International Journal of Health and Pharmaceutical Sciences

ISSN 2278 0564 Review Article

NASAL DRUG DELIVERY SYSTEM: FACTOR AFFECTING, APPLICATIONS AND RECENT DEVELOPMENTS
Patel Nirav S. 1*, Solanki Priyen R.2, Vaja Tushar S.3, Shah Dixit K.4 1,2,3,4 Department of Pharmaceutical Sciences, Sardar Patel University, Vallabh Vidyanagar, Anand, Gujarat-388 120 *nirav.patel99@yahoo.com ABSTRACT Nasal delivery is a promising drug delivery option where common drug administration (e.g., intravenous, intramuscular, or oral) are inapplicable. In more recent years many drugs have been shown to achieve a better systemic bioavailability by self-medication through the nasal route than by oral administration. Pharmaceutical industries are looking at nasal drug delivery options as a viable alternative to traditional routes of administration for systemic drugs. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cutoff at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. The physiology of the nose presents obstacles, but offers a promising route for non-invasive systemic delivery of numerous therapies and debatably drug delivery route to the brain. Intranasal micro-emulsions, gels and microspheres have gained increased interest in recent years as a delivery system for protein and peptides through nasal route. Since building a more efficient nasal drug delivery device requires not only better device design but a far more versatile technology platform; one that delivers optimal nasal deposition, with formulation flexibility to work successfully with the many variables of the formulation itself. Thus present review focuses on innovations in nasal drug delivery devices. KEY WORDS Nasal Drug Delivery, transportation routes, Mucociliary clearance, Delivery devices. INTRODUCTION Oral drug delivery is the most desirable route for drug administration whenever systemic effects are intended. Therefore, it is not surprising that the prediction of human oral bioavailability of new drug candidates is currently targeted from the earliest stages of drug discovery and development programs. [1,2] However, although the oral route remains the most popular for systemic drug administration, low oral bioavailability of some compounds has prompted the search of more effective routes for their systemic delivery. [3] In ancient times the Indian Ayurvedic system of medicines used nasal route for administration of drug and the process is called as Nasya. It has been used for local effects extensively in decongestant and local activity. But, in recent times nasal drug delivery is being considered as a preferred route of drug delivery for systemic bioavailability. Advances in biotechnology have made available a large number of protein and peptide drug for the treatment of a variety of diseases. These drugs are

unsuitable for oral administration because they are significantly degraded in the gastrointestinal tract or considerably metabolized by first pass effect in the liver. Even the parenteral route is inconvenient for long term therapy. Nasal route has also been considered for the administration of vaccines. The interest in intranasal route for therapeutic purposes arises from the anatomical, physiological and histological characteristics of the nasal cavity, which provides rapid systemic drug absorption and quick onset of action. BENEFITS AND LIMITATION OF NASAL DRUG DELIVERY [4, 5, 6, 7] Benefits: Drugs which cannot be absorbed orally may be delivered to the systemic circulation through nasal drug delivery system.

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Better nasal bioavailability for smaller drug molecules. Faster delivery to the blood stream and higher blood levels compared with oral medications. Can be easily administered to the unconscious patients A Highly vascularized sub-epithelial layer allowing for rapid and direct absorption into the systemic circulation, avoiding first-pass hepatic metabolism. Improve patient compliance and comfort compared with intravenous administration. For CNS drugs, better site for rapid onset of action; E.g. Inhalation anesthesia, morphine, etc.

The bioavailability of larger drug molecules can be improved by means of absorption enhancer or other approach. Limitation of Nasal Delivery: Surface area for absorption is less when compared to gastrointestinal tract Absorption enhancers used to improve nasal drug delivery system may have histological toxicity which is not yet clearly established. Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation. There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form.

ANATOMY AND PHYSIOLOGY OF NASAL CAVITY: [8,9]

The nasal cavity is divided into two symmetrical halves by the nasal septum, a central partition of bone and cartilage; each side opens at the face via the nostrils and connects with the mouth at the naso pharynx. The nasal vestibule, the respiratory region and the olfactory region are the three main regions of the nasal cavity. The lateral walls of the nasal cavity includes a folded structure which enlarges the surface area in the nose to about 150cm2 .This folded structure includes three turbinates : the superior, the median and the inferior. In the main nasal airway, the passages are narrow, normally only 1-3mm wide, and this narrows structure enables the nose to carry out its main functions. During inspiration, the air comes into close contact

with the nasal mucosa and particles such as dust and bacteria are trapped in the mucous. Additionally, the inhaled air is warmed and moistened as it passes over the mucosa; and the high blood supply in the nasal epithelium. The sub mucosal zone of the nasal mucosa directly to the systemic circulation, thus avoiding first pass metabolism Another, perhaps more familiar, major function of the nose is olfactory region is located on the roof of the nasal cavity. The nasal cavity is covered with a mucous membrane which can be divided into non-olfactory and olfactory epithelium areas. The non-olfactory area includes the nasal vestibule, which is lined with skin-like cells, and respiratory region, which has an atypical airways epithelium.

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NEED FOR DEVELOPMENT OF NASAL DELIVERY: Nasal drug delivery is a useful delivery method for drugs that are active in low doses and show no or minimal oral bioavailability. The nasal route circumvents hepatic first pass elimination associated with the oral delivery: it is easily accessible and suitable for self-medication. Currently, two classes of nasally delivered therapeutics are on the market. The first one comprises low molecular weight and hydrophobic drugs for the treatment of the nasal mucosa and sinus, including decongestants, topical steroids, and antibiotics. The second class encompasses a few drugs, which have sufficient nasal absorption for displaying systemic effects. Important candidates are the compounds, generally administered by injection and hardly absorbed after oral administration, due to their instability in gastrointestinal tract, poor absorption properties, and their rapid and extensive biotransformation. [10, 11] MECHANISM OF DRUG ABSORPTION:
14] [12, 13,

supply means that drugs absorbed via the nasal route have a rapid onset of action, which can be exploited for therapeutic gain. Contact time and mucociliary clearance [17, 18, 19] The length of time the drug is in contact with the absorbing tissue will influence how much drug crosses the mucosa. In the nasal cavity this is influenced by the rate at which the drug is cleared from the absorption site by mucociliary clearance and by metabolism. While the mucociliary clearance of deposited particles is advantageous if the particles are likely to be hazardous, the clearance of a deposited drug is clearly not beneficial if it prevents absorption. The site of deposition in the nasal cavity profoundly affects the rate of mucociliary clearance of a drug moiety: Particles deposited on ciliated regions (for example, the turbinates) of the mucosa are immediately available for clearance. Particles deposited on non-ciliated regions (for example, the anterior of the nasal cavity) will move more slowly (such particles will land on mucus which is being dragged through the cavity from ciliated areas). Particles which deposit on the nasopharyngeal regions will be swallowed immediately and are therefore not available for nasal absorption. Disease [20] The rate of mucociliary clearance can be affected by the pathophysiological condition of the nasal cavity and this will also affect the rate of clearance of administered drug. Such conditions include rhinitis, the common cold, sinusitis, asthma, nasal polyposis, Sjogrens and Kartageners syndromes. In addition, environmental factors such as humidity, temperature and pollution can also affect the rate of nasal clearance. Enzymatic degradation [21, 22, 23] The nasal secretions possess a wide range of enzymes and enzymes are also present in the epithelium of the nasal cavity. Low bioavailability of some nasally administered peptides results from their enzymatic degradation in the nasal cavity. Some examples of enzyme which may play role in enzymatic degradation of drugs are carboxyl esterase, aldehyde dehydrogenases, epoxide hydrolases, glutathione Stransferases and Cytochrome P 450 isoenzymes have been found in nasal epithelial cells. The proteolytic enzymes (amino peptidases and proteases) were also found and they play an important role in degradation of calcitonin and insulin.

Several mechanisms have been proposed but the following two mechanisms have been considered predominantly. A. Paracellular route: Paracellular route involves an aqueous of transport. It is slow and passive. In this route there is an inverse loglog correlation between the molecular weight of watersoluble compounds and intranasal absorption. Drugs with a molecular weight greater than 1000 Daltons shows poor bioavailability. Insulin, mannitol and propranolol were absorbed through this mechanism. B. Transcellular route: Transcellular route includes transport of drug through a lipoidal route. This route is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Cell membranes may be crossed by drugs by an active transport route via carrier-mediated means or transport through the opening of tight junctions. For example, Chitosan, a natural biopolymer from shellfish, opens tight junctions between epithelial cells to facilitate drug transport. FACTORS INFLUENCING NASAL DRUG ABSORPTION [15] The following factors affect the drug absorption 1. Nasal physiological factors Blood supply [16] The nasal mucosa is highly vascular. This property facilitates its physiological role in heat exchange and also potentially, drug absorption. The rich blood

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Immunological clearance [15] The immune system functions to recognize and eliminate foreign materials. Antibodies are secreted in the nasal cavity and may be found in high concentrations in the mucus layer where they are able to neutralize antigens presented to the nasal mucosa. Foreign proteins delivered to the body are capable of eliciting an immune response and indeed antibodies have been detected in nasal secretions in response to the intranasal administration of insulin. Clearly this situation is undesirable since the therapeutic molecule will undergo degradation and the patient is likely to suffer with symptoms associated with allergic diseases such as hayfever. Transporters and efflux systems [24, 25, 26] The absorption of drugs into systemic circulation and CNS through nasal route is of great interest. Multidrug resistance transporters have been identified which may be involved in the transportation of hydrophobic and amphiphilic drugs. The apical area of ciliated epithelial cells and sub mucosal vessels of the human olfactory region contain Pgp is an efflux transporter which plays an important role in avoiding the influx of drugs from nasal membrane. 2. Physicochemical properties of drugs Some physicochemical properties of drugs (molecular weight, lipophilicity, stability and solubility) can influence nasal absorption. Molecular weight [27, 28, 29, 30, 31] The molecular weight of the drug influence absorption of the drug through the nasal route. The lipophilic drugs have direct relationship between the MW and drug permeation whereas water soluble compounds depict an inverse relationship. The rate of permeation is highly sensitive to molecular size for compounds with MW 300 Daltons. Lipophilic-hydrophilic balance [32, 33, 34] Lipophilic drugs such as propranolol, progesterone and fentanyl are well absorbed from the nasal cavity, exhibiting pharmacokinetic profiles similar to those obtained after intravenous administration. These drugs are absorbed quickly and efficiently across the nasal membrane via Transcellular mechanisms. Whenever lipophilicity is too high, the drug permeation through the wall may be reduced because drug does not dissolve easily in the aqueous environment of nasal cavity. Stability [35, 36] Biological, chemical and physical drug stability studies are a major consideration in all process during the development of new drug formulations. The biological stability of nasally administered drugs may reduce due to the metabolism of drugs by defensive

enzymatic mechanisms by nasal cavity. To overcome this difficulty a variety of strategies may be followed, mainly through the use of prodrugs and enzymatic inhibitors. Solubility [15, 34, 35] For drug absorption, drug dissolution is a prerequisite because molecularly disperse form of a drug may cross the bio-membranes. Therefore the drug must be dissolved in the nasal cavity fluid before absorption. Drug allowed enough contact with the nasal mucosa which may show slow absorption. Drugs with poorly soluble in water may require high doses hence can cause a problem. The problem can be overcome by enhancing drug solubility using various techniques. 3. Formulation factors Viscosity [37, 38, 39] Formulation with higher viscosity has a better contact time thus increases the absorption. At the same time, high viscosity enhanced the permeability of drugs. This has been observed during nasal delivery of insulin, acyclovir and Metoprolol. pH [39] The pKa of drug and pH at the absorption site plays important role in absorption of drug through nasal route. Thus the stability can achieve by proper selection of pH of formulation. However, the pH of formulation should be near on human nasal mucosa (5.06.5) to prevent the sneezing. Pharmaceutical form [40] Nasal drops are the simplest and the most convenient nasal pharmaceutical dosage form, but the exact amount of drug delivered is not easily quantified and often results in overdose. Moreover, rapid nasal drainage can occur when using this dosage form. Instead of powder sprays solution and suspension sprays are preferred because powder spray may cause nasal mucosa irritation. Nowadays nasal gel has been developed for accurate drug delivery. This increases the nasal absorption by enhancing the drug residence time and diminishing MCC. Pharmaceutical excipients [15, 35] In nasal formulations pharmaceutical excipients are selected accordingly to their functions. The most commonly used excipients are Solubilizers, buffer components, antioxidants, preservatives, humectants, and gelling agents or viscosity modifiers. APPLICATION OF NASAL DRUG DELIVERY SYSTEM: Local delivery [41] For the natural treatment of topical nasal disorders the drug is administered through nasal route. Among

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the most common examples are antihistamines and corticosteroids for rhino sinusitis, and nasal decongestants for cold symptoms. In fact, relatively low doses are effective when administered through nasal route with less systemic toxic effects. Systemic delivery [42, 43, 44, 45, 46] The intranasal administration of drugs is an effective way for systemic availability of drugs as compared to oral and intravascular routes. Actually, it seems to present fast and extended drug absorption, and it has been supported by many studies planned to compare intranasal drug delivery against oral and parenteral administration. Examples include analgesics (morphine), cardiovascular drugs as propranolol and carvedilol, hormones such as levonorgestrel, progesterone and insulin, antiinflammatory agents as indomethacin and ketorolac, and antiviral drugs (acyclovir). Some examples which are available in the market include zolmitriptan and sumatriptan for the treatment of migraine and cluster headaches. Nasal vaccines [47, 48, 49] Nasal mucosa is the first site of contact with inhaled antigens and therefore, its use for vaccination, especially against respiratory infections, has been extensively evaluated. In fact, nasal vaccination is a promising alternative to the classic parenteral route, because it is able to enhance the systemic levels of specific immunoglobulin G and nasal secretary immunoglobulin A. Examples of the human efficacy of intranasal vaccines include those against influenza A and B virus, proteosomainfluenza, adenovirusvectored influenza, group B meningococcal native, attenuated respiratory syncytial virus and parainfluenza 3 virus.

CNS delivery through nasal route [50] Intranasal route has promising approaches for delivery of drugs to the brain. The delivery of drugs to the CNS from the nasal route may occur via olfactory neuroepithelium. The transport via trigeminal nerve system from the nasal cavity to CNS has also been described. Drug delivery through nasal route into CNS has been reported for Alzheimer. RECENT NASAL DRUG DELIVERY DEVICES AND TECHNIQUES: Developing a more efficient nasal drug delivery device requires not only better device design but a far more versatile technology platform; one that delivers optimal nasal deposition, with formulation flexibility to work successfully with the many variables of the formulation itself. Drug formulation and delivery devices can be mutually adapted and matched for optimal characteristics to reach the desired therapeutic target. 1. DirectHalerTM Technology : [51] Direct-Haler A/S has invented and developed a novel nasal delivery device and nasal delivery principle. The innovation takes advantage of the patients anatomy to improve nasal delivery effectiveness and convenience. The integrated nasal device and delivery method enables nasal delivery of very fine particles, without the risk of pulmonary deposition. The DirectHaler Nasal device has successfully been used in clinical trials, and has confirmed patient acceptability. The single-use, disposable device is for both mono and bi-dose delivery, in a pre-metered, prefilled dose format. The device offers effective, accurate, repeatable and hygienic dosing, and is intuitively easy-to-use

2.

Bi-Directional Nasal Delivery : [52-54]

Bi-directional nasal delivery devices offer a unique solution for nasal delivery of drugs and

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vaccines. Bidirectional delivery devices improve distribution to the nasal mucosa in general and can target the sinus ostia and organized nasal lymphatic tissues, while at the same time preventing lung deposition. Breath actuation and controlled particle release secure a reliable, efficient and safe delivery of vaccines to the target sites within the nasal passages with maximum patient comfort. Breath Powered, Bidirectional Delivery consists of a mouthpiece and a sealing nozzle; Blowing into the device cause the soft palate to close, isolating the nasal cavity As the patient continues to blow the device is triggered, releasing drug into the air flow and carrying it deep into the nasal cavity At the back of the nose, the air flow passes through a communication between the nasal passages and exits

through the other nostril in the opposite direction By permitting delivery of nasal formulation to the target sites in the nose, benefits can be gained from increased absorption and lower dose. Any dispersion technology for liquid and powder particles can be combined with the bidirectional nasal delivery concept, adding to its versatility Deposition studies of bi-directional delivery using gamma scintigraphy have shown significantly improved deposition patterns compared with traditional nasal spray pumps. Phase I nasal vaccination trials have shown a several fold increase in the immune response as compared with vaccine delivery by traditional spray devices. Patient acceptance and compliance for the bi-directional device are excellent thanks to the two-point device fixation and breathe actuation. Bidirectional delivery can be useful in vaccine delivery, topical and systemic nose to brain delivery.

3.

ChiSys Nasal Delivery West Drug Delivery of Lionville, Pa (US) and Nottingham, UK, have developed ChiSys, a patent protected versatile transmucosal delivery system based on the bioadhesive excipient chitosan. Chitosan is an interesting and versatile molecule, as it has been used extensively in a number of field ranging from woundhealing, slimming aid and cosmetics to a wastewater treatment flocculent. Recently, chitosan has been the subject of interest in a number of pharmaceutical and drug delivery studies, as evidenced by its many appearances in literature. West believes chitosan works well as a

bioadhesive excipient; it is theorised that its positively charged molecules interact with the negatively charged sialic acid residues present in mucus, thereby retaining drug compound at the mucosal surface for an extended period of time. 4. Controlled Particle Dispersion(CPD) [55] Controlled Particle Dispersion (CPD) is a technology platform that pharmaceutical companies can use to deliver most compounds regardless of characteristics or target conditions. Whether the applications are systemic or topical, solutions or suspensions, CPD meets the demands of today and tomorrows full nasal

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delivery product line. CPD offers a vast improvement in efficacy and performance while presenting design flexibility for maximum compliance. Rather than build a single device, Kurve Technology developed CPD a comprehensive nasal drug delivery technology platform. Using new principals such as vortical flow, CPD effectively disrupts inherent nasal cavity airflows to deliver compounds to the entire nasal cavity, the olfactory region and the paranasal sinuses. CPD optimizes droplet size and trajectory to saturate the nasal cavity, lengthens compound residence time, and minimizes deposition to the lungs and stomach. This leads to more effective and efficient treatments than delivery via traditional nasal spray bottles that deliver compounds only as far as the anterior portion of the nasal cavity. CPDs adjustable variables include: Droplet size variability from 3 to 50 m Atomization rate

5.

Delivery of solutions, suspensions and dry powder Small and large molecules, Proteins and peptides Preservative-free, unit-dose ampoules Targeted deposition including to the paranasal sinuses and the olfactory region Variable medication volumes in the device and in the nasal cavity Wide viscosity range

MAD Nasal-Mucosal Atomizer: MAD Nasal-Mucosal Atomization Device delivers intranasal medication in a fine mist which enhances absorption and improves bioavailability for fast and effective drug delivery. By eliminating the need to establish an IV, delivery is rapid which is useful for treating various emergencies, ENT, anesthesia and pediatric conditions. [56]

Features and Benefits of MAD No needle - No shot Safe and Painless Medications absorb directly into the brain via olfactory mucosa Rapidly Effective Exact dosing, exact volume, Atomizes in any position Controlled administration Drug administration is quick, No sterile technique is required Minimal Resource Utilization

6.

NasoNeb Nasal Nebulizer: [57] A new double barrel atomization device from ASL Pharmacy offers hope for chronic sinusitis patients. The NasoNeb Nasal Nebulizer may be used for the administration of compounded tobramycin, clarithromycin, mupirocin, meropenem and other antibiotics, anti-fungals, mucolytics and corticosteroids.

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FUTURE PROSPECTIVE OF NASAL DRUG DELIVERY: Nasal Drug delivery is an attractive route of administration for some systemically acting drugs with poor oral bioavailability, and has advantages in terms of improved patient acceptibilityand compliance compared with parentral adminidtration. New technologies include improved nasal formulations; site specific release, carrier-based systems, advanced spray formulations, atomized mist technology, preservative free system and integrated formulation development are strictly needed for success of drug delivery through nasal mucosa.

For success of nasal drug delivery Researchers may focus on: Development of delivery technologies to increase efficacy and reduce side effects by target delivery with variations potential of the drug Development of new technologies to deliver macromolecules with utilization of biotechnology and high technology Development of integrated/improved nasal formulations Development of integrated device development for successful delivery of therapeutics.

Delivery Means and Devices for Intranasal Administration of Drugs Drugs Adrenal corticosteroids Jelly Antihistaminics Buserelin Formulations Calcitonin Cocaine Dopamine Estradiol- 17 Gentaminin Hyoscine(scopolamine Insulin Isosorbide dinitrate Naferelin acetate Nitroglycerin Oxytocin Progesterone Vaccines Vitamin B12 Xylometazoline Delivery Devices Nasal spray, nasal drops, nasal insufflators, submucosal injections into the anterior tip of inferior turbine, metered dose aerosol Nasal spray, nasal drops Nasal spray, ointment Nose drops Nasal spray, nose drops, cotton pledget, gauge packtail, insufflators, rubbing with cocaine mud Nasal spray Nasal spray, nasal drops, microsyringe Nasal spray Nasal spray, nasal drops Metered pump sprayer, metered dose aerosolized spray, fixed volume aerosol spray, nasal spray, nasal drops, cotton pledget Nasal spray(iso mack spray Nasal spray, tobacco snuff, injected into dogs frontal sinus Metered dose spray. Instilled through Teflon i.v. Catheter Nasal spray, nasal drops, cotton pleadget, aerosol activated spray, rhynyl (a plastic application tube), graded polyethylene tube,direct instillation by tuberculin syringe and 25G needle Nasal spray by an atomizer connected to a respiratory pump, nasal spray by gas atomizer, nasal solution administered by micropipette Inhalation aerosol, nasal spray, nasal aerosol spray, nebulizer aerosol, nasal drops Nose drops, insufflators Nasal spray, nose drops

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