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The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers (n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.

The present study evaluated if mixtures prepared by spray-drying an aqueous dispersion of Amioca starch and Carbopol 974P could be used as matrix for oral sustained drug delivery. The influence of the Amioca/Carbopol 974P ratio (0/100, 25/75, 50/50, 60/40, 85/15, 90/10, 95/5 and 100/0) and the pH and ionic strength (mu) of the dissolution medium on the drug release was investigated. The matrices composed of the spray-dried mixtures with 10% or 15% Carbopol 974P sustained the drug release over the longest time period. At this Carbopol concentration, shear viscosity measurements indicated the formation of an optimal network between the polymer chains of Amioca starch and Carbopol 974P, forming a rigid gel layer offering resistance to erosion during the dissolution experiments.

A matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose (EC) pipe surrounding a drug containing HPMC-Gelucire 44/14 core, was evaluated in vitro and in vivo. In an aqueous medium, the HPMC-Gelucire core forms a gel plug, which releases the drug-through the open ends of the EC pipe--by means of erosion. The influence of hydrodynamic and mechanical stress and the effect of different 'physiologically relevant' dissolution media on the in vitro drug release were investigated. From these in vitro dissolution tests, it was concluded that the EC pipe has a protective effect on the drug containing HPMC-Gelucire core. It largely protects the core against hydrodynamics and mechanical stress. Furthermore, drug release from the matrix-in-cylinder system was only slightly affected by the composition of the dissolution medium. A randomised crossover in vivo study in dogs revealed that the matrix-in-cylinder system containing propranolol hydrochloride has an ideal sustained release profile with constant plasma levels maintained over 24 h. Moreover, administration of the matrix-in-cylinder system resulted in a 4-fold increase in propranolol bioavailability when compared with a commercial sustained release formulation (Inderal).

The objective of the study was to develop a sustained release system consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing hydroxypropyl methylcellulose (HPMC)-Gelucire 44/14 core, yielding a monolithic matrix system applicable in the domain of sustained drug release. The influence of HPMC substitution type and viscosity grade was investigated through dissolution testing and erosion studies. All sustained release systems showed a nearly constant drug release profile with only 40% of the drug released after 24 h. To achieve complete drug release after 24 h, the core formulation and the dimensions of the hollow pipe were modified. Changing the composition of the core did not result in the intended zero-order drug release. Shortening the length of the ethylcellulose cylinder accelerated drug release, while modifying the diameter did not affect the drug release rate. The drug dissolution profile and the release mechanism were independent of drug solubility. Increasing the drug loading caused a small increase of the drug release rate, but did not alter the release mechanism.

The objective was to determine the gastrointestinal (GI) transit times of pellets in piglets at different time points around weaning, as transit times are essential criteria to develop oral drug delivery systems. Nondisintegrating radio-opaque pellets were given orally in order to define the transit times by radiography. The radiographs were analysed with a software programme to calculate the number of pellets present in the different parts of the GI tract. In suckling piglets, the gastric emptying was faster (75% in 1.5 to 3.5 h), and the colonic accumulation (to 73%) was greater than in weaned piglets (3 days, 2 and 3 weeks postweaning, 65% gastric emptying in 18 h, 75% in 17 h, and 75% in 7 h, respectively; maximal colonic accumulations of 48%). Immediately after weaning, the transit was markedly prolonged but shortened with increased postweaning time (3 days, 2 and 3 weeks postweaning, 85% excretion in 175.5, 77, and 50.5 h, respectively). Three weeks postweaning, the transit was no longer affected by weaning as transit times were similar to values reported in growing and adult pigs, and retention appeared to be restricted to the stomach and the colon. These data are of crucial importance in the design of enteric-coated formulations for oral administration of vaccines and therapeutics to young piglets and for human research using the pig model.

Sustained release mini-matrices (multiple unit dosage form) were developed by means of hot-melt extrusion using ibuprofen as the model drug and ethyl cellulose as sustained release agent. Ibuprofen release from the ibuprofen-ethyl cellulose matrices (60:40 w/w) was too slow (20% in 24 h). Other excipientia (hydroxypropyl methylcellulose and xanthan gum) were added to the formulation to increase the drug release. Changing the viscosity and substitution type of HPMC, the amount of HPMC, the drug load and the HPMC:EC ratio modified the in vitro drug release. Burst release was noticed for the formulations containing HPMC and a nearly time independent drug release was seen for the xanthan gum based mini-matrices. Drug release from the mini-matrices was mainly diffusion controlled and swelling played an important role to obtain complete drug release. The formulations were at least 12 months stable during storage at 60% RH and room temperature. At a higher relative humidity and temperature the drug release increased.

The influence of the compression force on the physical properties, the in vitro release and the in vivo behavior of ocular minitablets is evaluated in the present study. The bioerodible minitablets (Ø 2 mm, 6 mg) were produced at different compression forces. The crushing strength, friability, water uptake, hydration and swelling of the minitablets both in vitro as well as in vivo after application in the cul-de-sac were evaluated. The friability remained below 1% only for the minitablets made at 0.500 and 0.750 kN. The crushing strength measured was 3.53+/-0.98, 12.34+/-1.69 and 18.64+/-2.37 N for minitablets made at 0.250, 0.500 and 0.750 kN, respectively. The full hydration time equalled 20 and 30 min for minitablets compressed at 0.250 kN and 0.500-0.750 kN, respectively. Increasing the compression force resulted in a decreased swelling capacity. The in vivo release was evaluated in healthy volunteers using a non-invasive method to measure the apparent sodium fluorescein concentration in the tearfilm-cornea compartment as a function of time. The longest residence time of the fluorescent tracer at the administration site was obtained by the minitablets compressed at 0.750 kN. The in vitro release was evaluated with three different dissolution methods: the reciprocating cylinder method, vials in an oscillatory shaking bath and a static method with vials. The best correlation with the in vivo behavior of the matrix minitablets was obtained with the shaking bath method.

The purpose of this study was to evaluate the biocompatibility of different Amioca/poly(acrylic acid) and Amioca/Carbopol 974P co-spray dried mixtures with an alternative mucosal irritation test using slugs. The irritation potential of the mixtures was measured by the amount of mucus produced during a repeated 30-min contact period. Additionally, membrane damage was assessed by measuring the protein and enzyme release from the body wall of slugs after treatment. All the Amioca/poly(acrylic acid) co-spray dried mixtures (50:50 and 25:75 ratios) induced slight irritation of the mucosal tissue as was demonstrated by the significantly increased mucus production however no increased protein and enzyme release was detected. Co-spray dried Amioca/Carbopol 974P mixtures containing 40% and more Carbopol 974P demonstrated a significantly higher mucus production and release of cytosolic LDH, indicating membrane damage. The total mucus production of the slugs treated with the co-spray dried mixtures containing up to 20% Carbopol 974P was significantly higher compared to the blank slugs. However, these mixtures induced no membrane damage since no additional effect on the protein release and no enzyme release was detected. By co-spray drying up to 20% Carbopol 974P could be incorporated without showing a distinct sign of irritation. These mixtures can be considered as potentially safe bioadhesive carriers.

Starch-g-poly(acrylic acid) copolymers or grafted starches synthesized by 60Co irradiation or chemical modification and co-freeze-dried starch/poly(acrylic acid) mixtures were evaluated on their ex vivo bioadhesion capacity. The buccal absorption of testosterone from a bioadhesive tablet formulated with the grafted starches or starch/poly(acrylic acid) mixtures was investigated. The results were compared to a reference formulation (physical mixture of 5% Carbopol 974P and 95% Drum Dried Waxy Maize). Rice starch-based irradiated grafted starches showed the best bioadhesion results. Partial neutralization of the acrylic acid with Ca(2+) ions resulted in significantly higher bioadhesion values compared to the reference. Ca(2+) and Mg(2+) partially neutralized maltodextrin-based irradiated grafted starches showed significantly higher bioadhesion values compared to the reference formulation. The chemically modified grafted starches showed significantly higher adhesion force values than for the reference tablet. None of the co-freeze-dried starch/poly(acrylic acid) mixtures showed significantly higher bioadhesion results than the reference (Bonferroni test, P<0.05). A chemically modified grafted starch could sustain the 3 ng/ml plasma testosterone target concentration during +/- 8 h (T(>3 ng/ml)). By lyophilization of a partially neutralized irradiated grafted starch, the in vivo adhesion time (22.0 +/- 7.2 h) and the T(>3 ng/ml) (13.5 +/- 1.3 h) could be increased. The absolute bioavailability of the lyophilized formulation approached the reference formulation. Some of the grafted starches showed to be promising buccal bioadhesive drug carriers for systemic delivery.

The present study investigates the use of a polymer mixture containing Carbopol 974P and drum dried waxy maize starch to obtain prolonged drug release to the anterior eye segment. Two dosage forms with this composition are compared: a hydrated polymer dispersion and a minitablet. A model fluorescent tracer is used to study the ocular release and diffusion from the two dosage forms in humans. To evaluate the prolongation in the cornea/tearfilm compartment, the Apparent Fluorescein TurnOver (%/min) is calculated. The parameters Cmax, tmax, and C9h are used to characterize the pharmacokinetics of Na-fluorescein in the anterior chamber. Furthermore, the swelling behavior of the minitablet is evaluated macroscopically, while the degree of interaction with mucin is characterized by rheological measurements. Calculation of an acceptability score and a slug irritation potential is performed to evaluate user acceptability. In contrast to the hydrated dispersion, the minitablet significantly decreases the Apparent Fluorescein TurnOver (%/min) (P<0.05) and increases the apparent fluorescence in the anterior chamber 9 h after application of the preparation. Rheological data demonstrate the presence of elastic interactions between the polymer and mucin. The dry core of the minitablet becomes fully hydrated after approximately 2 h and is subsequently transformed into a highly concentrated gel. The acceptability of the minitablet is comparable to that of the polymer dispersion. Prolonging the release of Na-fluorescein to the anterior eye segment is only feasible with the dry preparation.

The purpose of this study is the investigation of possible adverse effects of a powder formulation containing drum-dried waxy maize (DDWM) starch and Carbopol 974 P (90/10) on the nasal mucosa of rabbits and the foot mucosa of slugs after multiple administrations. In the rabbit, the effect of the formulation was measured by the release of proteins and lactate dehydrogenase (LDH) from the nasal mucosa with a new non-invasive in vivo method and also by histopathology. The mucosal toxicity of the formulation was evaluated using slugs by measuring the effect on the body weight and the amount of mucus produced during a repeated contact period. Additionally, the release of proteins, lactate dehydrogenase and alkaline phosphatase from the body wall of the slugs after a repeated treatment was measured. Twenty four hours after the powder administration to the rabbits the release of the marker molecules was comparable with the negative controls. The histopathological study showed only a slight increase of granulocytes in the epithelium. The formulation induced a higher mucus production in the slugs but no additional effects were detected on the body weight and on the release of proteins. No enzymes were released from the body wall. The results indicate that the effect of the bioadhesive powder consisting of DDWM/Carbopol 974 P (90:10, w/w) on the mucosa was negligible.

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.

The objective of developing a double matrix system consisting of a hot stage extruded starch pipe surrounding a hot stage extruded and drug-containing starch core, was to obtain a monolithic matrix system applicable in the domain of sustained drug release. The behaviour of the systems was evaluated through dissolution testing and through a randomised crossover bioavailability study on nine male volunteers. All double matrix systems showed in vitro a nearly constant drug release profile after an initial slower release phase of 4 h. This initial slower release phase was avoided by loading the starch pipe with a small amount of drug. The in vitro dissolution profiles did not reflect the in vivo behaviour of the systems. Although the in vitro dissolution profiles of two selected double matrix systems were slower than the profile of a commercially available sustained release formulation, they performed less well in vivo. However, the t75%Cmax ratios of the evaluated double matrix systems versus a reference immediate release formulation indicated an acceptable sustained release behaviour, superior to that of hot stage extruded starch-based single matrices. Therefore the disclosed drug delivery systems could be applied in the domain of sustained drug delivery. Besides, the continuous production of the double matrix systems offers an advantage from a manufacturing point of view.

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.

In this study insulin was administered nasally to rabbits as a dry powder formulation. The powders consisted of drum-dried waxy maize starch (DDWM) or maltodextrins with different DE values and Carbopol 974 P. The powders were prepared by freeze-drying a dispersion of these excipients with insulin. Bioavailabilities obtained with the powder formulations containing DDWM/Carbopol 974 P (5 and 10%) were significantly higher (p<0.05) than those containing maltodextrins-Carbopol 974 P mixtures. The bioavailability of the powder formulation containing DDWM and 10% Carbopol 974 P was significantly higher (14.4%) than the bioavailability of the same mixture containing 5% Carbopol 974 P (9.9%). The bioavailability, t(max) and C(max) values of the formulation with 5% Carbopol 974 P were significantly higher in comparison with the formulation without Carbopol 974 P. 10% Carbopol 974 P was required when maltodextrins were used in order to obtain a significantly higher bioavailability compared with the formulations without Carbopol 974 P. Freeze-drying seemed a prerequisite for a good bioavailability from the powder formulation as well as the ratio of insulin versus bioadhesive powder (1 IU and 2 IU/mg of bioadhesive powder).