STRATEGIES AND PROSPECTS OF NASAL DRUG DELIVERY SYSTEMS

STRATEGIES AND PROSPECTS OF NASAL DRUG DELIVERY SYSTEMS

Gannu Praveen Kumar*¹, S. Kiran ²

Department of Pharmaceutics, St. Peters Institute of Pharmaceutical Sciences ¹, 2-4-1211, Vidhyanagar Hanamkonda, Warangal – 506001, Andhra Pradesh, India

Talla Padmavathi College of Pharmacy ², Urus, Kareemabad, Warangal, Andhra Pradesh, India

ABSTRACT:The recent advancement of nasal drug delivery systems has increased enormously and is gaining significant importance. Intranasal therapy has been an accepted form of treatment in the Ayurvedic system of Indian Medicine. The non-invasive delivery of nasal drug delivery systems made to exploit for the development of successful treatment. The advantages, disadvantages, mechanism of action and application of nasal drug delivery system in local delivery, systematic delivery, nasal vaccines and CNS delivery are explained lucidly. The relevant aspects of biological, physicochemical and pharmaceutical factors of nasal cavity that must be considered during the process of discovery and development of new drugs for nasal delivery as well as in their incorporation into appropriate nasal pharmaceutical formulations are also discussed. Nasal route is more suitable for those drugs which cannot be administered orally due to gastric degradation or hepatic first pass metabolism of the drug. Intranasal drug delivery is found much promising route for administration of peptides and protein drugs. Much has been investigated and much more are to be investigated for the recent advancement of nasal drug delivery systems.

INTRODUCTION: Nasal mucosa has been considered as a potential administration route to achieve faster and higher level of drug absorption because it is permeable to more compounds than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH of the nasal mucus and less dilution by gastrointestinal contents ¹.

In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration. Nasal therapy is the recognized form of treatment in the Ayurvedic systems of Indian medicine, and also called as NASAYA KARMA ². Nasal drug delivery which is practiced since years, has been given a new lease of life.

It is a useful delivery method for drugs that are active in low doses and show no minimal oral bioavailability such as proteins and peptides. One of the reasons for low degree of absorption of peptides and proteins via the nasal route is rapid movement away from the absorption site in the nasal cavity due to the mucociliary clearance mechanism.

The nasal route circumvents hepatic first pass elimination associated with the oral delivery. It is easily accessible and suitable for self-medication. During the past several decades, the feasibility of drug delivery via the nasal route has received increasing attention from pharmaceutical scientists and clinicians.

Drug candidates ranging from small metal ions to large macromolecular proteins have been tested in various animal models. It has been documented that nasal administration of certain hormones and steroids results in more complete absorption ^{3, 4}. This indicates the potential value of the nasal route for administration of systemic medications as well as utilization of this route for local effects. For many years, drugs have been administered nasally for both topical and systemic action.

Topical administration includes the treatment of congestion, rhinitis, sinusitis and related allergic or chronic conditions and has resulted in a variety of different medications including corticoids, antihistamines, anticholinergic and vasoconstrictors. In recent years, increasing investigations of the nasal route have focused especially on nasal application for systemic drug delivery. Only a few nasal delivery systems used in experimental studies are currently in the market to deliver therapeutics into the nasal cavities, i.e., nasal drops as multiple or single dose formulation, aqueous nasal sprays, nasal gel pump, pressurized MDIs and dry powder inhalers.

Intranasal delivery is currently being employed in treatments for migraine, smoking cessation, acute pain relief, osteoporosis, nocturnal enuresis and vitamin B₁₂ deficiency. Other examples of therapeutic areas under development or with potential for nasal delivery include cancer therapy, epilepsy, anti-emetics, rheumatoid arthritis and insulin-dependent diabetes. This review article provides a brief overview of the advantages & limitations of nasal drug delivery system, anatomy of nasal cavity, mechanism of nasal absorption, barriers to nasal absorption, strategies to improve nasal absorption, nasal drug delivery formulation issues and applications of nasal drug delivery systems.

Advantages ⁵:The main advantages include are;

1)      Drug degradation that is observed in the gastrointestinal tract is absent.

2)      Hepatic first pass metabolism is avoided.

3)      Rapid drug absorption and quick onset of action can be achieved.

4)      The bioavailability of larger drug molecules can be improved by means of absorption enhancer or other approach.

5)      The nasal bioavailability for smaller drug molecules is good.

6)      Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug delivery.

7)      Studies so far carried out indicate that the nasal route is an alternate to parenteral route, especially, for protein and peptide drugs.

8)      Convenient for the patients, especially for those on long term therapy, when compared with parenteral medication.

9)      Drugs possessing poor stability in g.i.t. fluids are given by nasal route.

10)  Polar compounds exhibiting poor oral absorption may be particularly suited for this route of delivery.

Disadvantages ⁶: Any delivery system poses certain disadvantages. The limitations of nasal delivery are;

1)      The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established.

2)      Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation.

3)      Nasal cavity provides smaller absorption surface area when compared to GIT.

4)      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.

5)      Certain surfactants used as chemical enhancers may disrupt and even dissolve the membrane in high concentration.

6)      There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration.

Anatomy & Physiology of Nasal Cavity: The nasal cavity is divided into two halves by the nasal septum and extends posterior to the nasopharynx, while the most anterior part of the nasal cavity, the nasal vestibule, opens to the face through the nostril. The nasal cavity consists of three main regions. Thay are nasal vestibule, olfactory region and respiratory region. The surface area in the nose is enlarged about 150cm² by the lateral walls of the nasal cavity which includes a folded structure. It has a very high surface area compared to its small volume. This folded structure consists of three turbinate’s - the superior, the median and the inferior. The main nasal airway having the narrow passages usually has 1-3mm wide and these narrows structures are useful to nose to carry out its main functions.

The nasal cavity is covered with a mucous membrane which can be divided into two areas i.e.; non-olfactory and olfactory epithelium. In non-olfactory area includes the nasal vestibule which is covered with skin-like stratified squamous epithelium cells where as in respiratory region, it has typical airways in the epithelium covered with numerous microvilli, resulting in a large surface area available for drug absorption and transport. In this way the mucus layer is propelled in a direction from the anterior towards the posterior part of the nasal cavity. The goblet cells are present in the mucus membrane which covers the nasal turbinate and the atrium. It secretes mucus as mucus granules which swell in the nasal fluid to contribute to the mucus layer.

The mucus secretion is composed of about 95% water, 2 % mucin, 1% salts, 1% of proteins such as albumin, immunoglobulins, lysozyme and lactoferrin, and 1% lipids. The mucus secretion gives immune protection against inhaled bacteria and viruses. It also performs a number of physiological functions. It covers the mucosa, and physically and enzymatically protects it. The mucus has water-holding capacity. It exhibits surface electrical activity. It permits efficient heat transfer. It acts as adhesive and transports particulate matter towards the nasopharynx ⁷.

Mechanism of Nasal Absorption: The absorbed drugs from the nasal cavity must pass through the mucus layer. It is the first step in absorption. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. The principle protein of the mucus is mucin which has the tendency to bind to the solutes, hindering diffusion. Additionally, structural changes in the mucus layer are possible as a result of environmental changes. The two mechanisms that include there

• First mechanism: It involves an aqueous route of transport, which is also known as the paracellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water soluble compounds. The molecular weight greater than 1000 Daltons show poor bioavailability ⁸.
• Second mechanism: It involves transport through a lipoidal route known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drugs can also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions. For example chitosan, a natural biopolymer from shell fish opens tight junctions between epithelial cells to facilitate drug transport ⁹.

FIG. 1: PARTS OF NASAL CAVITY (a) NASAL VESTIBULE, (b) PALATE, (c) INFERIOR TURBINATE, (d) MIDDLE TURBINATE, (e) SUPERIOR TURBINATE (OLFACTORY MUCOSA), (f) NASOPHARYNX

FIG. 2: CELL TYPES OF THE NASAL EPITHELIUM SHOWING CILIATED CELL (A), NON-CILIATED CELL(B), GOBLET CELLS(C), GEL MUCUS LAYER (D), SOL LAYER (E), BASAL CELL (F) AND BASEMENT MEMBRANE (G)

Barriers to Nasal Absorption: Nasal drug delivery systems are considered as a profitable route for the formulation scientist because it has easy and simple formulation strategies. The therapeutic efficacy and toxicities of intra-nasally administered drug products are influenced by number of factors. The following factors are the barriers to the absorption of drugs through nasal cavity.

• Low Bioavailability: Lipophilic drugs are generally well absorbed from the nasal cavity compared to polar drugs. The pharmacokinetic profiles of lipophilic drugs are often identical to those obtained after an intravenous injection and bioavailability approaching 100%. A good example of this is the nasal administration of Fentanyl, where the T_max for both intravenous and nasal administration are shown to be very rapid (7 min or less) and the bioavailability was near 80%. The most important factor limiting the nasal absorption of polar drugs and especially large molecular weight polar drugs such as peptides and proteins is the low membrane permeability.

Drugs can cross the epithelial cell membrane either by the transcellular route exploiting simple concentration gradients, by receptor mediated or vesicular transport mechanisms, or by the paracellular route through the tight junctions between the cells. Polar drugs with molecular weights below 1000 Da generally pass the membrane using the latter route. Larger peptides and proteins pass through the nasal membrane using an endocytotic transport process but only in low amounts.

• Low Membrane Transport: Another important factor is low membrane transport which is the general rapid clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism. This is especially the case for drugs that are not easily absorbed across the nasal membrane. It is shown that for both liquid and powder formulations that are not mucoadhesive, the half life of clearance ranges in the order of 15–20 min. It is further suggested that the deposition of a formulation in the anterior part of the nasal cavity can decrease clearance and promote absorption as compared to deposition further back in the nasal cavity. Most nasal sprays of various marketed preparations deliver the formulation to a limited area in the anterior part of the nasal cavity as opposed to nasal drops which deliver to a larger area further back in the nasal cavity ¹⁰. The use of bioadhesive excipients in the formulations is an approach to overcome the rapid mucociliary clearance.

Factors influencing Nasal Drug Absorption: Several factors affect the systemic bioavailability of drugs which are administered through the nasal route. They include physiochemical properties of the drugs, anatomical and physiological properties of the nasal cavity and the type and characteristics of selected nasal drugs delivery system. These factors play key role for most of the drugs in order to reach therapeutically effective blood levels after nasal administration. The factors influencing nasal drug absorption are described as follows.

Physiochemical properties of Drug:

• Molecular Size: The molecular size of the drug influence absorption through the nasal route. The lipophilic drugs have direct relationship between the molecular weight 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 ¹¹.
• Lipophilic-Hydrophilic Balance: The hydrophilic and lipophilic nature of the drug also affects the process of absorption. By increasing lipophilicity, the permeation of the compound normally increases through nasal mucosa. Although the nasal mucosa is found to have some hydrophilic character, it appears that these mucosae are primarily lipophilic in nature and the lipid domain plays an important role in the barrier function of these membranes. Lipophilic drugs like naloxone, buprenorphine, testosterone and 17a-ethinyl- oestradiol are almost completely absorbed when administered intranasal route ^{12, 13}.
• Enzymatic degradation in Nasal Cavity: In case of peptides and proteins having low bioavailability across the nasal cavity, these may have possibility to undergo enzymatic degradation in the lumen of the nasal cavity or during passage through the epithelial barrier. These both sites have exopeptidases (mono-aminopeptidases, di-aminopeptidases) which have the capability to cleave peptides at their N and C termini and endopeptidases (such as serine and cysteine) which can attack internal peptide bonds.

Nasal Effect Factors:

• Membrane Permeability: Nasal membrane permeability is the most important factor, which affect the absorption of the drug through the nasal route. The water soluble drugs and particularly large molecular weight drugs like peptides and proteins have low membrane permeability. So the compounds like peptides and proteins are mainly absorbed through the endocytotic transport process in low amounts. Water-soluble high molecular weight drugs cross the nasal mucosa mainly by passive diffusion through the aqueous pores (i.e. tight junctions).
• Environmental pH: The environmental pH plays an important role in the efficiency of nasal drug absorption. Small water-soluble compounds such as benzoic acid, salicylic acid, and alkaloid acid show that their nasal absorption in rat occurrs to the greatest extent at those pH values where these compounds are in the nonionised form. However, at pH values where these compounds are partially ionized, substantial absorption is found. This means that the nonionised lipophilic form diffuses through the nasal epithelial barrier via transcellular route, whereas the more lipophilic ionized form passes through the aqueous paracellular route ¹⁴.
• Mucociliary Clearance (MCC): Mucociliary clearance is one of the functions of the upper respiratory tract to prevent noxious substances (allergens, bacteria, viruses, toxins etc.) from reaching the lungs. When such materials adhere to or dissolve in the mucus lining of the nasal cavity, they are transported towards the nasopharynx for eventual discharge into the gastrointestinal tract ¹⁵. Clearance of this mucus and the adsorbed/dissolved substances into the GIT is called the MCC. This clearance mechanism influence the absorption process, since the dissolved drugs in the nasal cavity are discharged by the both the mucus and the cilia which is the motor of the MCC. The mucus transport rate is 6 mm/min. It is of utmost importance that the MCC is not impaired in order to prevent lower respiratory tract infections.
• Rhinitis: Rhinitis is a most frequently associated common disease. This condition impairs the bioavailability of the drug. It is mainly classified into allergic rhinitis and common. The symptoms are hyper secretion, itching and sneezing mainly caused by the viruses, bacteria or irritants. Allergic rhinitis is the allergic airway disease, which affects 10% of population. It is caused by chronic or acute inflammation of the mucous membrane of the nose. These conditions affect the absorption of drug through the mucus membrane due the inflammation.

Delivery Effect Factors: The factors that affect the delivery of drug across nasal mucosa are surfactants, dose pH, osmolarity, viscosity, particle size and nasal clearance and drug structure. These can be used to enhance the absorption.

• Formulation (concentration, pH, osmolarity): The pH of the formulation and nasal surface can affect drug permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5 because lysozyme is found in nasal secretions, which is responsible for destroying certain bacteria at acidic pH. Under alkaline conditions, lysozyme is inactivated and the tissue is susceptible to microbial infection. In addition to avoiding irritation, it results in obtaining efficient drug permeation and prevents the growth of bacteria.

Concentration gradient plays very important role in the absorption / permeation process of drug through the nasal membrane due to nasal mucosal damage. Examples for this are nasal absorption of L-Tyrosine which is shown to increase with drug concentration in nasal perfusion experiments. The absorption of salicylic acid is found to decline with concentration. This decline is likely due to nasal mucosa damage by the permanent. The osmolarity of the dosage form affects the nasal absorption of the drug.

The sodium chloride concentration of the formulation affects the nasal absorption. The maximum absorption is achieved by 0.462 M sodium chloride concentration. The higher concentration not only causes increased bioavailability but also leads to the toxicity to the nasal epithelium.

• Drugs distribution and deposition: The drug distribution in the nasal cavity is one of the important factors which affect the efficiency of nasal absorption. The mode of drug administration effects the distribution of drug in nasal cavity, which in turn will determine the absorption efficiency of a drug. The absorption and bioavailability of the nasal dosage forms mainly depend on the site of disposition. The anterior portion of the nose provides a prolonged nasal residential time for disposition of formulation and this enhances the absorption of the drug.

The posterior chamber of nasal cavity will use for the deposition of dosage form. It is eliminated by the mucociliary clearance process and hence shows low bioavailability ¹⁶. The site of disposition and distribution of the dosage forms mainly depend on delivery device, mode of administration, physicochemical properties of drug molecule.

• Viscosity: A higher viscosity of the formulation increases contact time between the drug and the nasal mucosa thereby increasing the time for permeation. At the same time, highly viscous formulations interfere with the normal functions like ciliary beating or mucociliary clearance and thus alter the permeability of drugs.

Strategies to improve Nasal Absorption: Various strategies used to improve the bioavailability of the drug in the nasal mucosa are to improve the nasal residence time, to enhance nasal absorption and to modify drug structure to change physicochemical properties. Any one or combinations of the approaches are used for enhancing the absorption and bioavailability of the formulations. Several methods that facilitate the nasal absorption of drugs are as follows;

• Nasal Enzyme Inhibitors: Nasal metabolism of drugs can be eliminated by using the enzyme inhibitors. For the formulations of proteins and peptide molecule development, enzyme inhibitors like peptidases and proteases are used. The absorption enhancers like salts and fusidic acid derivatives also show enzyme inhibition activity to increase the absorption and bioavailability of the drug ¹⁷. The other enzyme inhibitors commonly used for the enzymatic activity are trypsin, aprotinin, borovaline, amastatin, bestatin and boroleucin inhibitors.

Some of the chemical penetration enhancers are Surfactants (Polyozyethylene-9-lauryl ether (Laureth-9), Saponin), Bile salts (Trihydroxy salts (glycol- and taurocholate), Fusidic acid derivatives (STDHF), Chelators (Salicylates, Ethylenediaminetetraacetic acid (EDTA), Fatty acid salts (Oleic acid, Caprylate (C8), Caprate (C10), Laurate (C12), Phospholipids (Lysophosphatidylcholine (lyso-PC), Di-decanoyl – PC, Glycyrrhetinic acid derivates (Carbenozolone, Glycyr-rhizinate), Cyclodextrins (α, ß, and γ- cyclodextrins and their de-rivatives, Glycols (n- glycofurols and n- ethylene glycols) ¹⁸.

• Prodrug approach: Prodrug approach is mainly meant for optimizing favorable physicochemical properties such as solubility, taste, odor, stability, etc. Prodrug is usually referred as promoiety. It is to cover the undesired functional groups with other functional groups. This prodrug approach is mainly to improve the nasal bioavailability especially for the proteins and peptides to enhance the membrane permeability along with increased enzymatic stability.

The prodrug undergoes enzymatic transformation to release the active medicament, when it crosses the enzymatic and membrane barrier. The absorption of peptides like angiotensin II, bradykinin, caulein, carnosine, enkephalin, vasopressin and calcitonin are improved by preparing enamine derivatives. These agents show absorption enhancement with prodrug approach.

• Structural modification: Modification of drug structure without altering pharmacological activity is one of the lucrative ways to improve the nasal absorption. The chemical modification of drug molecule has been commonly used to modify the physicochemical properties of a drug such as molecular size, molecular weight; pka and solubility are favorable to improve the nasal absorption of drug. Chemical modification of salmon calcitonin to ecatonin (C-N bond replaces the S-S bond) shows better bioavailability than salmon calcitonin.
• Particulate Drug Delivery: Design of a particulate drug delivery system plays an increasingly important role in absorption enhancement. Microspheres, nanoparticles and liposomes are all particulate systems which can be used as carriers to encapsulate an active drug. The properties of these can be varied to maximize therapeutic efficacy. Overall, this can result in increased absorption efficacy and stability and reduced toxicity of the active ingredient. Systems can be designed to be mucoadhesive to increase the retention time and facilitate sustained release. Microspheres mainly increase the absorption and bioavailability by adhering to the nasal mucosa and increase the nasal residence time of drug ¹⁹.

The microspheres prepared by using polymers like dextran, chitosan; biodegradable starch microspheres successfully improved the bioavailability of various drugs. Liposomes are amphiphilic in nature are well characterized for favorable permeation of drugs through the biological membranes, so the water soluble drugs can be delivered through the nasal route.

Nasal Drug Delivery System Dosage Forms: The selection of dosage form depends upon the drug being used, proposed indication, patient population and last but not least, marketing preferences. Four basic formulations must be considered, i.e. solution, suspension, emulsion and dry powder systems.

Liquid Nasal Formulations: Liquid preparations are the most widely used dosage forms for nasal administration of drugs. They are mainly based on aqueous state formulations. Their humidifying effect is convenient and useful, since many allergic and chronic diseases are often connected with crusts and drying of mucous membranes. Microbiological stability, irritation and allergic rhinitis are the major drawbacks associated with the water based dosage forms because the required preservatives impair mucociliary function and the reduced chemical stability of the dissolved drug substance and the short residence time of the formulation in the nasal cavity are major disadvantages of liquid formulations ²⁰. The several types dosage forms available in liquid form are described below.

• Instillation and Rhinyle Catheter: Catheters are used to deliver the drops to a specified region of nasal cavity easily. The formulation is placed in the tube. One end is positioned in the nose, and the solution is delivered into the nasal cavit