In silico modelling of drug-polymer interactions for pharmaceutical formulations

Abstract

Selecting polymers for drug encapsulation in pharmaceutical formulations is usually made after extensive trial and error experiments. To speed up excipient choice procedures, we have explored coarse-grained computer simulations (dissipative particle dynamics (DPD) and coarse-grained molecular dynamics using the MARTINI force field) of polymer-drug interactions to study the encapsulation of prednisolone (log p = 1.6), paracetamol (log p = 0.3) and isoniazid (log p = -1.1) in poly(L-lactic acid) (PLA) controlled release microspheres, as well as the encapsulation of propofol (log p = 4.1) in bioavailability enhancing quaternary ammonium palmitoyl glycol chitosan (GCPQ) micelles. Simulations have been compared with experimental data. DPD simulations, in good correlation with experimental data, correctly revealed that hydrophobic drugs (prednisolone and paracetamol) could be encapsulated within PLA microspheres and predicted the experimentally observed paracetamol encapsulation levels (5-8% of the initial drug level) in 50 mg ml(-1) PLA microspheres, but only when initial paracetamol levels exceeded 5 mg ml(-1). However, the mesoscale technique was unable to model the hydrophilic drug (isoniazid) encapsulation (4-9% of the initial drug level) which was observed in experiments. Molecular dynamics simulations using the MARTINI force field indicated that the self-assembly of GCPQ is rapid, with propofol residing at the interface between micellar hydrophobic and hydrophilic groups, and that there is a heterogeneous distribution of propofol within the GCPQ micelle population. GCPQ-propofol experiments also revealed a population of relatively empty and drug-filled GCPQ particles.

Figure 1.

Quaternary ammonium palmitoyl glycol chitosan (GCPQ) and poly(lactic acid) (PLA).

Figure 2.

(a) Mapping in the coarse-grained parametrization of GCPQ; (b) a coarse-grained model of GCPQ using 16 coarse grain interaction sites: four palmitoyl group interaction sites (green), one carbonyl group interaction site (brown), six chitosan ring interaction sites (orange), four glycol side chain interaction sites (red) and one quaternary ammonium group interaction site (blue). (c) Mapping in the coarse-grained parametrization of propofol; (d) a coarse-grained model of propofol consisting of five interaction sites, two sites for the ring (green), two sites for the methyl groups (green) and one site for the hydroxyl group (purple).

Figure 3.

(a) The encapsulation of prednisolone within various PLA microspheres: initial polymer, prednisolone levels were 50 mg ml⁻¹ and 5 mg ml⁻¹, respectively. Numbers in parentheses are the concentration of prednisolone (mg ml⁻¹) in the final experimental formulation; the asterisk represents statistically significant difference between experimental encapsulation efficiencies (p < 0.05); filled bar, experimental; open bar, simulation. (b) Simulated distribution of prednisolone (green) in PLA (red) microsphere formulations: initial polymer, prednisolone levels were 50 mg ml⁻¹ and 5 mg ml⁻¹, respectively; equilibrium encapsulation efficiency was 11.1% and 33.3% for PLA 1 and PLA 2 microspheres, respectively. Polysorbate 80 is represented by a pair of blue and purple beads, while water is represented as small light blue dots.

Figure 4.

(a) The encapsulation of paracetamol within PLA 1 microspheres; initial polymer levels were 50 mg ml⁻¹, experimental encapsulation efficiencies are not statistically significantly different (p > 0.05; open square, PLA 1 simulation; filled square, PLA 1 experiment). (b) Simulated distribution of paracetamol (green) in PLA 1 (red) microspheres at various initial drug loads; initial polymer levels were 50 mg ml⁻¹ and equilibrium encapsulation efficiencies were 22%, 5.9% and 8.3% when initial drug levels of 5 mg ml⁻¹, 9 mg ml⁻¹ and 12 mg ml⁻¹ were used, respectively. Polysorbate 80 is represented by a pair of blue and purple beads, while water is represented as small light blue dots.

Figure 5.

The encapsulation of isoniazid within various polymers at various initial isoniazid drug levels; initial polymer levels were 50 mg ml⁻¹ (filled square, PLA 1; filled triangle, PLA 2). Inset: simulated distribution of isoniazid (green) within PLA 2 (red) microspheres; initial isoniazid level = 12 mg ml⁻¹, initial polymer level = 50 mg ml⁻¹ and 0% encapsulation was recorded at equilibrium. Polysorbate 80 is represented by a pair of blue and purple beads, while water is represented as small light blue dots.

Figure 6.

(a) The release of isoniazid from PLA 2 microspheres; 1.05 mg ml⁻¹ of isoniazid was encapsulated by 50 mg ml⁻¹ PLA 2 microspheres at the start of the release experiment. (b) DPD simulation of isoniazid (green) release from PLA 2 (red) microspheres after 72 ns; (c) DPD simulation of isoniazid (green) release from PLA 2 (red) microspheres after 96 ns; (d) DPD simulation of isoniazid (green) release from PLA 2 (red) microspheres after 96.002 ns, isoniazid released as a burst at just over 96 ns.

Figure 7.

(a) An unfiltered dispersion of GCPQ micelles in water (8 mg ml⁻¹; scale bar, 200 nm). (b) Snapshots taken at the end of the simulations showing the molecular arrangement in GCPQ micelles composed of six polymer fragments (DP = 8), either alone or in the presence of propofol (yellow and purple); in the three-dimensional view, the chitosan backbone (dark yellow) along with the hydrophilic glycol (red) and quaternary ammonium ion (blue) groups form the micelle surface while the palmitoyl chains (green) comprise the micelle hydrophobic core, and chloride counter ions (dark brown) and water molecules (blue) are seen in the background. (c) A slice through the micelle, key as in (b). (d) A snapshot of a propofol containing GCPQ micelle showing very little incorporation of propofol in the micelles. (e) A snapshot of a propofol loaded GCPQ micelle showing an abundance of propofol molecules loaded into the micelle; propofol is located mainly at the interface between the hydrophilic and hydrophobic groups. (f) Density plots showing the average propofol density within the micellar systems, micelle 1 (the larger micelle) possesses a lower drug density (propofol 1) when compared with micelle 2 (the smaller micelle, propofol 2; black line, micelle 2; red line, propofol 2; blue line, micelle 1; green line, propofol 1). (g) An unfiltered formulation of GCPQ (8 mg ml⁻¹) and propofol (5.4 mg ml⁻¹) nanoparticles (arrow 2) in water, relatively empty GCPQ micelles are also present (arrow 1; scale bar, 200 nm). (h) The experimental encapsulation of propofol within GCPQ micelles.