Nasal drug delivery has always been a key development area for both pharmaceutical and device development companies, presenting many opportunities and challenges. The physiology of the nose presents obstacles, but offers a promising route for local as well as systemic delivery of various therapeutic and debatably a drug delivery route to the brain. To assess the therapeutic viability of intranasal drug delivery several approaches should be considered, attending, specifically, to the nature of disease condition (acute or chronic) and intended effects (local, systemic or central nervous system (CNS)) of drug treatment. Drugs formulated as liquids, suspensions, or powders can be administered to the nasal cavity (for local action), can transport across the epithelial tissue to enter the blood (for systemic action), and for drugs that cross the blood-brain barrier (BBB), can subsequently enter the brain (brain targeting). Direct delivery of intranasal drugs to the brain has been proposed, but is not universally established.
Drug products available in the market
A range of nasally delivered drug products has been introduced in world market by leading pharmaceutical players in nasal drug delivery during recent decades. Locally-acting drugs, including therapies for allergic rhinitis, nasal congestion and infections, account for over 75 per cent of the current nasal drug delivery market, which is estimated to be worth US $3,000 million per annum with an average growth rate of approximately 10 per cent per year. Nasal formulations commercially available in the market, for local delivery are azelastine (Meda Pharmaceuticals), beclomethasone (GlaxoSmithKline), budesonide (AstraZeneca), levocabastine (Jansen-Cilag), mometasone (Schering-Plough), olapatadine (Alcon Laboratories), sodium cromoglicate, triamcinolone acetonide (Sanofi-Aventis), for seasonal and perennial rhinosinusitis, mupirocin (GlaxoSmithKline) for eradication of nasal staphylococci and oxymetazoline HCl (Schering-Plough HealthCare Products) in nasal congestion.
The drugs marketed for systemic delivery are estradiol (Servier Laboratories) in hormone replacement therapy, desmopressin (Ferring Pharmaceuticals) for control of dehydration in diabetes insipidus, nicotine (Pfizer) for smoking cessation, cyanocobalamin (Strativa Pharmaceuticals) in treatment of vitamin B12 deficiency, oxytocin (Novartis) for lactation stimulation, buserelin (Aventis) in treatment of prostate cancer, salmon calcitonin (Novartis) in treatment of postmenopausal osteoporosis, all peptides normally only administered by injection because of low membrane permeability and susceptibility to degradation by enzymes in the gastrointestinal tract, sumatriptan (GlaxoSmithKline), zolmitriptan (AstraZeneca), ergotamine (Novartis), butorphanol (Bristol-Myers Squibb) for treatment of migraine, where a rapid onset of action is beneficial; and nafarelin (Roche Laboratories) in management of endometriosis. The market for nasal administration of systemically acting drugs is estimated to be growing at around 33 per cent per annum, and 16 of the 20 major pharmaceutical companies have active nasal drug delivery programmes. It is remarkable that more than half of the systemically acting products were approved during the 1990s.
Nastech, Britannia Pharmaceuticals, Intranasal Technologies, Bentley Pharmaceuticals and West Pharmaceutical Services are actively developing novel nasal formulations for conventional generic drugs (e.g. apomorphine, triptans, morphine, midazolam, fentanyl, non-steroid anti-inflammatory drugs), as well as for peptides and proteins (e.g. leuprolide, parathyroid hormone, insulin, interferon) in situations where the nasal route would be beneficial for the therapeutic efficacy of the drug. Furthermore, the nasal cavity is being explored by vaccine companies like MedImmune Inc., Heska, Addison Biological Laboratory, Berna Biotech, Intervet, ID Biomedical, West PS, Chiron, and DelSite Biotehmologicals for vaccination (e. g. live attenuated influenza vaccine (MedImmune Inc) for flu prevention).
The potential size of the intranasal delivery market for a given drug will depend not only on the clinical efficacy of the therapy, but also on the profile of the patients involved, and the acceptability of the dosing regimens and administration methods currently in use. The benefits of nasal delivery must be able to prove their worth against a range of other delivery methods.
Formulations for intranasal delivery
Intranasal delivery devices; Droppers liquid dosage forms; Instillation catheters; Unit dos containers; Squeeze bottles; Pump spray; Compressed air nebulizer; Metered dose inhalers; Pressurized metered dose inhalers; Insufflators; Airless preservative free spray Solution: Suspension; Emulsion; Microemulsion; Nanoemulsion; (As nasal drops, nasal spray etc.)
Semisolid dosage forms: Gels; Ointments
Solid dosage forms: Microspheres; Nanoparticles; Powders
Nose to brain
The central nervous system (CNS) disorders remain the world's leading cause of disability and its economic impact is huge. It has been estimated that in the 21st century the costs associated with CNS disorders are an order of magnitude more than those associated with cancer. Large patient counts and huge economic impact make the CNS drug market potential and lucrative, although risky. Treatment of CNS disorder is the greatest challenge because of a variety of formidable obstacles in effective drug delivery and maintaining therapeutic concentration in the brain. The clinical failure of much potentially effective therapeutics for CNS disorders is often not due to a lack of drug potency but rather to shortcomings in the method by which the drug is delivered. The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCF) are the major bottleneck in drug delivery to the brain. The drugs used against central nervous system diseases should reach the brain via the BBB/BCF which restricts the passage of hydrophilic and large lipophillic molecules to the brain.
Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the BBB. Essentially 100 per cent of large-molecule drugs and greater than 98 per cent of small molecule drugs do not cross the BBB. Therapeutics can be introduced directly into the CNS by intracerebroventricular or intraparenchymal injections (glycopeptides and aminoglycoside antibiotics for meningitis), intracranial injection, intrathecal injection (beclofan for spasiticity), and surgical implants; however, for multiple dosing regimens these delivery methods are invasive, risky, and expensive techniques requiring surgical expertise. Nasal delivery has come to the forefront as an alternative to invasive delivery methods to bypass the BBB and rapidly target therapeutics directly to the CNS. There is considerable interest in exploring nose for targeting drugs to the brain in the treatment of various CNS disorders. The olfactory region located in the upper remote parts of the nasal passages offers the potential for certain compounds to circumvent the BBB and enter into the brain. Nasal delivery provides a cost-effective and user-friendly alternative to injection. Recent development have been highlighted the possibility of exploring the nose for direct transport of drugs to brain in man. Evidence that nose to brain transport is also taking place in man is steadily accumulating in various reports and research papers. Drug delivery into CNS through intranasal route has been reported either in humans or animal models of Alzheimer's disease, brain tumours, epilepsy, pain, schizophrenia, and sleep disorders. These studies have suggested great potential of intranasal drug delivery for treating various central nervous system diseases.
Nasal delivery
The nasal delivery is getting explored for delivering the non-peptide small and macromolecules and neuropeptides bypassing the BBB, prevent local toxicities and achieve rapid, improved, and prolonged central nervous system / brain drug delivery. However, it is important to consider not only the net delivery of the drug to the CNS, but also the ability of the drug to reach the relevant target site within the central nervous system. A precondition to a successful development of nose to brain drug delivery system is to administer the drug to the olfactory region and retain it there for prolonged time through suitable devices, techniques and formulations. Hence, the future developments will be towards achieving the maximum therapeutic benefit by improving these areas of research. More suitable devices are getting developed to maximize the delivery of formulation to olfactory region, and techniques to maximize transmucosal transport. However, it was also stated that intranasal route presents several limitations which must be overcome to develop a successful nasal medicine. Physiological conditions, physicochemical properties of drugs and formulations are the most important factors determining nasal drug absorption. It is also important to note that the nasal passages vary significantly in both shape and dimensions, not only between individuals but also at different points in time for a given individual. Overcoming this variability is one of the critical issues in successful delivery device design.
Several claims have been made in favour of developing nasal formulations containing liposomes, microspheres, microemulsions, nanoemulsions, nenogels, mucoadhesive powders and nanoparticles for intranasal drug delivery. These systems can include, besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and mucoadhesive polymers in order to improve the stability, membrane penetration and retention time in nasal cavity. In fact, it is not clear if those formulations increase drug absorption by transporting encapsulated drug across the membrane or just because they enhance the nasal retention time and stability of the drug. However, their use is in widespread growth and the results have been very promising.
Future need
At present, the required drugs are usually either given by injection, have a not totally appropriate plasma profile or display unwanted pharmacological effects due to inappropriate dosing regiments. In future, we should expect to see a range of novel nasal products reaching the market. It is envisaged that these products will be in the first instance primarily comprise products for crisis treatment such as treatment of acute pain, panic attacks, sleep induction, erectile dysfunction, nausea, heart attacks, Parkinson's disease, etc. Further, in the future we should also see improved nasal products for treatment of long term illnesses such as diabetes, growth deficiency, osteoporosis, endometriosis, fertility treatment. In the area of vaccines the future should also see a range of novel nasal vaccines introduced to include DNA-based vaccines especially for vaccination against respiratory diseases. Finally, it will be interesting to follow the developments in the area of nose to brain delivery and to ascertain whether it will prove possible to control and enhance the use of the route of delivery for treatment of diseases where rapidly achieved and high concentrations of drug in the brain are essential for an efficient therapeutic response. The era of nasal drug delivery is growing. Intranasal delivery of drugs will demand increasingly sophisticated delivery devices to ensure accurate and repeatable dosing. Thus, new efforts are needed to make this route of delivery more efficient and popular.
(The authors are with A. R. College of Pharmacy & G. H. Patel Institute of Pharmacy, Vallabh Vidyanagar - 388 120)