Synthesis and characterization of electrically responsive poly(acrylamide)-grafted-chondroitin sulfate hydrogel for transdermal drug delivery application

Abstract

Electrically-responsive transdermal delivery systems (ETDS) were developed utilizing poly(acrylamide)-grafted-chondroitin sulfate (PAAm-g-CS) copolymer. A nitrogen environment based free radical polymerization was used to synthesize electrically responsive PAAm-g-CS copolymer. This PAAm-g-CS hydrogel was used as drug reservoir and cross-linked blend films of CS and poly(vinyl alcohol) as rate controlling membranes (RCM). The drug permeation decreased with increase in the concentration of glutaraldehyde and RCM thickness; while drug permeation was increased with increasing electric stimulus from 2 to 8?mA. Nearly, three-fold increase in flux was observed with the application of electric stimulus. The permeation study under “on–off” electric stimulus suggested that the higher drug permeation was observed under “on” condition of electric stimulus and permeation was decreased when electric stimulus was “off”. The histopathology evaluation confirmed the changes in skin structure when electrical stimulus was applied. Hence, the PAAm-g-CS hydrogel could be a resourceful material for on-demand discharge of medication.     

Skin permeation of buflomedil form adhesive matrix patches

The main objective of this research work was to fabricate and evaluate adhesive matrix-type transdermal patches of buflomedil hydrochloride, employing different ratios of pressure sensitive adhesives (PSAs) by solvent casting technique. The adhesive matrix-type transdermal patches were evaluated by their in vitro physicochemical properties such as thickness, moisture content, weight variation, drug content uniformity, etc. The effects of PSAs ratio, drug loading, and concentration of permeation enhancer were evaluated thoroughly. Ex vivo skin permeation studies with kinetic modeling of adhesive matrix patches were systematically evaluated. Based on the above observations, the best optimized buflomedil hydrochloride-loaded adhesive matrix-type transdermal patch was further characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction study, and differential scanning calorimetry analyses. Drug containing adhesive matrix patches showed sustained release property without showing any incompatibility in adhesive matrix system. Hence, adhesive matrix-type transdermal patches of buflomedil hydrochloride can be used as a potential carrier for sustained transdermal delivery of hydrophilic drugs like buflomedil hydrochloride.     

Mixed matrix membranes as potential transdermal devices for gemfibrozil release

Aim of this work was the development of mixed matrix membranes as potential devices for transdermal controlled release of gemfibrozil (2,2‐dimethyl‐5‐(2,5‐dimethylphenoxy) pentanoic acid). The effect of the hydrophilic NaX zeolite and of drug loading on the release kinetics of the drug was investigated. The material used as membrane matrix was polydimethylsiloxane. Scanning electron microscopy analysis showed as zeolite crystals were well embedded into the polymeric matrix. Membrane characterizations by means of swelling ratio, moisture uptake, and erosion degree determination indicated low swelling degree and moisture uptake, and the absence of erosion. This results confirmed as these membranes did not promote bacterial growth and skin irritation. The performance of the membranes was evaluated by performing in vitro release studies and percutaneous tests through the stratum corneum taken from the skin of rabbit ear. In vitro experiments indicated as the best system was the membrane containing 12 wt % of zeolite and 2.6 wt % of gemfibrozil (PDMS‐2.6GEM‐12NaX) and so it was used in the percutaneous tests. In this case, the permeation rate was lower owing to the presence of an additional resistance applied by rabbit skin. An interesting result was the linear behavior indicating that the permeation of the drug thorough the device occurred with zero‐order kinetic which is the feature of the transdermal controlled delivery systems. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41698.     

Refining natural rubber matrix for electrically stimulated transdermal drug delivery

This work focuses on the enhancement of transdermal delivery of indomethacin (IN) from natural rubber matrix by deproteinization, the addition of ethylene glycol (EG) as a plasticizer, and the enlarged matrix size under electrical field. The starting double-centrifuge natural rubber (DCNR) was deproteinized to produce the deproteinized natural rubber (DPNR). Both DCNR and DPNR patches were fabricated by the UV curing method, and blended with EG to enhance the IN loading and release–permeation. Using a pig skin to simulate the human skin, the IN release–permeation was found to increase with increasing plasticizer, removed protein, and applied electrical potential.     

Preparation and characterization of novel hybrid of bio‐assisted mineralized Zn‐Al layered double hydroxides using chitosan as a template

The purpose of this study was to prepare and characterize a novel nanohybrid prepared from the template‐assisted mineralization of Zn‐Al Layered Double Hydroxide (LDH) onto the surface of Chitosan (CSI), with an emphasis on morphology, biocompatibility, and its use as an efficient drug carrier agent. The as prepared LDH is highly crystalline, with platelet‐like morphology and curved tactoids when nucleated onto the surface of CSI. Our results indicate that the ? OH and ? NH functional moieties on CSI can direct an ordered structure of LDH, due to the electrostatic interaction between biopolymer and inorganic lamellae. We have been successful to intercalate an anti‐inflammatory drug, Sodium Ibuprofen (Ibu), into LDH, through conventional coprecipitation method. LDHs are endowed with great potential for delivery vector because their stacked layers lead to safe reservation of biofunctional molecules or genes, and their ion exchangeability and solubility in acidic media (pH < 4) give rise to the controlled release of drug molecules. According to the cell‐growth studies, LDHs are found as cell viable up to the concentration of 500 μg/mL. This study reveals that LDH not only plays a role of a biocompatible‐delivery matrix but also facilitates a significant increase in the delivery efficiency. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Preparation of a biodegradable poly(vinyl alcohol)–starch composite film and its application in pesticide controlled release

With the herbicide 2,4‐dichlorophenoxyacetic acid (2,4‐D) as a model drug, a series of poly(vinyl alcohol)–starch (PVA–ST) composite films for controlled drug release were prepared by a casting method. The morphology, structure, and release properties were systematically investigated. The results show that when the PVA–ST composite film containing 2,4‐D (PSD) was immersed in water, the drug‐release rate was high, whereas the introduction of sodium montmorillonite (Na‐MMT) and an alginate ion‐crosslinking structure to PSD significantly reduced the release rate and maintained the sustained release of the model drug for a longer period. A leaching experiment through the soil layer showed that the PSD drug‐loaded film with Na‐MMT and the alginate ion‐crosslinking structure (PSDMA) possessed good release properties. The cumulative leached amount of the herbicide 2,4‐D after eight irrigations was reduced to 57.6% from 100%. In addition, the PSDMA film showed favorable mechanical and thermal properties. This composite film is expected to have potential applications in the fields of agriculture, drug delivery, and more. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45051.     

经皮给药系统的研究进展和发展趋势

作者从被动扩散、化学促渗、电磁技术、波动技术、微纳米技术和及其综合使用 6个方面 ,系统地综述了近两年来国内外在经皮给药领域 ,尤其是促进药物的经皮渗透方面 ,于基础研究和应用等几个方面所取得的进展 ,指出了各种方法的最新研究成果、存在的问题以及发展趋势     

Colon‐specific oral delivery of vitamin B2 from poly(acrylamide‐co‐maleic acid) hydrogels: An in vitro study

Hydrogels, composed of poly(acrylamide‐co‐maleic acid) were synthesized and the release of vitamin B₂ from these gels was studied as a function of the pH of the external media, the initial amount of the drug loaded, and the crosslinking ratio in the polymer matrix. The gels containing 3.8 mg of the drug per gram gel exhibit almost zero‐order release behavior in the external media of pH 7.4 over the time interval of more than their half‐life period (t_1/2). The amount of the drug loaded into the hydrogel also affected the dynamic release of the encapsulated drug. As expected, the gels showed a complete swelling‐dependent mechanism, which was further supported by the similar morphology of the swelling and release profiles of the drug‐loaded sample. The hydrophilic nature of the drug riboflavin does not contribute toward the zero‐order release dynamics of the hydrogel system. On the other hand, the swelling osmotic pressure developed between the gels and the external phase, due to loading of the drug by equilibration of the gels in the alkaline drug solution, plays an effective role in governing the swelling and release profiles. Finally, the minimum release of the drug in the swelling media of pH 2.0 and the maximum release with zero‐order kinetics in the medium of pH 7.4 suggest that the proposed drug‐delivery devices have a significant potential to be used as an oral drug‐delivery system for colon‐specific delivery along the gastrointestinal (GI) tract. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 1133–1145, 2002; DOI 10.1002/app.10402     

Polyacrylamide‐g‐alginate‐based electrically responsive hydrogel for drug delivery application: Synthesis,characterization, and formulation development

An electrically responsive hydrolyzed polyacrylamide‐grafted‐sodium alginate (H‐PAAm‐g‐SA)‐based membrane‐controlled transdermal drug delivery systems were developed and evaluated. The grafting reaction was confirmed by Fourier transform infrared spectroscopy, elemental analysis, and thermogravimetric analysis. On application of electric stimulus, the swollen H‐PAAm‐g‐SA hydrogel was deswelled in the vicinity of electrodes. The drug release was greater in the presence of electric stimulus when compared with passive diffusion, and it was found to be dependent on the applied electric current strength, concentration of H‐PAAm‐g‐SA copolymer in the reservoir, and cross‐link density of rate‐controlling membrane. A pulsatile pattern of drug release was observed when the electric stimulus was switched “on” and “off.” The skin histopathology study suggested that, after application of an electrical stimulus, changes were in the structure of stratum corneum. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Controlled drug release of silicone‐based adhesive‐containing cross‐linked siloxane powders as a reservoir

We prepared pressure‐sensitive adhesive (PSA)‐containing cross‐linked siloxane powders (CS) as a reservoir for a transdermal drug delivery system (TDDS) and evaluated their sustained drug‐release properties. PSA, as a patch‐type adhesive, was synthesized by a hydrosilylation reaction of vinyl‐terminated polysiloxanes with hydrogen‐terminated polydimethylsiloxanes. CS was also prepared via a hydrosilylation process with vinyl‐terminated polydimethylsiloxane, 1,3,5,7‐tetramethyl‐1,3,5,7‐tetravinyltetracyclosiloxane ( ), hydrogen‐terminated polydimethylsiloxane, and dimethylhydrogenmethyl oligomeric siloxane copolymer. The results of release performances using ascorbic acid as a model drug showed a cumulative linear slope over a week, indicating a constant release performance. Our data suggest that this siloxane TDDS could be useful for constant drug release over a long period. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42154.     

Design,Development, and Delivery of Salbutamol Sulfate from an Adhesive Matrix System

The objective of the present investigation was to design, develop, and evaluate the skin delivery of salbutamol sulfate from a drug-in-adhesive matrix type transdermal patch formulation. Initial formulation design and development experiments were conducted to optimize the formulation parameters before skin delivery in rats. The effects of two different types of pressure sensitive adhesives and permeation enhancers on skin transport of salbutamol sulfate across excised rat skin were investigated methodically. For ex-vivo skin permeation studies, the percutaneous absorption of salbutamol sulfate from a drug-in-adhesive matrix patch across excised rat skin were evaluated using a modified Franz-diffusion cell apparatus at a skin temperature (32°C). Further the fabricated adhesive matrix patches were also characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction study, and differential scanning calorimetry analyses. Drug containing adhesive matrix patches showed sustained release property without showing any incompatibility in adhesive matrix system. This suggests that the transdermal application of salbutamol sulfate in a drug-in-adhesive matrix type transdermal patch may be used for the treatment for asthma patients.     

Release of diclofenac through gluteraldehyde crosslinked poly(vinyl alcohol)/poly(acrylic acid) alloy membranes

A controlled‐release preparation of diclofenac sodium for transdermal administration has been developed. Poly(vinyl alcohol) (PVA) and PVA/poly(acrylic acid) (PAA) alloy membranes were prepared from a solvent‐casting technique using different PVA/PAA (v/v) ratios. The release of the drug from the membrane was evaluated under in vitro conditions at pH 7.4. The delivery system provided linear release without time lag, burst effect, and boundary layer resistance. Effects of variables such as film thickness and PVA/PAA ratio on the permeation behavior of the polymeric membranes were discussed. The optimal PVA/PAA was determined as 50/50. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 72–77, 2004     

Thermal,electrical, and mechanical properties of tween 80/span 80–based organogels and its application in iontophoretic drug delivery

The present study describes the preparation and characterization of the Tween 80/Span 80 and sunflower oil–based organogels. Organogels were characterized using microscopy, X‐ray diffraction, thermal, mechanical, and electrical techniques. The properties were found to be dependent on the proportion of the water : surfactant mixture. The in vitro drug release studies were performed under electrical potential. The drug release in the presence of electrical current was compared with the passive drug release. The drug release from the organogels followed the zero‐order kinetics suggesting diffusion mediated release. The preliminary results suggested that the organogels may be used as drug carriers in iontophoretic drug delivery. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41419.     

Design and optimization of alginate−chitosan−pluronic nanoparticles as a novel meloxicam drug delivery system

The inflammation and pain associated with osteoarthritis are treated with nonsteroidal anti‐inflammatory drugs (NSAIDs). This treatment is accompanied by several side effects; therefore local intra articular (IA) NSAID injection can be more efficient and safe than systemic administration or topical use. In this study, alginate?chitosan?pluronic nanoparticles were considered as a new vehicle for IA meloxicam delivery. These novel nanoparticles were prepared using an ionotropic gelation method and were optimized for variables such as alginate to chitosan mass ratio, pluronic concentration, and meloxicam concentration using a 3‐factor in 3‐level Box‐Behnken design. To optimize the formulation, the dependent variables considered were particle size, zeta potential, entrapment efficiency, and mean dissolution time (MDT). The nanoparticles morphology was characterized by FESEM and AFM. The potential interactions of the drug‐polymers were investigated by ATR‐FTIR and DSC, and the delivery profile of meloxicam from the nanoparticles was obtained. The average particle size of the optimized nanoparticles was 283 nm, the zeta potential was ?16.9 mV, the meloxicam entrapment efficiency was 55%, and the MDT was 8.9 hours. The cumulative released meloxicam amount from the composite nanoparticles was 85% at pH 7.4 within 96 h. The release profile showed an initial burst release followed by a sustained release phase. The release mechanism was non‐Fickian diffusion. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42241.     

亲水性聚氨酯压敏胶经皮给药应用性能研究

针对目前经皮给药制剂发展急需性能优良的亲水性新型压敏胶基质,制备了亲水性聚氨酯压敏胶。对一些影响压敏胶贴剂力学性能的因素进行了考察,并重点研究了载药压敏胶贴剂经皮释放规律。结果表明,该聚氨酯压敏胶贴剂具有良好的药物控释能力,适用于经皮给药系统。     

Effect of drug loading and laser surface melting on drug release profile from biodegradable polymer

The biodegradable polymer such as poly(l ‐lactic acid) is promising in drug delivery applications because it allows for drug release in a controlled manner. In a polymer‐based drug delivery system, drug release is controlled by polymer degradation and drug loading concentration. In this study, effect of drug concentration on drug release profile is investigated through polymer crystallinity, chain mobility, and polymer degradation, as characterized by the wide‐angle X‐ray diffraction, differential scanning calorimetry, and gel permeation chromatography, respectively. The addition of drug has been shown to accelerate polymer degradation and drug release rate. With a low drug concentration, the slow polymer degradation kinetics results in an induction period of drug release, during which a limited amount of drug is released. The induction period is undesirable because it delays drug release and effectiveness. Since drug release is controlled by polymer degradation, which is a function of polymer crystallinity, laser surface melting is conducted to reduce polymer surface crystallinity and modify its degradation. The effect of laser crystallinity modification on drug release is investigated. A numerical model is also implemented based on hydrolysis and diffusion mechanisms to investigate the effects of drug loading and laser surface melting on polymer degradation and drug release process. It has been demonstrated that laser treatment shortens the induction period of drug release while keeps the release rate unmodified, as desired in drug delivery applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 4147–4156, 2013     

Poly(methyl methacrylate)/poly(ethylene glycol)/poly(ethylene glycol dimethacrylate) micelles: Preparation,characterization, and application as doxorubicin carriers

A crosslinked amphiphilic copolymer [poly(ethylene glycol) (PEG)–poly(methyl methacrylate) (PMMA)–ethylene glycol dimethacrylate (EGDM)] composed of PMMA, PEG, and crosslinking units (EGDM) was synthesized by atom transfer radical polymerization to develop micelles as carriers for hydrophobic drugs. By adjusting the molar ratio of methyl methacrylate and EGDM, three block copolymer samples (P0, P1, and P2) were prepared. The measurement of gel permeation chromatography and ¹H‐NMR indicated the formation of crosslinked structures for P1 and P2. Fluorescence spectroscopy measurement indicated that PEG–PMMA–EGDM could self‐assemble to form micelles, and the critical micelle concentration values of the crosslinked polymer were lower than those of linear ones. The prepared PEG–PMMA–EGDM micelles were used to load doxorubicin (DOX). The drug‐loading efficiencies of P1 and P2 were higher than that of P0 because the crosslinking units enhanced the micelles' stability. With increasing drug‐loading contents, DOX release from the micelles in vitro was decreased, and in the crosslinked formulations, the release rate was also slower. An in vitro release study indicated that DOX release from the micelles for the linear samples was faster than that for crosslinked micelles. The drug feeding amount increased and resulted in an increase in the drug‐loading content, and the loading efficiency decreased. These PEG–PMMA–EGDM micelles did not show toxicity in vitro and could reduce the cytotoxicity of DOX in the micelles; this suggested that they are good candidates as stable drug carriers. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39623.     

Enzyme‐based hydrogels containing dextran as drug delivery carriers: Preparation,characterization, and protein release

Novel enzyme‐based hydrogels for drug delivery were prepared by combining dextran with 5,5′‐azodisalicylic acid using isophorone diisocyanate as the crosslinking agent. The structure of the resultant dextran/5,5′‐azodisalicylic acid hydrogels was determined by infrared spectra, and the properties of the hydrogels were characterized by swelling measurements and scanning electron microscopy analysis. It was found that changing the concentration of 5,5′‐azodisalicylic acid affected the crosslinking density of the hydrogels and resulted in significant differences in the water swelling property and degradability of the hydrogels. Compared with their degradability, the degradation of the hydrogels seemed to be more pronounced by azoreductase in cecum content medium than that by hydrolysis in phosphate buffer solution (PBS). Also, the release rate of the protein in cecum content medium was faster than that in PBS. Attributing to the results of the resultant hydrogels described earlier, it could be concluded that dextran/5,5′‐azodisalicylic acid hydrogels could be used as a potential enzyme‐based carrier for colon‐specific drug delivery. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Cold flow measurement of transdermal drug delivery systems (TDDS)

Cold flow, the movement of adhesive beyond the edge of a transdermal drug delivery system (TDDS) or between the release liner slit, can affect the quality of the drug product and result in patient use issues such as difficulty in removal from packaging and unintentional removal of the product during wear due to increased tackiness on the edge and backing of the TDDS. In this study, different techniques for measuring cold flow of United States marketed transdermal drug delivery systems are assessed including a wiping method with various ways of calculating cold flow, a macroscopic rating method and a microscope evaluation. The amount of cold flow measured from the wiping method was dependent upon the calculation method. Assessment of cold flow may be a combination of quantitative and qualitative methods. Appearance criteria can assess potential use issues caused by cold flow if TDDS are difficult to remove from pouches and if release liners detach from the adhesive matrix during attempted removal due to cold flow adhering the backing to the pouch. A quantitative cold flow method captures the degree to which cold flow extends beyond the perimeter of the backing and through the release liner slit. The method(s) selected by a TDDS manufacturer to measure cold flow should be applicable to the individual product and scientifically justified.     

Design and study of the potential of crosslinked cationic polymers as drug delivery systems for dermal application

Crosslinked carriers based on cationic monomer [2‐(acryloyloxy)ethyl]trimethylammonium chloride or 2‐(dimethylamino)ethyl methacrylate were developed and investigated as new platform for ibuprofen transdermal delivery. Series of networks of varied composition and structure were synthesized and characterized by FTIR spectroscopy and following swelling kinetics in different solvents. Dermal safety tests to examine the skin irritation and sensitization potential of the network films were performed in vivo. Chosen network compositions were loaded with ibuprofen by swelling in its ethanol solution. The structures of the drug carriers were investigated by scanning electron microscopy. Ibuprofen release from the developed drug delivery systems was followed in phosphate buffer solution at 37 °C. The investigation proved the feasibility of the developed cationic copolymer networks as effective platforms with modified ibuprofen release for potential dermal application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46420.