Spray drying conditions and encapsulating composition effects on formation and properties of sodium diclofenac microparticles

This paper reports the preparation and characterization of sustained release sodium diclofenac microparticles by spray drying. Aqueous dispersions of ethyl cellulose (Surelease®) and Eudragit RS 30 D® were evaluated as controlled release polymers. The product properties (product moisture, size distribution, particle morphology, flow properties, total drug load, in-vitro dissolution studies, and encapsulating efficiency) were determined as a function of inlet temperature of the spray drying, the feed flow rate and composition of the microencapsulating formulation. In general, lower values of the product moisture content were observed at higher drying temperatures. The spray-dried product was composed mainly by rounded-shape and multi-size particles. The mean particle diameters of the Eudragit based microparticles tended to be slight bigger than the Surelease based microparticles. The spray dried microparticles showed delayed drug dissolution rates, sustaining the drug release for several hours. These findings confirm the feasibility of the spray drying for preparation of microparticles with sustained release properties. The physical and chemical properties of the microparticles can be changed by varying the spray drying parameters as well as the microencapsulating formulation.     

热熔挤出过程药物在聚己内酯中的分散形态及对药物释放行为的影响

以聚己内酯(PCL)为基体、2种难溶性药物布洛芬(BF)和双氯芬酸钠(DS)为模型药物,采用热熔挤出(HME)技术制备了2种载药体系;通过差示扫描量热法、X射线衍射和扫描电镜等表征了药物在PCL基体中的分散形态,探讨了药物分散形态对其释放行为的影响。结果表明,低熔点的药物BF以无定形态均匀分散于PCL中;而高熔点的药物DS仍以结晶形态分散于PCL中(药物颗粒直径约0.5μm)。在原药溶解度相差不大的情况下,由于在挤出过程2种药物的分散形态不同,挤出产物中BF的释放速率明显快于DS。     

Synthesis,characterization, and in vitro drug‐release properties of 2‐hydroxyethyl methacrylate copolymers

2‐Hydroxyethyl methacrylate was copolymerized with acrylamide, N‐vinyl‐2‐pyrrolidone, and n‐butyl methacrylate by free‐radical solution polymerization with α,α′‐azobisisobutyronitrile as an initiator at 70 ± 1°C. The average molecular weights and molar compositions of the resultant copolymers were determined with gel permeation chromatography and ¹H‐NMR spectroscopy data, respectively. Diclofenac or 2‐[(2,6‐dichlorophenyl)amino]benzene acetic acid, a nonsteroidal anti‐inflammatory drug, was chemically attached to the copolymers by transesterification reaction in the presence of N,N′‐dicyclohexylcarbodiimide to give macromolecular prodrugs. All the synthesized polymers were characterized with Fourier transform infrared, ¹H‐, and ¹³C‐NMR spectroscopy techniques. The polymer–drug conjugates were hydrolyzed in cellophane member dialysis bags containing aqueous buffered solutions (pH 8) at 37°C, and the hydrolysis solutions were detected by UV spectrophotometer at selected intervals. The results showed that the drug could be released by selective hydrolysis of the ester bond from the side chain of the drug moiety. The release profiles of the drug indicated that the hydrolytic behavior of polymeric prodrugs strongly depends on the hydrophilicity of the polymer. The results suggest that the synthesized copolymers could be useful carriers for the release of diclofenac in controlled‐release systems. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 2403–2409, 2007     

Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes

Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4′-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug–drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10?µmol?L^–1 diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25?µmol?L^–1 and Ki?=?4.473?µmol?L^–1 in human liver microsomes. Curcumin’s mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100?µmol L^–1. The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.     

Interpolyelectrolyte complexes of Eudragit® E PO with sodium alginate as potential carriers for colonic drug delivery: monitoring of structural transformation and composition changes during swellability and release evaluating

Background: With a view to the application in oral colon drug delivery systems, swelling and release behavior of synthesized interpolyelectrolyte complexes (IPEC) between sodium alginate and Eudragit® EPO were investigated. Method: The microenvironmental changes in IPECs structure as a function of pH during swellability testing were investigated using FT-IR spectroscopy and elementary analysis. Results: All samples of IPECs (Z = 0.66–1.25) during swelling were transformed to a similar structure with approximately the same composition. The release of the model drug diclofenac sodium was significantly delayed from matrices made up of the IPECs and independent from the composition of polycomplexes. Conclusion: According to the obtained results, these IPECs can be considered to have potential in colonic drug delivery as combined pH- and time-dependent systems.     

Formulation and evaluation of diclofenac potassium fast-disintegrating tablets and their clinical application in migraine patients

The aim of this study was to prepare fast-disintegrating tablets (FDTs) of diclofenac potassium with sufficient integrity as well as a pleasant taste, using two different fillers and binders: Tablettose 70® and Di-Pac^®. Tablets were made with direct compression method. Tablet properties such as porosity, hardness, and disintegration time were determined. Diclofenac potassium determinations were carried out using a validated spectrophotometric method for the analysis of drug. Furthermore, in vivo experiments were carried out to compare the analgesic effect and the time to relieve migraine headache between the commercial tablets and FDTs of diclofenac potassium against placebo. Results showed that FDTs of diclofenac potassium with durable structure and desirable taste can be prepared using both fillers and binders but tablets prepared with Di-Pac had a better taste so the tablet formulation containing Di-Pac was chosen for in vivo experiments. Placebo controlled in vivo trial demonstrated that 50 mg diclofenac potassium, administered as a single dose of FDTs or commercial tablets, was effective in relieving the pain and both of them were superior to placebo.     

Photocatalytic degradation of diclofenac using hybrid MIL-53(Al)@TiO2 and MIL-53(Al)@ZnO catalysts

In this work, TiO₂ and ZnO were incorporated successfully into a MIL-53(Al) metal–organic framework (MOF) to form nanocomposites via a facile post-modification technique. The hybrid MIL-53(Al)@TiO₂ and MIL-53(Al)@ZnO were characterized by several characterization tests. The X-ray diffraction (XRD), Fourier-transform infrared (FTIR), and field-emission scanning electron microscopy (FE-SEM) analyses showed evidence of the successful incorporation of TiO₂ and ZnO within the MIL-53(Al) framework. The thermal gravimetric analysis (TGA) analysis demonstrated the excellent thermal stability of MIL-53(Al)@TiO₂ and MIL-53(Al)@ZnO, while diffuse reflectance spectroscopy (DRS) determined the direct optical band gaps of MIL-53(Al)@ZnO and MIL-53(Al)@TiO₂ to be 3.24 and 3.34 eV, respectively. The composites were also tested for the photocatalytic degradation of diclofenac (DCF) as a micropollutant. The DCF degradation efficiency of the photocatalysts was ranked in the following order: MIL-53(Al)@TiO₂ > MIL-53(Al) > TiO₂ > ZnO > MIL-53(Al)@ZnO. The incorporation of TiO₂ enhanced the optical properties of MIL-53 (Al), which was confirmed with the superior photodegradation efficiency of MIL-53(Al)@TiO₂ (>85% in 2 h) as compared to the pristine MIL-53(Al) (around 80% in 2 h). The improvement in the photodegradation of the hybrid-MOF is mostly associated with the possible dual function of the adsorption and photodegradation mechanisms. The reusability of MIL-53(Al) and its composites was inspected over 3 cycles of photodegradation experiments with DCF. The photocatalytic activity of MIL-53(Al)@TiO₂ remained unchanged (>90%), while for MIL-53(Al) and MIL-53(Al)@ZnO a slight drop was observed over three cyclic degradation experiments. Fluorescence measurements revealed that the hydroxyl radical is an important reactive oxygen species produced by all the photocatalysts that aid in the photodegradation of DCF. Furthermore, the kinetic modelling of the photoreaction identified a second-order kinetics for all catalysts. Experiments with scavengers showed that hydroxyl radicals played a major role in the photocatalytic process, and it was found that only 2 h of treatment was sufficient to obtain a considerable chemical oxygen demand (COD) reduction of 58%.     

Encapsulation of diclofenac sodium with acidic copolymer hydrogels based on PEG/poly(N‐isopropylacrylamide‐co‐2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) semi‐interpenetrating network using in situ loading technique

A pH‐ and temperature‐responsive semi‐interpenetrating copolymer PEG6000/poly(NIPA‐co‐AMPS) (PEG/AMPS‐co‐NIPA SIPN), for short PEG SIPN, was made by ammonium persulfate‐initiated suspension copolymerization of N‐isopropylacrylamide, 2‐acrylamido‐2‐methylpropanesulphonic acid, and N,N′‐methylene‐bis‐acrylamide (MBAA; crosslinker) in the presence of PEG6000. The PEG SIPN copolymer matrices containing nanostructures made in the high‐temperature copolymerization resulted in channels for PEG and facile migration of drugs. In drug encapsulation or drug‐loading process, one can easily ignore or pay less attention to the interaction between a drug and its encapsulation materials; however, the ignored interactions may induce problems in drug properties or the release behavior in use. Sodium diclofenac (DFNa) precipitates as the carboxylic acid form in an acidic environment, and it is challenging to encapsulate sodium diclofenac in such an acidic matrix without precipitation of the sparingly soluble acid form of DFNa on the surface of the polymer substrate. To avoid bulky precipitation in drug loading, an in situ loading technique was developed for producing gel spheres with DFNa uniformly distributed in the polymer matrix. The technique is based on fast polymerization of spherical droplets of a pregel solution in which the drug is dissolved. Diffusion‐loading prodrugs were made in comparison with in situ loading prodrugs in thermal, release kinetics, and release behavior. Drug release profiles (in pH 7.4 phosphate buffer) show that the new drug loading technique gives controlled release during a period of about 7 days at 37°C. By contrast, gel spheres loaded with sodium diclofenac using the conventional diffusion technique produced almost total release of the drug within about 24 h. The thermal stability of sodium diclofenac, the PEG/AMPS‐co‐NIPA SIPN, and the prodrugs made with the SIPN and sodium diclofenac was studied. A near zero‐order release kinetics was found in the in vitro release of sodium diclofenac with in situ loading PEG SIPN prodrug. We have, for the first time, studied sodium diclofenac release behavior from the PEG SIPN hydrogel systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

双氯芬酸钠速缓双释口腔膜剂的制备及质量评价

目的 制备可用于口腔局部用药的双氯芬酸钠速缓双释膜剂,并考察其质量特性.方法 以喷雾干燥法制备速缓双释口腔膜剂,单因素法优化制备工艺条件,评价工艺优化后口腔膜剂的外观、厚度和耐折度,采用紫外分光光度法和桨碟法分别对口腔膜剂的药物含量和药物释放度进行评价.结果 双氯芬酸钠速缓双释膜剂光滑透明,无明显气泡,平均厚度为0.0...