High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals

Abstract

Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Figure 1

Design of polymer carriers to tailor solubilization for highly hydrophobic drugs of interest. (A) In the excipient development pipeline, high-throughput controlled polymer synthesis and screening tools can expedite the identification and production of specialized oral drug formulations. In this scheme, (B) the cyclic imide groups of phenytoin and nilutamide motivated the (C) synthon approach to construct excipients combinatorially with precipitation inhibitor and hydrophilic units. (D) For spray-dried dispersions with the leading excipient, the NIPAm inhibitor units adsorbed onto amorphized phenytoin to increase the apparent drug solubility by over an order of magnitude.

Figure 2

High-throughput precipitation inhibition screening across polymer chemical compositions. Heat map array plots represent supersaturated drug concentrations (average of N = 3) of phenytoin and nilutamide over 180 min in PBS solution at 37 °C with polymer synthons 1–5. Across each row in the arrays, the composition of the inhibiting monomer is increasing from 0 to 100 mol %. Experiments were prepared with a total drug concentration of 1000 μg/mL. Details are provided in the Supporting Information.

Figure 3

Representative 2D NMR experiments for poly(NIPAm70-co-DMA30) in deuterated PBS solution. (A) NOESY NMR spectroscopy shows that aromatic protons of phenytoin (600 μg/mL) were in close spatial proximity to the NIPAm isopropyl protons of the polymer (900 μg/mL). The inset shows a 1D spectrum sliced at at 7.4 ppm (red dashed line) from the NOESY spectrum. (B) The measured reduced diffusion coefficient phenytoin (red circle) decreased with increasing polymer concentration in agreement with predictions from a calculated K_b of 44 ± 12 L/mol (red dashed line). The TMSP standard diffusivity (gray diamond) was unaffected.

Figure 4

In vitro dissolution tests of representative solid dispersions. Dissolution profiles of phenytoin and nilutamide show supersaturated drug concentration over time for drug only (×, dashed black) and formulations spray dried at 10 wt % (◇, solid dark orange) and 25 wt % (▽, solid dark green). Experiments were prepared with a total drug concentration of 1000 μg/mL. Error bars represent the range of collected data for N = 2.

Figure 5

In vivo pharmacokinetics (PK) study of select solid dispersions. PK drug plasma concentration over time is compared between (A) controls phenytoin only (○, solid gray) and HPMCAS spray dried at 10 wt % (□, dashed red) and (B) poly(NIPAm-co-DMA) formulations at 46% NIPAm content at 10 wt % (△, dashed blue) and 70% NIPAm content spray dried at 10 (▽, solid orange) and 25 wt % (◇, dashed green). The (C) area under the curve (AUC) and (D) AST/ALT ratio at 6 h provide respective metrics of oral bioavailability and liver toxicity (the dashed red line denotes the AST/ALT of a control animal). All values show the mean + standard error of the mean for N = 3. * denotes statistical significance using one-way ANOVA, Welch, and Tukey’s HSD tests at p = 0.05.