A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases

Abstract

Neurodegenerative diseases are becoming prevalent as the population ages. Geniposide could inhibit oxidative stress, reduce apoptosis, protect neuron, and has been used for therapy of the neurodegenerative diseases. The bioavailability of geniposide by nasal route is greater than that by oral administration. However, mucociliary clearance is a rate-limiting factor for nasal route administration. The objective of this study was to develop and evaluate a mucoadhesive, thermoreversible in situ nasal gel of geniposide. The poloxamers (P407, P188) and the hydroxypropyl methylcellulose were used as thermoreversible and mucoadhesive polymers, respectively. Borneol was used as a permeation enhancer. The hydrogel was prepared with the cold method and optimized by the response surface methodology-central composite design. Gelation temperature, pH, clarity, gel strength, mucoadhesive strength, in vitro and ex vivo release kinetics of formulations were evaluated. The optimized amounts of poloxamer407 (P407), poloxamer188 (P188) and hydroxypropyl methylcellulose were determined to be 19.4–20.5%, 1.1–4.0% and 0.3–0.6% respectively. The second-order polynomial equation in terms of actual factors indicated a satisfactory correlation between the independent variables and the response (R2 = 0.9760). An ANOVA of the empirical second-order polynomial model indicated the model was significant (P<0.01). P407, P188, P407×P188, P4072 and P1882 were significant model terms. The effects of P407 on gelation temperature were greater than those of other independent variables. The pH values of all the formulations were found to be within 6.3–6.5 which was in the nasal physiological pH range 4.5–6.5. The drug content, gel strength, mucoadhesive strength of the optimized formulations were 97–101%, 25–50 sec and 4000–6000 dyn/cm2 respectively. The in vitro release kinetics of cumulative release of geniposide was fitted to the zero-order model. The ex vivo cumulative release kinetics of geniposide was fitted to the Weibull model. This study concludes that the release of geniposide is controlled by gel corrosion, and that the permeation of geniposide is time-dependent. The more residence time, mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases is of compliance and potential application.

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer’s Disease Treatment

“…Mucoadhesion performance of these formulations were assessed on a mucin disc ( Figure 5). In the literature, when the concentration of HPMC increased from 0.1% to 1.0% in P407/P188/HPMC gel, an increase in mucoadhesive strength was measured from 4560 dyn/cm 2 to 1 0935 dyn/cm 2 [23]. Surprisingly, in our case, no difference was observed between mucoadhesion properties of the gel formulated either without or with 0.5 wt% HPMC or chitosan.…”

“…Indeed, Soliman et al showed that P188 increased the Tsol-gel and mucoadhesive force of in situ thermo-sensitive gels for the vaginal administration of sildenafil [22]. Recently, Poloxamer 407 was used alone or with mucoadhesive polymer to prepare in situ hydrogels for therapy of neurodegenerative disease including Alzheimer's disease [23,24].…”

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…In comparison, chamber configurations can deliver a uniform density through larger membranes (diameter ≥24 mm), with a reduced reading variation (Srinivasan et al, 2015). Both excised mucosa and cell layers require an equilibrium time (∼30 min or 60 min (Röhm et al, 2017;Lungare et al, 2016;Wang et al, 2017;Li et al, 2006) before performing the permeation study, which then consists of taking aliquots from the basal compartment at regular intervals (Gonçalves et al, 2016). The deposition of a reproducible and uniform amount of drug on the tissue is thus crucial as it will directly influence the gradient concentration and could thus introduce variation in the permeability (Upadhyay et al, 2017).…”

Adhesive thermosensitive gels for local delivery of viral vectors

“…Common mucoadhesive agents include dopamine, hydroxypropyl methylcellulose, poly(acrylic acid) derivatives (i.e. carbopols) and polycarbophil (Aka‐Any‐Grah et al, ; De Souza Ferreira, Da Silva, Borghi‐Pangoni, Junqueira, & Bruschi, ; Gong, Lu, Li, Shan, & Wu, ; Wang, Jiang, Wang, & Bie, ; Zhu, Zhai, Zhang, Leng, & Ding, ). Polycarbophil (PCB, also named Noveon AA‐1) is a well‐studied mucoadhesive agent with strong adhesive properties that has been used in a wide range of biomedical applications and is also generally recognized as safe by the FDA (Carvalho et al, ; De Souza Ferreira et al, ; Kerec, Bogataj, Mugerle, Gašperlin, & Mrhar, ; Zhu et al, ).…”