Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation.

Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab's anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.

Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic pKa values, spray solvent solubility can be dramatically increased by using an acid to ionize the API. Specifically, we show that acetic acid can increase API solubility in MeOH:H2O by 10-fold for a weakly basic drug, gefitinib (GEF, pKa 7.2), by ionizing GEF to form the transient acetate salt. The acetic acid is removed during drying, resulting in a SDD of the original GEF free base having performance similar to SDDs sprayed from solvents without acetic acid. The increase in solvent solubility enables large scale manufacturing for these challenging APIs by significantly increasing the throughput and reducing the amount of solvent required.

Correction: Adam et al. Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture. Pharmaceutics 2022, 14, 555.

Figure Legend [...].

Engineering Advances in Spray Drying for Pharmaceuticals.

Spray drying is a versatile technology that has been applied widely in the chemical, food, and, most recently, pharmaceutical industries. This review focuses on engineering advances and the most significant applications of spray drying for pharmaceuticals. An in-depth view of the process and its use is provided for amorphous solid dispersions, a major, growing drug-delivery approach. Enhanced understanding of the relationship of spray-drying process parameters to final product quality attributes has made robust product development possible to address a wide range of pharmaceutical problem statements. Formulation and process optimization have leveraged the knowledge gained as the technology has matured, enabling improved process development from early feasibility screening through commercial applications. Spray drying's use for approved small-molecule oral products is highlighted, as are emerging applications specific to delivery of biologics and non-oral delivery of dry powders. Based on the changing landscape of the industry, significant future opportunities exist for pharmaceutical spray drying.

Correction: Mudie et al. In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets. Pharmaceutics 2021, 13, 1257.

The authors wish to make the following corrections to this paper [...].

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets.

Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom-up approach (absolute average fold error of AUC0-inf < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug-drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration-time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.