Nasal delivery systems and their effect on deposition and absorption

Due to nasal anatomy and physiology, with a non-ciliated area in the anterior part of the nasal cavity and a ciliated region in the more posterior part of the nose, the site of deposition is of importance for the nasal mucociliary clearance and retainment of a formulation in the nose. Many drug delivery devices for nasal application of liquid, semisolid and solid formulations were investigated in respect to their deposition in the nasal cavity. The site of deposition and the deposition area depend on several parameters which are related to the delivery device, such as mode of administration, particle size of the formulation and velocity of the delivered particles. Several in vitro and in vivo methods have been used to study distribution and clearance of intranasally delivered therapeutics. The relationship between deposition, absorption and related bioavailability of the nasally applied formulation has been shown.     

Toxicological Implications of Nasal Formulations

Various nasal formulations have been tested for their suitability to deliver drugs through the nasal cavity. This route is especially of interest where the dose of drug is small and the drug may undergo an extensive first-pass metabolism and/or decomposition while passing through the gastrointestinal tract. Unfortunately, the nasal mucosa does not have same type of tolerability to all drugs and additives used in formulations. Some chemicals may damage the nasal epithelia or alter the mucociliary defensive mechanism of the nose. There also is a possibility that the drug can transport directly from nasal cavity to the brain via the olfactory route. Several methods have been developed to study the impact of drugs and excipients on the integrity of the nose. In some cases, the in vitro results did not correlate well with in vivo data, due to lack of reproducibility of the natural body environment, and some in vitro methods may not be sensitive enough and thus may complicate interpretation of the results. This review provides a toxicological evaluation of different drugs and additives used to optimize a nasal formulation. Certain chemicals are now routinely used as additives in nasal formulations. Although these compounds are most likely safe, if they are used over the long term, they may damage the epithelia of the nose. For multidose preparations, preservatives are often included in nasal delivery systems and may cause ciliotoxic effects. Both physicochemical parameters of drugs as well as formulation materials should be considered in evaluating the overall effect ofa drug product on the nose. Therefore, any prior knowledge of the effect of drugs and additives on the nasal epithelia ultimately will assist in the development of nasal products. Furthermore, as the sites of absorption in the nasal cavity are somewhat limited, evaluation of the long-term tolerability of a nasal formulation is of great importance.     

The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.     

Nasal residence of insulin containing lyophilised nasal insert formulations, using gamma scintigraphy.

Bioadhesive dosage forms are a potential method for overcoming rapid mucociliary transport in the nose. A lyophilised nasal insert formulation previously investigated in sheep demonstrated prolonged absorption of nicotine hydrogen tartrate suggestive of extended nasal residence, and increased bioavailability. The current study was performed to quantify nasal residence of the formulations using gamma scintigraphy, and to investigate the absorption of a larger molecule, namely insulin. A four-way crossover study was conducted in six healthy male volunteers, comparing a conventional nasal spray solution with three lyophilised nasal insert formulations (1-3% hydroxypropylmethylcellulose (HPMC)). The conventional nasal spray deposited in the posterior nasal cavity in only one instance, with a rapid clearance half-life of 9.2 min. The nasal insert formulations did not enhance nasal absorption of insulin, however an extended nasal residence time of 4-5 h was observed for the 2% HPMC formulation. The 1% HPMC insert initially showed good spreading behaviour; however, clearance was faster than for the 2% formulation. The 3% HPMC nasal insert showed no spreading, and was usually cleared intact from the nasal cavity within 90 min. In conclusion, the 2% HPMC lyophilised insert formulation achieved extended nasal residence, demonstrating an optimum combination of rapid adhesion without over hydration.     

Model of Disposition of Drugs Administered into the Human Nasal Cavity

A mathematical model was developed to describe the rate processes involved in the disposition of drugs placed in their delivery systems into the human nasal cavity. The model contains first-order parallel and sequential irreversible rate processes representing the convective drug and carrier transport by fluid flow, mucociliary clearance and peristalsis, drug release and absorption, and decomposition of the drug prior to its appearance in the systemic circulation. The numerical values of the parameters used are based on literature data from clearance studies of nonabsorbable markers deposited in the human nasal cavity, and data obtained under a variety of experimental conditions are consistent with the model. The effect of bioadhesive carriers is successfully simulated by reducing the mucociliary clearance rate constants for the transport from the posterior part of the nose into the gastrointestinal tract. The simulation shows that bioadhesion improves bioavailability and reduces the variability in absorption which might be caused by a variable pattern of deposition in the nose. Variable bioavailability could result from removal of the drug from the nasal cavity by sniffing, blowing, or wiping the nose, leading to different drug residence times in the nose. The model simulations further suggest that drug decomposition in the nose, while lowering bioavailability, also reduces variable absorption due to variable residence times of the drug in the nose.     

Surfactant systems for nasal zidovudine delivery: structural,rheological and mucoadhesive properties

Objectives Zidovudine is the antiretroviral drug most frequently used for the treatment of AIDS. Although its effectiveness is recognized, it undergoes extensive first‐pass metabolism and exhibits poor oral bioavailability. The nasal route is an option for enhanced therapeutic efficacy and to reduce the extent of the first‐pass effect. There are some mechanisms that limit intranasal absorption, such as mucociliary clearance, which rapidly removes the formulation from the nasal cavity. To improve the nasal residence time of zidovudine on the nasal mucosa, we aimed to develop a mucoadhesive surfactant system for zidovudine nasal administration. Methods Systems composed of PPG‐5‐CETETH‐20 as surfactant, oleic acid and water were characterized by polarized light microscopy, small‐angle X‐ray scattering and rheological measurements. Mucoadhesion was investigated by phase behaviour studies, rheological synergism and mucoadhesive strength determination. Key findings Results indicate that the original formulations were microemulsions that displayed phase transition to a lamellar phase when brought into contact with aqueous nasal simulated mucus. The phase transition was accompanied by an increase in system elasticity and, irrespective of phase behaviour, all the systems showed a good mucoadhesive force. Thus, a viscous and mucoadhesive liquid crystalline matrix could be formed when the formulations were in contact with simulated mucus, which may prolong the residence time of zidovudine in the nasal cavity. Conclusions These findings indicate a potentially useful system for nasal administration of zidovudine.     

Ciliary beat frequency of in vitro human nasal epithelium measured with the simple high-speed microscopy is applicable for safety studies of nasal drug formulations

Nasal drug formulations can be effective for local delivery of therapeutic drugs to the sinonasal mucosa or for systemic drug delivery by absorption directly into the bloodstream. The growing field of potential nasal therapies includes nasal vaccination and even treatment of neurodegenerative diseases. However, it is important that nasal drug formulations don't have a disruptive effect on the cilia and mucosa of nasal epithelium. Mucociliary clearance represents the first host defence of the respiratory tract that requires the coordinated beating of cilia. A key parameter to determine mucociliary clearance is ciliary beat frequency (CBF). The objective of this study was to validate the high-speed digital imaging for CBF measurements in nasal MucilAir™ in vitro model and to test its potential for ciliotoxicity studies to evaluate the safety of investigational nasal drug formulations. Our CBF measuring setup was first validated by benzalkonium chloride, a common-practice preservative with cilio-inhibiting effect. Next, MucilAir™ model was treated with mometasone nasal spray (Mommox®/Mometasone Sandoz®). Short term cilio-stimulatory effect and dose dependent effect of mometasone nasal spray were demonstrated. Post-treatment analysis showed un-altered ultrastructure of MucilAir™ model. In conclusion, characterization of the ciliary activity of nasal MucilAir™ in vitro model and its response to relevant agents with herein developed efficient and reproducible set up for CBF analysis show great potential of this model for airway ciliotoxicity studies.     

Site-specific drug delivery systems. III. Nasal drug delivery

The nasal cavity has a large surface and a rich blood supplied mucosa. Drugs absorbed by blood vessels pass directly into the systemic circulation, thereby avoiding first-pass metabolism. Numbers of factors limit the intranasal absorption of drugs, especially peptide and protein drugs. These factors are the epithelial and mucus barrier, the rapid mucociliar clearance and the enzymatic activity. Increasing the residence time of the drug formulation in the nasal cavity and a period of contact with nasal mucosa, may improve drug absorption. Approaches to increase the residence time of drug formulations in the nasal cavity usually involve the use of microspheres, liposomes and bioadhesive gels.     

Kinetic phenotypic diagnosis of N-acetylation polymorphism in patients based on ratio of urinary metabolites of salicylazosulfapyridine

This paper describes the clearance characteristics of two bioadhesive nasal delivery systems in the form of chitosan microspheres and chitosan solution, from the nasal cavity of conscious sheep. The pattern of deposition and clearance of the nasal dosage forms were evaluated using a radioactive tracer and the non-invasive technique of gamma scintigraphy. The clearance of chitosan microsphere and solution formulations was compared with that of a control solution. The data show that the control was cleared rapidly from the sheep nasal cavity with a half-time of clearance (time taken for 50% clearance; t(50%)) of about 15 min. The bioadhesive chitosan delivery systems were cleared at a slower rate, with half-times of clearance of 43 min and 115 min, for solution and microsphere formulations respectively. From the results reported in this study it can be concluded that the chitosan delivery systems investigated had significantly reduced rates of clearance from the sheep nasal cavity, as compared to the control. Consequently, chitosan delivery systems have the ability to increase the residence time of drug formulations in the nasal cavity thereby providing the potential for improved systemic medication. The nasal clearance rates recorded in the sheep model mimic very closely the clearance rates found in a previous study using human subjects. It can also be concluded that the sheep can be considered a suitable model for in vivo nasal clearance studies of novel bioadhesive drug delivery systems.     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

In vivo evaluation of nicotine lyophilised nasal insert in sheep

The nasal route offers an attractive means of delivering a drug directly to the systemic circulation and avoiding hepatic first-pass metabolism, although rapid mucociliary clearance can be detrimental to nasal absorption. The in vitro and in vivo characteristics of a nasal insert formulation prepared by lyophilisation of a viscous HPMC gel solution designed to overcome this problem were studied. In vitro release of nicotine from the lyophilised insert was compared with powder and spray formulations. Stability and characterisation studies were carried out using dynamic vapour sorption, scanning electron microscopy and HPLC analysis. Nicotine formulations were administered to eight wether sheep in a randomised four-way cross-over study, and plasma nicotine assessed comparing the nasal insert formulation with conventional nasal powder, nasal spray and IV doses. In vitro release studies demonstrated prolonged nicotine release from the nasal insert formulation compared to a powder and liquid. In vivo plasma profiles appeared to show prolonged plasma nicotine levels compared to the conventional formulations, although T(max), C(max) and AUC parameters for the insert were not significantly different due to high variability in the pharmacokinetic data. In conclusion, the nasal insert displayed a promising prolonged plasma profile, which must be investigated further to provide statistical significance to prove the effect.     

Influence of formulation viscosity on drug absorption following nasal application in rats

The aim of this research is to clarify the influence of the viscosity of the nasal formulation on in vivo nasal drug absorption and its mechanism using an in vitro Caco-2 system. The drug solution was made viscous by the addition of dextran (Dex). The disappearance of FITC-labeled Dextran (FD, a marker of the dosing solution) applied with control solution followed monoexponential kinetics, while FD applied with Dex solution showed biexponential elimination. The mean residence time of FD in the nasal cavity was increased with the increase in Dex concentration. The nasal absorption of acyclovir was similar in the formulation with low viscosity, increased in the formulation with moderate viscosity and markedly decreased in the formulation with high viscosity. The result from the normal Caco-2 transport study could not explain the relation of in vivo drug absorption with viscosity, while the modified Caco-2 system provided data partly reflecting the change in in vivo absorption in rats. In conclusion, the residence of the applied solution in the nasal cavity was enhanced by the addition of Dex in a viscosity-dependent manner. Moderate viscosity of the dosing solution improved the in vivo nasal absorption of acyclovir, while higher viscosity decreased it.     

The biopharmaceutical aspects of nasal mucoadhesive drug delivery

Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut‐off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail. Nasal drug administration is presently mostly used for local therapies within the nasal cavity. Anti‐allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practised since ancient times. Nasally‐administered psychotropic drugs by native Americans, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known (Illum & Davis 1992). Nowadays, the nasal cavity is being actively explored for systemic administration of other therapeutic agents, particularly peptides and proteins (Illum 1992; Edman & Bjork 1992), as well as for immunization purposes (Lemoine et al 1998). To better understand the basis for nasal drug absorption and factors that can influence it, a brief review of the anatomy and physiology of the nose is appropriate.     

FDA已批准鼻用制剂的辅料分析及研究进展

因鼻腔构造的特殊性，在鼻用制剂处方中加入功能性辅料，可起到改善药物活性物质的透膜吸收或减少鼻黏膜纤毛的清除作用，对维持药物活性物质在目标区域的有效浓度，促进鼻黏膜吸收起着重要作用。本文通过对美国食品药品监督管理局近十年已批准上市的鼻腔制剂新药中使用的辅料进行汇总分析，并结合鼻用辅料目前研究进展与安全性评价情况对其进行综述，为开发鼻用制剂在辅料选择上提供思路和借鉴。     

Bioadhesive microspheres as a potential nasal drug delivery system

The rapid mucociliary clearance mechanism in the nasal cavity can be considered as an important factor when low bioavailabilities are obtained for drugs given intranasally. A nasal delivery system in the form of bioadhesive microspheres has been developed. Studies in human volunteers using gamma scintigraphy showed great differences in clearance times between 3 microsphere systems and two controls. The half life of clearance for starch microspheres was found to be in the order of 240 min as compared to 15 min for the liquid and powder control formulations. The microspheres form a gel-like layer in contact with the nasal mucosa that is cleared slowly from the nasal cavity. In vitro studies using model compounds (cromoglycate and Rose bengal) showed high degrees of loading capacities for the various microsphere systems. Using various physical and chemical approaches, it was possible to a certain degree to control the release of the compounds from the microsphere systems.     

Influence of the co-encapsulation of different excipients on the properties of polyester microparticle-based vaccine against brucellosis

The nasal cavity possesses many advantages as a site for drug delivery, such as; ease of administration, applicability for long-term treatments and a large surface area for absorption. One important limiting factor for nasal drug delivery is the limited time available for absorption within the nasal cavity due to mucociliary clearance. Several drug delivery systems including different kinds of microspheres have been tried for encapsulation of drugs and increasing the residence time in nasal cavity. In this study the clearance rate of three kinds of microspheres (Alginate, PLGA, and Sephadex) was determined by gamma-scintigraphy with lactose powder being used as negative control.

^99mTc labeled microspheres were prepared using technetium pertechnetate in the presence of a potent reducing agent, stannus chloride. The labeling procedure was set in a manner that each 3–5 mg of microspheres contained 2 MBq of radioactivity. Labeling efficiency was calculated by paper chromatography using acetone as a mobile phase. Each delivery system containing 2 MBq of activity was administered into right nostril of four healthy volunteers and 1 min static views were repeated each half an hour until 4 h. Clearance rates were compared using two regions of interest (ROIs); the initial site of deposition of particles, and all of the nasopharynx region. The clearance rate of each one of microspheres was calculated after applying the physical decay corrections.

The mean labeling efficiencies for Alginate, PLGA, and Sephadex microspheres were calculated as 60%, 59%, and 74%, respectively. The cleared percent of formulations from nasopharynx region after 4 h was determined as follows: PLGA microspheres 48.5 ± 8.2%; Alginate microspheres 45.0 ± 0.8%; Sephadex microspheres 63.1 ± 3.4%; lactose powder 74.5 ± 4.9%. Alginate and PLGA microspheres showed the lowest clearance rate compared to lactose powder (P < 0.0001 and P < 0.001, respectively), followed by Sephadex microspheres (P < 0.01). The clearance profiles of formulations from deposition ROI and nasopharynx ROI were identical.

This study shows that Alginate and PLGA microspheres have the highest mucoadhesion properties and are suitable nasal delivery systems. Futhermore, this study proves that limiting step for the nasal clearance of nasally administered particulate systems is their dislocation from the initial site of deposition, and their following interactions with mucus layer in the rest of the nasal passage does not significantly affect the clearance time.     

Enhanced bioavailability of metoclopramide HCl by intranasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties

The prolonged residence of drug formulation in the nasal cavity is of utmost importance for intranasal drug delivery. The objective of the present investigation was to develop a mucoadhesive in situ gel with reduced nasal mucociliary clearance in order to improve the bioavailability of the antiemetic drug, metoclopramide hydrochloride (MCP HCl). The in situ gelation upon contact with nasal mucosa was conferred via the use of the thermogelling poloxamer 407 whereas mucoadhesion and drug release enhancement were modulated via the use of mucoadhesive and polyethylene glycol (PEG) polymers respectively. The results revealed that the different mucoadhesives augmented the gel viscosity but reduced its sol–gel transition temperatures (T_sol–gel) and the drug release. The inclusion of PEG counteracted the effect of the mucoadhesive polymers whereby it decreased the gel consistency and increased the T_sol–gel as well as the in vitro drug release. The formulations with favorable sol–gel transition temperatures (25–32 °C) and high in vitro drug release (100% release in 60 min) were also rheologically stable upon storage. The mucoadhesiveness test was performed in vivo in rats, results showed that the carbopol-containing in situ gel prolonged the mucociliary transport time from 10 min (control solution) to 52 min (mucoadhesive gel) and maintained nasal mucosal integrity after 14-days application. The bioavailability study in rabbits revealed that the absolute bioavailability of MCP HCl was significantly increased from 51.7% in case of the oral drug solution to 69.1% in case of the nasal in situ gel. The study point to the potential of mucoadhesive nasal in situ gel in terms of ease of administration, accuracy of dosing, prolonged nasal residence and improved drug bioavailability.     

Nasal clearance in health and disease.

This paper reviews the anatomical and physiological factors of importance for nasal drug delivery and discusses in particular the influence of the nasal mucociliary clearance mechanism on the nasal absorption of drugs. The effect of nasal pathological conditions on the mucociliary clearance mechanism and the possible effect of such disease states on nasal drug transport are also discussed. Strategies for the exploitation of bioadhesive drug delivery systems and especially nasal absorption enhancers for the improvement of nasal drug delivery are evaluated to include considerations of the mechanism of action and correlation between the degree of bioadhesion and absorption enhancement and transport of drugs across the nasal membrane. A range of studies involving bioadhesive/absorption enhancer systems are detailed. A selected bioadhesive material, chitosan, which has been shown to have excellent absorption enhancer properties for a variety of drugs is discussed in some detail.     

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.     

Development and Evaluation of Nasal Formulations of Ketorolac

Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 θ m to 63 θ m did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.