spacer
home > ict > spring 2010 > on the nose
PUBLICATIONS
International Clinical Trials

On the Nose

Andrew Leary at Shandon Clinic examines the opportunities and challenges involved in intranasal drug delivery

Intranasal drug delivery has been recognised for some time as a potential alternative to the conventional oral route, particularly for systemic drugs with low oral bioavailability. There are, however, significant challenges which hamper the development of viable intranasal formulations. Advances in pharmaceutical technology have seen this area blossom in the last two decades, and it is expected that the next 10 years will see a wide variety of intranasal products come to market. Examples of agents which are already available for administration in intranasal formulations include nicotine (smoking cessation), desmopressin (diabetes insipidus), salmon calcitonin (postmenopausal osteoporosis), sumatriptan (migraine) and fentanyl (pain management).

The potential advantages of the intranasal delivery route are clear:

  • The nasal mucosa offers a large total surface area for absorption (approximately 150cm2)
  • The mucosa is richly supplied with blood vessels, allowing rapid absorption of both small molecules and some large, complex macromolecules
  • Nasal mucus is able to trap large molecules, and so function as a drug reservoir
  • Absorption takes place directly into the systemic circulation with avoidance of first-pass effect
  • There is protection from direct side effects on the gastro-intestinal system; also, absorption can be achieved even in situations of gastric dysmotility (nausea and vomiting)
  • There is a growing body of evidence to suggest that some low molecular weight substances can be delivered directly to the central nervous system by intranasal delivery, bypassing the blood-brain barrier

The key obstacle to successful intranasal delivery is the fact that many drugs have very low bioavailability via this route. This is particularly true of substances which are poorly soluble in water, as the limited volume of the nasal cavity precludes administration of more than around 100 to 150 microlitres per dose. Small lipophilic drugs are absorbed by passive diffusion, while small polar drugs are absorbed between adjacent epithelial cells through hydrophilic porous and tight junctions. Larger molecules such as peptides and proteins are absorbed by endocytosis or by specific transporters. Absorption of polar drugs is dependent on size; small molecules are fairly well absorbed, while large molecules (such as proteins) may only be absorbed by as little as one per cent.

The extent of nasal absorption of any given agent is influenced by nasal physiological factors, by the physicochemical properties of the drug concerned and by the way in which the drug has been formulated. Changes in vascular tone in the nasal mucosa (vasodilatation and vasoconstriction) and changes in mucociliary clearance (usual nasal transit time is 15 to 20 minutes) which occur with circadian rhythm and the menstrual cycle will have a bearing on bioavailability. There are a variety of metabolic enzymes in the nasal epithelium; for example, there are proteolytic enzymes which pose a major barrier to the absorption of peptide drugs. Important formulation effects include viscosity (increased viscosity usually results in increased absorption), pH (where it is important to strike a balance between ensuring the greatest quantity of non-ionised drug species and lowest possible potential for irritation of the nasal mucosa), and excipients (preferably non-irritant). Spray delivery of solutions or suspensions is preferable to drop formulations or powder sprays.

BOOSTING EFFICIENCY OF THE INTRANASAL ROUTE

Strategies to increase nasal drug absorption have included the delivery of more readily absorbed (such as lipophilic) prodrugs which readily convert to active parent drugs once in the bloodstream, and the co-administration of enzyme inhibitors, which prevent degradation of peptides prior to absorption. In addition, absorption enhancers have been widely used, as have various novel drug formulation technologies. A number of different substances have been used as absorption enhancers, including bile salts, fatty acids, and polymeric enhancers such as chitosan and cyclodextrins. These agents are thought to alter the permeability of the epithelial cell layer, perhaps by modifying the phospholipid bilayer, or by opening the tight junctions between cells. In general, they are of high molecular weight and are not absorbed themselves. Chitosan, a linear polysaccharide biopolymer derived from deacetylation of chitin (the primary component of the exoskeleton of crustaceans), also interacts with the nasal mucus layer, increasing the contact time for the drug to be transported across the membrane, and enhances the dissolution rate of low water soluble drugs. Cyclodextrins, which are cyclic oligosaccharides derived from bacterial digestion of cellulose, increase drug solubility and stability, and also interact with lipophilic components of biological membranes, changing their permeability. Mucoadhesive drug delivery systems, which may be derived from chitosan, cellulose or alginate, build on this enhanced absorption by prolonging the contact time between drug and nasal mucosa.

There has been recent interest in developing nasal formulations containing liposomes, microspheres or nanoparticles, usually with the inclusion of absorption enhancers, enzymatic inhibitors or mucoadhesive polymers. Liposomes are phospholipids vesicles composed of a lipid bilayer surrounding an aqueous core containing drugs or other substances. The drug is protected from enzymatic degradation within the liposome, which may be engineered in order to be mucoadhesive. Microspheres have a similar principle, but are usually based on mucoadhesive polymers (chitosan, alginate) rather than a lipid bilayer. Nanoparticles are solid colloidal particles with diameters ranging from one to 1,000nm; in which the drug may be dissolved, entrapped, encapsulated, adsorbed or chemically attached. Unfortunately, only the smallest nanoparticles penetrate the mucous membrane, and these are rapidly taken up by lymphoid tissue, limiting bioavailability. Nevertheless, they have potential application for the delivery of nasal vaccines.

CHALLENGES AND OPPORTUNITIES

It is possible to greatly improve the intranasal delivery of a wide variety of agents by applying the technologies outlined above. Once this has been achieved, there are other significant obstacles to overcome.

Firstly, many studies have shown an unacceptably high variability in absorption of drugs by this route, both between different subjects and within the same subject from dose to dose. This is of less relevance for drugs with a wide therapeutic index, but is unacceptable for drugs such as insulin, opiates and sedatives, where predictable delivery is very important. It is hoped that improvements in drug delivery technology will allow this obstacle to be overcome in many cases.

Secondly, a number of nasal drug development programmes have been halted by poor tolerability. Intra-nasal formulations may be associated with some transient adverse symptoms at the time of dosing (discomfort, runny nose, sneezing), but these are generally tolerated, particularly where the drug concerned is otherwise usually given as an injection. What is less acceptable, however, is chronic local irritation as a consequence of long-term use. This may be painful, may alter the bioavailability of the administered drug, and may inhibit the capacity of the nose to act as a filter for inhaled pathogens. It may increase the likelihood of upper respiratory infections and of epistaxis (nosebleeds). Successful companies will be those who can formulate their intranasal products in such a way that bioavailability is fairly predictable and the potential for local irritation is low. The potential applications of intranasal delivery are wide. This route may be used for the emergency administration of potentially life-saving agents outside the hospital or surgery setting. Examples include naloxone (opiate overdose), benzodiazepines (seizure disorder) and glucagons (hypoglycaemia). A number of studies have looked at the nasal route as a means of vaccine delivery. The nasal cavity is well-supplied with lymphoid tissue, and vaccine studies have looked at the administration of upper respiratory viruses (such as influenza, parainfluenza or respiratory syncitial virus) and other viruses which attack mucosal sites (such as HIV or Hepatitis B). Finally, over the last few years the intranasal route has emerged as a promising approach for the delivery of drugs directly to the brain. While the mechanisms are still unclear, research in a number of animal models suggests that delivery to the CNS is via the olfactory neuroepithelium, and may involve paracellular, transcellular or direct neuronal transport. This route is of particular interest to those searching for a treatment for Alzheimer’s disease, and a number of other conditions. So far, however, there is little evidence from humans to suggest that intranasal delivery is able to increase brain exposure when compared with the more conventional routes.

CONCLUSION

Intranasal administration provides a viable alternative to the oral or subcutaneous routes for the systemic delivery of a variety of different candidate drugs. There are challenges posed by this approach, but many of these are being overcome by improvements in pharmaceutical technology. There are a number of intranasal products already on the market; these are likely to be joined by many new formulations in the coming decade. The potential of this route for the administration of vaccines and for the direct delivery of drug to the brain is an exciting recent development.

References

  1. Pires A, Fortuna A, Alves G and Falcão A, Intranasal Drug Delivery: How, Why and What for?, J Pharm Pharmaceut Sci 12 (3): pp288-311, 2009
  2. Constantino HR, Illum L, Brandt G, Johnson PH and Quay SC, Intranasal delivery: Physicochemical and therapeutic aspects, Int J Pharmaceut 337: pp1-24, 2007

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Andrew Leary qualified as a doctor in Cape Town, South Africa. He followed internship with specialisation (Ireland and the UK) as a general physician and clinical pharmacologist; at the same time he obtained an MD based on original research in the area of hypertension. He has additional qualifications in pharmaceutical medicine, sports medicine and medicine of the elderly. He has been Director of Clinical Pharmacology at Shandon Clinic, a CRO specialising in bioavailability, bioequivalence and proof-of-concept pharmacokinetic studies, since 2000.
spacer
Andrew Leary
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

PPMA Group Industry Awards 2019

PPMA Group is today issuing a ‘Final Call for Entries’ to the 2019 PPMA Group Industry Awards. All companies within the packaging and processing sector are invited to submit their FREE submission by the deadline of 17 July 2019.
More info >>

White Papers

Modular Feeding Systems for Prefilled Syringes and Injection Devices

Dividella

The pre-filled syringe and injection device is an increasingly attractive presentation for both new and established parenteral pharmaceuticals. We will explore how innovative carton packaging solutions can enhance this presentation whilst meeting the stringent requirements of product protection.
More info >>

 
Industry Events

CPhI & P-MEC India

26-28 November 2019, India Expo Centre, Greater Noida, Delhi NCR, India

As the pharma industry looks increasingly towards India for high quality, low cost pharma solutions, CPhI & P-MEC India is the ideal event for companies wanting to pick up on the latest trends and innovations the market has to offer. At CPhI & P-MEC India, you will meet the movers and shakers from India's pharma machinery, technology and ingredients industries, giving you a competitive advantage that will help grow your business.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement