Improved bioavailability of darunavir by use of kappa-carrageenan versus microcrystalline cellulose as pelletisation aid.

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.

[1]  Ich Harmonised,et al.  INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE , 2006 .

[2]  P. Kleinebudde Use of a power-consumption-controlled extruder in the development of pellet formulations. , 1995, Journal of pharmaceutical sciences.

[3]  Irene T. Weber,et al.  Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro , 2003, Antimicrobial Agents and Chemotherapy.

[4]  J. Schwartz,et al.  Drug release from a multiparticulate pellet system. , 1996, Pharmaceutical development and technology.

[5]  P. Kleinebudde,et al.  Use of kappa-carrageenan as alternative pelletisation aid to microcrystalline cellulose in extrusion/spheronisation. I. Influence of type and fraction of filler. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  R. Haubrich,et al.  Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients , 2007, AIDS.

[7]  P. Kleinebudde,et al.  Influence of the Granulation Step on Pellets Prepared by Extrusion/Spheronization , 1999 .

[8]  Jean Paul Remon,et al.  Extrusion-spheronisation A literature review , 1995 .

[9]  P. Kleinebudde,et al.  Preliminary assessment of carrageenan as excipient for extrusion/spheronisation. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[10]  M. Youle Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. , 2007, The Journal of antimicrobial chemotherapy.

[11]  P. Kleinebudde,et al.  Effect of drying on extruded pellets based on κ-carrageenan , 2007 .

[12]  Peter Kleinebudde,et al.  Use of kappa-carrageenan as alternative pelletisation aid to microcrystalline cellulose in extrusion/spheronisation. II. Influence of drug and filler type. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[13]  P. Kleinebudde,et al.  Properties of pellets manufactured by wet extrusion/spheronization process using κ-carrageenan: Effect of process parameters , 2007, AAPS PharmSciTech.

[14]  Isaac Ghebre-Sellassie,et al.  Pharmaceutical Pelletization Technology , 2022 .