QbD-driven development of intranasal lipid nanoparticles for depression treatment

Abstract

Depression is a life-threatening psychiatric disorder and a multifactorial global public health concern. Current pharmacological treatments present limited efficacy, and are associated with several harmful side effects and development of pharmacoresistance mechanisms. Developing more effective therapeutic options is therefore a priority. This work aims at efficiently designing an antidepressant therapeutic surrogate relying on a dual strategy supported on lipid nanoparticles and intranasal delivery. For that purpose, the formulation was comprehensively optimized following a quality by design perspective. Critical quality attributes (CQAs) ranged from physicochemical to intranasal performance features. The optimized formulation was administered to mice in order to assess the antidepressive and anxiolytic effects by applying the forced swimming and marble-burying tests, respectively. A cross-analysis of the predictive models established for the set of 12 CQAs elicited the formulation containing similar proportion of solid and liquid lipids and lower surfactant concentration as the optimal one. Despite increasing the liquid lipid amount yielded smaller and more homogeneous particle size, and higher release rate, nanostructured lipid carriers (NLCs) provided an earlier and superior pig nasal mucosa permeability than nanoemulsions, along with better stability and cytotoxic profiles. Importantly, the intranasal delivery of the optimal lipid nanoparticle formulation reduced both depressive and anxiety-like behaviors, which positions these intranasal nanosystems in line with the hypothesis of provisioning timely and better acting antidepressant therapies. 1. Introduction Depression is a life-threatening mental disorder and a major public health concern, affecting more than 300 million people of all ages worldwide [1]. It leads to disability, noteworthy health-related costs and decreased quality of life, being considered a prominent risk factor for many other diseases, including neuropsychiatric, cardiovascular, and metabolic conditions [2,3]. Conventional pharmacological treatments for depression are considered relatively well defined. Antidepressant standard-of-care comprises oral selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine) and serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g.

Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation

“…Initially, the solubility of escitalopram and paroxetine was determined in triplicate, as described by Vitorino et al (2020) . Briefly, 0.5 g of solid lipid Precirol ® ATO 5 was melted in a controlled temperature water bath at 65°C.…”

“…The use of nanostructured lipid carriers (NLCs) for drug delivery has shown to be a reliable option for IN administration. NLCs are lipid nanoparticles obtained from oil/water emulsions, in which solid and liquid lipids are mixed with an aqueous emulsifier solution ( Vitorino et al, 2020 ). Other advantages of this type of formulation encompass the possibility to incorporate two drugs in the same nanoparticle (co-encapsulation), together with their biocompatibility, biodegradability, and physicochemical stability.…”

“…Thus, the goal of the present work was to optimize the IN delivery of escitalopram and paroxetine through a rational in vitro/in vivo approach. NLC formulations were initially developed based on our previous work with fluoxetine ( Vitorino et al, 2020 ). Modifications were performed considering the solubility of escitalopram and paroxetine, requiring the test of different lipids to maximize drug loading.…”

Quality by Design (QbD) Approach for Optimization and Characterization of Micro emulsion based Nasal formulation of Antipsychotic/Antischizophrenic Drug-Aripiprazole

“…Measurements were performed using small volume disposable zeta cell. 16,17 Viscosity: Viscosity of the formulations were determined using Brookfield cone and plate Rheometer using CPE spindle at the rotational speed of 5rpm, shear rate of 10 at 33.8±0.3°C. 14,15 pH measurement: The excipients used in the formulation decide the pH of the final preparation.…”

“…Each sample removed was replaced by an equal volume of diffusion media. [15][16][17] Stability studies: The optimized formulations were subjected to physical stability 8,9 testing for periods of 3 months at room temperature to study patient usage conditions. After 3 months of storage in Refrigerator condition (4°C), the formulations were examined periodically after 1, 2 and 3 months for physical stability by means of creaming, phase separation, or flocculation, accelerated centrifugation cycle (3000 × g for 15 min).…”