(T0930-03-21) Improving the Solubility and Absorption of the Low-Solubility Compound Aripiprazole by Electrospinning Nanofiber Formulation

Purpose: In recent drug development, there is a survey report that about 70% of drug candidates are poorly soluble compounds classified as BCS Class II or Class IV. Oral dosages such as tablets and capsules are effective when dissolved in the gastrointestinal tract and absorbed into the blood. Therefore, solubilization of poorly soluble compounds is an important challenge in recent drug development. In this study, we verified the effectiveness of Nanofiber formulations using Electrospinning method as a solubilization technique for poorly soluble compounds. Electrospinning method is a technique in which Nanofiber can be obtained from mixed solutions of drugs and polymers in one step. Electrospinning has the potential to be applied to many drug substances and polymers because the sample is not exposed to heat. Aripiprazole (BCS Class II) was used as a poorly soluble compound. Nanofibers were prepared using three polymer substrates. We evaluated dissolution and membrane permeability using the prepared nanofibers, and confirmed that the electrospinning method is an effective method for Aripiprazole.

Methods: Preparation of Aripiprazole nanofiber: Aripiprazole (ARI) and polymer matrix were mixed and dissolved in ethanol or acetone. The amount of preparation is as follows.
0.5g ARI + 2.0g Polyvinylpyrrolidone K 30(PVP K30) + 20mL Ethanol
0.5g ARI + 2.0 g Cellulose acetate + 30mL Aceton
0.5g ARI + 2.0g Hypromellose acetate succinate(HPMCAS) + 20mL Aceton
The prepared mixed solutions were sprayed under normal temperature and normal pressure using a labscale Electrospinning instrument (NS1) while applying a high voltage of up to 30 kV to obtain Nanofibers. Small volume dissolution test in FaSSGF: A small-volume dissolution tester (uDISS) was used to evaluate the dissolution properties of Aripiprazole Nanofibers. 20 mg of nanofibers were added to 20 mL of FaSSGF, and the Aripiprazole concentration in the solution was measured with an In-Situ UV probe while stirring at 200 RPM. Small volume dissolution/FLUX test in FaSSIF: >A small-volume dissolution/FLUX tester (uFLUX) was used to evaluate the dissolution/FLUX properties of Aripiprazole Nanofibers. The dissolution/FLUX test is an experimental system that reproduces the dissolution and absorption of drugs in the human gastrointestinal tract in vitro. 20 mL of FaSSIF was used for the Donor chamber of the uFLUX system, and 20 mL of Acceptor Sink Buffer (ASB) was used for the Acceptor chamber. The Donor and Acceptor chambers were separated by a PAMPA Membrane with an area of 1.54 cm².

Results: Small volume dissolution test in FaSSGF: Nanofibers with PVPK30 as the base material dissolved quickly, reaching 70 µg/mL in about 3 minutes, but the concentration did not increase any further. Cellulose Acetate and HPMCAS-based Nanofiber continued to slowly increase in concentration. Final concentrations were 117 µg/mL for Cellulose Acetate nanofiber and 136 µg/mL for HPMCAS nanofiber. Assessment of dissolution /FLUX in FaSSIF: The HPMCAS Nanofiber reached a maximum concentration of 79 µg/mL in the donor chamber 20 minutes after the start of the test. PVP K30 and Cellulose Acetate nanofibers had a maximum concentration of about 40 µg/mL. The solubility of all three types of nanofibers was higher than that of untreated aripiprazole, confirming the effect of nanofibers on improving solubility. The HPMCAS nanofiber showed the highest flux of 0.7 µg·cm^-2·min^-1 at approximately 60 minutes in membrane permeation from the donor chamber to the acceptor chamber, and then decreased with time. HPMCAS with the most improved solubility and membrane permeability was compared with amorphous solid dispersions (ASD) prepared by Hot Melt and physical mixtures. The nanofiber had the best maximum concentration, but the ASD by Hot Melt had the longest supersaturation retention time. Hot Melt ASD maintained a supersaturated state even after 4 hours from the start of the test. Nanofiber was also the highest in FLUX, followed by ASD by Hot Melt. Both had a higher FLUX than the untreated drug substance. The physical mixture showed almost the same dissolution behavior as untreated aripiprazole, but the membrane permeation was low. Therefore, HPMCAS itself does not have the effect of accelerating membrane permeation, but it was confirmed that HPMCAS was used to prepare nanofiber or ASD to accelerate membrane permeation.

Conclusion: Electrospinning technology was confirmed to be effective as a means of solubilizing poorly soluble compound Aripiprazole and improving bioavailability. Electrospinning is a manufacturing method that does not apply heat to raw materials, so it can be applied even when there is a difference in melting point between the drug substance and the polymer, and has the advantage of being applicable to polymers with high melting points such as PVP. Moreover, in the comparison using HPMCAS as the carrier material, it was confirmed that the supersaturation concentration and FLUX were higher than those of the solid dispersion obtained by Hot Melt. A large surface area can be obtained by forming nanofibers, which is thought to have contributed to the improvement of solubility and membrane permeation amount.

References: 1. Kumar, et al., Solid Lipid Nanoparticles: A Strategy to Improve Oral Delivery of the Biopharmaceutics classification system (BCS) Class II Drugs, Int. J. Pharm. & Biol., 9(4), 204-215(2018)
2. Soti PL, et al. Comparison of spray drying, electroblowing and electrospinning for preparation of Eudragit E and itraconazole solid dispersions. Int. J. Pharm., 494, 23-30(2015)

(Left) Electrospinning instrument NS1, (Right) Nanofiber preparation using NS1

Dissolution/FLUX test with Aripiprazole nanofibers.
(Left) Aripiprazole concentration in FaSSIF in the donor chamber, (Right) FLUX of Aripiprazole across the membrane

Dissolution/FLUX test with Aripiprazole_HPMCAS formulations.
(Left) Aripiprazole concentration in FaSSIF in the donor chamber, (Right) FLUX of Aripiprazole across the membrane