Drug Delivery Report

Edward T. Maggio
CEO, Aegis  Therapeutics LLC, 16870  W. Bernardo Drive, Suite 390, San Diego, CA 92127, US

Introduction

It has long been recognised  that  peptide  and protein drugs are among  the most useful and effective therapeutics yet discovered. However, the practical use of most peptide drugs has been confined to treatment of diseases having severe or life threatening consequences as a direct result of the requirement for administration  by injection. Recent advances in transmucosal drug delivery have created  a rebirth in interest in peptide  drugs. This was perhaps brought home most dramatically by the simultaneous approval of Exubera®, the first non-injectable insulin product to come along since the discovery of insulin, by both the European Commission and the FDA. Punctuating the point is the fact that  it was not one of the more recent biopharma  entries that  took this innovative step, but rather Pfizer, the largest, and one of the most successful, pharmaceutical companies  in the world.
Peptides often demonstrate high potency and high selectivity while exhibiting essentially no chemical toxicity. Because they are metabolised to naturally occurring amino acids, peptides  and proteins do not invoke xenobiotic metabolic processes,  nor do they accumulate significantly in organs - principle sources of small molecule drug toxicity. In spite of the many attractive  aspects of peptides  and proteins as potential  therapeutic agents, their susceptibility to denaturation, hydrolysis and poor absorption in the gastrointestinal tract makes them unsuitable  for oral administration, typically requiring administration  by injection. This remains their major shortcoming. In spite of this, more than  140 peptide  and protein drugs are in use today.
From a commercial perspective,  the opportunity for systemically-acting peptide  and protein drugs is potentially quite large. In 2003,  sales of approved  peptide  therapeutics in the US alone totalled more than  US$9 billion (MedAd News, 2003) and sales of therapeutic proteins grew to US$37 billion, with 2010 sales predicted  to exceed US$90 billion (Parmar, 2004). Among transmucosally-delivered drugs, the current global market for nasally-delivered medications  is valued at greater  than  US$6 billion (Devillers, 2003). While the growth  rate for topically- acting intranasal drugs, such as those used to treat allergic rhinitis, is about  10%,  the growth  rate for intranasal delivery of systemically-acting drugs is 30%  (Bommer,2002). This dramatically outpaces the growth  of the overall worldwide pharmaceutical market,  which is projected  to grow at 6-7%  during 2006 (Aitken, 2005).
Strong patient  desire to avoid repeated injections, both for peptides  and non-peptides alike, has spurred growing interest in researching  and developing alternate administration  routes.  While Exubera relies upon transmucosal absorption across the pulmonary mucosa of the lungs, a number  of alternative transmucosal delivery routes for macromolecular drugs, that  similarly circumvent the need for injection but offer greater  patient  convenience as well as certain cost and other commercial advantages,
are in clinical and preclinical development (Table 1). Each of these  alternate routes has both strong and weak points and the selection of the most propitious route  of
administration  is determined in large part by the properties of the individual drug in question  (e.g. solubility, total mass required per dose, localised biological action upon mucosal tissue, and so on).

A New  Class of Transmucosal Absorption Enhancement Agents

Over the past two decades, a large number  of molecules, encompassing at least a dozen chemical and biological approaches, have been screened  for the ability to enhance transmucosal  delivery of peptides. For the most part, these agents provide only  limited bioavailability or have been shown to be  irritating or toxic  to nasal mucosa. Facilitating the acceptance of these alternative transmucosal  delivery routes, a new class  of patented alkylsaccharide transmucosal  delivery enhancement agents exhibiting certain well-defined and highly specific structural characteristics was discovered by two researchers (Professors Dennis Pillion and Eli Meezan) and their colleagues working in the Department of Pharmacology and Toxicology at the University of Alabama, Birmingham (Pillion et al., 1994; 2006; Ahsan et al., 2001). This well-defined group of molecules has  been collectively designated as Intravail™  absorption enhancers to distinguish them from the many thousands of potential alkyl saccharides accessible from a combinatorial chemistry perspective. One of the most well-published members of this  group is tetradecyl maltoside (TDM).
Intravail™  absorption enhancers provide unsurpassed transmucosal  bioavailability, comparable  to that macromolecular therapeutics. This has  been well  described in a growing number of publications (Ahsan et al., 2003; Arnold et al., 2002; 2004; Maggio, 2005; Pillion et al., 1995; 2002; 2005). Some specific results for  TDM in a variety of animal models are summarised in Tables 3 and 4. From  a mechanistic perspective, it has  been demonstrated that these agents function to increase both paracellular and transcellular absorption. A recent study contrasts the unique ability  of Intravail™  alkyl saccharides to open tight junctions compared to non-Intravail™ alkyl saccharides which are essentially inert (Chen et al., 2005;).
Intravail™ agents are non-toxic, synthetic single chemical entities that are metabolised to CO and H O (Weber and Benning, 1984) and allow controlled transient mucosal permeation by both paracellular (tight-junction) and transcellular routes.  They allow for homogeneous aqueous solutions to be delivered through simple inexpensive metered nasal spray pumps - no particles, powders,  or complicated  pulmonary pumps.  Intravail™ agents  are compatible  with routine  formulation  and dispensing processes for ease of scale-up and production.
They have been shown to be non-irritating  when tested at 25%  in the rabbit eye (Draize test). Bronchoalveolar lavage fluid analysis of animals receiving pulmonary insulin in conjunction  with TDM, a highly effective absorption enhancer for insulin, shows no increase whatsoever in any of the well-accepted cell injury markers including lactate dehydrogenase, alkaline phosphatases, and N- acetylglucosaminidase (Hussain and Ahsan, 2005). The oral No Observable Effect Level (NOEL) for some Intravail™ compounds is approximately 20,000 to 30,000 mg per kg of body weight,  which extrapolates to approximately 1.2 to 1.8 kg for a 60 kg person.  The World Health Organization (WHO) specified oral Allowable Daily Intake (ADI) is approximately 15,000 times the amount that  would be administered intranasally on a daily basis. Controlled intranasal studies are presently underway  and, while it is obviously not appropriate to equate oral safety with nasal safety, the essential lack of oral toxicity of these  agents in relatively high amounts is certainly very encouraging in view of the extremely small amounts required to promote transmucosal drug absorption.
Recently Chen et al. (2005) examined cell viability of human  tracheal/bronchial epithelial cell derived mucociliary tissue upon prolonged exposure to static concentrations of various alkylsaccharides. These studies showed  essentially 100% cell viability at an exposure level that  is roughly 3- times the integrated exposure expected  for the nasal cavity, assuming a T1/2 for mucocilliary clearance  of 15 minutes. This lends further support  to the mild nature of Intravail™ agents  especially in light of the fact that  in vitro test have been shown repeatedly  in human  trials to overstate  actual in vivo intranasal toxicity. For example, in an extensive review of the scientific publications on this subject, Marple et al. (2004) analysed data taken from 14 in vivo studies of one of the most widely used nasal excipients, benzalkonium chloride, in which in vitro predictions of toxicity were compared to actual in vivo experience in human  volunteers. In every study examined, and in direct contrast  to the accompanying  in vitro results within each study, analysis of the in vivo data demonstrated that  even prolonged use of topical formulations  containing BAC caused no significant damage to the nasal mucosa.
An explanation  of this disparity is presented in a recent study examining biochemical indicators of proinflammatory effects, namely myeloperoxidase,  IL-6, and Substance  P, upon in vivo exposure to BAC (Riechelmann et al., 2004). The authors  conclude that  lack of proinflammatory  effects in vivo is probably the result of neutralisation of BAC by components of normal nasal secretions (the predominant components of which are albumin and lysozyme). This should not be too surprising since this is essentially a basic
function of the nasal secretions in the mucociliary clearance process. A more extensive review and bibliography describing the lack of correlation of in vitro and in vivo results may be found in Maggio (in press).

Extending the Range of Practical Transmucosal Drug Administration Routes

The effectiveness of Intravail™ agents  for transmucosal delivery in tissues other than  nasal mucosa has been demonstrated by a number  of investigators. For example, TDM has been shown to increase pulmonary absorption of insulin by a factor of about  threefold  (Hussain et al., 2003; Figure 3). A similar two- to threefold  increase in pulmonary absorption of low molecular weight heparin using TDM has also been reported (Yang et al., 2004; Yang, Arnold and Ahsan, 2005; Figure 4). This same group demonstrated
up to a fourfold increase in intestinal absorption of low molecular weight heparin achieving maximum bioavailability of roughly 8% (Yang et al., 2004).

Conclusions

Improvements  across the board in transmucosal drug delivery technology,  comprising new routes of administration, new delivery devices, and breakthroughs
in formulation  technology  are spurring a rebirth in interest in the broader  use of peptide  drugs. The need and the opportunity are clear since peptide  drugs have potential applications across the full spectrum  of human  disease. Driven by strong patient  desire to avoid repeated injections, the commercial opportunities for transmucosally- administered, systemically acting peptide  drugs is potentially quite large. Presently, revenues  for new peptide therapeutics are predicted  to exceed US$90 billion by
2010.  As further improvements continue  to be made,  this trend is likely to accelerate.

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