Article

Absorption Enhancing Excipients in Systemic Nasal Drug Delivery

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Abstract

Intranasal drug delivery is becoming an increasingly important form of drug administration for chronic and chronic-intermittent diseases. Important new applications currently in development include drugs for diabetes, osteoporosis, obesity, certain types of convulsive disorders, migraine headaches, symptomatic pain relief, nausea, and anxiety, among others. Transmucosal absorption across the nasal mucosa is generally limited to molecules less than 1,000 Da. Systemic delivery of larger molecules requires formulations with a suitable transmucosal absorption enhancer. More than one hundred potential transmucosal absorption enhancing excipients have been tested to date. Nearly all have failed due to poor effectiveness or unacceptable toxicity to the mucosal tissue. Alkylsaccharides, cyclodextrins, and chitosans have emerged as leading candidates for potential broad clinical applications allowing the development of convenient, patient-friendly, needle free formulations of small molecule drugs, as well as, peptide and protein drugs that can be administered at home, at work, or in other public and private settings outside of the doctor’s office or hospital environment.

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... Because DDM is soluble both in water and oils, it can be used in the formulations of hydrophilic and hydrophobic drugs [38]. Two mechanisms of action for absorption enhancement with DDM have been suggested, through paracellular and transcellular routes [38]. ...
... Because DDM is soluble both in water and oils, it can be used in the formulations of hydrophilic and hydrophobic drugs [38]. Two mechanisms of action for absorption enhancement with DDM have been suggested, through paracellular and transcellular routes [38]. First, as with many alkylsaccharides, it promotes transient loosening of tight cell junctions that allows permeation of the mucosal barrier [23], as shown in Caco-2 intestinal cells [39], human bronchial epithelial cells [40], T-84 and Caco-2 human carcinoma cells [32], and epithelial tissue [24]. ...
... The alkylsaccharide TDM has been shown to work long enough to facilitate drug absorption, after which the normal protective epithelial layer is restored [41]. Second, transcellular transport via vesicle carriers also has been demonstrated with TDM in rats (Fig. 2) [23] and with DDM in a porcine jejunal mucosal explant system [38,42]. Dodecyl maltoside enables the noninvasive delivery of a broad range of small-molecule drugs, peptides, and therapeutic proteins, through permeation of the nasal mucosal barrier that is controlled and transient without irritation [38]. ...
Article
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Intranasal drug administration is a commonly used route for therapeutic formulations, but there may be challenges associated with a lack of absorption and bioavailability, as well as damage to mucosal tissue. To address these issues, potential absorption enhancers that are generally nonirritating to nasal mucosal tissue have been investigated as excipients in intranasal formulations. Among those studied are alkylsaccharides, which are composed of sugars covalently coupled to at least one alkyl chain. Alkylsaccharides have been shown to be nontoxic and have been used in food products as emulsifiers. In clinical trials, alkylsaccharide excipients have demonstrated substantially increased absorption of therapeutic agents across mucosal membranes and have been shown to be applicable to a wide range of types of molecules and molecular weights. Because they are water and oil soluble, alkylsaccharide excipients can be used in formulations with both hydrophilic and hydrophobic drugs. They are also effective in safely stabilizing protein therapeutics. An example of an alkylsaccharide excipient is dodecyl maltoside (Intravail®; 511 Da, stable long term when stored cold), which provides absorption enhancement by paracellular and transcellular routes. Dodecyl maltoside has been shown to be generally nonirritating to the nose and to promote systemic bioavailability. Dodecyl maltoside is used in US Food and Drug Administration-approved intranasal formulations of sumatriptan for migraine headaches and diazepam nasal spray for patients with epilepsy with acute seizure clusters.
... Since long time, nasal route is being used to administer topical formulations for the treatment of nasal congestion and allergic rhinitis. More recently, this route has been used to administer drugs intended for systemic circulation in order treats various chronic diseases including diabetes, migraine, obesity and convulsive disorders (Maggio 2014). This type of expanded use of nasal route is due to advantages associated with it such as thin and well-vascularized mucosa, avoidance of first-pass metabolism, elimination of needlephobia attached with parenteral route and possible selfadministration leading patient convenience (Maggio 2014). ...
... More recently, this route has been used to administer drugs intended for systemic circulation in order treats various chronic diseases including diabetes, migraine, obesity and convulsive disorders (Maggio 2014). This type of expanded use of nasal route is due to advantages associated with it such as thin and well-vascularized mucosa, avoidance of first-pass metabolism, elimination of needlephobia attached with parenteral route and possible selfadministration leading patient convenience (Maggio 2014). Despite favorable conditions, nasal route has challenges such as short residence time due to high nasal secretion rate, limited volume of administered formulation which made only potent drug as favorable and the danger associated with long-term treatment (Kublik and Vidgren 1998;Illum 2003). ...
Article
Polymers are used in drug delivery devices for drug encapsulation and release. Natural polymers often have advantages such as biocompatibility, biodegradability and biologically recognizable moieties which support cellular activities, compared to synthetic polymers. Chitosan, a naturally occurring polysaccharide obtained from chitin, has recently drawn attention because chitosan is non-toxic, biocompatible, biodegradable, stable and sterilizable. The additional qualities of chitosan are the release rate of drug, easy modification, cross-linking ability with other polymers, antimicrobial properties, gel forming ability, bioadhesion, immunostimulation, activation of macrophages and gas permeability. Here, I review applications of chitosan in drug delivery. The properties of chitin and chitosan, and the mechanisms of drug release are also presented.
... Promoters enhancing drug bioavailability such as chitosan and cyclodextrins have an absorption enhancing effect that cancel out any modification caused in mucosa and act by opening the tight junctions (Bshara et al. 2014;Casettari and Illum 2014;Maggio 2014). Absorption enhancers in combination with hydrophilic drugs improve their absorption and induce reversible modifications on the structure of epithelial barrier (Savale and Mahajan 2017). ...
... Most absorption enhancers used in intranasal drug delivery are surfactants (laureth-9), bile salts, fatty acids (taurodihydrofusidate), and polymeric enhancers (chitosan, cyclodextrins, poly-L-arginine, and aminated gelatine) (Morita and Yamahara 2016). Absorption promoters enhance drug bioavailability and there can be a direct relation between the promoter's effect and the damage caused in the membrane (Maggio 2014). Surfactants, bile salts, fatty acids, phospholipids, and lyso-phospholipids modify cell structures and leaches out proteins or can even strip off the outer layer of the mucosa. ...
Article
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This review article highlights the importance and advantages of the drug delivery systems applied via the nasal route after endoscopic sinus surgery (ESS) for patients suffering from chronic rhinosinusitis. After ESS, patients often require ongoing topical and systemic medication. To reduce the incidence of immediate and delayed post-surgical complications, a variety of temporary postoperative nasal interventions are currently used. However, newly developed intranasal drug delivery devices can enhance tissue recovery after endoscopic sinus surgery by releasing therapeutic drugs locally, while providing structural support to reduce tissue adhesion and scaring. Intranasal drug delivery devices are promising next generation post-surgery devices, offering advantages for enhancing tissue recovery through release of loaded therapeutic drugs locally in a controlled manner over the required time-frame during postoperative healing. The mechanisms and effectiveness of these drug delivery systems initiate a new era in providing topical controlled drug delivery to the sinus tissue and can be a guide for the future development of specific effective therapies of preparations with other drugs that otherwise should be administered parenterally. Hence, further research is required to validate their efficacy.
... The novel alkyds are expected to be advantageous as pharmaceutical excipients. In particular, there is increasing interest in the application of low molecular weight polymers, typically low molecular weight chitosan (LMWC) as carriers for both conventional small molecule drugs and the new biologics (e.g., nucleic acids and proteins) to enhance drug absorption and bioavailability, and to improve controlled drug release at specific body sites [15][16][17]. Chae et al. reported that the absorption of LMWC with low molecular weight of 3.8 kDa increased more than 20 times when compared with high molecular weight variants of 230 kDa in both in vitro using Caco-2 cell monolayers and in vivo using male Sprague-Dawley rats [15]. LMWC with molecular weight less than 10 kDa has been shown to possess more favorable characteristics as a drug carrier, particularly for oral protein delivery, when compared with higher molecular weight forms (>10 kDa) [16]. ...
... Chae et al. reported that the absorption of LMWC with low molecular weight of 3.8 kDa increased more than 20 times when compared with high molecular weight variants of 230 kDa in both in vitro using Caco-2 cell monolayers and in vivo using male Sprague-Dawley rats [15]. LMWC with molecular weight less than 10 kDa has been shown to possess more favorable characteristics as a drug carrier, particularly for oral protein delivery, when compared with higher molecular weight forms (>10 kDa) [16]. Bioavailability studies of orally administered LMWC-insulin conjugates in diabetic rats indicated that the intestinal absorption of insulin was significantly enhanced compared with conjugates prepared using chitosan of molecular weight more than 10 kDa [17]. ...
Article
Novel alkyds of short, medium, and long oil length were synthesized using a two-stage alcoholysis-polyesterification method from bio-sourced starting materials. Alcoholysis reaction mixtures of palm kernel oil and glycerol underwent transesterification to convert triglycerides to monoglycerides within 3 h. Kinetic studies showed that the polyesterification reaction rates obeyed second order kinetics up to 15 min, followed by chain branching and crosslinking. The alkyd chemical structure was confirmed by nuclear magnetic resonance and Fourier Transform infrared spectroscopy. Gel permeation chromatography revealed that the average molecular weight of the alkyds was confined to <2,000 Da which is advantageous for the production of nanoscale drug carriers. Differential scanning calorimetry showed that the alkyds possess low glass transition temperatures within a very narrow range of −49.3°C–−52.7°C. Thermogravimetric analysis revealed good thermal stability with alkyd degradation occurring above 200°C. Cell viability assay confirmed that the alkyds were non-toxic to 3T3 mouse fibroblasts following exposure of cell cultures for 24 h to solutions of concentration ranging from 3 to 100 μg/mL. These findings highly recommend consideration of the novel, bio-sourced alkyds for pharmaceuticals manufacture and controlling drug delivery.
... The novel alkyds are expected to be advantageous as pharmaceutical excipients. In particular, there is increasing interest in the application of low molecular weight polymers, typically low molecular weight chitosan (LMWC) as carriers for both conventional small molecule drugs and the new biologics (e.g., nucleic acids and proteins) to enhance drug absorption and bioavailability, and to improve controlled drug release at specific body sites [15][16][17]. Chae et al. reported that the absorption of LMWC with low molecular weight of 3.8 kDa increased more than 20 times when compared with high molecular weight variants of 230 kDa in both in vitro using Caco-2 cell monolayers and in vivo using male Sprague-Dawley rats [15]. LMWC with molecular weight less than 10 kDa has been shown to possess more favorable characteristics as a drug carrier, particularly for oral protein delivery, when compared with higher molecular weight forms (>10 kDa) [16]. ...
... Chae et al. reported that the absorption of LMWC with low molecular weight of 3.8 kDa increased more than 20 times when compared with high molecular weight variants of 230 kDa in both in vitro using Caco-2 cell monolayers and in vivo using male Sprague-Dawley rats [15]. LMWC with molecular weight less than 10 kDa has been shown to possess more favorable characteristics as a drug carrier, particularly for oral protein delivery, when compared with higher molecular weight forms (>10 kDa) [16]. Bioavailability studies of orally administered LMWC-insulin conjugates in diabetic rats indicated that the intestinal absorption of insulin was significantly enhanced compared with conjugates prepared using chitosan of molecular weight more than 10 kDa [17]. ...
Article
Full-text available
This paper describes the preparation of palm oil alkyd emulsions. The palm oil alkyds were first synthesized by fusion cooks by using palm kernel oil (PKO), phthalic anhydride (PA) and glycerol (Gly). The resulting alkyds were then converted into emulsions through emulsion inversion point (EIP) method by adding water and surfactants. These emulsions could be blended with natural rubber (NR) latex. One potential application of the emulsions is in modifying the NR at the latex phase and could lead to improved properties for specific uses.
... The ability of cyclodextrins, and in particular methylated-β-cyclodextrin, in enhancing the nasal absorption of drugs has already been reported [32,34] and mainly attributed to their capacity to reversibly remove phospholipids and cholesterol from the membrane's external bilayer, thus temporarily increasing their permeability without toxic effects. A possible transient opening of the tight junctions, as a consequence of such interactions, has also been speculated [57]. ...
Article
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A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer. Moreover, randomly methylated β-Cyclodextrin (RAMEB) was used to improve the low drug solubility. A screening DoE was applied for a systematic examination of the effect of varying the formulation components proportions on gelation temperature, gelation time and pH. Drug-loaded gels at different clonazepam-RAMEB concentrations were then prepared and characterized for gelation temperature, gelation time, gel strength, mucoadhesive strength, mucoadhesion time, and drug release properties. All formulations showed suitable gelation temperature (29–30.5 °C) and time (50–65 s), but the one with the highest drug-RAMEB concentration showed the best mucoadhesive strength, longest mucoadhesion time (6 h), and greatest release rate. Therefore, it was selected for cytotoxicity and permeation studies through Caco-2 cells, compared with an analogous formulation without RAMEB and a drug solution. Both gels were significantly more effective than the solution. However, RAMEB was essential not only to promote drug release, but also to reduce drug cytotoxicity and further improve its permeability.
... Substances acting as those enhancers may comprise solvents and cosolvents, cyclodextrins, EDTA, surfactants, lipids, bile salts, fatty acids (especially oleic acid) and mucoadhesive polymers (e.g., chitosan). These materials may have a direct effect on absorption or interfere with normal nasal function by impairing ciliary function and membrane integrity [9,[28][29][30]. Due to that, safety of the employed substances is of special interest and must be evaluated along with the formulation. ...
Article
This special report gives an insight in the rationale of utilizing the nasal cavity for drug administration and the formulation as well as characterization of nasal preparations. As the nose is an easy-to-access, noninvasive and versatile location for absorption, this route of delivery will play an increasingly important role in future drug product development both for new and repurposed drugs. The nose can be utilized for local and systemic delivery including drug delivery to the central nervous system and the immune system. Typical formulation strategies and future developments are reviewed, which nowadays mostly comprise liquid formulations. Although they are straight forward to develop, a number of aspects from choice of solvent, osmolarity, pH, viscosity and more need to be considered, which determine formulation characteristics, not at least nasal deposition. Nasal powders offer higher stability and, along with more sophisticated nasal devices, may play a major role in the future.
Chapter
Polymers are major components of drug delivery systems in terms of drug encapsulation and release. Natural polymers offer advantages such as biocompatibility, biodegradability and biologically-recognizable moieties, which support cellular activities, compared to synthetic polymers. Chitosan, a naturally-occurring polysaccharide obtained from chitin, has drawn much attention in the pharmaceutical field because chitosan possess valuable properties such as non-toxic, biocompatibile, biodegradable, stable and sterilizable. The additional qualities of chitosan such as controlling the release rate of drug, scope for modification, cross-linking ability with other polymers, antimicrobial properties, gel forming ability, bioadhesion, immunostimulation, activation of macrophages, and gas permeability, make chitosan one of the most versatile co-polymer for drug delivery. This chapter discusses applications of chitosan in drug delivery, along with drug delivery systems that can be developed based on chitosan. Furthermore, the properties of chitin and chitosan and the mechanisms of drug release from chitosan-based drug delivery systems are presented.
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This review focuses on the role of chitosan and chitosan derivatives in drug delivery and in pharmaceutical industries as excipients. Chitin is one of the most abundant polysaccharides found in nature. Chitosan is a cationic natural polysaccharide obtained by deacetylization of chitin and generally considered as a safe, biocompatible and biodegradable material. The use of chitosan has been postulated in numerous areas of biopharmaceutical research such as mucoadhesion, permeation enhancement, vaccine technology, gene therapy and wound healing. Recent applications of chitosan are in ophthalmic, nasal, sublingual, buccal, periodontal, gastrointestinal, colon-specific, vaginal, transdermal drug delivery and mucosal-vaccine and gene carrier. It can also be used in the pharmaceutical industry in direct tablet compression, as tablet disintegrant, for the production of controlled release solid dosage form or for the improvement of drug dissolution Keywords: Chitosan, chitin, derivatives of chitosan, chitosan microspheres, biodegradable polymer 1. Introduction: Chitin is known biodegradable natural polymers based on polysaccharides, which is obtained from crustacean shell (e.g. crab, shrimp, lobster), some insect (e.g. true fly, Sulphur butterfly) and fungi like yeasts and plants 1, 2. Principally occurs in animals of the phylum Arthopoda 2 .
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Experimentally determined total and regional deposition data are presented for breathing monodisperse aerosols of a wide particle size range at different patterns through the mouth and nose. From these data simple analytical expressions were derived for the efficiencies of the nasal passages, larynx, upper and lower ciliated thoracic airways and the nonciliated portion of the lungs in collecting particles from inspired aerosols. Thus, empirical expressions are now available for the calculation of total and regional deposition in the human respiratory tract for particles of any size and density inspired at any pattern through the mouth or nose.
Article
We have recently shown that intranasal administration of mouse [D-Leu-4]-OB3 reconstituted in Intravail(®) to male Swiss Webster mice resulted in significantly higher uptake and bioavailability when compared with commonly used injection methods of delivery. In this study, we examined the effects of intranasal delivery of mouse [D-Leu-4]-OB3 in Intravail(®) on energy balance, glucose regulation, insulin secretion and serum levels of osteocalcin, a specific and sensitive marker of bone formation. Genetically obese C57BLK/6-m db/db mice were allowed food and water ad libitum and given either Intravail(®) alone or mouse [D-Leu-4]-OB3 in Intravail(®) for 14 days by intranasal instillation. Mouse [D-Leu-4]-OB3 reduced body weight gain, daily food intake, daily water intake and serum glucose by 11.5, 2.2, 4.0 and 61.9%, respectively. Serum insulin levels in db/db mice given mouse [D-Leu-4]-OB3 were approximately threefold lower than those in mice receiving Intravail(®) alone. Mouse [D-Leu-4]-OB3 elevated serum osteocalcin in db/db mice by 28.7% over Intravail(®) treated control mice. The results of our study indicate that intranasal delivery of biologically active mouse [D-Leu-4]-OB3 in Intravail(®) is feasible and has significant effects on regulating body weight gain, food and water intake, serum glucose, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.
Article
The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl-beta-cyclodextrin (DM beta CD) greater than alpha-cyclodextrin (alpha-CD) greater than beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) greater than gamma-cyclodextrin (gamma-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5'-nucleotidase (5'-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HP beta CD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5'-ND and total absence of LDH activity. On the other hand, 5% DM beta CD caused extensive removal of the membrane-bound 5'-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.
Article
Bile salts have been found to be effective absorption promoters of insulin across mucosal barriers, i.e., nasal and gastrointestinal. One of the mechanisms proposed for absorption enhancement is the dissociation of insulin oligomers to monomers, rendering a higher insulin diffusivity. alpha-Chymotryptic degradation and circular dichroism studies were used to characterize such a transition. When zinc insulin (hexamers) and sodium insulin (dimers) were subjected to alpha-chymotryptic degradation, a 3.2-fold difference in the apparent first-order rate constants was observed (zinc insulin being slower than sodium insulin), representing the intrinsic difference in the concentration of total associated species in solution (three times). In the presence of a bile salt, sodium glycocholate (NaGC), the rate of degradation of both zinc and sodium insulin increased in an asymptotic manner. A maximum increase of 5.4-fold was observed for zinc insulin at a 30 mM NaGC concentration and a 2.1-fold increase was noted for sodium insulin at 10 mM NaGC, both values being close to the theoretical numbers of 6- and 2-fold as predicted by the complete dissociation of hexamers and dimers to monomers. The result indicates dissociation of insulin oligomers to monomers by bile salt micelles, probably by hydrophobic micellar incorporation of monomeric units. Circular dichroism studies also revealed progressive attenuation of molecular ellipticities at negative maxima of 276, 222, and 212 nm for zinc insulin solution in the presence of NaGC. Therefore, both alpha-chymotryptic degradation and circular dichroism studies have consistently demonstrated that the bile salts may be capable of dissociating insulin oligomers to monomers, a fact which may play an important role in enhancing insulin bioavailability.
Article
The absorption of insulin (from porcine pancreas) in rabbits after the nasal administration of aqueous preparations containing insulin and five kinds of cyclodextrins (CyDs) in phosphate buffer solution at pH 7.0 was investigated. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease in glucose concentrations were observed following the simultaneous administration of insulin and CyD such as alpha- and heptakis (2,6-di-O-methyl)-beta-CyD (DM-beta-CyD). The largest enhancing effect on the nasal absorption of insulin was obtained by DM-beta-CyD. To evaluate the duration of the absorption-enhancing effect of CyDs, preadministration (administration of CyD 0.5, 6, 12 and 24 h before insulin administration) was performed. The area under plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration of DM-beta-CyD 6, 12 and 24 h before nasal administration. The absorption-enhancing effect disappeared 24h after the preadministration. These findings demonstrate that CyDs enhance the nasal absorption of insulin, and the recovery of the membrane transport barrier function in nasal mucosa is achieved, at the latest, 24 h after the administration of CyDs.
Article
Proteolytic enzyme inhibitors were examined as absorption enhancers for the nasal delivery of vasopressin (AVP) and desmopressin (1-d-8-DAVP) in rats. Aprotinin, soybean trypsin inhibitor, and camostat mesilate were used as enzyme inhibitors. The nasal absorption of AVP and 1-d-8-DAVP was evaluated by measuring its antidiuretic effect. Nasal administration of AVP (0.005 IU/kg) or 1-d-8-DAVP alone (2.5 ng/kg) produced a small antidiuretic effect. Coadministration with aprotinin (1000 and 10000 KIU/kg) or soybean trypsin inhibitor (1.25 and 6.25 mM) did not change the antidiuretic effect. However, coadministration with camostat mesilate (1 to 50 mM) significantly increased the antidiuretic effect and, thus, the nasal absorption of AVP and 1-d-8-DAVP. The activities of aminopeptidase, cathepsin-B, and trypsin in the nasal mucosal tissue of rats were 7 nmol/min/mg protein, 0.7 nmol/min/mg protein, and 4.6 pmol/min/mg protein, respectively. Aprotinin and soybean trypsin inhibitor inhibited only the trypsin activity, whereas camostat mesilate inhibited aminopeptidase and trypsin activities. Aprotinin (MW 6500) and soybean trypsin inhibitor (MW 8000), with relatively high molecular weights, may not permeate into the nasal mucosal tissue. In contrast, camostat mesilate is slowly absorbed (8%/hr) and could inhibit the proteolytic activity in the nasal mucosa, resulting in enhanced nasal absorption of AVP and 1-d-8-DAVP.
Article
The absorption enhancing effect of alpha-, beta-, and gamma-cyclodextrin (CD), dimethyl-beta-cyclodextrin (DM beta CD), and hydroxypropyl-beta-cyclodextrin (HP beta CD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DM beta CD to the insulin solution resulted in a high bioavailability, 108.9 +/- 36.4% (mean +/- SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% alpha-CD gave rise to an insulin bioavailability of 27.7 +/- 11.5% (mean +/- SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the alpha-CD-containing solution as compared to the DM beta CD preparation. The other CDs, HP beta CD (5%), beta-CD (1.8%), and gamma-CD (5%), did not have significant effects on nasal insulin absorption. DM beta CD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DM beta CD is a potent enhancer of nasal insulin absorption in rats.
Article
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.
Article
A series of polyethylene glycols (PEGs) ranging in molecular weight from near 600 to over 2000 daltons was used to study the effects of three absorption enhancers (sodium glycocholate, sodium lauryl sulfate, and polyoxyethylene 9 lauryl ether) on the molecular weight permeability profile of the nasal mucosa of the rat. Molecular weight-permeability properties were studied both by following changes in the excretion of the polyethylene glycols as a function of their molecular size and by examining the nasal mucosa for morphologic changes following exposure to the PEG/enhancer mixtures. Each absorption enhancer was found to affect the mucosa and its permeability in a unique manner. At a 1% concentration, sodium glycocholate only slightly affects tissue morphology and does not significantly alter the molecular weight permeability profile of the mucosa. In contrast, 1% sodium lauryl sulfate causes severe alteration of the mucosa and also greatly increases the absorption of both the PEG 600 and the PEG 2000 oligomers. Polyoxyethylene 9 lauryl ether was found to exert its action in a concentration-dependent manner. At a concentration of 0.1%, few changes were seen in either mucosal integrity or permeability. At a 1% concentration, however, a significant alteration in the structure of the mucosal tissues as well as a profound increase in the permeability of the mucosa to the PEGs was observed. Correlation of mucosal integrity with the effectiveness of an enhancer indicates that some of these compounds appear to be acting by altering the structure of the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The ability of a novel permeation enhancer, sodium tauro-24,25-dihydrofusidate (STDHF), to increase the systemic delivery of human growth hormone (hGH) after intranasal administration was investigated in rat, rabbit, and sheep. Formulations of hGH with STDHF exhibited greatly enhanced nasal absorption at concentrations of STDHF above its critical micelle concentration. The increase in bioavailability was 11-fold in rats and in rabbits and 21-fold in sheep for formulations containing 0.5% STDHF as compared to those without STDHF. Glycocholate or taurocholate at 0.5% was three to five times less effective than STDHF at enhancing hGH absorption in rats. Additionally, the pulsatile absorption kinetics observed after intranasal delivery more closely resemble the endogenous secretory pattern of hGH than those obtained following subcutaneous administration.
Article
The site dependence of the absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin was studied in rats. Insulin absorption was estimated on the basis of the cumulative hypoglycemic response from 0 to 4 hr postdose, relative to that after intramuscular insulin. Insulin was administered with or without adjuvants to isolated rectal, nasal, and buccal absorption sites. Laureth-9, a nonionic surfactant which irreversibly removes membrane proteins or lipids, promoted insulin absorption from each site. The rectal, nasal, and buccal routes were 30% as effective as the i.m. route. The enhancing effects of Na salicylate and Na2EDTA, which have reversible mechanisms of permeability enhancement, were specific for rectal absorption. With these adjuvants, rectal insulin was 30-40% as effective as i.m. insulin, but nasal and buccal doses were less than 5% as effective as i.m. doses. This specificity can be at least partly explained by considering the site-to-site differences in membrane histology, although differences in pore size and membrane biochemistry might also contribute. The protease inhibitor aprotinin was ineffective in increasing insulin efficacy via each route, either alone or in combination with laureth-9.
Article
Nasal absorption of insulin in rats was enhanced by addition of sodium glycyrrhetinate (GA Na), dipotassium glycyrrhizinate (GZ K2), and carbenoxolone (glycyrrhetinic acid hydrogen succinate) disodium salt (GAHS Na2). The latter agent was the most effective. On addition of 1% GAHS Na2, plasma immunoreactive insulin levels in rats showed a maximum level of 0.75 mU/ml at 15 min and plasma glucose levels were decreased to about 25 mg/dl after nasal administration of 10 U/kg insulin. In a comparison of the absorption rates of insulin by nasal and intravenous (i.v.) routes in rats, nasal absorptions of 10 U/kg insulin in the presence of 1% GAHS Na2, 0.5% GA Na and 1% GZ K2 were 26.5%, 13.2% and 14.5% of that in the case of a 5 U/kg i.v. dose, respectively. Hemolytic activies of GAHS Na2, GA Na and GZ K2 were milder than those of Na caprate and Na laurate, and nasal leucine aminopeptidase activity was more strongly inhibited by GAHS Na2 than by medium chain fatty acid salts, sodium glycocholate, GA Na or GZ K2. Therefore, it is suggested that GAHS Na2 is a very useful promoter which dose not irritate the nasal mucosal membrane or degrade insulin.
Article
The enhancement of nasal insulin absorption by sodium taurodihydrofusidate (STDHF) was studied in rabbits and rats. Using identical nasal formulations remarkable interspecies differences were observed. The fusidate derivative at 1% (w/v) enhanced nasal insulin bioavailability from 0.9 to 5.2% and from 0.3 to 18.0% in rabbits and rats, respectively. In both species the insulin formulations with STDHF resulted in strong hypoglycemic responses. Coadministration with the trypsin inhibitor aprotinin tended further to increase insulin bioavailability in rats and decrease insulin bioavailability in rabbits; however, these aprotinin effects were not statistically significant. Addition of the aminopeptidase inhibitor bacitracin to the STDHF containing formulation did not have any effect on insulin bioavailability in rats. Hence, STDHF is a potent enhancer of nasal insulin absorption, probably both by facilitating insulin transport through the nasal mucosa and possibly also by inhibiting enzymatic degradation. Further, interspecies differences and, experimental animal conditions can greatly affect nasal drug absorption.
Article
An octapeptide and a protein, of molecular weights 800 and 34,000, respectively, were found to have nasal bioavailabilities of 73 and 0.6%, respectively, in the rat. This data, combined with reported values for 23 other compounds, indicated good availability without adjuvants for all molecules up to 1000 molecular weight (mean 70%, SD between compounds 26%, n = 15) with a decline in availability above this value. The relationship between absorption and molecular weight was modeled assuming competition between constant clearance from the nasal cavity and molecular weight-dependent transport through the mucosa. Deviations of absorption from values predicted by this model did not correlate with factors such as charge, hydrophobicity, or susceptibility to aminopeptidases, but the relative absorption of cyclic and cross-linked peptides and proteins was significantly greater than that of linear peptides. It is argued that the most likely route for transport is through junctions between cells and that surface-active adjuvants (MW 6000) which markedly enhance insulin uptake may act by rendering hydrophobic areas of contact of the junctional proteins temporarily hydrophilic. The nasal route is suitable for efficient, rapid delivery of many molecules of molecular weight less than 1000. With the use of adjuvants, this limit can be extended to at least 6000 and possibly much higher.
Article
The purpose of this investigation was to develop a method to quantitate insulin absorption, and to compare insulin absorption from various noninjection sites of administration. Log dose/effect curves were established for i.m. insulin in adult male rats. The effects measured were the maximum change in plasma glucose concentration and the cumulative percentage of change in plasma glucose concentrations from 0 to 4 hr. Both log dose/effect curves gave similar results when calculating the efficacy of other routes, relative to i.m. Nasal, buccal, sublingual and rectal absorption sites were isolated by ligation procedures or with physical barriers. Rectal insulin was more efficacious than nasal, buccal and sublingual insulin, when administered without an absorption-promoting adjuvant. However, the efficacy relative to i.m. insulin was low for each route, probably due to a combination of slow membrane permeation and metabolism at the absorption site. Administration in a solution containing 5% sodium glycocholate, an absorption-promoting adjuvant, increased insulin efficacy by each route. The rank order was nasal greater than rectal greater than buccal greater than sublingual, with nasal and rectal insulin being roughly half as efficacious as i.m. insulin. Orally administered insulin, at doses 5 times higher than administered by other routes, and with Na glycocholate, produced no hypoglycemic response.
Article
The comparative effects of intranasal and subcutaneous insulin on blood glucose and insulin levels are described in non-obese type II diabetics, in the fasting state and following a standard meal. In the fasting studies, intranasal insulin (30 units) produced a single early insulin peak. Elevated insulin levels and their hypoglycaemic effect persisted for less than 2 h whereas with subcutaneous insulin (8 units) elevated insulin levels and evidence of hypoglycaemic action were still present at 4 h. By contrast, in the meal studies both forms of insulin had similar effects on serum insulin levels and blood glucose. Moreover elevated insulin levels and evidence of reduction in post-prandial hyperglycaemia were now present at 4 h with both intranasal and subcutaneous insulin administration. Intranasal insulin in combination with a test meal now produced a biphasic insulin profile more closely resembling the normal insulin response to a meal, and reflecting the combined effects of endogenous and exogenous insulin.
Article
There has been an increasing number of studies of allergic rhinitis in recent years, 1 and although our knowledge of pathogenesis and pathophysiology is still incomplete, it is now possible to link some of the clinical manifestations to basic mechanisms and to advance a hypothesis for the pathogenesis of allergic rhinitis. Knowledge about anatomy and physiology of the nose is necessary to understanding the pathophysiology and treatment of rhinitis, and this chapter will start with a short review of normal structure and function. A more detailed description is given elsewhere.~'2 Structure of the Nasal Mucosa The internal nose is deeper than suggested by the visible nose; the length is some 10-12 cm (tip of the nose to the pharyngeal wall) (Figure 1). Because of the prominence of the turbinates, each of the two cavities is a 2- to 4-mm wide slit. This complex arrangement indicates that the nose, which also accounts for nearly 50% of the total resistance to air flow, has tasks other than that of a simple conductive airway. The nasal cavity is lined with an ordinary airway epithelium of the ciliated pseudostratified type (Figure 2). There are two types of glands in lamina propria; about 100,000 small seromucous glands (8/mm2) 3 and 250 large serous glands in the anterior part of the nose. 4 It is unknown to what extent the latter, not existing in the bronchi, contribute to the watery discharge so characteristic of rhinitis. The blood vessels can be classified functionally into resistance, exchange, and capacitance vessels. The tone of the resistance vessels (small arteries, arterioles, and arteriovenous anastomoses) determines regional blood flow, and the tone of the capacitance vessels (veins and cavernous sinusoids) determines nasal patency. Transport to and from the interstitial fluid takes place
Article
The metabolism of octyl beta-D-[U-14C]glucoside, ]1-14C]dodecyl beta-D-maltoside and [1-14C]hexadecyl beta-D-glucoside was studied after oral administration to mice. The beta-glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage products, sugars and long-chain alcohols, entered the pathways of lipid and carbohydrate metabolism. It appears that alkyl beta-glycosides are suitable as additives in food and feed.
Article
The transepithelial transport of biosynthetic human growth hormone (hGH) formulated with the absorption enhancers didecanoyl-L-alpha-phosphatidylcholine (DDPC) and alpha-cyclodextrin (alpha-CD) was studied after intranasal administration to rabbits. Plasma concentrations of the hormone were determined until 240 min post administration by ELISA, and the absolute bioavailability was estimated to be in the vicinity of 20%. The localization of hGH was studied 15 min after application of the powder formulation in the initial absorptive phase. To visualize the hormone, a two-step indirect immuno-gold technique was used on semithin and ultrathin cryosections and Epon sections. Polyclonal rabbit anti-hGH was used as primary antibody and gold-conjugated goat anti-rabbit IgG as secondary antibody, succeeded by silver enhancement. Growth hormone was mainly found in the cytoplasm and nuclei of ciliated cells, showing distinct morphological signs of early necrosis, and in lamina propria, including the venules. Minute amounts of hGH were found in endocytotic vesicles in morphologically normal epithelial cells and in the intercellular compartment. We conclude that the major transport route of hGH formulated with absorption enhancers DDPC and alpha-CD was transcellular through lethally damaged ciliated cells.
Article
A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a "pulse-chase" study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.
Article
Insulin was administered to rats via nosedrops in the presence or absence of various alkylglycosides; systemic insulin absorption was measured as a fall in blood D-glucose concentration in animals made hyperglycemic by xylazine/ketamine anesthesia. Nosedrops (0.04 ml) containing alkylglycosides or regular porcine insulin alone were without effect. Nosedrops containing both a small amount of alkylglycoside (0.03-0.50%) and insulin (2 U regular porcine) caused a rapid decrease in blood D-glucose levels and a concomitant increase in serum immunoreactive insulin levels. The maximal hypoglycemic response was observed between 60 and 120 min after delivery of nosedrops. Decylmaltoside was less effective at enhancing systemic insulin absorption than dodecylmaltoside, tridecylmaltoside, or tetradecylmaltoside, whereas octylmaltoside was totally ineffective. Dodecylsucrose, a compound which differs from dodecylmaltoside only in one carbohydrate residue, had a similar effect on blood D-glucose values when it was included in the nosedrop formulation with insulin. Decylsucrose was considerably less potent than dodecylsucrose at enhancing systemic absorption of insulin. Nonylglucoside was effective at promoting insulin absorption from nosedrops only when used at higher doses (0.25-0.50%), whereas heptylglucoside and hexylglucoside were ineffective. These results indicated that nosedrops containing insulin plus an extremely low concentration (0.03%) of an absorption-enhancing agent such as tetradecylmaltoside can be used to lower blood D-glucose values.
Article
A series of alkylglycosides with various alkyl chain lengths and carbohydrate residues were tested for their ability to enhance systemic absorption of insulin after topical ocular delivery in anesthetized rats. Several reagents, including tetradecyl-, tridecyl- and dodecylmaltoside and dodecylsucrose, were potent stimulators of insulin absorption when used at concentrations as low as 0.125%. Other alkylglycosides such as decylsucrose, decylmaltoside, nonylglucoside, octylmaltoside, heptylglucoside and hexylglucoside were less potent or ineffective as absorption-enhancing reagents. By comparison, the bile salt sodium glycocholate was effective only when used at concentrations of 0.5% or greater. All of the reagents were effective only when used at concentrations above their critical micelle concentration and the most hydrophobic alkylglycoside reagents were the most efficacious at promoting systemic insulin absorption. The possible utilization of eyedrops containing insulin plus an absorption-enhancing alkylglycoside reagent in humans is discussed.
Article
The nasal absorption of insulin using dimethyl-beta-cyclodextrin (DM beta CD) as an absorption enhancer in rabbits was studied. The nasal administration of insulin/DM beta CD liquid formulations did not result in significant changes in serum insulin and blood glucose concentrations. In contrast, previous experiments in rats showed that the addition of DM beta CD to the liquid nasal formulation resulted in an almost-complete insulin absorption, with a concomitant strong hypoglycaemic response. Apparently, the effect of the cyclodextrin derivative on insulin absorption differs between animal species following nasal delivery of insulin/DM beta CD solutions. On the other hand, nasal administration of the lyophilized insulin/DM beta CD powder dosage form in rabbits resulted in increased serum insulin concentrations, and a maximum decrease in blood glucose of about 50%. The absolute bioavailability of the nasally administered insulin/DM beta CD powder was 13 +/- 4%, compared to 1 +/- 1% for both an insulin/DM beta CD liquid and an insulin/lactose powder formulation. It is concluded that insulin powder formulations with DM beta CD as an absorption enhancer are much more effective than liquid formulations.
Article
The mechanism of paracellular expansion by absorption enhancers, e.g., EDTA, sodium caprate (C10), and decanoylcarnitine (DC), was studied, the focus being on the process of actin microfilament contraction in the tight junction. The effects of various inhibitors such as KN-62 (a specific inhibitor of Ca2+/calmodulin dependent protein kinase), H7 (a protein kinase C (PKC) inhibitor), and W7 (a calmodulin antagonist) were examined on the paracellular expansion by the enhancers in Caco-2 cells. From the experimental results, the following mechanisms were suggested. EDTA activates PKC by depletion of extracellular calcium via chelation resulting in expansion of the paracellular route. C10 increases the intracellular calcium level by an interaction with the cell membrane independent of cell polarity resulting in contraction with actin microfilament. DC interacts specifically with the apical membrane to increase the intracellular calcium level, but the mechanistic details subsequent to the increase of calcium are not clear.
Article
The objective of this Review is to summarize and critique recent findings and applications of both unmodified and modified cyclodextrins for in vivo drug delivery. This review focuses on the use of cyclodextrins for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. This Review primarily focuses on newer findings concerning cyclodextrin derivatives which are likely to receive regulatory acceptance due to improved aqueous solubility and safety profiles as compared to the unmodified cyclodextrins. Many of the applications reviewed involve the use of hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) and sulfobutylether-beta-cyclodextrins (SBE-beta-CDs) which show promise of greater safety while maintaining the ability to form inclusion complexes. The advantages and limitations of HP-beta-CD, SBE-beta-CD, and other cyclodextrins are addressed.
Article
To visualize the transport pathway(s) of high molecular weight model compounds across rat nasal epithelium in vivo using confocal laser scanning microscopy. Furthermore, the influence of nasal absorption enhancers (randomly methylated beta-cyclodextrin and sodium taurodihydrofusidate) on this transport was studied. Fluorescein isothiocyanate (FITC)-labelled dextrans with a molecular weight of 3,000 or 10,000 Da were administered intranasally to rats. Fifteen minutes after administration the tissue was fixed with Bouin. The nasal septum was surgically removed and stained with Evans Blue protein stain or DiIC18(5) lipid stain prior to visualization with the confocal laser scanning microscope. Transport of FITC-dextran 3,000 across nasal epithelium occurred via the paracellular pathway. Endocytosis of FITC-dextran 3,000 was also shown. In the presence of randomly methylated beta-cyclodextrin 2% (w/v) similar transport pathways for FITC-dextran 3,000 were observed. With sodium taurodihydrofusidate 1% (w/v) the transport route was also paracellular with endocytosis, but cells were swollen and mucus was extruded into the nasal cavity. For FITC-dextran 10,000 hardly any transport was observed without enhancer, or after co-administration with randomly methylated beta-cyclodextrin 2% (w/v). Co-administration with sodium taurodihydrofusidate 1% (w/v) resulted in paracellular transport of FITC-dextran 10,000, but morphological changes, i.e. swelling of cells and mucus extrusion, were observed. Confocal laser scanning microscopy is a suitable approach to visualize the transport pathways of high molecular weight hydrophilic compounds across nasal epithelium, and to study the effects of absorption enhancers on drug transport and cell morphology.
Article
The major focus of this review is on the molecular structure and functions of proteins that are involved in the formation of tight intercellular junctions and some methods used to modulate intercellular junctions. Tight junctions are a barricade for paracellular delivery of molecules such as peptides and proteins. Understanding the molecular structure and functions of intercellular junction proteins may provide the possibility of systematically designing molecules that can regulate tight junctions. Regulation of proteins involved in the formation of intercellular junctions may open avenues to modulating the porosity of intercellular junctions to improve paracellular drug delivery.
Article
Medium chain fatty acids (MCFAs) are used to enhance the permeability of mucosal tissues to hydrophilic drugs, but their mechanism of action is largely unknown. In this study, the absorption-enhancing effects of the sodium salts of two MCFAs, capric acid (C10) and lauric acid (C12), were studied in monolayers of human intestinal epithelial Caco-2 cells. Both MCFAs induced a rapid increase in epithelial permeability to the hydrophilic marker molecule sodium fluorescein. Inhibition of phospholipase C and inhibition or activation of various kinases and buffering of intracellular calcium indicated that the effects on epithelial permeability were mediated through phospholipase C-dependent inositol triphosphate/diacylglycerol pathways. Surprisingly, the inositol triphosphate and diacylglycerol pathways were found to have opposing effects on paracellular permeability. Exposure to the MCFAs also resulted in a concentration dependent reduction of cellular dehydrogenase activity and ATP levels. C10, but not C12, induced redistribution of the tight junction proteins ZO-1 and occludin. These results indicate that the two MCFAs have partially different and more complex mechanisms than previously recognized, which has important implications for their use in vivo.
Article
The effect of a soybean-derived sterol mixture (SS) and a steryl glucoside mixture (SG) as enhancers of the nasal absorption of insulin in rabbits was investigated. SS consists of beta-sitosterol (Sit), campesterol (Camp), stigmasterol (Stig) and brassicasterol (Bras), and SG is a mixture of their monoglucosides. For each component of SS tested for efficacy in promoting the systemic absorption of nasally administered insulin, the following order was observed: Sit> or =Camp>Stig. This finding was in agreement with the order of the enhancers' lipophilicity. In the case of SG, the effect of beta-sitosterol beta-D-glucoside (Sit-G) was significantly greater than that of SG. The pharmacological bioavailability was 6.7% for SG and 11.3% for Sit-G in the suspension dosage forms. SG showed a greater degree of enhancement of insulin permeation through the nasal mucosa than SS. To elucidate the contribution of SG to the enhanced absorption, insulin permeation through an artificial membrane and the nasal mucosa was investigated in vitro, and the results were compared with those for SS. The findings suggest that SG and SS have some effect on nasal mucosa lipids.
Article
Cyclodextrins are used in nasal drug delivery as absorption enhancing compounds to increase the intranasal bioavailability of peptide and protein drugs. The most effective cyclodextrins in animal experiments are the methylated derivatives, dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, which are active at low concentrations ranging between 2% and 5%. However, large species differences between rats, rabbits and humans exist for the nasal absorption enhancement by cyclodextrins. Based on toxicological studies of the local effects of cyclodextrins on the nasal mucosa dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin are considered safe nasal absorption enhancers. Their effects were quite similar to controls (physiological saline), but smaller than those of the preservative benzalkonium chloride in histological and ciliary beat frequency studies. In these studies, and in a study of the release of marker compounds after nasal administration, methylated beta-cyclodextrins were less toxic than sodium glycocholate, sodium taurodihydrofusidate, laureth-9 and L-alpha-phosphatidylcholine. Systemic toxicity after nasal cyclodextrin administration is not expected, because very low doses of cyclodextrins are administered and only very small amounts are absorbed. The mechanism of action of cyclodextrins may be explained by their interaction with the nasal epithelial membranes and their ability to transiently open tight junctions.
Article
During this century, several investigators reported that certain viruses, metals, drugs, and other solutes could bypass systemic circulation and enter the brain and/or cerebrospinal fluid directly following nasal administration. Although evidence clearly suggests that the olfactory epithelium and its olfactory cells play a major role, little is known about the mechanisms of direct transport of solutes into the brain. An overview of what is known about these mechanisms may aid in further research in this field, including studies of direct drug delivery to the central nervous system. This review, in addition to summarizing the literature to date, clearly describes the intricate association of the anatomical features involved in direct entry of solutes into the brain following nasal administration. To aid in the understanding of the possible routes a solute can take after nasal administration, the anatomy of the olfactory epithelium and surrounding tissues is described, and a detailed scheme delineating the emerging pathways is presented. Techniques used in delineating these pathways and studies supporting a particular pathway are discussed in greater detail. Finally, some factors influencing the direct transport of solutes to the cerebrospinal fluid and brain are summarized.