INTRODUCTION:

Nasal drug delivery is a successful course of management from the ancient days. There are numerous medications which give improved systemic availability through nasal course. This route turns into a significant tool in the treatment of different disorders^[1]. Traditionally, the nasal cavity is utilized for the treatment of nearby diseases, such as rhinitis and nasal blockage. However, in the past few decades nasal drug delivery has been paid much more attention as a promising drug administration route for the systemic therapy^[2]. This novel drug delivery system promotes the prominently ease and convenience of administration, deliverance of accurate dose as well as to prolong residence time of drug in contact with mucosa, that problems generally encountered in semisolid dosage forms^[3].

The nasal course is a potential course for systemic availability of drugs restricted to intravenous administration. This is because of the large surface area, permeable, endothelial covering, high total blood flow, the avoidance of first pass metabolism^[4]. Intranasal route is considered for the drugs that are ineffective orally. Nasal medication can also provide a route of entry to the brain that bypasses the blood-brain barrier because of the fact that olfactory receptor cells are in direct contact with the central nervous system^[5,6]. The absorption from the nasal cavity decreases as the molecular size increases^[7]. Mucoadhesive preparations are developed to build the contact time between the dosage form and mucosal layers of nasal cavity resulting in improved medication absorption^[8].

Insitu gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and solvent exchange.

Advantages of intranasal drug delivery system^[9,10,11]

1 Increase in residence time of drug in nasal cavity.

2 Low dose is required.

3 The quick absorption and onset of action should be there.

4 Improved bioavailability of drug.

5 Decreased in the frequency of drug administration.

6 Avoid degradation of drug in gastrointestinal tract resulting from acidic or enzymatic degradation.

7 It may show minimized local and systemic side effects. Direct transport into systemic circulation and CNS.

8 Lower risk of overdose to CNS and improved patient compliance. Self medication is also possible.

Disadvantages of conventional nasal drug delivery system-

1 There is a mechanical loss of dosage form into the other parts of the respiratory tract like lungs.

2 High risk of local side effects, Irreversible harm of the cilia on the nasal mucosa.

3 Inconvenient to patients when compared to oral delivery system.

4 Nasal cavity provides smaller absorption surface area compared to GIT.

5 Nasal congestion due to cold or allergies may interface with method of delivery.

6 Frequent use of this route may result in mucosal damage.

Nasal anatomy and Physiology:

Nose has three regions which incorporate the vestibular, respiratory, and olfactory. The septum divides the nose into two nasal pits. The nasal passage which runs from the nasal vestibule to the nasopharynx has a depth of approximately 12-14cm [12]. The surface region of nose is about 150 cm2 and the anatomy of nose is shown in Figure 1. The respiratory region is responsible for systemic drug delivery. Respiratory region consist of goblet cells, basal cells, ciliated and non ciliated columnar cells. The cells of cilia region consist of 300 microvilli which give numerous surface area for drug absorption. The movement of cilia follows wave like pattern and this transfer the particles to the pharynx for ingestion [13]. Mucus layer covers the nasal passage membrane that is restored every 10 to 15 minutes. In adults mucosal secretion pH ranges from 5.5 to 6.5 and among children it ranges from 5.5 to 6.7. Particles are entrapped by mucus layer and cilia clear these particles from nasal cavity. Particles are cleared from nose with in each 20 min. [14,15].

1. Vestibular region:

Most anterior part of the nasal cavity is nasal vestibule, simply inside the nostrils. About 0.6cm the nasal section is covered by a stratified squamous and keratinized epithelium with sebaceous glands, which is responsible for filtering out the air borne particles. Nasal respiratory mucosa is the significant section for conveying drugs systemically^[16,17].

2. Respiratory region:

The respiratory region is the essential region for systemic drug delivery. The respiratory region comprises of non-ciliated and ciliated columnar cells, basal cells and goblet cells. The respiratory region contains three nasal turbinates: superior, middle, and inferior which project from the lateral wall of each of the nasal cavity^[18,19].

3. Olfactory region:

The olfactory region is to be found in the top of the nasal cavity. It plays a vital role in transportation of drugs to the brain and the CSF. When the drug is administered intranasally, it can enter into the brain by means of three different paths. The first one is the systemic pathway by which the drug is absorbed into the systemic circulation and afterward 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]^[20].

Fig. 1: Anatomy of Nasal Cavity

Mechanism of nasal drug Absorption:

The nasal absorption of drugs for systemic or CNS impact occurs when it goes through the mucus layer and epithelial membrane before reaching the blood circulation or passes directly to the CNS^[21,22]. The first step in the absorption of drug from the nasal cavity is passage through the mucus. Small, uncharged particles effectively go through this layer. However, large or charged particles may find it harder to cross.

There are several mechanisms for absorption across the mucosa. These comprise transcellular or simple diffusion across the membrane, paracellular transport via movement between cell and transcytosis by vesicle carriers. There are different mechanism by which the medications across the olfactory membrane to reach CNS^[23]. The primary mechanism involves direct exchange of the drug to essential neurons of the olfactory epithelium and transport to the olfactory bulb by intracellular axonal transport with following possible distribution into more distant brain tissues^[24]. The second mechanism relies upon the drug permeation over the olfactory epithelial cells, either by transcellular or paracellular systems followed by uptake into CNS. The last one utilizes pinocytosis by olfactory neuron^[25].

Types of Dosage forms and Delivery Systems for Nasal Delivery^[26]

The specific types of dosage forms which are used to deliver formulations into the nose are significant in determining the nasal absorption profiles of medications. Nasal formulation depends upon the therapeutic need of the specific drug particle, duration of action and duration of therapy. Both controlled release and conventional release drug delivery are possible through nasal route. Various different nasal dosage forms which have been developed include the following:

1 Nasal drops

2 Nasal powders

3 Nasal sprays (solutions, suspensions)

4 Nasal gels

5 Nasal ointments

Specialized systems:

Liposomes, Microspheres, Nanoparticles, Nasal inserts, Microemulsions, Hydrogels.

Factors Influencing Nasal Drug Absorption:^{[27,28,29,30]}

I. Biological Factors

· Structural features

· Biochemical changes

· Physiological factors

· Blood flow

· Nasal secretions

· pH of the nasal cavity

· Mucociliary clearance and ciliary beat reoccurrence

· Pathological conditions

· Environmental factors

· Temperature

· Humidity

II. Physicochemical Properties of Drugs

· Molecular weight

· Size

· Solubility

· Lipophilicity

· Pka and Partition coefficient

III. Physicochemical Properties of Formulation

· Drug Concentration, Dose and Dose Volume

· Viscosity

· pH and mucosal irritancy

· Osmolarity

· Volume of solution applied

IV. Device Related Factors:

· Particle size of the droplet/powder

· Size and pattern of dispersion

I. Biological Factors:

Structural features:

Nasal epithelium mainly consists of different type of cells, show variety in nasal absorption and because of other factors such as presences of microvilli, cell density, surface area and number of cells^[31].

Biochemical changes:

Enormous number of enzymes such as oxidative and conjugative enzymes, peptidases and proteases are principally act on nasal mucus which is enzymatic barrier for delivery of drugs. These enzymes are responsible for the degradation of drugs in the nasal mucosa^[32].

Physiological factors:

· Blood flow:

The nasal mucosal film is very rich in vasculature and plays an significant role in thermal regulation and humidification of the inhaled air, and in this way the drug absorption will depend upon the vasoconstriction and vasodilatation of the blood vessels^[33].

· Nasal secretions:

The permeability of drug through the nasal mucosa is influenced by consistency of nasal secretion. Approximately 1.5-2.1ml of mucus is produce day by day in nasal cavity.

· pH of the nasal cavity:

Nasal cavity pH in adult is 5.5-6.5 and 5.0-7.0 in infants. An adjustment in the pH of mucus can influence the ionization and thus increase or decrease the permeation of drug, depending on the nature of the drug. The perfect pH of a formulation should be within 4.5–6.5^[34].

· Mucociliary clearance:

The muco-ciliary clearance is inversely related to the residence time, and therefore it is inversely proportional to the absorption of drugs administered^[35].

· Pathological conditions:

Intranasal pathologies such as infections, nasal surgery, cold and hypersensitive rhinitis may influence the nasal muco-ciliary transport process. Nasal pathology also alters mucosal pH, thus affects the absorption of drugs^[36].

Environmental factors:

· Temperature:

Temperatures in the range of 24°C cause a moderate reduction in the rate of MCC (Mucociliary clearance). A linear increase in ciliary beat frequency occurs with increase in temperature, which in turn influences the properties of the mucous membrane.

II. Physicochemical Properties of Drugs:

· Molecular Weight:

The penetration of drugs (less than 300 Dalton) is insignificantly influenced by the physicochemical properties of the drug and may affect the drug absorption^[37].

· Chemical Form:

The Chemical form of a drug play important role in absorption. Absorption may be influenced by conversions of the drug into a salt or ester form^[38].

· Polymorphism:

Absorption of the drug is influencd by polymorphism which in turn influences the dissolution rate and solubility of drugs through biological membranes^[40].

· Solubility and Dissolution Rate:

Solubility is important parameter of drug absorption. For better absorption, drug should get dissolve. If dissolution rate of drug is good then absorption of drug is better^[41].

· Lipophilicity:

If lipophilicity of drug goes on increasing, the permeation of the compound through the nasal mucosa increases because of high lipophilicity, though it has some hydrophilic character. Lipophilic compounds easily cross biological membrane through the transcellular route^[42].

· Pka and Partition coefficient:

The pH partition theory states that non ionized species are absorbed well, when compared with ionized species and hence it is the same in the case of nasal absorption as well. In biological tissues, drug concentration increases with increase in the lipophilicity or partition coefficient of the drug^[43].

III. Physicochemical Properties of Formulation:

· Drug Concentration, Dose and Dose Volume: These are three interrelated parameters that impact the performance of the nasal delivery:

· Therapeutic dose: upper limit 25mg/dose

· Higher the drug concentration, higher the permeation

· Dose volume: 0.05–0.15ml/dose^[44]

· Viscosity:

A higher viscosity of the formulation, increases the contact time between the drug and the nasal epithelial mucosa, thereby increasing permeation time^[45].

· pH:

The pH of the formulation can effect the drug permeation. pH of the nasal formulation should be adjusted in the range of 4.5–6.5 to avoid irritation. Avoiding irritation results in obtaining effective drug permeation and prevents the growth of bacteria. Nasal secretions contain lysozyme, which at acidic pH, destroys certain bacteria^[46].

· Osmolarity:

Optimum osmolarity should be maintained because it causes shrinkage of the nasal epithelial mucosa. This results in increased permeation of the compound because of structural changes^[47].

Principle involved in Insitu Gelling:

The insitu gelling of nasal formulations is that the nasal formulations absorbs the nasal fluid after administration and forms gel in the nasal cavity^[48]. Insitu gel phenomenon based upon liquid solution of drug formulation and converted into semi-solid mucoadhesive key depot^[15]. The bioadhesive properties of the gels help in keeping get in touch with between gel and mucosa and acts as a release controlling matrix system.

Mucoadhesive polymers:

Mucoadhesion can be defined as the state in which two materials are held together for a long period. Mucoadhesive polymers make an adhesive force between formulation and nasal mucosa, to enter the tissue surface and in this way improve the retention time of the drug in the nasal cavity^[49]. Because of bioadhesion, there is a decrease in the mucocilliary clearance of formulation. Mucoadhesive polymers are water soluble and water insoluble polymers^[50].

Examples of mucoadhesive polymers:

Pectin, Gellan gum, Chitosan, Pleuronics, Xyloglucan, Alginic acid, Carbopol.

Characteristics of mucoadhesive polymers^[^51]:

1 Should be non toxic.

2 It should form a non-covalent bond with the membrane surface.

3 It should be non-irritant to the biological membrane.

4 It should adhere quickly on the biological membrane.

5 The polymer should be stable during the shelf life.

6 It should permit incorporation of the drug and allow its release.

7 It should be economically low/cheap.

Approaches of in Situ gel Drug Deliver^[52]

There are four generally defined mechanisms utilized for triggering the insitu gel formation of biomaterials: Physiological stimuli (e.g., temperature and pH), physical changes in biomaterials (e.g., solvent exchange and swelling), chemical reactions (e.g., enzymatic, chemical and photo-initiated polymerization).

1. Thermally trigged system:

In this mechanism, Insitu gel is formed by the use of polymers that changes from sol-gel by changing physiological temperature of the body. The biomaterials are used to form insitu gel. At that point when temperature increases, these biomaterials lead to changes from sol to gel and form insitu gel^[53].

2. pH triggered systems:

Insitu gel is also prepared by changing pH of the gel which is depends on physiologic stimuli. All the pH-sensitive polymers contain acidic or basic groups that either accept or discharge proton, are utilized. Swelling of hydro gel increases as the external pH increases in the case of weakly acidic groups, however decreases if polymer contains weakly basic groups^[54].

3. Swelling:

In this mechanism, Insitu gel is prepared when material absorbs water from surroundings and gets swollen.

4. Diffusion:

In this method hardening of polymer matrix occur when diffusion of solvent from polymer solution into nearby tissue takes place^[55].

Evaluation Parameters of Nasal in-Situ Gels

1. Appearance:

Insitu gel is examined visually for in sol and gel form^[56].

2. pH: pH of insitu nasal gel is measured with the assistance of pH meter^[57].

3. Clarity:

The clarity might be determined by visual inspection under the black and white background^[58].

4. Viscosity:

The viscosity and rheological properties of the polymeric formulations, either in solution or in gel made with artificial tissue fluid, may be determined with various viscometer like Brookfield viscometer, cone and plate viscometer^[16].

5. Texture analysis:

The consistency and cohesiveness of formulation might be determined using texture analyzer which for the most indicates the syringe ability of sol so the formulation can easily administered in-vivo.

6. Drug content:

Take 1ml of formulation and adjust to 10ml in volumetric flask and then dilute with 10ml of distilled water, 1ml from this solution again diluted with distilled water up to 10ml. after this take absorbance of prepared solution at a specific wavelength of the drug by using U.V visible spectroscopy.

7. Gel Strength:

Depending on the mechanism of the gelling agent used a predetermined amount of gel is prepared in beaker, from the sol form. This gel containing beaker is raised at certain rate, so pushing a probe slowly through the gel. This parameter can be evaluated using a Rheometer^[59].

8. Sol-gel transition temperature and gelling time:

For In-Situ gel forming systems, the sol-gel transition temperature and pH should be determined. Gelling time is the time required for the primary recognition of gelation of in-situ gelling system^[60].

9. Sterility testing:

Sterility testing is carried out as per the IP 1996. Incubate the formulation for not less than 14days at 300˚-350˚C in the fluid thioglycolate medium to discover the development of bacteria and at 200˚-250˚C in soyabean casein digest medium to discover the development of fungi in formulation^[61].

10. In vitro drug release studies:

For in-situ formulations to be administered by oral, ocular, the drug release studies are carried out by using the plastic dialysis cell. The cell is comprised of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane. The sol form of the formulation is placed in the donor compartment. The assembled cell is then shaken horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media, this receptor solution is analyzed for the drug release using analytical receptor media and placed on a shaker water bath at required temperature. Samples are withdrawn periodically and analyzed^[62].

CONCLUSION:

Insitu gel is a novel approach for nasal drug delivery system which prolongs the contact time between the medication and absorptive site. This system allows drug direct delivery to the CNS by the olfactory pathway through the mucosa, and provides benefits such as patient compliance and comfort, low exposure and fewer side effects. When drug is administered through nasal route then first pass metabolism gets reduced, less enzymatic reaction occurrence and prevent gastro intestinal tract Ulceration. Utilization of biodegradable, water soluble, thermo sensitive, pH sensitive polymer for the nasal insitu gel formulations can make them progressively suitable and amazing drug delivery system.

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Received on 11.06.2020 Modified on 21.07.2020

Asian J. Res. Pharm. Sci. 2021; 11(1):58-64.

DOI: 10.5958/2231-5659.2021.00010.2