Investigation of Stabilized Amorphous Solid Dispersions to Improve Oral Olaparib Absorption

OLA is a potent inhibitor of poly ADP ribose polymerase (PARP), a drug approved as a first-in-class for PARPi [1], and is widely used to treat cancers associated with BRCA1 and BRCA2 mutations, such as ovarian cancer, breast cancer, and prostate cancer [2]. The commercial product of OLA is Lynparza tablets, which are administered orally as two 150 mg tablets (300 mg) twice a day, with a total daily dose of 600 mg [3]. Despite its many therapeutic benefits, OLA is classified as a class IV molecule according to the Biopharmaceutics Classification System (BCS) due to its low solubility and low permeability [4]. OLA has a low solubility of approximately 0.1 mg/mL in aqueous solution, with a basic pKa of −1.25 and an acidic pKa of 12.07 [5].

Generally, poorly water-soluble drugs, such as OLA, have low oral absorption and bioavailability due to their low solubility, leading to increased administered doses and decreased patient compliance [6]. Therefore, improving the solubility of poorly soluble drugs is important in the development of oral dosage forms [7]. To enhance the solubility of poorly soluble drugs such as OLA, various techniques have been devised, including particle size reduction, prodrugs, polymeric nanoparticles, lipoidal microspheres, inclusion complexes, salt formation, and lipid-based formulations [8,9]. However, these methods have several limitations, including low drug loading capacity, complex physical structures, instability, potential toxicity of materials, and changes in drug distribution and elimination [9].
Solid dispersion systems have been widely used to enhance the solubility and bioavailability of water-insoluble drugs [10]. Additionally, extensive research has been conducted on solid dispersions for BCS class IV drugs like OLA [11,12,13,14]. Solid dispersion is defined as the dispersion of one or more drugs at the molecular level within a polymer carrier matrix and can be prepared using methods such as the melting method, the solvent-evaporation method, and the solvent-wetting method [15]. Solid dispersions have the advantage of not requiring special equipment compared to other solubilization technologies, and the preparation process is simpler than that of techniques using materials such as nanoparticles or nano-emulsions [16]. Additionally, many poorly soluble drugs have been approved and marketed through solid dispersions [17]. One of the fundamental principles of solid dispersion formulation is to achieve an amorphous state, which is considered to be more soluble than the crystalline state [18]. Therefore, the selection of polymers that effectively enhance solubility and provide stability to the amorphous form is important in solid dispersion systems [19].
To date, solubility studies of OLA have only reported on self-microemulsifying drug delivery systems (SMEDDSs) and nano-based formulations, with studies on OLA-loaded solid dispersions (OLA-SDs) being difficult to find [20,21]. In this study, we attempted to develop OLA-SDs by selecting appropriate polymers that can enhance solubility and prevent recrystallization. After determining the solubility characteristics of OLA in aqueous solution, the solubility of OLA in various polymers was investigated. Subsequently, OLA-SDs were prepared using the selected polymers through spray drying. The physicochemical properties of the prepared OLA-SDs were assessed using SEM, DSC, PXRD, and FT-IR. The dissolution rate and surface characteristics of the OLA-solid dispersion in aqueous solution were evaluated. Finally, the improvement in bioavailability was evaluated by comparing crystalline OLA, amorphous OLA without polymers, and OLA-SD through in vivo pharmacokinetics (PK) studies in rats. A concise overview of the research design is shown in Scheme 1.

2.1. Materials