Formulation and molecular docking simulation study of luliconazole nanosuspension–based nanogel for transdermal drug delivery using modified polymer

The purpose of study was to formulate nanosuspension-based nanogel of luliconazole (LLZ) for transdermal delivery to enhance its skin retention and effectiveness using modified starch ester. Nanosuspensions show promising results with size of 369.1–745.4 nm having PDI 0.193–0.344 and zeta potential 22–45 mV. These nanosuspensions form micelles and hydrophobic core of it provides the reservoir for LLZ with better drug loading and binding interaction. Drug loading was confirmed by percent drug entrapment efficiency (PDEE) and PDI. Molecular docking simulation (MDS) provides detail insight of LLZ polymer complexation at hydrophobic cavity of micelles and revealed that there was binding between drug and polymer in aqueous milieu having interaction energy ranges from ?7.1 to ?6.0 kcal/mol. Nanosuspensions so made were incorporated into gel by using Carbopol 934 ® and tested for % drug content, spreadability, pH, and viscosity with ranges of 101.62–97.71, 28.94–34.38 (gcm/s), 6.91–7.21, and 4802.62–9461.83 (cp), respectively. Nanogel also evaluated for stability and skin permeation study using human cadaver skin (HCS). In vitro skin permeation study indicated that the amount of LLZ permeated through skin from nanogel (71.042–83.818 μgcm ?2) was higher than standard cream (70.085 μgcm ?2). Nanogel increased the accumulation of LLZ in HCS ~3 times than standard cream. The transdermal flux was greater for standard cream (123.79 μgcm ?2), whereas smaller for nanogel (50.394–82.743 μgcm ?2) due to skin retention. Nanosuspension-based gel are able to especially favor LLZ accumulation into skin, provide better drug loading, improve stability, and efficacy. Thus, targeting older antibiotics such as LLZ and formulating into nanosystem utilized to expand its usefulness to physicians to treat illnesses caused by resistant fungal strains.     

Formulation and evaluation of thermoreversible,mucoadhesive in situ intranasal gel of rizatriptan benzoate

The present study was aimed to formulate and evaluate in situ thermoreversible intranasal gel of an antimigraine drug rizatriptan benzoate. The poloxamer 407 and carbopol 934 were used as thermoreversible and mucoadhesive polymers respectively. The gels were prepared with cold method. The phase transition temperature was determined with visual method. The gels were evaluated for their pH, mucoadhesive strength, in vitro release and ex vivo drug permeation through goat nasal mucosa. The histopathological study of the nasal mucosa was carried out to check for its damage during drug permeation. The 18 % w/v poloxamer solution was found to be showing phase transition at physiologic conditions (34–35 °C). As the percentage of carbopol 934 was increased from 0.1 to 0.5 % w/v the gelling temperature was found to be decreased. All formulations were showing mucoadhesive strength above 4,000 dynes/cm². Drug permeation studies have indicated that the drug permeation rate can be increased by using carbopol 934 above 0.3 % w/v concentration. The histopathological evaluation of nasal mucosa after drug permeation study has not shown any evidence of damage. Thus in situ thermoreversible mucoadhesive gel of rizatriptan benzoate can be a promising approach to treat migraine.     

Calculation of skin permeability coefficient for ionized and unionized species of indomethacin.

The contribution of ionized and unionized species to the overall permeation of weak electrolytes through the skin was investigated to determine the effect of pH in the vehicle on the permeability of indomethacin (IDM), as a model drug, through hairless rat skin. The permeability of IDM through polydimethylsiloxane (silicone) and poly(2-hydroxyethyl methacrylate) (pHEMA) membranes which may reflect lipid and aqueous pathway, respectively, was also measured for comparison. As the pH in the vehicle increased, there was an exponential increase in the skin permeation rate of IDM. The permeation rate of IDM through the silicone membrane was constant independent of pH, whereas that through the pHEMA membrane increased with increasing pH, similar to the skin permeation. The permeability coefficients of ionized and unionized species through the skin estimated using the skin permeation rates and solubilities of IDM at various pHs were 1.50 x 10(-7) and 2.79 x 10(-5) cm/s, respectively. These results indicated that the permeation of ionized species greatly contributed to the total permeation of IDM at higher pH, and that the total permeation rate of IDM was determined by the permeation of unionized species at lower pH. These contributions depend on the pH and pKa values and the ratio of permeability coefficient of each species. It was also confirmed that the skin has at least two kinds of permeation pathways and these two species permeate through a different pathway.     

Effects of application voltage and cathode and anode positions at electroporation on the in vitro permeation of benzoic acid through hairless rat skin

The enhancing effect of electroporation on the in vitro skin permeation of benzoate was evaluated. Needle and ring electrodes made of Ag/AgCl were connected to an electrical power source, which produced exponentially decaying pulses. The needle electrode was kept in contact with the skin surface, and the ring electrode was positioned either on or under the skin. The electrical pulse was applied to abdominal hairless rat skin at 150-600 V every minute from 4 to 6 h during the 10-h permeation experiment. Skin permeation of benzoate was promoted by electroporation and the effect was increased by application of a higher voltage. No immediate recovery to the control flux, however, was observed for high voltage groups after turning off the voltage application. When the cathode and anode were separated by the skin membrane by setting in the epidermal and dermal sides, respectively, an iontophoretic effect may also play a role in benzoate flux. These results indicated that the drug permeation by electroporation is the result of passive diffusion and an iontophoretic effect as well as the electroporation effect.     

Effect of tretinoin inclusion in dimethyl-beta-cyclodextrins on release rate from a hydrogel formulation

The aim of this work was to study the release, permeation and skin retention profiles of 0.05% tretinoin hydrogel formulations in which tretinoin was in free form or complexed with dimethyl-beta-cyclodextrin in a stoichiometry of 1:4. Theoretically, this complexation will mainly allow to: overcome drug’s low water solubility and low stability; enhance the drug permeation by promoting skin absorption and alleviate drug inducing local irritation. In vitro release, permeation and skin retention tests were performed in both formulations in order to compare the main advantages of this complexation. The influence of the thermodynamic activity on the drug release profile was also investigated. This study proved that tretinoin inclusion complexes formulation with excess of cyclodextrins had better release profile than the free tretinoin formulation. It was concluded that in this study, thermodynamic activity was not the driving force for the release rate improvement observed with cyclodextrins. Probably, this improvement was due to the increased availability of tretinoin near the membrane surface. In fact, the percentage of total drug that had been retained in the skin was 0.41?±?0.08% for complexed tretinoin gel and 0.17?±?0.04% for the free tretinoin gel.     

刺激响应型有机小分子凝胶的研究进展

智能型凝胶是近年来有机小分子凝胶的研究重点, 其中刺激响应型有机小分子智能凝胶对外界微小的物理、化学刺激, 如温度、光、pH、离子强度或电场等能够感知并在响应过程中有显著的响应行为性. 较系统地综述了刺激响应型有机小分子智能凝胶的结构特点和近年来的研究进展, 并展望了该类有机小分子智能凝胶的应用前景.     

Characteristics of charged networks under an electric stimulus

The electrokinetic phenomena of poly(2-acrylamido-2-methyl-1-propane sulfonic acid-co-n-butylmethacrylate) were examined to investigate physical changes of the gel under an applied electric current. When an electrical stimulus was applied to a piece of the gel, without being in contact with an electrode, reversible gel bending was observed. The bending degree was directly proportional to the intensity of the applied electric stimulus. This was explained by ‘depletion polarization’ of ionic species under the stimulus. The swelling of the gel surface facing the anode increased, due to the decreased ionic strength of the boundary layer upon electric stimulation, while gel shrinking occurred at the cathode. When the gel is in direct contact with electrodes, deswelling of the gel was observed at the anode side, while water seepage occurred at the cathode side. This observation was attributed to the electro-osmosis inside the gel, combined with local pH changes around the electrodes resulting from electrochemical reactions, particularly water electrolysis. © 1994 John Wiley & Sons, Inc.     

Enhanced skin permeation of cationic drug ketotifen through excised guinea pig dorsal skin by surfactants with different electric charges

Using excised guinea pig dorsal skin, we examined the effects of three surfactants, anionic sodium dodecylsulfate (SDS), cationic n-dodecyltrimethylammonium bromide and non-ionic n-dodecyl-beta-D-maltoside, all of which commonly have an n-dodecyl group, on in vitro skin permeation of the cationic drug ketotifen. All these three surfactants increased the skin permeation of ketotifen. Among the surfactants tested, anionic SDS had the largest enhancement effects, and significantly increased the permeation at concentrations over 1 mM. The enhancement effect of the same anionic surfactant on the permeation of anionic salicylate was smaller and similar to that of cationic n-dodecyltrimethylammonium. The enhancement effects of SDS on ketotifen permeation were more marked than those of the cationic surfactant but differed from previous findings of their effects on other drugs permeation. Analysis of the retention of ketotifen in the skin suggested that SDS-induced increase in the transfer of hydrophilic ketotifen to the skin is the main reason for the marked increase in skin permeation.     

Design and feasibility assessment of topically applied drug formulations for electroporation

Few studies have been reported on the design of topical formulations consisting of electrodes and active drugs for electroporation as a means to increase skin permeability of the drugs, although many studies were reported for the effect of this physical means using aqueous drug solutions. We, therefore, designed a prototypic reservoir and matrix topical formulations that are suitable for electroporation in the present study. Plate-plate Ag electrodes and sodium diclofenac were used as model electrodes and the drug, respectively. The in vitro skin permeations of the drug obtained from the reservoir and matrix formulations were slightly higher than that from an aqueous suspension. This may be due to slightly higher electric field in the skin barrier for the presently designed formulations than that for the aqueous suspension. The present feasibility test suggests that these reservoirs and matrix formulations are useful prototypic topical formulations for electroporation application to improve the drug permeability through skin.     

The effect of submicron emulsion systems on transdermal delivery of kaempferol

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.     

Dynamic Release of Propranolol HCl from Cationic Ion–Exchanger–Loaded Calcium Alginate Beads

The dynamic release of drug propranolol HCl from the propranolol HCl–resin complex (PRC) loaded calcium alginate beads has been studied in the buffer media of pH 1.2 at the physiological temperature 37°C. The PRC encapsulated beads demonstrated nearly 58.04% release while naked PRC particles released 98.00% drug in 24 h in the gastric fluid. The amount of drug released was found to increase with and decrease in the amount of sodium alginate in the beads. Similarly, with the increase in the amount of entrapped PRC particles within the beads, the quantity of drug released was also observed to increase. The degree of crosslinking of beads also affected the release kinetics. Interestingly, the release from naked PRC particles followed ‘first‐order’ kinetics while PRC particles, entrapped in calcium–alginate beads, exhibited ‘diffusion controlled’ release behavior as indicated by liner nature of fractional release vs. √t plot.     

Influence of isosorbide dinitrate concentration on its skin permeability from adhesive matrix devices.

Adhesive matrix devices containing a model drug, isosorbide dinitrate (ISDN), were prepared with three different types of pressure sensitive adhesives (PSAs). ISDN permeation through excised hairless rat skin from the different devices was measured in vitro. For each PSA type, the steady state permeation rate of ISDN increased proportionally with an increase of ISDN concentration in the PSA and reached a maximum level at a certain concentration. Although the concentrations reaching the maximum skin permeation level varied among PSA types, the maximum rate for each PSA type was largely similar to that for ISDN aqueous suspension. The release rate of ISDN from devices was too fast to influence the skin permeation rate for all devices. In the PSA of devices showing maximum skin permeability, ISDN crystalline was observed by polarizing microscopy and differential scanning calorimetry. These results suggest that the skin permeation of ISDN from adhesive matrix devices was controlled by the thermodynamic activity of the drug in the PSAs.     

Nano-formulations for transdermal drug delivery: A review

The different applications of nano-formulations (vesicles or nanoparticles and nanoemulsions) have been widely studied. Here, the classification, characteristics, transdermal mechanism, and application of the most popular nano-formulations in transdermal drug delivery system are reviewed.     

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocimum sanctum) and turpentine oil

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 microg/cm(2)/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 microg/ml, was much lower than required steady state plasma concentration of 3-5 microg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.     

Development,Characterization, and Evaluation of Liposomes and Niosomes of Bacitracin Zinc

The skin permeation of bacitracin zinc in liposomes and niosomes after topical application were elucidated in the present study with the to increase its penetration capacity and, hence, efficiency. The formulations of bacitracin zinc were prepared by film hydration method and characterized for vesicle shape, size, entrapment efficiency, and drug permeation across rat skin and also evaluated for their stability. Formulation with niosomes demonstrated a better skin permeation potential, sustained release characteristic, and higher stability as compared to liposomes. The ability of liposomes and niosomes to modulate drug delivery makes the two vesicles useful to formulate topical bacitracin zinc.     

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak^®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate–EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.     

Flow Through Diffusion Cell Method: A Better Approach to Study Drug Release Behavior as Compared to Traditional Dissolution Test Method

Co‐polymeric hydrogels consisting of N‐vinyl‐2‐pyrrolidone (NVP) and acrylic acid (AAc) were synthesized and evaluated for release of a model drug, i.e., vitamin B₁₂. Release studies in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 7.4), at 37°C, showed the hydrogels to be pH sensitive. An in vitro release study by ‘traditional dissolution test’ (TDT) showed that percent drug released from the hydrogel was nearly 8.6±2.1 and 83.2±4.8 in the media of pH 1.2 and 6.8, respectively. However, in order to incorporate in vivo GI conditions such as acidic pH and high water content in the stomach, low water content and the presence of a semi–solid mass in the large intestine, a new test model, called flow through diffusion cell (FTDC) was also used. The two approaches yielded almost different release profiles. The gels were characterized by thermogravimetric analysis and FTIR spectroscopy.     

In Vitro Skin Permeation Enhancement of KIOM-MA-128 by Monoolein Cubosomes

Monoolein (MO) cubosomes were investigated in terms of in vitro skin permeation enhancer of KIOM-MA-128 (MA-128), a natural product known to be efficacious against atopic dermatitis. First, an aqueous suspension of MA-128 was prepared by homogenizing the powder in Pluronic F-127 (a dispersant) solution in water. The Pluronic F-127 concentration and the pH have no significant effect on the size and the zeta potential of MA-128 particles. The mean diameters and the zeta potentials fell within 1000–1500 nm and ?10 to ?20 mV, respectively. The sedimentation rate of the particles was lower at a higher concentration of the polymeric dispersant, possibly because the polymeric surfactant can act as a spring and push away approaching particles. The size of MO cubosomes was tens to hundreds of nanometers and exhibited black and white stripes. Cumulative amount of MA-128 permeated through hairless mouse skin was obviously higher when the cubosome was included in the MA-128 suspensions. However, the cumulative permeation amount was inversely proportional to the content of cubosomes, when the contents of cubosome in the suspension increased from 0.5% to 2.0% with MA-128 concentrations kept constant (2%).     

Heterogeneous polyelectrolyte gels as stimuli-responsive membranes

Stimuli-responsive membranes may act as “on–off switches” or “permeability valves”, producing patterns of pulsatile release, where the period and rate of mass transfer can be controlled by external or environmental triggers (e.g. pH, temperature, electric field). In this work, composite-heterogeneous polyelectrolyte gel (composite-HPG) membranes consisting of polymethacrylic acid (PMAA) gel particles dispersed within a polydimethylsiloxane (PDMS) network were developed and evaluated as pH-responsive membranes.The mechanism of permeability control for caffeine and vitamin B₁₂ through composite-HPG membranes was determined to be a synergistic function of membrane hydration and the percolating volume fraction of PMAA gel. Larger changes in permeation as a function of pH were achieved when both hydration and percolation effects occurred together than when either of these effects occurred on their own. Vitamin B₁₂ permeation was observed when the hydrated gel volume fraction was above approximately 0.38, but not below. Furthermore, the percolating fraction of composite-HPG membranes containing 28% (dry basis) PMAA gel particles was manipulated via pH to fall above (pH 7) or below (pH 3) this transition in permeability, resulting in membranes that delivered solutes of high molecular weight (vitamin B₁₂) with large on/off delivery ratios (160).     

Crosslinked Alginate Films as Rate Controlling Membranes for Transdermal Drug Delivery Application

The present investigation was undertaken to prepare and evaluate the crosslinked sodium alginate (SA) films as rate controlling membranes (RCM) for transdermal drug delivery application. The drug free films of SA were prepared by mercury substrate method and evaluated for thickness uniformity, tensile strength and water vapor permeation (WVP). The films were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Drug diffusion characteristics of the films were studied using diclofenac diethylamine as a model drug. The prepared membranes were thin, flexible and smooth. Tensile strength measurement and DSC analysis suggested that as the crosslink density increases, the tougher membranes were formed. The WVP and drug diffusion were dependent upon the crosslink density and thickness of the films. The permeability was decreased with increasing crosslink density and thickness of the films. The molar mass between the crosslinks and crosslink density were calculated using empirical equations. The primary skin irritation study indicated that the prepared membranes were less irritant and safe for transdermal application.