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VOLUME: 08, Issue 04, Paper id-IJIERM-VIII-IV, August 2021
106EXPLORING THE POTENTIAL OF NASAL IN-SITU GEL FOR ENHANCED DRUG DELIVERY
Gaddam Swetha Reddy
Asst. Professor, Department of Pharmaceutical Chemistry, Princeton College of Pharmacy, Hyderabad, Telangana, India
Ajmeera Rajya Laxmi
Asst. Professor, Department of Pharmaceutical Chemistry, Princeton College of Pharmacy, Hyderabad, Telangana, India
Abstract - Numerous medical and biomedical applications, including controlled drug delivery, have developed as a result of advancements in in situ gel technologies over the past few decades. In order to meet the ever-increasing demands of the pharmaceutical and medical industries, numerous novel in situ gel-based delivery matrices have been developed and manufactured. In situ gel forming drug delivery is a type of mucoadhesive drug delivery system that is liquid at room temperature but gels when it comes into contact with body fluids or changes in pH. The drug is released in a controlled and sustained manner from the gel that forms as a result of temperature modulation, pH change, the presence of ions, and ultraviolet irradiation. When conventional drug administration methods, such as intravenous, intramuscular, or oral, are inapplicable, nasal delivery offers a promising alternative. Many drugs have recently been shown to be more bioavailable through the nasal route than through the oral route. This has been attributed to the nasal mucosa's dense vasculature and highly permeable structure, as well as avoiding hepatic first-pass elimination, gut wall metabolism, and/or gastrointestinal tract destruction. The nose's physiology has some challenges, but it offers a promising path for the noninvasive systemic delivery of many therapies and a questionable route for drug delivery to the brain. As a result, the focus of this review is on the delivery of drugs through the nose, various aspects of the anatomy and physiology of the nose, the mechanisms by which drugs are absorbed through the nose, and various nasal drug delivery systems and their uses in drug delivery.
Keywords: Nasal In Situ Gel, Absorption Enhancer, Nasal Formulation, Mucoadhesive Drug Delivery System, Microsphere Based Drug Delivery System.
1 INTRODUCTION
Due to their ease of administration, oral administration is the preferred and most convenient method of drug administration. Be that as it may, in many occurrences oral organization isn't attractive when the medication goes through huge corruption by means of first pass impact in liver. Subsequently, absence of fundamental ingestion through the gastrointestinal plot prompted research on backup courses of action of medication conveyance, for example, parenteral, intramuscular, subcutaneous, intranasal, transdermal etc.
Intranasal (IN) organization is a needle free and subsequently an optimal option in contrast to the parenteral
course for fundamental medication conveyance. For systemic absorption, the nasal mucosa has a dense vasculature and a highly permeable structure. Nasal administration of drugs is simple and convenient. Evasion of first pass digestion is the fundamental benefit of nasal course of medication delivery.
Intranasal conveyance is harmless, basically easy, doesn't need sterile planning and it is effectively and promptly regulated by the patient or a doctor for example in a crisis setting.
When developing new therapies, extending the life of an existing drug, or enhancing its profile, it makes sense to take into account intranasal
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107 administration due to these advantageousproperties.
2 ANATOMY AND PHYSIOLOGY OF NASAL CAVITY
It is essential to have a clear understanding of the nose's anatomy and physiology in relation to the characteristics of the delivery system when studying drug absorption from the nasal mucous membrane. The nasal passage that connects the nasal vestibule to the nasopharynx has a depth of approximately 12 to 14 centimeters. The mucosa is shielded from inspired air because the nasal cellular apparatus is in close contact with mucus in this passage.
The nasal cavities are divided into three distinct functional zones, namely olfactory, respiratory, and vestibular regions.6 The zones are arranged in the order of order from anterior to posterior.
The vestibular area is covered by a common pseudostratified epithelium that serves as a baffle system. The long hairs on this epithelium may filter airborne particles. The olfactory segment is lined with a specialized type of pseudostratified columnar epithelium known as olfactory epithelium, which contains receptors for the sense of smell. The respiratory area is normally covered by a dense layer of mucus that is constantly moving towards the posterior apertures of the nasal cavity by a powerful system of motile cilia.6 The respiratory area has a surface that is lined by a pseudostratified columnar epithelium. Along the nasal cavity's dorsal roof, you'll find this segment. Some types of cells in the olfactory mucosa are: basal cells, Bowman's glands, supporting (sustentacular) cells, and bipolar neurons The olfactory nerve (cranial nerve I) is made up of the axons of bipolar neurons.
2.1 Nasal Epithelium
Skin covers the nostrils, with a squamous and transitional epithelium covering the anterior third of the nasal cavity, an olfactory epithelium covering the upper
portion, and a typical airway epithelium covering the remaining portion, which is ciliated, pseudostratified, and columnar5.
The epithelial cells in the nasal vestibule are stratified, squamous, and keratinized with sebaceous glands. The nasal vestibule is extremely resistant to dehydration, can withstand noxious environmental substances, and prevents substances from permeating. The atrium is a transitional epithelial region with pseudostratified columnar cells with microvilli posterior and stratified squamous cells anterior.
2.2 Blood Supply to Nasal Cavity Blood is abundantly supplied to the nasal vasculature to support the basic functions of the nasal cavity, including olfaction, mucociliary clearance, heating and humidification, and immunological functions. The internal and external carotid arteries, as well as the facial and maxillary arteries, supply blood to the body. The nose's named arteries are,
Sphenopalatine artery, a branch of maxillary artery.
Anterior ethmoidal artery, a branch of ophthalmic artery.
Branches of the facial artery supplying the vestibule of the nasal cavity.
There are a lot of blood vessels in the nasal mucosa's lamina propria. There are three ways in which they differ from the vasculature in the tracheobronchial tree. The first is the nose's venous sinusoid. The second is a nose arteriovenous anastomosis. Third are the nasal vasculature shows repetitive changes of clog leading to the nasal cycle.
One of the characteristics of nasal blood vessels has been described as the endothelial basement membrane's porosity. For rapid fluid movement through the vascular wall, the capillaries just below the surface epithelium and surrounding the glands are ideal.
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108 3 NASAL DRUG DELIVERY SYSTEMDiverse therapeutic compounds can be delivered locally and systemically using intranasal (IN) delivery. Nasal administration is one of the non-invasive routes that offers promising potential as a viable alternative for the delivery of some medications. Thus there has been a flood of revenue that has prompted numerous examinations including the nasal hole as a practical site for the organization of much remedial agents.
3.1 Advantages
Compared to other epithelial surfaces, the nasal epithelium is thin, porous, and highly vascularized. For the purpose of initiating therapeutic action, this guarantees a high degree of absorption and rapid transport of absorbed substances into the systemic circulation.
A basement membrane of porous endothelial cells that does not impede the drug's movement into the bloodstream.
The substances that are absorbed are transported directly into the systemic circulation, avoiding the typical first-pass metabolic effect that occurs after oral drug administration.
Drugs can sometimes bypass the blood-brain barrier and be absorbed directly into the central nervous system (CNS) following nasal administration.
Drugs, particularly proteins and peptides, can be made more bioavailable thanks to the nasal epithelium's lower enzymatic activity than the GIT or liver. Likewise, catalyst inhibitors are more viable following nasal than oral application in view of a more serious level of weakening in the last option than in the previous.
The realization of pulsatile drug delivery, such as insulin, human
growth hormone, and others. is greater in NDD.
Self-medication of the nose not only reduces therapy costs but also increases patient compliance. Nasal lavage can be used to get rid of any drug that hasn't been absorbed, and the risk of overdosage is low.
Companies have the opportunity to extend the life cycle of their products by reformulating existing drugs into NDD products.
4 BIOLOGICAL FACTORS
First, physiological factors include mucociliary clearance, which involves the combined action of the mucus layer and cilia. The tips of the cilia are in contact with and transport the superficial viscoelastic mucus layer toward the nasopharynx, while the less viscous lower layer of mucus is relatively stationary.
This is one of the major factors in drug clearance from the nasal cavity. Second, the nasal mucosa contains a wide variety of metabolic enzymes. However, this may limit the bioavailability of drugs given through the nose; These enzymes have a lower activity level than those in the GIT and liver. In addition, pathological conditions such as rhinitis and the common cold can affect drug absorption from the nasal cavity, and the pH of the nasal cavity also affects drug permeation.
An adjustment of the pH of bodily fluid can influence the ionization and increment or decline the penetration of medication relying upon the idea of the drug.
5 PHYSICOCHEMICAL PROPERTIES OF DRUGS
Various physicochemical characteristics of drug can also affect nasal absorption of the drug.
Sub-atomic Weight and Size: The drug's absorption rate is influenced by its molecular weight, particularly in the case of hydrophilic compounds. The nasal route can effectively deliver drugs up to
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109 1000 Daltons. Unless penetrationenhancers are used, absorption significantly decreases when the molecular weight is greater than 1000 Daltons. The existence of a strong linear correlation between the log percentage of a drug absorbed through the nose and the log molecular weight of water-soluble compounds lends credence to the involvement of aqueous channels in the absorption of water-soluble molecules through the nose. The nasal cavity has been found to contain particles larger than 10 m, according to reports. Particles between 2 and 10 micrometers have the potential to remain in the lungs, while particles smaller than 1 micrometer are exhaled.
Dissolution and Solubility: A significant factor in determining drug absorption through biological membranes is drug solubility. If the drug is not sufficiently soluble in the desired vehicles, it can hinder a formulator's ability to formulate a product as well as the drug's absorption. Because nasal secretions are more watery, a medication should be able to dissolve more easily in water. Before being absorbed, particles that are deposited in the nostrils must be dissolved. Absorption may not be observed if the drug remains in the nostrils as particles or is removed from the nasal cavity.
Compound Structure: The chemical form in which a drug is delivered to the nasal mucosa can have a significant impact on how well it is absorbed. Changes in a drug's absorption, for instance, can occur when it is converted into a salt or ester form. The rise in lipophilicity that followed esterification, which increased the rate and extent of nasal absorption, is linked to this phenomenon.
6 NASAL FORMULATIONS
The particular drug molecule's therapeutic need, duration of action, and duration of therapy all play a role in the design of the nasal formulation. Nasal
administration is an option for both controlled release and conventional release drug delivery. A wide variety of nasal formulations have been studied to date, including,
1. Nasal drops 2. Nasal powders
3. Nasal sprays (solution/suspension) 4. Nasal mucoadhesive particulate
delivery (micro/nanoparticles, liposomes)
5. Nasal gel
6. Nasal ointments 7. Nasal microemulsions
7 EVALUATION OF NASAL IN SITU GEL SYSTEM
Clarity is one of the parameters that can be used to evaluate and characterize in situ gels: Under a black and white background, a visual inspection was used to determine the clarity of the formulated solution.
The study of texture: Using a texture analyzer, the formulation's firmness, consistency, and cohesiveness are evaluated. This primarily reveals the sol's syringeability, allowing the formulation to be easily administered in vivo.
Point of Gelation: At this temperature, the liquid phase transforms into a gel.
Temperatures between 30°C and 36°C would be ideal for thermoreversible nasal gel's gelation. The temperature at which formulations would not flow when test tubes were tilted to a 90° angle as the temperature gradually increased was referred to as the gelation point. pH and ion dependent polymers change from sol to gel when their pH changes or they come into contact with nasal fluid.
The Gels' pH: Each batch's pH was measured with a pH meter that had been calibrated beforehand with buffers of pH 4 and pH.
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