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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.

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CsA = cyclosporin A; dDAVP = 1-deamino-8-D-arginine vasopressin; DPI = dry-powder inhaler; FSH = follicle-stimulating hormone; hGH = human growth hormone; MDI = metered-dose inhaler; MMAD = mass median aerodynamic diameter; PTH = parathyroid hormone; r-Con-IFN = recombinant-methionyl interferon consensus; r-huG-CSF = recombinant-methionyl human granulocyte colony-stimulating factor; TI = technosphere-insulin formulation; TSH = thyroid-stimulating hormone.Available online http://respiratory-research.com/content/2/4/198 IntroductionThe techniques of recombinant DNA technology have been well refined during the past 20 years such that it is now possible to produce, under good manufacturing practice conditions, commercial quantities of therapeutic peptides and proteins. It is expected that, during the next decade, an even greater number of molecular targets will be identified for treatment of various diseases. These are exciting developments, not only for scientists, but also for patients, because such biotherapeutic agents are very specific in their actions, and thus will greatly improve the quality of life for the majority of patients.Hundreds of bioengineered proteins and peptides are either already on the market or are undergoing clinical investigation; these include growth factors, hormones, monoclonal antibodies, cytokines and anti-infective agents, among others. However, these compounds have unusual characteristics that present considerable challenges to formulation scientists. The combination of their large molecular size, hydrophilicity and lability (both chemical and enzymatic) virtually exclude their formulation in traditional dosage forms such as tablets and capsules. Consequently, most proteins and peptides currently on the market are injectable. AbstractThe large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinantmethionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

Capillary electrophoresis (CE) represents a decisive step forward in stereoselective analysis. The present paper deals with the theoretical aspects of the quantitation of peak separation in chiral CE. Because peak shape is very different in CE with respect to high performance liquid chromatography (HPLC), the resolution factor Rs, commonly used to describe the extent of separation between enantiomers as well as unrelated compounds, is demonstrated to be of limited value for the assessment of chiral separations in CE. Instead, the conjunct use of a relative chiral separation factor (RCS) and the percent chiral separation (% CS) is advocated. An array of examples is given to illustrate this. The practical aspects of method development using maltodextrins--which have been proposed previously as a major innovation in chiral selectors applicable in CE--are documented with the stereoselective analysis of coumarinic anticoagulant drugs. The possibilities of quantitation using CE were explored under two extreme conditions. Using ibuprofen, it has been demonstrated that enantiomeric excess determinations are possible down to a 1% level of optical contamination and stereoselective determinations are still possible with a good precision near the detection limit, increasing sample load by very long injection times. The theoretical aspects of this possibility are addressed in the discussion.

1 Direct myocardial effects of the S(-)-and R(+)-enantiomers of bupivacaine were compared in the guinea-pig isolated papillary muscle by recording transmembrane action potentials with the standard microelectrode technique. 2 In 5.4 mm K+, at a stimulation rate of 1 Hz, the maximal rate of depolarization ( was reduced to 59.9 + 1.4% (n = 10) of control (mean+ s.e.mean) in the presence of 10puM R(+)-bupivacaine, and to 76.7 + 1.2% (n = 14) in the presence of the same concentration of S(-)-bupivacaine. This was mainly due to a difference in time constant at which block dissipated during the diastolic period. Recovery was slower in the presence of R(+)-bupivacaine. The slower recovery in the presence of R(+)-bupivacaine resulted also in a more pronounced frequency-dependent block of f,,,X.3 Time constants for recovery from use-dependent block became significantly faster for both enantiomers on hyperpolarization, while no significant change was observed at depolarization. At all membrane potentials recovery was slower in the presence of R( + )-bupivacaine. 4 The action potential duration (APD) was shortened to a greater extent in the presence of R(+)-bupivacaine over a large range of stimulation frequencies.5 We conclude that S(-)-bupivacaine affects VP"X and APD in the guinea-pig papillary muscle less than the R( + )-enantiomer at different rates of stimulation and resting membrane potentials.

The aim of this study was to establish a collagen matrix-based nasal primary culture system for drug delivery studies. Nasal epithelial cells were cultured on derivatised (Cellagen membrane CD-24), polymerised (Vitrogen gel) and fibrillar (Vitrogen film) collagen substrata. Cell morphology was assessed by microscopy. The cells were further characterised by measurement of ciliary beat frequency (CBF), transepithelial resistance (TER), permeation of sodium fluorescein, mitochondrial dehydrogenase (MDH) activity and lactate dehydrogenase (LDH) release upon cell exposure to sodium tauro-24, 25 dihydrofusidate (STDHF). Among the three collagen substrata investigated, the best epithelial differentiated phenotype (monolayer with columnar/cuboidal morphology) occurred in cells grown on Cellagen membrane CD-24 between day 4 and day 11. Cell culture reproducibility was better with Cellagen membrane CD-24 (90%) in comparison with Vitrogen gel (70%) and Vitrogen film (< 10%). TER was higher in cells grown on Vitrogen gel than on Cellagen membrane CD-24 and Vitrogen film. The apparent permeability coefficient (Papp x 10(-7)cm s(-1)) of sodium fluorescein in these conditions was 0.45+/-0.08 (Vitrogen gel) and 1.91+/-0.00 (Cellagen membrane CD-24). Except for LDH release, CBF and cell viability were comparable for all the substrata. Based on MDH activity, LDH release, CBF, TER and permeation studies, Cellagen membrane CD-24- and Vitrogen gel-based cells were concluded to be functionally suitable for in-vitro nasal drug studies. Vitrogen film-based cultures may be limited to metabolism and cilio-toxicity studies.

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