Dental resin as controlled release layer for the development of an innovative long-acting intra-oral delivery system.

The objective of the present study was to develop a novel long-acting intra-oral delivery system (LIDS) to overcome the frequent administration by the nonparenteral route with Huperzine A (HupA) as a model drug. HupA-LIDS was prepared using a magnetic drug delivery with dental resin as release controlling layer for long-term release of HupA. The factors that influenced the drug release comprised of the type and amount of pore formers, the speed of shaker, resin layer weight and drug loading. These factors were evaluated and optimized. The in-vitro release studies showed that the system was able to deliver HupA in an approximately zero-order kinetic. The SEM study showed that the multiple orifices on the surface of a resin layer formed due to presence of pore formers, which contributed to the HupA release. The pharmacokinetic study in rabbits demonstrated the HupA-LIDS could be released in vivo for more than 8 days with prolonged Tmax and significantly reduced Cmax in comparison with commercial tablets. This study provided some pioneering ideas for developing intra-oral extended release drug delivery system using dental resin as release controlling materials. The optimized HupA-LIDS can make excellent sustained release and have the potential for the long-acting product in the therapy of Alzheimer's disease.

High Amount of Organic Matter during Caries Formation Reduces Remineralization and Resin Infiltration of Enamel Caries.

The amount of organic material in the cariogenic environment correlates with the amount of organic material incorporated in carious enamel. The incorporated organic material may be expected to reduce the pore volumes available for remineralization and resin infiltration, but these expected outcomes have not yet been quantified. We tested the effect of the amount of organic content in the cariogenic agent on remineralization and the resin-occluded pore volume in artificial subsurface enamel caries. An acid gel (organic-rich; G1) and an aqueous solution (organic-poor; G2) were used to induce subsurface lesions in human enamel. Undemineralized histological sections were prepared, microradiographed, and then submitted to resin infiltration in vitro. The enamel component volumes (mineral, organic, remineralizable [total water volume], loosely and firmly bound water volumes, and resin-occluded volume) were measured (by microradiography and polarizing microscopy) at histological sites (n = 38, G1; n = 34, G2). The main outcomes were the differences between the experimental and the predicted volumes (Δremineralizable and Δresin-occluded volumes). Resin infiltration was confirmed by confocal scanning laser microscopy. Compared to G2, G1 presented more incorporated organic volume and lower Δremineralizable volume (p = 0.003; Hedges g = 0.66; power = 0.87), a lower increase in loosely bound water volume (p = 0.0013; Hedges g = 0.74; power = 0.93), a lower remineralization volume in the surface layer (p = 0.017; Hedges g = 0.68; power = 0.8), and a lower Δresin-occluded volume (p = 0.0015; Hedges g = 0.73; power = 0.92). In conclusion, the higher amount of organic matter in the cariogenic gel negatively affected remineralization and the resin-occluded volume in subsurface lesions.

Improvement of side-effects and treatment on the experimental colitis in mice of a resin microcapsule-loading hydrocortisone sodium succinate.

CONTEXT: Extensive or long-time use of corticosteroids often causes many toxic side-effects. The ion exchange resins and the coating material, Eudragit, can be used in combination to form a new oral delivery system to deliver corticosteroids. OBJECTIVES: The resin microcapsule (DRM) composed by Amberlite 717 and Eudragit S100 was used to target hydrocortisone (HC) to the colon in order to improve its treatment effect on ulcerative colitis (UC) and reduce its toxic side-effects. METHODS: Hydrocortisone sodium succinate (HSS) was sequentially encapsulated in Amberlite 717 and Eudragit S100 to prepare the HSS-loaded resin microcapsule (HSS-DRM). The scanning electron microscopy (SEM) was employed to investigate the morphology and structure of HSS-DRM. The in vitro release and in vivo studies of pharmacokinetics and intestinal drug residues in rat were used to study the colon-targeting of HSS-DRM. The mouse induced by 2,4,6-trinitrobenzenesulfonic acid was used to study the treatment of HSS-DRM on experimental colitis. RESULTS: SEM study showed good morphology and structure of HSS-DRM. In the in vitro release study, > 80% of HSS was released in the colon environment (pH 7.4). The in vivo studies showed good colon-targeting of HSS-DRM (Tmax = 0.97 h, Cmax = 118.28 µg/mL of HSS; Tmax = 2.16 h, Cmax = 64.47 µg/mL of HSS-DRM). Moreover, the HSS-DRM could reduce adverse reactions induced by HSS and had good therapeutic effects on the experimental colitis. CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.

Antioxidant responses and renal crystal formation in rainbow trout treated with melamine administered individually or in combination with cyanuric acid.

In 2007 and 2008, renal stone formation and kidney damage in human infants were linked to consumption of melamine (MEL)-contaminated infant formula, as well as renal failure and death in pets due to pet food containing both MEL and cyanuric acid (CYA). The aim of this study was to examine the effects of MEL and CYA administered individually or in combination on concentrations of certain metabolites and enzyme activities that serve as markers for oxidative stress in kidney and liver of rainbow trout. In addition, the levels of muscle MEL and renal crystal formation were determined. Trout were fed MEL and/or CYA for 8 wk at 250, 500, or 1000 mg of each compound/kg in feed. Fish muscle residues of MEL exhibited a dose-response relationship. Coexposure of trout to MEL and CYA at the highest dose led to lower MEL residue concentrations in muscle compared to exposure to MEL alone. Renal MEL-CYA complexes were found in kidneys of fish treated with combined MEL and CYA. A dose response was evident with respect to both (1) number of trout displaying renal crystals and (2) number of crystals per fish. Changes in concentration of antioxidant parameters, such as glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase, were recorded in both tissues of MEL- and CYA-dosed trout. Lipid peroxidation was more pronounced in kidney than liver. Therefore, feed contaminated with both MEL and CYA could be problematic for fish, as MEL administered to trout, individually or in combination with CYA, may facilitate the onset of oxidative damage in trout.

Melamine in prenatal and postnatal organs in rats.

Melamine can be transferred to fetus in utero through placenta and to infant ex utero by breast feeding. In this study, we characterized the pharmacokinetics of melamine in prenatal and postnatal organs in rats. Single bolus of melamine was administered to pregnant rats at different gestational stages and to infants at different postnatal stages. Distribution of melamine in maternal serum was about 30% higher in late pregnancy than that in early pregnancy; and it was 2 folds higher in postnatal serum in early infants in young adulthood. Distribution of melamine in all postnatal organs was higher than that in prenatal organs. Postnatal kidneys in early infants had the highest maximum concentration and the lowest clearance of melamine than the other postnatal organs. It may relate to the high vulnerability to the toxicity of melamine in this population.

Light- and electronmicroscopic study of infiltration of resin into initial caries lesions--a new methodological approach.

It was the purpose of this pilot study to investigate resin infiltration into various types of initial subsurface caries lesions using a combined microscopic technique with polarized light microscopy and fluorescence microscopy and subsequent scanning microscopy with EDX-element analysis. Six extracted premolars with initial caries lesions were used. Five were infiltrated with resin after imbibition of the subsurface carious pore volume of enamel with sodium fluorescein solution. After light curing the unbound dye was removed by washing out in water. Serial sections were cut through the lesions and investigated with polarized light microscopy, fluorescence microscopy and simultaneously with both microscopic techniques. The same sections were then studied with scanning electron microscopy and EDX-element analysis to prove the infiltration of the resin into the lesions. The results showed, that the combination technique adds further morphologic information to infiltration behaviour of the resin. The individual volume of early acute lesions versus chronic lesions involving dentin, and the fluorescein bound by resin was well documented in serial sections. The EDX calcium and phosphorus signals correlate negatively with the lesion extension, and the carbon signal correlates positively, thus labelling the resin infiltration. It could be demonstrated that resin infiltration is dependent from the pore volume of the lesion. It can be concluded that the combined polarized light microscopy with fluorescence microscopy is an advantageous tool for studying infiltration of resin into hard tissues.

Plasma pharmacokinetics of melamine and a blend of melamine and cyanuric acid in rainbow trout (Oncorhynchus mykiss).

The objective of the study was to obtain pharmacokinetic parameters for melamine and blend of melamine (MEL) and cyanuric acid (CYA) in rainbow trout (Oncorhynchus mykiss). The single target dosage of MEL (20mg/kg bw) and the blend of MEL and CYA (5 and 1.67 mg/kg bw, respectively) were designed and plasma samples were collected at 30 min, 1, 4, 8, 12, 20, 24, 36, 48, 72, 144 and 240 h sequentially. An optimized method for simultaneous determination of MEL and CYA in plasma and animal tissues by LC-MS/MS was used. The data were shown to best fit a non-compartment model with first order processes of linear characters for melamine, with half-life (t(½)) of 32.2-32.9h, clearance (Cl(z/F)) of 35.9-36.6 ml/h/kg, and volume of distribution (V(ss)) of 1.67-1.74 l/kg. Withdrawal of CYA was much more rapid than that of MEL with higher Cl(z/F) (783.56 ml/h/kg) and shorter t(½) (7.92 h). T(max) of MEL20 and MEL5 were 12 and 20 h, respectively, which showed that T(max) of MEL5 was delayed when MEL and CYA were given together. The results are quite different from those in mammals and showed much slower elimination of MEL and CYA from rainbow trout body.

Molecular toxicology of substances released from resin-based dental restorative materials.

Resin-based dental restorative materials are extensively used today in dentistry. However, significant concerns still remain regarding their biocompatibility. For this reason, significant scientific effort has been focused on the determination of the molecular toxicology of substances released by these biomaterials, using several tools for risk assessment, including exposure assessment, hazard identification and dose-response analysis. These studies have shown that substances released by these materials can cause significant cytotoxic and genotoxic effects, leading to irreversible disturbance of basic cellular functions. The aim of this article is to review current knowledge related to dental composites' molecular toxicology and to give implications for possible improvements concerning their biocompatibility.

Estimating meat withdrawal times in pigs exposed to melamine contaminated feed using a physiologically based pharmacokinetic model.

Recently melamine was found to have contaminated the feed of multiple food production species leading to concern over the ability to establish an appropriate withdrawal interval and protect the safety of the food supply. To establish an appropriate withdrawal interval, a physiologically based pharmacokinetic (PBPK) model for melamine was developed for rats and extrapolated to pigs. The rat model underpredicted plasma concentrations, but better predicted tissue residues. Correlation values for plasma, kidney, and liver were 0.59, 0.76, and 0.73, respectively. The pig model underpredicted early plasma time points but had greater accuracy at later time points which is relevant to withdrawal times. Correlation (R(2)) between predicted and observed plasma values was 0.89 with a negative intercept of -0.76. The pig model estimated a withdrawal interval (based on kidney tissue residues) of 19.2 and 20.9h for single oral exposures of 3.0 and 5.12 mg/kg of melamine, respectively. Chronic oral dosing (3.0 and 5.12 mg/kg twice daily for 7 days) yielded withdrawal intervals of 20 and 21.3h, respectively. PBPK models, such as this one, provide evidence of the usefulness in species extrapolation over a range of dosing scenarios and can be used to protect the food supply after accidental exposure in the face of little in the target species.

[CT-based analysis of cement distribution in unipedicular vertebroplasty]. / CT-gestützte Analyse der Zementdistribution bei monopedikulärer Vertebroplastie.

BACKGROUND: Vertebroplasty and kyphoplasty are being increasingly used in the treatment of osteoporotic vertebral body fractures. Shortening the duration of operative time and radiation exposure as well as reduction of cannulation-related risks and costs are advantages of the unipedicular technique in contrast to less homogeneous cement distribution as a possible disadvantage. Biomechanical investigations have shown similar results with respect to strength and stiffness both for uni- and bipedicular vertebroplasty. Studies evaluating cement distribution with CT scans using a unipedicular approach have not been published yet. MATERIAL AND METHODS: We present a prospective study on 92 vertebral body fractures (Th8-L5) in 60 patients, aged 76.8 (60-95) years, which were treated by unipedicular vertebroplasty using a para-/transpedicular approach. We evaluated needle position, injected cement volume, and cement deposition based on CT scans. The vertebral body was divided into nine segments in a frontal plane view. The needle was placed in the middle third in 85.9% (79/92), in the right in 11.9% (11/92), and in the left third in 2.2% (2/92). Complications associated with cannulation were not observed. The injectable cement volume was 4.5 (1.5-9.0) ml. RESULTS: With respect to superior, middle, and inferior parts, filling of the middle third was achieved in 94.9%, of the right third in 76.1%, and of the left third in 80.4%. Only the right- and left-sided inferior segments showed a filling rate below 75%. Positioning the needle into the right or left third resulted in comparably high filling rates of the middle third (100/83.3%) but only 50.0/54.5% of the contralateral third of the vertebral body. CONCLUSION: Unipedicular vertebroplasty using a modified approach permits a reliable placement of the needle into the middle third of the vertebral body, which is the optimal position regarding cement distribution. Unipedicular vertebroplasty allows homogeneous filling and augmentation of vertebral bodies without need for a second cannulation.

Effect of polysulfonate resins and direct compression fillers on multiple-unit sustained-release dextromethorphan resinate tablets.

The purpose of this work was to investigate the effect of different polysulfonate resins and direct compression fillers on physical properties of multiple-unit sustained-release dextromethorphan (DMP) tablets. DMP resinates were formed by a complexation of DMP and strong cation exchange resins, Dowex 50 W and Amberlite IRP69. The tablets consisted of the DMP resinates and direct compression fillers, such as microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), and spray-dried rice starch (SDRS). Physical properties of tablets, such as hardness, disintegration time, and in vitro release, were investigated. A good performance of the tablets was obtained when MCC or SDRS was used. The use of rod-like and plate-like particles of Amberlite IRP69 caused a statistical decrease in tablet hardness, whereas good tablet hardness was obtained when spherical particle of Dowex 50 W was used. The plastic deformation of the fillers, such as MCC and SDRS, caused a little change in the release of DMP. A higher release rate constant was found in the tablets containing DCP and Dowex 50 W, indicating the fracture of the resinates under compression, which was attributable to the fragmentation of DCP. However, the release of DMP from the tablets using Amberlite IRP69 was not significantly changed because of the higher degree of cross-linking of the resinates, which exhibited more resistance to deformation under compression. In conclusion, the properties of polysulfonate resin, such as particle shape and degree of cross-linking, and the deformation under compaction of fillers affect the physical properties and the drug release of the resinate tablets.

Molecular properties of ciprofloxacin-Indion 234 complexes.

The purpose of this research was to formulate tasteless complexes of ciprofloxacin with Indion 234 and to evaluate molecular properties of drug complexes. The effect of batch and column process, complexation time, temperature, and pH on ciprofloxacin loading on Indion 234 is reported. Drug resin complexes (DRC) were characterized by infrared spectroscopy, thermal analysis, and x-ray diffraction pattern. Ciprofloxacin release from DRC is obtained at salivary and gastric pH and in the presence of electrolytes. The efficient drug loading was evident in batch process using activated Indion 234 with a drug-resin ratio of 1:1.3. Drug complexation enhanced with pH from 1.2 to 6, while temperature did not affect the complexation process. Infrared spectroscopy revealed complexation of -NH (drug) with Indion 234. DRC are amorphous in nature. Drug release from DRC in salivary pH was insufficient to impart bitter taste. Volunteers rated the complex as tasteless and agreeable. Complete drug release was observed at gastric pH in 2 hours. The drug release was accelerated in the presence of electrolytes. Indion 234 is inexpensive, and the simple technique is effective for bitterness masking of ciprofloxacin.

Drug release properties of polyethylene-glycol-treated ciprofloxacin-Indion 234 complexes.

The polyethylene glycol (PEG) treatment of ciprofloxacin-Indion 234 complex was aimed to retard rapid ion exchange drug release at gastric pH. Ciprofloxacin loading on Indion 234 was performed in a batch process, and the amount of K(+) in Indion 234 displaced by drug with time was studied as equilibrium constant K(DM). Drug-resin complex (DRC) was treated with aqueous PEG solution (0.5%-2% wt/vol) of different molecular weights (MWs) for 2 to 30 minutes. The PEG-treated ciprofloxacin-Indion 234 complex was evaluated for particle size, water absorption time, and drug release at gastric pH. During drug loading on Indion 234, the equilibrium constant (K(DM)) increased rapidly up to 20 minutes with efficient drug loading. Increased time of immersion of the drug resinate in PEG solutions significantly retained higher size particles upon dehydration. The larger DRC particles showed longer water absorption times owing to compromised hydrating power. The untreated DRC showed insignificant drug release in deionized water; while at gastric pH, ciprofloxacin release was complete in 90 minutes. A trend of increased residual particle size, proportionate increase in water absorption time, and hence the retardation of release with time of immersion was evident in PEG-treated DRC. The time of immersion of DRC in PEG solution had predominant release retardant effect, while the effect of molecular weight of PEG was insignificant. Thus, PEG treatment of DRC successfully retards ciprofloxacin ion exchange release in acidic pH.

Development of a novel nasal nicotine formulation comprising an optimal pulsatile and sustained plasma nicotine profile for smoking cessation.

A novel nasal formulation, in the form of a nicotine-Amberlite resin complex powder has been developed that provided an optimal combined pulsatile and sustained plasma nicotine profile for smoking cessation. The adsorption isotherms of nicotine hydrogen tartrate salt on two types of Amberlite resins (IRP69 and IR120) were evaluated and the subsequent in vitro release properties of nicotine from the nicotine-Amberlite complex powders were tested using a Franz diffusion cell. Amberlite IRP69 and Amberlite IR120 are similar cationic exchange materials with the same ion-exchange capacity but due to a smaller particle size range (10-150 microm) Amberlite IRP69 had a better flow property and a better adsorptive capacity than Amberlite IR120. The material is used as an excipient in marketed pharmaceutical formulations. The highly water soluble salt, nicotine hydrogen tartrate, displayed good adsorption onto both types of Amberlite resin. The maximum adsorption of nicotine onto Amberlite IRP69 was 1.071 mg drug per mg resin. The cumulative release of drug from nicotine hydrogen tartrate-Amberlite complex powders showed that the higher the drug loading, the faster was the rate of release of the drug. Based on these results, various nicotine hydrogen tartrate-Amberlite IRP69 powder formulations containing different ratios of free to bound drug (50% to 100% bound) and a control solution were prepared and evaluated in a sheep model by nasal administration. The nicotine plasma profiles demonstrated that an initial rapid peak plasma level of nicotine followed by a sustained elevated level could be achieved by adjusting the ratio of free to bound nicotine in the Amberlite powder formulation. The curves obtained from some of the formulations were comparable to those predicted from a computer-generated pharmacokinetic model.

Estudo sobre a biocompatibilidade da polisulfona sob a forma de partículas e bastöes / Study of biocompatibility of particles and rods of polysulfone

Foi estudada comparativamente a resposta do músculo tríceps sural e reto do abdome de ratos Wistar à implantação da polisulfona (PSU) e do polietileno de ultra alto peso molecular (UHMWPE) sob a forma de bastões e partículas, por um período de até 52 semanas. Ao final, a PSU foi considerada como tendo a mesma biocompatibilidade do UHMWPE, segundo os critérios utilizados.

Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis.

BACKGROUND: Active distal ulcerative colitis is often resistant to topically acting oral formulations. We speculated that the left side of the colon is underexposed to orally-dosed topical agents in patients with active distal colitis. METHODS: Twenty-two healthy volunteers (12 males, aged 22-47 years), and 10 patients (6 males, aged 33-73 years) with active left-sided ulcerative colitis ingested a Eudragit-coated gelatine capsule containing 111In-labelled amberlite resin on four successive days. Regional colonic distribution, transit times and percentage of daily dose resident were calculated from the average of four serial gamma camera images on the 4th day. RESULTS: (mean [95% CI]). When compared to controls, patients with colitis had significantly faster total colon transit (24.3 h [9.5-39.1] vs. 51.7 h [41.1-62.3]) as well as faster proximal colon transit (18.7 h [9.1-28.3] vs. 36.7 [28.5-44.9]), and distal colon transit (3.1 h [-0.5 to 6.8] vs. 15.0 h [10.5-19.5]), respectively (all P < 0.01). Material was asymmetrically distributed in health (proximal colon 69% [63-76] vs. distal colon 31% [24-37]). This asymmetry was more extreme in colitis, with corresponding values of 91% [85-96] vs. 9% [4-15]. As a result colitics had less material in the left-sided colon (9% [4-15] vs. 31% [24-37]), P < 0. 001. Colitics had a significantly lower percentage of the daily dose resident within the left side of the colon compared to controls (13% [-2 to 28] vs. 63% [44-81]), P < 0.01. CONCLUSIONS: Delayed release oral formulation is asymmetrically distributed within the colon in health. This asymmetry is exaggerated in active left-sided ulcerative colitis and, together with faster colonic transit, results in reduced exposure of the distal colon to orally-dosed topical agents.

Bioavailability of components of resin-based materials which are applied to teeth.

Chemical components of many materials used in dental practice can move into the local biophase, where they can have beneficial or adverse effects. The strongest indirect evidence that components of resin-based materials used in dentistry can move into the biophase are the many reports of allergic dermatitis in dental personnel. Direct measurement of component release has shown that triethylene glycol dimethacrylate (TEGDMA), hydroxyethyl methacrylate (HEMA), and, in the case of some orthodontic cements, bis-glycidyl methacrylate and benzoyl peroxide can move into an aqueous medium from a range of resin-based materials which are applied to teeth as part of oral care. In the case of resin composite restorations, HEMA and TEGDMA are available in microgram quantities via the salivary surface in the minutes and hours after clinical placement and via dentin and pulp in the hours and days after placement. Fortunately, moderate thickness of dentin protects pulp tissue against local toxicity. There are no data which suggest that systemic toxicity is a risk with any of these materials. There are some case reports of allergic responses to the monomers in patients, but the incidence of such responses appears at present to be much lower than that in dental personnel.

Immunoconjugates of doxorubicin and murine antihuman breast carcinoma monoclonal antibodies prepared via an N-hydroxysuccinimide active ester intermediate of cis-aconityl-doxorubicin: preparation and in vitro cytotoxicity.

Doxorubicin (DXR) conjugated to murine monoclonal antibodies (MoAb) raised against human breast tumor cells demonstrated a MoAb-specific, molar ratio-dependent in vitro cytotoxicity. These conjugates were prepared on a scale sufficient to allow for subsequent clinical trials (1 to 3 g of MoAb per conjugation reaction). The conjugation reaction proceeded via an N-hydroxysuccinimide (NHS) active ester intermediate of cis-aconityl-DXR (CA-DXR), resulting in a cis-aconitate acid-sensitive linker between the DXR and MoAb. Molar ratios of DXR to MoAb ranged from 40 to 45. The immunoreactivity of conjugated MoAb was only slightly decreased from naked MoAb. When immunoconjugates were incubated with MoAb-reactive tumor cells for 3 hours, specific cell-killing was observed. If the exposure time was lengthened to 18 hours, however, nonspecific killing resulted. Incubation of the immunoconjugate with the nonspecific adsorbant Amberlite XAD-2 caused an average 30% decrease in the DXR-to-MoAb molar ratio, suggesting a population of drug that is tightly but noncovalently associated with MoAb.