Preparation and release profiles of pH/temperature-responsive carboxymethyl chitosan/P(2-(dimethylamino) ethyl methacrylate) semi-IPN amphoteric hydrogel

Thermo- and pH-responsive semi-IPN polyampholyte hydrogels were prepared by using carboxymethyl chitosan and P(2-(dimethylamino) ethyl methacrylate) with N N'-Methylenebisacrylamide (BIS) as crosslinking agent. It was found that the semi-IPN hydrogel shrunk most at the isoelectric point (IEP) and swelled when pH deviated from the IEP. Its swelling ratio dramatically decreased between 30 and 50 °C at pH 6.8 buffer solution. It also showed good reversibility. The UV results showed that when the pH values of drug release medium were 3.7, 6.8, and 9 at 25 °C, the cumulative release rates reached 83.1, 51.5, and 72.2%, respectively. The release rate of coenzyme A (CoA) was higher at 50 °C than 37 and 25 °C at pH 6.8 solution. The release rate decreased with increasing the content of carboxymethyl chitosan at 25 °C in pH 6.8 solution. The results showed that semi-IPN hydrogel seems to be of great promise in pH/temperature drug delivery systems.     

Biomineralized polysaccharide beads for dual-stimuli-responsive drug delivery

Biomineralized polysaccharide-coated alginate beads containing PNIPAAM were prepared. The resulting beads can be used as carriers for sustained pH/temperature-sensitive drug delivery. Characterizations using SEM, EDS, FTIR, and POM revealed that the beads were covered by the calcium-phosphate-mineralized alginate/chitosan membrane. The drug-release behavior was examined using indomethacin as a model drug, and the release profile of the developed materials was found to be responsive to pH and temperature. The release profile could be sustained under neutral conditions, indicating that the mineralized polysaccharide membrane could prevent the permeability of the encapsulated drug and reduce the drug release rate.     

Ionically crosslinked alginate/carboxymethyl chitin beads for oral delivery of protein drugs

Complex beads composed of alginate and carboxymethyl chitin (CMCT) were prepared by dropping aqueous alginate-CMCT into an iron(III) solution. The structure and morphology of the beads were characterized by IR spectroscopy and scanning electron microscopy (SEM). IR confirmed electrostatic interactions between iron(III) and the carboxyl groups of alginate as well as CMCT, and the binding model was suggested as a three-dimensional structure. SEM revealed that CMCT had a porous morphology while alginate and their complex beads had a core-layer structure. The swelling behavior, encapsulation efficiency, and release behavior of bovine serum albumin (BSA) from the beads at different pHs were investigated. The BSA encapsulation efficiency was fairly high (>90%). It was found that CMCT disintegrated at pH 1.2 and alginate eroded at pH 7.4 while the complex beads could effectively retain BSA in acid (>85%) and reduce the BSA release at pH 7.4. The results suggested that the iron(III)-alginate-CMCT bead could be a suitable polymeric carrier for site-specific protein drug delivery in the intestine.     

Entrapment and release of sodium polystyrene sulfonate (SPS) from calcium alginate gel beads

The release of sodium polystyrene sulfonate (SPS) from calcium alginate hydrogel beads has been studied. It has been shown that the structure of the cross-linked calcium alginate network is of primary importance in the retention and/or release of the SPS. This has been evidenced by studying the influence of Ca²⁺ concentration, molar masses (M_n) and the ratio of mannuronic acid/guluronic acid components. A minimum in the SPS release is observed in relation with the organization of the network structure. Conditions inducing the organization of a strong gel (e.g. high Ca²⁺ concentration for example) are not always related to a low release. A good control of release is found when a compromise between a well-structured hydrogel and sterical consideration of SPS is reached.     

Release property of temperature-sensitive alginate beads containing poly(N-isopropylacrylamide)

The graft copolymer (APN) of alginate and poly(N-isopropylacrylamide) (PNIPAM) were synthesized and APN beads were prepared by dropping the aqueous solution of the copolymer into an aqueous solution of Ca(2+) solution. Alginate chains were employed to play a role in forming beads by electrostatic interactions with a multivalent ion, Ca(2+). Grafted PNIPAM segments were adopted to act as a valve for the pores of the beads, since they exhibit the properties of thermal contraction and expansion. The percent of release of blue dextran from APN beads was higher at 40 degrees C than at 25 degrees C. The difference in the release between two temperatures became more distinguishable when the content of PNIPAM in APN beads is higher. Below lower critical solution temperature (LCST), the expanded PNIPAM would close the pores of the beads, resulting in a lower release rate. Above LCST, the thermally contracted polymer would open the pores, resulting in a higher release rate. The percent of release from APN beads were investigated when the temperature of the release medium is altered. The release rate was relatively low at 25 degrees C. The temperature, however, changed up to 40 degrees C, a marked increase in the release rate was observed. These trends were found to be reproducible when the temperature was repeatedly altered between 25 and 40 degrees C. As a result, a stepwise response to the temperature alteration was obtained.     

Preparation of filled temperature-sensitive poly(N-isopropylacrylamide) gel beads

Temperature-sensitive filled poly(N-isopropylacrylamide) (PNIPAAm) gel beads with diameters in the range of millimeters were prepared using the alginate technique. The polymerization and cross-linking reaction of NIPAAm in the presence of inorganic filling particles was performed in spherical networks of Ca-alginate forming interpenetrating networks (IPN). Thermo-sensitive gel beads could be obtained by washing these IPN with EDTA solution. The PNIPAAm gel beads were analyzed by optical methods to observe there swollen diameter in dependence on the temperature. The diameters of the swollen gel beads were in the range of 0.1 - 2 mm. The influence of the monomer to cross-linker ratio (MCR) and the filling materials (ferrofluid, BaTiO₃, TiO₂, and Ni,) were studied. The phase transition temperature (T_pt) was only weakly influenced by the MCR and the filling material remaining at around 34°C.     

Rapid deswelling of sodium alginate/poly(N-isopropylacrylamide) semi-interpenetrating polymer network hydrogels in response to temperature and pH changes

In this study, temperature-/pH-responsive semi-interpenetrating polymer network (semi-IPN) hydrogels based on linear sodium alginate (SA) and cross-linked poly(N-isopropylacrylamide) (PNIPAAm) were prepared. The semi-IPN hydrogels reached an equilibrium deswelling state within 6 h in response to temperature or pH stimuli. Compared with the conventional PNIPAAm hydrogel, their dewelling rate in response to temperature was improved significantly, owing to the formation of a porous structure within the hydrogels in the presence of ionized SA during the polymerization process. Moreover, the deswelling process could be well described with a first-order kinetics equation and it is possible to design any hydrogel with the desired deswelling behavior through the control of the SA content in the semi-IPN hydrogels.     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

海藻酸钠/聚(N-异丙基丙烯酰胺)半互穿网络水凝胶的制备及性能研究

由海藻酸钠(SA)和聚(N-异丙基丙烯酰胺)(PNIPAAm)制得的半互穿网络水凝胶具有温度及pH敏感特性。在酸性(pH=1.3)和弱碱性条件(pH=7．4)下，研究了温度对该凝胶溶胀度的影响，结果表明，该凝胶溶胀度均随着温度的提高而下降，但在pH=1．3时，溶胀度小于PNIPAAm水凝胶的；在pH=7．4时，结果正好相反。在25℃和37℃的条件下，分别考察pH对该凝胶溶胀度的影响，结果表明，在25℃时该凝胶有良好的pH敏感性，而在37℃时，敏感性不明显。同时也发现该凝胶对pH、温度的脉冲刺激有较快的响应性。     

Entrapment of ethyl vanillin in calcium alginate and calcium alginate/poly(vinyl alcohol) beads

Electrostatic extrusion was applied to the encapsulation of 3-ethoxy-4-hydroxybenzaldehyde (ethyl vanillin) in calcium alginate and calcium alginate/poly(vinyl alcohol) beads. The calcium alginate/poly(vinyl alcohol) hydrogel spheres were formed after contact with the cross-linker solution of calcium chloride, followed by the freeze-thaw method for poly(vinyl alcohol) gel formation. The entrapment of aroma in beads was investigated by FTIR and thermal analysis (thermogravimetry/differential thermal gravimetry; TGA/DTG). The mass loss in the temperature range of 150?C300°C is related to degradation of the matrix and the release of ethyl vanillin. According to the DTG curve, the release of ethyl vanillin occurs at about 260°C. TGA measurements of the stored samples confirmed that formulations were stable for a period of one month. FTIR analysis provides no evidence for chemical interactions between flavour and alginate that would alter the nature of the functional groups in the flavour compound.     

Elucidation of the Mechanism of Enhanced Insulin Uptake and Release from pH Responsive Hydrogels

Summary: Environmentally responsive hydrogels composed of poly(methacrylic acid-g-ethylene glycol) (P(MAA-g-EG)) have shown promise for oral insulin delivery due to their pH responsive complexation behavior. A series of hydrogel formulations were polymerized with varying amounts of crosslinker and varying monomer volume fraction. The mesh size of the network depended primarily on pH, varying from 8.0 to 27.2 nm. Insulin loading efficiency varied directly with crosslink density, ranging from 42.7 to 84.9% of available insulin loaded into the hydrogels. The release of insulin was performed with each polymer formulation at 5 pH levels ranging from 2.7 to 6.8. Insulin release was less than 20% for all formulations tested with insulin for the duration of the 3 hour release study for all pH levels considered except when the pH was 6.8, at which point the release occurred as a burst. Loading studies performed with insulin glargine, an insulin analog with an increased pI, showed the same trends as native insulin. However, the release of insulin glargine only occurred at a pH level above that of the pI of the protein. These results indicate that hydrogen bonds and ionic interactions between the protein and P(MAA-g-EG) may strongly influence its loading and release behavior in vitro.     

Preparation and characterisation of thermoresponsive poly[(N-isopropylacrylamide-co-acrylamide-co-(hydroxyethyl acrylate)] microspheres as a matrix for the pulsed release of drugs

Despite the large number of publications and patents concerning pH/thermoresponsive polymers, few data are available concerning the preparation of thermoresponsive cross-linked microspheres from preformed polymers. Therefore, N-isopropylacrylamide-co-acrylamide-co-(2-hydroxyethyl acrylate) copolymers were obtained as a new thermoresponsive material with a lower critical solution temperature (LCST) around 36 degrees C, in phosphate buffer at pH 7.4, and with a cross-linkable OH group in their structure. The LCST value was determined both by UV spectroscopy and microcalorimetric analysis. These copolymers were solubilised in acidified aqueous solution below their LCST, dispersed in mineral oil, and transformed into stable microspheres by cross-linking with glutaraldehyde. The thermoresponsive microspheres were characterised by optical and scanning electron microscopy, degree of swelling, and water retention. The pore dimensions of the microspheres and the retention volumes of some drugs and typical compounds were evaluated at different temperatures by liquid chromatography. Indomethacin, as a model drug, was included in the microspheres by the solvent evaporation method. Finally, the influence of temperature and of temperature cycling on drug release was investigated.     

Extended release of Gliclazide from highly stabilized calcium alginate/poly(acrylamide) beads for diabetes management

In the present work, stability of calcium alginate beads has been remarkably improved by a novel strategy which consists of in situ formation of poly (acrylamide) within the calcium ions cross-linked sodium alginate beads. The resulting beads have been found to be stable for more than 48 h, in the physiological fluid (PF) of pH 7.4, while the plain alginate beads disintegrated within a couple of hours. The release of the anti-diabetic drug Gliclazide (Glz) from the beads was investigated under physiological conditions. The enhanced stability and prolonged release was also confirmed by an in vivo study on Albino Wistar rats.     

Thermogelling hydrogels of poly(ε-caprolactone-co-D,L-lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-D,L-lactide) and poly(ε-caprolactone-co-L-lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-L-lactide) aqueous solutions

Thermogelling poly(ε-caprolactone-co-D,L -lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-D,L -lactide) and poly(ε-caprolactone-co-L -lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-L -lactide) triblock copolymers were synthesized through the ring-opening polymerization of ε-caprolactone and D,L -lactide or L -lactide in the presence of poly(ethylene glycol). The polymerization reaction was carried out in 1,3,5-trimethylbenzene with Sn(Oct)₂ as the catalyst at various temperatures, and the yields were about 96%. The molecular weights and polydispersities (M_w/M_n) by gel permeation chromatography were in the ranges of 5140–6750 and 1.35–1.45, respectively. The differential scanning calorimetry results showed that the melting temperatures of the poly(ε-caprolactone) components were between 30 and 40 °C. By the subtle tuning of the chemical compositions and microstructures of these triblock copolymers, the aqueous solutions underwent sol–gel transitions as the temperature increased, with the suitable lower critical solution temperature in the range of 17–28 °C at different concentrations. Transesterification in the polymerization process generated the redistribution of sequences, which remarkably affected the sol–gel transition temperature. The amphiphilic copolymers formed micelles in aqueous solutions with a diameter of 62 nm and a critical micelle concentration of about 0.032 wt % at 20 °C. Micelles aggregated as the temperature increased, leading to gel formation. The sol–gel transition was studied, with a focus on the structure–property relationship. It is expected to have potential applications in drug delivery and tissue engineering. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4091–4099, 2007     

Inorganic–organic hybrid alginate beads with LCST near human body temperature for sustained dual‐sensitive drug delivery

In order to obtain dual‐stimuli‐responsive (temperature/pH) alginate beads that exhibit LCST close to human body temperature for sustained drug release applications, poly (NIPAAm‐co‐AAm) hydrogel (with LCST 37.5°C) were selected and associated with calcium alginate to prepare inorganic–organic hybrid biomineralized polysaccharide alginate beads via a one‐step method in this paper. Scanning electron microscopy (SEM) and energy dispersive X‐ray spectrometer (EDS) results demonstrated that calcium phosphate could not only be found in the surface but also in the cross‐section of biomineralized polysaccharide beads. Both equilibrium swelling and indomethacin release behavior were found to be pH‐ and thermo‐responsive. In addition, indomethacin release profile could be sustained with a inorganic–organic hybrid membrane: the release amount reached 96% within 4 hr for the unmineralized beads, while a drug release of only 64% obtained after subjecting the biomineralized polysaccharide beads to the same treatment. These results indicate that the biomineralized polysaccharide membrane could prevent the permeability of the encapsulated drug and reduce the drug release rate effectively. The studied system has the potential to be used as an effective smart sustainable delivery system for biomedical applications. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and characterization of star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties

Star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties were synthesized through the ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate (DTC) initiated by cholic acid with hydroxyl groups. Through the control of the feed ratio of the initiator cholic acid to the monomer DTC, a series of star oligomers/polymers with different molecular weights were obtained. The star oligomers/polymers were characterized with Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, combined size exclusion chromatography/multi‐angle laser light scattering analysis, wide‐angle X‐ray scattering, polarizing light microscopy, and differential scanning calorimetry. Compared with linear poly(2,2‐dimethyltrimethylene carbonate), these star oligo/poly(2,2‐dimethyltrimethylene carbonate)s had much faster hydrolytic degradation rates. With one of the star oligomers/polymers, a microsphere drug‐delivery system of a submicrometer size was fabricated with a very convenient ultrasonic dispersion method that did not involve toxic organic solvents. The in vitro drug release was studied. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6688‐6696, 2006     

Carboxymethyl poly(L‐histidine) as a new pH‐sensitive polypeptide at endosomal/lysosomal pH

A carboxymethyl poly(L ‐histidine) has been synthesized as a new pH‐sensitive polypeptide at endosomal/lysosomal pH. Because of its poor water solubility at physiological pH, an application of poly(L ‐histidine) with a pK_a around 6.0 has been limited in spite of the native possession of the pH‐dependent property change at endosomal pH. Although the unmodified poly(L ‐histidine) suddenly precipitates out of the aqueous medium above pH 6.0 as the result of the deprotonation of the imidazole groups, the water solubility of the resulting carboxymethyl poly(L ‐histidine) has been improved at physiological pH. A solution turbidity measurement proved that no significant effect on a rapid aggregate formation or phase separation of serum proteins is induced by carboxymethyl poly(L ‐histidine). Hemolysis assay showed that the carboxymethyl poly(L ‐histidine) enhances membrane disruptive ability at endosomal/lysosomal pH. The cellular uptake of luciferase in the presence of the carboxymethyl poly(L ‐histidine) increases intracellular luciferase activity, which suggests that the carboxymethyl poly(L ‐histidine) makes the luciferase escape from lysosomal degradation. The carboxymethyl poly(L ‐histidine) would be the fundamental compound for designing various drug carriers with the pH sensitivity at endosomal/lysosomal pH. Copyright © 2007 John Wiley & Sons, Ltd.     

Formulation characterization and in vitro evaluation of acacia gum–calcium alginate beads for oral drug delivery systems

In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross‐linking agent and sodium diclofenac (SD), as a model drug, acacia gum–calcium alginate matrix beads were formulated. The response surface methodology based on 3² factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers‐blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm³), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R_8h,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug‐excipients compatibility by powder X‐ray diffraction, differential scanning calorimetry, thermo‐gravimetric analysis, and Fourier transform‐infrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum–calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD‐loaded beads appears to follow the controlled‐release (Hixson‐Crowell) pattern involving a case‐2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix.     

Temperature-sensitive polyamidoamine dendrimer/poly(N-isopropylacrylamide) hydrogels with improved responsive properties

Novel temperature-sensitive poly(N-isopropylacrylamide)/amine-terminated polyamidoamine dendrimer G6-NH2 hydrogels with fast responsive properties were synthesized by forming semi-interpenetrating polymeric networks. In contrast to the conventional PNIPA hydrogel, these new gels showed rapid shrinking rate at the temperature above lower critical solution temperature (LCST), and exhibited higher equilibrium swelling ratio at room temperature. All these properties might be attributed to the incorporation of polyamidoamine dendrimer G6-NH2, which forms water-releasing channels and increases the hydrophilicity of PNIPA network. The novel hydrogels have potential applications in drug and gene delivery.     

Release of chlorambucil from poly(N-isopropylacrylamide) hydrogels with beta-cyclodextrin moieties

The present work is focused on investigating the behavior of controlled drug release poly(N-isopropylacrylamide) (PNIPA) hydrogels in the presence of beta-cyclodextrin (beta-CD). For this purpose, three types of NIPA hydrogels with beta-CD moieties were synthesized with different architectures according to our previous studies. An anti-cancer drug (chlorambucil, CLB), which can form an inclusion complex with beta-CD, was selected for loading and in vitro release studies. The drug was loaded into hydrogels via a swelling method. DSC was used to study the interactions between the CLB molecules and the polymers. The results indicate that the CLB-polymer interactions are at the molecular level. Loading CLB into these polymers can result in an evident decrease in the glass transition temperature (T(g)), and the variation of T(g) (DeltaT(g)) depends on the structures of the polymers and their beta-CD content. The controlled release experiments show that the presence of beta-CD can markedly enhance CLB release from shrunken PNIPA hydrogels and increase the ratio of CLB released in total drug loading content. Release profile of CLB from hydrogels 1a-c and 4 at pH 1.4 and 7.4, at 37 degrees C.