Preparation and in vitro evaluation of new pH‐sensitive hydrogel beads for oral delivery of protein drugs

New biodegradable pH‐responsive hydrogel beads based on chemically modified chitosan and sodium alginate were prepared and characterized for the controlled release study of protein drugs in the small intestine. The ionotropic gelation reaction was carried out under mild aqueous conditions, which should be appropriate for the retention of the biological activity of an uploaded protein drug. The equilibrium swelling studies were carried out for the hydrogel beads at 37°C in simulated gastric (SGF) and simulated intestinal (SIF) fluids. Bovine serum albumin (BSA), a model for protein drugs was entrapped in the hydrogels and the in vitro drug release profiles were established at 37°C in SGF and SIF. The preliminary investigation of the hydrogel beads prepared in this study showed high entrapment efficiency (up to 97%) and promising release profiles of BSA. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

玉米醇溶蛋白/鱼腥草黄酮复合纳米颗粒的制备及释放特性

为提高鱼腥草黄酮(The flavonoids of Houttuynia cordata,HCF)的稳定性,本研究制备了玉米醇溶蛋白/鱼腥草黄酮复合纳米颗粒(Zein/HCF composite nanoparticles,NZH)并对其进行表征,探究zein、HCF不同质量比对NZH的影响。结果表明,HCF与zein之间存在氢键、疏水及静电相互作用;加入HCF后,NZH熔融温度增加,热稳定性提高。随HCF的增加NZH平均粒径、PDI先减小后增大,zeta电位绝对值先增大后减小。其中,NZH-3(zein:HCF为20:3)的平均粒径、PDI值最小、粒径分布峰最窄、zeta电位绝对值最大,微观结构呈均匀分散的圆球状。HCF的加入使复合纳米颗粒具有较高的DPPH、ABTS自由基清除能力。与游离HCF相比,NZH-3具有较好的热处理保护能力。在模拟消化过程中,NZH-3经胃液消化120 min后HCF释放率仅为22.31%,在肠液消化中出现突释现象,胃肠液消化240 min,HCF释放率达到75.66%。NZH-3在模拟胃肠液中的释放趋势均符合Ritger-Peppas模型,但释放机制不同,胃液中属非Fick扩散机制,肠液中属Fick扩散机制。     

Preparation and properties of core–shell alginate–carboxymethylchitosan hydrogels

BACKGROUND: Hydrogels of alginate (ALG) with partially carboxymethylated chitosan (CMCHI) have been produced for drug delivery, based on the interactions between the negative groups and an ionic crosslinker. In the present work, CMCHI was used to evaluate the influence of amino groups that are positively charged at pH = 4 and 6 on the ALG–CMCHI core–shell hydrogel preparation. An ANOVA statistics tool was used to evaluate the effect of composition, pH and chitosan chemical nature on the morphology and swelling properties of the hydrogels in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). RESULTS: The ALG–CMCHI core–shell hydrogels presented smaller (ca 2.3 µm) and more homogeneous microparticles than those with unmodified chitosan (ca 5.5 µm). The ALG–CMCHI hydrogels showed higher thermal stability and lower degree of swelling in SGF (314%) compared to those with chitosan (708%), since in the former hydrogels the protective layers that surround the particles are negatively charged. CONCLUSION: CMCHI can replace chitosan in the production of core–shell hydrogels with improved properties since the negative charge surrounding the ALG–CMCHI particles favours a lower degree of swelling. The results point out a possible prevention of burst release in SGF, sustaining the swelling ability of the ALG–CMCHI core–shell hydrogels in SIF, promising appropriate drug release. Copyright © 2009 Society of Chemical Industry     

A new photocrosslinkable hydrogel based on a derivative of polyaspartic acid for the controlled release of ketoprofen

A novel photocrosslinkable and pH-sensitive hydrogel used for drug delivery was developed based on polyaspartic acid. Polysuccinimide (PSI) was modified by hydrazine and acryloyl chloride. The unreacted imide rings of PSI were hydrolyzed. Hydrogels were formed by photocrosslinking without any crosslinker or photoinitiator. Products were characterized by FT-IR and solid-state ¹³CNMR analysis. The swelling behaviors of hydrogel in various pH values were studied. Ketoprofen (KP) was chosen as a model drug. Two drug loading methods were compared. The release kinetics of KP was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) at 37 °C. The results showed that drug-loaded hydrogels were resistant to SGF, and hence they could be useful for oral drug delivery. There would be a wide range of applications for controlled drug delivering system.     

3D cubic mesoporous silica microsphere as a carrier for poorly soluble drug carvedilol

The present work was proposed not only to exploit the potential of 3D cage-like mesoporous silica SBA-16 with a well-defined spherical morphology as a carrier for poorly soluble drugs, but also to compare the drug loading and release properties of 3D cubic SBA-16 with that of classic 2D hexagonal MCM-41. SBA-16 microsphere with highly ordered mesostructures was synthesized by a facile method using block co-polymer F127 as template, cetyltrimethylammonium bromide (CTAB) as co-template and tetraethyl orthosilicate (TEOS) as silica source. Carvedilol (CAR), an antihypertensive agent, was used as a model drug and loaded into mesoporous silica via solvent deposition method at drug-silica ratio of 1:3. In vitro dissolution was performed in both simulated intestinal fluid (SIF, pH 6.8) and simulated gastric fluid (SGF, pH 1.2). Of particular interest was that in SIF both MCM-41 and SBA-16 samples exhibited promoted dissolution profile for CAR as compared to its corresponding crystalline form which exhibited poor dissolution behavior. This dissolution-enhancing effect might be due to the non-crystalline state and increased surface area of confined CAR as well as the hydrophilic nature of silica. In comparison with MCM-41, SBA-16 displayed a more rapid release profile in both SIF and SGF, which may be ascribed to the 3D interconnected pore networks and the highly accessible surface areas. The suitability of the utilization of SBA-16 microsphere as carriers will open new avenues for the formulation of poorly soluble drugs.     

Synthesis and characterization of novel pH-, ionic strength and temperature- sensitive hydrogel for insulin delivery

A series of novel silane crosslinked hydrogel was prepared from kappa carrageenan (KC), acrylic acid (AA) using vinyltriethoxysilane (VTESi). Potassium persulphate initiated the grafting and copolymerization reactions between reactants. In addition, the condensation of the hydroxyl groups of KC and VTESi resulted into crosslinking. Novelty of this work is the use of VTESi as crosslinker for such a composition of hydrogel. The structure of prepared hydrogels was characterized by Fourier transform infrared spectroscopy. The analysis of spectra confirmed the presence of feed components in the prepared hydrogels. Thermogravimetric analysis showed an increase in the stability of the hydrogels either having high AA contents or crosslinker amount. The effect of feed components, pH (buffer, non-buffer), electrolytic media and temperature on the swelling behaviour of the hydrogels is reported here.Most promising results with high swelling ratio were observed in hydrogel having low monomeric ratio (KC:AA = 1:7). pH response of this hydrogel in acidic and neutral pH makes it suitable for drug delivery application. Insulin, a protein based drug was selected as a model drug. It requires its delivery in small intestine for proper action; therefore its release behaviour was studied in-vitro in simulated stomach and intestinal fluids. The release profile of insulin showed negligible release in simulated gastric fluid (SGF) and sustained release in simulated intestinal fluid (SIF). The obtained results are in good agreement with the swelling response of this hydrogel. The weak structure of this hydrogel makes it preferable for drug delivery, as it is able to get crumbled after releasing the drug for 6 h at neutral pH.     

Synthesis and evaluation of sucrose‐containing polymeric hydrogels for oral drug delivery

Biodegradable and biocompatible copolymeric hydrogels based on sucrose acrylate, N‐vinyl‐2‐pyrrolidinone, and acrylic acid were designed and synthesized. Because of the growing importance of sugar‐based hydrogels as drug delivery systems, these new pH‐responsive sucrose‐containing copolymeric hydrogels were investigated for oral drug delivery. The sucrose acrylate monomer was synthesized and characterized. The copolymeric hydrogel was synthesized by free‐radical polymerization. Azobisisobutyronitrile (AIBN) was the free‐radical initiator employed and bismethyleneacrylamide (BIS) was the crosslinking agent used for hydrogel preparations. Homopolymeric vinyl pyrrolidone hydrogels were also prepared by the same technique. The hydrogels were characterized by differential scanning calorimetry, thermogravimetric analysis, and scanning electron microscopy. Equilibrium swelling studies were carried out in enzyme‐free simulated gastric and intestinal fluids (SGF and SIF, respectively). These results indicate the pH‐responsive nature of the hydrogels. The gels swelled more in SIF than in SGF. A model drug, propranolol hydrochloride (PPH), was entrapped in these gels and the in vitro release profiles were established separately in both enzyme‐free SGF and enzyme‐free SIF. The drug release was found to be faster in SIF. About 93 and 99% of the entrapped drug was released over a period of 24 h in SGF and SIF, respectively. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 2597–2604, 2002     

Effect of proteolytic enzymes in gastrointestinal fluids on drug release from polyelectrolyte complex microspheres based on partially phosphorylated chitosan

This study investigated the effect of proteolytic enzymes on in vitro release of ibuprofen from phosphorylated chitosan (PCS) microspheres in simulated gastric fluid (SGF) (pH 1.4) and simulated intestinal fluid (SIF) (pH 7.4). To reduce the enzymatic degradability and to enhance the sustained release property, polyelectrolyte complex microspheres based on PCS were developed and characterized. The ibuprofen release from PCS microspheres was found to be sustained more effectively than that from CS microspheres in the medium containing proteolytic enzymes. It was concluded that the PCS microspheres can be used more successfully as sustained oral drug‐delivery vehicles than CS microspheres due to their lesser enzymatic degradability. Copyright © 2004 Society of Chemical Industry     

pH响应性P(AA-co-C8PhEO10Mac) 水凝胶的制备及其对L-抗坏血酸的控释性能

采用自由基交联共聚法合成了具有pH敏感性的水凝胶聚丙烯酸-co-甲基丙烯酸辛基酚聚氧乙烯醚酯〔P(AA-co-C8PhEO10Mac)〕,考察了不同单体配比的水凝胶在不同pH的缓冲溶液中的溶胀性、溶胀动力学和退溶胀动力学。通过浸泡法在水凝胶中载入L-抗坏血酸,初步研究了模拟胃肠液中,凝胶对L-抗坏血酸的释放行为。结果表明,凝胶兼具快速的溶胀和退溶胀速率,良好的pH敏感性等特征;载药凝胶在模拟肠液(SIF,pH=7.4)中对药物的累计释放率明显大于在模拟胃液(SGF,pH=1.4)中的累计释放率,增大丙烯酸的用量使累计释放率先升高后降低。采用滤纸片法研究了甲基丙烯酸辛基酚聚氧乙烯醚酯(C8PhEO10Mac)对大肠杆菌、酿酒酵母的抑制作用,结果显示,在10～50 mmol/L的测试浓度水平,C8PhEO10Mac对二者均无明显的抑制作用。     

Doxorubicin‐loaded poly(butylcyanoacrylate) nanoparticles produced by emulsifier‐free emulsion polymerization

ABSTRACT: Doxorubicin‐loaded poly(butylcyanoacrylate) (PBCA) nanoparticles (NPs) were prepared by an emulsifier‐free emulsion polymerization technique. The pH values of the polymerization medium and the weight ratios of doxorubicin to butylcyanoacrylate had a significant effect on the mean particle size. The particle diameter determined by transmission electron microscopy showed that the nanoparticles were predominantly less than 50 nm. Drug loading and entrapment efficiency increased with increasing pH of the medium. The surface tension of the polymerization media increased with increasing polymerization time and reached a plateau after 4 h. Doxorubicin‐loaded PBCA NPs carried a positive charge, and the zeta potential of drug‐loaded nanoparticles increased with the increase of the polymerization pH. Molecular weight, analyzed by gel permeation chromatography, showed that the nanoparticles mainly consisted of oligomers of PBCA. The release rate of doxorubicin from nanoparticles in biological phosphate buffer was very slow, with a half‐life of 111.43 h. The results indicate that drug‐loaded nanoparticles can be prepared by an emulsifier‐free emulsion polymerization technique and that the resulting nanoparticles might be suitable for targeting drug delivery vehicles for clinical application. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 517–526, 2000     

Structural change and swelling mechanism of pH‐sensitive hydrogels based on chitosan and D,L‐lactic acid

Graft copolymerization of D,L ‐lactic acid (LA) onto chitosan (CS) was attempted without using a catalyst. pH‐sensitive hydrogels were obtained which are based on two different components: a natural polymer and a synthetic polymer. These polyester substituents provide the basis for hydrophobic interactions that contribute to the formation of hydrogels. The swelling mechanisms in enzyme‐free simulated gastric fluid (SGF, pH 2.2) or simulated intestinal fluid (SIF, pH 7.4) at 37°C were investigated. Meanwhile, structural changes of the graft copolymers in the different pH buffers were studied by FTIR, and these are discussed together with the swelling mechanisms. The effect of pH on the water uptake of hydrogel was investigated by using McIlvaine buffer with the same ionic strength. The morphological change of hydrogels in different aqueous solutions is investigated by scanning electron microscopy (SEM). © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 3186–3192, 1999     

Photopolymerized pH‐sensitive semi‐IPN: Synthesis,water uptake analysis,and preliminary drug release study

A series of pH‐sensitive semi‐IPN hydrogels, composed of varying amounts of monomer acrylic acid(AAc), crosslinker N,N′ methylene bisacrylamide, polymer cellulose acetate (CA) were synthesized via photoinitiated polymerization in dimethyl formamide (DMF) medium. The CA/P (AAc) hydrogels were characterized by FTIR, and TG analysis. The equilibrium water uptake data was used to determine various network parameters. For all the samples synthesized, the swelling exponent “n,” initial diffusion coefficient D and average diffusion coefficient D_ave were found to be in the range of 0.51–0.72, 3.16 to 7.14 × 10^?6 cm² min^?1 and 94.16–120.56 cm² min^?1, respectively. The hydrogel demonstrated fair pH‐dependent swelling behavior, with nearly 20% swelling in the medium of pH 1.0 and 615% in the medium of pH 7.4 at 37°C, respectively. The gel showed excellent swelling–deswelling cycles which were interpreted quantitatively by first order kinetic swelling and deswelling models. Finally, the preliminary insulin release study, carried out in the media of varying pH, observed almost 16% release of entrapped drug in the simulating gastric fluid (SGF) of pH 1.0 in first 2 h and nearly 51% in next 6 h in simulating intestinal fluid(SIF) of pH 7.4 at 37°C. POLYM. ENG. SCI., 53:2129–2140, 2013. © 2013 Society of Plastics Engineers     

Degradation of Polymer-Drug Conjugate Nanoparticles Based on Lactic and Itaconic Acid

Tuberculosis (TB) is still a significant threat to human health. A promising solution is engineering nanoparticulate drug carriers to deliver anti-TB molecules. Itaconic acid (ITA) potentially has anti-TB activity; however, its incorporation in nanoparticles (NP) is challenging. Here we show an approach for preparing polymer-ITA conjugate NPs and a methodology for investigating the NP degradation and ITA release mechanism. The conjugate was synthesized by the two-directional growing of polylactic acid (PLA) chains, followed by capping their extremities with ITA. The poly(lactate)-itaconate PLA-ITA was then used to formulate NPs. The degradation and drug release processes of the polymer conjugate NPs were studied qualitatively and quantitatively. The molecular structures of released species were characterized by using liquid NMR spectroscopy and mass spectrometry. We discovered a complex NP hydrolysis process forming diverse oligomers, as well as monomeric lactic acid (LA) and drug ITA. The slow degradation process led to a low release of free drugs, although raising the pH from 5.3 to 7.4 induced a slight increase in the amounts of released products. TEM images showed that bulk erosion is likely to play the primary role in the degradation of PLA-ITA NPs. The overall results and methodology can be of interest for understanding the mechanisms of NP degradation and drug release of this new polymer-drug conjugate system.     

Nanoparticles composed of PLGA and hyperbranched poly (amine-ester) as a drug carrier

A new hyperbranched poly (amine-ester)-poly (lactide-co-glycolide) (HPAE-co-PLGA) copolymer was synthesized by ring-opening polymerization of D, L-lactide, glycolide and a fourth generation branched poly (amine-ester) (HPAE-OHs4) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT-IR, ¹H-NMR (¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Two methods, double emulsion (DE) and nanoprecipitation (NP), were employed to fabricate the polymeric nanoparticles. Isoniazid (INH) was loaded as a model antitubercular drug. Influence of the preparation conditions on the nanoparticles size, encapsulation efficiency and release profile in vitro was investigated. Their entrapment efficiency (EE) to INH could reach 96% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The results showed that the HPAE-co-PLGA copolymer nanoparticles have a promising potential in hydrophilic drug delivery system.     

Spray-dried nanoparticle-loaded pectin microspheres for dexamethasone nasal delivery

Abstract

In this study, we present the development of an innovative dry powder dexamethasone (Dex) nasal delivery system comprising Dex-loaded lipid/alginate nanoparticles incorporated within pectin microspheres (Dex/NPs-loaded pectin microspheres; DNM). DNM microspheres were characterized by the mean diameter of 2.76?±?0.10?µm, zeta-potential of –36.2?±?1.1?mV, and drug loading of 3.3?±?0.3%. The morphology study revealed irregular microsphere surface forming external voids. In contact with simulated nasal fluid, DNM microspheres demonstrated desirable property of moderate swelling and ensured stronger mucoadhesion compared with conventional Dex-loaded pectin microspheres. The strategy of Dex incorporation within the lipid/alginate NPs resulted in prolonged Dex release in relation to Dex being directly entrapped within the conventional pectin microspheres. DNM microspheres showed excellent biocompatibility and rendered Dex permeation across the selected epithelial cell model similar to that of Dex solution. In conclusion, balanced biopharmaceutical properties of the proposed nasal Dex delivery system provides the potential for prolonged contact time with nasal mucosa, prolonged therapeutic effect, and improved patient compliance.     

Irradiated Ch/GG/PVP-based stimuli-responsive hydrogels for controlled drug release

Hydrogels based on gamma (γ) irradiated chitosan (pre-irradiated), guar gum, and polyvinyl pyrrolidone were crosslinked with various concentrations of (3-mercapto propyl)trimethoxysilane and fabricated by solution casting technique for the drug delivery applications. High molecular weight chitosan (Ch) possesses lower solubility and higher viscosity, these problems overcame by γ irradiation, which also generated hydrophilicity and effect of irradiated Ch on controlled drug release was assessed. FTIR analysis showed the development of chemical and physical interactions and confirmed the incorporation of characteristic peaks. SEM micrographs revealed porous structure of the prepared hydrogels. Swelling analysis of the hydrogels was performed in distilled water, buffer, and electrolyte mediums. All the hydrogel samples showed higher swelling at acidic pH and lower swelling at neutral and basic pH. These pH-responsive characteristics made these RCGP hydrogels an important contender for injectable controlled drug release. The ampicillin sodium drug was loaded and in vitro controlled release mechanism was evaluated in the PBS, SIF, and SGF which shown out of all prepared hydrogels (RCGP-1, RCGP-2, and RCGP-3), RCGP-1 has exhibited 87.4% release in PBS and 81.3% in SIF in 180 min.     

Quinone propionic acid‐based redox‐triggered polymer nanoparticles for drug delivery: Computational analysis and in vitro evaluation

Redox‐responsive polymers with pendant quinone propionic acid groups as a redox trigger were optimized by computational modeling to prepare efficient redox‐triggered polymer nanoparticles (NPs) for drug delivery. Lipophilicities at complete reduction of redox‐responsive polymers (<5000 Da) constructed with adipic acid and glutaric acid were remarkably reduced to range from ?6.29 to ?0.39 compared with nonreduced state (18.87–32.46), suggesting substantial polymer solubility reversal in water. Based on this hypothesis, redox‐responsive NPs were prepared from the synthesized polymers with paclitaxel as model cancer drug. The average size of paclitaxel‐loaded NPs was 249.8 nm and their reconstitutions were stable over eight weeks. In vitro drug release profiles demonstrated the NPs to release >80% of paclitaxel over 24 h at a simulated redox‐state compared with 26.5 to 41.2% release from the control. Cell viability studies revealed that the polymer was nontoxic and the NPs could release paclitaxel to suppress breast cancer cell growth. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40461.     

Preparation of Poly (methacrylic acid)–Graphene Oxide Nanocomposite as a pH-Sensitive Drug Carrier Through in-situ Copolymerization of Methacrylic Acid with Polymerizable Graphene

A polymerizable Graphene Oxide (Graphene Oxide Monomer, GOM) was synthesized through attaching vinyl groups onto graphene oxide sheets. GOM was copolymeized with methacrylic acid in different ratios. Obtained nanocomposites were characterized by FT-IR, XRD, SEM and EDX to study their properties. Naproxen was entrapped in these pH-sensitive nano-carriers and the in vitro release profiles were established in both enzyme-free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4) respectively. It was observed that the drug release in SIF was higher, hence the prepared nanocomposite could be considered as a suitable carrier for colon specific drug delivery.     

A nanoparticulate raloxifene delivery system based on biodegradable carboxylated polyurethane: Design,optimization, characterization,and in vitro evaluation

Biodegradable carboxylated polyurethanes with three molecular weights were synthesized to prepare a nanoparticulate sustained delivery system of raloxifene hydrochloride, the drug with poor bioavailability. The nanoparticles were prepared by coprecipitation method. Optimal conditions for the preparation of nanoparticles were obtained using Box–Behnken design. Independent factors were ratio of polymer to drug, M_w of polymer and speed of magnetic stirrer. Dependent variables include zeta potential, polydispersity index (PdI), particle size, and loading efficacy (LE). Results of the fractional factorial design based on an analysis of variance demonstrated that the model for particle size, zeta potential, PdI and loading efficacy was statistically significant. The size of nanoparticles in design experiments were 46–96 nm in diameter and had entrapment efficiency of 84–92%. The nanoparticles were evaluated for in vitro release and showed a sustained release profile (24.19% ± 4.35% after 4 weeks), following the Fickian diffusion‐based release mechanism. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39668.     

Synthesis of Grafted Hydrogels as Mono-Divalent Cation Exchange for Drug Delivery

pH-sensitive acrylic acid grafted polyvinylalcohol (AAc-g-PVA) hydrogels has been prepared by gamma irradiation. The maximum grafting yield was at monomer concentration 50% and dose 50 kGy. The swelling, network parameters, thermogravimetric analysis, activation energy and scanning electron microscope of the grafted hydrogels were evaluated. Hydrogel demonstrate high swelling at pH 6.8. The deswelling of the swollen gel in Ni²⁺ and Cu²⁺ cations solution was explained on the basis of mono-divalent cation exchange. The release of antihistaminic chlorphenamine maleate hydrochloride (CPM) was faster in gastric fluid (SGF) of pH 1.1 than in intestinal fluid (SIF) of pH 6.8.