Dual crosslinked pH‐ and temperature‐sensitive hydrogel beads for intestine‐targeted controlled release

Novel drug‐loaded hydrogel beads for intestine‐targeted controlled release were developed by using pH‐ and temperature‐sensitive carboxymethyl chitosan‐graft‐poly(N,N‐diethylacrylamide) (CMCTS‐g‐PDEA) hydrogel as carriers and vitamin B₂ (VB₂) as a model drug. The hydrogel beads were prepared based on Ca²⁺ ionic crosslinking in acidic solution and formed dual crosslinked network structure. The structure of hydrogel and morphology of drug‐loaded beads were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The study about swelling characteristics of hydrogel beads indicated that the beads had obvious pH‐ and temperature‐sensitivity. In vitro release studies of drug‐loaded beads were carried out in pH 1.2 HCl buffer solution and pH 7.4 phosphate buffer solution at 37°C, respectively. The results indicated that the dual crosslinked method could effectively control the drug release rate under gastrointestinal tract (GIT) conditions, which was superior to traditional single crosslinked beads. In addition, the effects of grafting percentage, pH value, and temperature on the release behavior of the VB₂ were investigated. The drug release mechanism of CMCTS‐g‐PDEA drug‐loaded beads was analyzed by Peppa's potential equation. According to this study, the dual crosslinked hydrogel beads based on CMCTS‐g‐PDEA could serve as suitable candidate for drug site‐specific carrier in intestine. Copyright © 2009 John Wiley & Sons, Ltd.     

明胶水凝胶电刺激响应行为的研究

制备了戊二醛交联的明胶水凝胶 ,并研究了其吸水率、力学性能和电刺激响应行为 .结果表明 ,在NaCl溶液中 ,明胶水凝胶的平衡溶胀比随NaCl溶液的浓度增大而减小 ,经 0 0 1mol LNaCl溶液充分溶胀的明胶水凝胶膜其弹性模量为 4.2 9kPa ,抗张强度为 5 11kPa ,断裂伸长率为 110 %.在NaCl溶液中于非接触的直流电场作用下 ,明胶水凝胶向电场负极弯曲 ,凝胶的弯曲速度和弯曲偏转程度随外加电场的增大而增大 ,随NaCl溶液离子强度的增大出现临界最大值 .在周期性电场作用下 ,其弯曲响应行为具有良好的可逆性 .通过聚电解质凝胶弯曲理论初步解释了其弯曲机理 .     

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel showing a low swelling and an increased chemical stability in acidic medium. Ibuprofen, as a model drug, was loaded by soaking into INU-MA1 and INU-MA1-SA hydrogels and its release from these matrices was evaluated in simulated gastrointestinal fluids. INU-MA1 hydrogel showed the ability to quickly release the entrapped drug thus indicating its potential as a matrix for an oral formulation. INU-MA1-SA hydrogel showed a pH-responsive drug delivery. Therefore it is a promising candidate for controlled drug release in the intestinal tract.     

Release of lysozyme from the branched polyelectrolyte-lysozyme complexation

On the basis of the discretely charged sphere model of lysozyme, the release behavior of lysozyme from the branched polyelectrolyte-lysozyme complexation is investigated by adding salt and changing the pH values of the solution. It is found that, with the increase of the salt ionic strength of the solution, the lysozymes are gradually released from the oppositely charged polyelectrolyte as a result of the screening of electrostatic attraction between the two ionic species by adding the salt. Interestingly, there exists a critical salt ionic strength at which all proteins are released from the branched polyelectrolyte, and the polyelectrolyte-protein complexation is broken completely. Beyond the critical value, the increase of the salt ionic strength causes self-association of the proteins released from the branched polyelectrolyte-protein complexation. The self-association of the protein is detrimental in biological systems. By calculating the second virial coefficient, we found that the optimal salt content for the dispersion of proteins coincides with the critical ionic strength, because the second virial coefficient reaches its maximum at the critical ionic strength. Similarly, increasing the pH value of the solution can also release the lysozymes from the polyelectrolyte, because the increase of pH value of the solution changes the charge distribution and net charge of the lysozyme, weakens the attraction between lysozymes mediated by polyelectrolyte, and finally leads to the dissolution of the complexation of branched polyelectrolyte with lysozymes in strong alkaline solution. In addition, by exploring the effect of architecture of the polyelectrolyte on the release behavior of proteins, we found that it is more difficult to release proteins from the branched polyelectrolyte than from the linear polyelectrolyte.     

Donnan permselectivity in layer-by-layer self-assembled redox polyelectrolye thin films

Redox polyelectrolyte multilayers have been assembled with use of the layer-by-layer (LBL) deposition technique with cationic poly(allylamine) modified with Os(bpy)(2)ClPyCHO (PAH-Os) and anionic poly(styrene)sulfonate (PSS) or poly(vinyl)sulfonate (PVS). Different behavior has been observed in the formal redox potential of the Os(II)/Os(III) couple in the polymer film with cyclic voltammetry depending on the charge of the outermost layer and the electrolyte concentration and pH. The electrochemical quartz crystal microbalance (EQCM) has been used to monitor the exchange of ions and solvent with the external electrolyte during redox switching. At low ionic strength Donnan permselectivity of anions or cations is apparent and the nature of the ion exclusion from the film is determined by the charge of the topmost layer and solution pH. At high electrolyte concentration Donnan breakdown is observed and the osmium redox potential approaches the value for the redox couple in solution. Exchange of anions and water with the external electrolyte under permselective conditions and salt and water under Donnan breakdown have been observed upon oxidation of the film at low pH for the PAH-Os terminating layer. Moreover, at high pH values and with PVS as the terminating layer EQCM mass measurements have shown that cation release was masked by water exchange.     

麦饭石含量对载药复合凝胶小球释药性能的影响

以瓜尔胶-g-聚丙烯酸/麦饭石复合水凝胶(GG-g-PAA/MS)和海藻酸钠(SA)为原料,双氯芬酸钠(DS)为模拟药物,采用离子凝胶法制备了载药复合凝胶小球,考察了pH敏感性以及MS含量对复合凝胶小球的包封率、载药率、溶胀性和药物释放行为的影响.结果表明:凝胶小球具有明显的pH敏感性,在不同pH介质中溶胀率和释放速率...     

聚乙烯醇硫酸钾水凝胶电机械化学行为研究

通过将交联聚乙烯醇硫酸酯化的方法制备了一种新型电刺激响应性聚乙烯醇硫酸钾(PVSK)智能水凝胶,并探讨了溶液离子强度和pH对PVSK水凝胶的溶胀吸水率、机械性能以及电机械化学行为的影响.结果表明,制备的PVSK水凝胶的平衡溶胀比随NaCl溶液离子强度的增大而减小,在pH2.39～10.83范围内基本不受溶液pH的影响;经不同离子强度和pH的NaCl溶液充分溶胀的PVSK水凝胶具有良好的机械性能,在非接触的直流电场作用下,该水凝胶向电场负极弯曲,凝胶的弯曲速度和弯曲偏转量随外加电场强度的增加而增大,随NaCl溶液离子强度的增大出现临界最大值,但不随溶液pH(2.08～10.53)的改变而改变;在循环电场作用下,PVSK水凝胶的电机械化学行为具有良好的可逆性.     

Design of polyvinyl alcohol hydrogel as a controlled-release vehicle for rectal administration of dl-propranolol-HCl and atenolol

Preparations of beta-blockers, propranolol-HCl and atenolol, in poly(vinyl alcohol) (PVA) hydrogel were designed for the therapeutic treatment of hypertension by transrectal delivery. In vitro release characteristics and plasma drug concentration profiles after rectal administration in rats and dogs were examined. The PVA hydrogels containing beta-blockers were prepared by a low-temperature crystallization method. The release of beta-blockers from hydrogel preparations was consistent with Fickian diffusion (Higuchi model); the drug release versus the square root of release time profile gave a straight line over 60% of the total release process. The release of beta-blockers from hydrogel preparations increased at higher concentrations of PVA in the hydrogel preparations and was not affected by the pH of hydrogel preparations. Plasma concentrations of beta-blockers after rectal administration of hydrogels were higher than those after administration of suppositories (Witepsol H-15) in rats and dogs. The drug plasma concentrations increased at higher concentrations of PVA in hydrogel preparations. In the case of propranolol, which is a hepatic high-clearance drug, area under the blood concentration curve, 0-8 h after rectal administration of a hydrogel preparation (20% w/w PVA, pH 7.0) was 2.16 times and 5.26 times higher than those obtained with Witepsol H-15 suppository and oral administration, respectively. Rectal administration with PVA hydrogels is a favorable route for a hepatic high-clearance drug such as propranolol.     

Diffusion of Oligonucleotides from within Iron‐Cross‐Linked,Polyelectrolyte‐Modified Alginate Beads: A Model System for Drug Release

An analytical model to describe diffusion of oligonucleotides from stable hydrogel beads is developed and experimentally verified. The synthesized alginate beads are Fe³⁺‐cross‐linked and polyelectrolyte‐doped for uniformity and stability at physiological pH. Data on diffusion of oligonucleotides from inside the beads provide physical insights into the volume nature of the immobilization of a fraction of oligonucleotides due to polyelectrolyte cross‐linking, that is, the absence of a surface‐layer barrier in this case. Furthermore, the results suggest a new simple approach to measuring the diffusion coefficient of mobile oligonucleotide molecules inside hydrogels. The considered alginate beads provide a model for a well‐defined component in drug‐release systems and for the oligonucleotide‐release transduction steps in drug‐delivering and biocomputing applications. This is illustrated by destabilizing the beads with citrate, which induces full oligonucleotide release with nondiffusional kinetics.     

Electroresponsive Behavior of Sulfonated Benzal Poly(vinyl alcohol) Hydrogel Under Direct-Current Electric Field

A novel sulfonated benzal poly(vinyl alcohol) (S-B-PVA) hydrogel was prepared by sulfonating benzal poly(vinyl alcohol) hydrogel with concentrated sulfuric acid, and its swelling properties, mechanical properties, and electroresponsive behavior in Na₂SO₄ solutions were studied. The results indicated that the water take-up ability of the hydrogel decreased with the increasing ionic strength of Na₂SO₄ solution. The Young's modulus, elongation at break and tensile strength of the hydrogel swollen in deionized water is 8.38 MPa, 22.2% and 3.14 MPa, respectively. The hydrogel swollen in Na₂SO₄ solution bent toward the cathode under non-contact dc electric fields, and its bending speed and equilibrium strain increased with the increasing of applied voltage. The electroresponsive behavior of the hydrogel was also affected by the electrolyte concentration of external Na₂SO₄ solution, and there is a critical ionic strength of 0.1 at which the maximum equilibrium strain of the hydrogel occurs. Under a cyclically varying electric field, the hydrogel exhibited a good reversible bending behavior.     

Ion binding to polyelectrolytes: Monte Carlo simulations versus classical mean field theories

The influence of ion size and surface charge model in titrations of ionizable polyelectrolytes is studied by means of the Semi Grand Canonical Monte Carlo simulation method in the context of the primitive model. Three models describing a discrete distribution of charged functional groups on the polyelectrolyte and different values for the radius of the background electrolyte spanning from ionic to hydrated radii values were analyzed. The polyelectrolyte titrations were simulated by calculating the degree of ionization versus pH curves at two ionic strengths. The results allow us to quantify the impact of the sizes of the background salt ions and surface functional groups of the polyelectrolyte on the dissociation degree. This influence is explained in terms of the effectiveness of the screening of the charged surface sites. Finally, by comparison with the Non-Linear Poisson–Boltzmann model, the influence of ionic correlations and finite size of the solution ions is assessed.     

A Mathematical Study on Effect of 2-Hydroxyl Ethyl Acrylate on Controlled Drug Diffusion from Smart Hydrogels Based on Poly(acrylamide-co-hydroxy ethyl acrylate-co-acrylic acid)

A series of poly (AM-co-HEA-co-AA) hydrogels have been synthesized and characterized by varying 2-hydroxy ethyl acrylate (HEA) content in the range of 0–16.22% in feed. The swelling ratio of resulting hydrogels was drastically decreased 10 times, i.e., from 101.12 to 9.23 in an almost linear fashion; but the dimensional stability of these hydrogels was increased significantly from 5 to 46 days with increasing HEA content. The hydrogels exhibited Smart nature in varying pH (2–10), temperature (15–65°C), ionic strength of NaCl solution (0.1M-1.5M), and different cation chloride salt solution having same ionic strength (0.1M). The swelling mechanism was shifted from non-Fickian to Fickian (at pH 2–7), super case to non-Fickian (at pH 10) with increasing HEA content. The controlled release of model drug (salicylic acid) from these hydrogels was investigated using early-time, late-time and Etters diffusion models and compared with the experimental data. It was observed that early model doesn't fit, but Etter and late-time model fitted excluding the initial phase. However, it was also observed that with increasing HEA content, the applicability of Etter's model improved, and for 16.22% HEA containing hydrogel Etters model was fitted in the full range, indicating that by varying hydrogel composition, the diffusion characteristics can be altered.     

两性聚电解质溶液的分子热力学模型和分子动力学模拟

从带电硬球混合物出发采用化学缔合理论建立了聚电解质和两性聚电解质溶液的分子热力学模型.用考虑溶剂的粘滞力和热浴随机力作用的分子动力学(MD)方法模拟了聚电解质和两性聚电解质溶液的渗透系数.对模型预测结果和MD模拟结果进行了比较,表明基于化学缔合理论的分子热力学模型可以用于聚电解质溶液和两性聚电解质溶液热力学性质的预测,对于均聚电解质溶液效果令人满意,对由直径不同的离子构成的聚电解质溶液,模型的预测效果变差,有待进一步改进.该模型对两性聚电解质溶液渗透系数的预测效果比对聚电解质溶液的预测效果更好.     

Activity of counterions in hydrogels based on poly(acrylic acid) and poly(methacrylic acid): Potentiometric measurements

The behavior of partially ionized weakly crosslinked gels based on poly(acrylic acid) and poly(methacrylic acid) undergoing contraction in the presence of a low-molecular-mass salt is studied experimentally. The concentration dependences of the enthalpies of swelling of gels in water and aqueous solutions with potassium chloride concentrations of 1, 10, and 100 mmol/L are determined via the method of isothermal calorimetry. On the basis of the obtained data, the enthalpy parameter of interaction between a polymer network and a medium is estimated as a function of the amount of the salt. This parameter does not exceed 0.3 and monotonically decreases with an increase in the concentration of the salt. The Donnan potential of gels depending on the concentration of KCl in the external solution is measured via the method of potentiometry with the use of capillary electrodes, and the activity of potassium counterions in the medium of hydrogel is calculated. The main factor that causes contraction of polyelectrolyte gels in a solution of a low-molecular-mass salt is a decline in the activity of counterions that leads to a decrease in the osmotic pressure inside the gel. A decline in activity may be associated with both a reduction in the activity coefficient and ionic association processes in the hydrogel.     

Surface modification by deposition of IPA plasma and gellan gum/chitosan hybrid hydrogel onto thermoplastic polyurethane for controlled release of N‐acetylcysteine

A thin film system composed of gellan gum and chitosan was fabricated through a combination of polyelectrolyte blend and hybrid hydrogel gelation for controlled release of drug. In this study, precursor isopropyl alcohol (IPA) was used to plasma deposit on the surface of thermoplastic polyurethane (TPU) to form a hydrophilic film. The features of the thin film were evaluated using water contact angle (WCA) measurement, scanning electron microscopy (SEM), Fourier transform infra‐red (FTIR), UV/Vis spectroscopy, and studies of controlled release of drugs. The hybrid hydrogel, pH‐sensitive, was tested at pH values of 1.2 and 7.4 of buffer solution and at a temperature of 37°C to observe its swelling ratio and drug delivery properties with N‐acetylcysteine as a drug material for controlled release. Furthermore, at pH 7.4, the hybrid hydrogel has an outstanding release ratio of up to about 90% absorption amounts of N‐acetylcysteine after 8 hr. The mechanism of drug release from thin film devices (n = 0.684) is anomalous (non‐Fickian) transport, the value of n lies between 0.43 and 0.85.     

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets

Hydrophilic matrix tablets with controlled drug release have been used extensively as one of the most successful oral drug delivery systems for optimizing therapeutic efficacy. In this work, magnetic resonance imaging (MRI) is used to study the influence of various pHs and mechanical stresses caused by medium flow (at rest, 80, or 150 mL/min) on swelling and on pentoxifylline release from xanthan (Xan) tablets. Moreover, a bimodal MRI system with simultaneous release testing enables measurements of hydrogel thickness and drug release, both under the same experimental conditions and at the same time. The results show that in water, the hydrogel structure is weaker and less resistant to erosion than the Xan structure in the acid medium. Different hydrogel structures affect drug release with erosion controlled release in water and diffusion controlled release in the acid medium. Mechanical stress simulating gastrointestinal contraction has no effect on the hard hydrogel in the acid medium where the release is independent of the tested stress, while it affects the release from the weak hydrogel in water with faster release under high stress. Our findings suggest that simultaneous MR imaging and drug release from matrix tablets together provide a valuable prognostic tool for prolonged drug delivery design.     

Bioinspired self-assembly supramolecular hydrogel for ocular drug delivery

Based on a recent report concerning endogenous agents (i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein (ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide (NapFFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate (Dexp) to generate a NapFFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery. The NapFFKKFKLKL/Dexp hydrogel formed instantly after the complexation of NapFFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy (TEM), fluorescent spectrum, circular dichroism (CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release. Following a single intravitreal injection, the proposed NapFFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis (EAU) rat model, we demonstrated that the resulting NapFFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting NapFFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders (i.e., uveitis).     

Design of a rate- and time-programming drug release device using a hydrogel: pulsatile drug release from kappa-carrageenan hydrogel device by surface erosion of the hydrogel

We have found that a repetitive pulsatile drug release with a certain time interval is observed from a monolithic hydrogel device by surface erosion of the hydrogel. As a model system of pulsatile drug release, dibucaine hydrochloride and kappa-carrageenan hydrogel were chosen as a drug and a device, respectively. Electrostatic interactions between dibucaine hydrochloride and kappa-carrageenan polymer segments are strong, since dibucaine hydrochloride is positively charged and each disaccharide repeating unit of kappa-carrageenan chains has one sulfate group. Dibucaine hydrochloride was loaded into the hydrogel by immersing dry kappa-carrageenan hydrogel disks in a dibucaine hydrochloride solution for 24 h. The pulsed release of dibucaine hydrochloride from the device was observed every 50 min between 30 and 250 min after the release starts. The weight of kappa-carrageenan hydrogel decreases in an oscillatory manner with time in distilled water. The oscillatory changes observed in the hydrogel weight in distilled water are considered to be caused by influx and efflux of water molecules into and from the surface and core of the hydrogel and by polymer liberation from the hydrogel. This phenomenon was well explained by our kinetic model [Colloids and Surfaces B 8 (1996) 93-100]. The time interval between pulses observed in drug release coincides with that observed in the oscillatory weight change of the hydrogel. From these, it was concluded that the pulsatile release of dibucaine hydrochloride from the device was caused by the pulsatile liberation of swollen kappa-carrageenan hydrogel from the surface of the device.     

Evaluation of the adsorption trends of a low molecular-weight polyelectrolyte with a site-binding model

The site-binding model is very useful for describing the adsorption of ions and small ionized molecules. It has been slightly modified to include multi-site adsorption of larger molecules such as oligomers and low molecular weight polyelectrolytes. We describe alterations of the classical model and the results of calculations for adsorption of polyacrylic acid onto titanium dioxide as an example. The triple layer model is used to relate charge densities to interfacial potential profiles. Comparison between adsorption trends and the surface layer composition as a function of pH and ionic strength demonstrates the prominent influence of ions binding in the adsorption process. The site-binding model makes it easy to simulate the ions displacement associated with polyelectrolyte adsorption. Strongly bound electrolyte anions prevent polyacrylic acid from adsorbing, and, in contrast, electrostatic screening due to cation condensation makes it easier. Calculations of the pH change in the solution, due to adsorption, are also made by comparing ionization ratios of both the surface and polymer units in the adsorbed layer and before adsorption. Trends in electrokinetic potentials as a function of the solution's parameters are evaluated assuming the identity of the shearing surface and the inner boundary of the diffuse layer. All data compare well with experimental values. The very good agreement betwen the experiment and model calculations supports the fact that (small) polyelectrolyte molecules adsorb essentially flat on the surface.     

电场下离子型聚合物复合囊泡结构变化的分子动力学模拟

利用粗粒化分子动力学模拟研究了电场作用下离子型聚合物复合囊泡形变与破裂的过程.定量分析了囊泡破裂过程中的结构变化,包括囊泡的形变程度、破裂速度、组分分布以及破裂后的结构.研究表明,电场强度较弱时,囊泡表面所吸附的聚电解质首先脱落,囊泡由球形结构转变为椭球结构.随着电场强度增大,离聚物的离子侧基发生重新排布,囊泡表面电荷的有序结构被破坏,导致囊泡的结构无法维持而破裂,囊泡塌缩,分裂形成离聚物团簇,并进一步破裂为小尺寸的离聚物聚集体,均匀分散于溶液中.本文利用分子动力学模拟明确了电场中离子型高分子复合囊泡破裂过程的分子机理,为药物释放技术的优化及发展提供了理论支持.