Silicone microspheres for pH-controlled gastrointestinal drug delivery

Silicone microspheres containing pH-sensitive hydrogels are prepared, characterized and evaluated for their potential pH-controlled gastrointestinal (GI) drug delivery. The pH-sensitive hydrogels are semi-interpenetrating polymer networks (semi-IPN(s)) made of varying proportions of poly(methacrylic acid-co-methylmethacrylate) (Eudragit (EUD) L100 or EUD S100) and crosslinked polyethylene glycol 8000 (P8000C). Up to 35 wt% hydrogel particles of mean volume diameters from 89 to 123 microm, medicated with 15 wt% prednisolone (PDN), are encapsulated, with 100% efficiency, into morphologically acceptable silicone microspheres in the 500-1000 microm size range, by a modified emulsion vulcanization method. Microspheres are eluted for 9 h with isotonic fluids at pH values increasing from 1.2 to 7.4, to simulate transit across the GI regions. PDN release depends on dissolution medium pH and on hydrogel composition, which determines hydrogel pH-sensitivity. With the P8000C-EUD L100 (1:2) semi-IPN, the release shows a marked peak at pH 6.8. The P8000C-EUD S100 (1:2) semi-IPN causes a gastroprotection and an almost uniform distribution of released drug between media at pH 6.8 and 7.4. With the P8000C-EUD S100 (1:1) semi-IPN, the dose fraction released to gastric fluid increases to match the values for the media at pH 6.8 and 7.4. With the pH-insensitive, highly swelling, P8000C, the largest dose fraction is released to the gastric medium and release is of Fickian type. With semi-IPNs, release depends weakly on the buffer molarity of the dissolution medium, a reduction from 0.13 to 0.032 of which renders the release rate to the media at pH 6.8 and 7. 4 more uniform.Copyright     

Cross-linked guar gum hydrogel discs for colon-specific delivery of ibuprofen: formulation and in vitro evaluation

Hydrogel discs of guar gum cross-linked with glutaraldehyde were prepared as vehicles for colon-specific drug delivery. Ibuprofen was chosen as model drug. The discs were evaluated for such parameters as size, shape, weight, and drug loading. Swelling (buffer uptake) and in vitro drug release study, in presence and absence of rat caecal contents, was performed in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) to evaluate the effect of various formulation parameters like guar gum concentration, amount of cross-linking agent, and cross-linking time on drug release. Cross-linking resulted in significant reduction in swelling of guar gum. Significant increase in drug release was observed in medium containing rat caecal content. Percent drug release increased with increasing glutaraldehyde concentration. Cross-linking time and guar gum concentration did not have any significant effect on drug release in the range studied.     

Preparation and Characterization of Docetaxel-PLGA Nanoparticles Coated with Folic Acid-chitosan Conjugate for Cancer Treatment

The conjugation of chitosan (CS) and folic acid (FA) was prepared and used to coat PLGA nanoparticles (NPs) that are loaded with Docetaxel (DTX) to target cancer cells that have lower pH and overexpression of folate receptors in comparison to normal cells. Three formulations had been prepared to reach the highest loading capacity (LC%) and encapsulation efficiency (EE%) and to study the effect of the amount of FA-CS on the drug release. The sizes, charges, homogeneity, surface morphology, LC% and EE% of the NPs were determined. The NPs were characterized using FTIR and XRD. In vitro release profiles of DTX from PLGA NPs, at pH 5.5 and 7.4 were determined. Finally, in vitro cytotoxicity assay on three cancer cell lines (RPMI 2650, Calu-3, and A549) was studied. The sizes of the three formulations ranged between 250.3±1.7 and 356.3±17.7. All prepared formulations showed acceptable monodispersity with highly positive charges. The EE% was above 85% and the LC% ranged between 6-35%. The in vitro release of DTX show an inverse relation to the amounts of FA-CS used and the pH of the dissolution medium. Coated PLGA NPs showed a significant difference in RPMI 2650, Calu-3, and A549 cell viability in comparison to free DTX. The NPs components were safe and non-toxic to human cells. In conclusion, coating PLGA NPs with FA-CS may be used as a good carrier for chemotherapeutic agents that selectively target carcinogenic tissues.     

Mucoadhesive and floating chitosan-coated alginate beads for the controlled gastric release of amoxicillin

This work focused on the development of mucoadhesive and floating chitosan-coated alginate beads as a gastroretensive delivery vehicle for amoxicillin, towards the effective eradication of Helicobacter pylori, a major causative agent of peptic ulcers. Alginate was used as the core bead core polymer and chitosan as the mucoadhesive polymer coating. Amoxicillin-loaded alginate beads coated with 0.5% (w/v) chitosan (ALG/0.5%CHI) exhibited excellent floating ability, high encapsulation efficiency, high drug loading capacity, and a strong in vitro mucoadhesion to the gastric mucosal layer. In vitro, amoxicillin was released faster in simulated gastric fluid (pH 1.2, HCl) than in simulated intestinal fluid (phosphate buffer, pH 7.4). ALG/0.5%CHI could be prepared with a > 90% drug encapsulation efficiency and exhibited more than 90% muco-adhesiveness, 100% floating ability, and achieved sustained release of amoxicillin for over six hours in SGF.     

A novel pH sensitive N-succinyl chitosan/alginate hydrogel bead for nifedipine delivery

A novel N-succinyl chitosan(Suc-Chi)/alginate hydrogel bead was prepared by the ionic gelation method for the controlled delivery of nifedipine. The structure and surface morphology of the hydrogel were characterized by FTIR and SEM, respectively. Factors influencing the swelling ability of the hydrogel bead were also investigated, such as the ratio of Suc-Chi and alginate (X(1)), the weight ratio of drug to polymer (X(2)), the volume ratio of alginate/Suc-Chi to CaCl(2) (X(3)), crosslinking time (X(4)), CaCl(2) concentration (X(5)). In addition, the delivery behavior of nifedipine from the hydrogel bead was studied. The amount of nifedipine released from the hydrogel bead at pH 1.5 was relatively low (11.6%), while this value approached 76% at pH 7.4. The results clearly suggested that the Suc-Chi/alginate hydrogel bead may be a potential polymeric carrier for drug delivery in the intestinal tract. The release of nifedipine from the hydrogel bead at various pH values was analysed by a semi-empirical equation and it was found that the drug release mechanisms were either 'anomalous transport' or 'case-II transport'.     

LITERATURE ALERTS

Hydrogel discs of guar gum cross-linked with glutaraldehyde were prepared as vehicles for colon-specific drug delivery. Ibuprofen was chosen as model drug. The discs were evaluated for such parameters as size, shape, weight, and drug loading. Swelling (buffer uptake) and in vitro drug release study, in presence and absence of rat caecal contents, was performed in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) to evaluate the effect of various formulation parameters like guar gum concentration, amount of cross-linking agent, and cross-linking time on drug release. Cross-linking resulted in significant reduction in swelling of guar gum. Significant increase in drug release was observed in medium containing rat caecal content. Percent drug release increased with increasing glutaraldehyde concentration. Cross-linking time and guar gum concentration did not have any significant effect on drug release in the range studied.     

Effect of some formulation parameters on flurbiprofen encapsulation and release rates of niosomes prepared from proniosomes

Proniosomal gels or solutions of flurbiprofen were developed based on span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60), and span 80 (Sp 80) without and with cholesterol. Nonionic surfactant vesicles (niosomes) formed immediately upon hydrating proniosomal formulae. The entrapment efficiency (EE%) of flurbiprofen (a poorly soluble drug) was either determined by exhaustive dialysis of freshly prepared niosomes or centrifugation of freeze-thawed vesicles. The influence of different processing and formulation variables such as surfactant chain length, cholesterol content, drug concentration, total lipid concentration, negatively or positively charging lipids, and the pH of the dispersion medium on flurbiprofen EE% was demonstrated. Also, the release of the prepared niosomes in phosphate buffer (pH 7.4) was illustrated. Results indicated that the EE% followed the trend Sp 60 (C(18))>Sp 40 (C(16))>Sp 20 (C(12))>Sp 80 (C(18)). Cholesterol increased or decreased the EE% depending on either the type of the surfactant or its concentration within the formulae. The maximum loading efficiency was 94.61% when the hydrating medium was adjusted to pH 5.5. Increasing total lipid or drug concentration also increased the EE% of flurbiprofen into niosomes. However, incorporation of either dicetyl phosphate (DCP) which induces negative charge or stearyl amine (SA) which induces positive charge decreased the EE% of flurbiprofen into niosomal vesicles. Finally, in vitro release data for niosomes of Sp 40 and Sp 60 showed that the release profiles of flurbiprofen from niosomes of different cholesterol contents is an apparently biphasic release process. As a result, this study suggested the potential of proniosomes as stable precursors for the immediate preparation of niosomal carrier systems.     

Modeling of swelling and drug release behavior of spontaneously forming hydrogels composed of phospholipid polymers

Physically cross-linked hydrogel had been investigated in order to make use of oral polypeptide drug delivery carrier. By using 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymer, we had prepared a spontaneously forming hydrogel showing controllable dissociation via pH changes. In this study, the dissociation and release of polypeptide drugs from the MPC polymer hydrogel loaded with polypeptide drugs, which had been prepared from aqueous solutions containing water-soluble poly[MPC-co-methacrylic acid (MA)] (PMA) and poly[MPC-co-n-butyl methacrylate (BMA)] (PMB) had been executed. The polymer concentration was 10 wt.% and PMA/PMB feed ratio (A/B feed ratio) was 5/5. Insulin labeled with fluorescein-4-isothiocyanate (FITC) and cytochrome c had been loaded for the examination of the release behavior. The hydrogel in pH 1.8 aqueous solution would be swelling, for the hydrogel would absorb outside water. However, during this process, the polymer is dissoluting out from the hydrogel due to the widening of the polymer network. The cytochrome c followed anomalous transport while insulin depended on the swelling and dissolution of the polymer chains. The hydrogel showed surface erosion in neutral condition, although the hydrogel is composed of two different polymer possessing divergent physical properties. The release followed anomalous transport, but the erosion rate slightly changed with as the hydrophobicity of the loaded drugs. The total amount of the drugs released in neutral condition was larger compared to the acidic condition. When the eroded percentage and the release percentage were compared with each other, it showed that release was slightly slower than erosion, indicating that the erosion was controlling the release phenomenon.     

Drug diffusion mechanism through pH-sensitive hydrophobic/polyelectrolyte hydrogel membranes.

Methylmethacrylate/dimethylaminoethyl methacrylate cross-linked with divinylbenzene is a pH-sensitive hydrogel. We have studied the diffusion mechanisms of drugs with different water solubilities through this hydrogel. A water-soluble model drug (aminopyrine) was used to study the diffusion coefficient changes in different pHs. The results showed a water-content dependent diffusion for this pH-sensitive polycationic hydrogel. However, decreasing the solubility of the drug and increasing the hydrophobic character of the polymer by changing the pH caused a greater affinity (or partition coefficient) between the hydrogel and the drug. Aminopyrine diffusion was shown to follow the free-volume theory, suggesting the 'pore' type mechanism for water soluble drugs, while the 'partition' or 'solution-diffusion' mechanism better described the slow diffusion of water insoluble solutes through this pH-sensitive hydrogel. Comparing the swelling interface number for aminopyrine release through this pH-sensitive hydrogel showed a non-Fickian mechanism in the hydrated form of the hydrogel (pH 1.2), while Fickian in the dehydrated form (pH 7.4).     

Characterization of drug release and diffusion mechanism through hydroxyethylmethacrylate/methacrylic acid pH-sensitive hydrogel

Hydroxyethylmethacrylate/methacrylic acid copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk free radical polymerization method. The permeability studies of this pH-sensitive hydrogel to drugs with different water solubilities showed a water-content dependent diffusion or pore mechanism for ephedrine HCl (water-soluble model drug), whereas, a partition or solute-diffusion mechanism for indomethacin (a water-insoluble drug) was seen. Data analysis of release tests, according to the swelling interface number and Peppas equation for ephedrine HCl in pH 7.4, showed a biexponential model kinetic, whereas in pH 1.2 a swelling-controlled mechanism was seen. Indomethacin was released by an anomalous or non-Fickian release kinetics.     

Characterization of Drug Release and Diffusion Mechanism Through Hydroxyethylmethacrylate/Methacrylic Acid pH-Sensitive Hydrogel

Hydroxyethylmethacrylate/methacrylic acid copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk free radical polymerization method. The permeability studies of this pH-sensitive hydrogel to drugs with different water solubilities showed a water-content dependent diffusion or pore mechanism for ephedrine HCl (water-soluble model drug), whereas, a partition or solute-diffusion mechanism for indomethacin (a water-insoluble drug) was seen. Data analysis of release tests, according to the swelling interface number and Peppas equation for ephedrine HCl in pH 7.4, showed a biexponential model kinetic, whereas in pH 1.2 a swelling-controlled mechanism was seen. Indomethacin was released by an anomalous or non-Fickian release kinetics.     

两亲性PCL-PVP聚合物水凝胶负载布洛芬-精氨酸药物共晶制备及体外释放研究

目的：制备两亲性聚己内酯-聚乙烯吡咯烷酮（PCL-PVP）聚合物水凝胶用于负载布洛芬-精氨酸药物共晶并考察其体外释放行为。方法：采用溶剂挥发法制备物质的量比1：1布洛芬-精氨酸药物共晶;通过自由基溶液聚合法制备PCL-PVP聚合物凝胶。将布洛芬-精氨酸共晶负载于PCL-PVP聚合物凝胶上,考察不同亲疏水比例载药物共晶凝胶（PCL：PVP=1：9,3：7,5：5）在pH 5.8,7.4的PBS中的体外释放行为。结果：在pH 5.8 PBS中,布洛芬释放速率及释放量受载药凝胶亲疏水比例影响较大,释放72 h后, PCL：PVP=3：7的载药凝胶累积释放量达到约80%,为3组凝胶中的最大值。在pH 7.4 PBS中,不同亲疏水比例的载药凝胶的释放速率差别不大,布洛芬的释放速率较pH 5.8 PBS中的释放速率明显增大,在释放开始12 h后三者累积释放率均已接近或超过80%。结论：药物共晶的体外释放受多种因素影响,两亲性PCL-PVP聚合物凝胶可用于布洛芬-精氨酸药物共晶的载体,具有一定控释作用。     

Novel pH-sensitive hydrogels for colon-specific drug delivery

The purpose of this study is to develop novel intestinal specific drug delivery systems with pH-sensitive swelling and drug release properties. Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Cubane-1,4-dicarboxylic acid (CDA), linked to two 2-hydroxyethyl methacrylate (HEMA) groups, was the cross-linking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate), and APAS in the presence of cubane cross-linking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1) and intestinal fluids (SIF, pH 7.4). The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug–polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1 and pH 7.4) at 37°C. Detection of the hydrolysis product by UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of HPAS as an azo derivative of 5-amino salicylic acid (5-ASA).     

Injectable and biodegradable poly(organophosphazene) gel containing silibinin: its physicochemical properties and anticancer activity

The biodegradable poly(organophosphazene) hydrogels were developed as a locally injectable drug carrier for a hydrophobic silibinin to overcome its limited bioavailability. The aqueous solution of poly(organophosphazene) enhanced the solubility of silibinin up to 2000 times compared with that of phosphate buffered saline (0.0415 vs. 84.55 mg/mL). Both aqueous polymer solutions with and without silibinin showed a sol-gel transition as a function of temperature. A faster in vitro degradation rate of the gel and drug release rate from the gel at pH 6.8 than those at pH 7.4 were observed when the degradation and release study on hydrogels were conducted at 37 °C. Silibinin was sustainedly released from the hydrogel mainly by a diffusion-controlled mechanism. The silibinin released from the hydrogel was shown to be effective considering the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the HT-29 xenografted mice model, the intratumorally injected hydrogel containing silibinin exhibited a good antitumor effect in comparison with the control groups. The Western blotting indicated that one of the reasons for the enhanced antitumor effect of the hydrogel system was the sustained antiangiogenic effect of silibinin. The poly(organophosphazene) gels are expected to be an effective candidate of the locally injectable drug carrier for silibinin.     

Box-Behnken效应面法优化盐酸左氧氟沙星胃漂浮缓释片处方

目的：探讨Box-behnken效应面法在优化盐酸左氧氟沙星胃漂浮缓释片处方过程中的应用。方法：以盐酸左氧氟沙星为模型药物,采用湿法制粒压片法制备左氧氟沙星胃漂浮缓释片剂。利用Box-behnken实验设计,考察三种缓释材料HPMCK 4M、卡泊姆CP934P及海藻酸钠(SA)对不同时间点释药性能和对漂浮片漂浮性能的影响,通过二项式方程拟合建立因素与响应值之间的数学关系以优化处方,对体外释药数据进行方程拟合,探讨其释药机理。结果：通过优化后的最佳处方为HPMC K4M 30 %、卡泊姆CP934P 12.3 %、海藻酸钠(SA) 28.6%,优化处方的实测值与预测值之间的偏差较小;药物的释药机制为骨架溶蚀与药物扩散双重作用。结论：Box-behnken效应面法优化法建立的模型可以用于盐酸左氧氟沙星缓释片处方的优化。     

Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing carbopol-934P as mucoadhesive polymer and ethyl cellulose as carrier polymer were prepared by an emulsion-solvent evaporation technique. Results of preliminary trials indicate that quantity of emulsifying agent, time for stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. Microspheres were discrete, spherical, free flowing and showed a good percentage of drug entrapment efficiency. An in vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3(2) full factorial design was employed to study the effect of independent variables, drug-to-polymer-to-polymer ratio (amoxicillin-ethyl cellulose-carbopol-934P) (X(1)) and stirring speed (X(2)) on dependent variables, i.e. percentage mucoadhesion, drug entrapment efficiency, particle size and t(80). The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage after 1 h was 80% and the particle size was 109 μm. A sustained drug release was obtained for more than 12 h. The drug-to-polymer-to-polymer ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microspheres to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make a contribution to H. pylori complete eradication.     

Swelling behaviour and controlled drug release from cross-linked κ-carrageenan/NaCMC hydrogel by diffusion mechanism

We studied a model system of controlled drug release using beta-carotene and κ-carrageenan/NaCMC hydrogel as a drug and a device, respectively. Different concentrations of genipin were added to crosslink the beta-carotene loaded beads by using the dripping method. Results have shown that the cross-linked beads possess lower swelling ability in all pH conditions (pH 1.2 and 7.4), and swelling ratio decreases with increasing genipin concentration. Microstructure study shows that cross-linking has enhanced the stability and structure of the beads network. Determination of diffusion coefficient for the release of encapsulated beta-carotene indicates less diffusivity when beads are cross-linked. Swelling models using adaptive neuro fuzzy show that using genipin as a cross-linker in the kC/NaCMC hydrogels affects the transport mechanism. The model shows very good agreement with the experimental data that indicates that applying ANFIS modelling is an accurate, rapid and simple way to model in such a case for controlled release applications.     

A thermo- and pH-sensitive hydrogel composed of quaternized chitosan/glycerophosphate

The quaternized chitosan was synthesized by the reaction of chitosan and glycidyltrimethylammonium chloride (GTMAC) and named as N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC). A novel hydrogel system composed of HTCC/glycerophosphate (HTCC/GP) with thermo- and pH-sensitivity was synthesized and used as an intelligent drug carrier. The formulation was solution below or at room temperature, which allowed it injectable and to incorporate living cells, proteins, enzymes or other therapeutic drugs easily. Once the surrounding temperature was up to 37 degrees C, the system was transformed to a non-flowing hydrogel, and the formed hydrogel can release the trapped drug as a function of pH values. The swelling behavior of the system and the release profiles of doxorubicin hydrochloride (DX) as a model drug at different pH values were investigated. At acidic condition the hydrogel dissolved and released drug quickly, while it absorbed water and released drug slowly at neutral or basic conditions. Hydrogel composed of chitosan hydrochloride and glycerophosphate (CS/GP) was also prepared to compare with HTCC/GP hydrogel. The HTCC/GP hydrogel in this study was transparent which made it suitable for some specific uses such as ocular drug formulation.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20–100 μm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20-100 microm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.