Development of a pH-responsive imprinted polymer for diclofenac and study of its binding properties in organic and aqueous media

Three different molecularly imprinted polymers (MIPs) for drug delivery of diclofenac in gastrointestinal tract were synthesized employing bulk polymerization method and their binding and release properties were studied in different pH values. Methacrylic acid (MAA), methacrylamide (MAAM) and 4-vinyl pyridine (4VP) were tested as functional monomers and ethylene glycole dimethacrylate (EDMA) was used as a cross-linker monomer in polymeric feed. Binding properties and imprinting factor (IF) of MIPs were studied in comparison with their non-imprinted ones (Blank) in organic and aqueous media. Diclofenac release in aqueous solvents at pH values of 1.5, 6.0 and 8.0, simulating gastrointestinal fluids, were also studied. The results indicated the specific binding of diclofenac to imprinted polymers. Duo to the stronger non-specific bounds in aqueous solutions, IF values decreased in water compared to acetonitrile as an organic medium. Our results proved that all polymers represented pH-responsive diclofenac delivery at above conditions. The data showed that imprinted polymer, prepared by MAA had superior properties, in comparison with other polymers, for minimum release (14%) of drug in gastric acid and maximum release (90%) in basic condition. The results indicated that diclofenac imprinted polymer could be used as a pH-responsive matrix in preparation of a new drug delivery system for diclofenac.     

Development of molecularly imprinted polymer as sustain release drug carrier for propranolol HCL

Applications of molecularly imprinted polymer (MIPs), is rapidly increasing, especially in the drug delivery field. Molecularly imprinted polymers are the molecular traps, which can entrap the specific molecule and also control its release. Polymer complexes were prepared with and without propranolol HCl as templates, MAA (methacrylic acid) as monomer and EGDMA (ethyleneglycol dimethacrylate) as crosslinker by solvent polymerization technique. Drug release pattern from these polymer complexes were compared and maximum drug release in 12?h was consider to optimize the ratio of MAA and EGDMA. Since, the maximum propranolol HCl release from polymer complex was low (62.15%) in optimized batch, inclusion complex of drug with β-cyclodextrin were prepared for the higher drug release (80.32%). The selected polymer complexes were treated with methanol for complete removal of the drug to form MIPs. These MIPs were reloaded with the drug and subjected for drug release. The release patterns from reloaded MIP’s were observed to be slightly quicker than their corresponding MIP’s.     

Development and characterization of molecularly imprinted polymers for controlled release of citalopram

In this work, the use of molecularly imprinted polymers (MIPs) for citalolpram as anti-depressant drug was studied. Imprinted polymers were prepared from methacrylic acid (MAA; functional monomer), ethylene glycol dimethacrylate (EGDMA; cross-linker), and citalopram (as a drug template) using bulk polymerization method. The polymeric devices were further characterized by FT-IR, thermogravimetric analysis, scanning electron microscopy, and binding experiments. The dissolution media employed in controlled release studies were hydrochloric acid at the pH level of 4.3 and phosphate buffers, at pH levels of 7.2 and 10.1, maintained at 37.0 and 25.0 ± 0.5°C. Results showed the ability of MIP polymers to control the release of citalopram. In all cases, the imprinted polymers showed a higher affinity for citalopram and a slower release rate than the nonimprinted polymers. At the pH level of 4.3 and at the temperature of 25°C, slower release of citalopram imprinted polymer occurred.     

Synthesis and characterization of paclitaxel-imprinted nanoparticles for recognition and controlled release of an anticancer drug

Imprinted nanoparticles as drug delivery carriers have been considered because owing to their cross-linked network, they act as the drug reservoir for controlled release. In this study, selective MIPs nanoparticles of paclitaxel (PTX) were successfully developed for application in the biological molecular recognition and in the design of new anticancer drug delivery systems. The MIPs nanoparticles prepared by miniemulsion polymerization technique using methacrylic acid (MAA) and methyl methacrylate as non-covalent functional monomer, ethylene glycol dimethacrylate and trimethylolpropane trimethacrylate (TRIM) as cross-linker agent, azobisisobutyronitrile as initiator, and hexadecane as hydrophobic agent. In order to prepare of MIP nanoparticles, the synthesis conditions and effective parameters, such as: cross-linker agent, different molar ratios of template–functional monomer–cross-linker agent, were investigated. In addition, the effect of different molar ratios of template and monomers on polymers binding and morphology were characterized. Structure and thermal properties of MIPs were confirmed by FT-IR spectroscopy and thermogravimetric analysis. Imprinted nanoparticles showed significant drug loading and encapsulation efficiency, 17.8 and 100 %, respectively. The particle size of MIP nanoparticles varies between 187 and 726 nm, according the SEM images and laser light scattering data. The imprinted nanoparticles showed satisfactory affinity (84 %) to PTX with a binding of 12 times higher than non-imprinted nanoparticles in biological samples when MAA and TRIM were used as functional and cross-linker monomer, respectively. Results from release experiments of MIPs showed a very slow and controlled release of PTX which would be helpful for sustained drug delivery.     

Dipyridamole recognition and controlled release by uniformly sized molecularly imprinted nanospheres

We used novel synthetic conditions of precipitation polymerization to obtain uniformly sized molecularly imprinted nanospheres of dipyridamole for application in the design of new drug delivery systems. In addition, the morphology, drug release, and binding properties of molecularly imprinted polymers (MIPs) were studied, and the effects of morphology on other properties were investigated. The MIPs prepared by acetonitrile/chloroform (19:1, v/v) were uniformly sized nanospheres with an average mean diameter of approximately 88 nm at a wetted state, 50 nm at a dry state, and a polydispersity index of 0.062. The imprinted nanospheres showed excellent binding properties and had 62.7% of template binding compared with 17.1% of its blank polymer. The imprinted nanospheres with 67.5 (mg template/of polymer) of binding capacity had better imprinting efficiency than the 50.5% of binding capacity shown by irregularly shaped MIP particles that were prepared by chloroform. The molecular binding abilities of imprinted nanospheres in human serum were evaluated by HPLC analysis (binding about 77% of dipyridamole). Results from release experiments of MIPs showed a very slow, controlled, and satisfactory release of dipyridamole. The loaded drug was released up to 99% in 17 days for nanospheres and 22 days for irregularly shaped particles.     

阿司匹林表面印迹微球的制备与药物缓释性能评价

采用表面印迹技术,选取γ-氨丙基三甲氧基硅烷(APTS)和甲基丙烯酰氯修饰的硅胶为载体,以阿司匹林(Asp)为模板分子,丙烯酰胺(AM)为功能单体,乙二醇二甲基丙烯酸酯(EDGMA)为交联剂,在乙腈溶液中合成了阿司匹林表面分子印迹聚合物微球(MIPs)和非印迹聚合物微球(NIPs)。通过紫外、红外光谱、扫描电镜、透射电镜、热重分析以及吸附实验进行了表征并进行了药物扩散实验。结果表明,MIPs平衡吸附量可达164.40μmol/g,对苯甲酸(BA)和水杨酸(SA)的分离因子达到3.15和3.32,有很好的热稳定性和选择性吸附能力;MIPs持续释药时间是NIPs的2.6倍,有很好的缓释效果和应用价值。     

Effect of Poly (Ethylene Glycol) Molecular Weight and Microparticle Size on Oral Insulin Delivery from P(MAA‐g‐EG) Microparticles

Five years of successful work in our lab have shown that graft copolymer networks of poly(methacrylic acid‐g‐ethylene) [P(MAA‐g‐EG)], are very promising candidates for oral drug delivery. In an acidic environment, these copolymers form interpolymer complexes, protecting the active agent from the harsh environment of the gastrointestinal tract. At high pH, these complexes dissociate, causing the polymer to swell and release the drug. Films of P(MAA‐g‐EG) with a monomer ratio of 1:1 (MAA:EG) were prepared by free radical solution UV‐polymerization, washed in order to remove the unreacted monomer, and crushed to form microparticles with different particle size distribution. Previous studies in our lab have focused on using polymer disks in their swelling studies. The swelling properties of polymer disks vs. crushed particles were investigated via equilibrium swelling experiments in this study. Another goal in this study is to compare different PEG chain length (MW‐400 and MW‐1000) and different particle size (150–212 microns, 90–150 microns and 25–90 microns) in their loading and release behavior. After 6 hours of exposing the polymer with the insulin solution we achieved approximately 90% of insulin loading.     

Exploiting β-cyclodextrin as functional monomer in molecular imprinting for achieving recognition in aqueous media

A series of molecularly imprinted polymers (MIPs) for 4,4′-(1,4-phenylenediisopropylidene)bisphenol (BPP) were prepared by using β-cyclodextrin (β-CD) as functional monomer, toluene 2,4-diisocyanate (TDI) or 4,4′-Diphenylmethane diisocyanate (DDI) as the cross-linker. The results of binding experiments showed that the MIPs can bind the template selectively in aqueous media. The binding specificity mechanism of the polymers was investigated in detail. The template molecule is too large and cannot be included in the cavity of one β-CD molecule. The mutual orientation of β-CD molecules in the imprinted polymers is regulated by molecular imprinting, so that they can cooperatively bind the template molecule. It is suggested that the major contribution to the recognition ability of the imprinted polymer was the stereo-shape effect inherent in the MIPs. The study indicated that hydrophobic effects play an important role in the recognition process.     

Biopharmaceutical evaluation of diclofenac sodium controlled release tablets prepared from gum karaya--chitosan polyelectrolyte complexes

The phenomena of polymer interactions and formation of polyelectrolyte complexes (PECs) of oppositely charged polymers have been the focus of interest in fundamental and applied research. Such PECs may possess unique properties that are different from those of individual polymers. In the present study, attempts were made to prepare PECs of negative colloid gum karaya (GK) and positively charged polysaccharide chitosan (CH). The association and factors affecting the interactions between GK and CH were studied by pH and conductivity studies. The dried complexes were characterized by X-ray diffraction, Fourier transformed Infrared (FTIR) Spectroscopy, Scanning Electron Microscopy. The PECs were utilized for encapsulation of diclofenac sodium. Selected polyelectrolyte microparticles were compressed into tablets and were compared with commercial sustained release product Voveran SR?. Positive results of the study indicated the applicability of PECs in the design of oral controlled release drug delivery systems.     

Effect of poly (ethylene glycol) molecular weight and microparticle size on oral insulin delivery from P(MAA-g-EG) microparticles

Five years of successful work in our lab have shown that graft copolymer networks of poly(methacrylic acid-g-ethylene) [P(MAA-g-EG)], are very promising candidates for oral drug delivery. In an acidic environment, these copolymers form interpolymer complexes, protecting the active agent from the harsh environment of the gastrointestinal tract. At high pH, these complexes dissociate, causing the polymer to swell and release the drug. Films of P(MAA-g-EG) with a monomer ratio of 1:1 (MAA:EG) were prepared by free radical solution UV-polymerization, washed in order to remove the unreacted monomer, and crushed to form microparticles with different particle size distribution. Previous studies in our lab have focused on using polymer disks in their swelling studies. The swelling properties of polymer disks vs. crushed particles were investigated via equilibrium swelling experiments in this study. Another goal in this study is to compare different PEG chain length (MW-400 and MW-1000) and different particle size (150-212 microns, 90-150 microns and 25-90 microns) in their loading and release behavior. After 6 hours of exposing the polymer with the insulin solution we achieved approximately 90% of insulin loading.     

Removal and destruction of endocrine disrupting contaminants by adsorption with molecularly imprinted polymers followed by simultaneous extraction and phototreatment

This study presents a method to regenerate molecularly imprinted polymers (MIPs) used for the selective removal of endocrine disrupting compounds from aqueous effluents. Regeneration was based on solvent extraction under UV irradiation to regenerate the polymer and the solvent while destroying the contaminants. Acetone was selected as the best solvent for irradiation of estrone (E1), 17beta-estradiol (E2) and ethinylestradiol (EE2) using either UVC (254 nm) or UV-vis. A MIP synthesized with E2 as template was then tested for the extraction of this compound from a 2 microg/L loaded aqueous solution. E2 was recovered by 73+/-11% and 46+/-13% from the MIPs and a non-imprinted control polymer synthesized under the same conditions, respectively, after a single step elution with acetone. The irradiated polymers and acetone were reused for an additional extraction-regeneration cycle and showed no capacity decrease.     

Extraction and purification of penicillin G from fermentation broth by water-compatible molecularly imprinted polymers

Highly selective molecularly imprinted polymer (MIP) was synthesized by using methacrylic acid as functional monomer, trimethylolpropane trimethacrylate as cross-linker, chloroform as porogen and penicillin G potassium as template molecule. These imprinted polymers were used as solid-phase extraction sorbent for the selective extraction of penicillin G from the fermentation broth samples. Various parameters affecting the extraction efficiency of the MIP particles such as; effects of pH, wash and eluent solutions were evaluated. Molecular recognition properties and selectivity of these MIPs were estimated and the obtained results revealed high affinity for the target antibiotic. Equilibrium binding experiments were done to assess the performance of the MIP relative to non imprinted polymer (NIP). After optimizing the extraction parameters in molecularly imprinted solid-phase extraction (MISPE), successful imprinting was confirmed by comparison of the recoveries from the fermentation broth, ranging between 24–26% (RSD 4.1–4.5%, n = 4) for the NIPs and 83–88% (RSD 3.1–3.4%, n = 4) for the MIPs.     

Hydrogels Formed by Cross-Linked Polyvinylalcohol as Colon-Specific Drug Delivery Systems

Polyvinylalcohol (PVA) of different molecular weights was cross-linked with succinyl, adipoyl, or sebacoyl chloride to obtain hydrogel-forming polymers and to determine their suitability as colon-specific drug delivery systems. Diclofenac sodium, propranolol hydrochloride, and vitamin B6 hydrochloride were used as hydrophilic model drugs with colon-specific release that should yield high concentrations in the large intestine, minimizing release in the upper part of the gastrointestinal tract. Spray-dried mixtures of the drugs and the polymer (at a 1 : 2 w/w ratio) were prepared, and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, and 7.4. The results indicated the ability of the cross-linked polymers to slow the release of the drugs analyzed with respect to the pure drug dissolution at each pH. The lengthening of the cross-linker acyl chain was noted to decrease drug release further.     

Smart tetrazole-based antibacterial nanoparticles as multifunctional drug carriers for cancer combination therapy

Due to multidrug resistance of cancer tissues and immune-suppression of cancerous patients during chemotherapy in one hand and the use of tetrazole derivatives in medicine because of its anticancer, antifungal, and antiviral properties, on the other, we were encouraged to design novel smart antibacterial nanocomposites-based polymer of tetrazole as dual anticancer drug delivery systems. The structures of nanocomposites characterized by FTIR, ¹H NMR, FESEM-EDX, and TGA analyzes and antibacterial activity of smart carriers were evaluated by determination of minimum inhibitory concentration (MIC) values against some bacteria and fungi. Then, the pH-responsive manner of both nanocomposites was proved by checking their release profiles at pH of the physiological environment (pH 7.4) and pH of tumor tissues (mildly acidic). Finally, the potential antitumoral activity of these nanocomposite systems against MCF7 cell lines was evaluated by MTT assay and cell cycle studies. The results demonstrated that the novel developed nanocomposites not only meet our expectations about simultaneous release of two anticancer drugs according to the predicted profile but also showed antibacterial and anticancer properties in vitro experimental. Moreover, it was proved that these carriers have tremendous potential in multifunctional drug delivery in cancer therapy.     

Molecularly imprinted fluorescent-shift receptors prepared with 2-(trifluoromethyl)acrylic acid

Methacrylic acid (MAA) and 2-(trifluoromethyl)acrylic acid (TFMAA) were used to prepare molecularly imprinted polymers exhibiting diastereoselectivity for cinchona alkaloids. Fluorescent spectra of the cinchona alkaloid exhibit a characteristic shift through binding to these polymer particles, originating most likely from the highly acidic residues in the imprinted polymers acting as a proton donator. Our results show that TFMAA based imprinted polymers can be used as polymer reagents for quantitating the cinchona alkaloid bound to the polymers without bound/free separation.     

Different approaches to synthesize carnosine selective imprinted polymers

Selective recognition of proteins by synthetic molecularly imprinted polymers is one of the interesting topics in biosciences. Carnosine (β-alanyl-l-histidine) and related histidine containing peptides are distributed in a wide range of tissues in vertebrate organisms. These peptides have been extensively studied because of their important physiological properties besides their metal chelation property. In this study, preparation of carnosine specific imprinted polymers (MIPs) for the recognition of imidazole containing peptides with and without copper ion is reported. Carnosine and copper–carnosine complex were employed as template molecules where 4-vinylpyridine and ethylenglycol dimethacrylate were chosen as monomer and crosslinker, respectively. The selectivity and binding studies of copper–carnosine imprinted polymer showed high selectivity toward both carnosine (template peptide) and the cupric ion. The selectivity of copper–carnosine imprinted polymer was 65% and carnosine imprinted polymer was approximately 40%. These results indicate that specific recognition of carnosine is depending on the basis of metal coordination     

Degradation of omeprazole induced by enteric polymer solutions and aqueous dispersions: HPLC investigations

Two reversed-phase high-performance liquid chromatography (RP-HPLC) methods were developed to investigate the degradation of the acid-labile proton-pump-inhibitor omeprazole in organic polymer solutions and aqueous dispersions of enteric coating polymers (Eudragit L-100, S-100, CAP, HP-55, HPMCAS-HF, -LF, and shellac). The overall goal of the study was to determine the influence of the polymer structure on the degradation of omeprazole, i.e., whether the acid structure of the enteric coating polymers caused an instability of the proton pump inhibitor. Moreover, it was investigated whether a difference in omeprazole degradation could be detected between organic polymer solutions and aqueous dispersions. pKa values of the polymers and pH values of the aqueous dispersions were determined to see whether there was a correlation with the extent of degradation of omeprazole induced by enteric polymers. As the polymers containing phthalate moieties are very susceptible to hydrolysis, the influence of free phthalic acid on omeprazole stability was investigated. Finally, the degradation kinetics of omeprazole in organic polymer solutions were determined. Omeprazole degradation is more pronounced in aqueous polymer dispersions than in organic polymer solutions. The influence of organic polymer solutions on the stability of omeprazole depends on the amount of acidic groups in the polymeric structure, whereas the influence of aqueous polymer dispersions depends on the pH value of the dispersion. The amount of free acids present in some polymers as by-products also cause a degradation of the proton pump inhibitor. Among all investigated polymers, shellac showed the least influence on the stability of omeprazole. The decomposition of omeprazole in organic polymer solutions followed first-order kinetics. The decrease of omeprazole peak area in organic polymer solutions was in the order Eudragit L-100> HPMCAS-HF>shellac.     

Subpicomolar sensing of delta-opioid receptor ligands by molecular-imprinted polymers using plasmon-waveguide resonance spectroscopy

Here we report, for the first time, the formation of a biomimetic covalently imprinted polymeric sensor for a target ligand, the delta-opioid G-protein coupled receptor agonist DPDPE, which reproducibly exhibits subpicomolar binding affinity in an aqueous environment. In addition to having a well-defined and homogeneous binding site, the imprinted polymer template is quite stable to storage in both the dry and wet states and has at least 6 orders of magnitude higher affinities than exhibited by similar peptide-based molecular-imprinted polymers (MIPs) thus far. A highly sensitive optical detection methodology, plasmon-waveguide resonance spectroscopy, was employed, capable of measuring binding in real time and discriminating between ligand molecules, without requiring labeling protocols (fluorophores or radioisotopes). The DPDPE-imprinted polymer showed a broad structure-activity relationship profile, not unlike that found for protein receptors. Such sensitivity and robustness of MIPs suggests potential applications ranging from biowarfare agent detection to pharmaceutical screening.     

分子印迹技术在药物缓释领域的研究进展

分子印迹技术是制备对特定分子结构具特异性识别功能的聚合物的一项重要技术,其在药物缓释领域的应用越来越引起研究者们的重视。在介绍了分子印迹技术的概念及原理的基础上,提出了应用于药物传输领域的分子印迹聚合物所应当具备的特性,综述了近年来分子印迹技术在药物传输领域的研究进展。并指出:为提高聚合物作为药物载体的生物顺应性,在水相中对聚合物的合成、可控自由基聚合制备规格统一的聚合物及将分子印迹聚合物应用于智能医用材料领域将成为日后研究的主流。     

Comparative Study of Aqueous and Organic Enteric Coatings of Chlorpheniramine Maleate Tablets

Two acrylic polymers (Eudragit® L 12.5 P and L 30 D) and a cellulosic polymer (cellulose acetate trimellitate, CAT) in organic and aqueous formulations were used in order to obtain an enteric coating on tablets containing clorpheniramine maleate as a water-soluble model drug. The coating of tablets was executed in a coating pan in similar conditions for each kind of solvent. The coated tablets were tested according to the delayed-release test of USP 23 (Method A). In our experimental conditions different amounts of polymers were needed to obtain an enteric coating. The lowest amount was in the case of Eudragit L 30 D (aqueous), after which appeared Eudragit L 12.5 P (organic), CAT (organic), and finally, CAT (aqueous) as the polymer that needed to be of the highest amount. During the dissolution test differences in the size and aspect of the tablets were observed according to the polymers. Acrylic polymers did not show changes in size and aspect, but CAT polymers showed a notable increase in size. me different behavior of the tablets during the dissolution test can explain the differences observed in the adjustment of the release data. The release data were tested assuming common kinetic models. In the present study it was observed that Eudragit L polymers release the drug in a first-order kinetic and that CAT releases it according to a zero-order kinetic.