesion and rheology (viscosity), were also detected. Higher permeability of nicotine was observed through a hydrophilic membrane than through a hydrophobic membrane. Natural rubber and silicone were used as the adhesive bases, respectively. The silicone adhesive showed the highest adhesion among all adhesive formulations. To increase the adhesion of natural rubber, a tackifier (polyisoprene) and a secondary tackifier (terpene polymer; Px 1150) were incorporated into the formulations to achieve acceptable adhesion. The nicotine permeation through silicone adhesive and three natural rubber adhesives with the secondary tackifier (2%, 4%, and 6% Px 1150) was close to that from a commercially available patch (Habitrol), although the loading amount of nicotine was not the same. A longer lag time during the in vitro permeation study of nicotine was required for the adhesives prepared in our laboratory than for the commercially available patch.

The effect of clobetasol 17-propionate (CP), a potent corticosteroid, in various cream bases on the permeation through artificial membrane was sought. Four formulations were then chosen for a further in vivo skin blanching assay. After calculation of the relationship between in vivo flux0-8 hr determined from a surface recovery technique and in vitro release rate0-8 hr of CP from various formulations, a high correlation coefficient of 0.9996 was achieved. Therefore, the in vitro release study could be used as an index to predict and evaluate the in vivo penetration capacity of CP cream to screen the effective formulation preclinically. After a series of in vivo investigations in this study, it was concluded that myristic acid-added formulations may show a bioequivalence with commercial Dermovate. Furthermore, the flux calculated from the surface recovery technique and delta E detected from the skin blanching assay may be useful as parameters evaluating the quality and effectiveness of CP cream.

A new, simple and precise method using ion-pair high-performance liquid chromatography was developed for the determination of piroxicam in ointment and plasma. A reversed-phase system was used, consisting of a 5-μm NOVA-PAK C18 column with acetunitrile-water (42:58 v/v) containing 0.01M tetrabutylammoniium phosphate and adjusted to pH 7.5 by phosphoric acid as the mobile phase. The flow rate was 0.8 ml/min and the effluent was monitored at 355 nm. The sensitivities of this method were 2 ng/ml levels of piroxicam in ointment and plasma samples using indomethacin as internal standard.