TY - JOUR
T1 - A Combinatorial Approach with Microneedle Pretreatment and Thermosensitive Gel Loaded with Rivastigmine Lipid Nanoparticle Formulation Enables Brain Delivery via the Trigeminal Nerve
AU - Permana, Andi Dian
AU - Mahfud, Muhammad Alif Sya’ban
AU - Munir, Miftakul
AU - Aries, Arni
AU - Rezka Putra, Amal
AU - Fikri, Ahsanal
AU - Setiawan, Herlan
AU - Mahendra, Isa
AU - Rizaludin, Asep
AU - Ramadhani Aziz, Anugerah Yaumil
AU - Djabir, Yulia Yusrini
AU - Arsyad, Aryadi
AU - Harahap, Yahdiana
AU - Saputri, Wahyu Dita
AU - Fajarwati, Ria
AU - Darmawan, Noviyan
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024
Y1 - 2024
N2 - Alzheimer’s disease (AD) often leads to dementia, causing cognitive decline and increased care needs. Rivastigmine (RV) is a key AD treatment, but its brain delivery is limited by the blood-brain barrier (BBB). Aside from oral, olfactory, and intradermal injection (i.d.) routes, the application of polymeric microneedles via the trigeminal nerve on the facial skin as a pretreatment, followed by a solid lipid nanoparticle RV-loaded thermosensitive gel (PMN-SLN-RV-TG), is an alternative to deal with the problems. This study aims to determine the optimal formula for PMN-SLN-RV-TG application and assess its brain delivery ability compared to conventional routes. The optimum SLN-RV formula had a particle size <200 nm and sustained release for 72 h, which was selected for the SLN-RV-TG formulation. SLN-RV-TG was transformed into a gel at normal skin temperature (32-37 °C), with good physical properties and nontoxic behavior. The ideal PMN formula was able to penetrate the dermal layer as an alternative to i.d. administration. Ex vivo dermatokinetics showed significant improvement of PMN-SLN-RV-TG application (p < 0.05) compared to without PMN application. In vivo pharmacokinetic studies on rats also revealed that the PMN-SLN-RV-TG had superior pharmacokinetic parameters (Cmax, AUC, t1/2, and MRT) compared to other groups (p < 0.05). Radiolabeling SLN-RV with 99mTc showed good physical properties, with a radiochemical yield of >95%. In vivo distribution studies of PMN-SLN-RV-TG application exhibited a higher brain:blood ratio than i.v. administration after 5 h, as well as being safe for the brain due to a good histological profile. These results show that PMN-SLN-RV-TG application via the trigeminal nerve on the facial skin has strong potential delivery to the brain for AD treatment.
AB - Alzheimer’s disease (AD) often leads to dementia, causing cognitive decline and increased care needs. Rivastigmine (RV) is a key AD treatment, but its brain delivery is limited by the blood-brain barrier (BBB). Aside from oral, olfactory, and intradermal injection (i.d.) routes, the application of polymeric microneedles via the trigeminal nerve on the facial skin as a pretreatment, followed by a solid lipid nanoparticle RV-loaded thermosensitive gel (PMN-SLN-RV-TG), is an alternative to deal with the problems. This study aims to determine the optimal formula for PMN-SLN-RV-TG application and assess its brain delivery ability compared to conventional routes. The optimum SLN-RV formula had a particle size <200 nm and sustained release for 72 h, which was selected for the SLN-RV-TG formulation. SLN-RV-TG was transformed into a gel at normal skin temperature (32-37 °C), with good physical properties and nontoxic behavior. The ideal PMN formula was able to penetrate the dermal layer as an alternative to i.d. administration. Ex vivo dermatokinetics showed significant improvement of PMN-SLN-RV-TG application (p < 0.05) compared to without PMN application. In vivo pharmacokinetic studies on rats also revealed that the PMN-SLN-RV-TG had superior pharmacokinetic parameters (Cmax, AUC, t1/2, and MRT) compared to other groups (p < 0.05). Radiolabeling SLN-RV with 99mTc showed good physical properties, with a radiochemical yield of >95%. In vivo distribution studies of PMN-SLN-RV-TG application exhibited a higher brain:blood ratio than i.v. administration after 5 h, as well as being safe for the brain due to a good histological profile. These results show that PMN-SLN-RV-TG application via the trigeminal nerve on the facial skin has strong potential delivery to the brain for AD treatment.
KW - Alzheimer’s disease
KW - polymeric microneedle
KW - rivastigmine
KW - solid lipid nanoparticle
KW - technetium-99m
KW - thermosensitive gel
UR - http://www.scopus.com/inward/record.url?scp=85210277046&partnerID=8YFLogxK
U2 - 10.1021/acsami.4c16024
DO - 10.1021/acsami.4c16024
M3 - Article
AN - SCOPUS:85210277046
SN - 1944-8244
VL - 16
SP - 68388
EP - 68406
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 49
ER -