A Review on Intranasal Drug Delivery System with Recent Advancement
Gourishankar College of Pharmacy (D. Pharm) Limb, Satara.
The aim of the present research is to explain the recent advancement of nasal drug delivery system. Intranasal Therapy has been an accepted form of treatment in the Ayurvedic system of Indian Medicine. The attention in intranasal delivery of drugs as a non‐invasive is increased. We have also discussed advantages, disadvantages, mechanism of action and application of nasal drug delivery system in local delivery, systematic delivery, and Nasal vaccine and CNS delivery of the drug. We are discussed here relevant aspects of biological, physicochemical and pharmaceutical factors of nasal cavity that must be considered during the process of innovation and advance of new drugs for nasal delivery as well as in their incorporation into appropriate nasal Pharmaceutical formulations. 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 development of nasal drug delivery system.
Oral route is the most desirable and convenient method of drug administration as their no difficulty of manufacture and administration. Failure of adequate absorption through the gastrointestinal tract led to research on alternate routes of drug delivery. Researchers developed the parenteral route of drug administration to solve the above problem. For the past few decades, the transdermal route has been selected for delivery of certain drugs. However, its use is limited due to low permeability of the skin to many drugs.
Now a day, researchers have been on selected nasal mucosa as an alternate route to achieve faster and higher drug absorption. Knowledge of the nasal mucosa’s high permeability and use of the nasal route for drug administration can be traced to ancient times. Realization of the nasal mucosa as a therapeutically viable alternate route came in the last two decades.
The development of suitable nasal drug delivery system is still the challenges of researchers. A better knowledge on the properties of drug molecules, formulation matrices, the nasal mucosa itself and the drug delivery systems affect drug absorption through the nasal route, is invaluable.
A stable, safe and effective nasal product can be developed through appropriate and adequate Preformulation studies of drug. In the last few years, the nasal route has received a great deal of attention as a convenient and reliable method for the systemic administration of drugs, especially those which are ineffective orally and must be administered by injection.
From extensive literature search, it can be considered that the nasal delivery is suitable for drugs
With the following criteria:
- In effective orally
- Used chronically
- Used in small doses
- Rapid entry to the general circulation is desirable.
The major advantages associated with nasal drug deliver include:
· Rapid absorption, higher bioavailability, therefore, lower doses;
· Fast onset of therapeutic action;
· Avoidance of liver first pass metabolism;
· Avoidance of metabolism by the gastrointestinal tract;
· Avoidance of irritation of the gastrointestinal membrane;
· Reduced risk of overdose;
· Non-invasive, therefore, reduced risk of infectious disease transmission;
· Ease of convenience and self-medication;
· Improved patient compliance;
· Can be a beneficial adjunct product to an existing product;
· Mucociliary clearance reduces the residence time of drug;
· Not applicable to all drugs;
· Insufficient absorption due to lack of adequate aqueous solubility;
· Require high volume of dose (25-200 ml) depending on aqueous solubility of drug.
Anatomy of the nose:
The total surface area of human nasal cavities is about 150 cm2 and the total volume is about 15 ml. The nasal cavity is divided into two halves by the nasal septum. The volume of each cavity is Approximately 7.5 ml, having a surface area around 75 cm2. The anatomy and histology of the nasal cavity is shown in Fig. 1. The nasal cavity consists following three main regions:
The vestibular region:
It is located at the opening of nasal passages and is mainly responsible for restricting entry of air borne particles. It is considered to be less important of the three regions with regard to drug absorption.
The respiratory region:
The respiratory region is the major having the highest degree of vascularity. The respiratory region contains three nasal turbinates: superior, middle, and inferior which project from the side wall of each of the nasal cavity. The presence of these turbinates creates a turbulent air flow through the nasal passages ensuring a better contact between the inhaled air and the mucosal surface. The respiratory region is considered as the major site for drug absorption into systemic circulation. The mucosa consists of an epithelium resting on a basement membrane and a lamina propria. The anterior part of respiratory region is covered with squamous epithelium, while he posterior part covered by a pseudo stratified columnar epithelium. The cells of respiratory epithelium are covered by about 300 microvilli per cells. The presence of tight junction between neighboring epithelial cells prevents the free diffusion of hydrophilic molecules across the epithelial by the paracellular route.
The olfactory region:
The olfactory region is situated between the nasal septum and the lateral walls of each of the two nasal cavities and just below the cribriform plate of the ethmoid bone separating the cranial cavity from nasal cavity. The olfactory epithelium is a pseudostratified epithelium, comprising olfactory sensory neurons and two types of cells; basal cells that are able to differentiate neuronal receptor cells and sustentacular cells (supporting cell) that provide mechanical support by ensheathing neuronal receptor cells and maintain the normal extracellular potassium level for neuronal activity. The olfactory epithelium is covered by a dense and viscous layer of mucus, which is secreted from the tubuloalveolar Bowman’s glands and the supporting cells. The olfactory epithelium constitutes only about 5% of the total area of the nasal cavity in man.. It is about 10 cm2 in surface area, and it plays a vital role in drug delivery because it bypasses the BBB, delivering therapeutic drugs to CNS .
It should be noted that the blood supply to the nasal mucosa is pertinent with regards to systemic drug delivery. The arterial blood supply to the nasal cavity is derived from both the external and internal carotid arteries. The blood that is supplied to olfactory region by anterior and posterior Methmoidal branches come from the ophthalmic artery supply, which is branch of carotid artery.
These vessels supply the anterior portion of the nose. When the drug is administered intranasally, it can enter into the brain via three different paths. The first one is the systemic pathway by which the drug is absorbed into the systemic circulation and subsequently reaches the brain by crossing BBB (especially lipophilic drug). The others are the olfactory region and the trigeminal neural pathway by which drug is transported directly from the nasal cavity to CNS (cerebrospinal fluid and brain tissue). The trigeminal nerve receptors which are present in the nasal cavity are responsible for most chemoperception and are suggested to transport the drug directly to CNS of drugs to the brain and the CNS .
The deep and superfacila cervical lymph nodes were of special interest in intranasal drug delivery because they are known to receive lymphatic afferents from portions of the nasal passages and nasolabial areas, respectively. This pathway is thought to mediate the efflux of large molecules and/or immune cells from sites within the CNS to the lymphatic system. The connection between the brain and nasal lymphatics may offer a direct pathway from the brain interstitial fluid to the nasal submucosa that excludes direct contact with the cerebrospinal fluid.
Figure 1. Sagittal section of the nasal cavity showing the nasal vestibule (A), atrium (B), respiratory area: inferior turbinate (C1), middle turbinate (C2) and the superior turbinate (C3), the olfactory region (D) and nasopharynx (E). Reproduced with permission from ref. 
Figure 2. Cell types of the nasal epithelium with covering mucous layer showing ciliated cell (A), non-ciliated cell (B), goblet cells (C), mucous gel-layer (D), sol layer (E), basal cells (F) and basement membrane (G). Reproduced with permission from ref. 
The easy accessibility and higher surface area makes the nose a potentially viable drug delivery organ. Pharmaceutical product development is a crucial task which is directly dependent on its therapeutic objectives. Therefore, before product development, important biopharmaceutical aspects need to be considered-firstly, whether it is intended for: I- Localised delivery II- Systemic delivery III- Single or repetitive administration. The feasibility of being able to achieve the therapeutic objectives will determine whether the development of a nasal delivery system is appropriate . Comprehending the factors that can affect drug deposition, retention and absorption are essential to enable intelligent design of nasal formulations. Numerous physiological, anatomical, and pathological conditions must also be considered. Different types of nasal formulations available in the UK at the time of publication are enlisted in Table 1 . However, a major challenge in designing nasal drug delivery formulations is to introduce the drug into a suitable vehicle system that provides drug stability and ideal dispensing characteristics. Elements such as selection of specific pharmaceutical excipients, delivery devices and processing methods need careful consideration. A schematic illustration of all the key parameters of a successful nasal formulation is shown in Figure 3.
Figure 3. Consideration of formulation elements of nasal product development
Mechanism of Drug Absorption:
Passage of drug through the mucus is the first step in the absorption from the nasal cavity. Uncharged as well as small particles easily pass through mucus. However, charged as well as large particles may find it more difficult to cross. Some mechanisms have been proposed but the following two mechanisms have been measured predominantly.
· The first mechanism of drug absorption involves an aqueous route of transport (Paracellular route). Paracellular route is slow and passive. In above route there is an inverse log‐log correlation between the molecular weight of water‐soluble compounds and intranasal absorption. Drugs with a molecular weight greater than 1000 Daltons shows poor bioavailability.
· The second mechanism includes transport of drug through a lipoidal route (transcellular process). Transcellular 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.
Example: Chitosan opens tight junctions between epithelial cells and hence facilitate drug transport.
Factors Influencing Nasal Drug Absorption:
The following factors affect drug absorption-
1. Nasal physiological factors:
Rich supply of blood and a large surface area make the nasal mucosa an optimal location for drug absorption. Nasal absorption of drugs is influenced by blood flow rate, as it increases the amount of drug that passes through the membrane and hence reaching the general circulation. Several studies were made to evaluate this influence. For example, Kao et al. stated that nasal absorption of dopamine was relatively slow and incomplete probably due to its own vasoconstrictor effect. From above observations, it was concluded that vasoconstriction decreases nasal drug absorption by diminishing the blood flow. 
Mucociliary clearance (MCC) also referred to as Mucociliary apparatus it is the self‐clearing mechanism of the bronchi. Nasal mucus layer defend the respiratory tract by preventing the lungs from foreign substances, pathogens and particles carried by inhaled air. These agents adhere to the mucus layer and transported to the gastrointestinal tract. Above elimination is designated MCC and it influences significantly the nasal drug absorption. The MCC system has been described as a ‘‘conveyer belt’’ wherein cilia provide the driving force whereas mucus acts as a sticky fluid that collects and disposes foreign particles. Hence MCC efficiency depends on the length, density and beat frequency of cilia as well as the amount and viscoelastic properties of mucus. MCC may increased by all factors that increase mucus production, decrease mucus viscosity or increased ciliary beat frequency. In physiological conditions, mucus is transported at a rate of 5 mm/min and its transit time in human nasal cavity is reported to be 15‐20 min. The values which are not withen the range these references are abnormal and suggestive of impaired MCC. From the above discussion we can say that the residence time of the drugs in nasal mucosa increased and hence permeation may be enhanced when MCC decreases. When MCC increases permeation rate of drug is decreased. MCC does not work properly in the following pathological conditions. 
Internasally administration of drugs avoids gastrointestinal and hepatic first‐pass effect. Drugs may be metabolized in lumen of nasal cavity due to the presence of a broad range of metabolic enzymes in nasal tissues. Some examples of enzyme which may play role in enzymatic degradation of drugs are carboxyl esterase, aldehydes dehydrogenases, epoxide hydrolases, glutathione S‐transferases and Cytochrome P450 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, insulin and desmopressin. The pharmacokinetic and pharmacodynamic profile of drugs administered through nasal route may be affected by xenobiotic metabolizing enzymes.
Mechanism of Drug Absorption:
The principal step in the absorption of a drug from the nasal cavity is the passage through the mucus. Fine particles easily pass through the mucus layer; however, large particles may find some difficulties. Mucus contains mucin, a protein with the potential to bind with solutes and thus affect the diffusion process. Structural changes can occur within the mucus layer as a result of environmental or physiological changes. Subsequent to a drug’s passage through the mucus, there are numerous mechanisms for absorption through the mucosa. These include transcellular or simple diffusion across the membrane, paracellular transport via movement between cell and transcytosis by vesicle carriers. Several mechanisms have been proposed, but paracellular and transcellular routes dominate .
Paracellular transport is slow and passive. There is an inverse correlation between intranasal absorption and the molecular weight of water-soluble compounds. Poor bioavailability was reported for drugs with a molecular weight greater than 1000 Daltons.
The second mechanism involves transport through a lipoidal route that is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drugs also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions .Obstacles to drug absorption are potential metabolism before reaching the systemic circulation and inadequate residence time in the nasal cavity.
Drug Absorption Enhancement:
Nasal drops are one of the simplest and most convenient delivery systems among all formulations. The main limitation is the lack of precision in the administered dosage and the risk of contamination during use. Nasal drops can be delivered with a pipette or by a squeezy bottle. These formulations are usually recommended for the treatment of local conditions, but challenges include microbial growth, mucociliary dysfunction and non-specific loss from the nose or down back the throat.
operating actuator. Nasal sprays are comparatively more accurate than drops and generate precise doses (25 - 200 μl) per spray.Several studies have shown that nasal sprays can produce consistent doses of reproducible plume geometry. Formulation properties such as thixotropy, surface tension and viscosity can potentially influence droplet size and dose accuracy.
A gel is a soft, solid or semi-solid-like material consisting of two or more components, one of which is a liquid, present in substantial quantity. The semi-solid characteristics of gels can be defined in terms of two dynamic mechanical properties: elastic modulus G’ and viscous modulus G”.The rheological properties of gels depend on the polymer type, concentration and physical state of the gel. They can range from viscous solutions (e.g. hypromellose, methylcellulose, xanthan gum and chitosan) to very hard, brittle gels (e.g. gellan gum, pectin and alginate). Bioadhesive polymers have shown good potential for nasal formulations and can control the rate and extent of drug release resulting in decreased frequency of drug administration and improved patient compliance.
Nasal Micellar and Liposomal Formulations:
Different types of adjuvants can affect the drug absorption (described earlier, see section 5.1) and are often required to reach therapeutic plasma levels when hydrophilic macromolecular drugs such as peptides and proteins are delivered by the nasal route.Among other surfactants used, bile salts are often used as enhancers, e.g. as micellar solutions. Tengamnuay and Mitra  described the use of micelles of sodium glycocholate and micelles thereof mixed with fatty acid (linoleic acid) as absorption enhancers for the model dipeptide (D-Arg2)-kyotorphin and for insulin in rats. The effect of mixed micelles was synergistic and superior compared to the single enhancer. Mixed micelles of sodium glycocholate and linoleic acid reduced the blood glucose level after nasal insulin administration to 47% of the glucose level after an identical nasal dosage of unenhanced insulin. Pure sodium glycocholate resulted in a reduction to 55%. Regarding the mechanism, in a difference to the membrane solubilizing effect of pure bile salts, the mixed micelles were proposed to have an effect on the nasal paracellular pathway. Hereby, the bile salts were considered to act as solubilizing agents for the fatty acids thus making them more available at the nasal mucosa .
Nasal Suspensions and Emulsions:
Suspensions are rarely used or investigated as nasal drug delivery systems. Analogous to marketed aqueous ophthalmic suspensions of the soft corticosteroid, loteprednol etabonate (e.g. Alrex®, Bausch and Lomb Pharmaceuticals), a nasal aqueous suspension of same drug containing microcrystalline sodium carboxymethylcellulose for stabilisation and retention in the nasal cavity was patented by Senju Pharmaceuticalsfor oral drug delivery it has been reported by several authors that emulsions were superior to suspensions in enhancing the bioavailability of poorly soluble drugs and the trend is similar with nasal formulations. Absorption enhancement has been attributed to solubilisation of the drug and the lipophilic absorption enhancers in the composition. Similarly, other low solubility compounds have been formulated in emulsions to increase the drug solubility, e.g. diazepam  and testosterone.
Particulate nasal dosage forms are usually prepared by simply mixing the drug substance and the excipients, by spray-drying or freeze- drying of drug.Dry-powder formulations containing bioadhesive polymers for the nasal delivery of peptides and proteins was first investigated by Nagai et al. (1984).Water-insoluble cellulose derivatives and Carbopol® 934P were mixed with insulin and the powder mixture was administered nasally. The powder took up water, swelled, and established a gel with a prolonged residence time in the nasal cavity. Glucose reduction was one-third of that achieved using an i.v. injection of the same insulin dose. Powder formulations for nasal drug delivery have since been widely investigated, e.g. for a somatostatin analogue using cross-linked dextran and microcrystalline cellulose, for glucagon using microcrystalline cellulose.
Evaluation of nasal drug formulations :
In vitro nasal permeation studies Various approaches used to determine the drug diffusion through nasal mucosa from the formulation. There are two different methods to study diffusion profile of drugs.
(A) In vitro diffusion studies:
The nasal diffusion cell is fabricated in glass. The water-jacketed recipient chamber having total capacity of 60 ml and a flanged top of about 3mm; the lid has 3 opening, each for sampling, thermometer, and a donor tube chamber. The donor chamber is 10 cm long with internal diameter of 1.13 cm, and a donor tube chamber has total capacity of 60 ml and a flanged top of about 3mm; the lid has 3 openings, each for sampling, thermometer. The nasal mucosa of sheep was separated from sub layer bony tissues and stoned in distilled water containing few drops at genatamycininjection. After the complete removal of blood from muscosal surface, it is attached to donor chamber tube. The donor chamber tube is placed such a way that it just touches the diffusion medium in recipient chamber. Samples (0.5 ml) from recipient chamber are with draw at predetermined intervals, and transferred to amber colored ampoules. The samples withdrawn are suitably replaced. The samples are estimated for drug content by suitable analytical technique. The temperature is maintained at 37oC throughout the experiment.
(B) In Vivo Nasal Absorption studies:
Animal models for nasal absorption studies – The animal models employed for nasal absorption studies can be of two types, viz., whole animal or in vivo model and an isolated organ perfusion or ex vivo model. These models are discussed in detail below:
The surgical preparation of rat for in vivo nasal absorption study is carried out as follows: The rat is anaesthetized by intraperitoneal injection of sodium pentobarbital. An incision is made in the neck and the trachea is cannulated with a polyethylene tube. Another tube is inserted through the oesophagus towards the posterior region of the nasal cavity. The passage of the nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth. The drug solution is delivered to the nasal cavity through the nostril or through the cannulation tubing. Femoral vein is used to collect the blood samples. As all the probable outlets of drainage are blocked, the drug can be only absorbed and transported into the systemic circulation by penetration and/or diffusion through nasal mucosa.
The rabbit offers several advantages as an animal model for nasal absorption studies:
1. It permits pharmacokinetic studies as with large animals (like monkey)
2. It is relatively cheap, readily available and easily maintained in laboratory settings
3. The blood volume is large enough (approx. 300ml)
4. To allow frequent blood sampling (l-2ml). Thus, it permits full characterization of the absorption and determination of the pharmacokinetic profile of a drug. Rabbits (approx. 3 kg) are either anaesthetized or maintained in the conscious state depending on the purpose of study. In the anaesthetized model, intramuscular injection of a combination of ketamine and xylazine is given to anasthetized rabbit. The rabbit's head is held in an upright position and nasal spray of drug solution is administered into each nostril. The body temperature of the rabbit is maintained at 37°C during experiment with the help of a heating pad. The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.
Nasal drug delivery is a novel platform and it is a promising alternative to injectable route of Administration. There is possibility in the near future that more drugs will come in the market in the form of nasal formulation intended for systemic treatment. Development of a drug with a drug delivery system is influenced by several factors. For the treatment of long illnesses such as diabetis, osteoporosis, fertility treatment novel nasal products are also expected to be marketed. Bioavailability of nasal drug products is one of the major challenges in the nasal product development. In contrast, a huge amount of money is investigated by pharmaceutical companies in the development of nasal products, because of growing demand of nasal drug products in global pharmaceutical market. So for the avoidance of side effect and improve effectiveness of nasal products we should pay attention to basic research in nasal drug delivery.
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Received on 04.06.2018 Accepted on 28.06.2018
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