Nasal Bioavailability Research Articles

A Review on In-Situ Nasal Gel

In situ gelling drug delivery techniques have garnered a lot of interest in the last ten years. When exposed to a range of endogenous stimuli, such as temperature increases, pH shifts, and the presence of ions, they can gel from their sol-state prior to injection. Systems can be given in a number of ways to facilitate the injection of a local or systemic treatment. They can also be used as efficient carriers for drug-carrying nanoparticles and microparticles. either natural, synthetic, or combined with a semi-artificial polymer that exhibits in situ gelling activity. In order to extend the time spent at the site of action or absorption, coupling with mucoadhesive polymers is greatly desired for the development of such systems. Because of the nasal epithelium's high permeability, quick drug absorption, avoidance of hepatic first pass metabolism, increased medicine bioavailability, and less side effects, nasal drug administration is a better option than oral and parental routes. undesirable local and systemic effects, self-medication, direct administration to the central nervous system and systemic circulation, low dosage requirements, and improved patient compliance. It is possible to stop stomach ulcers from developing. Many drugs have higher oral bioavailability than nasal bioavailability, according to recent data. Therefore, nasal medications are the main topic of this review. Keywords: Bioavailability, In Situ Gel, Systemic Delivery, Nasal Drug Delivery System.

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions.

We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF). MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice. The particle size range of MF prepared with the bead mill treatment was 80-200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions. We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.

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

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

A Comprehensive Review on In-Situ Gel Drug Delivery System

Over the past ten years, in situ gelling drug delivery methods have attracted a lot of attention. Prior to injection, they are in a sol-state, and they can gel when exposed to a variety of endogenous stimuli, including temperature rise, pH changes, and the presence of ions. Such to accomplish the injection of a local or systemic medication, systems may be delivered by a variety of can also be employed effectively as carriers for nano- and microparticles that carry drugs. Natural or artificial or in conjunction with semi-artificial polymer exhibiting in situ gelling behaviour. For the development of such systems, coupling with mucoadhesive polymers is highly sought in order to prolong the duration spent at the site of action or absorption. Nasal drug administration is a superior option than oral and parental routes because of the high permeability of the nasal epithelium, rapid drug absorption, avoidance of hepatic first pass metabolism, improved bioavailability of the medication, and fewer adverse effects. adverse local and systemic effects, minimal dosage is required, Patient compliance has increased, direct distribution to the CNS and systemic circulation is available, and self-medication. The development of gastric ulcers can be prevented. Recent evidence indicates that many medications have greater oral bioavailability than nasal bioavailability. So, the focus of this review is on nasal drugs. Administration, various nasal architecture and physiology characteristics, the method of nasal absorption, and benefits, Evaluations of in situ gels' composition, use, and advantages and disadvantages.
 Keywords: Nasal formulation, sustained drug administration, mucoadhesive drug delivery system, and in-situ nasal gelation.

Same lung deposited dose in dog dosing a fine and coarse aerosol indicates no difference in intranasal filtration

A novel inhalation exposure system was developed with the aim to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog. It enables collecting PK data for multiple drug candidates in a single experiment by simultaneous administration of the drugs to the same animal. This facilitates a direct PK comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective. The system design was inspired by a clinical precision dosing dosimeter systems, which enhance dosing precision by synchronizing the aerosol delivery from the jet nebulizer with the inhalation to maximize the inhaled fraction of the nebulized dose.The performance of the novel system was validated in an in-vivo study, which included a comparison of the same nebulized dose delivered as a fine and a coarse aerosol. The drugs selected for this study were developed for local treatment of the lung via inhalation and were known to have low oral bioavailability due to being extremely poorly soluble and therefore expected to also have low nasal bioavailability. This would result in systemic exposure derived primarily from pulmonary absorption, which facilitated the PK assessment applied to determine the lung deposited dose.The jet nebulizer selected to generate a fine aerosol was designed for alveolar lung deposition and approved by U.S. Food and Drug Administration for lung ventilation imaging, and the nebulizer selected to generate a coarse aerosol was a standard nebulizer. The drugs were wet milled to a particle size considerably smaller than the nebulized droplets and the dispersed drug particles were therefore homogenously distributed in the droplet size distribution.Higher initial plasma concentrations were observed for the fine aerosol. This was expected, as the smaller droplets should deposit more efficiently in the peripheral regions of the lung, which consequently should lead to a faster absorption compared with the coarse aerosol from the standard nebulizer that should deposit more centrally. The fact that this could be observed supports that the novel system is an excellent tool in PK evaluations.Our study indicated that there was no difference in the systemic exposure between the fine and the coarse aerosol for the same nebulized dose, and thus the lung deposition was also the same. The considerable difference in the nebulized size distribution within the range relevant for available inhalation devices resulted in a negligible difference in intranasal filtration. The fraction of the nebulized dose that deposited in the lung was observed to be high in this study (mean of 21–30% and about 50% for one dog with a distinguished slow and deep breathing), which supports that the intranasal filtration was low. That a high fraction of the nebulized dose deposited in the lung indicates that an enhanced dosing precision was obtained with the novel system. The similar achieved lung doses of all three drugs, shows that the simultaneous administration of multiple drugs worked well.That the intranasal filtration was low is an important finding considering that devices for oropharyngeal delivery in dogs are applied in order to eliminate intranasal filtration. Oropharyngeal dosing is more invasive compared with oronasal dosing and avoiding utilizing that method can be considered a refinement measure from an animal research perspective.

COMBINATION OF METFORMIN AND CURCUMIN THERMOREVERSIBLE NASAL IN SITU GEL FORMULATION AND IN VITRO-EX VIVO EVALUATION FOR DIABETES-INDUCED ALZHEIMER’S DISEASE

The present research was focused to prepare the formulation containing combination of Metformin and Curcumin to control diabetes-induced Alzheimer’s in elderly population with the utilization of Poloxamer P188 (8%), a thermoreversible gelling polymer, and mucoadhesive polymers such as Carbopol 940, Sodium alginate and HPMC K100 in varying concentrations (0.5%, 1%, 1.5% and 2% respectively) to improve the absorption of drugs by increasing the contact time with nasal mucosa. The in situ gel was prepared by cold method and administered via nasal route to deliver the drug directly to CNS by bypassing BBB and to improve patient compliance, nasal bioavailability of drugs by cumulative its nasal retention time in nasal mucosa. Total 12 nasal in situ gels were prepared and evaluated for in vitro studies and ex vivo drug diffusion studies (goat nasal mucosa) and results were found to be satisfactory. Moreover, histopathological studies revealed that the preparation was safe to be used on nasal mucosa of goat. The prepared nasal in situ gel is an effective alternative to conventional method and can be used to treat diabetes-induced Alzheimer’s disease.

Spray Freeze Dried Lyospheres® for Nasal Administration of Insulin.

Pharmacologically active macromolecules, such as peptides, are still a major challenge in terms of designing a delivery system for their transport across absorption barriers and at the same time provide sufficiently high long-term stability. Spray freeze dried (SFD) lyospheres® are proposed here as an alternative for the preparation of fast dissolving porous particles for nasal administration of insulin. Insulin solutions containing mannitol and polyvinylpyrrolidone complemented with permeation enhancing excipients (sodium taurocholate or cyclodextrins) were sprayed into a cooled spray tower, followed by vacuum freeze drying. Final porous particles were highly spherical and mean diameters ranged from 190 to 250 µm, depending on the excipient composition. Based on the low density, lyospheres resulted in a nasal deposition rates of 90% or higher. When tested in vivo for their glycemic potential in rats, an insulin-taurocholate combination revealed a nasal bioavailability of insulin of 7.0 ± 2.8%. A complementary study with fluorescently labeled-dextrans of various molecular weights confirmed these observations, leading to nasal absorption ranging from 0.7 ± 0.3% (70 kDa) to 10.0 ± 3.1% (4 kDa). The low density facilitated nasal administration in general, while the high porosity ensured immediate dissolution of the particles. Additionally, due to their stability, lyospheres provide an extremely promising platform for nasal peptide delivery.

Nasal biocompatible powder of Geraniol oil complexed with cyclodextrins for neurodegenerative diseases: physicochemical characterization and in vivo evidences of nose to brain delivery

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPβCD) were selected as potential carriers for GER nose-to-brain delivery. Inclusion complexes were formulated and the biocompatibility with nasal mucosae and drug bioavailability into cerebrospinal fluid (CSF) were studied in rats. It has been demonstrated by DTA, FT-IR and NMR analyses that both the CDs were able to form 1:1 GER-CD complexes, arising long-term stable powders after the freeze-drying process. GER-HPβCD-5 and GER-βCD-2 complexes exhibited comparable results, except for morphology and solubility, as demonstrated by SEM analysis and phase solubility study, respectively. Even though both complexes were able to directly and safely deliver GER to CNS, GER-βCD-2 displayed higher ability in releasing GER in the CSF. In conclusion, βCD complexes can be considered a very promising tool in delivering GER into the CNS via nose-to-brain route, preventing GER release into the bloodstream and ensuring the integrity of the nasal mucosa.

Optimization and Evaluation of In situ Nasal Gel of Donepezil Hydrochloride

Introduction: The nasal route has been explored as a route of administration, due to the benefits it offers. The formulation in the form of in situ gel has been utilized for the local and systemic effect. This type of formulation first exists in sol form, but once they are administered, it undergoes gelation to form gel, and this approach can be used for successful drug delivery system. Methods: Thus, in the present study, formulation of in situ gel for nasal administration for donepezil hydrochloride (HCL), by the use of 32 factorial designs, to improve its nasal bioavailability, was developed by increasing its nasal retention time and arrive at an optimized formulation. The formulation was developed by the use of cold method, by incorporation of thermoreversible polymer poloxamer 407 and mucoadhesive agent tragacanth. The in situ gel was later evaluated for different parameters such as pH, gelation time gelation temperature, gel strength, drug content, mucoadhesion, viscosity, in vitro drug diffusion, and stability. Results: Based on results obtained, F5 formulation was found to be optimum. The concentration of 22.5% Poloxamer 407 with 0.07% tragacanth showed promising nasal drug delivery system for donepezil HCl, with enhanced residence time due to increase in viscosity and mucoadhesion characteristics. Conclusion: The use of in situ gel formulation thus can effectively and safely improve the nasal residence time and absorption of donepezil HCl.

Comparative evaluation of intranasally delivered quetiapine loaded mucoadhesive microemulsion and polymeric nanoparticles for brain targeting: pharmacokinetic and gamma scintigraphy studies

BackgroundTreatment in neurological disorders like schizophrenia requires continuous presence of drug in the brain for a prolonged period of time to achieve an effective therapeutic response. Delivery of antipsychotic drug quetiapine in the form of conventional delivery systems suffers from low oral bioavailability, first-pass metabolism, and frequent dosing. In addition to that biological obstacles present at the brain interface also hinders the transport of quetiapine across the brain. In the present study, nasal delivery of quetiapine loaded nanoparticles and microemulsion formulation were designed to evaluate their individual in vivo potential to achieve brain targeting. Chitosan-based polymeric nanoparticles and mucoadhesive microemulsion systems were developed through ionic gelation and water titration method respectively.ResultsMicroemulsion showed globule size lower than 50 nm with 95% drug loading while, nanoparticles exhibited 65% drug loading with particle size of 131 nm. Nasal diffusion study showed highest diffusion with chitosan-based mucoadhesive microemulsion over nanoparticles suggesting permeation-enhancing effects of chitosan. Due to the overall hydrophilic nature, quetiapine-loaded nanoparticles could not diffuse superiorly across nasal mucosa, hence, showed 1.3 times lesser diffusion compared to mucoadhesive microemulsion. Pharmacokinetics in rats showed highest brain concentration and 1.9-folds higher nasal bioavailability with mucoadhesive microemulsion over nanoparticles suggesting direct brain transport through olfactory route bypassing blood-brain barrier.ConclusionHigher quetiapine transport with mucoadhesive microemulsion suggested that synergistic effects like tight junction modulation by chitosan and unique composition facilitating smaller globule size could be responsible for higher brain transport. Imaging study by gamma scintigraphy also supported pharmacokinetic outcomes and concluded that mucoadhesive microemulsion could be a promising nanocarrier approach for non-invasive nose to brain delivery.Graphical abstract

New Opportunity to Formulate Intranasal Vaccines and Drug Delivery Systems Based on Chitosan.

In an attempt to develop drug delivery systems that bypass the blood–brain barrier (BBB) and prevent liver and intestinal degradation, it was concluded that nasal medication meets these criteria and can be used for drugs that have these drawbacks. The aim of this review is to present the influence of the properties of chitosan and its derivatives (mucoadhesion, permeability enhancement, surface tension, and zeta potential) on the development of suitable nasal drug delivery systems and on the nasal bioavailability of various active pharmaceutical ingredients. Interactions between chitosan and proteins, lipids, antigens, and other molecules lead to complexes that have their own applications or to changing characteristics of the substances involved in the bond (conformational changes, increased stability or solubility, etc.). Chitosan and its derivatives have their own actions (antibacterial, antifungal, immunostimulant, antioxidant, etc.) and can be used as such or in combination with other molecules from the same class to achieve a synergistic effect. The applicability of the properties is set out in the second part of the paper, where nasal formulations based on chitosan are described (vaccines, hydrogels, nanoparticles, nanostructured lipid carriers (NLC), powders, emulsions, etc.).

An ultrasensitive UPLC-MS/MS assay for the quantification of the therapeutic peptide liraglutide in plasma to assess the oral and nasal bioavailability in beagle dogs.

Aim: An ultrasensitive UPLC-MS/MS assay for liraglutide was developed and validated according to US FDA and EMA guidelines and applied to the quantification of plasma concentrations after intravenous, nasal and oral administration of liraglutide to beagle dogs. Results: Liraglutide isolation was performed with a combined protein precipitation and solid-phase extraction protocol. The calibrated concentration range of 0.1-200ng/ml was linear with correlation coefficients >0.998. Precise analysis was achieved through the utilization of an isotopically labeled internal standard. Absolute bioavailability of liraglutide after nasal and oral administration of liraglutide to beagle dogs was 0.03 and 0.006%, respectively. Conclusion: The assay matches the performance in sensitivity of the previously applied immunoassay and optimally covers the therapeutic range of liraglutide.

Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration.

Despite encouraging preclinical results, mechanisms of CNS drug delivery following intranasal dosing of nanoemulsions remain incompletely understood. Herein, the transport characteristics of intranasally administered nanoemulsions are investigated using mathematical modeling and simulation. A compartmental model was developed to describe systemic and brain pharmacokinetics of drug solutions following intranasal dosing in rodents. The association between transport processes and CNS drug delivery was predicted using sensitivity analysis. Published pharmacokinetic data for four drugs; dosed as a nanoemulsion and aqueous solution were modeled to characterize differences in transport processes across formulations. The intranasal model structure performed in a drug agnostic fashion. Sensitivity analysis suggested that though the extent of CNS drug delivery depends on nasal bioavailability, the CNS targeting efficiency is only sensitive to changes in drug permeability across the nasal epithelium. Modeling results indicated that nanoemulsions primarily improve nasal bioavailability and drug permeability across the olfactory epithelium, with minimal effect on drug permeability across the non-olfactory epithelium. Using mathematical modeling we outlined dominant transport pathways following intranasal dosing, predicted the association between transport pathways and CNS drug delivery, predicted human CNS delivery after accounting for inter-species differences in nasal anatomy, and quantified the CNS delivery potential of different formulations in rodents.

DEVELOPMENT OF METOCLOPRAMIDE HYDROCHLORIDE IN SITU GEL: NASAL DELIVERY AND PHARMACOKINETICS IN NEW ZEALAND RABBITS

Objective: Systemic bioavailability of metoclopramide hydrochloride (MCH) is 32–80% by oral route. The study was targeted to develop in situ gel of MCH for nasal delivery and to study its pharmacokinetics in healthy rabbits. Pre-systemic metabolism can be overcome.
 Methods: Poloxamer 407 (P407) aqueous solutions were prepared by cold method. In 32 factorial design, independent variables were Carbopol 934P and polyethylene glycol 6000 (PEG 6000), and dependent responses were gelation temperature, mucoadhesive strength, and drug release. A Pharmacokinetic study was carried out in New Zealand rabbits. The optimized in situ gel (1 mg/ml) was compared with marketed Reglan® (2 mg/2 ml) injection. Area under the curve (AUC), Cmax, and Tmax were estimated.
 Results: F2 was an optimized formulation. The study showed that P407 solutions formed a gel at nasal temperature 34°C having mucoadhesive strength 806.12±3.45 dyne/cm2. MCH release was found to be 93.74±1.31% within 6 h. Histopathological examination of formulation F2 exhibited safety to the nasal mucosa. The pH of formulations was 5.1±0.1 to 5.6±0.1 in the range of pH of nasal cavity. Plasma samples were analyzed by liquid chromatography/mass spectroscopy (LC/MS). The area under curve AUC0-4 for in situ gel by nasal route was 2716±4.617 ng/h/ml and for marketed solution by intravenous route was 2874±1.0816 ng/h/ml. These were comparable. Nasal bioavailability was found 94.50% from in situ gel. Duration of action was longer, and steady-state concentration was found for in situ gel.
 Conclusion: In situ gel was capable to release MCH in systemic circulation. In vivo study in rabbits has proved the improved bioavailability of MCH administered nasally. The optimized gel preparation was found to be promising for improved bioavailability.

Quantitative Estimation of the Effect of Nasal Mucociliary Function on in Vivo Absorption of Norfloxacin after Intranasal Administration to Rats.

Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.

Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application.

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

Non-Invasive Nasal Hydromorphone with High Bioavailability for Rapid Onset and Non-Dissociative Acute Pain Control: A Feasibility Study

Aim: To test the hypothesis that intranasal hydromorphone could mimic IV administration parameters for use in acute pain situations such as battle field injury, EMS first response and breakthrough cancer pain. Methods: A single healthy volunteer was recruited to a monocentric, open label, randomized, four-way crossover pharmacokinetic study, with 7 days washout period between treatments (more than 70 times the terminal elimination half-life). The use of a single subject minimized the effect of person to person variability in metabolism. For small molecule drugs (i.e., MW<1,000 Daltons) nasal bioavailability in the presence of alkylsaccharide absorption enhancers is predominantly a function of molecular weight and is expected to be high. Unexpected impediments to nasal delivery are likely due to local mucosal irritation or vasoconstriction, which can reduce bioavailability. According to an analysis of FDA data by eHealthMe, of 18,420 people reported to have side effects when taking hydromorphone, only 1 person reported vasoconstriction. The subject received 2 mg oral hydromorphone vs. 3 different formulations of 2 mg intranasal hydromorphone administered using a 100 μl Aptar multidose spray pump (Aptar Group, Crystal Lake, IL). Hydromorphone concentrations were evaluated by HPLC-MS/MS. Bioavailability was calculated using trapezoidal methodology to determine area under the curve. Results and conclusion: Moderate euphoria was observed for all dosage forms, nasal and oral. Oral concentrations were fairly low at all reportable time periods, with Tmax at minute 60 and Cmax 1.5 ng/mL. All intranasal formulations exhibited a greatly improved Tmax of 10 minutes and improved Cmax values. IN-3 had a significantly better Cmax value of 6.6 ng/ml respectively and drug effect was noted as early as minute 1, experienced as a moderate euphoria which lasted until minute 120, then tapering off. We believe the proprietary formulations of intranasal hydromorphone should be further investigated and developed.

Development of zolmitriptan transfersomes by Box–Behnken design for nasal delivery: in vitro and in vivo evaluation

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box–Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2) and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin (X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of 93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1 µm. The formulations were found to be physically stable upon storage at room temperature up to 2 months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.

Modulating nasal mucosal permeation using metabolic saturation and enzyme inhibition techniques.

Presystemic elimination resulting from local enzymatic degradation can play a key role in limiting the bioavailability of intranasally administered drugs. The aim of this study was to evaluate the transfer of a metabolically susceptible drug across the nasal mucosa to illustrate the relative contributions of drug diffusivity and metabolic susceptibility on overall nasal mucosal permeation and to understand the effects of changes in enzymatic activity on the transfer across nasal epithelial and submucosal tissues. The concentration-dependent permeation of melatonin, a CYP450 substrate, across excised bovine nasal olfactory and respiratory explants was studied along with quantifying the extent of melatonin 6-hydroxylation. Microsomal preparations were also used to determine the kinetic parameters for melatonin to 6-hydroxymelatonin biotransformation. Enzyme saturation at higher melatonin concentrations and inclusion of a CYP450 inhibitor both resulted in the significant increase in melatonin permeation across the nasal mucosa. Metabolic loss of melatonin during nasal permeation demonstrates CYP450 activity in the nasal epithelium and submucosal tissues. The extent of biotransformation of melatonin during its transport across the nasal mucosal explants suggests that, although the nasal route bypasses hepatic first-pass metabolism, nasal bioavailability can be significantly influenced by mucosal enzymatic activity.