Temperature/near-infrared light-responsive conductive hydrogels for controlled drug release and real-time monitoring.

Stimuli-responsive hydrogels with adaptable physical properties show great potential in the biomedical field. In particular, the collection of electrical signals is essential for precision medicine. Here, a simple strategy is demonstrated for achieving controlled drug release and real-time monitoring using an interpenetrating binary network consisting of a graphene aerogel and a poly(N-isopropylacrylamide) hydrogel with incorporated polydopamine nanoparticles (PDA-NPs). Owing to the good physical properties of graphene and the embedded PDA-NPs, the hybrid hydrogel shows enhanced mechanical properties and good electrical conductivity. In addition, the hybrid hydrogel also shows dual thermo- and near-infrared light responsiveness, as revealed by the controlled release of a model drug. In addition, as the hydrogel exhibits detectable changes in resistance during drug release, the drug-release behavior of the hydrogel can be monitored in real time using electrical signals. Moreover, owing to the abundance of catechol groups on the PDA-NPs, the hybrid hydrogel shows good tissue adhesiveness, as demonstrated using in vivo experiments. Thus, the developed hybrid hydrogel exhibits considerable practical applicability for drug delivery and precision medicine.

In vivo and in vitro bioactivity of a "precursor of apatite" treatment on polyetheretherketone.

We recently developed a surface treatment, "precursor of apatite" (PrA), for polyetheretherketone (PrA-PEEK) via a simple, low-temperature process aiming to achieve stronger and faster adhesion to bone. The treatment involves three steps: H2SO4 immersion, exposure to O2 plasma discharge, and alkaline simulated body fluid (alkaline SBF) treatment. This method produces homogeneous fine particles of amorphous calcium phosphate on the PEEK, and we confirmed that PrA-PEEK had excellent apatite formation ability in an SBF immersion test. In the present study using PEEK implants in rabbit tibia, mechanical tests, and histological and radiological analyses revealed that PrA provided the PEEK substrate with excellent bone-bonding properties and osteo-conductivity at early stages (4 and 8 weeks), extending to 16 weeks. In vitro study using MC3T3-E1 cells revealed via XTT assay that PrA on the PEEK substrate resulted in no cytotoxicity, though PrA treatment seemed to suppress gene expression of integrin ß-1 and Alp after 7-day incubation as shown by real-time PCR. On the whole, PrA treatment succeeded in giving in vivo bone-bonding properties to the PEEK substrate, and the treatment is a safe and promising method that can be applied in clinical settings. There was an inconsistency between in vivo and in vitro bioactivity, and this discrepancy indicated that apatite formation does not always need activation of osteoblasts at very early stage and that optimal conditions at cell and organism level may be different. STATEMENT OF SIGNIFICANCE: Polyetheretherketone (PEEK) is an attractive engineering polymer used for spine and dental surgery. To further improve clinical outcome of PEEK-based materials, we developed "Precursor of apatite" (PrA) treatment on the PEEK surface to confer bone-bonding properties. The advantages of this treatment are that it does not require high-temperature processing or special chemicals, and it is inexpensive. The present study clarified excellent in vivo bone-bonding property of PrA treatment. In addition, the results revealed important insights indicating that optimal conditions, especially wettability and crystallinity in calcium phosphate, differ at cell and organism levels. Moreover, our results indicated that prediction of in vivo bioactivity should be done in combination with multiple in vitro tests.

An in situ photocrosslinkable platelet rich plasma - Complexed hydrogel glue with growth factor controlled release ability to promote cartilage defect repair.

The repair of articular cartilage injury is a great clinical challenge. Platelet-rich plasma (PRP) has attracted much attention for the repair of articular cartilage injury, because it contains various growth factors that are beneficial for wound repair. However, current administration methods of PRP have many shortcomings, such as unstable biological fixation and burst release of growth factors, all of which complicate its application in the repair of articular cartilage and compromise its therapeutic efficacy. In this study, based on our previously reported photoinduced imine crosslinking (PIC) reaction, we developed an in situ photocrosslinkable PRP hydrogel glue (HNPRP) through adding a photoresponsive hyaluronic acid (HA-NB) which could generate aldehyde groups upon light irradiation and subsequently react with amino groups, into autologous PRP. Our study showed that HNPRP hydrogel glue was cytocompatible and could be conveniently and rapidly prepared in situ, forming a robust hydrogel scaffold. In addition, our results demonstrated that HNPRP hydrogel not only achieved controlled release of growth factors, but also showed strong tissue adhesive ability. Therefore, HNPRP hydrogel was quite suitable for cartilage defect regeneration. Our further in vitro experiment showed that HNPRP hydrogel could promote the proliferation and migration of chondrocytes and bone marrow stem cells (BMSCs). In vivo testing using a rabbit full-thickness cartilage defect model demonstrated that HNPRP hydrogel could achieve integrative hyaline cartilage regeneration and its therapeutic efficacy was better than thrombin activated PRP gel. STATEMENT OF SIGNIFICANCE: In this study, we have developed a photocrosslinkable platelet rich plasma (PRP) - complexed hydrogel glue (HNPRP) for cartilage regeneration. The in situ formed HNPRP hydrogel glue showed not only the controlled release ability of growth factors, but also strong tissue adhesiveness, which could resolve the current problems in clinical application of PRP. Furthermore, HNPRP hydrogel glue could promote integrative hyaline cartilage regeneration, and its reparative efficacy for cartilage defect was better than thrombin activated PRP gel. This study provided not only an effective repair material for cartilage regeneration, but also developed an advanced method for PRP application.

Effect of intra-alveolar placement of 0.2% chlorhexidine bioadhesive gel on the incidence of alveolar osteitis following the extraction of mandibular third molars. A double-blind randomized clinical trial

Alveolar osteitis (AO) is a common complication after third molar surgery. One of the most studied agents in its prevention is chlorhexidine (CHX), which has proved to be effective. OBJECTIVES: The aim of this randomized double-blind clinical trial was to evaluate the efficacy of 0.2% bioadhesive chlorhexidine gel placed intra-alveolar in the prevention of AO after the extraction of mandibular third molars and to analyze the impact of risk factors such as smoking and oral contraceptives in the development of AO. Study DESIGN: The study was a randomized, double-blind, clinical trial performed in the Ambulatory Surgery Unit of Hospital Vall d'Hebron and was approved by the Ethics Committee. A total of 160 patients randomly received0.2% bioadhesive gel (80 patients) or bioadhesive placebo (80 patients).RESULTS: 0.2% bioadhesive chlorhexidine gel applied in the alveolus after third molar extraction reduced the incidence of dry socket by 22% compared to placebo with differences that were not statistically significant. Smoking and the use of oral contraceptives were not related to higher incidence of dry socket. Female patients and the difficulty of the surgery were associated with a higher incidence of AO with statistically significant differences.0.2% bioadhesive chlorhexidine gel did not produce any of the side effects related to chlorhexidine rinses. CONCLUSIONS: A 22% reduction of the incidence of alveolar osteitis with the application of 0.2% bioadhesive chlorhexidinegel compared to placebo with differences that were not statistically significant was found in this clinical trial. The lack of adverse reactions and complications related to chlorhexidine gel supports its clinical use specially in simple extractions and adds some advantages compared to the rinses in terms of duration of the treatment and reduction of staining and taste disturbance

In vivo toxicity and biodistribution of intraperitoneal and intravenous poly-L-lysine and poly-L-lysine/poly-L-glutamate in rats.

The combination of two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), has shown excellent postsurgical antiadhesive properties. However, the high molecular, positively charged PL is toxic in high doses, proposed as lysis of red blood cells. This study aims to elucidate the in vivo toxicity and biodistribution of PL and complex bound PLPG comparing intravenous and intraperitoneal administration. Fifty-six Sprague-Dawley rats were used in a model with repeated blood samples within 30 min examining blood gases and blood smears. Similarly, FITC labelled PL were used to track bio distribution and clearance of PL, given as single dose and complex bound to PG after intravenous and intraperitoneal administration. Tissue for histology and immunohistochemistry was collected. Blood gases and blood smears as well as histology points to a toxic effect of high dose PL given intravenously but not after intraperitoneal administration. The toxic effect is exerted through endothelial disruption and subsequent bleeding in the lungs, provoking sanguineous lung edema. FITC-labelled PL experiments reveal a rapid clearance with differences between routes and complex binding. This study advocates a new theory of the toxic effects in vivo of high molecular PL. PLPG complex is safe to use as antiadhesive prevention based on this toxicity study given that PL is always intraperitoneally administered in combination with PG and that the dose is adequate.

Fibrin chain cross-linking, fibrinolysis, and in vivo sealing efficacy of differently structured fibrin sealants.

In this study, we compared the sealing characteristics and efficacy of a fibrin sealant with reduced plasminogen (FS-rplg) and a fibrin sealant with aprotinin as a fibrinolysis inhibitor (FS-apr). The relevant sealing characteristics including clot structure, fibrin chain cross-linking, and clot lysis were tested in the laboratory. The sealing efficacy was then investigated in a follow-up animal model to determine differences in the in vivo sealing properties. A total of 46 animals were available for the final analysis with 23 animals in each treatment arm. In conclusion, we saw differences in vitro between FS-rplg and FS-apr in ultrastructure and α-chain cross-linking rates as well as in the rate of fibrinolysis. These differences may explain the significantly enhanced sealing efficacy in FS-apr compared to FS-rplg shown in vivo in a rabbit intestinal model.

Enhanced tissue penetration-induced high bonding strength of a novel tissue adhesive composed of cholesteryl group-modified gelatin and disuccinimidyl tartarate.

The aim of this study was to evaluate the effect of cholesteryl group content on the bonding strength of a novel tissue adhesive composed of cholesteryl group-modified geletin (CholGltn) and disuccinimidyl tartarate (DST). The bonding strength of this tissue adhesive with fresh arterial media reached a maximum at a CholGltn content of 70% in the CholGltn/gelatin (Gltn) mixture, which then decreased with increasing CholGltn content with a fixed succinimidyl group:amino group ratio of 1:1. The maximum bonding strength obtained was 6-fold higher compared with that of the original Gltn. Furthermore, maximum peeling strength was also obtained at a CholGltn content of 70% in the CholGltn/Gltn mixture and at a similar succinimidyl group:amino group ratio. The highest peeling strength was 8-fold higher compared with Gltn and 6-fold higher compared with commercial aldehyde-based adhesive. After exposure of FITC-labeled Gltn or CholGltn to aortic smooth muscle cells (SMCs), which are abundant in arterial media, CholGltn integrated effectively with the surface of SMCs. This indicated that FITC-labeled CholGltn anchors into the cell membrane of SMCs. From these results, it was demonstrated that tissue adhesive composed of a CholGltn/Gltn mixture and DST showed improved penetration into arterial media compared with adhesive composed of Gltn and DST. This behavior supports the suggestion that the hydrophobic cholesteryl group in Gltn contributes to the enhanced bonding/peeling strength. This novel tissue adhesive may become a useful material in the clinical field for the treatment of aortic dissection.

Bioadhesive microspheres for bioavailability enhancement of raloxifene hydrochloride: formulation and pharmacokinetic evaluation.

Raloxifene hydrochloride (R-HCl), a BCS class II drug, remains a mainstay in the prevention and pharmacologic therapy of osteoporosis. Its absolute bioavailability, however, is 2% due to poor solubility and extensive first pass metabolism. The present study describes two simultaneous approaches to improve its bioavailability, complexation of R-HCl with cyclodextrin(s), and formulation of mucoadhesive microspheres of the complex using different proportions of carbopol and HPMC. Microspheres were pale yellow in color, free-flowing, spherical, and porous in outline. The particle size ranged between 3 and 15 µm, and entrapment efficiency was found to be within 81.63% to 87.73%. A significant improvement in the solubility of R-HCl was observed, and it differed with the combination of excipients used. X-ray diffraction and differential scanning calorimetry studies revealed that enhancement in drug solubility was resulted due to a change in its crystallinity within the formulation. Microspheres possessed remarkable mucoadhesion and offered controlled drug release, lasting up to 24 h. They produced a sharp plasma concentration-time profile of R-HCl within 30 min post-administration to Wistar rats. [AUC](0-24 h) was found to be 1,722.34 ng h/ml, and it differed significantly to that of pure drug powder (318.28 ng h/ml). More than fivefold increase in AUC and more than twofold increase in MRT were observed. FT-IR studies evidenced no interaction among drug and excipients. The results of this study showed that mucoadhesive microspheres could be a viable approach to improve the pharmacokinetic profile of R-HCl.

Lipid-core nanocapsules restrained the indomethacin ethyl ester hydrolysis in the gastrointestinal lumen and wall acting as mucoadhesive reservoirs.

The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from lipid-core nanocapsules (NC) is converted into indomethacin (IndOH) in the intestine lumen, intestine wall or after the particles reach the blood stream. NC-IndOEt had monomodal size distribution (242 nm; PDI 0.2) and zeta potential of -11 mV. The everted rat gut sac model showed IndOEt passage of 0.16 micromol m(-2) through the serosal fluid (30 min). From 15 to 120 min, the IndOEt concentrations in the tissue increased from 6.13 to 27.47 micromol m(-2). No IndOH was formed ex vivo. A fluorescent-NC formulation was used to determine the copolymer bioadhesion (0.012 micromol m(-2)). After NC-IndOEt oral administration to rats, IndOEt and IndOH were detected in the gastrointestinal tract (contents and tissues). In the tissues, the IndOEt concentrations decreased from 459 to 5 microg g(-1) after scrapping, demonstrating the NC mucoadhesion. In plasma (peripheric and portal vein), in spleen and liver, exclusively IndOH was detected. In conclusion, after oral dosing of NC-IndOEt, IndOEt is converted into IndOH in the intestinal lumen and wall before reaching the blood stream. The complexity of a living system was not predicted by the ex vivo gut sac model.

Evaluation of the mechanical properties and drug release of cross-linked Eudragit films containing metronidazole.

The mechanical properties of casted Eudragit E-100 films were tested for the combined effect of two cohesion promoters (succinic or citric acid) and triacetin as a plasticizer. The prepared films were elastic, self-adhesive, transparent and pale yellow in colour. Films containing either of the tested cohesion promoters showed a significant reduction in both tensile strength and Young's modulus on increasing triacetin and/or cohesion promoter concentration. Films containing 7% (w/w) succinic acid and 45% (w/w) triacetin gave the highest elongation of the tested films at any given stress with a maximum of 1050% elongation. Optimal bonding to human skin surface (tack) with the highest peel adhesion (588 cN/cm) was observed with these films denoting good self-adhesive properties. In vitro metronidazole (MN) release from the plasticized Eudragit E-100 films was monitored for the influence of incorporation of cohesion promoters, secondary polymer (Eudragit RL or RS) as well as drug loading. Both cohesion promoters were seen to improve MN release from the films with the maximum drug flux (0.334 mg cm(-2) h(-1)) observed with 1.75% (w/w) succinic acid. The tested secondary polymers were also found to improve MN release from the tested films. The highest MN release was observed with 20% (w/w) Eudragit RL which gave 0.77 mg cm(-2) released after 3 h compared with only 0.34 mg cm(-2) for plain films. MN release from the films was increased by increasing drug load. Calculating the release rate constant (K(r)) showed a linear increase with the increase in drug load.

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases.

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.

Biochemical and histopathological findings of N-butyl-2-cyanoacrylate in oral surgery: an experimental study.

OBJECTIVES: The increasing use of cyanoacrylates in dentistry, particularly as an adhesive and sealing glue, has raised concerns regarding its potential toxicity in humans. Several different forms of these compounds including methyl- (MCA), ethyl- (ECA), isobutyl-, isohexyl-, and octyl CA have been developed to eliminate tissue toxicity. N-butyl-2-cyanoacrylate is becoming an increasingly popular method for wound closure under low tension. Despite their increasing use, pharmacologic effects of these substances on liver and kidney functions are not widely known. The objective of the present study was to investigate possible immediate and long-term systemic effects of N-butyl-2-cyanoacrylate in oral surgery. STUDY DESIGN: Ten male Wistar rats weighing 220 to 270 g were used in the study. Straight incisions were made to the buccal mucosa of the animals. N-butyl-2-cyanoacrylate adhesive (Indermil) was applied and wounds were closed primarily. Blood specimens were taken periodically from the vena cava of the animals before the surgical procedure and 2, 14, 21, and 65 days after the surgical procedure. The blood specimens of those taken before the application of the adhesive were defined as the control group; blood specimens that were taken 2, 14, 21, and 65 days from the application were defined as study group. The stored plasma samples were analyzed for blood urea nitrogen (BUN), creatinine (CRE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBI), total protein (TP), albumin (ALB), and amylase (AML). In addition to biochemical parameters, histopathological examination was performed. Blood parameter values of the control and study groups were statistically compared with the Duncan test (P < .05). RESULTS: There were no significant differences in the values of BUN, CRE, ALT, AST, TBI, TP, ALB, and AML between the control and at 2, 14, 21, and 65 days. CONCLUSION: The present study shows that N-butyl-2-cyanoacrylate is a suitable adhesive applicable in oral surgery.

A mucoadhesive in situ gel delivery system for paclitaxel.

MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell.

What happens to hemostatic agents in contact with urine? An in vitro study.

BACKGROUND AND PURPOSE: As the indications for topical hemostatic agents increase in urology, the question arises: what happens to these agents when they enter the urinary collecting system? To answer this question, we performed a series of in-vitro experiments mixing three hemostatic agents with normal and sanguineous urine. MATERIALS AND METHODS: Four commercially available topical hemostatic products: oxidized regenerated cellulose (Surgicel; Ethicon, Somerville, NJ), fibrin sealant (Tisseel VH Kit; Baxter Health Care Corporation, Irvine, CA), gelatin matrix hemostatic sealant (FloSeal; Baxter Health Care), and polyethylene glycol (CoSeal; Cohesion Technologies, Palo Alto, CA) were studied. Human urine (10 mL) was added to samples of each substance; this was done in triplicate. The 12 sample tubes were then capped and placed on a tube shaker at slow speed and 37 degrees C. Observations regarding consistency of the material were made at 6, 12, 24, 48, 72, 96, and 120 hours (5 days). Gelatin matrix hemostatic sealant was further tested in urine with various amounts of blood or blood clot; observations were again recorded out to 5 days. RESULTS: Surgicel maintained its solid form when it initially came in contact with urine, but over a period of 5 days, it transformed into a mucoid substance with visible free-floating fibers. It did not dissolve completely in urine within 5 days. Gelatin matrix was immediately transformed by urine into a fine colloidal suspension that did not change over the 5 days of the study. Fibrin glue, after mixing of the two components (fibrinogen and thrombin) directly in the urine, and polyethylene glycol immediately formed a solid clot at the bottom of the test tube on contact with the urine. When the mixture of fibrin sealant was allowed to form for 15 minutes and then added to urine, it again maintained a solid form. After 72 hours, the fibrin glue became a semisolid gelatinous plug. On analysis at 5 days, the fibrin sealant clot had transformed into a cohesive mucoid gel, and the polyethylene glycol clot had not changed. The gelatin matrix hemostatic sealant, when in contact with blood or blood clot, appeared to either become part of a clot or to remain in a colloidal suspension. At 5 days, all clots had dissolved to fine particulate suspensions, and the gelatin matrix appeared as a fine suspension. CONCLUSION: Fibrin glue and oxidized regenerated cellulose maintain a solid form when initially placed in direct contact with urine and then assume a semisolid gelatinous state, which is still present at 5 days. Polyethylene glycol forms a solid clot initially and does not change after 5 days. Only hemostatic gelatin matrix remained as a fine particulate suspension in both normal and sanguineous urine. The implications of these findings with regard to sealing the renal parenchyma or small violations of the collecting system after percutaneous or laparoscopic surgery await in-vivo testing.

Fast-dissolving mucoadhesive microparticulate delivery system containing piroxicam.

We have studied the feasibility of preparing fast-dissolving mucoadhesive microparticulate delivery systems containing amorphous piroxicam to improve drug residence time on sublingual mucosa and drug dissolution rate. Two new mucoadhesive carriers, Eudragit L100 (EuLNa) and Eudragit S100 (EuSNa) sodium salts, both characterized by a fast intrinsic dissolution rate, have been selected. Microparticles containing piroxicam and EuLNa (series 1) or EuSNa (series 2) in ratios from 15/85 to 85/15% (m/m) were prepared by spray drying. The morphology and physical state of the microparticles and the effect of the microparticle composition on the piroxicam release and mucoadhesion were investigated. Piroxicam loaded into the microparticles was found to be in the amorphous form at all drug/copolymer ratios. This feature was ascribed to the presence of an H-bond between the NH of piroxicam and a CO of the copolymers. The formation of solid solutions improved the dissolution rate and the apparent drug solubility. The mucoadhesive properties were affected by the drug/copolymer ratio and in series 2 the microparticles containing more than 50% (m/m) of piroxicam did not show mucoadhesive properties. The delivery system made of piroxicam and EuLNa in the ratio 70/30% (m/m) appears to be the most promising because it contains the lowest amount of polymer able to confer mucoadhesive properties and increase apparent drug solubility.

Bioadhesive oesophageal bandages: protection against acid and pepsin injury.

The rate of acid and pepsin diffusion through solutions of sodium alginate was measured using in vitro techniques. Previous work has demonstrated that solutions of alginate may adhere to the oesophagus for up to 60 min; this work measured their ability to protect the oesophageal epithelial surface from damage caused by refluxed acid and pepsin. Franz diffusion cells were used to measure the rate of acid and pepsin diffusion through an alginate layer. The effect of the type of alginate, alginate concentration and depth of alginate applied were investigated. The rate of both acid and pepsin diffusion was significantly reduced (ANOVA analysis; P<0.05) in the presence of an alginate solution compared to the control. A 2% (w/v) alginate solution with a high guluronic acid component, in a layer of 0.44 mm depth, demonstrated the greatest reduction in acid diffusion with a permeation coefficient 14% than that of a control value. All three alginates demonstrated significant reductions in acid diffusion with both increasing depth and increasing concentration, as expected. Pepsin diffusion was also significantly reduced as the depth and concentration of applied alginate increased. This study demonstrates that an adhesive layer of alginate present within the oesophagus will limit the contact of refluxed acid and pepsin with the epithelial surface.

Absorption of ethyl 2-cyanoacrylate tissue adhesive.

The aim of this study was to investigate absorption of ethyl 2-cyanoacrylate glue when used as a tissue adhesive. Ethyl 2-cyanoacrylate was applied subcutaneously to four rats; its presence in blood and urine was investigated by using High Pressure Liquid Chromatography. Blood samples were drawn at baseline and after 2, 4, 6, 24, 48, 54, 78, 96 hours following application. Urine samples were obtained at baseline and after 4, 24, 48, 72, 96 hours. Administration of ethyl 2-cyanoacrylate resulted in its absorption of unchanged ethyl 2-cyanoacrylate and unknown metabolites, in plasma and urine.

Formulation and evaluation of limonene-based membrane-moderated transdermal therapeutic system of nimodipine.

The aim of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2% w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing 4% w/w of limonene as a penetration enhancer. The permeability flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer (9 to 28%). The effect of pressure-sensitive adhesives such as TACKITE A 4MED on the permeability of nimodipine through EVA membrane 2825 (28% w/w vinyl acetate) or membrane/rat skin composite also was studied. The permeability flux of nimodipine from the chosen EVA 2825 (with 28% vinyl acetate content) was 159.72 +/- 1.96 microg/cm2/hr, and this flux further decreased to 141.85 +/- 1.54 microg/cm2/hr on application of pressure-sensitive adhesive (TACKWHITE A 4MED). However, the transdermal permeability flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/rat skin composite was found to be 126.59 +/- 2.72 microg/cm2/hr, which is 1.3-fold greater than the required flux. Thus, a new transdermal therapeutic system for nimodipine was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED and 2% w/w HPMC gel as reservoir containing 4% w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nimodipine, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 20 hr with improved bioavailability in comparison with the immediate release tablet dosage form.

Pharmacodynamic-pharmacokinetic profiles of metformin hydrochloride from a mucoadhesive formulation of a polysaccharide with antidiabetic property in streptozotocin-induced diabetic rat models.

The antidiabetic property of a formulation containing metformin hydrochloride and detarium gum has been evaluated in streptozotocin model of experimental rats. Both the gum and metformin hydrochloride possess antidiabetic properties to varying degrees. The pharmacokinetics of metformin from the mucoadhesive dosage forms indicated that for metformin alone, the area under the curve (AUC) values were 125.6 and 135.6 mgh/ml at 200 and 400 mg/kg BW, respectively. For the mucoadhesive products using the same dose levels, the AUCs were modified to 102.4 and 150.2 in detarium gum and 59.9 and 80.4 in NaCMC. The results indicate that detarium gum is a good excipient for the formulation of metformin mucoadhesive delivery systems when compared with NaCMC. The gum also showed promising antidiabetic effect and should be cautiously used as it may lead to depressed blood-glucose levels beyond the desired levels.

Evaluation of mucoadhesive properties of chitosan microspheres prepared by different methods.

The mucoadhesive properties of chitosan microspheres prepared by different methods were evaluated by studying the interaction between mucin and microspheres in aqueous solution. The interaction was determined by the measurement of mucin adsorbed on the microspheres. A strong interaction between chitosan microspheres and mucin was detected. The intensity of the interaction was dependent upon the method of preparation of chitosan microspheres and the amount of mucin added. The extent of mucus adsorption was proportional to the absolute values of the positive zeta potential of chitosan microspheres. The zeta potential in turn was found to be dependent upon the method of preparation of microspheres. The adsorption of type III mucin (1% sialic acid content) was interpreted using Freundlich or Langmuir adsorption isotherms. The values of r2 were greater for Langmuir isotherm as compared with Freundlich isotherm. The adsorption of a suspension of chitosan microspheres in the rat small intestine indicated that chitosan microspheres prepared by tripolyphosphate cross-linking and emulsification ionotropic gelation can be used as an excellent mucoadhesive delivery system. The microspheres prepared by glutaraldehyde and thermal cross-linking showed good stability in HCl as compared with microspheres prepared by tripolyphosphate and emulsification ionotropic gelation.