Laurent Schueller

Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment

Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and (2) were stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which levels declined slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20mg/kg dose (200 nm) were similar with two different surfactants used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as long-acting injectable.

Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate

The interconversion of the ethanolate, hydrate and amorphous form of TMC114 ((3-[(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxypropyl)-carbamic acid hexahydrofuro-[2,3-b]furan-3-yl ester) in open conditions was characterized. TMC114 hydrate and ethanolate form isostructural channel solvates. The crystal structure of TMC114 was obtained from single crystal X-ray diffraction, confirming that it is a channel solvate. Ethanol and water can exchange with one another. TMC114 ethanolate converts into TMC114 hydrate at moderate or high relative humidity (RH) at 25 degrees C, and it converts back into the ethanolate in ethanol atmosphere. The hydration level of the hydrate is determined by the environmental humidity. TMC114 hydrate collapses to the amorphous product when water is removed by drying at low RH or increasing temperature. TMC114 ethanolate becomes amorphous at elevated temperature in a dry environment below the desolvation temperature. Amorphous TMC114 obtained by dehydrating the hydrate during storage at room temperature/<5% RH, by increasing the temperature, or via desolvating the ethanolate by heating, converts into the hydrate at moderate or high RH at ambient conditions, and into TMC114 ethanolate in an ethanol atmosphere. Under ambient conditions, TMC114 ethanolate may convert into the hydrate, whereas the opposite will not occur under these conditions. The amorphous form, prepared by melting-quenching shows a limited water uptake. Whereas TMC114 ethanolate is stable in the commercialized drug product, special conditions can trigger its conversion.

Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240.

TMC240 is a very poorly soluble and poorly permeating HIV protease inhibitor. In order to enhance its oral bioavailability, a fast dissolving inulin-based solid dispersion tablet was developed. During the dissolution test in water (0.5% or 1.0% SLS), this tablet released at least 80% of TMC240 within 30min, while a tablet with the same composition, but manufactured as physical mixture, released only 6% after 2h. In a subsequent single-dose study in dogs (200mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00ng/mL) in all animals (n=3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (C(max)=1.8ng/mL, AUC(0-7 h)=3.0ngh/mL). In the latter treatment group, ritonavir co-administration (10mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC(0-7 h)=108ngh/mL; F(rel)=3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in the presence of ritonavir (AUC(0-7 h)=6.7ngh/mL). The current data demonstrate that a solid dispersion of TMC240 in an inulin matrix allows considerable improvement in the release of poorly water-soluble TMC240, both in vitro in the presence of a surfactant and in vivo upon oral administration.

Improved bioavailability of darunavir by use of κ-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.

Powder for reconstitution of the anti-HIV-1 drug TMC278 - Formulation development, stability and animal studies

Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of TMC278 in 0.01 M HCl. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening to formulate powders for reconstitution by spray-drying. The selected powders for reconstitution were compared to clinical tablets of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. The spray-dried powders for reconstitution made up of TMC278/PVP-VA 64 1:9 (w/w) and TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w) showed ease of suspendability, nearly complete dissolution of the drug and acceptable stability after one month storage at 25 and 40 degrees C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). The absence of differences in vivo and in vitro between the powders made an eventual choice very difficult, yet their advantageous in vivo behaviour and flexible dosing possibility may provide a starting point for paediatric formulations.

Development of an implantable infusion pump for sustained anti-HIV drug administration

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.

Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man

Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach.

Impregnation of Fenofibrate on mesoporous silica using supercritical carbon dioxide

Low oral bioavailability can be circumvented by the formulation of the poorly water soluble drug in ordered mesoporous silica (OMS-L-7). Fenofibrate is an orally administered, poorly water-soluble active pharmaceutical ingredient (API), used clinically to lower lipid levels. Fenofibrate was loaded into silica using two methods: incipient wetness and supercritical impregnation. This study investigates the impact of loading and the impact of varying supercritical carbon dioxide (scCO2) processing conditions. The objective is to enhance Fenofibrate loading into silica while reducing degree of the drug crystallinity, so as to increase the drugs dissolution rate and its bioavailability. The comparison of both impregnation processes was made in terms of impregnation yields and duration as well as physical characterization of the drug. While incipient wetness method led to a Fenofibrate loading up to 300 mgdrug/gsilica in 48 h of impregnation, the supercritical impregnation method yielded loading up to 485 mgdrug/gsilica in 120 min of impregnation duration, at 16 MPa and 308 K, with a low degree of crystallinity (about 1%) comparable to the crystallinity observed via the solvent method. In addition to the enhancement of impregnation efficiency, the supercritical route provides a solvent-free alternative for impregnation.

Co-administration of darunavir and a new pharmacokinetic booster: Formulation strategies and evaluation in dogs

Various formulations for combination of the anti-HIV protease inhibitor darunavir (DRV) and TMC41629, a pharmacokinetic booster for DRV, were studied. TMC41629 (a BCS-IV compound) was formulated in capsules, as polyethylene glycol 400 (PEG400) solution, binary or ternary self-microemulsifying drug delivery system (SMEDDS), inclusion complex with hydroxypropyl-beta-cyclodextrin (HPbetaCD) or polyvinylpyrrolidone-co-vinylacetate 64 (PVP/VA64) extrudate. In addition, tablets were prepared using unmilled or micronized powder and a disintegrant. On co-administration with DRV tablets in dogs, DRV plasma concentration levels were boosted by TMC41629, the PVP/VA64 extrudate achieving the highest DRV levels (2-fold increase). Yet, with extrudate prepared with both compounds, no boosting effect was observed, likely due to transition of DRV from crystalline solvate to amorphous state. Therefore, a co-formulation, combining DRV as crystalline solvate with amorphous TMC41629, was developed. DRV/kappa-carrageenan 80/20% (w/w) beads coated with TMC41629 released at least 80% within 1h in 0.01M HCl with 0.5% sodium lauryl sulphate, TMC41629 dissolving faster than DRV. In dogs, the DRV exposure increased 2.7-fold with the TMC41629-coated beads relative to DRV alone, yet remained lower, but less variable, than following co-administration as separate formulations. Coating of TMC41629 on DRV/kappa-carrageenan beads is a suitable technique for co-formulation, whereby TMC41629 can function as a booster of DRV.