基质pH及促渗剂对阿昔洛韦水凝胶贴剂体外透皮性能的影响

分别制备了基质pH为5.0、6.0、7.5的不含促渗剂的阿昔洛韦水凝胶贴剂,在基质pH 6.0的处方中加入不同浓度的月桂氮革酮、Ⅳ.甲基吡咯烷酮(NMP)、薄荷醇、吐温-80、聚乙二醇(PEG)400作为促渗荆,以考察基质pH及促渗剂对阿昔洛韦透过离体小鼠皮肤的影响.结果表明,基质pH升高,阿昔洛韦的透皮速率增大.与不含促渗剂的基质pH6.0处方组对照,NMP、PEG 400单用不能提高阿昔洛韦的渗透速率,4%的吐温-80、薄荷醇和月桂氮革酮均可提高阿昔洛韦的经皮渗透.     

Novel Biomaterial for Transdermal Application: In vitro and In vivo Characterization

The objective of the present study was to evaluate a novel film forming biomaterial for its potential application in the preparation of unilaminate transdermal adhesive matrix systems. The biomaterial, Damar Batu (DB), was tried alone and in combination with Eudragit RL100 as a matrixing agent in the preparation of transdermal patches. Developed transdermal patches of Diltiazem hydrochloride (DH) were evaluated for thickness uniformity, weight uniformity, folding endurance and drug content. USP dissolution apparatus V was used for in vitro drug release studies. Modified Franz diffusion cell used for permeation study using excised human cadaver skin. Total 6 formulations were developed and on the basis of in vitro drug release and in vitro skin permeation profile F5 composed of DB: Eudragit RL100 (60:40) and carrying 20 %w/w DH was selected as an optimized formulation for in vivo study. The in vivo study results showed that F5 achieved the Cmax of about 269.76?±?1.52?ng/mL in 6?h and sustained the release of the drug till 24?h. The skin irritation study results proved that the novel biomaterial is non-sensitizing and non-irritating. Drug-polymer interaction study carried out to check the compatibility of drug and polymer showed the intactness of the drug in the formulation proving the compatibility of the polymer. It can be proposed from the outcome of the present study that by applying suitable adhesive layer and backing membrane, DB: Eudragit RL100 (60:40) transdermal patches can be of potential therapeutic use.     

In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3?mA/cm²) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6?h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~?4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C_max (~ 3-fold) and AUC_0-α (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3?mA/cm²) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.     

Transdermal Permeation of Alniditan by Iontophoresis: In Vitro Optimization and Human Pharmacokinetic Data

Purpose. The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT_1D agonist for the treatment of migraine. Methods. An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. Results. i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin, ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. Conclusions. This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.     

Glibenclamide Nanocrystals in a Biodegradable Chitosan Patch for Transdermal Delivery: Engineering,Formulation, and Evaluation

Glibenclamide (GBD) nanocrystals (D₅₀ = 429 nm) were engineered by applying combined precipitation and homogenization procedures. GBD crystallinity was maintained during the nanonization process as revealed by differential scanning calorimetry and X-ray analyses. Nanonized and micronized GBD were incorporated into chitosan solutions to fabricate transdermal delivery systems (TDDSs), nano- and micro-GBD, respectively. The fabricated TDDSs displayed satisfactory physicochemical characteristics without substantial aggregation of GBD nanocrystals during the casting and drying procedures. Within 24 hours, about 85 ± 3.1% of the GBD content was released from nano-GBD, compared to 61 ± 3.9% from micro-GBD. Cumulative permeation of GBD from nano-GBD after 24 hours was 498 ± 33.35 compared to 362 ± 25.25 μg/cm² from micro-GBD. The calculated flux across rat skin for nano-GBD was 23.14 compared to 13.64 μg/cm²/h for micro-GBD, with an enhancement factor of 1.7. In vivo assessment clearly revealed the enhanced efficacy of nano-GBD to reduce blood glucose levels and counteract the induced hyperglycemia in tested animals compared to micro-GBD (p < 0.5). Simultaneously, the nano-GBD was able to maintain higher drug concentration for longer time (24 hours, p < 0.5) and minimize intense action and hypoglycemia associated with GBD oral therapy (p < 0.5).     

Reservoir Based Fentanyl Transdermal Drug Delivery Systems: Effect of Patch Age on Drug Release and Skin Permeation

Purpose  To understand and evaluate the stability and skin permeation profiles of fentanyl reservoir systems as a function of patch age. Methods  Drug release and skin permeation studies were performed using a modified USP apparatus 5 with a novel sample preparation technique. Results  The amount of fentanyl present in the EVA/adhesive layer (EAL) increased from about 17% of label claim (LC) at 5 months to 25% LC at 22 months. The increase in the drug concentration was mainly observed in the peripheral EAL. Simultaneously, the alcohol content of the patch decreased as a function of patch age. A significant effect of patch age on the drug content in the EAL and the drug release from the system was observed; however, skin permeation studies did not indicate an increase in drug delivery rate. Conclusions  Novel sample preparation technique with USP Apparatus 5 allowed determination of in vitro skin permeation rates for fentanyl transdermal patches with different designs. Permeation rates with cadaver skin as substrate were found not to change with patch age despite changing drug concentration in the EAL.     

Matrix-Type Transdermal Patches of Verapamil Hydrochloride: In Vitro Permeation Studies Through Excised Rat Skin and Pharmacodynamic Evaluation in Rats

The objectives of this study were to develop matrix-type transdermal patches of verapamil hydrochloride (VRP) with pectin as a matrix polymer to investigate the influence of several terpenes on in vitro permeation of VRP through rat skin and to evaluate pharmacodynamic activity of transdermal formulations in rats. Matrix-type transdermal patches containing VRP were prepared using pectin as a matrix agent and propylene glycol as a plasticizer agent. Terpenes such as nerolidol, d-limonene, eucalpytol, menthone, and menthol were also used as a chemical enhancer to improve the skin penetration of VRP. The permeation studies were perfomed using Franz-type diffusion cells and full-thickness excised abdominal rat skin. Effects of terpenes on the permeation parameters of VRP were evaluated. In vitro skin permeation studies showed that nerolidol was the most promising enhancer among the enhancers examined in the present study, followed by d-limonene. Pharmacodynamic activity of the transdermal patches containing nerolidol or d-limonene was evaluated in rats by the measurement of systolic blood pressure for 360 min with the use of the tail cuff method. VRP transdermal patches significantly decreased the systolic blood pressure after 30 min and transdermal patches containing nerolidol and d-limonene maintained the decrease in blood pressure during the observation of 360 min.     

Dimethylamino Acid Esters as Biodegradable and Reversible Transdermal Permeation Enhancers: Effects of Linking Chain Length,Chirality and Polyfluorination

Purpose  Series of N,N-dimethylamino acid esters was synthesized to study their transdermal permeation-enhancing potency, biodegradability and reversibility of action. Effects of chirality, linking chain length and polyfluorination were investigated. Materials and Methods   In vitro activities were evaluated using porcine skin and four model drugs—theophylline, hydrocortisone, adefovir and indomethacin. Biodegradability was determined using porcine esterase, reversibility was measured using electrical resistance. Results  No differences in activity were found between (R), (S) and racemic dodecyl 2-(dimethylamino)propanoate (DDAIP). Substitution of hydrocarbon tail by fluorocarbon one resulted in loss of activity. Replacement of branched linking chain between nitrogen and ester of DDAIP by linear one markedly improved penetration-enhancing activity with optimum in 4–6C acid derivatives. Dodecyl 6-(dimethylamino)hexanoate (DDAK) was more potent than clinically used skin absorption enhancer DDAIP for theophylline (enhancement ratio of DDAK and DDAIP was 17.3 and 5.9, respectively), hydrocortisone (43.2 and 11.5) and adefovir (13.6 and 2.8), while DDAIP was better enhancer for indomethacin (8.7 and 22.8). DDAK was rapidly metabolized by porcine esterase, and displayed low acute toxicity. Electrical resistance of DDAK-treated skin barrier promptly recovered to control values. Conclusion  DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate for future research.     

Studies on Optimizing In Vitro Transdermal Permeation of Ondansetron Hydrochloride Using Nerodilol,Carvone, and Limonene as Penetration Enhancers

The present investigation was carried out to formulate a terpene-based hydroxypropyl cellulose (HPC) gel drug reservoir system for its optimal transdermal permeation of ondansetron hydrochloride. The HPC gel formulations containing ondansetron hydrochloride (3% w/w) and selected concentrations of either nerodilol (0% w/w, 1% w/w, 2% w/w, 3% w/w, and 4% w/w), carvone (0% w/w, 2% w/w, 4% w/w, 8% w/w, and 10% w/w), or limonene (0% w/w, 2% w/w, 3% w/w, and 4% w/w) were prepared and subjected to in vitro permeation of the drug across rat epidermis. All the 3 terpene enhancers increased the transdermal permeation of ondansetron hydrochloride. The optimal transdermal permeation was observed with 3% w/w of nerodilol (175.3 ± 3.1 μg/cm^2.h), 8% w/w of carvone (87.4 ± 1.6 μg/cm^2.h), or 3% w/w of limonene (181.9 ± 0.9 μg/cm^2.h). The enhancement ratio (ER) in drug permeability with 3% w/w nerodilol, 8% w/w carvone, and 3% w/w limonene were 21.6, 10.8, and 22.5, respectively, when compared with that obtained without a terpene enhancer (control). However, there was 1.04-, 2.09-, and 2.17-fold increase in the optimal drug flux obtained with carvone, nerodilol, and limonene, respectively, when compared with the desired drug flux (84 μg/cm^2.h). It was concluded that the HPC gel drug reservoir systems containing either 3% w/w nerodilol or 3% w/w limonene act as optimal formulations for use in the design of membrane-controlled transdermal therapeutic system (TTS) of ondansetron hydrochloride.     

Occlusive Properties of Monolayer Patches: In Vitro and in Vivo Evaluation

Purpose. Patches can cause a different grade of skin occlusion, depending on matrix composition and thickness, backing layer material. The aim of this work was to verify if in vitro water vapour permeability (WVP) values are predictive of transepidermal water loss (TEWL) and Fourier-transform infrared (FTIR) spectroscopy values measured in vivo after 24 h of methacrylic or acrylic monolayer patches application. The correlation between both in vivo methods has been evaluated. Methods. The WVP, TEWL and FTIR measurements were performed by using four patches made of a methacrylic or an acrylic polymeric system (250 and 500 m thickness on a polyurethane backing layer). A fifth patch was made of the methacrylic matrix on a polyvinyl chloride backing layer. Results. A good correlation was found between TEWL values and IR water/lipid absorbance ratios. The in vitro WVP values are in a good correlation with the results of both in vivo methods: TEWL = –0.01WVP + 21.31 (R² = 0.9312); FTIR water/lipid ratio = –0.01WVP + 27.15 (R² = 0.9447). Conclusions. The in vitro method proposed for measuring the WVP is predictive of the degree of occlusion resulting from the in vivo application of monolayer patches.     

Transdermal delivery system for zidovudine: in vitro, ex vivo and in vivo evaluation

The objective of this study was to prepare a transdermal delivery system (TDS) for zidovudine (AZT) with a combination of menthol and oleic acid as penetration enhancers incorporated in hydroxypropyl methylcellulose, and to evaluate ex vivo as well as in vivo permeation across rat skin. It was found that AZT in gel formulation was stable in both refrigerated as well as accelerated stability conditions for 3 months and further, the gel did not significantly retard the permeability of AZT across the skin in comparison with solution formulation. Ex vivo steady state flux of AZT across rat skin from gel was 2.26 mg cm(-2) h(-1), which is sufficient to achieve therapeutic plasma concentrations. Intravenous pharmacokinetic parameters of AZT in rats were determined and used together with ex vivo flux data to generate theoretical plasma profiles of AZT and compared with plasma concentrations achieved after application of TDS. Further, steady state plasma concentrations of drug following multiple applications of TDS were determined and good correlations between ex vivo and in vivo data were observed. In addition, the combination of penetration enhancers used at 2.5% w/w in this study proved efficient in achieving sufficient enhancement in the transdermal permeability of AZT across rat skin with reduced skin irritation potential when compared with individual penetration enhancers at higher concentrations.     

Transdermal fennel essential oil nanoemulsions with promising hepatic dysfunction healing effect: in vitro and in vivo study

Fennel (Foeniculum vulgare Mill.) is a member of family Apiaceae. Trans-anethole, the major component of Fennel essential oil (FEO), possesses antioxidant and hepatoprotective effects. Transdermal nanoemulsions (NEs) are advanced colloidal systems for systemic and controlled drug delivery through the stratum corneum barrier. FEO NEs were prepared using the oil Lauroglycol^? 90, as it provides a larger NE existence zone than Captex^® 300, in the constructed phase diagrams. Six systems were prepared using Tween20/propylene glycol (S/CoS) in the ratios 2:1 and 3:1 with oil to S/CoS mass ratios 1:9, 2:8 and 3:7. Physicochemical characterization revealed optimum properties regarding thermodynamic stability, droplet size and pH with a Newtonian flow pattern. In vitro permeation study in rat skin revealed the highest cumulative amount permeated (µg/cm²), flux and permeability coefficient values for F4 made up of 2% FEO, 4.67% Lauroglycol^? 90, 60% S/CoS in the ratio 3:1. Results of the in vivo hepatic dysfunction study in rats indicate promising significant amelioration of liver function reflected in ALT, AST, ALP, bilirubin, albumin, malondialdehyde and ammonia plasma levels. The results signify the promising approach of FEO NEs in achieving remedy of liver toxicity. The most promising effect is inherent to F4 which imparts a more positive effect than FEO.     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies

Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor (NF)-κB, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.     

Enhanced Permeation of an Antiemetic Drug from Buccoadhesive Tablets by Using Bile Salts as Permeation Enhancers: Formulation Characterization,In Vitro,and Ex Vivo Studies

Buccal bioadhesive bilayer tablets of prochlorperazine maleate were designed and formulated by using buccoadhesive polymers such as hydroxypropylmethyl cellulose, Carbopol 934P, and sodium alginate. Physicochemical characteristics like the uniformity of weight, hardness, thickness, surface pH, drug content, swelling index, microenvironment pH, in vitro drug release, and in vivo buccoadhesion time of the prepared tablets were found to be dependent on the type and composition of the buccoadhesive materials used. The effect of bile salts on the permeation was studied through porcine buccal mucosa and it was found that out of three bile salts incorporated (sodium glycholate, sodium taurocholate, and sodium deoxycholate), sodium glycholate enhanced the permeation rate of prochlorperazine maleate by an enhancement factor of 1.37.     

Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: In vitro vs. in vivo studies

This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification–evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10 h and maintained for 48 h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller® pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.     

Controlled release of huperzine A from biodegradable microspheres: In vitro and in vivo studies

This paper describes the effect on Sun Protection Factor (SPF) of the combination of inorganic and organic filters in sunscreen products as determined by an in vitro method. O/W emulsions containing inorganic filters, such as titanium dioxide and zinc oxide, combined with 18 EU-authorized UV-B organic filters were tested. SPF measurements were carried out using a spectrophotometer equipped with an integrating sphere.

This study observed a synergic effect when titanium dioxide was combined with either anisotriazine or octyldimethylPABA. The combination of zinc oxide with 11 UV-B organic filters also exhibited a similar synergy; however, the measured SPF was systematically lower than the protection factor achieved with titanium dioxide.     

Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation

Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X₁ (Capryol^®), Smix X₂ (a mixture of Labrasol^®/Transcutol^®, 1:2 w/w) and water X₃ were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X₁, X₂, and X₃) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector^® gel, the optimized ME showed the highest cumulative amount of DE permeated after 8 h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12 h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug.