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Formulation and Delivery - Chemical

(T1130-08-50) Influence of Nanoparticle Composition on the Dutasteride Follicular Accumulation

Tuesday, November 11, 2025
11:30 AM - 12:30 PM CT
Purpose: Dutasteride (DUT) has gained interest as a potent 5α-reductase inhibitor for the treatment of androgenic alopecia (AGA). However, DUT’s clinical use is limited by the serious adverse effects associated with its oral intake [1]. Hence, there is a great interest of a local therapy that minimizes such side effects. Hence, the purpose is to develop, characterize, and evaluate the follicular accumulation of DUT-loaded polymeric nanosystems for the AGA treatment.

Methods: Polycaprolactone (PCL) lipid-core nanocapsules and PCL and Poly (lactic-co-glycolic acid) (PLGA) nanospheres were prepared via the interfacial deposition method of PCL and PLGA polymers [2,3]. In vitro drug release was measured at 12, 24, 36, and 48 h. In vitro skin penetration tests were conducted with full-thickness porcine ear skin mounted in a Phoenix DB-6 diffusion cell assembly (diffusional area = 1.77 cm2). For each tested sample, 500 µL formulation was added to the donor chamber. The formulations remained in contact with the stratum corneum for 12 or 24 h, while the receptor chamber was filled with 15 mL of 0.5% SDS aqueous solution. DUT was recovered from skin layers by the differential tape-stripping method [4]. The targeting factor (Tf) was calculated as the ratio of DUT in HFs compared to the total amount of DUT recovered from all skin layers in both time points [5]. DUT recovered from all skin layers was quantified by HPLC, with a method that was previously validated following the International Conference on Harmonization (ICH) guidelines [6]. Component compatibility was assessed by Differential Scanning Calorimetry (25 to 280 °C) and Thermogravimetric Analysis (25 to 500 °C), both were conducted under a nitrogen-controlled atmosphere with a flow rate of 50 mL min-1 and a heating rate of 10 °C min-1. Tests were performed on isolated polymers and nanosystem composites.

Results: Three types of nanocarriers were produced: large PCL nanocapsules (hydrodynamic size: 459.7 ± 4.88 nm; PDI: 0.25 ± 0.01; zeta potential: -22.7 ± 0.56 mV; EE%: 78.5 ± 3.92), PLGA nanospheres of intermediate size (size: 233.3 ± 6.32 nm; PDI: 0.03 ± 0.002; zeta potential: -15.5 ± 0.9 mV; EE%: 80.9 ± 5.00), and small PCL nanospheres (size: 173.3 ± 5.75 nm; PDI: 0.05 ± 0.03; zeta potential: -12.8 ± 1.92 mV; EE%: 86.1 ± 4.65). Differential Scanning Calorimetry and Thermogravimetric Analysis indicated that the excipients in all nanosystems are compatible with the drug. DUT undergoes a thermal degradation event at 284°C and exhibits fusion at 248°C. It is possible to observe that PCL is more miscible with the drug and may have better solubilization (Figure 1). All nanocarriers exhibited a slow and incomplete release after 48 h (Figure 2). PCL nanocapsules released 40% of DUT, while PCL nanospheres released 30%, and PLGA nanospheres only released 18% of DUT over 48 h. Likely, the PCL presence favored DUT solubilization, which may increase the in vitro release of DUT more than that of PLGA. This is also shown in the release profile, since PLGA nanospheres controlled DUT release more than the other nanocarriers. In vitro skin penetration tests (Figura 3. A-B) showed that in 12 h, PLGA nanospheres reached the highest DUT accumulation in HFs compared to the other nanocarriers. In 24 h, DUT diffused to all skin layers, with PCL nanosphere resulting in the lowest DUT accumulation in hair follicles. This diffusion is also reflected in the Tf. The Tf is an index that allows a comparison between the targeting potential of different nanocarriers. It ranges between 0 and 1; 1 meaning all the applied drug accumulated in the HFs at that time; conversely, 0 means no drug is found in the HFs. PCL nanocapsules reached a Tf of 0.33 ± 0.10 in 12 h, but it decreased to 0.19± 0.02 in 24 h. Conversely, nanospheres were able to keep the Tf for 24 h. PCL nanosphere had a Tf of 0.30 ± 0.04 in 12 h, which increased to 0.33 ± 0.07 in 24 h. While PLGA performed better with a Tf of 0.47 ± 0.12 in 12 h, it slightly decreased to 0.45 ± 0.20 in 24 h, but it was statistically superior compared to PCL nanospheres (p < 0.0008).

Conclusion: PLGA nanospheres maintained the target effect of DUT over 24 h, indicating a promising alternative for AGA treatment. However, more studies are needed to assess the safety, the clinical effect, and the long-term efficacy in human patients.

References: 1. Andrade JFM, Verbinnen A, Bakst A, Cunha-Filho M, Gelfuso GM, Gratieri T. Topical dutasteride for androgenic alopecia: current state and prospects. Therapeutic Delivery. , 1–13 (2024).
2. Barbalho GN, Matos BN, Da Silva Brito GF, et al. Skin Regenerative Potential of Cupuaçu Seed Extract (Theobroma grandiflorum), a Native Fruit from the Amazon: Development of a Topical Formulation Based on Chitosan-Coated Nanocapsules. Pharmaceutics. 14(1), 207 (2022).
3. Badri W, El Asbahani A, Miladi K, et al. Poly (ε-caprolactone) nanoparticles loaded with indomethacin and Nigella Sativa L. essential oil for the topical treatment of inflammation. Journal of Drug Delivery Science and Technology. 46, 234–242 (2018).
4. dos Santos GA, Ferreira-Nunes R, Dalmolin LF, et al. Besifloxacin liposomes with positively charged additives for an improved topical ocular delivery. Sci Rep. 10(1), 19285 (2020).
5. Andrade JFM, Matos BN, Rocho RV, et al. Evaluation of Dutasteride-Loaded Liposomes and Transfersomes for Follicular-Targeting for Androgenic Alopecia Topical Treatment. Pharmaceutics. 16(12), 1524 (2024).
6. Ushirobira CY, Afiune LAF, Pereira MN, Cunha-Filho M, Gelfuso GM, Gratieri T. Dutasteride nanocapsules for hair follicle targeting: Effect of chitosan-coating and physical stimulus. International Journal of Biological Macromolecules. 151, 56–61 (2020).

Acknowledgements: CNPQ Universal (Proc. N. 402587/2021-9); FAPDF Learning 1930002145/2023-93.

Figure 1. Thermal analyses of DUT polymeric nanocarriers. (A) thermogravimetry (TGA) first derivative curves of DUT, PCL, PLGA, their physical mixture (1:1 w/w), and the DUT-loaded nanocarriers in nitrogen atmosphere; (B) Differential scanning calorimetry (DSC) curves of DUT, PCL, PLGA, their physical mixture (1:1 w/w), and the DUT-loaded nanocarriers.

Figure 2. Release of DUT from NP-PCL459, NP-PCL173, and NP-PLGA233 over 48 h. Data expressed as mean + SD (n = 6).

Figure 3. DUT amounts recovered from stratum corneum, hair follicles, and viable skin after 12 h (A) and 24 h (B) during skin penetration test in vitro with NP-PCL459, NP-PCL173, and NP-PLGA233. (C) Follicular targeting factor of DUT-loaded ethosomes NP-PCL459, NP-PCL173, and NP-PLGA233 after 12 and 24 h of in vitro skin penetration tests. Data are expressed as
mean # SD (n = 6). *p < 0.04, *** p < 0.0008, and **** p <0.0001.