Jody Voorspoels

Buccal absorption of testosterone and its esters using a bioadhesive tablet in dogs.

AbstractPurpose. 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.

Ex vivo bioadhesion and in vivo testosterone bioavailability study of different bioadhesive formulations based on starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures

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.

Local treatment of bacterial vaginosis with a bioadhesive metronidazole tablet.

OBJECTIVES Oral metronidazole is still the drug of choice in the treatment of bacterial vaginosis. Yet, side effects have been reported, and dosage as well as duration of therapy are still controversial. This study presents a possible alternative treatment using a single dose of metronidazole administered in a vaginal bioadhesive tablet. STUDY DESIGN Double blind, randomised, placebo-controlled trial. SUBJECTS The 116 patients were allocated to placebo; metronidazole 100; 250; 500mg in a 1:1:1:1 ratio. RESULTS A cure rate of 64% was obtained with a single 100mg dose of metronidazole formulated in a bioadhesive vaginal tablet compared to a cure rate of 29% in the placebo group. The cure rates with the higher doses were similar 61.5% for 250mg dose and 68% for the 500mg dose. No side effects were reported. CONCLUSIONS Treatment of bacterial vaginosis with a single application of 100mg metronidazole in a bioadhesive vaginal tablet was found to be a valid alternative. Further research in relation to tablet shaping and optimal dose finding might increase the cure rate.

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.

Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core

In this study, hot-melt co-extrusion was evaluated as a technique for the production of fixed-dose combination products, using ethylcellulose as a core matrix former to control the release of metoprolol tartrate and a polyethylene oxide-based coat formulation to obtain immediate release of hydrochlorothiazide. By lowering the concentration of the hydrophilic additive polyethylene oxide in the plasticized ethylcellulose matrix or by lowering the drug load, the in vitro metoprolol tartrate release from the core was substantially sustained. The in vitro release of hydrochlorothiazide from the polyethylene oxide/polyethylene glycol coat was completed within 45 min for all formulations. Tensile testing of the core/coat mini-matrices revealed an adequate adhesion between the two layers. Raman mapping showed no migration of active substances. Solid state characterization indicated that the crystalline state of metoprolol tartrate was not affected by thermal processing via hot-melt extrusion, while hydrochlorothiazide was amorphous in the coat. These solid state characteristics were confirmed during the stability study. Considering the bioavailability of metoprolol tartrate after oral administration to dogs, the different co-extruded formulations offered a range of sustained release characteristics. Moreover, high metoprolol tartrate plasma concentrations were reached in dogs allowing the administered dose to be halved.

Pharmacokinetics of florfenicol after treatment of pigs with single oral or intramuscular doses or with medicated feed for three days.

The pharmacokinetics of florfenicol, a structural analogue of thiamphenicol, were studied in six pigs after single oral and intramuscular doses of 15 mg/kg bodyweight, and after feeding them with medicated feed containing 250 mg/kg for three days, a concentration which provided approximately the same dose rate of the drug. The oral doses contained a specially prepared pelleted formulation of the drug. The bioavailability of the drug was similar for the oral and intramuscular doses. Florfenicol was absorbed rapidly from the feed and its concentration in plasma remained between 2 and 6 μg/ml - above the minimum inhibitory concentration values for common pig pathogens - during the three days.

Hot-melt co-extrusion: requirements, challenges and opportunities for pharmaceutical applications

Co‐extrusion implies the simultaneous hot‐melt extrusion of two or more materials through the same die, creating a multi‐layered extrudate. It is an innovative continuous production technology that offers numerous advantages over traditional pharmaceutical processing techniques. This review provides an overview of the co‐extrusion equipment, material requirements and medical and pharmaceutical applications.

Preliminary efficacy study of a bioadhesive vaginal metronidazole tablet in the treatment of bacterial vaginosis.

Bacterial vaginosis is a common cause of vaginitis, characterized by replacement of lactobacilli-dominated fluor with a mixed flora containing Gardnerella vaginalis, various anaerobic bacteria and Mycoplasma hominis. Metronidazole is the drug of choice in the treatment of bacterial vaginosis, but dosage and duration of therapy are still controversial. The current recommendation is a treatment with metronidazole orally with 500mg twice daily for seven days (Centers for Disease Control 1989), but a 2-g single-dose oral metronidazole regimen has been shown to be as effective (Lugo-Miro et a1 1992). However, metronidazole has some unpleasant side-effects and is contraindicated in the first trimester of pregnancy. Alternative therapy has been sought as a clindamycin vaginal cream (Schmitt et a1 1992). Recently, an increasing interest in the development of vaginal bioadhesive tablets has been shown because of the advantages of maintaining a certain drug level locally and enabling lower dosing frequency and a lower amount of drug administered (Brannon-Peppas 1993). This study has been designed to evaluate the efficacy of a single vaginal metronidazole bioadhesive tablet application vs a standardized oral treatment with metronidazole. The bioadhesive formula has already succesfully been used as a buccal bioadhesive tablet containing miconazole nitrate to treat candidiasis (Bouckaert et a1 1992). In a double-blind study the patients were randomly allocated to receive a bioadhesive vaginal tablet (weight 1 g; diam. 20 mm) with 100 mg metronidazole or a placebo vaginal tablet. The bioadhesive matrix consisted of a modified starch/polyacrylic acid mixture (Bottenberg et al 1991). Both groups were compared with a third arm of the study where patients were given the conventional oral metronidazole treatment consisting of two 500-mg doses daily of Flagyl over seven days. In the case of treatment with the bioadhesive tablet, a single tablet was applied to the cervix at the out-patient clinic. The bioadhesive tablet was fixed on the portio uteri previously cleaned with a dry tamp. The tablet was applied with tweezers or forceps. Patients were asked to record the loss of a tablet. The patient’s complaints,

Development of sustained and dual drug release co-extrusion formulations for individual dosing

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification.

Enteric protection of naproxen in a fixed-dose combination product produced by hot-melt co-extrusion.

In this study hot-melt co-extrusion is used as processing technique to manufacture a fixed-dose combination product providing enteric protection to naproxen incorporated in the core and immediate release to esomeprazole magnesium embedded in the coat. The plasticizing effect of naproxen and triethyl citrate (TEC) was tested on the enteric polymers investigated (Eudragit(®) L100-55, HPMC-AS-LF and HPMCP-HP-50). Core matrix formulations containing HPMC-AS-LF, TEC and a naproxen load of 15, 30 and 50% were processed and characterized. The in vitro naproxen release in 0.1N HCl was prevented for 2h for all formulations. The physicochemical state of the drug in the extrudates was determined and a stability study was performed. Intermolecular interactions between naproxen and polymer were identified using attenuated total reflection Fourier-transform infrared (ATR FT-IR) spectroscopy. When esomeprazole magnesium was formulated in a polyethylene oxide 100K:polyethylene glycol 4K (1:1) matrix, separated from the naproxen-containing layer, the formulation could be easily processed and complete in vitro drug release was observed after 45 min. When co-extruding the core/coat dosage form it was observed that a third layer of polymer, separating the naproxen loaded enteric formulation in the core from the coat, is required to prevent degradation of the acid-labile esomeprazole magnesium at the core/coat interface.