Exploring the feasibility of biopolymers as potential carriers in the formulation of amorphous solid dispersions – Gelatin 50PS & BSA

Adequate aqueous solubility of active pharmaceutical ingredients (APIs) is a crucial factor for therapeutic effectiveness. Today, more than fifty percent of the new potential APIs are exhibiting poor aqueous solubility/dissolution rate, leading to low and erratic absorption from the gastro-intestinal (GI) tract and hence low bioavailability. This presents a challenge for pharmaceutical scientists, as many chemicals are abandoned early in the development phase unless there is a reasonable approach to modify or formulate these APIs. Many different formulation strategies have been developed to overcome the solubility problem for poorly water soluble APIs over the past decades.

Among those, formulation of amorphous solid dispersions (ASDs) is a promising one. Because of the lack of the long range order of molecules (characteristic for crystalline solids), amorphous solids are the most energetic solid state of a material and result in higher solubility and dissolution rate. However, the higher free energy is responsible for inherent thermodynamic instability as structural relaxation, nucleation and crystal growth can occur during storage or dissolution in the GI tract. Therefore, instead of using pure amorphous drugs, in general, the API should be dispersed at a molecular level within an inert carrier in the solid state to form an ASD (“glass solution”). The presence of the carrier is necessary to improve the physical stability of amorphous API through inter-molecular interactions, anti-plasticization effect, physical barriers to the nucleation/crystallization process (by increased viscosity) and the reduction in chemical potential of the drug. Moreover, the carrier plays an important role in maintaining supersaturation and in inhibiting precipitation following in-vivo dissolution in the GI-tract.

In most cases, hydrophilic (semi-)synthetic polymers or a combination of (semi-)synthetic polymeric materials are selected as carriers for ASDs as is evident from a large number of studies reported in scientific literature. However, and maybe surprisingly, biopolymers (e.g. proteins, polysaccharides, etc.) have rarely been used as carriers in the formulation of ASDs although interactions between drugs and biomolecules have already been studied widely in pharmacokinetics as a crucial factor in regulating drug distribution, free drug concentrations and metabolism of various drugs. A significant challenge in their application as carriers for ASDs, however, is their stability when exposed to harsh environmental conditions potentially resulting in chemical degradation (e.g. fragmentation, deamidation, hydrolysis or oxidation) and/or physical instability (aggregation, precipitation, conformational changes or denaturation). In fact, many biopolymer-unfavourable conditions (heat, shear stress) are frequently encountered during common ASD-manufacturing processes such as spray drying, hot-melt extrusion, milling or freeze drying.

Hence, a thorough investigation to understand the relationship between processing and physicochemical properties or micro-structure of the biomolecule and the poorly soluble drug at the molecular or bulk level was required. Based on the above rationale, this PhD-project explored whether biopolymers could be feasible carriers to prepare amorphous solid dispersions. In spite of this, the present research project addressed the feasibility of gelatin (50PS) and BSA as model carriers in order to understand the role of formulation and process factors/parameters. In addition, their outcome is also bench marketed against already established (semi-)synthetic polymers (HPMC, PVP, (Soluplus®) and PVPVA). Moreover, to be widely applicable, twelve structurally different, poorly soluble (= BCS Class II), model drugs were selected: carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir, ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen. In the first place, biopolymer-compatible manufacturing techniques were desired. After production was enabled, the physicochemical state of these novel and thus unique ASD systems was examined by means of solid-state analysis, dissolution testing, stability, etc.

Furthermore, solubility and supersaturation tests were also performed to check how these biopolymers behave in solution compared to yet established ones. Finally, since most biopolymers are digestible, the effect of their intraluminal enzymatic digestion was evaluated too during dissolution of these systems. In the end, a critical review of all collected data tackles the million dollar question whether or not biopolymers have the potential to become valuable alternatives compared to the already established (semi-)synthetic carriers within the ASD community. As will become apparent, still some work has to be done. Therefore a sneak peek into some preliminary data and future prospects for follow-up research are also highlighted.

See the article

Pas, Timothy; Van den Mooter, Guy (Supervisor)
Exploring the feasibility of biopolymers as potential carriers in the formulation of amorphous solid dispersions – Gelatin 50PS & BSA
PHD THESIS, 2020-08

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