Electrically controlled drug release from nanostructured polypyrrole coated on titanium

Previous studies have demonstrated that multi-walled carbon nanotubes grown out of anodized nanotubular titanium (MWNT-Ti) can be used as a sensing electrode for various biomedical applications; such sensors detected the redox reactions of certain molecules, specifically proteins deposited by osteoblasts during extracellular matrix bone formation. Since it is known that polypyrrole (PPy) can release drugs upon electrical stimulation, in this study antibiotics (penicillin/streptomycin, P/S) or an anti-inflammatory drug (dexamethasone, Dex), termed PPy[P/S] or PPy[Dex], respectively, were electrodeposited in PPy on titanium. The objective of the present study was to determine if such drugs can be released from PPy on demand and (by applying a voltage) control cellular behavior important for orthopedic applications. Results showed that PPy films possessed nanometer-scale roughness as analyzed by atomic force microscopy. X-ray photoelectron spectroscopy confirmed the presence of P/S and Dex encapsulated within the PPy films. Results from cyclic voltammetry showed that 80% of the drugs were released on demand when sweep voltages were applied for five cycles at a scan rate of 0.1 V s(-1). Furthermore, osteoblast (bone-forming cells) and fibroblast (fibrous tissue-forming cells) adhesion were determined on the PPy films. Results showed that PPy[Dex] enhanced osteoblast adhesion after 4 h of culture compared to plain Ti. PPy-Ti (with or without anionic drug doping) inhibited fibroblast adhesion compared to plain Ti. These in vitro results confirmed that electrodeposited PPy[P/S] and PPy[Dex] can release drugs on demand to potentially fight bacterial infection, reduce inflammation, promote bone growth or reduce fibroblast functions, further implicating the use of such materials as implant sensors.     

Dexamethasone electrically controlled release from polypyrrole-coated nanostructured electrodes

One of the key challenges to engineering neural interfaces is to reduce their immune response toward implanted electrodes. One potential approach to minimize or eliminate this undesired early inflammatory tissue reaction and to maintain signal transmission quality over time is the delivery of anti-inflammatory biomolecules in the vicinity of the implant. Here, we report on a facile and reproducible method for the fabrication of high surface area nanostructured electrodes coated with an electroactive polymer, polypyrrole (PPy) that can be used to precisely release drug by applying an electrical stimuli. The method consists of the electropolymerization of PPy incorporated with drug, dexamethasone (DEX), onto a brush of metallic nanopillars, obtained by electrodeposition of the metal within the nanopores of gold-coated polycarbonate template. The study of the release of DEX triggered by electrochemical stimuli indicates that the system is a true electrically controlled release system. Moreover, it appears that the presence of metallic nanowires onto the electrode surface improves the adherence between the polymer and the electrode and increases the electroactivity of the PPy coating.     

Redox-responsive gels with tunable hydrophobicity for controlled solubilization and release of organics

The hydrophobicity of the chemical environment within a redox-responsive polymer gel synthesized by copolymerization of hydroxybutyl methacrylate (HBMA) and vinylferrocene (VF) can be controlled by tuning the oxidation state of the redox-responsive moiety, ferrocene. When ferrocene is in the uncharged reduced state, the gel is hydrophobic and selectively extracts butanol from aqueous solution. Upon oxidation to ferricenium ions, charge is induced at the ferrocene sites making the gel hydrophilic, with a reduced capacity for butanol relative to water. Equilibrium distribution coefficients and separation factors provide quantitative evidence for this changing preference for butanol depending on oxidation state. The selection of the monomer constituting the polymer backbone, HBMA, was based on an initial screening using the Hansen solubility parameters of commercially available monomers. The effect of the various constituents of the gel on the gel's butanol extraction ability has been ascertained experimentally.     

Albumin-crosslinked alginate hydrogels as sustained drug release carrier

To take advantage of the drug-binding ability of albumin as a component of drug delivery system, we have prepared hydrogels consisting of alginic acid (AL) and recombinant human serum albumin (rHSA) by dehydrating condensation using N-hydroxysuccininimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. As rHSA content increased, the swelling ratio of the hydrogel decreased, indicating rHSA functioned as a crosslinker. In fact, trypsin treatment solubilized the hydrogel. Salicylic acid, which has high affinity for rHSA, was loaded most on the hydrogel of the highest rHSA content despite the lowest swelling ratio. Meanwhile, drugs with less affinity for HSA such as o-anisic acid and benzoic acid were preferably loaded on the hydrogel having the highest swelling ratio but the lowest HSA content. The release of salicylic acid from the hydrogel sustained longer than o-anisic acid and benzoic acid, reflecting the affinity of the drug for HSA. Furthermore, the hydrogel could carry much of positively charged dibucaine by the interaction with anionic alginic acid and showed highly sustained release. Since the safety of AL and rHSA in medical use is guaranteed, rHSA-crosslinked AL hydrogel is expected to use as a sustained drug release carrier for drugs having affinity for HSA and those with cationic charge.     

Magnetic nanocarriers with tunable pH dependence for controlled loading and release of cationic and anionic payloads

Superparamagnetic nanocarriers with tunable pH dependence of the surface charge are designed by a simple co-precipitation method. By exploiting electrostatic interactions, cationic or anionic payloads can be adsorbed and desorbed depending on the pH. On three different resulting nanocarrier systems, experiments of loading and release of gold nanoparticles as well as effective siRNA loading and in vitro delivery on human cells are performed.     

药物控、缓释体系的缓释同步性研究

通过插层技术合成了醋酸洗必泰-盐酸特比萘芬/蒙脱土(CA-TBNF/MMT)药物控、缓释纳米中间体,利用XRD对其结构进行了表征,结果表明CA-TBNF已进入MMT层间,层间距变化明显。最小抑菌浓度与缓释浓度匹配,从层间解析出的CA与TB-NF在协同作用下对细菌和真菌都有较好的杀菌效果。实验证明两种药物可实现同步缓释。     

温敏性聚己内酯-聚N-异丙基丙烯酰胺作为抗癌药物载体的制备与药物释放的研究

以卟啉衍生物为内核,采用可逆加成-断裂链转移(RAFT)聚合法合成了温度敏感性聚己内酯-聚N-异丙基丙烯酰胺。用FT-IR、1 H NMR、GPC、TEM、分子荧光、变温紫外、粒度分布等手段对聚合物进行了表征,并以紫杉醇为模型药物分子,进行了药物释放测试。结果表明,聚合物自组装后,形成了平均直径为100nm左右的胶束。这种内部亲脂外部亲水的核壳结构能够稳定地载药,在温度为15℃的DMF中,12h内释放了37%的药物,而在温度为38℃的DMF中,12h药物释放量为81.4%。这种两亲性大分子聚合材料对紫杉醇的释放具有温度敏感性,有望在抗癌药物的控制释放领域得到广泛应用。     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

铁炭复合磁靶向缓释药物载体材料的制备--制备条件对铁炭复合材料磁性能的影响

研究了一种新型铁炭复合磁靶向缓释药物栽体材料的制备方法。用医用活性炭和纳米四氧化三铁粉末球磨制成铁炭复合材料,该材料表面包硅处理后用氢气高温还原,得到可以作为磁靶向缓释药物栽体的铁炭复合材料。考察了制备过程中的包硅和还原工艺条件对铁炭复合材料磁性能的影响。     

A remotely triggered drug release system with dot array-like configuration for controlled release of multiple drugs

Near-infrared (NIR) light as noninvasive external stimuli to trigger on-demand drug release has attracted great attention in recent years. However, the current existing NIR-related drug delivery systems (DDSs) still have difficulty in controlling the release of the individual drug separately. In the present work, a dot array-like DDS was developed for accurately controlling the release of multiple drugs. Each dot had a drug core and an outer protective layer. The outer protective layer consisted of lauric acid (LA) and polylactic acid (PLA). LA is a kind of phase-change material (PCM) with melting point of 43.8 °C. When loaded with polypyrrole nanoparticles (PPy NPs) that acted as photothermal transducers, the outer protective layer became NIR light responsive and was able to convert light into heat to melt the LA. As a result, the drugs stored inside were released. By changing the PPy loading, NIR light power density, and mass ratio of LA to PLA, the drug release profile could be carefully controlled. Such a NIR-responsive DDS may find great potential applications in treating diseases that require long-term therapies using more than one drug.     

Injectable magnesium-doped brushite cement for controlled drug release application

Dicalcium phosphate dihydrate (CaHPO₄·2H₂O), also known as brushite, is one of the important bioceramics for bone regeneration. However, fast setting of the brushite cement under physiological conditions has limited its clinical use. Furthermore, brushite cement without any additives normally has poor injectability due to the liquid–solid phase separation. In the present study, magnesium-doped β-tricalcium phosphate (Mg-β-TCP) with chemical formula of β-Ca_2.96?x Mg _x (PO₄)₂ was used to prepare injectable brushite cements with improved physicochemical properties. β-TCP containing different amounts of Mg²⁺ ions were reacted with monocalcium phosphate monohydrate [Ca(H₂PO₄)₂·H₂O, MCPM] in the presence of water to furnish corresponding brushite cement. The samples were characterized using X-ray diffractometry, Fourier transform infrared spectroscopy and field emission scanning electron microscopy. The effect of magnesium ions on the structural, mechanical, and setting properties of the cements is reported. Our results indicate that the presence of Mg²⁺ ions increases the degree of injectability, setting time, and mechanical properties of the brushite cement. The compressive strength of brushite cement was substantially increased upon incorporation of Mg²⁺ ions. Furthermore, the setting times of the brushite cement were significantly improved. Gentamicin sulfate, amoxicillin and ampicillin trihydrate were incorporated into the Mg-brushite cement, and their release profiles showed a sustained drug release over 14 days. Cumulative releases of 99.3, 87, and 79 % were observed for gentamicin sulfate, amoxicillin, and ampicillin trihydrate, respectively.     

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.     

Comparison of two polymeric carrier formulations for controlled release of hydrophilic and hydrophobic drugs

Two temperature sensitive drug carriers, poly (N-isopropylacrylamide-co-acrylic acid) (PNIPA-co-AA) and poly (N-isopropylacrylamide-vinyl pyrrolidone-acrylic acid) (PNIPA-VP-AA), were successfully synthesized through free radical mechanism. The diameters of PNIPA-co-AA and PNIPA-VP-AA particles can be regulated to be less than 100 nm, which were related to surfactant sodiumdodecyl sulfate and initiator ferrous ammonium sulfate, respectively. The lower critical solution temperature (LCST) of them can be manipulated to be higher than 40 °C, which was correlated to amount of acrylic acid (AA) that was copolymerized with NIPA. Hydrophilic anti-tumor drugs, 5-fluorouracil (5-Fu) and hydrophobic drug thalidomide were entrapped into PNIPA-co-AA and PNIPA-VP-AA, respectively. For different interaction mechanism between drug and carrier, 5-Fu was prone to be entrapped in PNIPA-co-AA with loading efficiency larger than 10% (w/w), while thalidomide was entrapped in PNIPA-VP-AA up to 80% (w/w). Fluorescein, an angiography agent, was used to evaluate the drug loading mechanism between PNIPA-VP-AA and poor water-soluble drug. In vitro drug release behavior from these two drug carriers were significantly different and showed temperature dependent, which demonstrated that PNIPA-co-AA and PNIPA-VP-AA are promising candidates for different controlled drug delivery system.     

Controllable fabrication of hollow TiO2 spheres as sustained release drug carrier

TiO₂ hollow spheres with controllable size were successfully synthesized through a hydrothermal silica etching method; SiO₂ cores were easily removed without the use of a toxic reagent. The parameters for the synthesis of SiO₂ cores and TiO₂ hollow spheres, including stirring time, ammonia concentration, tetrabutyl titanate content, hydrothermal time, and reflux time, were systematically investigated. SiO₂ cores and TiO₂ hollow structure were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray spectra (EDX), X-ray photoelectron spectroscopy (XPS), and N₂ adsorption-desorption isotherms. The results revealed that the mean diameter of SiO₂ was ∼280 nm when the concentration of ammonia was 4.8 M and the stirring time was 0.5 h. For hollow TiO₂, when the operation process was optimized (ammonia volume 0.35 mL, TBOT addition 1.5 mL, hydrothermal time 3 h, and reflux time 3 h), the average size and the shell thickness were 270 and 100 nm, respectively. The process exhibited a high drug loading capacity (33.12 ± 0.01%) and encapsulation rate (99.03 ± 0.24%) due to its high specific surface area of 121.62 m²·g⁻¹. In addition, TiO₂ hollow spheres displayed pH-responsive sustained-controlled drug release behavior in vitro which released 80% of doxorubicin at 5.0 pH within 120 h, its release kinetic showed that it fits well with Zero-order kinetic equation, demonstrating that DOX·HCl/hollow TiO₂ maintains constant release rate, and the investigation of blood compatibility showed that the hemolysis rate of hollow TiO₂ did not exceed 3% in the concentration range of 100 and 4000 μg/mL, further confirming that prepared hollow TiO₂ is a relatively safe medical inorganic material.     

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.     

Dithiocarbamate chitosan as a potential polymeric matrix for controlled drug release

Objective: To develop a polymer matrix for controlled release of drugs, chitosan, a linear aminopolysaccharide, was chemically modified to dithiocarbamate chitosan (DTCC) to afford a matrix where metal–drug complexes could be attached and released in a controlled manner depending on the binding nature between the drugs and the metals.

Materials and methods: DTCC was treated with metal-tetracycline (Tc) complexes to prepare DTCC–Ca(II)–Tc, DTCC–Mg(II)–Tc, DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc.

Results: The binding amount of Tc was in the order of DTCC–Zn(II)–Tc?≈?DTCC–Mg(II)–Tc?≈ DTCC–Ca(II)–Tc?>?DTCC–Cu(II)–Tc. The biphasic binding profiles, where Tc binding increased initially and then decreased, were shown for DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc. In a flow method, Tc was released slowly from DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc compared with Tc release from DTCC–Tc. In parallel with the results of the release experiment, DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc presented a prolonged antibacterial activity in an antibacterial test. The antibacterial activity of DTCC–Ca(II)–, –Mg(II)– and –Zn(II)–Tc complexes lasted for 28–44 days, while free Tc and DTCC–Tc lasted for 7–12 days.

Discussion and conclusion: Taken together, our data suggest that DTCC could be used for a polymeric matrix for controlled release of drugs such as Tc, which possess functional groups for ionic and/or coordinate bond with metals.     

Study of mesoporous silica/magnetite systems in drug controlled release

Ordered mesoporous materials like SBA-15 have a network of channels and pores with well-defined size in the nanoscale range. This particular silica matrix pore architecture makes them suitable for hosting a broad variety of compounds in very promising materials in a range of applications, including drug release magnetic carriers. In this work, magnetic nanoparticles embedded into mesoporous silica were prepared in two steps: first, magnetite was synthesized by oxidation-precipitation method, and next, the magnetic nanoparticles were coated with mesoporous silica by using nonionic block copolymer surfactants as structure-directing agents. The materials were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), N(2) adsorption, and scanning electron microscopy (SEM). The influence of magnetic nanoparticles on drug release kinetics was studied with cisplatin, carboplatin, and atenolol under in vitro conditions in the absence and in the presence of an external magnetic field (0.25 T) by using NdFeB permanent magnet. The constant external magnetic field did not affect drug release significantly. The low-frequency alternating magnetic field had a large influence on the cisplatin release profile.     

Fabrication and dissolution behavior of hollow hydroxyapatite microspheres intended for controlled drug release

Hollow hydroxyapatite (HA) microspheres were fabricated by a simple spray drying method in this study. Moreover, the dissolution behavior of these hollow HA microspheres after immersion in simulated body fluid (SBF) was also studied. The results indicated that the dissolution of the HA microspheres in SBF is not homogeneous in a layer-by-layer fashion but was preferential at different locations of the particle surface. Generically, dissolution preferentially occurs on the location with looser structure and high porosity of the microspheres. The degradable HA microspheres are expected to have potential applications in bone local drug delivery systems.