An Outlook on In-Situ Mucoadhesive Gel for Nasal Delivery

The review was carried out to discuss in detail about the insitu gel nasal drug delivery system as these system have better systemic bioavailability through nasal route as compared to oral route of administration. In-situ gel is a novel dosage form for nasal delivery of various drugs. It is infusing into the nasal cavity as low viscous solution and after sometime it forms gel when it contact with the nasal mucosa. The main advantage of using nasal delivery is avoidance of first pass metabolism, high permeability of some drugs in nasal epithelium, quick drug absorption across this membrane, rapid onset of action, improved patient compliance and comfort, sustained and prolonged action in comparison to other drug delivery systems. The formation of gel depends on factors like temperature modulation, pH change, presence of ions, ultra violet irradiation, polymorphism, dissolution rate, solubility, viscosity and osmolarity. The review was focused on anatomy and physiology of nose, advantages, disadvantages, mechanism of drug delivery to the nose, types of dosage form for nasal delivery, barriers in nasal drug delivery, factors influencing nasal absorption, mucoadhesive polymer used in nasal drug delivery system and evaluation of in-situ gel nasal drug delivery system. L.Karpagavalli 1 , B.Senthilnathan 2 *, A.Maheswaran 3 and N.Narayanan 4 1, 2* Associate Professor, Department of Pharmaceutics, Jaya college of paramedical sciences, Jaya College of Pharmacy, Thiruninravur, Tamil Nadu, India. 3 Principal, Jaya college of paramedical sciences, Jaya College of Pharmacy, Thiruninravur, Tamil Nadu, India. 4 Research Director (Post graduate studies), Jaya college of paramedical sciences, Jaya College of Pharmacy, Thiruninravur, Tamil Nadu, India. Submitted: 26 July 2015 Accepted: 1 August 2015 Published: 25 August 2015 www.ijppr.humanjournals.com Citation: B.Senthilnathan et al. Ijppr.Human, 2015; Vol. 4 (1): 113-128. 114 INTRODUCTION The most commonly used route of administration for systemic effect is oral administration. But for some drug the systemic effect was not in desirable condition due to oral bioavailability and promoted for the search of more effective route for systemic delivery [1] . Usually the nasal cavity is used for the treatment of local diseases they are rhinitis, migraine, cold, pain and nasal congestion. In recent years it has been proved that many drugs achieved better systemic bioavailability through nasal route [2] . The various formulations used by nasal route are nasal gel, spray, powders, etc. Transmucosal route of drug delivery (i.e. the mucosal lining of the nasal, rectal, vaginal, ocular, oral cavity) nasal mucosa is the major route of administration to achieve faster and higher level of drug absorption [1] . This is due to the anatomy and physiology of nasal passage that is porous endothelial membrane, large surface area, high total blood flow, the avoidance of first pass metabolism and readily accessibility [3][4] . In-situ is a Latin term which means ‘In its original place or in position’. Insitu gel is a type of dosage form in which the medicament is in solution form before administration into the body, after administered it undergoes gelation to form a gel [5] . Due to its accessibility, nasal drug administration is considered as an alternative route for systemic circulation instead of intravenous administration [6] . Nasal drug delivery also provides a way to the brain that circumvents the blood-brain barrier because the olfactory receptor cells are in contact with central nervous system directly [7] . The nasal route is an attractive not only for delivery of vaccines due to large surface area and low proteolytic activity but also it improves the patient compliance and decrease the production cost compared to parenteral production [8] . Due to their high permeability the nasal route show only smaller molecular weight drugs the absorption will be more. For large molecular weight drugs or hydrophilic drugs show low bioavailability or no absorption due to the less permeable to the protease drugs in the nasal membrane so the drugs cleared rapidly before reaching the blood stream that is the drug does not pass through the mucosal barrier [9] . Penetration enhancers such as surfactants, bile salts and phospholipids increases the drug penetration but in site of clinical use the toxicity test proved that the permeation enhancers has some limitation due their irreversible damage [10,11] . Even though the number of challenges for the researchers to overcome some disadvantages in conventional nasal products and to make effort for the new nasal formulation. www.ijppr.humanjournals.com Citation: B.Senthilnathan et al. Ijppr.Human, 2015; Vol. 4 (1): 113-128. 115 Anatomy and physiology of Nose The nose is divided into two cavities by presence of septum between them and it extends posterior to the nasal pharynx. The surface area of nasal is about 150 cm 2 and the volume of nasal cavity is approximately 15 ml. Nose has three regions they are vestibular, respiratory and olfactory [12] . The most anterior part of the nasal cavity is vestibule; it opens through the nostril breathing and olfactory plays a major role of human nose in transportation of drugs to the brain. But for systemic drug delivery the respiratory region is important [13] . The respiratory epithelium consists of basal cells, mucus containing goblet cells, ciliated columnar and non-ciliated columnar cells. These cells facilitate active transport processes such as exchange of water, ions between the cells and cilia motility [14] . The cilia are a hair like microvilli which is 300 in numbers. They provide large surface area for the drug absorption and the movement of cilia is like a wave and it helps to transport the particles to the pharynx for ingestion. Below the epithelium the blood vessels, nerves, serous glands, secretory glands are found. There is a presence of capillaries network which is responsible for drug absorption. The epithelium covered by a mucus layer is renewed every 10 to 15 minutes. The pH of the mucus secretion ranges from 5.5 to 6.5 and for children it ranges from 5.0 to 6.7. The mucus layer entrapped the particles which are cleaned by the cilia and they cleared within 20 minutes [15] . Advantages of nasal drug delivery [16] [17]  Rapid drug absorption  Non-invasive  Easy administration  Good bioavailability  Improved patient compliance and convenience.  Large surface area for drug absorption  Rapid action  Less side effects  The nasal drug is used when the drug which are not suitable for oral route.  Crosses blood brain barrier.  First pass metabolism is avoided. www.ijppr.humanjournals.com Citation: B.Senthilnathan et al. Ijppr.Human, 2015; Vol. 4 (1): 113-128. 116 Disadvantages for nasal drug delivery  Removal of drug is not possible in nasal cavity.  Less number of drugs are given by nasal route.  Nasal irritant drugs are not given through this route.  Less than 25-200 μl volume of drugs given by this route.  Lower molecular weight drugs are only given by this route.  Frequently use of this route causes mucosal damage.  The drug absorption may cause allergic problems.  The reached amount of drug may vary in different regions (brain, spinal cord). Mechanism of nasal drug delivery The first step involved in the absorption of drug in nasal cavity is crossing the mucus membrane, because small, uncharged particles were passing through the mucus easily. But charged large molecule does not pass easily through the mucus membrane. The protein present in the mucus layer is Mucin, which binds with the solutes that delays the diffusion and structural changes in the mucus layer are also possible because of environmental changes (i.e. pH, temperature, etc.) [18] . During the drug passage in mucus there are several mechanisms for absorption across the mucosa thus includes simple diffusion, Para cellular transport between cell and transcytosis by vesicle carriers. The restrictions to the drug absorption are essential for metabolism before reaching the systemic circulation and limited residence time in the cavity. Several mechanisms have been proposed but the following two mechanisms have been considered predominantly. The first mechanism is known as paracellular route which involves an aqueous route for transportation. This is slow and passive route. There is log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. The drugs with a molecular weight greater than 1000 Daltons are having poor bioavailability [19] . The second mechanism is known as transcellular route which involves transportation through the lipoid route and it is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. The drugs cross the cell membrane by active transport through carrier mediated or opening of tight junctions [20] . www.ijppr.humanjournals.com Citation: B.Senthilnathan et al. Ijppr.Human, 2015; Vol. 4 (1): 113-128. 117 Types of dosage form for nasal delivery The type of dosage form which is used to deliver the formulation into the nose is important by determining the nasal absorption profiles of drugs. The selection of dosage form depends on the drug indication, development and patient population for different nasal dosage form that includes: nasal drops [21] , nasal powders, nasal sprays (solutions, suspensions) [22] , nasal gels, specialized system (liposomes, microspheres, etc.) [23] , nanoparticles, nasal inserts, micro emulsions, and hydrogels [24] . Barriers for nasal drug delivery