Complexation as an approach to entrap cationic drugs into cationic nanoparticles administered intranasally for Alzheimer's disease management: preparation and detection in rat brain

<p><i>Objective</i>: Complexation was investigated as an approach to enhance the entrapment of the cationic neurotherapeutic drug, galantamine hydrobromide (GH) into cationic chitosan nanoparticles (CS-NPs) for Alzheimer’s disease management intranasally. Biodegradable CS-NPs were selected due to their low production cost and simple preparation. The effects of complexation on CS-NPs physicochemical properties and uptake in rat brain were examined.</p> <p><i>Methods</i>: Placebo CS-NPs were prepared by ionic gelation, and the parameters affecting their physicochemical properties were screened. The complex formed between GH and chitosan was detected by the FT-IR study. GH/chitosan complex nanoparticles (GH-CX-NPs) were prepared by ionic gelation, and characterized in terms of particle size, zeta potential, entrapment efficiency, <i>in vitro</i> release and stability for 4 and 25 °C for 3 months. Both placebo CS-NPs and GH-CX-NPs were visualized by transmission electron microscopy. Rhodamine-labeled GH-CX-NPs were prepared, administered to male Wistar rats intranasally, and their delivery to different brain regions was detected 1 h after administration using fluorescence microscopy and software-aided image processing.</p> <p><i>Results</i>: Optimized placebo CS-NPs and GH-CX-NPs had a diameter 182 and 190 nm, and a zeta potential of +40.4 and +31.6 mV, respectively. GH encapsulation efficiency and loading capacity were 23.34 and 9.86%, respectively. GH/chitosan complexation prolonged GH release (58.07% ± 6.67 after 72 h), improved formulation stability at 4 °C in terms of drug leakage and particle size, and showed insignificant effects on the physicochemical properties of the optimized placebo CS-NPs (<i>p</i> > 0.05). Rhodamine-labeled GH-CX-NPs were detected in the olfactory bulb, hippocampus, orbitofrontal and parietal cortices.</p> <p><i>Conclusion</i>: Complexation is a promising approach to enhance the entrapment of cationic GH into the CS-NPs. It has insignificant effect on the physicochemical properties of CS-NPs. GH-CX-NPs were successfully delivered to different brain regions shortly after intranasal administration suggesting their potential as a delivery system for Alzheimer’s disease management.</p

Intranasal galantamine/chitosan complex nanoparticles elicit neuroprotection potentials in rat brains via antioxidant effect

Background: Alzheimer’s disease is a common cause of dementia in the elderly. Galantamine hydrobromide (GH) is an anti-Alzheimer cholinesterase inhibitor that has an intrinsic antioxidant effect. In a previous study, GH was complexed with chitosan to prepare intranasal GH/chitosan complex nanoparticles (CX-NP2). The nanoparticles were located in rat brains 1 h after nasal administration and showed pharmacological superiority to GH nasal solution without showing histopathological toxicity. Objective: This study aimed to investigate whether the long-term administration of CX-NP2 leads to biochemical toxicity in rat brains compared to GH nasal solution. Methods: CX-NP2 dispersion and GH solution were administrated intranasally to male Wistar rats for 30 days (3 mg/kg/day). Malondialdehyde (MDA), lipid peroxidation marker, glutathione (GSH), superoxide dismutase (SOD) activity and tumor necrosis factor-α (TNF-α) were assessed in the brain extracts in all groups. Results: There was statistically insignificant difference between the CX-NP2 and GH nasal solution treated groups in all biochemical toxicity parameters assessed. Interestingly, MDA and TNF-α levels in the CX-NP2-treated group significantly decreased compared to the control group. Also, GSH level and SOD activity were significantly enhanced in CX-NP2 treated group compared to the control group. Conclusions: CX-NP2 did not induce a statistically significant oxidative stress or neuroinflammation in rat brains after 30-day treatment, they rather elicited neuroprotective potentials

A new design for a chronological release profile of etodolac from coated bilayer tablets: In-vitro and in-vivo assessment

Repeated dose medication usually maximizes adverse effects, while sustained release systems did not offer a fast onset of action. Etodolac was formulated to enable pulsatile and sustained drug release, which was chronologically more suitable as an anti-inflammatory drug. Eudragit® RSPO, Eudragit® RLPO, and HPMC K15M were added in the sustained release layer and tried in different ratios. Croscarmellose sodium or sodium starch glycolate were used as superdisintegrants for the fast release layer offering the loading dose for rapid onset of drug action. Bilayer tablets were successively coated with Opadry®II, HPMC K4M and E5 (1:40), and Surelease®. All formulations complied with the Pharmacopeial standards for post-compression parameters. In-vitro release profile illustrated a lag-time of 4 h followed by a rapid loading dose release for 2 h. A prolonged steady state release with a t1/2 of 11 h lastly occurred. The coated bilayer tablet showed pulsatile and sustained release effects in rats. The licking time and swelling degree were tested and results demonstrated significant difference (P < 0.05) between the sustained anti-inflammatory action of formulation C1 compared to other groups. Therefore the new chronological design could provide a consistent drug release over 24 h with good protection against associated symptoms of gastric release. Keywords: Pulsatile release, Sustained release, Etodolac, Bilayer tablet, Opadry, Sureleas

Evaluation of chamomile oil and nanoemulgels as a promising treatment option for atopic dermatitis induced in rats

Background: Atopic dermatitis is a chronic inflammatory skin disease that remarkably affects the quality-of-life of patients. Chamomile oil is used to treat skin inflammations. We evaluated the efficacy of chamomile oil and nanoemulgel formulations as a natural alternative therapeutic option for atopic dermatitis. Research design and methods: Formulations were developed comprising chamomile oil: olive oil (1:1), Tween 20/80 or Gelucire 44/14 as surfactant-cosurfactant mixtures, propylene glycol (10%w/w), water and hydroxypropyl methylcellulose (3%w/w). In-vitro physicochemical characterization, stability testing and in-vivo assessment of inflammatory biomarkers and histopathological examination of skin lesions were conducted in rats induced with atopic dermatitis. Results: Nanoemulgels G1 and X1 which displayed the smallest particle size of 137.5 ± 2.04 and 207.1 ± 5.44 nm, good homogeneity and high zeta-potential values of –26.4 and –32.7 mV were selected as the optimized emulgel. Nanoemulgels were nonirritating of pH value 5.56, readily spreadable, and were physically stable following 10 heating-cooling cycles. Treatment with nanoemulgels showed a two-fold decrease in duration of skin healing and no spongiosis compared to chamomile oil. Levels of biomarkers were reduced after topical application of both nanoemulgels and chamomile oil. Conclusion: Nanoemulgels are a potential cost effective, safe topical carrier system for chamomile in treating atopic dermatitis

Nanotechnology-based drug delivery systems for Alzheimer's disease management: Technical, industrial, and clinical challenges

Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from ‘paper to clinic’ and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management