Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

Area of Science:

• Pharmaceutical Technology
• Drug Delivery Systems
• Pharmacokinetics

Background:

• Paclitaxel (PTX) is a potent chemotherapy agent with poor oral bioavailability.
• Developing effective oral formulations for PTX remains a significant challenge in cancer therapy.
• Solid dispersion technology offers a potential strategy to enhance the oral delivery of poorly soluble drugs like PTX.

Purpose of the Study:

• To develop and characterize novel orally administrable tablets containing amorphous paclitaxel (PTX) solid dispersion granules (SDG).
• To evaluate the in vitro dissolution and in vivo pharmacokinetics (PK) of the developed PTX SDG tablets in beagle dogs.
• To compare the oral bioavailability of the PTX SDG tablets with a reference oral solution and intravenous formulation.

Main Methods:

• Amorphous PTX solid dispersion granules (SDG) were prepared using fluid bed technology with an optimized composition.
• Solid-state properties of the SDG were characterized.
• In vitro dissolution studies were conducted in simulated gastric fluid.
• In vivo pharmacokinetic studies were performed in beagle dogs comparing SDG tablets, an oral solution (Oraxol™), and intravenous Taxol®, with co-administration of a P-gp inhibitor (HM38101).

Main Results:

• PTX release from SDG tablets (SDG-T) was rapid, reaching maximum dissolution within 20 minutes in simulated gastric fluid.
• The mean absolute bioavailability (BA%) of PTX from SDG-T was 8.23%, compared to 6.22% for Oraxol™ solution, relative to intravenous Taxol®.
• The relative bioavailability of PTX from SDG-T compared to Oraxol™ solution was 132.25% at a 60 mg oral dose.
• Oral administration of SDG-T with a P-gp inhibitor in dogs resulted in sustained plasma PTX concentrations (10-150 ng/mL) for 24 hours.

Conclusions:

• Novel orally administrable paclitaxel tablets containing solid dispersion granules (SDG) were successfully developed using fluid bed technology.
• The developed PTX SDG formulation exhibits rapid in vitro dissolution and enhanced oral bioavailability in beagle dogs.
• This formulation represents a promising approach for oral paclitaxel delivery, warranting further investigation in pre-clinical and clinical studies.