pH响应性可控释放材料

智能可控释放材料由于具有多种潜在的用途而引起广泛关注.其中,具有pH响应性的可控释放材料被认为是较易获得并对外界环境刺激响应较敏感的一类智能响应性材料.本文综述了具有不同结构的pH响应性可控释放材料的研究进展,包括pH响应性微胶囊、pH响应性聚合物微球、pH响应性水凝胶、pH响应性介孔材料的制备、可控释放作用及其应用.     

内盐凝胶的制备及对烟酰胺的控释

以甲基丙烯酸二甲基氨基乙酯(DMAE-MA)、衣康酸(IA)、亚甲基双丙基酰胺(BIS)和过硫酸钾(KPS)为原料在室温下制备内盐凝胶。研究了原料配方对凝胶形成的影响、内盐凝胶的吸水动力学及溶胀机制、凝胶的pH值敏感性以及对烟酰胺的负载与负载凝胶在不同pH值介质中的释放行为,并用红外光谱对凝胶结构进行了表征。结果表明,n(IA)/n(DMAEMA)>1后将降低单体的转化率,不利于凝胶的形成;内盐凝胶不具有高吸水性,其吸水溶胀机制符合Fickian扩散;在pH值为12的缓冲溶液中溶胀率比在pH值为3的缓冲溶液中高;凝胶对烟酰胺的负载率可以超过200%。在25℃下,烟酰胺在pH值为3的介质中释放比在pH值为12的介质中释放快。     

pH敏感性壳聚糖/聚乙烯醇水凝胶的制备及其性能研究

制备了pH敏感性壳聚糖/聚乙烯醇(CS-PVA)水凝胶,研究了该水凝胶在室温下不同pH值介质中的溶胀比。发现在酸性溶液中,凝胶的溶胀比远大于在碱性溶液中的溶胀比,且其在不同pH值溶液中具有可逆溶胀-收缩行为,对药物氟哌酸具有缓释效果。     

pH-sensitive sodium alginate/calcined hydrotalcite hybrid beads for controlled release of diclofenac sodium

Objective: The aim of this study was to prepare pH-sensitive sodium alginate/calcined hydrotalcite (SA/CHT) hybrid bead with improved the burst release effect of the drug.

Materials and methods: A series of pH-sensitive SA/CHT hybrid beads were prepared by using Ca²⁺ cross-linking in the presence of diclofenac sodium (DS) and SA. The structure and drug loading of the beads were characterized by Fourier transform infrared spectroscopy and X-ray diffraction. The swelling and the drug release of the fabricated beads were investigated by the pH of test medium and CHT content.

Result: The formed positively charged hydrotalcite layers were adsorbed on the negatively charged SA polymer chains through electrostatic interaction and act as inorganic cross-linkers in the three-dimensional network. Compared to pure SA beads, the incorporation of CHT enhanced the drug encapsulation efficiency, improved the swelling behaviors and slowed the drug release from the hybrid beads.

Discussion and conclusions: The electrostatic interaction between hydrotalcite and SA has restricted the movability of the SA polymer chains, and then slowed down swelling and dissolution rates in aqueous solutions. The results provided a simple method to moderate drug release and matrix degradation of the SA beads.     

包覆型高铁酸钾缓释剂的制备及性能表征

以切片石蜡为包覆壁材,以高铁酸钾为芯材,采用熔化悬浮冷凝法制得包覆型高铁酸钾。实验结果表明：分散方式对包覆率的影响很大,当搅拌速度为800r／min,超声时间为30min时,包覆率可达到85.5％;采用红外光谱、X射线衍射和扫描电镜对包覆后的产品进行了性能表征,结果发现,切片石蜡对高铁酸钾的包覆并没有破坏高铁酸钾的组分活性,包覆后高铁酸钾的缓释符合Q=kt^n动力学模型,而且持续缓释性能良好,切片石蜡与高铁酸钾质量比为3：1、5：1和10：1的包覆产品的理论缓释半衰期分别可达到7.5天、2.6月和17.0年。     

Swelling and aspirin release study: cross-linked pH-sensitive vinyl acetate-co-acrylic acid (VAC-co-AA) hydrogels

The objective of this work was to develop new pH-sensitive hydrogels to deliver gastric mucosal irritating drugs to the lower part of the gastrointestinal tract. For this purpose, cross-linked vinyl acetate-co-acrylic acid (VAC-co-AA) hydrogels were synthesized by using N, N, methylene bisacrylamide (MBAAm) as a cross-linking agent. Different ratios of 90:10, 70:30, 50:50, 30:70, and 10:90 of VAC-co-AA were synthesized. All of the compositions were cross-linked using 0.15, 0.30, 0.45, and 0.60 mol percent MBAAm. Swelling and aspirin release were studied for 8 hour period. The drug release data were fitted into various kinetic models like the zero-order, first-order, Higuchi, and Peppas. Hydrogels were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. In addition to the above, these hydrogels were loaded with 2%, 8% and 14% w/v aspirin solutions, keeping the monomeric composition and degree of cross-linking constant. In conclusion, it can be said that aspirin can be successfully incorporated into cross-linked VAC/AA hydrogels and its swelling and drug release can be modulated by changing the mole fraction of the acid component in the gels.     

Synthesis and characterization of poly(N-vinylcaprolactam)-based spray-dried microparticles exhibiting temperature and pH-sensitive properties for controlled release of ketoprofen

Poly(N-vinylcaprolactam) (PNVCL) and poly(N-vinylcaprolactam-co-acrylic acid) (poly(NVCL-co-AA)) were synthesized by solution-free radical polymerization and displayed thermo-responsive behavior, with lower critical solution temperatures (LCSTs) of 35?°C and 39?°C, respectively. The incorporation of AA unities made the poly(NVCL-co-AA) sensitive to both pH and temperature. They were exploited in this work in preparing microparticles loaded with ketoprofen via spray-drying to modulate the drug release rate by changing pH or temperature. The interaction between polymer and drug was studied using X-ray diffractometry, Raman spectrometry and scanning electron microscopy (SEM). The biocompatibility of pure polymers, free ketoprofen as well as the spray-dried particles was demonstrated in vitro by low cytotoxicity and a lack of nitric oxide production in macrophages at concentrations as high as 100?µg/ml. The release profile of ketoprofen was evaluated by in vitro assays at different temperatures and pH values. Drug diffusion out of PNVCL’s hydrated polymer network is increased at temperatures below the LCST. However, when poly(NVCL-co-AA) was used as the matrix, the release of ketoprofen was primarily controlled by the pH of the medium. These results indicated that PNVCL and the novel poly(NVCL-co-AA) could be promising candidates for pH and temperature-responsive drug delivery systems.     

pH-sensitive hydrogels based on semi-interpenetrating network (semi-IPN) of chitosan and polyvinyl pyrrolidone for clarithromycin release

The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for clarithromycin. The hydrogels were synthesized by cross-linking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). These semi-IPNs were studied for their content uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release and their release kinetics. The hydrogels showed more than 97% content of clarithromycin. These hydrogels showed high swelling and mucoadhesion under acidic conditions. The swelling may be due to the protonation of a primary amino group on chitosan. In acidic condition, chitosan would be ionized, and adhesion could have occurred between the positively charged chitosan and the negatively charged mucus. In the alkaline condition, less swelling and mucoadhesion was noticed. In vitro release study revealed that formulation containing chitosan (2% w/v) and PVP (4% w/v) in the ratio of 21:4 showed complete drug release after 12?h. Release profile showed that all the formulations followed non-Fickian diffusion mechanism. The cross-linking and compatibility of clarithromycin in the formulation was studied by Fourier transform infrared (FTIR) spectroscopic analysis, differential scanning calorimetry (DSC) and powder X-ray diffraction (p-XRD) study, which confirmed proper formation of semi-IPN and stability of clarithromycin in the formulations. The surface morphology of semi-IPN was studied before and after dissolution in simulated gastric fluid (SGF, pH 1.2) which revealed pores formation in membrane after dissolution. The results of study suggest that semi-IPNs of chitosan/PVP are potent candidates for delivery of clarithromycin in acidic environment.     

pH-sensitive hydrogels based on semi-interpenetrating network (semi-IPN) of chitosan and polyvinyl pyrrolidone for clarithromycin release

The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for clarithromycin. The hydrogels were synthesized by cross-linking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). These semi-IPNs were studied for their content uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release and their release kinetics. The hydrogels showed more than 97% content of clarithromycin. These hydrogels showed high swelling and mucoadhesion under acidic conditions. The swelling may be due to the protonation of a primary amino group on chitosan. In acidic condition, chitosan would be ionized, and adhesion could have occurred between the positively charged chitosan and the negatively charged mucus. In the alkaline condition, less swelling and mucoadhesion was noticed. In vitro release study revealed that formulation containing chitosan (2% w/v) and PVP (4% w/v) in the ratio of 21:4 showed complete drug release after 12 h. Release profile showed that all the formulations followed non-Fickian diffusion mechanism. The cross-linking and compatibility of clarithromycin in the formulation was studied by Fourier transform infrared (FTIR) spectroscopic analysis, differential scanning calorimetry (DSC) and powder X-ray diffraction (p-XRD) study, which confirmed proper formation of semi-IPN and stability of clarithromycin in the formulations. The surface morphology of semi-IPN was studied before and after dissolution in simulated gastric fluid (SGF, pH 1.2) which revealed pores formation in membrane after dissolution. The results of study suggest that semi-IPNs of chitosan/PVP are potent candidates for delivery of clarithromycin in acidic environment.     

Preparation and characterization of pH-sensitive vesicles made of cholesteryl hemisuccinate

pH-sensitive vesicles are designed to promote efficient release of entrapped agents in response to low pH. In this study, such vesicles were prepared from cholesteryl hemisuccinate (CHEMS) in Tris-HCl buffer. Vesicles prepared by this direct hydration method had a small particle size of 74.1 nm based on intensity of Gaussian and a size of 65.8 nm based on volume of Gaussian. The mean zeta potential was about -73mV, indicating that the vesicle system was stable. Entrapment efficiency for calcein by these vesicles was measured at 37 ± 2.36%, which is higher than that by phospholipid MLVs. These calcein loaded vesicles exhibited excellent stability at pH 7.4 and underwent rapid destabilization upon acidification as showed by calcein release. However these vesicles were unstable in Fetal Bovine Serum (FBS). Optimization of formulation might improve their stability in serum.     

Sorption of zinc by novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid

Novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid were applied as adsorbents for the removal of Zn²⁺ ions from aqueous solution. In batch tests, the influence of solution pH, contact time, initial metal ion concentration and temperature was examined. The sorption was found pH dependent, pH 5.5 being the optimum value. The adsorption process was well described by the pseudo-second order kinetic. The hydrogels were characterized by spectral (Fourier transform infrared—FTIR) and structural (SEM/EDX and atomic force microscopy—AFM) analyses. The surface topography changes were observed by atomic force microscopy, while the changes in surface composition were detected using phase imaging AFM. The negative values of free energy and enthalpy indicated that the adsorption is spontaneous and exothermic one. The best fitting isotherms were Langmuir and Redlich-Peterson and it was found that both linear and nonlinear methods were appropriate for obtaining the isotherm parameters. However, the increase of temperature leads to higher adsorption capacity, since swelling degree increased with temperature.     

Preparation and characterization of curcumin thermosensitive hydrogels for intratumoral injection treatment

Objectives: This paper describes the development and optimization of curcumin thermosensitive hydrogels (CTH), a kind of gel injection for intratumoral injection treatment.

Methods: Aimed at increasing the content and stability of effective components, an optimal formulation of CTH was chosen based on the results from orthogonal tests and the optimal pH was determined by stability test. To investigate the hydrogels drug release in vitro, residence time by RP-HPLC and therapeutic effects on ascitic hepatocarcinoma cell strain with high metastasis potential in lymphatic system (HCA-F) solid tumors in mice.

Key findings: The selected optimal formulation of CTH was: 0.2% curcumin, 20% poloxamer 407, 4% poloxamer 188, 8% polyethylene glycol 400, 12% 1,2-propanediol and pH was 6.0. The drug release determined by RP-HPLC fit to the Higuchi model. The residence time of CTH was longer than the curcumin suspensions. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice.

Conclusions: The CTH prepared in this test demonstrates proper gel temperature and viscosity. It improves the solubility of curcumin with a relatively long period of drug release in vitro and residence time. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice.     

Preparation and characterization of pH sensitive comb-shaped chitosan material for the controlled release of coenzyme A

A novel kind of pH sensitive comb-shaped copolymer P(CS-Ma-PEGMA) was synthesized with chitosan (CS), maleic anhydride (Ma) and Poly (ethylene glycol) methacrylate (PEGMA) by grafting and co-polymerization. The structure of P(CS-Ma-PEGMA) was characterized by FT-IR and ¹H-NMR, and it was found that PEGMA was grafted onto CS and PEGMAylated chitosan was soluble. The copolymer was subjected to coenzyme A adsorption study in order to assess its application in biomedical area. The factors affecting release behavior, such as concentration and pH were discussed in this paper. The higher concentration of the copolymer showed higher absorbance peak than the lower one. The pH of the solution also had significant impact on the release of coenzyme A, and the mechanism of adsorption was suggested. The results suggested that the novel copolymer could be used as drug delivery carrier.     

New cellulose-lignin hydrogels and their application in controlled release of polyphenols

Novel superabsorbant cellulose-lignin hydrogels (CL) were prepared by a new two-step procedure consisting in dissolving cellulose in an alkaline solution with further mixing with lignin, followed by the chemical crosslinking with epichlorohydrin. The crosslinking occurrence was verified by Fourier Transform Infrared spectroscopy (FT-IR). The effect of the structure features of cellulose-lignin hydrogels on their dehydration heat was evaluated by Differential Scanning Calorimetry (DSC). The Scanning Electron Microscopy (SEM) images reveal some morphological aspects of the hydrogels. The degree as well as the rate of swelling in a mixture of water:ethanol = 19:1 were estimated. The possible application of these hydrogels as controlled release systems was tested. Polyphenols known as having a wide range of biological effects were selected to be incorporated in such hydrogels by an optimal procedure. The extract of grapes seeds from the Chambourcin type was used as a source of polyphenols (PF). The amount of the incorporated polyphenols was estimated by UV-VIS measurements. Characterization of the hydrogels containing polyphenols was performed by FTIR spectroscopy. Some parameters were estimated based on the registered spectra, as H-bond energy (E_H), the asymmetric index (a/b) and the enthalpy of H-bond formation (ΔH). The modifications of the thermal behavior and morphology induced by the presence of the polyphenols in hydrogels were highlighted by DSC and SEM, respectively. The release of polyphenols from CL hydrogels depended on the lignin content from matrices, as assessed by spectral studies. Both loading with polyphenols and their release can be controlled by the composition of the hydrogels. The kinetic of polyphenols release was studied.     

Temperature-triggered gelation and controlled drug release via NIPAAm/NVP-based hydrogels

Novel physically crosslinked hydrogels based on N-isopropylacrylamide and 1-vinyl-2-pyrrolidinone were synthesised using photopolymerisation. The gelation behaviour of the copolymers was investigated using modulated differential scanning calorimetry, oscillatory rheological analysis and the test tube inversion method. A number of the samples gelled spontaneously under physiological conditions and importantly did not undergo syneresis within the desired temperature window. Two active pharmaceutical ingredients (APIs), diclofenac sodium and procaine hydrochloride, were entrapped within the thermogelling materials by increasing external test temperature. The temperature-triggered gelation of the copolymer gels was used as a means of controlling the release of the APIs, and was found to retard the dissolution rate significantly.     

Preparation and characterization of amidated pectin based hydrogels for drug delivery system

In the current studies attempts were made to prepare hydrogels by chemical modification of pectin with ethanolamine (EA) in different proportions. Chemically modified pectin products were crosslinked with glutaraldehyde reagent for preparing hydrogels. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), organic elemental analysis, X-ray diffraction studies (XRD), swelling studies, biocompatibility and hemocompatibility studies. Mechanical properties of the prepared hydrogels were evaluated by tensile test. The hydrogels were loaded with salicylic acid (used as a model drug) and drug release studies were done in a modified Franz’s diffusion cell. FTIR spectroscopy indicated the presence of primary and secondary amide absorption bands. XRD studies indicated increase in crystallinity in the hydrogels as compared to unmodified pectin. The degree of amidation (D _A) and molar and mass reaction yields (Y _M and Y _N) was calculated based on the results of organic elemental analysis. The hydrogels showed good water holding properties and were found to be compatible with B-16 melanoma cells & human blood.     

共聚物水凝胶温度及pH敏感行为的研究

用自由基聚合法合成了NVP／HEMA和NVP／HEMA／AAm共聚物水凝胶材料,研究了温度、pH值、离子强度等因素对凝胶溶胀性能的影响。结果表明水凝胶的溶胀度随着温度的升高而减少;水凝胶在酸性溶液中溶胀,在碱性溶液中收缩,显现出良好的pH值敏感性;水凝胶的溶胀度随着离子强度的增加而减少。     

Preparation and characterization of thermoresponsive poly(N-isopropylacrylamide-co-acrylic acid) hydrogels: studies with electroactive probes

A new method of preparing thermoresponsive hydrogels consisting of N-isopropylacrylamide (NIPA) and acrylic acid (AA), with a well-defined concentration of an electroactive probe, 1,1'-ferrocenedimethanol (Fc(MeOH)2), is described, and a comparison of the physical and electrochemical properties of NIPA-AA gels with those of aqueous solutions is presented. The NIPA-AA gels undergo a discontinuous volume phase transition at 45 degrees C; this transition results in a release of approximately 40% of the solution mass from the gel phase. Characterization of hydrogels with electroactive probes is performed using electroanalytical techniques and FTIR and UV/vis spectroscopies. Steady-state voltammetry and chronoamperometry at platinum disk microelectrodes are used to measure the diffusion coefficient of Fc(MeOH)2 in gels under a wide range of experimental conditions. Similar diffusion coefficients for Fc(MeOH)2 in NIPA-AA gels are obtained by either electroanalytical technique at temperatures lower than 20 degrees C. The uncertainty in the Fc(MeOH)2 concentration in the gels, resulting from the discontinuous volume change transition, necessitated the use of concentration-independent chronoamperometric data (i.e. the chronoamperometric response divided by the steady-state current obtained at sufficiently long times) to obtain reliable diffusion coefficient values for Fc(MeOH)2. For temperatures above the volume phase transition, changes of concentration of Fc(MeOH)2 are detected in a copolymeric collapsed phase.