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.     

Swelling behavior of hydrogels for colon‐site drug delivery

Hydrogels based on n‐alkyl methacrylate esters (n‐AMA), acrylic acid, and acrylamide crosslinked with 4,4′‐di(methacryloylamino)azobenzene were prepared. Swelling behavior of the hydrogels was studied by the immersion of slabs in buffered solutions at pH 2.2–7.4. The diffusion of water into the slabs was discussed on the stress relaxation model of polymer chains. The results obtained are in good agreement with Schott's second‐order diffusion kinetics. The constants A and B of Schott's kinetics equation depend on the balance of hydrophobicity/hydrophilicity, the rigidity/flexibility, and the degree of crosslinking. The factors that exert the greatest influence on the swelling behavior of the gels include the degree of crosslinking, the lengths of the n‐AMA side chains, and pH values. By adjusting these factors, the degree of swelling of the hydrogels in the small intestine can be controlled, and consequently the drugs may avoid being released before arriving in the colon. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 2835–2842, 2002; DOI 10.1002/app.10259     

Hydrogels from scleroglucan and ionic crosslinkers: Characterization and drug delivery

The polysaccharide scleroglucan (Sclg), exploited as a matrix suitable for modified drug delivery, was crosslinked in the presence of three ions: borate, aluminum, and iron. A rheological investigation indicated the main differences between the hydrogels in their viscoelastic linear response: the Sclg/borax system showed the highest strength when deformed by elongation, whereas the strength of the other systems broke down, in terms of viscosity, at much lower values of the imposed strain. Tablets prepared from the gels showed remarkable differences in their water uptake and dimensional swelling. On the other hand, the tablets, loaded with drugs of different steric hindrances, showed similar release behavior, regardless of the crosslinking agent. Scanning electron microscopy analysis was related to the delivery and rheological profiles. Texture analysis, carried out on tablets swollen for 5 h, showed different values of cohesion. Furthermore, when the generalized Maxwell model was applied to the relaxation data, the obtained mechanical spectra showed a more pronounced solidlike character of the Sclg/iron network in comparison with the prevailing viscous behavior of the other matrices. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system

In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca²⁺. The pH‐sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl₂/chitosan gelation medium. Finally, the release studies of BSA‐loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17–21) were much higher than those at pH 1.2 (2–2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan‐coated calcium‐CMC beads, compared with that (44.4%) in the bare calcium‐CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan‐coated calcium‐CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site‐specific release in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3164–3168, 2007     

Kinetic degradation and controlled drug delivery system studies for sensitive hydrogels prepared by gamma irradiation

Ternary mixtures of N‐vinyl‐2‐pyrrolidone/itaconic acid and gelatin were irradiated by gamma rays at 30 kGy/s and at ambient temperature to prepared poly (NVP/IA and G) hydrogels. Poly (NVP/IA) hydrogels were prepared in different compositions (NVP/IA) mole ratio, (100/0), (98/1.5), (96.5/3.5), and (93/7.0) at 30 kGy. Then adding gelatin at different content (5, 10, 15, 20) mg to the best composition (NVP/IA/H₂O) (93/7)% for the characterization of network structure of these hydrogels, kinetic swelling drug release behavior and Scan Electron Microscope was studied. The equilibrium degree of swelling for P(NVP/IA) and P(NVP/IA/G) copolymer and the swelling‐degradation kinetics were also studies. According to dynamic swelling studies, both the diffusion exponent and the diffusion coefficient increase with increasing content of (IA), whereas, the addition of gelatin to (NVP/IA) composition by different content did not lead to any significant change in swelling percent. Also, the swelling behavior of copolymer hydrogels in response to pH value of the external media was studied, it is noted that the highest swelling values were at pH 4. The in vitro drug release behavior of these hydrogels was examined by quantification analysis with a UV/VIS spectrophotometers. Chlorpromazine hydrochloride was loaded into dried hydrogels to investigate the stimuli‐sensitive property at the specific pH and the drug release profile of these pH‐sensitive hydrogels in vitro. The release studies show that the highest value of release was at pH 4 which can be used for drug delivery system. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Development of polyampholyte hydrogels based on laponite for electrically stimulated drug release

Polyampholyte hydrogels (PAHs) composed of laponite, polyacrylamide and poly(3‐acrylamidopropyl)trimethylammonium chloride crosslinked with ethylene glycol dimethacrylate were synthesized and characterized for their sensitivity to external conditions and their ability to control the release of the active drug agent paracetamol. Three PAHs were synthesized by taking the weight ratio of laponite to total monomer as 7, 15 and 29%. PAHs were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis and swelling measurements carried out in various media. Equilibrium and pulsatile swelling studies were performed on all hydrogels to determine to what extent the hydrogels would respond to changes in environmental pH, ionic strength and electric field, and how fast that response would be. Paracetamol was loaded into the hydrogels, and was released into buffered solutions as a function of pulsatile changes in pH and electric field. © 2014 Society of Chemical Industry     

Evaluation of alginate–chitosan bioadhesive beads as a drug delivery system for the controlled release of theophylline

This study describes the preparation of mucoadhesive alginate–chitosan beads containing theophylline intended for colon‐specific delivery. The calcium alginate beads were coated with chitosan by the ionotropic hydrogelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The release profiles of theophylline from the beads were determined by ultraviolet–visible absorption measurement at 272 nm. Scanning electron microscopy was used for morphology observation. The in vitro mucoadhesive tests for particles were carried out with the freshly excised jejunum of Sprague‐Dawley rats. The bead particles, which ranged in size from 200 to 400 μm, exhibited excellent mucoadhesive properties. The results showed that the formulated coated beads succeeded in controlling the release of theophylline over a 24‐h period. In conclusion, the release of theophylline was found to be dependent on the composition of the beads, the component polymer and its possible interactions, and the bioadhesiveness. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Photopolymerized hydrogel composites from poly(ethylene glycol) and hydroxyapatite for controlled protein delivery in vitro

The incorporation of hard particles into soft hydrogels can improve the mechanical properties and provide necessary bioactivity to the hydrogels for desired biomedical applications. Hydrogel composites containing hydroxyapatite (HA) are promising materials for orthopedic applications. In this study, injectable poly(ethylene glycol) (PEG) hydrogel precursor solutions containing HA particles and model protein bovine serum albumin (BSA) were synthesized in situ by photopolymerization. In vitro BSA release properties from the hydrogel composites containing various amounts of HA were investigated and discussed. Fourier transform infrared spectroscopy and scanning electron microscopy were employed to investigate the interaction between HA and the hydrogel network and the morphology of the hydrogel composites. It is found that PEG hydrogel composites containing HA sustained the release of BSA for at least 5 days and the presence of HA slowed down BSA release. Photopolymerized hydrogel composites containing HA may find potential use as a drug delivery matrix for orthopedic tissue engineering. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Electrically controlled release of 5-fluorouracil from conductive gelatin methacryloyl-based hydrogels

Herein, electro-responsive hydrogels were obtained by incorporation of poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT/PSS) into the gelatin methacryloyl (GelMA) by using photopolymerization technique. Hydrogels were characterized by FTIR and scanning electron microscopy analyses. Cytotoxicity tests were performed by L929 cell lines to determine cell compatibility. Swelling tests were conducted to investigate the water uptake capacity of hydrogels. 5-fluorouracil (5-FU) was selected as a model drug as it is known as a topical drug for some skin cancer type treatment. The release of 5-FU from the hydrogel was provided in efficient and controlled manner at simulated skin cancer (pH = 5.5) and under 0 and 1.5 V. The simulated drug delivery experiments conducted in vitro revealed that the drug releasing amount was higher when voltage is applied to the hydrogels. All results visualized that the obtained GelMA-based PEDOT/PSS hydrogels with enhanced electrical properties could be a potential candidate as an electrically sensitive drug carrier for treatment of skin cancer in the future applications. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 46914.     

Dynamic swelling behavior of pH‐sensitive anionic hydrogels used for protein delivery

There have been many attempts to use anionic hydrogels as oral protein delivery carriers because of their pH‐responsive swelling behavior. The dynamic swelling behavior of poly(methacrylic acid‐co‐methacryloxyethyl glucoside) and poly(methacrylic acid‐g‐ethylene glycol) hydrogels was investigated to determine the mechanism of water transport through these anionic hydrogels. The exponential relation M_t/M_∞ = ktⁿ (where M_t is the mass of water absorbed at time t and M_∞ is the mass of water absorbed at equilibrium) was used to calculate the exponent (n) describing the Fickian or non‐Fickian behavior of swelling polymer networks. The mechanism of water transport through these gels was significantly affected by the pH of the swelling medium. The mechanism of water transport became more relaxation‐controlled in a swelling medium of pH 7.0, which was higher than pK_a of the gels. The experimental results of the time‐dependent swelling behaviors of the gels were analyzed with several mathematical models. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1606–1613, 2003     

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     

Stimuli-responsive hybrid microgels for controlled drug delivery: Sorafenib as a model drug

Microgels (MGs) are synthetic colloidal hydrogel particles made of three dimensional polymer networks. Their chemical composition is crucial for their use as intelligent drug release systems operated by temperature control. Herein, several MGs using N-isopropylacrylamide (Nipam)/N-isopropylmethacrylamide (Nipmam), chitosan and acrylic/methacrylic acid have been synthesized by free radical polymerization reactions (NC MGs) and the effects of surfactants and different reaction times on size and swelling properties have been investigated. MGs have been identified and characterized by dynamic light scattering and atomic force microscopy, and finally used to optimize the encapsulation protocol of the hydrophobic drug sorafenib. The drug delivery system here described has encapsulation efficiency of 40% and releases 10% of the entrapped drug over about 16 h after the temperature is raised above the volume phase transition temperature. Data suggest that MGs with optimized composition may act as properly instructed entities able to trap and release biomolecules following external stimuli.     

Microemulsion of erythromycine for transdermal drug delivery

The aim of this work was to prepare an erythromycin (EM) microemulsion (EM‐ microemulsion) for transdermal EM delivery using isotropic mixtures of oil and aqueous phases. The prepared EM‐microemulsion is a white dispersion, with a suitable viscosity for transdermal delivery. In stability experiments, the EM‐microemulsion showed no marked change in appearance for up to 3 weeks at 25°C. In accelerated stability experiments at 37 and 60°C, however, precipitated crystalline EM particles were observed in the EM‐microemulsion. Diffusion of EM into the skin exhibited a first order release profile. Fluorescein (FL)‐microemulsion penetrated to the dermis layer of skin. In conclusion, we confirmed that EM‐microemulsion could serve as an excellent transdermal carrier of EM. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Properties of pH‐dependent tertiary amine‐based gels as potential drug delivery matrices

The rheological and morphological properties and in vitro theophylline release of tertiary amine‐based microgels were evaluated. The testing of such a formulation through in vitro diffusion experiments revealed that the release of theophylline from the microgels was pH‐dependent and differs significantly with respect to a nonresponsive gel like scleroglucan (Scl). The microgels were obtained from 2‐(diethyl amino) ethylmethacrylate (DEA) in the presence of a bifunctional crosslinker at pH 8–9. As the resulting microgels are pH‐responsive and an increase in viscosity from high to low pH range is exhibited, the in vitro release of theophylline as model drug was studied at different pHs of both the matrix and the receptor medium. The release behaviors of PDEA‐based microgels were compared to nonresponsive natural gel Scl, studied previously. For microgels, diverse release patterns were found at different acidity conditions. This observation seems to be related to complex diffusion phenomena and the different gel structure obtained for samples prepared at dissimilar pH. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 4035–4040, 2007     

Evaluation of the influence of spirulina microalgae on the drug delivery characteristics of genipin cross-linked chitosan hydrogels

Abstract

Chitosan-spirulina hydrogels were prepared by crosslinking of chitosan with genipin, in presence of spirulina microalgae. The swelling ratios and kinetic parameters of the hydrogels in distilled water, pH:2 and pH:7.4 solutions and the drug 5-Fluorouracil delivery capacities of the hydrogels were determined by gravimetric and spectrophotometric analyses, respectively and the results were statistically evaluated. The morphological structures, thermal and mechanical properties of the hydrogels were investigated using related techniques. Furthermore, cytotoxicity test was performed for assessment of biocompability of the hydrogels.The all results indicate that spirulina significantly improves the drug delivery properties of the genipine cross-linked hydrogels.     

Nanocrystal technology for drug formulation and delivery

With the development of modern technology like high throughput screening, combinatorial chemistry and computer aid drug design, the drug discovery process has been dramatically accelerated. However, new drug candidates often exhibit poor aqueous or even organic medium solubility. Additionally, many of them may have low dissolution velocity and low oral bioavailability. Nanocrystal formulation sheds new light on advanced drug development. Due to small (nano- or micro- meters) sizes, the increased surface-volume ratio leads to dramatically enhanced drug dissolution velocity and saturation solubility. The simplicity in preparation and the potential for various administration routes allow drug nanocrystals to be a novel drug delivery system for specific diseases (i.e. cancer). In addition to the comprehensive review of different technologies and methods in drug nanocrystal preparation, suspension, and stabilization, we will also compare nano- and micro-sized drug crystals in pharmaceutical applications and discuss current nanocrystal drugs on the market and their limitations.     

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.     

Characterization and degradation behavior of agar-carbomer based hydrogels for drug delivery applications: solute effect

In this study hydrogels synthesized from agarose and carbomer 974P macromers were selected for their potential application in spinal cord injury (SCI) repair strategies following their ability to carry cells and drugs. Indeed, in drug delivery applications, one of the most important issues to be addressed concerns hydrogel ability to provide a finely controlled delivery of loaded drugs, together with a coherent degradation kinetic. Nevertheless, solute effects on drug delivery system are often neglected in the large body of literature, focusing only on the characterization of unloaded matrices. For this reason, in this work, hydrogels were loaded with a chromophoric salt able to mimic, in terms of steric hindrance, many steroids commonly used in SCI repair, and its effects were investigated both from a structural and a rheological point of view, considering the pH-sensitivity of the material. Additionally, degradation chemistry was assessed by means of infrared bond response (FT-IR) and mass loss.