Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

Abstract

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.

Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications

“… 1 Hydroxypropyl cellulose (HPC) Not specified by WHO for human use Lethal dose, 50% (LD 50 ) (rat intravenous administration: 0.25 g/kg) * 52 , 68 2 Hypromellose (HPMC) Estimated daily intake (EDI) of 5.50 g for Human LD 50 (mouse, IP): 5 g/kg LD 50 (rat, IP): 5.2 g/kg * 52 , 68 3 Leucine It is generally regarded as a nontoxic and non-irritant material Only moderately toxic by the subcutaneous route. LD 50 (rat, IP): 5.379 g/kg IV-52.6% 52 , 69 , 70 4 Poloxamer F68, F127 No adverse effects at IV administration up to 0.5 g/kg/day in dogs 0.5 g/kg/day to rabbits LD 50 (mouse, IP): 1 g/kg, LD 50 (rat, IV): 7.5 g/kg Poloxamer F68: 52 , 68 IM-0.2%, IV-0.6%, 5 Polyethyleneglycol (PEG) 400 The WHO has set an estimated acceptable daily intake of polyethylene glycols at up to 10 mg/kg body-weight LD 50 (mouse, IV): 8.6 g/kg LD 50 (rat, IV): 7.3 g/kg IM-20%, 52 , 68 IV-75.58% 6 Polysorbate 80 …”

Comparison of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol-Loaded Self-Emulsifying Granule and Solid Self-Nanoemulsifying Drug Delivery System: Powder Property, Dissolution and Oral Bioavailability

“…Although various methods are available for the preparation of solid self-emulsifying drug delivery systems (e.g., spray-drying, freeze-drying, rotary evaporation, and physical adsorption to solid carriers), these are unsuitable for industrial production due to the resulting low flow ability and poor blending properties [13,26]. Preparation of SEGS using fluid bed granulation is advantageous since it involves a simple granulation method and simultaneous operations (pre-blending, granulation, and drying) using a single piece of equipment [27].…”

“…Preparation of SEGS using fluid bed granulation is advantageous since it involves a simple granulation method and simultaneous operations (pre-blending, granulation, and drying) using a single piece of equipment [27]. The fluid bed granulation method allows the production of easily wettable small granules with good flow ability [26]; thus, the SEGS created using fluid bed granulation were expected to have good flow ability for a solid oral dosage form. Accordingly, to choose a binder for fluid bed granulation, the effect of the binder on the solubility of PLAG in 1% SLS solution was evaluated (Figure 3).…”

“…However, in the case of SEGS, the drug/surfactant/binder in solution was coated on the calcium silicate/MCC, causing a high drug to MCC ratio, which led to a better exposure in dissolution media for faster wettability and release of PLAG. Thus, the wettability of SEGS using fluid bed granulation was better than that of SNEDDS using the spray-drying method [26].…”

A pre-formulation study of a polymeric solid dispersion of paclitaxel prepared using a quasi-emulsion solvent diffusion method to improve the oral bioavailability in rats

“…However, the release performance of this highly dispersed solid solution was poor due to the lack of inhibiting ability of PEG6000 for a supersaturated state of PTX (Figure 1). Both HPMC 16,36 and PVP 17,36 have been used as polymeric precipitation inhibitors for PTX, but they were both inferior to HPMCAS in terms of precipitation inhibiting ability. In fact, a parallel comparison test has been conducted in our lab using a simple solvent method at a common PTX/polymer/WCB ratio (1:8:1, w/w/w).…”