Pretreatment effects of moxibustion on the skin permeation of FITC-dextran

This study was conducted to evaluate the pretreatment effects of different in vivo moxibustion on the permeation of a model high molecular compound, FITC-dextran, with a mean molecular weight of 4 kDa (FD-4), through excised hairless rat skin. Direct or indirect moxibustion (0.10 g moxa) was pretreated consecutively 4 times every 5 min on the abdomen of hairless rats, and the permeation of FD-4 was determined through the excised skin over 8h from 30 min after starting the first moxibustion. This consecutive moxibustion pretreatment showed a significant increase in the skin temperature as well as skin permeation of FD-4 compared with the control group (no moxibustion pretreatment). Quantitative parameters showed an increase in skin temperature and skin permeation: the area under the skin temperature over control temperature-time curve during one burning cycle (5.0 min) (AUCtemp) or the maximum skin temperature during moxibustion (Tmax) and the cumulative amount of FD-4 permeated through skin over 8h (Q8) or steady-state flux were increased by moxibustion pretreatment. Then, the effect of pedestal thickness (distance from the moxa cylinder and skin surface), shape of the moxa cylinder (5mm diameter, 13 mm height or 9 mm diameter, 7 mm height), burning materials (moxa or aromatic incense), pedestal component (paper, potato or ginger) and moxibustion pretreatment method (direct or indirect moxibustion) was evaluated on the AUCtemp or Tmax and Q8 or flux. The amount of protein leached from the skin surface was also determined as an inflammatory index by this moxibustion pretreatment. When the skin temperature was increased to 60 degrees C, the Q8 or flux as well as the amount of protein leached were markedly increased. When the skin temperature was controlled to 42 to 45 degrees C by an adequate selection of pedestal thickness, shape of the moxa cylinder, burning materials, pedestal component and moxibustion pretreatment method, on the other hand, protein leaching remained unaltered, but the Q8 or flux significantly increased with the Tmax. This study thus provides credible evidence that moxibustion pretreatment increases the skin permeation of high molecular compounds.     

Targeting of salicylate to skin and muscle following topical injections in rats.

The process of systemic absorption and tissue targeting efficacy of salicylate (SA) following intracutaneous (i.c.), subcutaneous (s.c.) and intramuscular (i.m.) injections of its sodium salt in rats were evaluated by determining the drug concentration at the injection site and surrounding tissues. After i.c. and s.c. injections, SA was absorbed into the systemic circulation from the muscular vessels as well as the cutaneous or subcutaneous vessels beneath the injection site, and the AUC of the drug in the muscle was extremely high. Following i.m. injection, SA was rapidly absorbed into the systemic circulation mostly from the muscular vein. These results suggested that i.c. and s.c. injections have high degrees of targeting efficacy to the muscle, whereas i.m. injection is not appropriate for drug retention in muscle. In contrast, most of the topically applied drug was absorbed from the cutaneous vessels, and little drug migration to the muscle was observed. Thus, the skin pharmacokinetics of SA after i.c. injection was also markedly different from those after topical application on the skin. These results suggested that the i.c. and s.c. injections may be a good means to improve the targeting ability of drugs to the muscle as well as the skin.     

Effect of molecular weight on the dermatopharmacokinetics and systemic disposition of drugs after intracutaneous injection

The aim of this study was to investigate the effect of molecular weight on the topical migration and systemic absorption of drugs, sodium salicylate (SA), calcein sodium (CAL) and FITC-dextrans (FD-4, FD-10, FD-20 and FD-40), after intracutaneous (i.c.) injection. The apparent diffusion coefficients in the skin (D(s)) of SA, CAL and FD-4 after i.c. injection were almost the same and slightly less than 1x10(-4)cm(2)/min. The D(s) value drastically decreased with molecular weight more than 10kDa. The plasma concentration-time curve after i.c. injection was predicted by the convolution method. The ratio of AUC (observed/predicted) was approximately unity for SA, CAL and FD-4 although the systemic absorption of only FD-4 was delayed. In contrast, the AUC ratios of FD-10, FD-20 and FD-40 were about 0.5, 0.2 and 0.06, respectively, and obviously decreased with the molecular weight. The elimination of FD-10, FD-20 and FD-40 from the skin was slow and the drugs tended to remain in the muscle. These results indicated the importance of diffusion in the skin and permeability through the blood vessels for local migration and systemic absorption of drugs after penetration into viable skin.     

Enhancement of topical delivery of a lipophilic drug from charged multilamellar liposomes

To enhance the topical delivery of rhodamine B base (Rho), a model lipophilic compound, the electrostatic interaction between the positive and negative components incorporated in the liposomal bilayer was utilized. The higher in vitro permeability to Rho in rat skin was observed with positive and neutral multilamellar liposomal preparations, the former was prepared with phosphatidylcholine (PC) and stearylamine (SA) and the latter with PC alone, than that given as a solution. Negative liposome composed of PC and dicetyl phosphate (DCP) showed lower skin permeability to Rho. To enhance the Rho retention in the skin, the electrostatic interaction between SA and DCP, which was confirmed by in vitro partition study, was utilized. By pretreating the skin surface with SA solution or empty SA liposome, the skin distribution of Rho given as DCP liposome was substantially enhanced, with increase in the PC distribution into the skin. The pretreatment effect of empty SA liposome was also observed in rats in vivo. In conclusion, it was found that negative DCP liposome provides better drug retention in the skin with lower skin permeability, and the topical drug delivery from DCP liposome was further enhanced by the pretreatment of the skin surface with empty SA liposome.     

Dermatopharmacokinetics of salicylate following topical injection in rats: effect of osmotic pressure and injection volume on salicylate disposition

Using advanced topical formulations containing potential chemical enhancer(s) or physical penetration-enhancing tools capable of delivering entrapped drug(s) directly into skin tissues with little influence of the stratum corneum barrier, local and systemic drug disposition may be markedly similar to direct injection into the skin and muscle. The objective of this study is to investigate the dermatopharmacokinetics and systemic drug disposition after topical application and topical injection. Salicylate (SA) disposition in the skin and muscle as administration sites, and in the systemic circulation were evaluated following intracutaneous (i.c.) injection of an isotonic solution of SA-Na (dose; 3.08 micromol). Subcutaneous (s.c.) and intramuscular (i.m.) injection were also evaluated for comparison. Dermatopharmacokinetics and systemic disposition of SA after i.c. and s.c. injections were analyzed using a 4-compartment model consisting of skin, muscle, and central and peripheral compartments, whereas SA disposition after i.m. injection was analyzed using a 3-compartment model consisting of muscle, and central and peripheral compartments. Moreover, the absorption rate constant of SA after i.c. injection (0.073 min(-1)) was slightly lower than that after s.c. injection (0.083 min(-1)), and much lower than that after i.m. injection (0.327 min(-1)). In addition, higher osmolarity and a larger volume of SA-Na injectant increased the retention of SA in the skin and decreased the absorption rate to the systemic circulation after i.c. injection. The effect of injection volume on SA disposition after i.c. injection was not so marked compared with that of osmotic pressure. These results are useful to design an injection-type topical delivery system.     

局部用辣椒碱传递体的制备及体内外评价

目的制备辣椒碱传递体，并评价其体内外皮肤渗透性。方法采用高剪切分散乳化均质机制备辣椒碱传递体，并对其大小与结构、包封率、释放度、体外皮肤渗透性和在大鼠组织的分布进行评价。结果辣椒碱传递体结构为小单室泡囊，平均粒径150.6 nm。包封率随脂质浓度增加而增加，当脂质浓度为8%时，包封率为96.7%。体外累积释放量随接受液中乙醇浓度的提高而增加，不同基质大鼠腹部皮肤体外辣椒碱累积透皮量为：传递体>霜剂和混悬液。不同种类皮肤辣椒碱累积透皮量为：小鼠>大鼠>人，人体皮肤辣椒碱累积透皮量为：表皮膜>真皮层和完整皮肤。辣椒碱注射液对大鼠腹腔多次注射体内分布为：骨头>血液>皮肤>肌肉，辣椒碱传递体大鼠腿部局部多次给药，体内分布为：骨头>皮肤>血液>肌肉。结论辣椒碱传递体包封率达到药典的规定(>80%)，辣椒碱传递体可以增加辣椒碱的皮肤透过性，皮肤种类及皮肤的不同层次影响辣椒碱传递体的皮肤透过性。多次注射及局部给药，辣椒碱在骨头及肌肉的分布类似，但在血液及皮肤的分布有所不同。     

Azathioprine transport through rat skin and its immunosuppressive effect

The objective of this research was to study the in vitro and in vivo percutaneous absorption of azathioprine with and without the effect of penetration enhancers. In vitro permeation of azathioprine was studied using a Franz diffusion cell and rat skin. Both azathioprine and 6-mercaptopurine were detected in the receiver solution with a reversed phase HPLC system. The steady state flux of azathioprine, permeability coefficient, and lag time were reported. Penetration enhancers such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), and urea were added to the donor compartment to increase the skin permeation of azathioprine. The flux of azathioprine was increased by 20.7%, and 22.4% using dimethylsulfoxide, and dimethylformamide respectively. The in vivo permeation was determined by measurement of antibody titers by the slide latex agglutination test. The in vivo permeation study showed that the titers of antibody induced in the rats were not affected by topical application of azathioprine solution. The results show that azathioprine has low flux to exert a systemic effect with and without penetration enhancers. However these results may support the use of topical azathioprine for the treatment of some dermatological disorders with minimum side effects.     

Influence of low-frequency massage device on transdermal absorption of ionic materials

The influence of a low-frequency massage device on transdermal absorption of sodium benzoate, ketoprofen and diclofenac sodium was investigated in rats. Electrode pads spread with a hydroxypropyl cellulose gel containing the drug model were placed on excised skin in vitro. The transdermal permeation studies were carried out in the treatment group with the pulse applied through electrode pads spread with the gel, the pretreatment group with the gel applied after the application of the pulse and in the control group in which the gel was applied without the pulse. In vivo, transdermal absorption of ketoprofen was examined in the same groups used for the in vitro study. The pharmacokinetics of ketoprofen in plasma after intravenous injection was also studied. The treatment group showed higher cumulative permeated amounts of the drug models than the control in vitro. However, the enhancing effect was not observed in the pretreatment group. In vivo, the plasma ketoprofen level increased temporarily after the pulse was applied and then increased gradually as compared with the control. Since the distribution of ketoprofen from the central to the peripheral compartment was enhanced by the pulse in the injection study, enhancement of the biodistribution of ketoprofen by the low-frequency pulse was suggested.     

Self Promotion of Deep Tissue Penetration and Distribution of Methylsalicylate After Topical Application

Purpose. To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient trie-thanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations. Methods. Flux of salicylate from MeS A and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed. Results. In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers. Conclusions. Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.     

Influence of different penetration enhancers on in vitro skin permeation and in vivo photoprotective effect of flavonoids

In the present study the permeation of two flavonoids (naringenin and hesperetin) through excised human skin mounted in Franz diffusion cells and its possible optimization following skin pretreatment with two penetration enhancers (d-limonene and lecithin) were determined. Hesperetin and naringenin were able to permeate through excised human skin; moreover, skin pretreatment with d-limonene and lecithin increased, to different degrees, their cutaneous permeation. On the basis of findings obtained in these in vitro experiments, we designed a schedule for a series of in vivo experiments, in which the protective effect of topically applied naringenin and hesperetin against UV-B-induced skin damage was assessed monitoring the extent of erythema in human volunteers by means of reflectance spectrophotometry. Hesperetin and naringenin from formulations containing the flavonoid alone were completely ineffective in decreasing UV-B-induced erythema. Furthermore, both d-limonene and lecithin have enhanced, to a significant extent, the photoprotective activity of naringenin and hesperetin. Taken together, these data demonstrate that hesperetin and naringenin may be successfully employed as topical photoprotective agents. However their topical activity needs to be optimized by using suitable penetration enhancers.     

Transdermal Delivery of the Synthetic Cannabinoid WIN 55,212-2: In Vitro/in Vivo Correlation

PURPOSE: The aim of the current investigation was to evaluate the percutaneous absorption of the synthetic cannabinoid WIN 55,212-2 in vitro and in vivo. METHODS: The in vitro permeation studies of WIN 55,212-2 in human skin, hairless guinea pig skin, a polymer membrane with adhesive, and a skin/polymer membrane composite were conducted in flowthrough diffusion cells. The pharmacokinetic parameters for WIN 55,212-2 were determined after intravenous administration and topical application of Hill Top Chambers and transdermal therapeutic systems (TTS) in guinea pigs. RESULTS: The in vitro permeation studies indicated that the flux of WIN 55,212-2 through hairless guinea pig skin was 1.2 times more than that through human skin. The flux of WIN 55,212-2 through human and guinea pig skin was not significantly higher than that through the corresponding skin/polymer membrane composites. The mean guinea pig steady-state plasma concentrations after topical 6.3 cm2 chamber and 14.5 cm2 TTS patch applications were 5.0 ng/ml and 8.6 ng/ml, respectively. CONCLUSIONS: The topical drug treatments provided significant steady-state plasma drug levels for 48 h. The observed in vivo results from the Hill Top Chambers and TTS patches in the guinea pigs were in good agreement with the predicted plasma concentrations from the in vitro data.     

Effect of liposomes and niosomes on skin permeation of enoxacin

The skin permeation and partitioning of a fluorinated quinolone antibacterial agent, enoxacin, in liposomes and niosomes, after topical application, were elucidated in the present study. In vitro percutaneous absorption experiments were performed on nude mouse skin with Franz diffusion cells. The influence of vesicles on the physicochemical property and stability of the formulations were measured. The enhanced delivery across the skin of liposome and niosome encapsulated enoxacin had been observed after selecting the appropriate formulations. The optimized formulations could also reserve a large amount of enoxacin in the skin. A significant relationship between skin permeation and the cumulative amount of enoxacin in the skin was observed. Both permeation enhancer effect and direct vesicle fusion with stratum corneum may contribute to the permeation of enoxacin across skin. Formulation with niosomes demonstrated a higher stability after 48 h incubation compared to liposomes. The inclusion of cholesterol improved the stability of enoxacin liposomes according to the results from encapsulation and turbidity. However, adding negative charges reduced the stability of niosomes. The ability of liposomes and niosomes to modulate drug delivery without significant toxicity makes the two vesicles useful to formulate topical enoxacin.     

Ionisation and the effect of absorption enhancers on transport of salicylic acid through silastic rubber and human skin

Propose: to investigate if salicylic acid (SA)-permeation through excised human skin (HS) and silastic rubber (SR) conforms to the pH-hypothesis and to assess the influence of a range of absorption enhancers on the transport of SA with and without a transmembrane pH-gradient. Methods: Franz cells were used to study SA permeation from solutions and saturated suspensions. McIlvaine buffers were used to maintain transmembrane pH-gradients. Membrane pretreatment was used to study the action of absorption enhancers. Results: the flux of SA from solutions was dependent upon the vehicle pH and permeant concentration was directly related to the degree of ionisation of the solute. Flux from suspensions was independent of pH, since the level of unionised drug, the predominant diffusing species, was maintained at the intrinsic saturated solubility at all pH values. The observed SA flux enhancement across human skin without a transmembrane pH-gradient was not significantly different from the enhancement with a pH-gradient for all of the absorption enhances used, except for dodecylamine. Conclusions: the results showed that SA permeation conformed to the pH-partition hypothesis. The evidence from absorption-enhancer pretreatment demonstrated that, under certain conditions, the transdermal penetration enhancement of a number of topical enhancing compounds, including Azone and oleic acid can be explained without recourse to ion-pair phenomena.     

Application of hydrotropy to transdermal formulations: hydrotropic solubilization of polyol fatty acid monoesters in water and enhancement effect on skin permeation of 5-FU

Objectives A hydrotropic formulation containing a percutaneous enhancer was developed for the transdermal formulation of a water‐soluble drug and the solubilizing mechanisms of a percutaneous enhancer in water by a hydrotropic agent were investigated. The enhancement effect was also compared with the hydrotropic formulation and the other formulations using ethanol, propylene glycol or mixed micelles. Methods Sodium salicylate (SA) and sodium benzoate (BA) were selected as hydrotropic agents, and polyol fatty acid ester (POFE) and 5‐fluorouracil (5‐FU) were selected as a percutaneous enhancer and a water‐soluble drug, respectively. Near‐infrared (NIR) spectrophotometric and ¹H NMR spectroscopic studies were carried out to investigate the solubilizing mechanisms. The mean particle size in the hydrotropic formulation was measured. The in‐vitro skin permeation of 5‐FU and the accumulation in the skin of propylene glycol monocaprylate (PGMC), one of the monoesters of POFE, from the hydrotropic formulation or the other formulations were investigated by using Franz‐type diffusion cell. Key findings The presence of SA and BA had a visible effect on the O–H stretching band of water in the NIR region. The surface tension of SA and BA aqueous solutions was found to decrease with an increase in SA or BA concentration. Although SA interacted with PGMC in the presence of water, it did not interact with PGMC in the absence of water. Mean particle size in a solution consisting of 5% (v/v) PGMC and 30% SA aqueous solution was approximately 14 nm. ¹H NMR spectroscopic studies indicated that the hydrotropic salts formed aggregates with which PGMC interacted from the outside. The hydrotropic formulation prepared in this study enhanced skin permeation of 5‐FU when compared with the other formulations. Conclusions SA and BA solubilized monoesters of POFE in water, and SA interacted with PGMC in water. The hydrotropic formulation prepared in this study significantly enhanced skin permeation of 5‐FU compared with the other formulations. The results suggest that a hydrotropic formulation containing PGMC may be a useful transdermal formulation for water‐soluble drugs.     

Effect of heparin injection on plasma protein binding of bilirubin and salicylate in rats

Intravenous heparin injection significantly increased the free bilirubin and salicylate fractions in the plasma of rats. This effect occurred within 2 min after injection of 500 U of heparin/kg and lasted for 15--45 min (bilirubin) or for greater than 45 min (salicylate). In vitro addition of heparin to plasma had no quantitatively significant effect on the protein binding of bilirubin and salicylate. The in vivo effect of heparin on protein binding was reversible by treating the plasma with activated charcoal, a procedure known to remove fatty acids from albumin. Since protein binding affects the pharmacokinetic characteristics and the pharmacological activity of drugs, the heparin--drug interaction may have significant clinical implications. Use of heparinized plasma for exchange transfusion in the treatment of neonatal jaundice may be hazardous.     

Deoxycholate hydrogels of betamethasone-17-valerate intended for topical use: In vitro and in vivo evaluation

The aim of this study was to evaluate the suitability of sodium-deoxycholate (Na-DOC) gels containing betamethasone-17-valerate (BMV) for topical application. The gels were characterized for rheological and textural properties. The in vitro flux of BMV from Na-DOC gels across rat skin was 2.5 (0.05% gel) and 8.5 times (0.1% gel) higher compared to the commercial cream (0.1%), respectively. The pharmacodynamic responses after in vivo topical application in rats were also determined. A significant correlation between anti-inflammatory activity and in vitro permeation of BMV was observed. Na-DOC gels produced significantly higher edema inhibition compared to commercial cream at all time intervals. Finally, according to the results of histology studies, Na-DOC gel has no irritant effect on the skin. In conclusion, Na-DOC gel formulation could be suggested as a promising alternative system for the topical application of BMV.     

Effect of fatty acids on the transdermal delivery of donepezil: in vitro and in vivo evaluation

The effect of fatty acids on the skin permeation of donepezil base (DPB) and its hydrochloride salt (DPH) were studied in vitro using hairless mouse and human cadaver skin. DPB and DPH were solubilized in propylene glycol (PG) containing 1% (w/v) fatty acid, after which the in vitro permeation through hairless mouse skin and human cadaver skin were evaluated using Keshary-Chien diffusion cells. The optimized formulation obtained from the in vitro study was then tested in rats for an in vivo pharmacokinetic study. The relative in vitro skin permeation rate of donepezil (DP) through the hairless mouse skin showed a parabolic relationship with increased carbon length of the fatty acid enhancers. Among the fatty acids tested, oleic acid for DPB and palmitoleic acid for DPH showed the highest enhancing effect, respectively. Both the permeation rates of DPB and DPH evaluated in human cadaver skin were in good correlation with those in hairless mouse skin, regardless of the presence of fatty acids. This suggests that the mouse skin model serves as a useful in vitro system that satisfactorily represents the characteristics of the human skin. Moreover, based on the in vitro results, the optimal formulation that could maintain the human plasma concentration of 50 ng/mL was determined to be 10mg DP with 1% (w/v) enhancer. When the DP transdermal formulations were applied to the abdominal skin of rats (2.14 cm(2)), the C(ss) was maintained for 48 h, among which the highest value of 52.21 ± 2.09 ng/mL was achieved with the DPB formulation using oleic acid. These results showed that fatty acids could enhance the transdermal delivery of DP and suggested the feasibility of developing a novel transdermal delivery system for clinical use.     

In vivo skin penetration of salicylic compounds in hairless rats.

The in vivo skin penetration of four salicylic compounds was investigated using a hairless rat model, which allowed for non-occluded, finite dose application, and free mobility of the rats throughout the test period. The model compounds were applied in equimolal concentrations of 0.4 mmol/g dimethyl isosorbide. At certain times (0.5-24 h) the rats were killed, and the amount of test compound on the skin surface, in the stratum corneum, and in the deeper viable skin layers was determined. Significant different skin concentrations were found with the following ranking: [(14)C]diethylamine salicylate>[(14)C]salicylic acid>[(14)C]salicylamide>[(14)C]butyl salicylate. In addition, the in vivo percutaneous rate of absorption was in the following order: [(14)C]butyl salicylate>[(14)C]salicylic acid> or =[(14)C]salicylamide>[(14)C]diethylamine salicylate. [(14)C]Butyl salicylate was rapidly absorbed and completely depleted from the surface 3 h post application. In comparison with [(14)C]salicylic acid, the ionic [(14)C]diethylamine salicylate had larger surface depots and penetrated the skin at a lower rate. The relatively hydrophilic [(14)C]salicylamide also had larger surface depots but much lower skin levels. For comparison, the in vitro permeation of the formulations was studied through freshly excised hairless rat skin using Franz diffusions cells, and an agreement between the techniques was found.     

Real-time measurement of microcirculation of skin by reflectance spectrophotometry.

A reflectance spectrophotometric measurement was developed to analyze the microcirculation of the skin in real time. The relative absorption (RA) spectra were obtained from skin tissue 10 times per second using a spectro-multi-channel-photodetector system. In this system, white light was projected onto the skin of the back of the anesthetized rat and the spectrum of the reflected light between 450 and 643 nm was analyzed. Two absorption peaks at wavelengths of about 540 and 577 nm were observed, corresponding to the absorption peaks in the oxyhemoglobin (HbO2) spectrum. Either phlebotomy or the i.v. injection of norepinephrine (NE) reduced the RA spectrum. Peaks of the reduction in spectrum [(RA spectrum before the treatment) - (RA spectrum after the treatment)] were observed at about 540 and 577 nm. Injection of NE (0.75-48 ng/100 g B.W., i.v.) reduced the RA value at 577 nm dose-dependently, suggesting a decrease in the skin blood flow due to vasoconstriction. In addition, the content of HbO2 and capillary permeation were measured at the same time after the i.v. injection of Evans blue (EB) dye. As indices of HbO2 content and capillary permeation, RA changes at 540 and 610 nm (the latter is an absorption peak in the EB spectrum) were measured in real time, respectively. Both RA values increased dose-dependently after the intradermal injection of histamine (0.3-100 micrograms/site), suggesting the presence of vasodilation and an increase in permeability. The time at which the RA value for HbO2 reached a maximum was shorter than that for EB. These observations suggest that the method described here can detect changes in the HbO2 content and permeation of skin microcirculation at the same time, and in real time.     

Design,development, physicochemical,and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied.