Modification of the soft tissue response to implanted materials through the use of an anti-inflammatory drug

The soft tissue response of adult rats to a drug-loaded copolymer hydrogel was studied histologically by using monoclonal antibodies specific for certain inflammatory cell types. A hydrogel was loaded with Diclofenac sodium, a non-steroidal anti-inflammatory drug, and designed to release the drug at a constant rate after implantation into muscle tissue. The sites of antibody binding were analysed automatically, by using an image analysis system, providing information on the number of inflammatory cells and their distribution relative to the hydrogel implant. The ability to measure these and other parameters is considered to be of major importance in the assessment of biocompatibility. The experiments demonstrate that Diclofenac sodium (25–30 µg ml^–1) reduced the number of macrophages and neutrophils found at the implant site compared with a PBS control. Diclofenac sodium did not have any effect on the T cell response.     

Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing herbal drug, curcumin (CUR), with different ratios of hydrophilic (hydroxyl propyl methyl cellulose K4M [HPMC K4M]) and hydrophobic (ethyl cellulose [EC]) polymeric systems by the solvent evaporation technique. Different concentrations of oleic acid (OA) were used to enhance the transdermal permeation of CUR. The physicochemical compatibility of the drug and the polymers was also studied by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Formulated transdermal films were physically evaluated with regard to drug content, tensile strength, folding endurance, thickness, and weight variation. All prepared formulations indicated good physical stability. In vitro permeation studies of formulations were performed by using Franz diffusion cells. The results followed Higuchi kinetics, and the mechanism of release was diffusion-mediated. Formulation prepared with hydrophilic polymer containing permeation enhancer showed best in vitro skin permeation through rat skin as compared with all other formulations. This formulation demonstrated good anti-inflammatory activity against carrageenan-induced oedema in Wistar albino rats similar to standard formulation.     

Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crosslinked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulation, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (∼ 98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect. Intravenous injection of the co-delivery TKPR-RCP mediated potent and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

     

Single-walled carbon nanohorns as drug carriers: adsorption of prednisolone and anti-inflammatory effects on arthritis

Prednisolone (PSL), an anti-inflammatory glucocorticoid drug, was adsorbed on oxidized single-walled carbon nanohorns (oxSWNHs) in ethanol-water solvent. The quantity of adsorbed PSL on the oxSWNHs was 0.35-0.54 g/g depending on the sizes and numbers of holes on the oxSWNHs. PSL was adsorbed on both the outside and the inside of the oxSWNHs, and released quickly in a couple of hours and slowly within about one day from the respective places. The released quantity in culture medium strongly depended on the concentration of the PSL-oxSWNH complexes, suggesting that PSL adsorbing on oxSWNHs and PSL in the culture medium were in concentration equilibrium. The local injection of PSL-oxSWNHs into the tarsal joint of rats with collagen-induced arthritis (CIA) slightly retarded the progression of the arthritis compared with controls. By histological analysis of the ankle joint, the anti-inflammatory effect of PSL-oxSWNHs was also observed.     

Enzyme-based amperometric platform to determine the polymorphic response in drug metabolism by cytochromes P450

"Personalized medicine" is a new concept in health care, one aspect of which defines the specificity and dosage of drugs according to effectiveness and safety for each patient. Dosage strongly depends from the rate of metabolism which is primarily regulated by the activity of cytochrome P450. In addition to the need for a genetic characterization of the patients, there is also the necessity to determine the drug-clearance properties of the polymorphic P450 enzyme. To address this issue, human P450 2D6 and 2C9 were engineered and covalently linked to an electrode surface allowing fast, accurate, and reliable measurements of the kinetic parameters of these phase-1 drug metabolizing polymorphic enzymes. In particular, the catalytic activity of P450 2C9 on the electrode surface was found to be improved when expressed from a gene-fusion with flavodoxin from Desulfovibrio vulgaris (2C9/FLD). The results are validated using marker drugs for these enzymes, bufuralol for 2D6, and warfarin for 2C9/FLD. The platform is able to measure the same small differences in K(M), and it allows a fast and reproducible mean to generated the product identified by HPLC from which the k(cat) is calculated.     

Implant compositions for the unidirectional delivery of drugs to the brain

The overall objective of this study was to design and characterize the properties of a bioadhesive trilayer sustained-release implant device for the unidirectional local delivery of anticancer compounds to the brain following the removal of glioblastoma multiforme tumors. Using acetaminophen as a model drug compound, we compressed trilayer wafers that contained (i) a bioadhesive layer, (ii) a drug layer that contained a lipid and a pore-forming hydrophilic polymer, and (iii) a third layer comprising a lipid substance. To maintain a unidirectional pathway of drug release from these trilayer wafers, the edges and the surface lipophilic layer were coated with molten wax followed by cooling of the wafer. These wafers were subsequently heat cured to promote interlayer adhesion in the device. Polyethylene oxide was utilized both as the bioadhesive layer and the pore-forming hydrophilic polymer. Glyceryl behenate was employed as the lipid. The drug release properties of the trilayer wafer were a function of (i) the molecular weight and concentration of polyethylene oxide in the drug-containing lipid layer, (ii) the presence of the bioadhesive layer on the wafer, and (iii) the lipid coating applied to the top and sides of the delivery system. The unidirectional release of the drug occurred from the device through the bioadhesive layer, and zero-order release kinetics resulted over a 10-day period after a 3-day lag time. During this period, <10% of the drug had been released from the wafer. All of the drug was released by 21?days.     

Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

There is an increasing interest on self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of poorly water-soluble drugs. However, development of SNEDDS is often driven by empiric, pseudo-ternary diagrams and solubility of drugs, and it is lacking a systematic approach for evaluating impact of excipients on the performance of formulations as well as the fate of drug. The aim of this study was to rationalize the SNEDDS development procedure and to get a better understanding on the role of excipients on the SNEDDS. The formulations consist of soybean oil or rapeseed oil, Cremophor^® RH40, Maisine? 35-1 and ethanol. Response surface methodology (RSM) was used in the development of SNEDDS. Significant advantages of RSM were found in reducing the work load and determining the impact of excipients on formulation characteristics. The most significant factor in influencing droplet size was the co-surfactant Maisine? 35-1, the droplet size increased with increasing concentration of Maisine? 35-1. It suggests that Maisine? 35-1 has double functions in the SNEDDS; it functions as co-surfactant to improve the emulsification of oil, meanwhile it also works as the oil phase and results in larger droplets. A significant reduction in droplet size was interestingly observed when fenofibrate was loaded in the vehicles, probably due to the surface activity of fenofibrate, promoting the self-emulsifying process. It was evident that drug precipitation during lipolysis was not affected by the level of co-solvent ethanol in the formulation, while it had pronounced impact on drug solubilization during the initial dispersion stage.     

Microemulsions as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs): a literature review

Abstract

Pain is a global crisis and significant efforts have gone into the development of drugs that can be used to treat pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that act to selectively relieve pain and inflammation without significantly altering consciousness. Although there have been many advancements with NSAIDs drug development; these drugs still present with severe adverse effects and toxicities, which often limits their use in many patients. Moreover, others are inadequate in relieving specific types of pain such as localized or nerve pain because of poor systemic absorption with conventional delivery systems. The topical route of drug delivery has been used to avoid many of these effects, but not without challenges of its own. The skin acts as an impermeable barrier to most polar drug candidate and absorption across the dermal membranes is often too slow and incomplete to produce meaningful therapeutic benefit. Nevertheless, the use of microemulsions as topical delivery systems for small molecule drug candidates like NSAIDs has been posited as a solution to this problem for years. This review focuses on the recent use of microemulsions as a probable solution to the challenges of transdermal drug delivery of NSAIDs and how microemulsions may be used to enhance the development of more effective but safer analgesic drug products for patients.     

Physical properties of solid dispersion of a nonsteroidal anti-inflammatory drug (M-5011) with Eudragit E

Some acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are poorly soluble in the stomach. In this study, M-5011, d-2-[4-(3-methyl-2-thienyl) phenyl] propionic acid, was used as a model substance. To increase the dissolution rate of M-5011, a solid dispersion of M-5011 was prepared by the powder mixing method using Eudragit E-100 (aminoacryl methacrylate copolymer) as a carrier. Evaluation by X-ray diffraction and differential scanning calorimetry (DSC) revealed that M-5011 easily formed a solid dispersion with E-100. The dissolution behavior of a physical mixture prepared immediately after mixing and the mixture stored for 14 days at 40°C were examined. It was observed that the former, containing a great deal of E-100, showed a fairly good dissolution behavior, and the latter had a better dissolution rate. The mechanism of the interaction of M-5011 and E-100 was investigated by infrared (IR) spectroscopy and nuclear magnetic resonance (NMR). The interaction was simulated by NMR using a monomer of Eudragit E-100.     

Structure,properties and response to heat treatment of melt-spun Al-Y and Al-La alloys

Al-Y and Al-La binary alloys containing 0.7–18 wt% (0.2–6.3 at%) Y and 0.9–18 wt% (0.2–4.2 at%) La, were rapidly solidified by chill-block melt-spinning to produce ribbons between 35 and 70 m thick. Microstructures were of the classical zone A/zone B type with a notable increase in Al lattice parameter for the Al-6.3 at% Y composition, which exhibited a Knoop hardness of 430±30 kg mm^–2 as-spun. Isochronal ageing for 2 h at 200–500 °C gave significant hardening at 200 and/or 300 °C for all of the more concentrated alloys, the largest responses being produced by Al-6.3 at % Y and Al-4.2 at % La at 200 °C. X-ray diffraction asspun indicated the presence of only Al and equilibrium Al₁₁La₃ in the Al-La alloy ribbons and Al and a non-equilibrium Al₄Y/Al₁₁Y₃ in the Al-Y ribbons. This non-equilibrium Al-Y phase was identified by X-ray diffraction as isomorphous with orthorhombic or tetragonal Al₁₁ La₃ with lattice parameters determined as a _o = 0.42 ± 0.02 nm (b _o = 1.26 ± 0.06 nm) and c _o = 0.97 ± 0.05 nm. TEM showed that it was present as an intercellular network with Energy dispersive spectroscopic analysis indicating an average composition Al-46 wt% Y consistent with the Al₄Y/Al₁₁Y₃ stoichiometry and diffraction patterns consistent with an orthorhombic or tetragonal cell with these lattice parameters. While no significant change in phase constitution of the Al-La ribbons was detected by X-ray diffraction as a result of heat treatment, the Al₁₁Y₃ in Al-Y ribbons was seen to be replaced by AI₃Y on heat treatment at 400 and 500 °C.     

Hollow structures as drug carriers:Recognition,response,and release

Hollow structures have demonstrated great potential in drug delivery owing to their privileged structure,such as high surface-to-volume ratio,low density,large cavities,and hierarchical pores.In this review,we provide a comprehensive overview of hollow structured materials applied in targeting recognition,smart response,and drug release,and we have addressed the possible chemical factors and reactions in these three processes.The advantages of hollow nanostructures are summarized as follows:hollow cavity contributes to large loading capacity;a tailored structure helps controllable drug release;variable compounds adapt to flexible application;surface modification facilitates smart responsive release.Especially,because the multiple physical barriers and chemical interactions can be induced by multishells,hollow multishelled structure is considered as a promising material with unique loading and releasing properties.Finally,we conclude this review with some perspectives on the future research and development of the hollow structures as drug carriers.     

屏蔽层对支架涂层药物缓释影响的体外研究

载药涂层的药物释放行为对于药物洗脱支架的临床治疗效果具有非常重要的意义。讨论了在聚碳酸酯载药涂层外面再加一层空白聚合物层（即屏蔽层）对药物释放的影响。从4方面的体外实验证明屏蔽层（drug free polymer layer,DFPL）可以防止聚碳酸酯载药涂层药物＂暴释＂的现象,并且屏蔽层厚度和释放速率不是简单的比例关系,以及不同的药物梯度和不同的屏蔽层材料对药物释放有不同的影响效果。     

Driver behavior during bicycle passing maneuvers in response to a Share the Road sign treatment

The interaction of motorists and bicyclists, particularly during passing maneuvers, is an area of concern to the bicycle safety community as there is a general perception that motor vehicle drivers may not share the road effectively with bicyclists. This is a particular concern on road sections with centerline rumble strips where motorists are prone to crowd bicyclists during passing events. One potential countermeasure to address this concern is the use of a bicycle warning sign with a “Share the Road” plaque. This paper presents the results of a controlled field evaluation of this sign treatment, which involved an examination of driver behavior while overtaking bicyclists. A series of field studies were conducted concurrently on two segments of a high-speed, rural two-lane highway. These segments were similar in terms of roadway geometry, traffic volumes, and other relevant factors, except that one of the segments included centerline rumble strips while the other did not. A before-and-after study design was utilized to examine changes in motor vehicle lateral placement and speed at the time of the passing event as they relate to the presence of centerline rumble strips and the sign treatment. Centerline rumble strips generally shifted vehicles closer to the bicyclists during passing maneuvers, though the magnitude of this effect was marginal. The sign treatment was found to shift motor vehicles away from the rightmost lane positions, though the signs did not significantly affect the mean buffer distance between the bicyclists and passing motorists or the propensity of crowding events during passing. The sign treatment also resulted in a 2.5 miles/h (4.0 km/h) reduction in vehicle speeds. Vehicle type, bicyclist position, and the presence of opposing traffic were also found to affect lateral placement and speed selection during passing maneuvers.     

Melt granulation and heat treatment for wax matrix-controlled drug release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.     

Tissue response to hafnium

The aim of the present experimental study was to evaluate the tissue response to hafnium (Hf) a reactive metal closely related to titanium (Ti) and zirconium (Zr). Hf has not been previously evaluated as implant material in a biologic environment. In a first experiment, 21 machined Hf non-threaded implants (test) and 21 similar Ti implants (control) were inserted in the abdominal wall of 21 rats. Animals were sacrificed after 8 days (6 rats), 6 (7 rats) and 12 weeks (8 rats). In a second experiment, 18 rabbits received 18 Hf and 18 Ti threaded implants in their tibiae, one implant in each tibia. The rabbits were sacrificed after 6, 12 and 24 weeks (6 animals/time interval). The bulk metal of the abdominal wall implants, embedded together with the surrounding tissue, was electrolytically dissolved and semithin (1 m) sections of the intact tissue–implant interface were evaluated by light microscopy (morphometry). Bone-implant contact and bone area within threads were evaluated in ground sections. In soft tissues, a fluid space containing predominantly monocytes/macrophages surrounded the abdominal implants at 8 days. At 6 and 12 weeks, a fibrous capsule, consisting of layers of macrophages and fibroblasts, surrounded the implants. Macrophages, including multinuclear giant cells, always formed the innermost layer in contact with the implant surface. No quantitative or qualitative difference in the tissue organization was detected between Ti and Hf implants. In rabbits, 6 weeks after insertion, the proximal two threads located within the cortical bone were filled with bone in contact with Hf and Ti. The distal threads contained bone marrow. After 12 and 24 weeks, mature bone was present in the proximal 3–4 implant threads. No statistically significant difference was found between Hf and Ti implants at any time periods. It is concluded that Hf is an interesting metal for biomedical applications in bone and soft tissue. © 2001 Kluwer Academic Publishers