Nasal Drug Research Articles

Review on in-situ nasal gel drug delivery system

The review was carried out to discuss in detail about the in-situ gel nasal drug delivery system as these system have better systemic bioavailability through nasal route as compared to oral route of administration. In-situ gel is a novel dosage form for nasal delivery of various drugs. It is infusing into the nasal cavity as low viscous solution and after sometime it forms gel when it contact with the nasal mucosa. The main advantage of using nasal delivery is avoidance of first pass metabolism, high permeability of some drugs in nasal epithelium, quick drug absorption across this membrane, rapid onset of action, improved patient compliance and comfort, sustained and prolonged action in comparison to other drug delivery systems. The formation of gel depends on factors like temperature modulation, pH change, and presence of ions, ultra violet irradiation, polymorphism, dissolution rate, solubility, viscosity and osmolarity. The review was focused on anatomy and physiology of nose, advantages, disadvantages, mechanism of drug delivery to the nose, types of dosage form for nasal delivery, barriers in nasal drug delivery, factors influencing nasal absorption, mucoadhesive polymer used in nasal drug delivery system and evaluation of in-situ gel nasal drug delivery system.

Lipid Nanoparticles for Nasal/Intranasal Drug Delivery.

Studies on the development of drug delivery systems have increased because these systems have particular characteristics that allow them to improve therapeutics. Among these, lipid nanoparticles (solid lipid nanoparticles, SLNs; and nanostructured lipid carriers, NLCs) have demonstrated suitability for drug targeting. The nasal administration of drug-loaded lipid nanoparticles showed effectiveness in treating central nervous system (CNS) disorders, particularly neurodegenerative diseases, because the nasal route (also called intranasal route) allows direct nose-to-brain drug delivery by means of lipid nanoparticles. Nonetheless, the feasibility of this application remains an open field for researchers. Drawbacks must be overcome before reaching the clinic (e.g., drug absorption at subtherapeutic levels, rapid mucociliary clearance). The intranasal administration of drugs for systemic absorption is effective for treating other conditions, such as cardiovascular diseases, infections, severe pain, and menopausal syndrome. In the near future, it is expected that patients will benefit from the advantages of lipid nanoparticle-based formulations, via the nasal/intranasal route, which bypasses the blood-brain barrier (BBB), avoiding first-pass metabolism and gastrointestinal degradation. This review discusses the use of SLNs and NLCs for nasal drug administration. A brief description of the nasal route and the features of SLNs and NLCs is initially provided.

Current status and promising future of nasal drug delivery.

鼻（鼻腔）は，生体にとって呼吸器系の入り口として必要不可欠な部位であると共に薬物投与部位としても古くから利用されてきた．鼻粘膜は低分子のみならず高分子物質に対しても比較的高い透過性を示すため，ペプチドやタンパク質に代表されるバイオ医薬品の投与部位としても利用され，1980年代頃より複数のペプチド薬物が鼻腔内投与製剤化され上市されるに至っている．また解剖学的には，鼻腔内で脳に直接つながっている経路（nose-to-brain経路）があることは古くから知られていたが，近年この経路が難治性中枢疾患治療薬の脳内送達において新たに着目されている．本稿では，鼻腔粘膜の構造と機能および鼻腔を薬物投与経路とする最近の基礎ならびに臨床研究の動向について紹介する．

In-Situ Nasal Gel-A Review

Over the few decades, advances in the in-situ gel technologies have spurred development in many medical and biomedical applications including controlled drug delivery. Many Novel In-Situ gel based delivery matrices have been designed and fabricated to fulfill the ever increasing needs of the pharmaceutical and medical fields. In-Situ gel drug delivery systems are sol form before administration in the body, but once administered, undergo gelation in-situ, to form gel. The formation of gel depends on factors like temperature modulation, pH change, presence of ions from which drug get released in sustained and controlled manner. In-Situ gels exhibit the properties of linear polymer solutions outside the body (allowing easy injection) but gel In-Situ within the body, providing prolonged drug release profiles. Recently, it has been shown that many drugs have better bioavailability by nasal route than the oral route. This has been attributed to reach vasculature and highly permeable structure of nasal mucosa coupled with avoidance of Hepatic-first pass metabolism. Thus this review focuses on nasal drug delivery, various aspects of nasal anatomy and physiology, nasal absorption mechanism, and In-Situ gels evaluations.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.

The Enhancement of Nasal Drug Absorption From Powder Formulations by the Addition of Sodium Carboxymethyl Cellulose.

For nasal drug absorption, powder formulations can be expected to provide many advantages. The first aim of this study was to examine drug absorption following nasal administration of powder formulations in rats. Pharmaceutical excipients are typically added to most powder formulations. The second aim was to investigate the change in nasal drug absorption of powder formulations in the presence of sodium carboxymethyl cellulose (CMC-Na). Model drugs used were norfloxacin (NFX), warfarin (WF), and piroxicam (PXC). The absorption from bulk powders is different from that of solutions. The absorption of PXC and WF from powder formulations was enhanced compared to those of the other solutions, while that of NFX, which has a low solubility, was decreased, suggesting that the nasal absorption of many drugs, except poorly soluble drugs, is enhanced when they are administered as powder formulations. CMC-Na enhanced the absorption of NFX and PXC. The presence of CMC-Na slightly decreased the absorption of WF. In vitro transepithelial transport from the powder formulation was not affected by the presence of CMC-Na. Furthermore, the nasal retention of the powder formulation was significantly increased in the presence of CMC-Na. In conclusion, the nasal absorption of many drugs, except those that are poorly soluble, can be increased by administering them as a powder formulation and the nasal absorption of the formulation is enhanced further in the presence of CMC-Na.

Nasal drug delivery: Design of a novel mucoadhesive and in situ gelling polymer

The aim of the present study was to establish a novel polymeric excipient for liquid nasal dosage forms exhibiting viscosity increasing properties, improved mucoadhesion and stability towards oxidation in solution.In order to achieve this goal, 2-mercaptonicotinic acid was first coupled to l-cysteine by disulfide exchange reaction and after purification directly attached to the polymeric backbone of xanthan gum by carbodiimide mediated amide bond formation. The resulting conjugate was characterized with respect to the amount of coupled ligand, the in situ gelling behavior, mucoadhesive properties and stability towards oxidation. Furthermore, the influence of preactivated polymers on ciliary beat frequency (CBF) of porcine nasal epithelial cells was investigated.Results showed, that 252.52±20.54μmol of the ligand was attached per gram polymer. No free thiol groups could be detected on the polymeric backbone indicating entire preactivation. Rheological investigations of polymer mucus mixtures revealed a 1.7-fold and 2.5-fold enhanced mucoadhesion of entirely preactivated xanthan (Xan-Cys-MNA) compared to thiolated xanthan (Xan-Cys) and unmodified xanthan (Xan). Tensile force evaluation reported a 2.87 and 5.11-fold higher total work of adhesion (TWA) as well as a 1.63 and 2.41-fold higher maximum detachement force of Xan-Cys-MNA compared to Xan-Cys and Xan. In the presence of H2O2 as an oxidizing agent Xan-Cys-MNA showed unlike Xan-Cys no increase in viscosity, indicating high stability towards oxidation. Addition of CaCl2 to Xan-Cys-MNA solutions caused a decrease in viscosity at nevertheless higher total viscosity. Results from CBF studies proved nasal safety for the novel conjugate.According to these results, entirely preactivated thiolated xanthan gum seems to be a promising excipient for nasal dosage forms in order to improve drug bioavailability.

P315 Enhanced nasal drug delivery with new exhalation delivery systems (EDS)

P315 Enhanced nasal drug delivery with new exhalation delivery systems (EDS)

The new therapy progress of recurrent nasal polyps

The worldwide incidence of nasal polyps is on the rise. Because of the etiology and pathogenesis of nasal polyps is indistinct, operative treatment is one of methods in the process of treating nasal polyps，it makes the treatment of nasal polyps become a difficult problem to recurrent easily after operation. Nasal polyps cause enormous inconvenience to patients，so it is very important to research effective treatment of nasal polyps.This paper expounds the concept of nasal polyps, recurrent nasal polyps, and the research progress on nasal endoscopic surgery,drugs,radioactive therapy and immunotherapy in order to explore better ways to treat nasal polyps and to promote the development of clinical research.

Application of RPMI 2650 as a cell model to evaluate solid formulations for intranasal delivery of drugs

During the development of intranasal drug delivery systems for local/systemic effect or brain targeting, it is necessary to assess its cytotoxicity and drug transport through nasal epithelium. In order to avoid animal experiments or the use of excised tissues, in vitro cell models, such as RPMI 2650 cells, are being preferred during recent years. Nevertheless, the deposition of solid formulations into nasal cell layers with further transepithelial transport rate of drugs has been poorly studied or reported.Thus, the purpose of this work is to further investigate RPMI 2650 cell line as an effective alternative to animal tissues for solid drug-loaded formulations cytotoxicity and drug permeation studies in order to become an option as a tool for drug discovery. Furthermore, we wanted to determine the extent to which the administration of drugs in particulate forms would differ in relation to the permeability of the same compounds applied as solutions. RPMI 2650 cells were cultured in submersed or at air-liquid interface conditions and characterized regarding transepithelial electrical resistance (TEER) and production of mucus. Pure ketoprofen (used as model compound) and five formulations loaded with same drug, namely solid lipid particles (Gelucire 43/01™), structured lipid particles (Gelucire 43/01™:Glyceryl monooleate) and aerogel microparticles (Alginate, Alginate:Pectin, Alginate:Carrageenan), were evaluated with RPMI 2650 model in terms of cytotoxicity and permeability of drug (applied as solution, dispersion or powder+buffer).RPMI 2650 cells were capable to grow in monolayer and multilayer, showing the same permeability as excised human nasal mucosa for sodium fluorescein (paracellular marker), with analogous TEER values and production of mucus, as referred by other authors. None of the powders showed cytotoxicity when applied to RPMI 2650 cells. Regarding permeation of drug through cell layers, not only the form of application of powders but also their physical and chemical properties affected the final permeation of active pharmaceutical ingredient. Aerogel microparticles administered directly to the cell layer (powder+buffer) exhibited the highest permeation-enhancing effect compared to the pure drug, which can be attributed to the mucoadhesive properties of the materials composing the carriers, proving to be an attractive formulation for nasal drug delivery.According to these results, RPMI 2650 showed to be a promising alternative to ex vivo or in vivo nasal models for cytotoxicity and evaluation of drug permeability of nasal drug-loaded formulations.

Nanoemulsion for Migraine Prophylaxis Nasal Drug Delivery: Preparation, Characterization and in vitro Evaluation.

Flunarizine dihydrochloride is used as a prophylaxis to migraine. Flunarizine dihydrochloride nanoemulsion was fabricated in this research work. Since, it is a low soluble high permeable drug, work was designed to enhance the solubility and the same can be administered as nasal drug delivery for faster onset of action and therapeutic effect. To fabricate a nanoemulsion of flunarizine dihydrochloride by using surfactant and co-surfactants. The experimental work involved compatibility studies by using FTIR, crystallinity study by XRD. The prepared nanoemulsion was studied by photon correlation spectroscopy by master sizer 2000 for the particle size analysis and characterized for D10, D50 and D90 MPS, span and uniformity. Further studies were conducted by Laser light scattering technique by delsa nano common and TEM. The study demonstrated that the formulations (FNE 1 -FNE 5) demonstrated the MPS of 14, 22.7, 326.7, 14.3 and 40.73 respectively. The formulae FNE1 and FNE5 demonstrated the MPS of 214.6±179.9 and 2118.6 ±1503.6 with the diameter of 127.8 and 1307, respectively. The zeta potential of FNE1 was -3.84 mV and other parameters such as TEM and drug release studies were also reported. The nanoemulsion of Flunarizine dihydrochloride was prepared successfully by using cremophor and labrafil which was better than the existed formula prepared by tween 80. The optimised formula demonstrated lower droplet size, satisfactory zeta potential, and high drug loading reproducible drug release profile.

Nasal drug absorption from powder formulations: The effect of three types of hydroxypropyl cellulose (HPC)

Despite the numerous advantages of powder formulations, few studies have described their nasal drug absorption. The first aim of this study was to compare the drug absorption from powder formulation with that from a liquid formulation in rats. Since pharmaceutical excipients are usually added to most powder formulations, the second aim of the study was to investigate the effect of hydroxypropyl cellulose (HPC) on nasal drug absorption from the powder. Three types of HPC with different polymerization degrees were used: HPC(SL), HPC(M), and HPC(H). The model drugs were warfarin (BCS Class I), piroxicam (BCS Class II), and sumatriptan (BCS Class III). The absorption of these model drugs in the powder form was higher than that from the solution. All HPCs failed to enhance warfarin absorption, while the piroxicam absorption was enhanced only by HPC(M). Sumatriptan absorption was not enhanced by HPC(SL), but by HPC(M) and HPC(H). The differences in nasal absorption of the three model drugs promoted by HPCs depend on the permeability and solubility of the drug. Moreover, the nasal retention of different formulations was increased by HPCs. Because HPCs showed no toxic effect on the nasal epithelium. These findings indicate that powder formulations supplemented with HPC are a valuable and promising approach to increase the nasal absorption of highly soluble and poorly permeable drugs.

Sulpiride microemulsions as antipsychotic nasal drug delivery systems: In-vitro and pharmacodynamic study

The present study aimed to develop microemulsion (ME) formulae for nasal delivery of sulpiride with high drug concentration to overcome sulpiride low oral bioavailability. Different oils, surfactants (S) and co-surfactants (CoS) were screened for the highest sulpiride solubilizing capacity. Glycerylmonooleate (GMO), Labrafil and Avocado were chosen as oily phases for ternary phase diagram construction. As nasal cavity accommodates limited administration volume, higher drug solubility and ME area (AT %) were used as assessment criteria. ME systems of the highest drug solubilities were subjected to physicochemical characterization such as drug content, pH, refractive index (RI), percent transmittance (%T), in-vitro release and ex-vivo permeation through the sheep nasal mucosa. Sulpiride solubility increased to 43.35 mg/ml with drug content more than 97%. The pH ranged from 4.25 to 5.75 while RI and %T values indicated that o/w type ME was formed. The pharmacodynamic performance, antipsychotic activity of sulpiride, concluded that intranasal ME is an effective alternate therapy for schizophrenia.

Jet-vortex spray freeze drying for the production of inhalable lyophilisate powders

Spray-freeze-dried powders were suggested for nasal, epidermal (needle-free injection) or pulmonary application of proteins, peptides or nucleic acids. In spray-freeze-drying processes an aqueous solution is atomized into a refrigerant medium and subsequently dried by sublimation. Droplet-stream generators produce a fast stream of monodisperse droplets, where droplets are subject to collisions and therefore the initial monodispersity is lost and droplets increase in diameter, which reduces their suitability for pulmonary application. In jet-vortex-freezing, a droplet-stream is injected into a vortex of cold process gas to prevent droplet collisions. Both the injection position of the droplet-stream and the velocity of the cold gas vortex have an impact on the size distributions of the resulting powders. A model solution containing mannitol (1.5%m/V) and maltodextrin (1.5%m/V) was sprayed at 5 droplet-stream positions at distances between 1mm and 30mm from the gas jet nozzle and 5 gas velocities (0.8–6.8m/s) at a process temperature of −100°C. Mean geometric diameters of the highly porous particles (bulk density: 0.012±0.007g/cm3) ranged between 55±4 and 98±4μm. Evaluation of the aerodynamic properties by Next-Generation-Impactor (NGI) analysis showed that all powders had high emitted doses (98±1%) and fine-particle fractions ranged between 4±1% and 21±2%. It was shown that jet-vortex freezing is a suitable method for the reproducible production of lyophilized powders with excellent dispersibility in air, which has a high potential for nasal and pulmonary drug delivery.

Relative vascular permeability and vascularity across different regions of the rat nasal mucosa: implications for nasal physiology and drug delivery.

Intranasal administration provides a non-invasive drug delivery route that has been proposed to target macromolecules either to the brain via direct extracellular cranial nerve-associated pathways or to the periphery via absorption into the systemic circulation. Delivering drugs to nasal regions that have lower vascular density and/or permeability may allow more drug to access the extracellular cranial nerve-associated pathways and therefore favor delivery to the brain. However, relative vascular permeabilities of the different nasal mucosal sites have not yet been reported. Here, we determined that the relative capillary permeability to hydrophilic macromolecule tracers is significantly greater in nasal respiratory regions than in olfactory regions. Mean capillary density in the nasal mucosa was also approximately 5-fold higher in nasal respiratory regions than in olfactory regions. Applying capillary pore theory and normalization to our permeability data yielded mean pore diameter estimates ranging from 13–17 nm for the nasal respiratory vasculature compared to <10 nm for the vasculature in olfactory regions. The results suggest lymphatic drainage for CNS immune responses may be favored in olfactory regions due to relatively lower clearance to the bloodstream. Lower blood clearance may also provide a reason to target the olfactory area for drug delivery to the brain.

Effects of nasal drug delivery device and its orientation on sprayed particle deposition in a realistic human nasal cavity

In this study, the effects of nasal drug delivery device and the spray nozzle orientation on sprayed droplets deposition in a realistic human nasal cavity were numerically studied. Prior to performing the numerical investigation, an in-house designed automated actuation system representing mean adults actuation force was developed to produce realistic spray plume. Then, the spray plume development was filmed by high speed photography system, and spray characteristics such as spray cone angle, break-up length, and average droplet velocity were obtained through off-line image analysis. Continuing studies utilizing those experimental data as boundary conditions were applied in the following numerical spray simulations using a commercially available nasal spray device, which was inserted into a realistic adult nasal passage with external facial features. Through varying the particle releasing direction, the deposition fractions of selected particle sizes on the main nasal passage for targeted drug delivery were compared. The results demonstrated that the middle spray direction showed superior spray efficiency compared with upper or lower directions, and the 10µm agents were the most suitable particle size as the majority of sprayed agents can be delivered to the targeted area, the main passage. This study elaborates a comprehensive approach to better understand nasal spray mechanism and evaluate its performance for existing nasal delivery practices. Results of this study can assist the pharmaceutical industry to improve the current design of nasal drug delivery device and ultimately benefit more patients through optimized medications delivery.

Is There Any Scientific Basis of Hawan to be Used in the Alzheimer's Disease Prevention/Cure?

Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system. As per modern science and ancient literature on medicine, nasal drug delivery systems are the best for the diseases related to brain and head. In older times Rishi Muni, ancient scholars and physicians used to recommend Hawan for mental peace and well being. Mritunjay Mantra also tells that sughandhim (aroma, fragrance) gives rise to good health. Om triambkum yajamahe, sughandhim puushtivardhanam, urvarukmev vandhanaat, mrityu mokshay mamritaat!!!! Hawan is a scientific experiment in which special herbs (Hawan Samagri) are offered in the fire of medicinal woods ignited in a specially designed fire pit called agni-kuñda. Aromatherapy was also employed in ancient times for a number of mental disorders. The hypothesis is based on action of Hawan components on Alzheimer Disease through integration of modern and ancient concepts. Hawan seems to be designed by the ancient scholars to fight with the diseases of the brain. Our review demonstrates that the components of Hawan are having a number of volatile oils that are specifically useful for AD through one or the other mechanism of action. Due to high temperature of fire the vapors of these oils enter into the central nervous system through nasal route. The routine of performing Hawan might keep the threshold value of the therapeutic components in the body and help in preventing AD. In the present manuscript authors have tried to highlight and integrate the modern and ancient concepts for treatment and prevention of AD. Keywords: Alzheimer disease, Apoptosis, Hawan, Inflammation, Mental Health, Rishis, Sanskar.

Investigation of betahistine dihydrochloride biocompatibility and nasal permeability in vitro

Betahistine dihydrochloride, which is widely prescribed for the treatment of symptoms associated with Meniere’s syndrome, is generally administered orally in solid or liquid formulations. There is a strong need of profound investigation of alternative routes of administration of betahistine to overcome difficulties related to oral administration. The aim of this study was to evaluate betahistine cytotoxicity and permeability in vitro and to assess the drug’s relevance for incorporation in drug delivery systems for nasal administration. RPMI epithelial model was used to evaluate drug permeability in vitro. The cytotoxicity of betahistine was assessed by MTT test. Chitosan microspheres were used as a betahistine delivery system. RPMI 2650 formed a thick, impermeable cell layer on the apical side of the filter inserts and developed enough TEER values to confirm confluence. According to the obtained results, BET showed high permeability coefficients (Papp values in the range 2.3×10−5 to 19×10−5) and could, therefore, be successfully used in nasal drug delivery formulations. Also, BET exhibited a good safety profile regarding nasal epithelium toxicity. A dose-dependent reduction in cell viability was observed. The microspheres as drug delivery systems affected BET permeation profiles due to the presence of chitosan as an absorption enhancer.

Challenges in nasal drug absorption: how far have we come?

The nasal route is commonly used for local delivery of drugs to treat inflammatory conditions. It is also an attractive route for systemic delivery of some drugs. Irrespective of intended use, administered drugs must permeate the epithelial or olfactory membrane to be effective. The enthusiasm for potential use of the nasal route for systemic drug delivery has not been met by comparable success. In this paper, the anatomical and physiological attributes of the nasal cavity and paranasal sinuses important for drug delivery and challenges limiting drug absorption are discussed. Efforts made so far in improving nasal drug absorption such as overcoming restrictive nasal geometry and paranasal sinuses accessibility, mucociliary clearance, absorption barriers, metabolism and drug physicochemical challenges are discussed. Highlights on future prospects of nasal drug delivery/absorption were discussed.

In situ gel: A Review

Oral route is technique which is used over a decades. It is most preferred and common technique for oral administration of drug in the body, but due to certain limitation such as absorption of drug, drug targeting to particular organ can cause problem for administration through oral route. To overcome these types of problem as well as for improvement of drug safety and efficiency a novel approach is developed for delivery of drug i.e. In-situ Nasal Drug Delivery System. In-situ gel is a process in which sol form before administration in the body, but once administrated, it undergo gelation in-situ, to form gel. Nasal drug delivery is one of alternative viable route of drug delivery is one of alternative and viable route of drug delivery. Nasal route is rich in vasculature and highly permeable. Nasal route is suitable for those drugs whose oral administration is problematic due to gastric irritation. The present review focused on anatomy of nasal system and criteria required of drug candidate to prepare a gel i.e. In-situ gel. Approaches towards various formulation of in-situ gel with respect to temperature, ph and physiochemical condition.The main role of polymers like Poloxamer, Pectine, Cellulose etc in body, absorption of drug by various methods. Various evaluation parameters which is consider during preparation of in-situ gel.