Nasal formulations

Fig. 17.13. Electropherograms obtained for the analysis of a nasal formulation for the determinations of benzalkonium chloride (BC) in the presence of active pharmaceutical ingredient (R91274) and other placebo ingredients. Conditions 75 mM sodium phosphate buffer, pH = 2.3, 35 cm fused silica capillary (effective length 28.5 cm) x 75 pm I.D., injection 10 s at 35mbar, 20°C, 15 kV (positive polarity) resulting in a current of approximately 95 pA, detection UV 215 nm.

Nasal formulations of modern sympathicomimet-ics like oxymetazoline and xylometazoline are effective. Rebound nasal congestion after withdrawal of sympathicomimetic-containing nose sprays or drops is a common phenomenon and patients should be advised to use these medicaments no longer than 3-5 days. Older per oral drugs like ephedrine and pseudo-ephedrine have no place in the therapy of rhinitis due to the risk of serious adverse reactions which are not in proportion to the indication. 

Ethylene glycols Formulation aid for nasal delivery Single and repeat-dose nasal toxicity (up to 14 days— intranasal rabbit) Mild local toxicity likely to be acceptable in clinical nasal formulations for short-term use 35... 

Solution-based systems are common to both nebulizers and nasal formulations. In general, water will form the greatest fraction of the formulation, but, in some cases, cosolvents such as ethanol and propylene glycol may be added for increased stability. Acidifying and alkalizing excipients may also be added to optimize pH from the perspective of the drug stability as well as the physiological effect on the airways. Similarly, iso-osmotic and iso-tonic solutions are preferred. 

Simple spray devices can deliver nasal formulations to the anterior portion of the nasal cavity. More sophisticated spray devices have been developed to deliver nasal formulations to the medial and posterior portions of the nasal cavity. 

Chitosan is a cationic polysaccharide produced from the deacetylation of chitin, a component of crab and shrimp shells [7,57,58], Chitin is composed of units of 2-deoxy-2-(acetylamino) glucose joined by glycosidic bonds that form a linear polymer. Ilium et al. [7,57,58] demonstrated the ability of chitosan to increase the bioavailability of insulin and other small peptides and polar macromolecules in different animal models. In both the sheep and rat models, the addition of chitosan at concentrations of 0.2%-0.5% to nasal formulations of insulin resulted in significant increases in plasma insulin and reductions in blood glucose. Reversibility studies indicated that the effect of chitosan on the nasal absorption of insulin... 

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

Several peptide products used in the treatment of diabetes mellitus, in addition to insulin, are currently administered by subcutaneous injection and these drugs are candidates for development of nasal formulations. Glucagon-like peptide-1 (GLP-l)-related peptides stimulate the insulin response to glucose and diminish the release of glucagon after a meal. These effects diminish the excessive postprandial increase in glucose observed after a meal in persons with type 2 diabetes mellitus. GLP-1-related peptides must be administered by subcutaneous injection before meals in order to be effective. This requirement for injection before each meal is likely to impact the utilization of these products by persons with type 2 diabetes. Exendin-4 is a GLP-1-related peptide with a molecular mass of 4.2 kDa. The development of a GLP-1-related peptide nasal formulation containing an absorption enhancer would allow patients to scll-administer one of these drugs just before a meal without the need for a subcutaneous injection. 

Epoetin alfa, recombinant erythropoietin, is a glycoprotein that simulates erythrocyte production. Epoetin alfa is administered three times weekly subcutaneously or intravenously. Epoetin is used to treat anemia in patients with chronic renal failure, HIV infection, and patients receiving chemotherapy [104]. Development of a safe, effective nasal formulation of epoetin alfa, containing an absorption enhancer could once again improve the efficacy of epoetin alfa therapy, and reduce the number of injections required in these sensitive patient populations. 

Leptin is a peptide hormone secreted by adipocytes. Recombinant human leptin has been investigated for its potential as an antiobesity agent [105,106]. Women with hypothalamic amenorrhea display reduced levels of leptin. Leptin administration to these women improves reproductive and neuroendocrine function [107], Nasal administration of leptin to rats in the presence of either TDM (1) or LPC [108] caused a significant increase in serum leptin levels. Increased serum leptin levels were associated with reduced food consumption [108], The development of an effective nasal formulation of leptin containing an absorption enhancer may allow more frequent dosing with leptin and thereby overcome the limited efficacy observed following subcutaneous injections of large doses of this hormone. 

Since the introduction of metered-dose inhalers, nasal solutions have increasingly been formulated as nasal sprays. Initially, aerosol-based systems containing chloro-fluorocarbons were employed however, the Montreal Protocol put an end to this. Thereafter, mechanical pumps or actuators were employed to deliver nasal formulations as sprays. These devices, using actuators, can precisely deliver as little as 25 pL and as much as 200 pL of a formulation. However, various factors must be considered in formulating the spray these include viscosity, particle size, and surface tension, all of which may affect the accuracy of the dose administered. 

Suspensions may also be used to deliver nasal formulations, though only rarely, since a number of complicating factors (e.g., particle size and morphology) must be considered. Suspensions offer the advantage of increasing residence time in the nasal cavity, thus possibly augmenting nasal bioavailability. 

In a pharmacokinetic-based study by Hedin et al. [94], hGH was administered with a nasal permeation enhancer, sodium tauro-24,25-dihydrofusidate (STDHF), in patients deficient in growth hormone (GH) using a reprocessed lyophilized form of hGH. The lyophilized material was formulated with STDHF and all the subjects received the formulation by both the nasal and subcutaneous routes. The dose given by the subcutaneous route was a standard dose of O.lIU/kg body weight (BW), whereas three different doses (of 0.2,0.4, and 0.8 IU/kg BW) of the nasal formulation were given. As compared with the subcutaneous route, all three nasal formulations showed a rapid increase in the plasma levels of hGH, with Y rn ix being reached 15-25 min after administration, as compared with 3-4 h in the case of the subcutaneous route. However, the Cmax was higher in the case of the latter route, and the nasal formulations touched baseline after 3-4 h, as compared with 14-18 h after subcutaneous delivery. 

Diazepam As mentioned earlier, because of shortcomings of rectal administration, the nasal delivery of diazepam has gained interest. The nasal bioavailability of diazepam in sheep was estimated and further compared with results obtained earlier in humans and rabbits [106] in this study, human and rabbit nasal bioavailability for the first 30min was reported to be 37 and 54%, respectively [113]. Diazepam solubilized in PEG 300 was used for nasal administration via a modified nasal device, a Pfeiffer unit dose (Princeton, NJ). The sheep received the nasal formulations in a fixed standing position such that the head was slightly tilted back. It was found that the serum concentration after administration of a 7-mg solution of diazepam was... 

There has been a report on chitosan utility in improving the intranasal absorption of high-molecular-weight (>10-kDa) therapeutic protein. Chitosan glutamate powder blend or granules with recombinant hGH have been evaluated for intranasal administration in sheep. Relative to subcutaneous injection the nasal formulations produced bioavailabilities of 14 and 15%, respectively [77],... 

A number of ciliotoxicity studies have pointed out a low correlation between the results obtained using different in vitro and in vivo methods [121], The effects of nasal formulations on the ciliary beat frequency in vitro are usually more expressed than in vivo, since in vivo, cilia are partially protected by the mucous layer and investigated formulation is eventually cleared from the nasal cavity due to the mucociliary clearance mechanism. Also, toxic effects of the formulations on the cilia in vivo may be reversible due to the constant nasal mucosal cell turnover [121]. 

In conclusion, in order to make predictions regarding the safety of the nasal formulation on mucociliary clearance, both in vitro and in vivo studies have to be performed. It is also essential to determine long-term use effects in animals and in humans if the nasal formulation is intended for subchronic or chronic administration. 

The administration of systemically acting products via the nasal route began in the 1980s. The peptide oxytocin, which stimulates uterine contraction and lactation, was one of the first nasally administered peptide hormones. Meanwhile, several peptide-based nasal formulations entered the market. Currently, more attention is being paid to this delivery system due to the increasing demands of new highly potent drug formulations. In addition, patients expectations for... 

A current trend is the development of nasal formulations without preservatives. In long-term treatments,... 

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