Development of a Prolonged-Release Pramipexole Transdermal Patch: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson’s disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK^® pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK^® 87-2852 and DURO-TAK^® 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19?±?102.90 μg/cm² with a continuous flux over 6.0 μg/(cm²·h) across human cadaver skin for 7 days. In vivo studies in rats indicated that PPX patch produced a significantly longer (p?<?0.001) half-life (t _1/2, 75.16?±?17.37 h) and mean residence time (MRT, 135.89?±?24.12 h) relative to oral tablets (Sifrol^®) and had a relative bioavailability of 51.64?±?21.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance.     

Topical Delivery of Fenoprofen Calcium <Emphasis Type="Italic">via</Emphasis> Elastic Nano-vesicular Spanlastics: Optimization Using Experimental Design and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

The aim of this study was to investigate the potential of surfactant-based nanovesicular system (spanlastics) for topical delivery of fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. FPCa-loaded spanlastics were prepared by thin film hydration (TFH) technique according to a full factorial design to investigate the influence of formulation variables on the drug entrapment efficiency (%EE), particle size (PS), deformability index (DI), and the % drug released after 24 h through the cellulose membrane (Q24h) using Design-Expert® software. The optimized formula (composed of Span 60 and Tween 60 as an edge activator at weight ratio of 8: 2 in presence of Transcutol P as a cosolvent in the hydration media) exhibited the highest %EE (49.91 ± 2.60%), PS of 536.1 ± 17.14 nm, DI of 5.07 ± 0.06 g, and Q24h of 61.11 ± 2.70%; it was also characterized for morphology and physical stability. In vitro release study of FPCa-loaded spanlastic gel and conventional FPCa gel through a synthetic membrane and hairless rat skin were evaluated. The skin permeation study revealed that spanlastic gel exhibited both consistent and prolonged action. Finally, the % inhibition of carrageenan-induced rat paw edema of spanlastic gel was three times higher than the conventional FPCa gel after 24 h. In conclusion, spanlastic-based gel could be a great approach for improving topical delivery of fenoprofen calcium, providing both prolonged and enhanced anti-inflammatory activity in the treatment of arthritis.     

Design and Evaluation of a Novel Felbinac Transdermal Patch: Combining Ion-Pair and Chemical Enhancer Strategy

The aim of this study was to design a novel felbinac (FEL) patch with significantly higher (P?<?0.05) skin permeation amount than the commercial product SELTOUCH® using ion-pair and chemical enhancer strategy, overcoming the disadvantage of the large application area of SELTOUCH®. Six complexes of FEL with organic amines diethylamine (DEA), triethylamine (TEA), N-(2′-hydroxy-ethanol)-piperdine (HEPP), monoethanolamine (MEtA), diethanolamine (DEtA), and triethanolamine (TEtA) were prepared by ion-pair interaction, and their formation were confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), infared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy (¹H-NMR). Subsequently, the effect of ion-pair complexes and chemical enhancers were investigated through in vitro and in vivo experiments using rabbit abdominal skin. Results showed that FEL-TEA was the most potential candidate both in isopropyl palmitate (IPP) solution and transdermal patches. Combining use of 10% N-dodecylazepan-2-one (Azone), the optimized FEL-TEA patch achieved a flux of 18.29?±?2.59 μg/cm²/h, which was twice the amount of the product SELTOUCH® (J?=?9.18?±?1.26 μg/cm²/h). Similarly, the area under the concentration curve from time 0 to time t (AUC_0-t ) in FEL-TEA patch group (15.94?±?3.58 h.μg/mL) was also twice as that in SELTOUCH® group (7.31?±?1.16 h.μg/mL). Furthermore, the in vitro skin permeation results of FEL-TEA patch was found to have a good correlation with the in vivo absorption results in rabbit. These findings indicated that a combination of ion-pair and chemical enhancer strategy could be useful in developing a novel transdermal patch of FEL.     

Formulation of Polyherbal Patches Based on Polyvinyl Alcohol and Hydroxypropylmethyl Cellulose: Characterization and <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation

The purpose of this research was to prepare and characterize polyherbal patches made from polyvinyl alcohol (PVA) and hydroxypropylmethyl cellulose (HPMC) with glycerine as a plasticizer. Polyherbal extracts were Luk-Pra-Kob recipes extracted with 95% ethanol. They were prepared by mixing the polymer solutions and glycerine in a beaker; subsequently, the polyherbal extracts were homogeneously mixed. Then, they were transferred into a Petri dish and dried in a hot-air oven at 70?±?2°C for 5 h. The dry polyherbal patches were evaluated for physicochemical properties by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a scanning electron microscope. They were studied for in vitro release and skin permeation of the marker active compound (E)-4-(3′,4′-dimethoxyphenyl)but-3-en-l-ol (compound D) using a modified Franz-type diffusion cell. The polyherbal patches made from PVA as a matrix layer were homogeneous, smooth, and compact relative to HPMC-containing polyherbal patches. The selected polyherbal patches made from PVA produced a release profile with an initial burst effect in which compound D release was 74.21?±?6.13% within 8 h, but compound D could permeate the pig skin only 37.28?±?5.52% and was highly accumulated in newborn pig skin at 35.90?±?6.72%. The in vitro release and skin permeation kinetics of compound D were fitted to the Higuchi model. The polyherbal patches made from PVA could be suitably used for herbal medicine application.     

Paliperidone-Loaded Nanolipomer System for Sustained Delivery and Enhanced Intestinal Permeation: Superiority to Polymeric and Solid Lipid Nanoparticles

Paliperidone (PPD) is the most recent second-generation atypical antipsychotic approved for the treatment of schizophrenia. An immediate release dose causes extrapyramidal side effects. In this work, a novel nanolipomer carrier system for PPD with enhanced intestinal permeability and sustained release properties has been developed and optimized. PPD was successfully encapsulated into a lipomer consisting of a specific combination of biocompatible materials including poly-ε-caprolactone as a polymeric core, Lipoid S75, and Gelucire® 50/13 as a lipid shell and polyvinyl alcohol as a stabilizing agent. The lipomer system was characterized by dynamic light scattering, TEM, DSC, and FTIR. An optimized lipomer formulation possessed a particle size of 168 nm, PDI of 0.2, zeta potential of ?23 mV and an encapsulation efficiency of 87.27%?±?0.098. Stability in simulated gastrointestinal fluids investigated in terms of particle size, zeta potential, and encapsulation efficiency measurements ensured the integrity of the nanoparticles upon oral administration. PPD-loaded nanolipomers demonstrated a superior sustained release behavior up to 24 h and better ex vivo intestinal permeation for PPD compared to the corresponding polymeric and solid lipid nanoparticles and drug suspension. The in vitro hemocompatibility test on red blood cells revealed no hemolytic effect of PPD-loaded lipomers which reflects its safety. The elaborated nanohybrid carrier system represents a promising candidate for enhancing the absorption of PPD providing a 2.6-fold increase in the intestinal permeation flux compared to the drug suspension while maintaining a sustained release behavior. It is a convenient alternative to the commercially available dosage form of PPD.     

Cellulose Buccoadhesive Film Bearing Glimepiride: Physicomechanical Characterization and Biophysics of Buccoadhesion

The present study aimed to develop buccoadhesive film of glimepiride with unique combination of polymers and to investigate its effect(s) on physicomechanical parameters, drug-release, and permeation of films. Drug-polymer interaction was examined by FTIR and DSC analysis. Films were prepared by solvent casting technique and characterized for film strength (320?±?8.5 g, 28.98?±?2.00 mJ), buccoadhesive strength (28.8?±?1.37 g, 3.04?±?0.32 mJ), and tensile strength (260?±?6.88 g, 18.00?±?0.44 mJ) by new instrumental techniques. Increase in polymer concentration augmented zeta potential of polymeric matrix-mucin mixture and exhibited strong buccoadhesion (electrical theory). Buccoadhesion was also influenced by particle size (adsorption theory) and swelling (wetting theory). Erosion behavior of films was observed in swelling and SEM studies. Film GM4 exhibited 98?±?2% in vitro drug release and 85?±?8% ex vivo drug permeation in 12 h with controlled diffusion mechanism. Films were compatible with oral probiotic microorganisms. Stability studies revealed no significant (P?<?0.05) variation in physicomechanical characteristics.     

Formulation and development of novel control release transdermal patches of carvedilol to improve bioavailability for the treatment of heart failure

The main aim of this study is to optimize and evaluate transdermal patch of Carvedilol by the use of different polymer and different permeation enhancers which help to release drug in controlled action and thereby increase the bioavailability of the drug. Main objective was to avoid first pass metabolism of Carvedilol. Transdermal patches were developed by solvent evaporation method. The combination of Eudragit RS-100 as rate controlling polymer and Span 80 as a permeation enhancer was found to be ideal formulation (Formulation F7) with maximum drug release i.e. 100.29 ± 0.44 % within 12 h. Formulation F7 showed maximum bioavailability and showed maximum drop of BP at 6 h. From this study the conclusion was, transdermal patch of Carvedilol which contains Eudragit RS-100 polymer and Span 80 as penetration enhancer produced sustained and continued drug release.     

Anti-inflammatory Effect from a Hydrogel Containing Nanoemulsified Copaiba oil (<Emphasis Type="Italic">Copaifera multijuga</Emphasis> Hayne)

Copaiba oil is used as a popular medicine in the Amazonian forest region, especially due to its anti-inflammatory properties. In this paper, we describe the formulation of hydrogel containing copaiba oil nanoemulsions (with positive and negative charges), its skin permeation, and its anti-inflammatory activity in two in vivo models: mouse ear edema and rat paw edema. Three hydrogels were tested (Carbopol^®, hydroxyethylcellulose and chitosan), but only Carbopol^® and hydroxyethylcellulose hydrogels presented good stability and did not interfere with the nanoemulsions droplet size and polydispersity index. In skin permeation assay, both formulations, positively charged nanoemulsion (PCN) and negatively charged nanoemulsion (NCN), presented a high retention in epidermis (9.76 ± 2.65 μg/g and 7.91 ± 2.46 μg/cm², respectively) followed by a smaller retention in the dermis (2.43 ± 0.91 and 1.95 ± 0.56 μg/cm², respectively). They also presented permeation to the receptor fluid (0.67 ± 0.22 and 1.80 ± 0.85 μg/cm², respectively). In addition, anti-inflammatory effect was observed to NCN and PCN with edema inhibitions of 69 and 67% in mouse ear edema and 32 and 72% in rat paw edema, respectively. Histological cuts showed the decrease of inflammatory factors, such as dermis and epidermis hyperplasia and inflammatory cells infiltration, confirming the anti-inflammatory effect from both copaiba oil nanoemulsions incorporated in hydrogel.     

Investigating superiority of novel bilosomes over niosomes in the transdermal delivery of diacerein: in vitro characterization,ex vivo permeation and in vivo skin deposition study

Skin is considered the most accessible organ of the body because of its underlying capillary network. However, stratum corneum (SC), the upper most layer of skin, represents major diffusional barrier for most drugs. Hence, the use of edge activators (EAs) in designing novel elastic vesicles is hypothesized to impart their lipid bilayer with ultra-flexibility to trespass SC by high self-optimizing deformability. To confirm this hypothesis, this work aimed at developing novel bilosomes by modulating conventional niosomal composition using different bile salts as EAs and investigating their superiority over niosomes for transdermal delivery of diacerein (DCN), as model drug. Bilosomes were prepared by thin film hydration (TFH) technique according to full 3¹.2² factorial design to select the optimal formulation using Design-Expert^® software. The optimal bilosomes (B6) showed nanosized vesicles (301.65?±?17.32?nm) and 100.00?±?0.00 % entrapment efficiency. Ex vivo permeation studies and in vivo evaluation revealed that B6 exhibited superior permeation and drug retention capacity compared to the conventional niosomal formulation and drug suspension. Furthermore, B6 was subjected to in vivo histopathological study using male Wistar rats which ensured its safety for topical application. Overall, the results confirmed the hypothesized superiority of bilosomes over niosomes for enhancing DCN flux across the skin.     

Development of alginate-reinforced chitosan nanoparticles utilizing W/O nanoemulsification/internal crosslinking technique for transdermal delivery of rabeprazole

Aims

First; to develop rabeprazole (RP)-alginate core coated chitosan nanoparticles (NP) utilizing water in oil (W/O) nanoemulsion technique. Second; formulation of transdermal patches loaded RP-NP that avoid drug peroral acid sensitivity and first pass effect.

Main methods

The influence of six factors on RP-NP formulation was investigated using Plackett–Burman (PB) design. The studied factors were considered for their effect on particle size (Y1) and loading efficiency (Y2). Formulation optimum desirability was identified; a proposed formulation was prepared and characterized. In vitro permeation of the prepared NP compared with RP was studied. Transdermal patches loaded drug or RP-NP were prepared and characterized. Patches ex vivo permeation through rat skin was studied, and kinetic analysis and permeation mechanism were investigated.

Key Finding

Chitosan, oil phase and surfactant to oil ratios had significant effects on Y1, while Y2 was significantly affected by the same variables affecting Y1 and span80-tween80 ratio. Scanning electron microscope imaging illustrated sphericity of the NP. The optimized RP-NP exhibited sustained release pattern. The prepared patches showed a minimal patch to patch variable. Patches loaded RP-NP exhibited substantial skin permeability and controlled drug release, and were in favor of Fickian diffusion.

Significance

Transdermal patches loaded RP-NP is effective drug delivery and alternative to drug peroral route.     

Ethosomes for skin delivery of ropivacaine: preparation,characterization and ex vivo penetration properties

Abstract

Ropivacaine, a novel long-acting local anesthetic, has been proved to own superior advantage. However, Naropin® Injection, the applied form in clinic, can cause patient non-convenience. The purpose of this study was to formulate ropivacaine (RPV) in ethosomes and evaluate the potential of ethosome formulation in delivering RPV transdermally. The RPV-loaded ethosomes were prepared with thin-film dispersion technique and the formulation was characterized in terms of size, zeta potential, differential scanning calorimetry (DSC) analysis and X-ray diffraction (XRD) study. The results showed that the optimized RPV-ethosomes displayed a typical lipid bilayer structure with a narrow size distribution of 73.86?±?2.40?nm and drug loading of 8.27?±?0.37%, EE of 68.92?±?0.29%. The results of DSC and XRD study indicated that RPV was in amorphous state when encapsulated into ethosomes. Furthermore, the results of ex vivo permeation study proved that RPV-ethosomes could promote the permeability in a high-efficient, rapid way (349.0?±?11.5?μg?cm^?2 at 12?h and 178.8?±?7.1?μg?cm^?2 at 0.5?h). The outcomes of histopathology study forecasted that the interaction between ethosomes and skin could loosen the tight conjugation of corneocyte layers and weaken the permeation barrier. In conclusion, RPV-ethosomes could be a promising delivery system to encapsulate RPV and deliver RPV for transdermal administration.     

Appraisal of Transdermal Water-in-Oil Nanoemulgel of Selegiline HCl for the Effective Management of Parkinson’s Disease: Pharmacodynamic,Pharmacokinetic, and Biochemical Investigations

In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson’s disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 μg/cm²/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S _mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.     

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.     

Non-ionic Surfactant Based <Emphasis Type="Italic">In Situ</Emphasis> Forming Vesicles as Controlled Parenteral Delivery Systems

Non-ionic surfactant (NIS) based in situ forming vesicles (ISVs) present an affordable alternative to the traditional systems for the parenteral control of drug release. In this work, NIS based ISVs encapsulating tenoxicam were prepared using the emulsion method. Tenoxicam-loaded ISVs were prepared using a 2².3¹ full factorial experimental design, where three factors were evaluated as independent variables; type of NIS (A), molar ratio of NIS to Tween®80 (B), and phase ratio of the internal ethyl acetate to the external Captex® oil phase (C). Percentage drug released after 1 h, particle size of the obtained vesicles and mean dissolution time were chosen as the dependent variables. Selected formulation was subjected to morphological investigation, injectability, viscosity measurements, and solid state characterization. Optimum formulation showed spherical nano-vesicles in the size of 379.08 nm with an initial drug release of 37.32% in the first hour followed by a sustained drug release pattern for 6 days. DSC analysis of the optimized formulation confirmed the presence of the drug in an amorphous form with the nano-vesicles. Biological evaluation of the selected formulation was performed on New Zealand rabbits by IM injection. The prepared ISVs exhibited a 45- and 28-fold larger AUC and MRT values, respectively, compared to those of the drug suspension. The obtained findings boost the use of ISVs for the treatment of many chronic inflammatory conditions.     

姜黄素共聚物胶束的制备与体外细胞毒评价

目的:制备一种姜黄素共聚物胶束以提高姜黄素的水溶性及其抗肿瘤活性。方法:采用乳化溶剂挥发法制备了载姜黄素的共聚物胶束(Cur/PTL1胶束),对其粒径、载药量、包封率和体外药物释放行为进行了考察;并采用MTT法考察了PTL1空白胶束和Cur/PTL1胶束的体外细胞毒作用。结果:制备了粒径在40 nm左右的载姜黄素共聚物胶束,载药量为9.78±0.29%,包封率为97.24±2.68%。体外药物释放实验表明,游离姜黄素在24 h内的药物累积释放率达到90%以上,而Cur/PTL1胶束在24 h内药物累积释放率为23.8%,能够持续释放14天,14天内累积释放率为85.9%,具有一定的缓释能力。MTT实验结果表明,当PTL1空白胶束浓度达到1 mg/mL时,细胞的存活率仍在90%以上;Cur/PTL1胶束组IC50为4.73±0.23μg/mL,游离姜黄素组IC50为6.42±0.35μg/mL。结论:实验结果表明,Cur/PTL1胶束可以作为一种有前景的纳米药物输送系统。     

Design and development of ethosomal transdermal drug delivery system of valsartan with preclinical assessment in Wistar albino rats

Abstract

Valsartan (VLT) is a highly selective and orally active antihypertensive drug. However, its oral administration is associated with drawbacks like low bioavailability. The objective of this study was to design and develop a transdermal delivery system for VLT using ethosomal carriers to investigate their enhanced transdermal delivery potential. VLT ethosomes were prepared by cold method. VLT ethosomes were characterized by scanning electron microscopy. The prepared ethanolic liposomes were characterized to be spherical having low polydispersity of nano-size range with good entrapment efficiency. ETC5 ethosomal suspension with 4% of phospholipon 90H and 40% of ethanol was found to have highest entrapment efficiency, i.e. 80.230?±?0.8748%. The permeation study of ethosomes was evaluated by ex vivo diffusion study through rat abdominal skin using Franz’s diffusion cells and ETC5 ethosomal suspension was found to have highest permeation with flux of 92.819?±?1.539?µg/cm²/h, when compared to the permeation profiles of drug solutions either in water or in a water–ethanol mixture. Transdermal application of ethosomal VLT on Wistar rats showed better and prolonged antihypertensive activity in comparison to orally administered VLT suspension by virtue of transdermal permeation through Wistar rat skin. Histopathological study of skin applied with ETC5 showed intercellular permeation across skin by dissolving intercellular lipids in epidermis without causing any rigorous changes in the skin cellular structure. In conclusion, ethosomes enabled the transdermal permeation of VLT, which amply proves its superiority over oral administration for antihypertensive treatment.     

Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation

Onychomycosis is a fungal infection of nail unit that is caused by dermatophytes. Oral Terbinafine hydrochloride (TBF-HCl) is being used for the treatment of onychomycosis since 24 years. The side effects caused by the systemic application and limitations of topical administration of this drug regarding the diffusion through nail lead to the development of a new formulation based on, TBF-HCl-loaded liposome. The newly obtained film formulations were prepared and characterized via several parameters, such as physical appearance, drug content, thickness, bioadhesive properties and tensile strength. In vitro and ex vivo permeation studies were performed to select an optimum film formulation for antifungal activity to show the efficiency of formulations regarding the treatment of onychomycosis. The in vitro release percentages of drug were found 71.6?±?3.28, 54.4?±?4.26, 56.1?±?7.48 and 46.0?±?2.43 for liposome loaded pullulan films (LI-P, LII-P) and liposome loaded Eudragit films (LI-E, LII-E), respectively. The accumulated drug in the nail plates were found 31.16?±?4.22, 24.81?±?5.35, 8.17?±?1.81 and 8.92?±?3.37 for LI-P, LII-P, LI-E and LII-E, respectively, which within therapeutic range for all film formulations. The accumulated drug in the nail plate was found within therapeutic range for all film formulations. The efficacy of the selected TBF-HCl-loaded liposome film formulation was compared with TBF-HCl-loaded liposome, ethosome, liposome poloxamer gel and ethosome chitosan gel formulations. It was found that TBF-HCl-loaded liposome film formulation had better antifungal activity on fungal nails which make this liposome film formulation promising for ungual therapy of fungal nail infection.     

Enhancement of Skin Permeation and Skin Immunization of Ovalbumin Antigen <Emphasis Type="Italic">via</Emphasis> Microneedles

The purpose of this study was to evaluate the use of different types of microneedles and doses of ovalbumin antigen for in vitro skin permeation and in vivo immunization. In vitro skin permeation experiments and confocal laser scanning microscopy revealed that hollow microneedles had a superior enhancing effect on skin permeation compared with a solid microneedle patch and untreated skin by efficiently delivering ovalbumin-fluorescein conjugate into the deep skin layers. The flux and cumulative amount of ovalbumin-fluorescein conjugate at 8 h after administering with various conditions could be ranked as follows: hollow MN; high dose?>?medium dose?>?low dose?>?MN patch; high dose?>?medium dose?>?low dose?>?untreated skin; high dose?>?medium dose?>?low dose?>?without ovalbumin-fluorescein conjugate. As the dose of ovalbumin-fluorescein conjugate was increased to 500 μg, the antigen accumulated in the skin to a greater extent, as evidenced by the increasing green fluorescence intensity. When the hollow microneedle was used for the delivery of ovalbumin into the skin of mice, it was capable of inducing a stronger immunoglobulin G immune response than conventional subcutaneous injection at the same antigen dose. Immunoglobulin G levels in the hollow MN group were 5.7, 11.6, and 13.3 times higher than those of the subcutaneous injection group for low, medium, and high doses, respectively. Furthermore, the mice immunized using the hollow microneedle showed no signs of skin infection or pinpoint bleeding. The results suggest that the hollow MN is an efficient device for delivering the optimal dose of antigen via the skin for successful immunization.     

Characterization of a liposome-based artificial skin membrane for in vitro permeation studies using Franz diffusion cell device

A prerequisite for successful transdermal or dermal drug therapy is the drug ability to penetration through the skin, especially stratum corneum (SC). The most acceptable technique for measuring skin permeation in vitro is the application of both the Franz diffusion cell device and the skin model. In the skin model, a liposome-based artificial skin membrane (LASM) consisting of tight layers of liposomes immobilized on a filter was prepared and characterized. Using porcine ear skin, rat skin and Strat-M? artificial membrane as control, the LASM was then evaluated in permeation studies with five active compounds: ferulic acid, paeoniflorin, albiflorin, tetrahydrocolumbamine, and tetrahydropalmatine. The scanning electron microscope images demonstrated complete filling of the membrane pores with lipids and the formation of a continuous liposomal coating. The contents of egg phosphatidylcholine (EPC) and cholesterol in LASM were measured to be 12.08?±?0.18 and 4.41?±?0.04?mg/cm², respectively. Moreover, revealed by the measurement of electrical resistance, the LASM remains intact for at least 12?h with the incubation of 20% ethanol. The results of permeation studies demonstrated a good correlation (r^2?=?0.9743, r?=?0.9871) of P_app values between the drugs’ permeation through LASM and porcine ear skin. In addition, by ATR-FTIR analysis, a slighter shift of CH₂ stretching frequency between LASM and porcine ear skin was observed compared with the shift between Strat-M? membrane and porcine ear skin. In summary, for the first time, the LASM has been proved to be a valuable alternative to porcine ear skin in permeation studies using Franz diffusion cell device.     

Drug in Adhesive Patch of Zolmitriptan: Formulation and In vitro /In vivo Correlation

The objective of the present study was to develop transdermal patch for zolmitriptan, determine its in vivo absorption using the rabbit skin. Solvent evaporation technique prepared zolmitriptan patch was settled in two-chamber diffusion cell combined with excised rabbit abdomen skin for permeation study. A sufficient cumulative penetration amount of zolmitriptan (258.5 ± 26.9 μg/cm² in 24 h) was achieved by the formulation of 4% zolmitriptan, 10% Azone, and adhesive of DURO-TAK® 87–4098. Pharmacokinetic parameters were determined via i.v. and transdermal administrations using animal model of rabbit. The results revealed that the absolute bioavailability was about 63%. Zolmitriptan could be detected with drug level of 88 ± 51 ng/mL after transdermal administration of 15 min. The in vivo absorption curve obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve, the correlation coefficient R is 0.84, and the result indicated that in vitro skin permeation experiments were useful to predict the in vivo performance. In addition, little skin irritation was found in the irritation study. As a conclusion, the optimized zolmitriptan transdermal patches could effectively deliver adequate drug into systemic circulation in short time without producing any irritation phenomenon and worth to be developed.KEY WORDS: chemical enhancer, drug-in-adhesive patch, in vitro/in vivo correlation, pharmacokinetic, zolmitriptan