Mucoadhesion of Latexes. II. Adsorption Isotherms and Desorption Studies

Adsorption isotherms of poly(styrene) latexes on rat intestinal mucosa were studied under static conditions and analyzed according to different isotherm classifications. Isotherms of latexes with a particle size up to 670 nm had the characteristic shape of a disperse adsorbate on a porous adsorbent. Plateaus were reached at latex concentrations of about 2.5 g/L. The results indicated an increase in adsorption with the size and the hydrophilicity of the latexes. Typically, a surfactant-free carboxylate latex of 230 nm had a plateau of 0.66 g/m², and a latex of 320 nm with added sodium dodecyl sulfate had a plateau of 0.881 g/m². Surfactant-free carboxylate latex of 2 µm had a Langmuirian isotherm with a plateau level of 2.616 g/m², which corresponded to a monolayer of adsorbed particles on the surface of mucosa. Desorption studies showed that the adsorption was irreversible. Adhesion to the mucous gel layer would therefore be limited by the mucus turnover.     

Fabrication of porous polyethyleneimine-functionalized chitosan/Span 80 microspheres for adsorption of diclofenac sodium from aqueous solutions

Porous surface-modified microspheres can have widespread applications in the removal of wastewater pollutants. In this study, using a nonionic surfactant (Span80) as the pore-forming agent and Zr⁴⁺ as the cross-linking agent, polyethyleneimine (PEI)-modified porous CYCTS/Span80 microspheres ((CYCTS/Span80)-@-PEI) were successfully prepared for the adsorptive removal of diclofenac sodium (DS) from wastewater. The adsorbent was characterized using Fourier-transform infrared spectroscopy, energy-dispersive X-ray spectrometry, scanning electron microscopy, and X-ray diffractometry. The activity of the porous (CYCTS/Span80)-@-PEI microspheres as adsorbents of DS was investigated by varying the experimental parameters (i.e., adsorbent dosage, adsorbent ratio, pH, contact time, temperature, and pollutant concentration). A possible adsorption mechanism was also discussed. The experimental results showed that the adsorption process followed a pseudo-second order kinetic model and the Langmuir adsorption isotherm model, in addition to the Freundlich isotherm model, indicating that the porous structure allowed multi-layer adsorption. Adsorption equilibrium was reached after 240 min at pH 5 and 303 K, yielding a maximum adsorption capacity of 572.67 mg/g. After five adsorption cycles, the removal rate of DS remained >80%, and the recovery rate was high. Therefore, we concluded that the porous (CYCTS/Span80)-@-PEI microspheres are efficient and inexpensive candidates for the removal of DS from wastewater.     

In vitro evaluation of the mucoadhesive properties of chitosan microspheres

The mucoadhesive properties of chitosan and chitosan microspheres were evaluated by studying the interaction between mucin and chitosan in aqueous solution by turbidimetric measurements and the measurement of mucin adsorbed on the microspheres. A strong interaction between chitosan microspheres and mucin was detected. Adsorption studies were carried out for the adsorption of mucin to chitosan microspheres with different crosslinking levels. The adsorption of type III mucin (1% sialic acid content), to chitosan microspheres followed Freundlich or Langmuir adsorption isotherms. When the contents of sialic acid was increased (i.e. type I-S mucin, 12% sialic acid content), the adsorption type followed more closely an electrostatic attraction type of isotherm. The heat of the adsorption was found to be 13–23 kJ/mol. A salt-bridge effect has been proposed for the interaction of the positively charged mucoadhesive chitosan microspheres with the negatively charged mucus glycoprotein. The extent of mucus adsorption was proportional to the absolute values of the positive zeta potential of chitosan microspheres and negative `zeta potential' of mucus glycoprotein. Factors leading to a reduction or a reversal of these absolute values (e.g. different crosslinking levels of chitosan microspheres, different types of mucin, different pH, or ionic strength of the medium used) led to a reduction in the amount adsorbed. The extent of this reduction depended upon the decreasing extent of the repective zeta potentials. Biological studies showed that chitosan microspheres were retained by a biological tissue; rat small intestine.     

Biosorption of ibuprofen using functionalized bean husks

The ability of bean husk, an agricultural waste, as a promising adsorbent for sequestering Ibuprofen from aqueous solution was investigated. Bean husk waste was modified using ortho-phosphoric acid. The prepared adsorbent was further characterized using FTIR, SEM, EDX and pH_pzc techniques respectively. FTIR revealed prominent functional groups for IBP adsorption, SEM showed several pores on activated bean husk making it suitable for trapping IBP molecules. EDX results of acid activated bean husk has the highest percentage of carbon by weight (84.21%) and (89.02%) by atom, respectively. pH_pzc studies revealed that the surface of the prepared adsorbent contains predominantly acidic groups: carboxyl (0.531 mmol/g), phenolic (0.845 mmol/g) and lactonic (0.021 mmol/g) totalling 1.397 mmol/g while basic group has 0.700 mmol/g. Operational parameters such as: contact time, pH, temperature, initial IBP concentrations and adsorbent dose were studied. Optimum IBP adsorption took place at a pH of 4.75. Isotherm studies were conducted using Langmuir, Freundlich, Temkin and Dubinin-Radushkevich isotherm models respectively. Langmuir isotherm aligned best with the adsorption data. The maximum monolayer adsorptive capacity of the modified adsorbent was 50.00 mg/g at 50 °C. Four different kinetic models viz; pseudo first order, pseudo second order, Elovich, and Intraparticle-diffusion were used to investigate the kinetic process. Adsorption data fitted the pseudo second order kinetic model most. Thermodynamic parameters revealed that the process is spontaneous and endothermic. The study revealed that bean husk is a good precursor for activated carbon preparation; it is an efficient, readily available, economically friendly alternative for the sequestration of ibuprofen from aqueous solution.     

Peptide Acylation by Poly(α-Hydroxy Esters)

Purpose. Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres were investigated concerning the possible acylation of incorporated peptides. Methods. Atrial natriuretic peptide (ANP) and salmon calcitonin (sCT) were encapsulated into PLA and PLGA microspheres. Peptide integrity was monitored by HPLC-MS analysis during microsphere degradation for four weeks. sCT fragmentation with endoproteinase Glu-C was used for identifying modified amino acids. Peptide stability in lactic acid solutions was investigated to elucidate possible mechanisms for preventing peptide acylation. Results. Both peptides were acylated by lactic and glycolic acid units inside degrading microspheres in a time-dependent manner. After 21 days, 60% ANP and 7% sCT inside PLA microspheres were acylated. Fragmentation of sCT with endoproteinase Glu-C revealed that besides the N-terminal amine group, lysine, tyrosine or serine are further possible targets to acylation. Stability studies of the peptides in lactic acid solutions suggest that oligomers are the major acylation source and that lower oligomer concentration and higher pH substantially decreased the reaction velocity. Conclusions. The use of PLA and PLGA for drug delivery needs substantially more circumspection. As, according to FDA standards, the potential hazards of peptide acylation products need to be assessed, our findings may have significant implications for products already on the market. Techniques to minimize the acylation reaction are suggested.     

Copper scavenging efficiency of adsorbents prepared from Raphia hookeri fruit waste

Low cost adsorbents prepared from the epicarp of Raphia hookeri fruit were used for the removal of copper (II) ion from aqueous solution. The effects of operational parameters such as pH, concentration and contact time, dosage as well as interference of other ions were studied. Optimum pH for raw and modified biomass were 5.0 and 5.5 with percentage removal of 75.08% and 95.62% respectively. Concentration of competing ions greatly reduced Cu²⁺ removal with both adsorbents while agitation speed had negligible effect on Cu²⁺ uptake. Adsorbents surfaces were activated as temperature increased thus enhancing adsorbent adsorption capacity at high temperature. Adsorption kinetic data fitted best into the pseudo second order model while the thermodynamics studies confirmed adsorption spontaneity and feasibility. The Freundlich adsorption isotherm best described the adsorption process and the Langmuir maximum monolayer adsorption capacity for the raw (RHE) and acid treated (ARHE) biomass were 81.97 and 103.09 mg/g respectively. Chemisorption predominate the Cu²⁺-ARHE system hence desorption efficiency was obtained to be 72.65% with CH₃COOH as eluent.     

Adsorption of Fluorescein Dyes on Albumin Microspheres

The surface characteristics of bovine and egg albumin microspheres were examined using four anionic dyes; sodium fluorescein, eosin, erythrosin, rose bengal, and the cationic dye rhodamine B. The adsorption isotherms of the dyes on unloaded albumin microspheres exhibited Langmuir behavior for dilute solutions of rose bengal, erythrosin, and eosin, suggesting monolayer formation in the initial stages of the sorption process. The adsorption capacity of the microspheres for the dyes (k ₂) and the affinity constants of the dyes for the microspheres (k ₁) were found to depend on both the polarizability and the hydrophobic properties of the dye, presumably reflecting the heterogeneous character of the microsphere surface. Further, the extent of sorption at higher dye concentrations was found to depend on the ability of the dye to form stable aggregates inside the microspheres and on environmental long-range forces acting at these sites. At both low and high dye concentrations, the amount adsorbed to the microsphere surface increased with increasing hy-drophobicity of the dyes. The lowest adsorption was observed for the nonsubstituted dye fluorescein, whereas the most hydrophobic dye used, rose bengal, was completely adsorbed onto the microsphere surface. The data suggest that the bovine albumin microsphere surfaces are highly hydrophobic and less porous than egg albumin microsphere surfaces.     

Excipient Interaction with Cetylpyridinium Chloride Activity in Tablet Based Lozenges

Purpose. The purpose of the investigation was to determine the effect of tablet excipients on the activity of cetylpyridinium chloride (CPC) and the relative interaction between excipients and CPC. Methods. An analytical assay was developed to evaluate the interaction between CPC and the excipients. In vivo activity was investigated using six volunteers by determining the reduction in colony forming units recoverable from the oropharynx after sucking each proprietary lozenge separately on different days. In vitro determinations investigated the relative antimicrobial activity of aqueous solutions of the lozenges and, the effect of pH and tablet base excipients on that activity against Staphylococcus aureus, Streptococcus pyogenes and Candida albicans. Results. Both in vivo and in vitro results showed that the tablet based lozenges had markedly reduced antimicrobial activities compared with previous results with a candy based lozenge (in vivo and in vitro) or the same concentration of aqueous CPC (in vitro}. Magnesium stearate suspensions in CPC 250 µg/ml indicated that magnesium stearate adsorbed CPC and at 0.4% lozenge weight and above significantly reduced the antimicrobial activity of CPC 250 µg/ml. Conclusions. The reduced activity of CPC in tablet based lozenges resulted from a decreased availability of CPC in solution due to an adsorption of CPC on magnesium stearate. To avoid this reduction in activity tablet based lozenges containing CPC 250 µg/ml, or similar concentrations, plus magnesium stearate should contain not more than 0.3% w/w lozenge weight of the lubricant.     

Adsorption of peptides to poly(D,L-lactide-co-glycolide): 1. Effect of physical factors on the adsorption

Four peptides, salmon calcitonin (sCT), the 8–22 amino acid portion of sCT (CT15), an LHRH superagonist, triptorelin (DP) and a somatostatin analogue (RC160) were studied for adsorption to poly(D,L-lactide-co-glycolide) (PLGA) as a function of peptide and polymer concentration. The adsorption of sCT and DP to the polymer showed a primary transient-equilibrium followed by a more rapid and extensive adsorption without reaching a concentration plateau for sCT which occurred earlier with higher peptide concentration. The amount of adsorption for CT15 was much lower than that for sCT and DP and RC160 showed no adsorption. Adsorption isotherms of sCT and DP were fitted to a Langmuir-type of relationship and the monolayer concentration was close to that observed in the kinetic studies or that calculated by the theoretical approach.     

Phenobarbital Adsorption from Simulated Intestinal Fluid,U.S.P., and Simulated Gastric Fluid,U.S.P., by Two Activated Charcoals

Adsorption of phenobarbital from simulated intestinal and gastric fluids by two activated charcoals was studied. Adsorption isotherm data were analyzed by the linearized Langmuir equation and by nonlinear least-squares regression employing both Langmuir and Freundlich models. These analyses indicated differences in the capacities of the two charcoals for phenobarbital which could not be completely explained by surface-area considerations.     

Evidence for the Formation of Amphotericin B-phospholipid Complexes in Langmuir Monolayers

Purpose. To study the interaction of the polyene antifungal amphotericin B with phospholipid Langmuir monolayers and to correlate with stability of phospholipid-stabilized drug emulsions. Methods. Pressure—area isotherms of mixed monolayers of amphotericin B (0–20 mol%) and different phospholipid types were recorded using conventional Langmuir trough methods. Emulsion stability of amphotericin B-containing lipid emulsions was measured using dynamic light scattering. Results. Incorporation of amphotericin B into monolayers composed of saturated phospholipids (Lipoid E80-3) had a profound effect on the shape of the isotherm. This effect was directly related to the concentration of amphotericin B in the monolayer. At high drug concentrations, the shape of the isotherms became progressively similar to that of pure DPPC, thus exhibiting regions attributable to phospholipid in different phase states. This effect on isotherm shape was not observed following incorporation of the drug into monolayers composed of the equivalent unsaturated lecithin (Lipoid E80). Conclusions. These results are interpreted as indicating the formation of an amphotericin B-phospholipid complex, resulting in phase separation within the monolayer. The extent and nature of this phase separation was dependent on both the concentration of drug in the system, and the saturation state of the phospholipid component. The relevance of these observations to the stability of amphotericin B drug emulsions stabilised by saturated and unsaturated phospholipid emulsifiers is discussed. These observations may also be relevant to the toxicity of these, and other novel amphotericin B formulations.     

Loading of Tetanus Toxoid to Biodegradable Nanoparticles from Branched Poly(Sulfobutyl-Polyvinyl Alcohol)-g-(Lactide-Co-Glycolide) Nanoparticles by Protein Adsorption: A Mechanistic Study

Purpose. Mucosal delivery of vaccine-loaded nanoparticles (NP) is an attractive proposition from an immunologic perspective. Although numerous NP preparation methods are known, sufficient antigen loading of NP remains a challenge. The aim of this study was to evaluate adsorptive loading of NP with a negatively charged surface structure using tetanus toxoid (TT) as a model vaccine. Methods. Blank NP, consisting of poly(sulfobutyl-polyvinyl alcohol)-g-(lactide-co-glycolide), as well as poly(lactide-co-glycolide) NP were prepared by a solvent displacement technique. The use of polymers with different degrees of substitution resulted in NP with different negative surfaces charges. Adsorption of TT to NP was performed varying to NP surface properties, protein equilibrium concentration, and loading conditions. Results. The protein adsorption was controlled by NP surface properties, and maximum TT adsorption occurred at highly negatively charged NP surfaces. Results from isothermal titration calorimetry and -potential measurement suggest an adsorption process governed by electrostatic interactions. The adsorption followed the Langmuir isotherm in the concentration ranges studied. TT withstood this gentle loading procedure in a nonaggregated, enzyme-linked immunoabsorbant assay-active form. Conclusions. The results demonstrate that negatively charged NP consisting of poly(sulfobutyl-polyvinyl alcohol)-g-(lactide-co-glycolide) are suitable for adsorptive loading with TT and may have potential for mucosal vaccination.     

Antibiotics adsorption from aqueous solutions using carbon nanotubes: a systematic review

Abstract

Over the past few years, antibiotics are considered as an emerging environmental and health challenges due to their genotoxic and mutagenic effects and persistence in natural ecosystems. Adsorption materials are widely used for water purification. Among them carbon nanotubes (CNTs) have attracted the attention of many researchers for removing water contaminants, especially antibiotics. CNTs have many advantages such as lower cost, and energy, less chemical mass and impact on the environment, large surface area and, greater chemical reactivity that make them suitable materials for water and wastewater treatment. Therefore, this review discussed the environmental and health impacts of antibiotics, the physical and chemical characteristics of CNTs, as well as parameters that influenced the efficiency of antibiotics removal using CNTs. Based on this review nanotubes in different forms of a walled nanotubes, double-walled, multi-walled and in combination are used. Most studies investigated the application of CNTs to remove antibiotics in the modified form or by other factors assistant that make them superior than other adsorbents for antibiotics removal. Review results also showed the maximum removal (100%) related to Metronidazole by multi-walled carbon nanotubes and contact time = 60?min, pH = 7, temperature = 30?±?2?°C and adsorbent dosage 0.1?g/L and ionic strength 0.2 NaCl. Also comparison of adsorption capacity showed the highest absorption capacity related to MWCNTS (1100?mg/g for Cephalexin). Adsorption isotherms study showed the best fitness relate to the Langmuir isotherm (R²= 0.999) and higher adsorption reaction rate in the nanotubes is because of better adsorption in the intermediate levels of CNTs.     

Impact of Regional Intestinal pH Modulation on Absorption of Peptide Drugs: Oral Absorption Studies of Salmon Calcitonin in Beagle Dogs

Purpose. To investigate the relationship between the modulation of intestinal pH and the oral absorption properties of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs. Methods. Studies were performed to characterize the disintegration of the formulation, intestinal pH changes, and the appearance of the peptide in the blood. Enteric-coated formulations containing sCT and various amounts of citric acid (CA) were tethered to a Heidelberg capsule (HC) and given orally to normal beagle dogs. Blood samples were collected and analyzed by radioimmunoassay (RIA). Intestinal pH was continuously monitored using the Heidelberg pH capsule (HC) system. The integrity of the HC-delivery system tether was verified by fluoroscopy. Results. The intra-individual variation in gastric emptying (GE) of the delivery system was large. There were also large inter-individual differences in the disintegration and absorption properties of the various formulations. However, the peak plasma concentrations of sCT were always observed when the intestinal pH declined. The average baseline intestinal pH was 6.1 ± 0.2 (mean ± SEM, n = 12). The intestinal pH reduction was 2.6 ± 0.4 (mean ± SEM, n = 12, ranged from 0.5 to 4.0 units from baseline). There was a good correlation between the time to reach the trough intestinal pH (t_pH,min) and time to reach the peak plasma concentration (t_conc,max) of sCT (t_conc,max = 0.95 × t_pH,min + 14.1, n = 11, r² = 0.91). Plasma C_max and area under the curve (AUC) increased with increasing amounts of CA in the formulations. Conclusions. The results of these studies demonstrate that the oral absorption properties of a model peptide drug, sCT, can be modulated by changing intestinal pH. sCT is a substrate for the pancreatic serine protease trypsin which has maximal activity at pH 5 to 6. Reducing intestinal pH presumably stabilizes sCT in the GI tract enabling greater absorption of the intact peptide.     

Freundlich and Langmuir isotherms as models for the adsorption of toxicants on activated charcoal

The Langmuir isotherm has been widely used to characterize the adsorption of solutes from aqueous solutions. Activated charcoal adsorption data obtained experimentally, using a wide range of adsorbate concentrations, fit the Langmuir isotherm poorly but evidence a good fit to the Freundlich isotherm. Statistical analysis reveals this to be also true of published data that was previously considered to adhere to the Langmuir isotherm. Over the range of possible adsorbate concentrations, the two isotherms predict rather different adsorption behavior. Of the two, the Freundlich isotherm is able to more fully account for observed antidotal effectiveness of activated charcoal in vivo. A method of graphical analysis is advanced that more readily distinguishes the relative goodness-of-fit of the two isotherms. This and the statistical paradigm employed to decide between the two competing hypotheses should allow the adsorption phenomena involving other adsorbents to be re-examined.     

Adsorptive removal of basic yellow 2 onto reed stem and poplar leaf: A comprehensive study

The potential of reed stem (RS) and poplar leaf (PL) as low-cost, widely available agricultural wastes for adsorption of a cationic dye (basic yellow 2) from aqueous solutions has been studied. In order to optimize the biosorption process, response surface methodology (RSM) has employed. The effect of pH, temperature, dye concentration, and adsorbent dosage have determined through central composite design (CCD) and the removal efficiency of both adsorbents has compared. The interaction of variables and their impact on dye removal process was evaluated. Results indicate that for achieving the highest efficiency, RS needed an alkali environment (pH = 10.2) and a lower dosage (0.38 g), and PL needed a more moderate environment (pH = 8.88) but more dosage (0.5 g). By utilization of experimental data, the thermodynamic parameters have been calculated. Results state that adsorption by RS was endothermic (ΔH = 7.6 KJ/mol) and has a positive entropy (ΔS = 38.0 J/Kmol) while the adsorption by PL was exothermic (ΔH = ?13.06 KJ/mol) and has a negative entropy (ΔS = ?37.3 J/Kmol). Kinetic studies were conducted at five different concentrations. It has revealed that RS has better fitted to the intraparticle diffusion model and PL has followed the pseudo-second-order model at all dye concentrations except one. Using Temkin, Freundlich and Langmuir correlations, the best adsorption isotherm for each adsorbent has determined. FTIR analysis have indicated the most effective functional groups on the surface of absorbents that effectively play role in biosorption processes.     

Structural Studies of EDTA-Induced Fibrillation of Salmon Calcitonin

Purpose. The purpose of this work was to determine the structure of an insoluble precipitate formed when mixing approximately equimolar amounts of ethylenediamine tetraacetic acid (EDTA) and salmon calcitonin (sCT). Methods. The interaction between EDTA and sCT was examined by measuring solution turbidity kinetics as a function of pH, ionic strength, and addition of ferric ions. Fourier-transformation infrared spectroscopy (FT-IR) identified changes in peptide secondary structure in presence of EDTA. Scanning and transmission electron spectroscopy revealed the macromolecular structure of the sCT/EDTA precipitate. Results. Aggregation of sCT in a time frame up to 1200 min cannot be induced by either pH (range 3.0-7.0) or ionic strength (up to 200 mM) alone, but is a noncovalent interaction between sCT and EDTA. In the pH range 5.0-7.0, a molar binding stoichiometry of sCT/EDTA in the precipitate of 1-3 was determined. We suggest coulombic binding of the free acidic groups of the EDTA to the side chains of the basic amino acids present in the sCT primary sequence. This results in bridging aggregation of the sCT molecules and their precipitation in aqueous solution. The aggregation reaction was blocked by the addition of ferric ions, which bind preferentially to the acidic groups of the EDTA. The sCT/EDTA precipitate redissolves in water in a pH-dependent manner. FT-IR measurements showed a progressive loss of the random coil structure of sCT in water in the presence of EDTA and a simultaneous strong increase in -structure. Scanning electron microscopy revealed a fine, sponge-like morphology of the isolated, solid sCT/EDTA precipitate. Transmission electron microscopy delivered final proof of the existence of extensive fibrillation in the sCT/EDTA mixture. Conclusions. EDTA induces rapid fibrillation of sCT in water and the partially reversible formation of a noncovalent, insoluble sCT/ EDTA precipitate.     

Adsorption,kinetics and thermodynamics of phenol removal by ultrasound-assisted sulfuric acid-treated pea (Pisum sativum) shells

In the present study, waste pea shells were used to synthesize an efficient adsorbent (ultrasound-assisted sulphuric acid-treated pea shells, USAPS) and was applied for phenol removal. The USAPS characterization was done by SEM-EDS, FT-IR, XRD, optical profilometry, BET, and PZC techniques. The use of ultrasound during the chemical activation significantly enhanced the adsorption properties. The adsorption of phenol was probed by varying pH (2–9), temperature (25–45°C), the USAPS dose (0.1–0.6 g/100ml), phenol concentration (50–500 mg/L), and inorganic salt addition (0.1 M KCl and 0.1 M CaCl₂). The maximum phenol uptake was found to be 125.77 mg/g for 500 mg/L of phenol concentration at pH 7 and 25°C with 0.1 g/100ml of the USAPS dose. Adsorption was negatively affected by an increase in temperature and the USAPS dose while 0.1 M KCl and 0.1 M CaCl₂ addition decreased the maximum phenol uptake from 125.77 mg/g to 103.45 mg/g and 84.11 mg/g, respectively. The time-dependent phenol removal was best explained by the pseudo-second-order kinetic model while equilibrium data were best explained by the Langmuir model. The thermodynamic study revealed the physical nature of adsorption with no structural alteration at the adsorbent-adsorbate interface.     

Buccal Transmucosal Delivery of Calcitonin in Rabbits Using Thin-Film Composites

Purpose. Salmon Calcitonin (sCT) is used to treat hypercalcemia resulting from Paget's disease and osteoporosis. sCT is available either in a sterile injectable form or nasal spray. Alternative and more cost-effective dosage forms for the delivery of calcitonin are needed. We sought to deliver sCT transmucosally using a previously reported mucoadhesive bilayer thin-film composite (TFC) via the buccal route. Methods. Forty micrograms of salmon calcitonin (200-IU) was loaded on preformed TFCs. In vitro release of sCT from TFCs was monitored in phosphate-buffered saline (10 mM, pH 7.4) at 37°C. Female New Zealand White rabbits (n = 6) were dosed with 40 g of sCT either by injection via the ear vein or by applying sCT-loaded TFCs directly on the buccal pouch. Blood was collected at various times, and the plasma sCT and calcium concentrations were quantified. WinNonlin® was used to determine the relevant pharmacokinetic parameters. Results. In vitro, over 80% of sCT was released from the TFCs within 240 min. Super Case-II transport was indicated as the primary release mechanism. Rabbits injected intravenously had C _max, Cls, Vss, and AUC_0-inf values of 75.1 ± 6.5 ng/mL, 20.7 ± 3.3 mL/min, 637 ± 141 mL, and 1925 ± 237 ng*min/mL, respectively. Rabbits dosed via the buccal route had C _max, Cls, and AUC_{0-400 min} values of 4.6 ± 1.6 ng/mL, 22.0 ± 5.9 mL/min, and 842.9 ± 209.7 ng*min/mL, respectively. The relative bioavailability for rabbits treated with the TFCs was 43.8 ± 10.9% with a CV of 24.9%. The reductions in plasma calcium levels after administration of sCT by both the intravenous and buccal route were comparable. Conclusions. The TFCs effectively delivered therapeutically efficacious amounts of sCT across the buccal mucosa in rabbits.     

Indirect Evidence that Drug Brain Targeting Using Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles Is Related to Toxicity

Purpose. To investigate the mechanism underlying the entry of the analgesic peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated with polysorbate 80. Methods. The investigations were carried out with PBCA NP and with non biodegradable polystyrene (PS) NP (200 nm diameter). Dalargin adsorption was assessed by HPLC. Its entry into the CNS in mice was evaluated using the tail-flick procedure. Locomotor activity measurements were performed to compare NP toxicities. BBB permeabilization by PBCA NP was studied in vitro using a coculture of bovine brain capillary endothelial cells and rat astrocytes. Results. Dalargin loading was 11.7 µg/mg on PBCA NP and 16.5µg/ mg on PS NP. Adding polysorbate 80 to NP led to a complete desorption. Nevertheless, dalargin associated with PBCA NP and polysorbate 80 induced a potent and prolonged analgesia, which could not be obtained using PS NP in place of PBCA NP. Locomotor activity dramatically decreased in mice dosed with PBCA NP, but not with PS NP. PBCA NP also caused occasional mortality. In vitro, PBCA NP (10 µg/ml) induced a permeabilization of the BBB model. Conclusions. A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80.