C. Muynck

Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use.

Abstract— The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in‐vitro and maximal adhesion time was evaluated in‐vivo in human subjects. In‐vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300 000–400 000 daltons. The presence of 0·1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in‐vivo bioadhesion was not strongly correlated to the in‐vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol. wt of 200000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300 000 daltons proved to be the most suitable formulations for a fluoride‐slow‐release tablet with bioadhesive properties. In‐vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA‐containing formulations and the CMC formulations had the fastest release. In‐vivo, fluoride levels with a minimum of 150 and a maximum of 1000 μg mL−1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride‐containing toothpaste. The release characteristics in‐vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.

Comparison of salivary fluoride concentrations after administration of a bioadhesive slow‐release tablet and a conventional fluoride tablet

Abstract— The in‐vitro and in‐vivo fluoride release of bioadhesive, slow‐release tablets prepared from a mixture of polyethylene glycol polymers, containing 0·1 mg of fluoride as NaF was studied, and their ability to sustain fluoride levels in saliva were compared with conventional fluoride tablets with the same fluoride content. In‐vitro release experiments showed that the bioadhesive tablets needed 8 h to release all their fluoride compared with < 1 h for the conventional fluoride tablets. In‐vivo, the bioadhesive tablets had a retention period of 6 h and could sustain a salivary fluoride level of more than 10 μm above the baseline for 7 h. The conventional fluoride tablets achieved a peak concentration of 0·5 Mm directly after dissolution in the mouth, but the fluoride level could not be sustained for longer than 1 h. A good agreement was found between the in‐vitro swelling behaviour of the bioadhesive tablets and their in‐vitro and in‐vivo release characteristics and their in‐vivo retention time.

Rectal Mucosa Damage in Rabbits After Subchronical Application of Suppository Bases

The effect of suppository bases on rabbit rectal mucosa was investigated using six triglyceride bases, polyethylene glycol, and a triglyceride base combined with monoglycerides or fatty acids and methyl esters of those acids. Rectal irritation was evaluated and scored according to defined pathological features. “Pure” triglycerides and a triglyceride to which a nonionic surfactant was added caused severe mucosal damage with ulceration and inflammation. Hyperemia was characteristic for irritation by polyethylene glycol suppositories. Mucosal damage by a pure triglyceride combined with monoglycerides or fatty acids and methyl esters of those acids was similar but statistically less pronounced than with all other bases.

Sucrose laurate gels as a percutaneous delivery system for oestradiol in rabbits.

In this study sucrose laurate was formulated in hydrogels and investigated as a suitable transdermal penetration enhancer for oestradiol. Using rabbits as an animal model, the absolute bioavailability and the skin irritation were evaluated after single and multiple application. Three hydrogels containing 60 mg% oestradiol were evaluated: Oestrogel, and two hypromellose gels containing 5 and 15% sucrose laurate (w/w), respectively.

Influence of fat composition on the melting behaviour and on the in vitro release of indomethacin suppositories

Abstract Thermal analysis was used to determine the influence of monoglycerides, a fatty acid-fatty acid methyl ester blend, fatty acid polyethylene glycol esters and indomethacin on the melting behaviour and hardening of triglyceride suppository bases. The influence of these additives on the in vitro release of indomethacin was also investigated. A correlation was seen between the melting point of the monoglycerides and the increase in melting point of the added triglyceride. The addition of indomethacin always resulted in higher melting temperatures. No important influence of the additives and the drug was observed on the hardening behaviour of the suppository bases. Indomethacin release, in vitro, was higher for polyethylene glycol and Suppocire AP formulations than for all other bases. The chemical composition and melting point of the monoglycerides added to the triglyceride can influence the in vitro release of indomethacin. Fatty acid-fatty acid methyl ester blends increased the release of indomethacin only when they were added to a lauric triglyceride (Witepsol H 15).

The Sorption of Isosorbide Dinitrate to Intravenous Delivery Systems

Abstract— The sorption of isosorbide dinitrate from 0.9% sodium chloride and 10% glucose solutions, by intravenous delivery systems has been investigated under simulated infusion conditions. Isosorbide dinitrate was stable in both 0.9% sodium chloride and 10% glucose solutions. Intravenous fluid containers, burettes, a syringe, infusion sets and end‐line filters were evaluated. Glass containers, methacrylate butadiene styrene burettes and polybutadiene giving sets did not sorb isosorbide dinitrate. Neither did polypropylene syringes when a 10% glucose solution was used. The sorption of isosorbide dinitrate to end‐line filters was unimportant but there was a significant loss to the PVC tubing used to connect the filter housing to the catheter.

Influence of Intravenous Administration Set Composition on the Sorption of Isosorbide Dinitrate

Abstract— The influence of the composition of administration sets on the sorption of isosorbide dinitrate was investigated in‐vitro. Isosorbide dinitrate solutions (250 μg mL−1) in 0·9% NaCl or 10% glucose were stored in glass containers and administered at a flow rate of 20 mL h−1. The influence of the concentration of different plasticizers (di‐ethylhexylphthalate, tri‐ethylhexyltrimelitate) in polyvinylchloride tubings was determined. Polybutadiene tubings of different mol. wt coextruded laminates of these polybutadienes with PVC of different composition and a polyethylene tubing were evaluated. The higher the Shore hardness of the PVC tubing, the lower the sorption. The infusion fluid played an additional role only for the tubings with high Shore hardness (> 70). The sorption of isosorbide dinitrate to polybutadiene tubings of different mol. wt was less than 2·5% after 5 h and was comparable with the sorption to the polyethylene tubing. When polybutadiene/PVC laminates were used, the sorption increased significantly and was in most cases dependent on the Shore hardness of the PVC (higher Shore hardness gave lower sorptions) and on the mol. wt of the polybutadiene (lower mol. wt resulted in higher sorption). Sorption was not dependent on the type of PVC plasticizer.

Sorption of isosorbide dinitrate to central venous catheters

Abstract— As several studies demonstrated the sorption of isosorbide dinitrate (ISDN) to intravenous delivery systems, a study on the sorption of ISDN to several central venous catheters was performed. Fourteen different catheters were perfused during a 2 h period, under simulated infusion conditions, with ISDN (250 μg mL−1) in 0·9% (w/v) sodium chloride. The drug loss to a polyethylene and a silicone catheter was 0·2 and 6·1%, respectively. The sorption to a polyvinylchloride heparin‐coated thermodilution catheter was 1–6·9% depending on the length of the catheter. The drug loss to polyurethane catheters of different composition varied between 3·8 and 28·9%. For polyurethane catheters composed of cycloaliphatic polyurethanes an inverse relation was shown between Shore A hardness and sorption.

Light stability of molsidomine in infusion fluids

Abstract— The influence of artificial light, daylight or stimulated sunlight on the stability of molsidomine was investigated. In static experiments an 80 μg mL−1 solution of molsidomine in saline was stored in an unprotected infusion bag. During dynamic experiments the molsidomine solution (80 μg mL−1) was dropped at 12·5 mL h−1 from an unprotected infusion bag, from an infusion bag covered with aluminium‐foil, or from an infusion bag protected with a UV‐cover. Either unprotected infusion tubing or infusion tubing with a UV‐filter were connected to the infusion bags. Static as well as dynamic experiments showed a half‐life of about 20 min for the unprotected molsidomine solutions, when placed behind a window during a sunny day. Protection from light of the infusion bag but not of the infusion tubing had only a minor influence on the drug half‐life. Protection of the infusion bag and the infusion tubing with a UV‐filter increased the half‐life to several days. These results confirm that both the infusion bag and the infusion tubing need adequate light protection during molsidomine administration.

The sorption of isosorbide-5-mononitrate to intravenous delivery systems

Abstract— The sorption of isosorbide‐5‐mononitrate, diluted in 0.9% NaCl or 10% glucose solutions, to intravenous delivery systems was investigated. Infusion bags, burettes, a syringe, infusion tubings and end‐line filters were tested in static and in dynamic experiments. No clinically significant sorption was detected during those experiments. The use of PVC tubings of different hardness did not influence the results.