Enhancing collagen based nanoemulgel for effective topical delivery of Aceclofenac and Citronellol oil: Formulation, optimization, in-vitro evaluation, and in-vivo osteoarthritis study with a focus on HMGB-1/RAGE/NF-κB pathway, Klotho, and miR-499a

Reem Abd Elhameed Aldeeb; Sherihan Salaheldin Abdelhamid Ibrahim; Islam Ahmed Khalil; Ghada Mohamed Ragab; Amira Ahmed El-Gazar; Amal Anwar Taha; Doaa Hussien Hassan; Asmaa Ahmed Gomaa; Mona Kamal Younis

doi:10.1007/s13346-024-01548-3

Enhancing collagen based nanoemulgel for effective topical delivery of Aceclofenac and Citronellol oil: Formulation, optimization, in-vitro evaluation, and in-vivo osteoarthritis study with a focus on HMGB-1/RAGE/NF-κB pathway, Klotho, and miR-499a

Drug Deliv Transl Res. 2024 Mar 19. doi: 10.1007/s13346-024-01548-3. Online ahead of print.

Authors

Reem Abd Elhameed Aldeeb¹, Sherihan Salaheldin Abdelhamid Ibrahim², Islam Ahmed Khalil³, Ghada Mohamed Ragab⁴, Amira Ahmed El-Gazar⁵, Amal Anwar Taha³, Doaa Hussien Hassan³, Asmaa Ahmed Gomaa⁶, Mona Kamal Younis³

Affiliations

¹ Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, 12566, Egypt. reem.eldeeb@must.edu.eg.
² Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University, Alexandria, Egypt.
³ Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, 12566, Egypt.
⁴ Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, 12566, Egypt.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, 12585, Egypt.
⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, 12585, Egypt.

PMID: 38502267
DOI: 10.1007/s13346-024-01548-3

Abstract

The majority of conventional osteoarthritis (OA) treatments are based on molecular adjustment of certain signaling pathways associated with osteoarthritis (OA) pathogenesis, however there is a significant need to search for more effective and safe treatments. This study centers around formulating Aceclofenac (ACF) with high bioavailability in combination with Citronellol oil and collagen. The optimal concentrations of Citronellol oil/D-Limonene oil, Tween 80, and Transcutol HP were determined using a pseudoternary phase diagram. The formulated nanoemulsions were studied for thermophysical stability. Thermodynamically stable formula were analyzed for droplet size, zeta potential, and in-vitro permeation. Then, collagen based nanoemulsion were prepared to capitalize on its efficacy in reducing osteoarthritis side effects and characterized for nano size properties. Formulae F10 and F10C were chosen as optimum nanosize formula. Hense, they were prepared and characterized as nanoemulgel dosage form. The nanoemulgel formulae F10NEG1 and F10CNEG1 showed reasonable viscosity and spreadability, with complete drug release after 4 h. These formulae were chosen for further In vivo anti-OA study. Collagen based ACF/citronellol emugel were able to modulate HMGB-1/RAGE/NF-κB pathway, mitigating the production of inflammatory cytokine TNF-α. They were also able to modulate Klotho and miR-499, reducing serum CTXII and COMP, by reducing the cartilage destruction. Histological investigations validated the efficacy, safety, and superiority of Aceclofenac in combination with Citronellol oil and collagen (F10CNEG1) over solo the treated group (F10NEG1 and blank). Hence, the findings of the current work encourage the use of this promising combined formula in treatment of OA patients.

Keywords: Aceclofenac; Citronellol; Collagen; D-Limonene; HMGB-1; Nanoemulgel; Nanoemulsion; Optimization; Osteoarthritis; Pseudo-ternary phase diagram.