Nasal peptide products

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. 

MARKETED PRODUCTS OF NASAL PEPTIDE AND PROTEIN FORMULATION... 

Table 1 Marketed products and pipeline of nasal peptide/protein formulation...

A range of nasal peptides such as desmopressin, buserelin, nafarelin and oxytocin, have been formulated into licensed nasal products. However, none of them contains a nasal absorption enhancer. Even though these nasal products are characterised by low peptide bioavailability they are efficacious, as low systemic levels are needed to exert a therapeutic effect. However, developing of novel safe and efficient nasal absorption enhancers is of great interest to improve bioavailability of presently marketed peptides and to provide sufficient nasal permeability of less potent biologicals [22]. 

Protein and peptide therapeutics currently represent eight of the top 100 prescription pharmaceuticals in the U.S., and biotechnology products are projected to account for 15% of the total US. prescription drug market by 2003. Of the protein and peptide products now on the market, many are administered as daily injections, though several are delivered by noninvasive routes. For example, desmopressin is delivered as a nasal spray, and deoxyribonuclease I is administered by inhalation. Although cyclosporin A is orally active, as yet there are no general means to confer oral bioavailability to peptides and proteins. A major advance in delivery of peptides was achieved with the introduction of a monthly injectable, biodegradable microsphere formulation of LHRH. 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

Peptide/protein uptake rates across the nasal epithelia are dependent upon molecular mass. Relatively small peptides, such as oxytocin, desmopressin and LHRH analogues, cross relatively easily and several such products used medically are routinely delivered nasally. Larger molecules (of molecular mass greater than 10 kDa) generally do not cross the epithelial barrier without the concurrent administration of detergent-like uptake enhancers. Long-term use of enhancers is prohibited due to their damaging cellular effects. 

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). 

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... 

Peptide YY (PYY) is a peptide hormone produced by L-cells in the intestinal tract after eating. It appears to act centrally to diminish appetite. It may serve normally to produce a sense of satiety. Diminished PYY production would be expected to cause increase in appetite and increased food intake. Hence, a biologically active PYY derivative, PYY 3-36, is under investigation as a potential agent to treat obesity and type 2 diabetes. A nasal PYY 3-36 product, if developed, would be an attractive alternative to injected PYY 3-36 because of the rapid and direct nose-to-brain drug transport that occurs following nasal drug delivery. 

Due to the lack of activity after oral administration for most peptides and proteins, administration by injection or infusion - that is, by intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration - is frequently the preferred route of delivery for these drug products. In addition, other non-oral administration pathways have been utilized, including nasal, buccal, rectal, vaginal, transder-mal, ocular, or pulmonary drug delivery. Some of these delivery pathways will be discussed in the following sections in the order of the increasing biopharmaceutic challenges to obtain adequate systemic exposure. 

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... 

Several products for the systemic delivery of peptide and protein drugs via the nasal route are currently available in the marketplace, as shown in Table 1. Most of these peptides, with molecular weights ranging from 1000 to 3400, have been conventionally used as injection forms. 

Numerous papers have reported on the possible utility of nasal administration of a variety of compounds, including peptide and protein drugs. However, only a small number of products are of clinical use for intranasal systemic delivery, as mentioned earlier. Especially, most peptide and protein drugs show insufficient nasal bioavailability, which may be one of the reasons for difficulties in development. To improve the nasal absorption of peptide and protein drugs, several strategies classified as follows have been intensively investigated and discussed during the last two decades ... 

With the exception of a few approved products for nasal administration of peptides and the very recent regulatory approvals of delivery systems for both pulmonary and buccal delivery of insulin, there is relatively little precedence with the worldwide regulatory approval process for non-invasive delivery systems incorporating protein or peptide pharmaceuticals. Consequently, there is limited specific information... 

Considerations of commercial viability have likely influenced the extent of exploratory research activity on the various non-invasive delivery options available for protein and peptide delivery. Currently, the buccal/ sublingual, nasal, transdermal, pulmonary, and oral routes of administration are receiving the most attention in the scientific and patent literature with some technologies showing promise as potentially feasible commercial products. The following sections examine each of these non-invasive delivery routes in greater detail. 

In 1992, Drejer et al. [31] investigated the pharmacokinetics of intranasal insulin containing a medium-chain phospholipid (didecanoyl-L-alpha-phosphatidylcho-line) as absorption enhancer in 11 normal volunteers. Intranasal insulin was absorbed in a dose-dependent manner with a mean plasma insulin peak 23 7 min after administration. Mean plasma glucose nadir was seen after 44 6min, 20min after intravenous injection. Moreover, intranasal administration of insulin resulted in a faster time-course of absorption than subcutaneous injection, and the bioavailability for the nasal formulation was 8.3% relative to an intravenous bolus injection when plasma insulin was corrected for endogenous insulin production estimated by C-peptide. 

In medicines with intended systemic action a certain pH may be necessary to guarantee sufficient absorption of the active substance. In that case a buffer with high capacity is chosen, although it will have a negative effect on cilia. The more pH deviates from the physiological value, the more irritation will be felt. An example is a licensed nasal spray with the peptide buserelin in a citrate buffer (pH 5.5-6). Its Summary of product characteristics (SPC) says nasal irritation may occur, sometimes leading to epistaxis or hoarseness, as well as changes in taste and smell. 

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