Bioadhesive grafted starch copolymers as platforms for peroral drug delivery: a study of theophylline release.

Nonirritant bioadhesive drug release systems based on starch-acrylic acid graft copolymers prepared by radiation of starch and acrylic acid mixtures with (60)Co were developed for buccal application. The release rate of theophylline (TPL), used as a model drug, depended on the ratio of starch to acrylic acid and on the presence of cations in the graft copolymers, but was practically not affected by the pH (between pH 3 and 7) of the dissolution medium nor by the type of starch used (corn, rice, or potato). Possible release mechanisms are discussed for specific conditions. In general, the release behavior of the graft copolymers was found to be non-Fickian, n value being between 0.6 and 0.96, suggesting that the release was controlled by a combination of tablet erosion and the diffusion of the drug from the swollen matrix. Incorporation of divalent cations into the graft copolymers led to a significant decrease in swelling erosion of the tablets as well as a substantial retardation of drug release. Highest work of adhesion was obtained with graft copolymers containing calcium ions as well as longer time of adhesion on dogs' gingiva.     

Optimisation of an in vitro procedure for the determination of the enzymatic inhibition potency of multifunctional polymers.

An in vitro procedure for the determination of the inhibition potency of multifunctional polymers towards the proteolytic enzyme trypsin was optimised. Carbopol((R)) 934P was used as the reference polymer. The enzymatic reaction was optimised and the HPLC method was validated. The optimal substrate concentration and enzymatic activity were determined aiming at extracting the linear or steady-state part of the metabolite concentration versus time curve of the enzymatic degradation reaction. A substrate concentration of 20 mmol/l N-alpha-benzoyl-L-arginine-ethylester and an enzymatic activity of 30 enzymatic units trypsin/ml were used. The degree of trypsin inhibition was expressed by the inhibition factor (IF), defined as the ratio of the enzymatic reaction rate without a polymer (control) to the reaction rate in the presence of a polymer. During the optimisation of the trypsin inhibition assay, formation of an ion complex between the substrate and the poly(acrylic acid) was observed. The complex formation was concentration dependent, but the influence on the enzymatic reaction was negligible as long as an excessive substrate concentration was present in the reaction medium. The optimised method allows to characterize, evaluate and compare the in vitro trypsin inhibition strength for most multifunctional polymers.     

The Belgian PCB/dioxin crisis-8 years later An overview

In January 1999, 50kg polychlorinated biphenyls (PCBs) contaminated with 1g dioxins were accidentally added to a stock of recycled fat used for the production of 500tonnes animal feed in Belgium. Although signs of poultry poisoning were noticed by February 1999, the extent of the contamination was publicly announced only in May 1999, when it appeared that more than 2500 poultry and pig farms could have been involved. This has resulted in a major food crisis, known worldwide as the "Belgian PCB/dioxin crisis". The crisis was resolved by the implementation of a large food monitoring program for the seven PCB markers (PCBs 28, 52, 101, 118, 138, 153 and 180). When PCB concentrations exceeded the tolerance levels of 100, 200 or 1000ng/g fat for milk, meat or animal feed, respectively, the 17 toxic polychlorinated dibenzodioxins and furans (PCDD/Fs) congeners were also determined. By December 1999, more than 55,000 PCB and 500 dioxin analyses were already done by Belgian and international laboratories. The highest concentrations of PCBs and dioxins and the highest percentage of affected animals were found in poultry. Several important consequences of the food crisis were: (1) the introduction in 1999 of norms for PCBs in feedstuffs and food in Belgium followed by the introduction in 2002 of European harmonized norms for PCDD/Fs in animal feed and food of animal origin; (2) the systematic national monitoring of food of animal origin; and (3) the creation of the Federal Agency for Food Safety in Belgium. The human health risk following this major incident was assessed with contradictory results. It was suggested that, since only a limited proportion of the food chain was contaminated, it is unlikely that adverse effects were inflicted in the Belgian population. However, another assessment suggests that neurotoxic and behavioural effects in neonates, together with an increase in the number of cancers, may be observed.     

Effect of Absorption Enhancers on Ciliated Epithelium: A Novel In Vivo Toxicity Screening Method Using Rotifers

Pharmaceutical Research -     

Plaque-inhibiting effect of bioadhesive mucosal tablets containing chlorhexidine in a 4-day plaque regrowth model

BACKGROUND AND AIM: Compliance in the use of daily oral antiseptics can probably be enhanced by prescribing easily-applied bioadhesive tablets which slowly release chlorhexidine (CHX). This could also be of use in patients with difficulties in rinsing or performing mechanical plaque control. The aim of the present study was to evaluate the capacity of bioadhesive tablets containing either 30 mg or 40 mg of CHX to inhibit de novo plaque formation. METHOD: In this single, examiner-blinded, crossover study, 22 volunteers between 21 and 25 years of age refrained from oral hygiene for 4 days. Bioadhesive mucosal tablets containing 30 mg or 40 mg of CHX were applied in the canine region. Rinses with a 0.2% CHX solution and placebo tablets served as controls. Plaque regrowth was evaluated with the Quigley-Hein Index modification of Turesky and by an automatic image analysis system (AIA) using slides of stained plaque. Rinsing and application of the tablets were done under supervision twice daily. RESULTS: According to the plaque index, plaque regrowth was significantly inhibited by CHX rinses ( P<0.001) and by tablets with 40 mg of CHX ( P<0.02) for all teeth and surfaces. Placebo tablets and 30-mg CHX tablets had no plaque-inhibiting effect. For taste, the subjects preferred the placebo and the 30-mg tablets more than the rinses and 40-mg tablets. In 3/22 of the subjects, superficial mucosal lesions were found at the side of application of the 40-mg tablets. Using the AIA system for evaluation of plaque regrowth, similar results for plaque inhibition were found. CONCLUSION: It can be concluded that bioadhesive mucosal tablets containing 40 mg of CHX can inhibit plaque regrowth as well as 0.2% CHX rinses. However, unpleasant taste and superficial mucosal lesions are local side effects to be considered.     

Physicochemical Properties of the Amorphous Drug,Cast Films,and Spray Dried Powders to Predict Formulation Probability of Success for Solid Dispersions: Etravirine

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.     

Trypsin inhibition, calcium and zinc ion binding of starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures for peroral peptide drug delivery.

Newly synthesised starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures were evaluated for their in vitro inhibition potency towards the proteolytic enzyme trypsin. Their Ca2+ and Zn2+ binding capacity was measured. Carbopol 934P was used as reference polymer. Starch-g-poly(acrylic acid) copolymers were prepared by chemical grafting and 60Co irradiation, the starch/poly(acrylic acid) mixtures by freeze-drying. The influence of preparation method, the ratio starch:acrylic acid, the neutralisation degree and for the freeze-dried polymers the influence of heat treatment after freeze-drying was investigated. All freeze-dried polymers showed a higher inhibition factor (IF) than the chemically grafted and 60Co irradiated starches, which all showed significantly lower IF than Carbopol 934P. The heat treated freeze-dried polymer Amioca/poly(acrylic acid) (1:1) showed a significantly higher IF than the reference polymer (Mann-Whitney test, p<0.05). The Ca2+ and Zn2+ binding capacity of all chemically grafted starches was much lower than for Carbopol 934P. Only the 60Co irradiated starches and freeze-dried polymers with ratio 1:3 approached the binding capacity of the reference polymer. The freeze-dried polymers showed the highest proteolytic enzyme inhibition potency. Freeze-drying and 60Co irradiation could result in the highest ion binding capacity. This combination of proteolytic enzyme inhibition activity and ion binding capacity makes these polymers hopeful excipients for successful oral peptide delivery.     

Buccal Absorption of Testosterone and Its Esters Using a Bioadhesive Tablet in Dogs

Purpose. As the oral bioavailability of testosterone is very low because of its high first pass effect, buccal administration might present a viable alternative. In this study a buccal bioadhesive tablet was used in order to sustain the delivery and bypass the liver. Methods. Testosterone and testosterone acetate, propionate, enanthate and decanoate were investigated. The influence of the concentration of testosterone (10–50%) and testosterone esters (30%) on in vitro bioadhesion was investigated. The absolute (IV) and relative (oral) bioavailability of 60 mg testosterone or an equivalent amount of testosterone ester was determined in castrated male dogs. Results. Both the in vitro detachment force and the work of adhesion decreased gradually with an increasing amount of testosterone and for an increasing chain length of the esters, except in the case of testosterone enanthate. The in vivo results revealed that the bioavailability of testosterone was significantly higher (p < 0.05) than that of the esters, which is probably due to the lower solubility of the esters. The mean absolute bioavailability of testosterone from the bioadhesive tablet was 14.1%, while the mean relative bioavailability was 1370%. The buccal administration of testosterone via the bioadhesive tablet allowed the maintenance of the plasma level at above 3 ng/ml for 15 to 24 h. Conclusions. Buccal absorption of testosterone was significantly higher than that of its esters.