Publications (3)7.85 Total impact
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Article: Improved bioavailability of darunavir by use of kappa-carrageenan versus microcrystalline cellulose as pelletisation aid.
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ABSTRACT: The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronization with kappa-carrageenan or microcrystalline cellulose (MCC) as pelletization aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2+/-3.5 h from MCC pellets (1301+/-301 microm) and 6.1+/-0.7 min from kappa-carrageenan pellets (966+/-136 microm). In contrast to kappa-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300 mg dose were more than 60-fold higher when formulated with kappa-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (F(rel)) was 155% with kappa-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in kappa-carrageenan pellets, likely due to their better disintegration behavior.European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 04/2009; 72(3):614-20. · 3.15 Impact Factor -
Article: Development of an implantable infusion pump for sustained anti-HIV drug administration.
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ABSTRACT: Factors such as insufficient drug potency, non-compliance and restricted tissue penetration contribute to incomplete suppression of Human Immunodeficiency Virus (HIV) and the difficulty to control this infection. Infusion via standard catheters can be a source of infection, which is potentially life threatening in these patients. We developed an implantable infusion pump, allowing to accommodate large volumes (16-50mL) of high viscous solutions (up to 23.96mPas at 39 degrees C) of anti-HIV agents and providing sustained release of medication: a standard Codman 3000 pump, which was initially developed to release aqueous solutions ( approximately 0.7mPas) into the spinal cord such as for pain medication, was transformed for release of viscous solutions up to 40mPas by adapting the diameter of the capillary flow restrictor, the capillary length and way of catheterisation--by placing the indwelling catheter in the vena cava. A pilot study of the pump implanted in 2 dogs showed continuous steady-state release of the protease inhibitor darunavir (25mg/dog/day administered for 25 days), thereby achieving plasma concentration levels of approximately 40ng/mL. Steady-state plasma levels were reproducible after monthly refill of the pumps. In conclusion, the implantable adapted Codman 3000 constant-flow infusion pump customized to anti-HIV therapy allows sustained release of anti-HIV medication and may represent an opportunity to reduce the pill burden and complexity of dosing schemes associated with common anti-HIV therapy.International Journal of Pharmaceutics 06/2008; 355(1-2):38-44. · 3.35 Impact Factor -
Article: Correlations between factors determining the pharmacokinetics and antiviral activity of HIV-1 non-nucleoside reverse transcriptase inhibitors of the diaryltriazine and diarylpyrimidine classes of compounds.
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ABSTRACT: To investigate the important factors that determine the bioavailability and the antiviral activity of the diaryltriazine (DATA) and diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 in animal species and humans using cell-based assays, physicochemical and computed parameters. This naturalistic study included 15 parameters ranging from molecular mechanics calculations to phase I clinical trials. The calculated parameters were solvent-accessible surface area (SASA), polar surface area and Gibbs free energy of solvation. Physicochemical parameters comprised lipophilicity (octanol/water partition coefficient [cLogP]), ionisation constant (pKa), solubility and aggregate radius. Cell-based assays included human colonic adenocarcinoma cell (Caco-2) permeability (transepithelial transport), drug metabolism and antiviral activity (negative logarithm of the molar effective concentration inhibiting viral replication by 50% [pEC50]). Exposure was tested in rats, dogs and human volunteers. Of the 15 parameters, eight correlated consistently among one another. Exposure (area under the plasma concentration-time curve [AUC]) in humans correlated positively with that in rats (r = 1.00), with transepithelial transport (r = 0.83), lipophilicity (r = 0.60), ionisability (r = 0.89), hydrodynamic radius of aggregates (r = 0.66) and with antiviral activity (r = 0.61). Exposure in humans was also seen to correlate negatively with SASA (r = -0.89). No consistent correlation was found between exposure in dogs and the eight parameters. Of the 14 DATA/DAPY molecules, 11 form aggregates with radii between 34 and 100 nm. We observed correlations between exposure in humans with exposure in rats, transepithelial transport (Caco-2 cells), ionisability, lipophilicity, aggregate radius and SASA in the class of DATA/DAPY NNRTI compounds. The lipophilic DATA/DAPY compounds form aggregates. It can be assumed that absorption in the intestinal tract and endocytosis in infected cells of these lipophilic compounds are governed by the common phenomenon of aggregate formation. As the lymphatic system offers a pathway for intestinal uptake of aggregates, this may offer a therapeutic advantage in the treatment of HIV-1 infection. Although it was not the objective of the study, we found that the rat was a better in vivo model than the dog for the prediction of systemic exposure in this particular set of compounds.Drugs in R & D 02/2004; 5(5):245-57. · 1.35 Impact Factor
