Simulated Nasal Fluid Research Articles

Assessment of intranasal in-situ gel efficacy of ethanolic extract of Mimosa pudica for anxiolytic and antidepressant activity: Formulation optimization and stability studies.

This research delves into the therapeutic potential of Mimosa pudica, known as chuimui or lajwanti in Hindi, for alleviating anxiety and depression, capitalizing on its diverse pharmacological activities. Renowned for analgesic, antidiarrheal, antiinflammatory, hepatoprotective, antiasthmatic, anti-ulcer, and antioxidant properties, the plant emerges as a promising herbal remedy for mental health. The study specifically accentuates its antidepressant and anxiolytic properties, aiming for minimal side effects compared to synthetic alternatives. Pre-formulation considerations involve optimizing the concentration of polymer for in-situ gelation. Preliminary phytochemical screening unveils the presence of bioactive compounds, including terpenoids, flavonoids, glycosides, alkaloids, quinines, phenols, tannins, and saponins, known for modulating neurotransmission and exhibiting anxiolytic effects. The concentration of deacetylated gellan gum for gelation is fine-tuned using simulated nasal fluid, emphasizing minimal viscosity. Compatibility studies using Fourier-transform infrared spectroscopy (FTIR) confirm the absence of significant drug-polymer interactions. Differential scanning calorimetry (DSC) provides insights into thermal behavior. Six trial batches with varying concentrations are prepared, and final formulations are evaluated for different physicochemical parameters. Stability studies are conducted under different conditions for three months. The comprehensive investigation aims to inspire advanced research into the manifold benefits of Mimosa pudica, particularly in mental health treatment, paving the way for potential herbal formulations with reduced side effects.

Dopamine and Citicoline-Co-Loaded Solid Lipid Nanoparticles as Multifunctional Nanomedicines for Parkinson's Disease Treatment by Intranasal Administration.

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application.

Nose-to-brain delivery of nano-engineered biomaterials for effective targeting to the brain

Thermoresponsive hydrogels provide a platform for sustained delivery of nanoparticles via nose-to-brain route by resisting mucociliary clearance to the enhanced mean residence time (MRT) of the formulation in the nasal cavity overcoming neurotoxicity induced by uncontrolled delivery of nanoparticles and accumulation in the brain when delivered alone. The reported study presents the synthesis of pullulan (PLN) based nanoparticles (PNP-EHBr) loaded with eletriptan hydrobromide (EHBr) via ionic gelation method having size between 26.65 nm and 29.59 nm after stability studies of 4 h incubation with an average zeta potential of 22.5 ± 0.1 mV and entrapment efficiency of 92.048%. F-127/F-68 based hyaluronic acid-co-pectin hydrogels of EHBr-loaded PLN nanoparticles thermoresponsive hydrogels (HAP-PNP-EHBr/T-Hg) were characterized via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, thermal analysis (TGA/DSC), and scanning electron microscopy and evaluated for their gelation time, gelation temperature, gel strength, cloud point, sol–gel fraction, ex-vivo permeation, etc. HAP-PNP-EHBr/T-Hg showed drug release in a controlled pattern in both phosphate-buffered saline (PBS) and simulated nasal fluid (SNF) i.e., 90.12 and 87.99, respectively, over 48 h, while PNP-EHBR, 99.44 and 97.53 in PBS and SNF, respectively, over 8 h. The controlled release and absorption of EHBr from HAP-PNP-EHBr/T-Hg and PNP-EHBr was estimated by an in-vivo pharmacokinetic study using high-performance liquid chromatography, MRT and area under the curve (AUC) were increased up to 11.337 ± 0.32 h and 3,104.73 ± 75.841 ng/mL*h, 11.088 ± 0.177 h and 3,906.64 ± 152.86 ng/mL*h in brain and blood respectively after IN administration. This work demonstrates the successful synthesis of a twofold drug delivery system with PLN-based nanoparticles (PNP-EHBr) loaded with EHBr laden F-127/F-68 based hyaluronic acid-co-pectin hydrogels (HAP-PNP-EHBr/T-Hg).

A technological comparison of freeze-dried poly-ɛ-caprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with clozapine for nose-to-brain delivery

Clozapine (CZP) is an atypical antipsychotic, the most effective for the treatment of resistant schizophrenia. With the aim of overcome the limitations of current dosage forms (tablets or suspensions) and routes of administration (oral and intramuscular), this research project proposes nanocarrier systems for intranasal (IN) administration of CZP. In particular, the systems have been developed for the direct nose-to-brain (N2B) route, which allows the direct delivery of the drug to the central nervous system (CNS), bypassing the blood-brain barrier (BBB). This study focusses on the development and investigation of two distinct types of lyophilized polymeric nanoparticles (NPs) consisting of poly- ɛ -caprolactone (PCL) or poly (lactic-co-glycolic acid) (PLGA). The lyophilized formulations were cryoprotected with 5 % (w/v) d-maltose for PLGA-NPs and 25 % (w/v) d-maltose for PCL-NPs. The NPs showed a size of approximately 200 nm, suitable for reuptake from the olfactory nerve to reach the brain directly after the IN administration. In vitro release studies performed in artificial cerebrospinal fluid (aCSF) and simulated nasal fluid (SNF) showed that PLGA NPs released 100 % of the drug in 4 days in SNF, while in aCSF they released about 80 % in 20 days. On the contrary, PCL-NPs released the entire amount of drug within 24 h in both fluids. Furthermore, preliminary in vitro mucoadhesion studies were performed on NPs in liquid form (suspensions) to compare the possible variation in their mucoadhesive properties with respect to powdered NPs, which were tested directly on pig nasal mucosa tissue, where permeability was also assessed. CZP-loaded NPs showed some interactions with mucin in vitro, but no ex-vivo mucoadhesiveness was demonstrated. Furthermore, the results of permeation indicated that the use of CZP-PCL-NPs did not increase the effective permeation of CZP into the mucosa; however, a faster onset of permeation compared to free CZP and a controlled profile were demonstrated. Toxicity studies on primary human olfactory mucosa cells extracted from volunteer patients and on MDCKII cells were also done. Finally, stability studies were carried out under different conditions: suspensions stored at 4 and 25 °C for 3 months, in SNF at 35 °C and in aCSF at 37 °C; dry powders were instead stored at 25 °C with 50 % relative humidity for 8 months. All the results demonstrated a greater stability of NPs in powder form and the absence of aggregation phenomena under artificial physiological conditions.

Preparation of Tamsulosin Hydrochloride-Loaded Mucoadhesive In Situ Gelling Polymeric Formulation for Nasal Delivery in Geriatrics.

This study aimed to prepare tamsulosin hydrochloride (HCl)-loaded in situ gelling formulation by using hydroxypropyl methylcellulose (HPMC), gellan gum, poloxamer 188, and benzalkonium chloride. Physicochemical evaluation of formulations included determination of pH, viscosity, gelation time, gel strength, drug content, and sterility. In silico study was performed to analyze interactions between polymers, drug, and mucin glycoprotein. In vitro degradation time, drug release, ex vivo mucoadhesion time, permeation, in vivo pharmacokinetics, and stability studies were performed to assess the formulation. Formulations were transparent and displayed acceptable physicochemical attributes. Tamsulosin HCl and polymers interacted via non-covalent interactions. HPMC formed hydrogen bonds, hydrophobic and van der Waals interactions with mucin protein while the drug formed hydrogen bonds only. Gel formulation degraded in simulated nasal fluid within 24 h. In situ gelling formulation showed 83.8 ± 1.7% drug release and remained adhered to the mucosa for 24.5 ± 1 h. A higher (~ 1.85 times) drug permeation was recorded through mucosa within 6 h by in situ gelling formulation when compared to control counterparts (aqueous solution of drug and in situ gelling formulation without poloxamer 188). Nasal administration of tamsulosin HCl by using in situ gelling formulation led to a ~ 3.3 and ~ 3.5 times, respectively, higher Cmax (maximum plasma concentration) and AUCtotal (total area under the curve) than the orally administered aqueous solution. Relative bioavailability of drug delivered by nasal in situ gelling formulation was 3.5 times the oral counterpart. These results indicated that the prepared in situ gelling formulation can act as a promising candidate for systemic administration of tamsulosin HCl.

Solid Lipid Nanoparticles Containing Dopamine and Grape Seed Extract: Freeze-Drying with Cryoprotection as a Formulation Strategy to Achieve Nasal Powders

(1) Background: DA-Gelucire® 50/13-based solid lipid nanoparticles (SLNs) administering the neurotransmitter dopamine (DA) and the antioxidant grape-seed-derived proanthocyanidins (grape seed extract, GSE) have been prepared by us in view of a possible application for Parkinson’s disease (PD) treatment. To develop powders constituted by such SLNs for nasal administration, herein, two different agents, namely sucrose and methyl-β-cyclodextrin (Me-β-CD), were evaluated as cryoprotectants. (2) Methods: SLNs were prepared following the melt homogenization method, and their physicochemical features were investigated by Raman spectroscopy, Scanning Electron Microscopy (SEM), atomic force microscopy (AFM) and X-ray Photoelectron Spectroscopy (XPS). (3) Results: SLN size and zeta potential values changed according to the type of cryoprotectant and the morphological features investigated by SEM showed that the SLN samples after lyophilization appear as folded sheets with rough surfaces. On the other hand, the AFM visualization of the SLNs showed that their morphology consists of round-shaped particles before and after freeze-drying. XPS showed that when sucrose or Me-β-CD were not detected on the surface (because they were not allocated on the surface or completely absent in the formulation), then a DA surfacing was observed. In vitro release studies in Simulated Nasal Fluid evidenced that DA release, but not the GSE one, occurred from all the cryoprotected formulations. Finally, sucrose increased the physical stability of SLNs better than Me-β-CD, whereas RPMI 2650 cell viability was unaffected by SLN-sucrose and slightly reduced by SLN-Me-β-CD. (4) Conclusions: Sucrose can be considered a promising excipient, eliciting cryoprotection of the investigated SLNs, leading to a powder nasal pharmaceutical dosage form suitable to be handled by PD patients.

Development of a Melting-Curve-Based Multiplex Real-Time PCR Assay for the Simultaneous Detection of Viruses Causing Respiratory Infection.

The prompt and accurate identification of the etiological agents of viral respiratory infections is a critical measure in mitigating outbreaks. In this study, we developed and clinically evaluated a novel melting-curve-based multiplex real-time PCR (M-m-qPCR) assay targeting the RNA-dependent RNA polymerase (RdRp) and nucleocapsid phosphoprotein N of SARS-CoV-2, the Matrix protein 2 of the Influenza A virus, the RdRp domain of the L protein from the Human Respiratory Syncytial Virus, and the polyprotein from Rhinovirus B genes. The analytical performance of the M-m-qPCR underwent assessment using in silico analysis and a panel of reference and clinical strains, encompassing viral, bacterial, and fungal pathogens, exhibiting 100% specificity. Moreover, the assay showed a detection limit of 10 copies per reaction for all targeted pathogens using the positive controls. To validate its applicability, the assay was further tested in simulated nasal fluid spiked with the viruses mentioned above, followed by validation on nasopharyngeal swabs collected from 811 individuals. Among them, 13.4% (109/811) tested positive for SARS-CoV-2, and 1.1% (9/811) tested positive for Influenza A. Notably, these results showed 100% concordance with those obtained using a commercial kit. Therefore, the M-m-qPCR exhibits great potential for the routine screening of these respiratory viral pathogens.

Carboxymethyl chitosan dopamine conjugates: Synthesis and evaluation for intranasal anti Parkinson therapy

With respect to the Parkinson's disease (PD), herein, we aimed at synthetizing and characterizing two novel macromolecular conjugates where dopamine (DA) was linked to N,O-carboxymethyl chitosan or O-carboxymethyl chitosan, being both conjugates obtained from an organic solvent free synthetic procedure. They were characterized by FT-IR, 1H NMR spectroscopies, whereas thermal analysis (including Differential Scanning Calorimetry and Thermal Gravimetric Analysis) revealed good stability of the two conjugates after exposure at temperatures close to 300 °C. Release studies in simulated nasal fluid elucidated that a faster release occurred since O-carboxymethyl chitosan-DA conjugate maybe due to the less steric hindrance exerted by the polymeric moiety. The CMCS-DA conjugates prepared in aqueous medium may self-assembly to form polymeric micelles and/or may form polymeric nanoparticles. TEM and Photon correlation spectroscopy lent support for polymeric nanoparticle formation. Moreover, such CMCS-DA conjugates showed antioxidant activity, as demonstrated by DPPH radical scavenging assay. Finally, cytocompatibility studies with neuroblastoma SH-SY5Y cells showed no cytotoxicity of both conjugates, whereas their uptake increased from 2.5 to 24 h and demonstrated in 40–66 % of cells.

Synthesis of an insulin-loaded mucoadhesive nanoparticle designed for intranasal administration: focus on new diffusion media.

Intranasal administration is a drug delivery approach to provide a non-invasive pharmacological response in the central nervous system with relatively small peripheral side effects. To improve the residence time of intranasal drug delivery systems in the nasal mucosa, mucoadhesive polymers (e.g., chitosan) can be used. Here, insulin-loaded chitosan nanoparticles were synthesized and their physiochemical properties were evaluated based on requirements of intranasal administration. The nanoparticles were spherical (a hydrodynamic diameter of 165.3nm, polydispersity index of 0.24, and zeta potential of +21.6mV) that granted mucoadhesion without any noticeable toxicity to the nasal tissue. We applied a new approach using the Krebs-Henseleit buffer solution along with simulated nasal fluid in a Franz's diffusion cell to study this intranasal drug delivery system. We used the Krebs-Henseleit buffer because of its ability to supply glucose to the cells which serves as a novel ex vivo diffusion medium to maintain the viability of the tissue during the experiment. Based on diffusion rate and histopathological endpoints, the Krebs-Henseleit buffer solution can be a substituent solution to the commonly used simulated nasal fluid for such drug delivery systems.

Polysaccharide-peptide complexes stabilized around nanoemulsion droplets: A new approach for nasal delivering of pramlintide and insulin

Insulin (HIns) and pramlintide (Pram) are peptide drugs currently used to modulate blood glucose concentrations in diabetic patients. Glucose metabolism impairment has also been described to occur in the brain of diabetic and non-diabetic Alzheimer's patients. In this context, restoring the brain glucose balance by HIns and Pram administration has been proposed as a therapeutic approach for Alzheimer's disease treatment. However, despite their potential application in therapeutics, clinical use of these peptides has some drawbacks as their metabolic instability via protease degradation and undesirable pharmacokinetic properties, besides being delivered by invasive and inconvenient administration routes. Considering the above mentioned, in this study, we describe the development of Pram and HIns polyelectrolyte complexes stabilized around nanoemulsion droplets as a new approach to delivering these peptides by nasal route. Firstly, dextran sulfate/Pram (PECDexS/Pram) and chitosan/HIns (PECChi/HIns) polyelectrolyte complexes were prepared and characterized according to their physicochemical properties. Polyelectrolyte complexes-coated nanoemulsions (NE-PECDexS/Pram and NE-PECChi/HIns) were then obtained and characterized according to size, zeta potential, morphology, drug recovery, and association efficiency. Both NE-PECDexS/Pram and NE-PECChi/HIns showed desirable nanotechnological properties before and after incubation in a simulated nasal fluid pH 5.5 at 37 °C and during 30-day storage at 8 °C. Negatively charged NE-PECDexS/Pram showed improved mucodiffusion properties and led to a more sustained permeation profile of Pram across the nasal epithelium. On the contrary, the positively charged NE-PECChi/HIns led to a faster mucosal permeation of HInS compared to the free peptide. These results could support future in vivo studies concerning the potential use of these new drug delivery systems for treating metabolic brain disorders by the nasal route.

Chitosan coated niosomes for nose-to-brain delivery of clonazepam: Formulation, stability and permeability studies.

Crossing the Blood Brain Barrier constitutes a challenge in drug administration to the brain. In this context, nose-to-brain delivery is explored as an alternative route in the treatment of central nervous system disorders, and nanotechnology constitutes a promising tool for drug delivery to the brain. In this work, we explored niosomes and chitosan-coated niosomes (chitosomes) as possible tools for nose-to-brain delivery of clonazepam. The formulations have been optimised using different chitosan concentrations and different preparation methods as Thin Layer Evaporation-paddle (TLE-P), Evaporation (E), and Solvent Displacement Technique (SDT). The most suitable formulations were loaded with clonazepam (CLZ) and a full physicochemical characterization was performed. Chitosomes presented a size of around 200 nm, PDI < 0.3, a positive surface charge, spherical shape and a CLZ encapsulation above 60%. Chitosomes were stable for 12 weeks under storage conditions at 4ºC, in simulated nasal fluid for 24 h as well as after a lyophilization-sonication process. A CLZ release of 50% was also achieved after 4 h in this media. The mucoadhesive properties of chitosomes were also confirmed, with a 1.5-fold reduction of CLZ toxicity after encapsulation and a 10-fold increase of its permeability.

Formulation of Intranasal Mucoadhesive Thermotriggered In Situ Gel Containing Mirtazapine as an Antidepressant Drug.

The purpose of the present work was to develop nanoemulsion-based formulations of mirtazapine for intranasal delivery using a spray actuator to target the brain for treating depression. Research on the solubility of medications in different oils, surfactants, co-surfactants, and solvents has been done. Using pseudo-ternary phase diagrams, the various ratios of the surfactant and co-surfactant mix were computed. Thermotriggered nanoemulsion was formulated using different concentrations of poloxamer 407 (i.e., 15%, 15.5%, 16%, 16.5% up to 22%). Similarly, mucoadhesive nanoemulsion using 0.1% Carbopol and water-based plain nanoemulsions were also prepared for comparative assessment. The developed nanoemulsions were analyzed for physicochemical properties, i.e., physical appearance, pH, viscosity, and drug content. Drug-excipient incompatibility was determined by Fourier transform infrared spectral (FTIR) analysis and differential scanning calorimetry (DSC). In vitro drug diffusion studies were conducted for optimized formulations. Among the three formulations, RD1 showed the highest percentage of drug release. Ex vivo drug diffusion studies were conducted on freshly excised sheep nasal mucosa with Franz diffusion cell simulated nasal fluid (SNF) for all three formulations up to 6 h, and the thermotriggered nanoemulsion (RD1) showed 71.42% drug release with 42.64 nm particle size and a poly dispersity index of 0.354. The zeta potential was found to be -6.58. Based on the above data, it was concluded that thermotriggered nanoemulsion (RD1) has great potential to be used as an intranasal gel for treating depression in patients. It can offer great benefits by reducing dosing frequency and improving bioavailability of mirtazapine by direct nose-to-brain delivery.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

A Preliminary Pharmacodynamic Study for the Management of Alzheimer's Disease Using Memantine-Loaded PLGA Nanoparticles.

Alzheimer's disease is becoming a common disorder of the elderly population due to shrinkage of the brain size with age and many other neurological complications. To provide an effective treatment option, memantine-encapsulated polymeric nanoparticles were prepared in the study. The nanoparticles were prepared by using nanoprecipitation followed by homogenization and ultrasonication methods, characterized on the basis of particle size, polydispersity index, and zeta potential. Further, in vitro release profile, cytotoxicity analysis, and Giemsa staining were conducted. To observe the efficacy of nanoparticles in scopolamine-induced Alzheimer models in vivo studies were also carried out. The results showed that nanoparticles were in the nano range with a particle size of 58.04nm and - 23mV zeta potential. The in vitro release was also sustained till 24h with ~ 100% release in selected media phosphate buffer saline, simulated nasal fluid, and artificial cerebrospinal fluid. The cytotoxicity results with ~ 98 to 100% cell viability and no morphological changes through Giemsa staining indicated that nanoparticles were not leading to cell toxicity. The gamma scintigraphy studies showed higher uptake of the drug in the target site through the intranasal route and pharmacodynamic studies indicated that nanoparticles were able to inhibit the spatial memory impairment significantly as compared to the control group. The findings clearly indicated that the developed memantine nanoparticles could act as an alternative approach for the management of Alzheimer's disease.

Design And Optimization of Midazolam Loaded Microemulsion Using Quality by Design (Qbd) Assisted Statistical Modelling

Introduction: More emphasize was given in the present work is application of QbD tools and DoE approach. The existing study was aimed towards development and characterization of Midazolam (MZM) loaded microemulsion (ME) for brain delivery through nasal route.Methods: Different QTPP and CQAs were identified initially and REM was prepared. Further D optimal design was employed with concentration of Oil (X1), concentration of Smix (X2) and concentration of water (X3) as significant independent variables (IVs). Globule size (Y1), %Transmittance (Y2) and Viscosity (Y3) were kept as important CQAs.Results: MLR models revealed that selected IVs have great impact on Y1 and Y3, especially main and interactive effect. The results were supported by contour plots (2D and3D) and predicated Vs actual plot. % PE values for check point batches were found less than 5% indicating accuracy of evolved MLR models. Further, control space was mapped from design space of overlay plot and out of control space, one batch was optimized and revised REM was prepared. Revised REM showed low risk potential of various IVs on selected CQAs. Optimized batch was tested for zeta potential, conductivity, Polydispersity index, viscosity, refractive index, isotropic number. Moreover, ex vivo permeation using sheep nasal mucosa in simulated nasal fluid (SNF). The study revealed that superior permeation than Midazolam suspension which is attributed to the incorporation of MZM into ME carrier.Conclusion: So, in a nutshell, it can be concluded that application of QbD approach and DoE concepts in MZM loaded ME yielded design space which will be useful for error free scale up plan implementation.

Preparation and Optimization of Leuprolide Acetate Nanoparticles Using Response Surface Methodology: In Vitro and Ex Vivo Evaluation.

This study aims to develop optimized leuprolide acetate (LA) nanoparticles (NPs) for intranasal delivery in the treatment of Alzheimer's disease. Box-Behnken Design was used to optimize LA polylactide-co-glycolic acid (PLGA) NPs. The independent variables chosen were PLGA concentration, surfactant concentration, and the ratio of water to oil phase, whereas the dependent variables were particle size and % entrapment efficiency. The optimized NPs were evaluated by in vitro drug release study, ex vivo diffusion study, histopathology study, hemolytic stability study, and stability in simulated nasal fluid (SNF). The optimized NPs had particle size of 182.6 ± 1.5 nm, polydispersity index (0.3), % entrapment efficiency (77.3 ± 0.6), and zeta potential (-5.6 mv ±0.2). The in vitro drug release indicated 96% of pure drug release in 6 h, whereas only 66.35% of the drug was released from the optimized formulation at 48 h. The ex vivo diffusion study indicated an apparent permeability coefficient of 5.0 + 0.3 × 104 for drug-containing NPs, which was higher than for plain drug solution (2.0 + 0.2 × 104). Sheep nasal toxicity and hemolytic study proved the safety of formulation. The optimized NPs were found to be stable in SNF. Thus, nanoparticulate formulation of LA was optimized by quality by design approach.

Chitosan/guar gum-based thermoreversible hydrogels loaded with pullulan nanoparticles for enhanced nose-to-brain drug delivery

The biopolymers-based two-fold system could provide a sustained release platform for drug delivery to the brain resisting the mucociliary clearance, enzymatic degradation, bypassing the first-pass hepatic metabolism, and BBB thus providing superior bioavailability through intranasal administration. In this study, poloxamers PF-127/PF-68 grafted chitosan HCl-co-guar gum-based thermoresponsive hydrogel loaded with eletriptan hydrobromide laden pullulan nanoparticles was synthesized and subjected to dynamic light scattering, Fourier transform infrared spectroscopy, thermal analysis, x-ray diffraction, scanning electron microscopy, stability studies, mucoadhesive strength and time, gel strength, cloud point assessment, rheological assessment, ex-vivo permeation, cell viability assay, histology studies, and in-vivo Pharmacokinetics studies, etc. It is quite evident that CSG-EH-NPs T-Hgel has an enhanced sustained release drug profile where approximately 86 % and 84 % of drug released in phosphate buffer saline and simulated nasal fluid respectively throughout 48 h compared to EH-NPs where 99.44 % and 97.53 % of the drug was released in PBS and SNF for 8 h. In-vivo PKa parameters i.e., mean residence time (MRT) of 11.9 ± 0.83 compared to EH-NPs MRT of 10.2 ± 0.92 and area under the curve (AUCtot) of 42,540.5 ± 5314.14 comparing to AUCtot of EH-NPs 38,026 ± 6343.1 also establish the superiority of CSG-EH-NPs T-Hgel.

Development of Eudragit® Nanoparticles for Intranasal Drug Delivery: Preliminary Technological and Toxicological Evaluation

Intranasal administration has assumed in the last years an increasing value as an alternative strategy for the systemic adsorption of drugs, as an alternative to oral and parenteral routes thanks to the high vascularized nasal mucosa. Nevertheless, different drug features may restrict its absorption through the nasal mucosa with an insufficient diffusion to the systemic circulation. Several technological strategies are under investigation to improve drug absorption during nasal formulation design and production. The use of bioadhesive polymers can be considered a valid approach to pursue the aforementioned goal. Based on this consideration, Eudragit® Retard RS100 and RL100 resins were selected as positively charged copolymers to prepare polymeric NPs with potential mucoadhesive properties suitable for intranasal application. NPs were produced by the Quasi-emulsion Solvent Evaporation (QESD) method and loaded with diclofenac acid (DIC) or its epolamine salt (DIEP). Preliminary investigations were performed to obtain the optimized blank formulation and drugs loaded NPs evaluating different parameters that can affect particles size and polydispersity. The optimized formulations unloaded and loaded with DIC and DIEP were further evaluated for their thermotropic behavior by differential scanning calorimetry. Mucoadhesive evaluation was assessed by measuring variation in zeta potential and by turbidimetric assay after incubation of particles with mucin in simulated nasal fluid (SNF) at 37 °C at different time points (0, 1 and 24 h) compared to the pure suspensions. Stability of DIC and DIEP loaded NPs was also evaluated in SNF to predict potential aggregation phenomena after nasal administration. Finally, in vivo experiments showed absence of toxicity on the nasal mucosa of mice.

UV Spectrophotometric Method for Quantification of Rivastigmine Tartrate in Simulated Nasal Fluid: Development and Validation

Background: Rivastigmine Tartrate belongs to the class of cholinesterase inhibitors in Anti-alzheimer’s disease with optimum therapeutic efficacy. Till now no validated method of its quantification has been reported in simulated nasal fluid. Objective: The current research investigation aims to develop a rapid, simple, and reliable UV spectrophotometric method for the quantitative determination of the pure form of Rivastigmine Tartrate in SNF. Method: A suitable method was developed by using double beam UV spectrophotometer and selection of a suitable solvent system for estimation of Rivastigmine Tartrate at absorbance maxima 263nm in SNF. The method was validated for various parameters like including accuracy, linearity and precision as per the International Conference on Harmonization guidelines. Results: The method developed by selecting simulated nasal fluid as the solvent system satisfied the optimum condition of the good quality peak at the selected wavelength. The results proposed the developed method for Rivastigmine Tartrate quantification in the simulated nasal fluid to be linear in the working concentration range of 5-60 µg/ml with a co-relation coefficient of 0.998. The % accuracy was found to be 99.8 -100.57. The % RSD values were &lt; 2 while LOD &amp; LOQ values were detected to be 0.316 and 1.053 respectively. Conclusion: The stated method was analyzed to be rapid, accurate, reliable, and precise. Further, it can be used in checking the quality control parameters of the Rivastigmine Tartrate in routine analysis.

Oxidized Alginate Dopamine Conjugate: In Vitro Characterization for Nose-to-Brain Delivery Application.

Background: The blood–brain barrier (BBB) bypass of dopamine (DA) is still a challenge for supplying it to the neurons of Substantia Nigra mainly affected by Parkinson disease. DA prodrugs have been studied to cross the BBB, overcoming the limitations of DA hydrophilicity. Therefore, the aim of this work is the synthesis and preliminary characterization of an oxidized alginate-dopamine (AlgOX-DA) conjugate conceived for DA nose-to-brain delivery. Methods: A Schiff base was designed to connect oxidized polymeric backbone to DA and both AlgOX and AlgOX-DA were characterized in terms of Raman, XPS, FT-IR, and 1H- NMR spectroscopies, as well as in vitro mucoadhesive and release tests. Results: Data demonstrated that AlgOX-DA was the most mucoadhesive material among the tested ones and it released the neurotransmitter in simulated nasal fluid and in low amounts in phosphate buffer saline. Results also demonstrated the capability of scanning near-field optical microscopy to study the structural and fluorescence properties of AlgOX, fluorescently labeled with fluorescein isothiocyanate microstructures. Interestingly, in SH-SY5Y neuroblastoma cell line up to 100 μg/mL, no toxic effect was derived from AlgOX and AlgOX-DA in 24 h. Conclusions: Overall, the in vitro performances of AlgOX and AlgOX-DA conjugates seem to encourage further ex vivo and in vivo studies in view of nose-to-brain administration.