Nasal Permeability Research Articles

Preparation and In vitro/Ex vivo Evaluation of Nanoemulsion-Based in Situ Gel for Intranasal Delivery of Lasmiditan

Lasmiditan (LAS) was formulated as a nanoemulsion based in situ gel (NEIG)with the aim of improving its oral bioavailability via application intranasally. The solubility of LAS in oils, emulsifiers, and co-emulsifiers was determined to identify nanoemulsion (NE)components. Phase diagrams were constructed to identify the area of nanoemulsification. LAS NE was formulated using the spontaneous nanoemulsification method. Four NEs (F19, F24, F31, and F34) containing 7-15 % oleic acid (OA) as an oily phase, 40-55% labrasol (LR), and transcutol (TC) as emulsifier mixture at (1:1), (2:1), (3:1), and (1:2) ratio with 30-53 % (w/w) aqueous phase, having suitable optical transparency of 95–98%, globule size of 104-140 nm and polydispersity of 0.253–0.382 were selected for ex vivo permeation study. F31 with the highest flux value (2.32 ± 0.01 mg/cm2.min) relative to the other NEs. It achieves an enhancement ratio of 3.3 as compared to LAS aqueous suspension (8% LAS) also it achieves a significantly higher value of permeability coefficient. F31 was selected for the incorporation of different percentages of pH-sensitive in situ gelling polymer (Carbopol 934) to prepare NEIGs 4,5 and 6. The gel strength, pH, gelation time, and viscosity were predicted for the prepared NEIGs. In vitro release and ex vivo, nasal permeation were determined for NEIG5, which exerts comparable release and permeation values as F31 with more residence time in order to overcome the normal nasal physiological clearance.

The Use of Rhinomanometry in Mouth Breathing: A Systematic Review of the Literature.

Introduction Mouth breathing generates imbalances in the musculature, in craniofacial morphofunctionality, and in the stomatognathic system. Therefore, it is essential to make a diagnosis of mouth breathing through the quantitative assessment of nasal permeability, which can be performed through rhinomanometry. Objective To investigate the effectiveness of rhinomanometry in the diagnosis of mouth breathing in pediatric patients through a systematic review of the literature. Data synthesis The guiding question was: "Is the use of rhinomanometry as an assessment tool effective in the diagnosis of mouth breathing in pediatric patients?". We conducted a search on the following databases: Latin American and Caribbean Center on Health Sciences Information (BIREME), Latin American and Caribbean Health Sciences Literature (LILACS), PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Scientific Electronic Library Online (SciELO), Web of Science, and Science Direct. The Health Sciences Descriptors (Descritores em Ciências da Saúde, DECS, in Portuguese) and Medical Subjects Headings (MESH) were combined with the Boolean operator AND in the search strategy: rhinomanometry AND mouth breathing AND diagnosis AND nasal pressure AND nasal airflow AND nasal resistance . Observational cohort and cross-sectional studies that addressed the effectiveness of rhinomanometry in the diagnosis of mouth breathing were included. The reviewers independently extracted the information and scored the review quality based on the Physiotherapy Evidence Database (PEDro) scale and the grading of evidence levels according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Of the 1,536 articles identified, only 3 were selected for the present review after the application of the eligibility criteria. Conclusion There is great concern regarding the assessment of nasal function. There was a lack of standardization of rhinomanometry to test the effectiveness of nasal resistance as an aid in the diagnosis of breathing mode.

Preparation, In-vitro, Ex-vivo, and Pharmacokinetic Study of Lasmiditan as Intranasal Nanoemulsion-based In Situ Gel.

Lasmiditan (LAS) is a recently developed antimigraine drug and was approved in October, 2019 for the treatment of acute migraines; however, it suffers from low oral bioavailability, which is around 40%. This study aimed to improve the LAS bioavailability via formulation as nanoemulsionbased in situ gel (NEIG) given intranasally and then compare the traditional aqueous-LASsuspension (AQS) with the two successful intranasal prepared formulations (NEIG 2 and NEIG 5) in order to determine its relative bioavailability (F-relative) via using rabbits. Two successfully prepared nanoemulsion (NE) formulas, a and b, were selected for the incorporation of different percentages of pH-sensitive in situ gelling polymer (Carbopol 934) to prepare NEIGs 1, 2, 3, 4, 5, and 6. The pH, gelation capacity, gel strength, and viscosity were predicted for the prepared NEIGs. The release (in vitro) and the nasal permeation (ex vivo) were determined for NEIG 2 and 5, and then both were subjected to pharmacokinetics in vivo studies. Eighteen male rabbits weighing 2.0 to 2.5 kg were employed in the parallel design study. The body surface area (BSA) normalization method was applied for LAS dose calculation. Serial blood samples were taken out and subjected to drug analysis using the HPLC method previously developed and validated by L. Santosh Kumar. Primary pharmacokinetics parameters, including maximum drug concentration in plasma (Cmax), time to reach C-max (T-max), and area under the concentration-time curve from time zero to affinity (AUCt0-∞) were calculated. Both NE (a and b), together with NEIG (2 and 5) formulas, were subjected to the stability study. Finally, a nasal ciliotoxicity study was carried out to evaluate the nasal toxicity of developed NEIGs 2 and 5. The results showed that NEIGs 2 and 5 could be selected as the optimized NEIGs as both achieved 100% permeation within 20 min and then released within 25 and 35 min, respectively, thus achieving 3.3 folds with higher permeation percentages as compared to the AQS. Both NEIGs 2 and 5 exerted comparable release and permeation values as the corresponding NE a and b with more residence time in order to overcome the normal nasal physiological clearance. The values of C-max, Tmax, and AUC0- ∞ for NEIG 2 and NEIG 5 were 8066±242 ng/ml, 0.75±0.05 h, 19616.86±589 ng. h/ml, and 7975.67±239 ng/ml, 1.0±0.05 h, 17912.36±537 ng. h/ml, respectively, compared to the traditional AQS, which is equal to 4181.09±125 ng/ml, 2±0.2 h, and 8852.27±266 ng. h/ml, respectively. It was discovered that NEIGs 2 and 5 had better intranasal delivery of LAS and could significantly (p<0.05) achieve a higher value of permeability coefficient (3.3 folds) and 2.5 folds improvement in bioavailability when compared to AQS. The NE a, NE b, NEIG2, and NEIG5 formulations showed good stability at various temperatures. According to the nasal ciliotoxicity study, the nasal mucosal membrane, which was treated with NEIG 5, showed irritation with a bit of damage. However, damage was not observed when it was treated with NEIG 2, indicating the biocompatibility of the last one to be selected as the optimum formula. NEIG 2 and NEIG 5 are promising new intranasal formulas with a faster onset of action and greater bioavailability than the oral dosage form (AQS). Finally, the selected optimum gold formula that will be ready for further clinical study is NEIG 2.

Quality by design approach for development and characterization of gabapentin-loaded solid lipid nanoparticles for intranasal delivery: In vitro, ex vivo, and histopathological evaluation.

"Quality by Design" (QbD) is a novel approach to product development that involves understanding the product and process, as well as the relationship between critical quality attributes (CQA) and critical process parameters (CPP). This study aimed to optimize the gabapentin-loaded solid lipid nanoparticle formulation (GP-SLN) using a QbD approach and evaluate in vitro and ex vivo performance. The GP-SLN formulation was created using the microemulsion method by combining Gelucire 48/16, Tween 80, and Plurol Oleique CC 497. The Box-Behnken experimental design was adopted to investigate the effects of independent factors on dependent factors. The GP-SLN formulation was assessed based on particle size and distribution, zeta potential, morphology, entrapment efficiency, release kinetics, permeation parameters, stability, and nasal toxicity. The nanoparticles had a cubical shape with a particle size of 185.3±45.6 nm, a zeta potential of -24±3.53 mV, and an entrapment efficiency of 82.57±4.02%. The particle size and zeta potential of the GP-SLNs remained consistent for 3 months and followed Weibull kinetics with a significantly higher ex vivo permeability (1.7 fold) than a gabapentin solution (GP-SOL). Histopathology studies showed that intranasal administration of the GP-SLN formulation had no harmful effects. The current study reports the successful development of a GP-SLN formulation using QbD. A sustained release of GP was achieved and its nasal permeability was increased. Solid lipid nanoparticles with optimum particle size and high entrapment efficiency may offer a promising approach for the intranasal delivery of drugs.

Transferrin functionalized poloxamer-chitosan nanoparticles of metformin: physicochemical characterization, in-vitro, and Ex-vivo studies

Object We report the preparation, characterization, and in-vitro therapeutic evaluation of Metformin-Loaded, Transferrin-Poloxamer-Functionalized Chitosan Nanoparticles (TPMC-NPs) for their repurposing in Alzheimer’s disease (AD). Significance Usefulness of this work to establish the repurposing of metformin for the treatment of AD. Methods The TPMC-NPs were prepared by ionic gelation method using sodium tripolyphosphate. The modification and functionalization were confirmed by FTIR and 1H-NMR spectroscopy. The physicochemical characterization was performed using DLS, FTIR,1H-NMR, CD spectroscopy, SEM, DSC, PXRD, HR-TEM, and hot-stage microscopy. Results The size, PDI, percent entrapment efficiency, and percent drug loading of TPMC-NPs were found to be 287.4 ± 9.5, 0.273 ± 0.067, 81.15 ± 7.17%, 11.75%±8.21%, respectively. Electron microscope analysis revealed smooth and spherical morphology. The transferrin conjugation efficiency was found to be 46% by the BCA method. CD spectroscopy confirmed no significant loss of the secondary structure of transferrin after conjugation. PXRD data indicated the amorphous nature of the TPMC-NPs. Hot-stage microscopy and DSC confirmed the thermal stability of TPMC-NPs. The in-vitro drug release showed a sustained release at pH 7.4. The DPPH assay displayed 80% antioxidant activity of TPMC-NPs in comparison with metformin and blank NPs. The in-vitro cytotoxicity assay revealed 69.60% viable SH- SY5Y cells at 100 µg/mL of TPMC NPs. The ex-vivo nasal ciliotoxicity and mucoadhesion studies showed no significant toxicity, and 98.16% adhesion, respectively. The nasal permeability study showed the release of metformin within 30 min from TPMC-NPs. Conclusion The obtained results suggested the usefulness of TPMC-NPs in the treatment of AD via the intranasal route.

Nasal-PAMPA: A novel non-cell-based high throughput screening assay for prediction of nasal drug permeability

In nasal drug product development, screening studies are vital to select promising compounds or formulations. The Parallel Artificial Membrane Permeability Assay (PAMPA), a high throughput screening tool, has been applied to evaluate drug permeability across several barriers such as the skin or blood–brain barrier. Herein, a new nasal-PAMPA model was optimized to predict nasal permeability, using a biorelevant donor medium containing mucin. The apparent permeability (Papp) of 15 reference compounds was assessed in six different experimental conditions, and the most discriminating and predictive model was applied to a test drug (piroxicam) and mucoadhesive powder formulations loading the same drug. The model with 0.5% (w/v) mucin in the donor compartment and 2% (w/v) phosphatidylcholine in the lipid membrane accurately distinguished high and low permeable compounds. Additionally, it exhibited the highest correlation with permeation across human nasal epithelial cells, RPMI 2650 (R2 = 0.93). When applied to powder formulations, this model was sensitive to the presence of mucoadhesive excipients and the drug solid state.Overall, the nasal-PAMPA model was more rapid than cell-based assays, without requiring specialized training or equipment, showing to be a promising in vitro tool that can be applied in drug and formulation screening for nasal delivery.

The use of acoustic rhinometry as a postoperative evaluation method in children with chronic hypertrophic rhinitis

acoustic rhinometry has opened new perspectives in the objective estimation of nasal physiology. With the help of this method, it is easy to determine the geometry of the nasal fossae, using minimal resources. The method offers an objective control of the surgery of the cartilages and bones of the nasal pyramid. That method represents an objective method of measuring nasal permeability, which in recent years is increasingly used in pediatric patients. In this study, we aim to evaluate nasal patency in children with chronic hypertrophic rhinitis. Study of nasal permeability using acoustic rhinometry in children with chronic hypertrophic rhinitis in order to evaluate the effectiveness of diode laser surgical treatment for hypertrophy of the inferior nasal turbinate. The study was conducted on 50 children with chronic hypertrophic rhinitis. The comparison group was represented by the control group, which includes 50 children without nose and paranasal sinus pathology. These children were selected from the number of patients hospitalized in the clinic with other forms of pathology. In patients from the study groups, nasal patency was evaluated at certain postoperative time intervals, in order to determine the efficiency of the applied surgical technique. There is a dynamic increase in nasal cavity volumes and ASTmin postoperatively in patients from the study group. Compared to the control group, the differences are insignificant, which indicates that the surgical treatment had an effect. Acoustic rhinometry is an objective method of evaluating the geometry of the nasal cavities, with a special role in the postoperative monitoring of patients with chronic hypertrophic rhinitis

Propranolol-Loaded Limonene-Based Microemulsion Thermo-Responsive Mucoadhesive Nasal Nanogel: Design, In Vitro Assessment, Ex Vivo Permeation, and Brain Biodistribution.

Propranolol is the first-line drug for managing migraine attacks. D-limonene is a citrus oil known for its neuroprotective mechanism. Thus, the current work aims to design a thermo-responsive intranasal limonene-based microemulsion mucoadhesive nanogel to improve propranolol efficacy. Microemulsion was fabricated using limonene and Gelucire® as the oily phase, Labrasol®, Labrafil®, and deionized water as the aqueous phase, and was characterized regarding its physicochemical features. The microemulsion was loaded in thermo-responsive nanogel and evaluated regarding its physical and chemical properties, in vitro release, and ex vivo permeability through sheep nasal tissues. Its safety profile was assessed via histopathological examination, and its capability to deliver propranolol effectively to rats' brains was examined using brain biodistribution analysis. Limonene-based microemulsion was of 133.7 ± 0.513 nm diametric size with unimodal size distribution and spheroidal shape. The nanogel showed ideal characteristics with good mucoadhesive properties and in vitro controlled release with 1.43-fold enhancement in ex vivo nasal permeability compared with the control gel. Furthermore, it displayed a safe profile as elucidated by the nasal histopathological features. The nanogel was able to improve propranolol brain availability with Cmax 970.3 ± 43.94 ng/g significantly higher than the control group (277.7 ± 29.71 ng/g) and with 382.4 % relative central availability, which confirms its potential for migraine management.

Intranasal nanotherapeutics for brain targeting and clinical studies in Parkinson's disease.

Parkinson's disease (PD) is the second leading neurodegenerative disease globally, impacting the quality of life of a large population. Millions of people are affected by PD, and it is estimated that the treatment cost of PD in the USA can rise to 79 billion dollars by 2037. Limited drugs are approved by USFDA, which only provides systematic relief. Further, the drug efficacy is challenged due to low drug-brain concentration due to first-pass metabolism and blood-brain barrier (BBB). Intranasal drug administration can offer several advantages over systemic administration for efficient brain delivery. Nose-to-brain (N2B) drug delivery can enhance brain bioavailability, reduce enzymatic degradation, and reduce systemic adverse effects. However, due to poor absorption from the nasal mucosa, intranasal administration can be challenging for hydrophilic drugs. The drug mucociliary clearance, retention time, and nasal enzymatic degradation can also affect N2B drug delivery. Nanocarriers can enhance residence time, improve nasal permeation, increase brain uptake, and reduce enzymatic degradation. This review discusses the roles and applications of various N2B nanocarriers to treat PD effectively and clinical trials of antiparkinson molecules. Lastly, safety aspects and prospects of potential nanotherapeutics for the effective treatment of PD are discussed.

Nose to brain delivery of naringin loaded transniosomes for epilepsy: formulation, characterisation, blood-brain distribution and invivo pharmacodynamic evaluation

The current work limns the preparation of naringin-loaded transnioosomes (NRN-TN) to enhance NRN solubility, permeation and bioavailability via nasal mucosa for intranasal delivery. NRN-TN was created by the thin-film hydration technique, and with the BBD (Box-Behnken design), optimisation was carried out. NRN-TNopt was characterised for the vesicle size, PDI (Polydispersity index), zeta potential, entrapment efficiency (EE) and in vitro NRN release. For further assessment, nasal permeation study, study of Blood-brain distribution, TEM (Transmission Electron Microscopy), and CLSM (Confocal Scanning Laser Microscopy) were conducted withal. The NRN-TNopt exhibited spherical as well as sealed vesicles with a considerable small size of 151.3 nm, an EE of 75.23 percent, a PDI of 0.1257, and an in vitro release of 83.32 percent. CLSM investigation revealed that the new formulation allows for higher NRN permeation across nasal mucosa than the NRN solution. The blood-brain distribution investigation revealed that intranasally administered NRN-TN had a greater Cmax and AUC0-24 h than orally administered NRN-TN. Seizure activity and neuromuscular coordination as measured by the rotarod test, biochemical estimate of oxidative stress indicators, and histological investigations demonstrated that the NRN-TN has superior anti-epileptic potential in comparison to the standard diazepam. In addition, nasal toxicity studies demonstrate that the NRN-TN formulation is safer for intranasal administration. This study confirmed that the created TN vesicle formulation is a valuable carrier for the intranasal administration of NRN for the treatment of epilepsy.

Spanlastics as a Potential Approach for Enhancing the Nose-To-Brain Delivery of Piperine: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Management of Epilepsy

The present study delineates the preparation of piperine-loaded spanlastics (PIP-SPL) to improve piperine (PIP) solubility, bioavailability, and permeation through nasal mucosa for intranasal delivery. PIP-SPL was formulated using the thin-film hydration method and optimization was performed using Box-Behnken design (BBD). PIP-SPL optimized formulation (PIP-SPLopt) was characterized for polydispersity index (PDI), vesicle size, entrapment efficiency, zeta potential, and in vitro PIP release. For further evaluation, blood-brain distribution study, transmission electron microscopy (TEM), nasal permeation study, and confocal scanning laser microscopy (CLSM) were performed withal. The PIP-SPLopt presented spherical and sealed shape vesicles with a small vesicle size of 152.4 nm, entrapment efficiency of 72.93%, PDI of 0.1118, and in vitro release of 82.32%. The CLSM study unveiled that the developed formulation has greater permeation of PIP across the nasal mucosa in comparison with the PIP suspension. The blood-brain distribution study demonstrated higher Cmax and AUC0-24h of PIP-SPL via the intranasal route in comparison to PIP-SPL via oral administration. The in vivo study revealed that the PIP-SPL has good antiepileptic potential in comparison with the standard diazepam, which was evinced by seizure activity, neuromuscular coordination by rotarod test, biochemical estimation of oxidative stress markers, and histopathological studies. Furthermore, nasal toxicity study confirm that the developed PIP-SPL formulation is safer for intranasal application. The current investigation corroborated that the prepared spanlastic vesicle formulation is a treasured carrier for the PIP intranasal delivery for the management of epilepsy.

Advances on the Treatment of Allergic Rhinitis by Traditional Chinese Medicine and Western Medicine

Background: Allergic rhinitis is a common and high incidence disease in clinic, which has a certain impact on the work, life and social activities of patients. Modern medicine still lacks effective treatment methods for such diseases. In recent years, clinical cases of children and adolescents have also increased year by year. Objective: In order to provide references for further study and practical treatment on allergic rhinitis, this paper summarized the advances on the treatment of allergic rhinitis by Traditional Chinese Method (TCM) and Western Medicine Method (WMM) in clinical practice and study. Method: Through detailed review and study of literatures, the theory and clinical experiences in TCM, WMM, and integrated treatment of the two were analyzed and summarized. Conclusions: TCM conducts personalized treatment for patients by syndrome differentiation. The main means are to regulate the body’s health Qi and Yang Qi. Drugs, acupuncture, psychology and other means of treatment are all used and the effects of treatment are very well. WMM mainly relieves the infiltration of local inflammatory cells, expands local capillaries, improves nasal permeability and alleviates the occurrence of allergic graduation by using kinds of drugs or surgery. Though both TCM and WMM are effective and have some common characteristics and each has its own characteristics, the combination of TCM and WMM has a good prospect and is more effective and can effectively reduce the adverse reactions of patients, because TCM is to change patients’ own constitution and the starting point of WMM is to eliminate the pathogen.

Sensitive RP-HPLC method of rivastigmine for applicative quantification of nanostructured lipid carriers

The present research work focuses on development of a rapid, simple, precise, accurate and robust RP-HPLC method for quantitative estimation of rivastigmine hydrogen tartrate (RIV-HT) in bulk and formulations. Systematic optimization of the method observed two critical parameters, viz. pH of mobile phase and mobile phase ratio that particularly affected peak area, tailing factor and number of theoretical plates. The optimized mobile phase consisted of ACN (0.05 % v/v triethylamine): 10 mM, pH 5.5 phosphate buffer: IPA (33:65:2 v/v). The limit of detection and limit of quantification values were observed to be 7.32 and 24.15 ng/mL, with a linearity range between 25-600 ng/mL. The proposed method was observed to be specific in presence of solution and solid-state stress conditions. It was also specific in the presence of formulation excipients, release and permeation medium. The method was applied to estimate encapsulation efficiency, in-vitro release profiles, and ex-vivo nasal permeation efficiency of RIV-HT loaded nanostructured lipid carriers. The obtained results advocate that the newly proposed method is sensitive compared to the previously published reports and can be explicitly utilized for estimating RIV-HT in bulk and nanoformulations.

Intranasal ondansetron microemulsion counteracting the adverse effects of cisplatin: animal study

BackgroundCisplatin is considered one of the most effective and commonly used chemotherapeutic drugs, but despite its high therapeutic effectiveness, most patients treated with cisplatin suffer from nausea and vomiting, neurotoxic side effects, and cerebral psychiatric disorders such as depression. Therefore, the aim of the current work was to explore whether a selective 5-HT3 receptor antagonist (Ondansetron) administered via the oral route or intranasally in microemulsion form would alleviate cisplatin’s adverse effects.MethodsThe selected ondansetron microemulsion was characterized in vitro for particle size, polydispersity, zeta potential, morphology, and nasal permeation, and in vivo in terms of anti-emetic and antidepressant activity, with the assessment of biochemical markers in brain homogenates.ResultsResults revealed that both orally administered ondansetron and intranasally administered microemulsion were able to counteract the pica effect by increasing food consumption, water intake, and decreasing kaolin intake. They were also able to increase BDNF, normalize IL-6, increase serotonin, and normalize NOx, MDA, GSSH/GSH as well as 8OHdG levels in rats’ brain homogenates. The intranasal ondansetron microemulsion displayed superiority compared to oral conventional ondansetron in terms of increasing food intake, reduction of stomach content, and normalization of serotonin turnover.ConclusionOndansetron microemulsion can be administered by an alternative route of administration (intranasal) rather than oral, for patients on cisplatin chemotherapy.Graphical

Nose-to-brain delivery of rotigotine redispersible nanosuspension: In vitro and in vivo characterization

Rotigotine (RTG) is an anti-Parkinson's drug approved by the USFDA to treat motor and non-motor symptoms of both early and advanced stages of the disease. However, issues like poor aqueous solubility, low oral bioavailability (<1%), first-pass metabolism, low systemic bioavailability (∼37%) and low brain bioavailability demean the therapy. This work developed poloxamer-stabilized RTG-Nanosuspension for intranasal (i.n.) administration. RTG-Nanosuspension was optimized using Box-Behnken design with critical variables affecting the responses, viz. particle size and PDI. The optimized RTG-Nanosuspension showed mean particle size of 73 nm and PDI of 0.286. Lyophilized RTG-Nanosuspension was also characterized for drug crystallinity, interactions, and morphology. The lyophilized RTG-Nanosuspension showed good stability and was a porous structure. The first 15 min of in vitro dissolution showed 95% cumulative drug dissolved from RTG-Nanosuspension formulation. RTG-Nanosuspension showed 20-fold increase in nasal permeation. The nasal ciliotoxicity study showed both RTG-Nanosuspension and drug dispersion were safe for i.n. delivery. An in vivo study showed that optimized RTG-Nanosuspension helped target RTG to the brain following i.n. administration. Overall, the RTG-Nanosuspension formulation showed potential in nose-to-brain delivery for targeted application in Parkinson's disease.

Development of cannabidiol nanoemulsion for direct nose to brain delivery: statistical optimization, in vitro and in vivo evaluation

Cannabidiol (CBD) is a prescribed drug for epilepsy but has low oral bioavailability and gastric instability. Because of the direct link between the nasal cavity and the central nervous system, intranasal administration of CBD as nanoemulsions which are the small sized lipid carriers seem to improve the bioavailability. CBD-nanoemulsions (NEs) were made using Capryol 90, Tween 80, and Transcutol P as oil, surfactant, and co-surfactant, respectively, following aqueous titration approach. Then, using the Box–Behnken design, CBD-NE was statistically optimised for the selection of desirable excipient concentrations in order to create the optimal CBD-NE formulation. As independent variables in the statistical design, Capryol 90 (oil; coded as A), Tween 80 (surfactant; coded as B), and Transcutol P (co-surfactant; coded as C) were used. The dependent variables were droplet size (DS; coded as R 1) and polydispersity index (PDI; coded as R 2). The average DS, PDI, and the zeta potential of the optimized CBD-NEs were observed to be 88.73 ± 2.67 nm, 0.311 ± 0.015, and −2.71 ± 0.52 mV respectively. Pure CBD and lyophilized CBD-NE Fourier-transform infrared spectra demonstrated no physicochemical interaction between excipients and the drug. Furthermore, differential scanning calorimetry and x-ray diffraction measurements revealed the amorphous CBD in the NE. As compared to pure CBD, the optimised CBD-NE showed considerably better in vitro drug release as well as ex vivo nasal permeability. The drug targeting efficiency and direct transport percentage of the optimised CBD-NEs were found to be 419.64% and 76.17%, respectively, in this research. Additionally, pharmacokinetic investigations after intranasal administration of CBD-NE revealed considerably higher drug concentrations in the brain with better brain targeting efficiency. As a result, the development of CBD-NE may be an excellent alternative for better intranasal delivery.

A comparative brain Toxico-Pharmacokinetics study of a developed tannic acid nanoparticles in the treatment of epilepsy

Epilepsy is the most popular neurological problem throughout the world. Tannic Acid (TA) is used with vitamin E (antioxidant) as desirable and safe in the treatment of epilepsy. We used central composite design (CCD) to optimize for the preparation of PLGA Nanoparticles (NPs) in the delivery of TA via intranasal to brain which gives results improvement of brain bioavailability. PLGA NPs was prepared through an emulsion solvent evaporation with the help of 3-factor, 4-level CCD to get a best optimized-NPs. 3-independent variables were chosen (PLGA, Vitamin E TPGS, and sonication time) for the optimization of best NPs. Coating of TA-PLGA-NPs with chitosan was done for enhanced antiepileptic efficacy and brain targeting as well as drug release followed by nasal permeation study. An optimized-NPs was optimized by the two variables (dependent and independent) based on the composition of PLGA (3.0%), Vitamin E TPGS (0.3%), and sonication time (5.0 min). The values of particle size, entrapment efficiency, PDI, and zeta potential were found 105.7 ± 11.02 nm, −22.3 ± 2.3 mV, 0.169 ± 0.002, and 69.31 ± 5.89% respectively based on selected dependent variables. Optimized-TA-PLGA-NPs were coated by the CS that gives the negative to positive ZP value followed by small increment of PS. On the basis of brain pharmacokinetics results, we found a great significantly (p < 0.001) enhancement of Cmax and area under curve (AUC)0–24 by treatment (intranasal and i.v.) of wistar rats. Finally, we found a great significant i.e. p < 0.001 results in the treatment of epilepsy models (increasing current electroshock & pentylenetetrazole-induced seizures with the administration of CS coated TA PLGA NPs due to their great mucoadhesive property. we also found a significant i.e. p < 0.001) enhancement of brain-bioavailability of TA followed by treated epilepsy rats due to the administration of CS coated TA PLGA NPs. There were no mortalities, neither variation morphologically of microstructure-of brain-as well as nasal-mucosa- tissues. We didn't observe no visual signs of inflammatory or necrosis that means no toxicological results.

Statistically designed vitamin D3 Encapsulated PLGA microspheres dispersed in thermoresponsive in-situ gel for nasal delivery

Vitamin D deficiency is a cause of concern across the world. It is a fat-soluble vitamin and exhibits two molecular forms (D2 and D3). The aim of the present study is the development and optimization of vitamin D3 loaded PLGA microspheres by using Box Behnken Design. Additionally, to enhance nasal permeation these microspheres were dispersed in the thermoreversible in-situ gel. Microspheres revealed particle size in the range of 9182 ± 1 nm with 75.5 ± 0.5%EE of vitamin D3. Polydispersity index and zeta potential of microspheres were found 0.509 and −7.56 mV, respectively confirming uniformity and colloidal stability. FTIR and DSC studies revealed no interaction between excipients and vitamin D3. Scanning electron microscopy demonstrated spherical morphology of microspheres. The thermoreversible in-situ dispersed with vitamin D3 loaded microspheres exhibit the gelation temperature between 35 °C to 37 °C. The viscosity of the gel was 35698–5032 cps. The gel strength was found 1.1 ± 0.2 mJ with hardness (27 g), adhesiveness (22 g), and stringiness (3.2 mm) measured by a texture analyzer. In vitro dissolution study revealed that microspheres showed 79% VD3 release. Whereas microspheres dispersed gel showed 69% of VD3 release up to one week as compared to an oily solution. The mucoadhesion of gel was found 19600 dyne/cm2 suggesting the extraordinary high mucoadhesive property. Ex vivo permeation study through goat's nasal mucosa suggests that gel formulation showed 2.5 folds high permeation than microspheres and solution. Thus, it could be a potential drug delivery system for the delivery of vitamin D3 via nasal route.

Thymoquinone-Enriched Naringenin-Loaded Nanostructured Lipid Carrier for Brain Delivery via Nasal Route: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Treatment of Depression

In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via the ultrasonication technique and optimized using a central composite rotatable design (CCRD). The optimized NLC exhibited the following properties: droplet size, 84.17 to 86.71 nm; PDI, 0.258 to 0.271; zeta potential, −8.15 to −8.21 mV; and % EE, 87.58 to 88.21%. The in vitro drug release profile showed the supremacy of the TQ-NGN-NLC in comparison to the NGN suspension, with a cumulative drug release of 82.42 ± 1.88% from the NLC and 38.20 ± 0.82% from the drug suspension. Ex vivo permeation study displayed a 2.21-fold increase in nasal permeation of NGN from the NLC compared to the NGN suspension. DPPH study showed the better antioxidant potential of the TQ-NGN-NLC in comparison to NGN alone due to the synergistic effect of NGN and TQ oil. CLSM images revealed deeper permeation of the NGN-NLC (39.9 µm) through the nasal mucosa in comparison to the NGN suspension (20 µm). Pharmacodynamic studies, such as the forced swim test and the locomotor activity test, were assessed in the depressed rat model, which revealed the remarkable antidepressant effect of the TQ-NGN-NLC in comparison to the NGN suspension and the marketed formulation. The results signify the potential of the TQ-enriched NGN-NLC in enhancing brain delivery and the therapeutic effect of NGN for depression treatment.

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System.

Neurological diseases continue to increase in prevalence worldwide. Combined with the lack of modifiable risk factors or strongly efficacious therapies, these disorders pose a significant and growing burden on healthcare systems and societies. The development of neuroprotective or curative therapies is limited by a variety of factors, but none more than the highly selective blood-brain barrier. Intranasal administration can bypass this barrier completely and allow direct access to brain tissues, enabling a large number of potential new therapies ranging from bioactive peptides to stem cells. Current research indicates that merely administering simple solutions is inefficient and may limit therapeutic success. While many therapies can be delivered to some degree without carrier molecules or significant modification, a growing body of research has indicated several methods of improving the safety and efficacy of this administration route, such as nasal permeability enhancers, gelling agents, or nanocarrier formulations. This review shall discuss promising delivery systems and their role in expanding the clinical efficacy of this novel administration route. Optimization of intranasal administration will be crucial as novel therapies continue to be studied in clinical trials and approved to meet the growing demand for the treatment of patients with neurological diseases.