Formulation development nasal formulations

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. 

Since a comprehensive listing of every potential peptide and macromolecule that could be delivered nasally is not possible, this section will focus on (1) the drugs currently in use as nasal products in humans, (2) drugs currently in use as injectables in humans that will gain increased utilization if and when they can be formulated for nasal delivery, and (3) drugs that are currently in development for utilization in humans (Table 20.2). 

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. 

Ilium, L. (1999), Bioadhesive formulations for nasal peptide delivery, in Mathiowitz, E., Chickering, D. E., and Lehr, C.-M., Eds., Bioadhesive Drug Delivery Systems, Fundamentals, Novel Approaches and Development, Marcel Dekker, New York, pp. 507-539. 

Methods to determine ciliary beat frequency and mucociliary transport in vitro and in vivo have been extensively reviewed elsewhere [84,121], In general, in vivo methods are more reliable for ciliotoxicity studies than in vitro methods and are essential to confirm the safety of nasal drug formulations. However, in vitro methods are more suitable for the large number of screening studies required during formulation development [122],... 

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

The medical device industry has developed many ways to dispense nasal formulations. Device technology is becoming more and more important, not only with... 

An alternative to the pulmonary route of administration is the nasal route, which is less demanding when it comes to formulation. With regard to, for example, particle size and simpler device development (5,90), examples are Minirin (Ferring), desmopression, and Suprecur (Sanofi-Aventis), buserelin, which are proteins formulated as nasal drops or nasal spray, where bioavailabdities of approximately 3% to 10% can be obtained. The formulations are just protein dissolved in purified water containing preservatives chlorbutanol and benzalkonium chloride (91,92). However, more advanced delivery systems are also used, for example, chitosan formulations where bioavailabihties of 14% to 15% compared to subcutaneous administration can be obtained (90). A recent review by nium (2007) gives more details on nanoparticulate systems used for nasal delivery (93) or consult Costantino et al. (2007) on the physiochemical and therapeutic aspects (5). 

The intranasal formulation is the preferred route of administration owing to ease of administration and fewer adverse effects, which mainly are local in nature. Adverse effects associated with the intranasal formulation include rhinitis, nasal irritation, and dryness. Hypersensitivity can develop with either formulation and should be considered before administering to patients with a suspected risk of hypersensitivity. 

Sumatriptan was specifically developed as an anti-migraine drug. Injectable sumatriptan has been shown to be more effective than injectable DHE at two hours but the rate of recurrence (30 0%) is higher than with DHE. Efficacy is better and delay to action is shorter with the injectable formulation. Both the nasal spray and the injectable formulation... 

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