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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 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.

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.

The aim of the present study was to design a microemulsion for catechin topical application. A mixture experimental design with five independent variables (X1: oil, X2: surfactant, X3: catechin, X4: cosurfactant and X5: water) was developed, and the response surface methodology was used to study the effect of formulation components on physiochemical characteristics and penetration capacity of a catechin-loaded microemulsion, and to obtain an optimal microemulsion formulation. The results showed that the drug-loaded microemulsion formation and characteristics were related to many parameters of the components. The transdermal amounts in receiver cells and skin deposition amount remarkably increased about 4.1–111.6-fold and 0.6–7.6-fold respectively. The lag time was significantly shortened from 10 h to 1.0–6.7 h. The optimal formulation with 20% surfactant, 30% cosurfactant and 2.6% Catechin was subjected to stability and irritation tests. The results showed that the physicochemical characteristics and catechin level of the drug-loaded microemulsion did not show significant degradation after 3 months of storage at 25 °C.The catechin-loaded microemulsion did not cause significant irritation compared to the water-treated group.

Water-in-oil submicron emulsions were used as carrier for the topical delivery of 5-fluorouracil (5FU). The effect of components such as level and hydrophilic-lipophilic balance (HLB) value of surfactant, type of cosurfactant, and drug concentration on the delivery capability of drug in the receptor fluid and in the various skin layers (stratum corneum, epidermis and dermis) were evaluated. The result showed the submicron emulsion could increase the transdermal and deposition of 5FU compared with the aqueous control. Submicron emulsion with surfactant at HLB of 6.0 had higher deposition amount of drug in epidermis layer. The deposition amount of drug in the skin layers increased with increased amounts of surfactant and drug loading of submicron emulsion. However, the 0.2% 5FU-load submicron emulsion showed a comparable deposition effect in various skin layers with the commercial product (5%, Efudix®), which indicated that the submicron emulsions could be a promising drug vehicle for topical application.

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.

In this study, submicron emulsions have been employed as a carrier for the topical application of kaempferol. The effect of components of submicron emulsions on the physicochemical properties and permeation capability of drug were evaluated. In case of drug-loaded submicron emulsions, the cumulative amount over 12 h (Q(12 h)), lag time and deposition in skin amount ranged from 13.0±3.4 to 236.1±21.2 µg/cm(2), 1.7 to 5.3 h, and 1.10 to 7.76 µg/cm(2), respectively, which indicated that the permeation parameters of kaempferol were markedly influenced by the component ratio. Kaempferol dispensed in isopropyl myristate was used as the control. The Q(12 h), lag time and deposition amount in skin were 4.2±1.8 µg/cm(2), 6.0 h and 2.25±0.60 µg/cm(2), respectively. The data showed that used appropriate submicron emulsions as vehicle could significantly increase the Q(12 h) and deposition amount in skin and shorten the lag time, demonstrating that submicron emulsions have a potent enhancement effect for kaempferol transdermal delivery.

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.

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.

1-[3-(Furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (CCK2) is an antitumor agent which was especially active against the growth of the renal cancer cell UO-31 (GI50 = 0.03 μm) and the two melanoma cancer cells UACC-257 (GI50

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

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%.

Excessive production of radical oxygen species in skin is a contributor to a variety of skin pathologies. Naringenin is a potent antioxidant. The purpose of the present study was to develop elastic liposomes for naringenin topical application. Naringenin-loaded elastic liposomes containing different amounts of Tween 80 and cholesterol were prepared. The physicochemical properties including vesicle size, surface charge, encapsulation efficiency, and permeability capacity were determined to evaluate the effect of components. The stability of formulation and skin irritation caused by drug-loaded elastic liposomes were also evaluated for assessment of the clinical utility of elastic liposomes. Saturated aqueous solution of naringenin and naringenin dissolved in 10% Tween 80 solution (5 mg/mL) were used as the control group. The result showed that in using elastic liposomes as carrier, the deposition amounts in the skin of naringenin were significantly increased about 7.3~11.8-fold and 1.2~1.9-fold respectively, when compared with the saturated aqueous solution and Tween 80 solution-treated groups. The level of drug was more than 98.89±3.90% after 3 months of storage at 4℃. In a skin irritation test, the result showed experimental formulation exhibit considerably less irritating than the positive control (paraformaldehyde-treated) group, suggesting its potential therapeutic application.

The aim of this study was to develop a simple and reliable high-performance chromatographic (HPLC) method for simultaneous analysis of adapalene and benzoyl peroxide in pharmaceutical formulation by response surface methodology (RSM). An optimized mobile phase composed of acetonitrile, tetrahydrofuran and water containing 0.1% acetic acid at a ratio of 25:50:25 by volume was successfully predicted by using RSM. An isocratic separation was achieved by using the condition. Furthermore, the analytical method was validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentration. Finally, the method was successfully applied to the analysis of a commercial product.

A simple and reliable high-performance liquid chromatographic method with ultraviolet detection (280 nm) has been developed for the simultaneous analysis of 12 bioactive components in San-huang-xie-xin-tang (SHXXT), a traditional Chinese medicine containing Rhei rhizome, Coptidis rhizome and Scutellariae radix. A relatively simple extraction procedure was employed and optimised, and separation of the components was obtained within 1 h using a reversed-phase column under gradient elution with acetonitrile and a buffer containing 0.01 M sodium 1-pentanesulphonate (pH 3). The lower limit of detection for the analytes ranged from 25 to 75 ng/mL. The correlation coefficients associated with each calibration curve were greater than 0.99. The precision and accuracy of the method ranged from 1.0 to 10.5% at low concentration levels, 0.8 to 8.7% at medium levels and 1.2 to 5.8% at high levels. In commercial products of SHXXT, baicalin and berberine were present in the highest amounts with levels up to 4.0 and 3.3%, respectively, in one sample. The HPLC method was able rapidly and efficiently to analyse constituents in crude herb and traditional Chinese medicinal preparations containing Rhei rhizome, Coptidis rhizome and Scutellariae radix.

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 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.

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.

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.

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.

The influences of some formulation variables and manufacturing processes of the release rates of propranolol from gelation of hydroxypropylmethylcellulose (HPMC) matrices tablets were investigated. The amount of propranolol was determined by UV–Vis spectroscopy at 290 nm. The effects of extended release of matrices tablets were evaluated by the in vitro dissolution test and were compared to the United States Pharmacopoeia (USP) monograph specifications. The results showed that the lowest viscosity grade of HPMC (Metolose 4000) used gave the least burst effect in the earlier stage. The drug/Metolose ratio was an important influence on the drug release; increasing the polymer content decreased the dissolution rate of the drug. The release rate was increased with increase in the tablet content of avicel. The release curve of experimental formulation with 17% avicel was optimal compared with the USP monograph specification; there was no burst effect in the earlier stage (the release percent at 1.5 h was 26.6%) and almost total drug was released from matrices tablet after 24 h (97.4%). The other factors such as lubricant level (0.5 to 2.0%), compaction pressure (100 to 200 kPa), brand of HPMC (HPMC 4000 from Shin Etsu or Methocel K4MP from Dow Chemical Co.), and manufacturing process (tabletted from wet-massed granules or by direct compression) appeared not to modify release rates. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1886–1890, 2004

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.

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 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 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 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.

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 study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X1), hydrogenated coconut oil (X2), and soybean oil (X3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X1X2,X1X3, andX2X3) showed more potential influence than that of the main factors (X1,X2, andX3). An optimal predicted formulation withY10 min,Y30 min,Y60 min, andY90 minrelease values of 12.3%, 36.7%, 73.6%, and 92.7% atX1,X2, andX3of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factorf2was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile.

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.

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 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 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.

Response surface methodology (RSM) was used to develop and optimize the mesomorphic phase formulation for a meloxicam transdermal dosage form. A mixture design was applied to prepare formulations which consisted of three independent variables including oleic acid (X(1)), distilled water (X(2)) and ethanol (X(3)). The flux and lag time (LT) were selected as dependent variables. The result showed that using mesomorphic phases as vehicles can significantly increase flux and shorten LT of drug. The analysis of variance showed that the permeation parameters of meloxicam from formulations were significantly influenced by the independent variables and their interactions. The X(3) (ethanol) had the greatest potential influence on the flux and LT, followed by X(1) and X(2). A new formulation was prepared according to the independent levels provided by RSM. The observed responses were in close agreement with the predicted values, demonstrating that RSM could be successfully used to optimize mesomorphic phase formulations.

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

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.

Hesperetin is one of the flavonoids and possess anti-inflammatory, UV-protecting and antioxidant effects. Permeation issues for topical delivery systems of such effects are occasionally problematic, and in view of the fact that microemulsions are potential carriers for transdermal delivery system, the objective of this study was to design an optimal microemulsion formulation by in vitro permeation study for hesperetin topical dosage form and determine its topical photoprotective effect and skin irritation by in vivo study. The hesperetin-loaded microemulsion showed an enhanced in vitro permeation compared to the aqueous and isopropyl myristate (IPM) suspension dosage form of hesperetin. In comparison, the effect of co-surfactant on the drug permeation capacity, propylene glycol showed highest permeation rate, followed by ethanol, glycerol and polyethylene glycol (PEG 400). Sunscreen agent padimate O, as a transdermal enhancer could increase the permeation rate of hesperetin. In case of in vivo study, the hesperetin-loaded microemulsion showed significant topical whitening effect and diminished skin irritation when compared with the non-treatment group, indicating that the hesperetin microemulsion could be used as an effective whitening agent.

The objective of this study was to prepare sodium nonivamide acetate (SNA) microemulsion for topical administration. Microemulsions consisted of a mixed surfactant of Tween 80 and Span 20 as surfactant, ethanol as cosurfactant, isopropyl myristate (IPM) as an oil phase and water as an external phase. The effect of composition of microemulsion including the ratio of oil phase/surfactant/aqueous phase, various cosurfactant and polymer on the character and permeability of microemulsion were evaluated. The mean droplet size of SNA microemulsions ranged from 64 to 208 nm. Microemulsions showed potent enhancement effect for SNA transdermal delivery by a 3.7-7.1-fold increase when compared with the control group. Microemulsion containing ethanol as cosurfactant had the highest enhancement effect. With incorporated polymer, the viscosity of microemulsions increased resulting in the decrease in penetration rate of SNA. However, the permeability of SNA delivered from microemulsion was higher than SNA from volatile vehicles (pH 4.2 buffer containing 25% ethanol) reported in an earlier study, therefore microemulsions could be an effective vehicle for topical delivery of SNA.

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