In situ nasal gel drug delivery: A novel approach for brain targeting through the mucosal membrane

Abstract

Recently, sustained and controlled drug delivery has become the demand, and research has been undertaken in achieving much better drug product effectiveness, reliability and safety. The in situ polymeric system has gained much attention, to develop a controlled release system. It has been used as a vehicle for local and systemic drug delivery. Nowadays, it has created much interest, because of its characteristics of high vascularization, high permeability, rapid onset of action, low enzymatic degradation, and avoidance of hepatic first pass metabolism. The main aim of this review is to provide knowledge of different mechanisms of nasal absorption and approaches for nasal drug delivery.

Keywords::

• brain targeting
• controlled release
• in situ gel system
• mucosal site
• nasal drug delivery

Introduction

For the past few decades, most of the routine drugs are being administered by parenteral and oral routes (Chaudhary et al. 2014). Although the oral route is convenient and cheap, sometimes inefficiencies such as low solubility of drug, and the first pass effect (orally absorbed drugs are transported via liver to the general circulation where they metabolized) (Gagandeep et al. 2014), may cause it to suffer from poor bioavailability (e.g. Griseofulvin) (Arida et al. 2007). The greater first pass effect of the drug (the rate and extent of the drug reaching systemic circulation), the lower the bioavailability. This route is also not suitable for unconscious patients (Illum 2007). Therefore, to solve this problem, the parenteral route is proposed, which is accurate, and enables immediate onset of reaction and 100% bioavailability, but it is unacceptable if the drug is proposed for the treatment of chronic disease, because this route also has a risk of embolism and attaining high concentrations, rapidly leading to greater risk of adverse effects. Therefore, a different route is preferred (Garg 2014). Also, the percutaneous (transdermal) route is used for controlled delivery of drug (stable blood levels) and does not suffer from first pass metabolism, but its use is limited due to low permeability of the skin to many drugs (Mao et al. 2004). To control these issues, nonparenteral routes, also called transmucosal routes, including the nasal, buccal, pulmonary, rectal and vaginal routes, are used. These routes have few benefits or advantages, such as the possibility of self-administration. The nasal mucosal route of administration achieves faster and higher level of drug absorption. This route has attained great attraction for drug delivery of various drugs (Garg and Goyal 2012).

Intranasal drug delivery (Mucoadhesive drug delivery system)

Traditionally, the medication for local diseases, such as rhinitis and nasal congestion, has not been administered through the nasal cavity. However, over the last few decades, intranasal (IN) delivery has been gaining much more attention as a promising route of drug administration for systemic therapy (Gavini et al. 2006). Presently, it is being recognized for the delivery of therapeutic compounds including biopharmaceuticals, and for topical nasal treatments such as antihistamines and corticosteroids, and also for systemic delivery of analgesics, sedatives, hormones, vaccines, and cardiovascular drugs by means of the nasal mucosa (Garg and Goyal 2014b). This is because of the anatomy and physiology of the nasal passage, such as the highly vascularized epithelium, ready accessibility, large surface area, permeable endothelial membrane, high total blood flow, and the prevention of first-pass metabolism (Mainardes et al. 2006). IN administration is a “needleless” and non- invasive method of drug delivery through the nose to the brain, and hence an alternative for systemic drug delivery (Alam et al. 2010). Therapy through IN administration has been an accepted as a form of treatment in the ayurvedic system of Indian medicine, and is called “Nasya Karma”. Drug delivery through the nose is uncomplicated and convenient, and can include the delivery of solutions, suspensions, powders, in situ gel, and ointments (Garg and Goyal 2014c).

The avoidance of first pass metabolism, quick onset of action, and lowered systemic exposure to drug are the main advantages of IN delivery. Nose-to-brain delivery of drug moieties are possible through the olfactory region, by neuronal and extracellular pathways located at the roof of the nasal cavity, whose neuroepithelium is the only part of the central nervous system (CNS) that is directly exposed to the external environment (Garg and Goyal 2014a). The therapeutic agents are carried to the CNS through the olfactory neuroepithelium by the trigeminal nerve systems and olfactory nerve pathways (Ali et al. 2010). In both intravenous as well as oral administration, the blood-brain barrier (BBB) restricts the brain's access to the drug. However, the intranasal route of delivery can also provide a route of entry to the brain that circumvents the BBB, because the olfactory receptor cells are in direct contact with the CNS (Wang et al. 2008).

Recently, the nasal mucosa has been examined as a possible route of administration to achieve a faster and higher level of drug absorption (Garg et al. 2012a). The nasal cavity provides a number of distinctive benefits, such as ease of access, good permeability mainly for lipophilic and low molecular weight drugs, low proteolytic activity, prevention of harsh environmental conditions and hepatic first pass metabolism, and potential direct delivery to the brain. Significantly, a number of invasive techniques in drug carrier systems, like the use of nanoparticles, liposomes, nanoemulsions, chemical modifications, the prodrug approach, and other invasive strategies like intraparenchymal, intraventricular, and intrathecal delivery are used to increase the CNS-targeting of drugs (Haque et al. 2012). Large investigative studies have shown that when administered intranasally, vaccines can encourage both local and systemic immune responses. Tables I and II show the advantages and limitations of intranasal delivery along with their respective associated factors.

Table I. Advantages (associated factors) of intranasal delivery (Sam et al. 1995).

Advantages	Factors
Improving patient compliance	• Trained person not required • Needle-free (painless) • Non-invasive • User- friendly • Self-medication possible
Rapid absorption and onset of pharmacologic action	• Highly vascularized mucosa • Large mucosal surface area
Good penetration	• For lipophilic drugs • For low molecular weight drugs
Direct delivery of drug to CNS system	• Bypass BBB, via olfactory region • Useful for local and systemic delivery
Avoids harsh environment	• Less chemical and enzymatic degradation
Low dose required	• Avoids first pass metabolism • Avoids GIT degradation • Lower side effects • High bioavailability

Table II. Limitations (associated factors) of intranasal delivery (Garg et al. 2014a).

Limitations	Factors
Reduced capacity of nasal absorption means low bioavailability	Due to pathologic conditions such as cold or allergies, which may significantly alter the nasal bioavailability
Sometimes, the drugs cause irritation and irreversible damage of the cilia on nasal mucosa	Due to constituents added in dosage forms
Defense mechanisms such as muco-ciliary clearance influence permeability of drug	Enzymatic barrier to permeability of drug
Disrupt and dissolve nasal membrane	Due to high concentration of absorption enhancers
High molecular weight compounds cannot be supplied (mass cut off - 1 kDa)	Volume of 25–200 l that can be distributed into the nasal cavity is inadequate

Barriers for nasal drug delivery

Low bioavailability, muco-ciliary clearance, and enzymatic degradation act as major barriers for nasal drug delivery. Some important characteristics of various barriers which mainly affect the nasal drug delivery are discussed below.

Low bioavailability (Illum 2000)

• Bioavailability of polar drugs is mainly low (about 10% for low molecular weight drugs and 1% for peptides such as calcitonin and insulin).

• With a large molecular weight, polar drugs have limited nasal absorption.

• Drugs can cross the epithelial cell membrane by the transcellular and paracellular routes between cells.

• Polar drugs with a molecular weight below 1000 Da will pass the membrane by the latter routes.

• Nasal absorption of polar drugs is enhanced by co-administration of absorption-enhancing agents.

• Polarity lipophilic:

1. LMW lipophilic -100% bioavailability

2. HMW amphipathic -10% bioavailability

3. Peptides < 1%

Examples

• Surfactants (Sodium lauryl sulfate, sodium dodecyl sulfate, phosphatidylcholines, laureth-9)

• Bile salts (Sodium glycocholate, sodium taurocholate, sodium deoxycholate)

• Fatty acids and their derivatives (linoleic acid)

• Phospholipids (lysophosphatidylcholine)

• Various cyclodextrin and cationic compounds like chitosan, poly-L-arginine, and poly-L-lysine

• Fusidic acid derivatives (sodium tauradihydrofusidate)

Muco-ciliary clearance (Soane et al. 1999)

It is an essential factor which involves the combined action of the mucus and cilia, which defend against inhaled foreign particles in the respiratory tract.

• Across the nasal mucosa, it leads to decreased transport of drugs because of high clearance.

• It has also been shown that for liquid and powder formulations which are not bioadhesive, the half-life for clearance is of the order of 15–30 min.

• The bioadhesive excipients are used in the formulations as an approach to overcome the rapid muco-ciliary clearance.

• The clearance may also be decreased by depositing the formulation in the anterior and less ciliated part of the nasal cavity, thus leading to improved absorption.

Enzymatic degradation (Garg et al. 2014d)

• When peptides and proteins cross the nasal mucosa, there is the possibility of an enzymatic degradation of the molecule in the lumen of the nasal cavity or during passage through the epithelial barrier, which can limit the bioavailability of the drug.

• These two sites contain exopeptidases such as mono and diamino peptidases, that can cleave peptides at their N and C termini, and endopeptidases such as serine and cysteine, which can attack internal peptide bonds. The use of enzyme inhibitors, cosolvents, and prodrugs may be the approaches to overcome this barrier.

Mechanism of drug absorption

The first step in the absorption of drug from the nasal cavity is passage through the mucus. Small, uncharged particles easily pass through this layer, though large or charged particles may find it more difficult to cross. The principle protein in the mucus is mucin, which has the potential to bind to solutes, hindering diffusion (Garg et al. 2014b). Structural changes in the mucus layer are possible as a result of environmental changes (i.e. pH, température, etc.) subsequent to a drug's passage through the mucus. Different mechanisms for absorption through mucosa exist (Garg et al. 2014c). They include transcellular (simple diffusion across the membrane) and paracellular transport (movement between cell and transcytosis by vesicle carriers). Drug absorbed can potentially be metabolized before reaching the systemic circulation, and has limited residence time in the cavity (Garg et al. 2011a). Different mechanisms, such as passive diffusion (transcellular), passive diffusion (paracellular), carrier-mediated transport, transcytosis, absorption, and efflux transport have been used for drug transport through the nasal epithelium (Garg et al. 2011b). Table III discusses some important comparisons between the two mechanisms, which are widely used in drug transport through the nasal epithelium.

Table III. Mechanism of drug passage through the mucus.

First mechanism (Paracellular process)

Second mechanism (Transcellular process)

• It has an aqueous route of transport. • The process occurs between the cell and transcytosis by vesicle carrier • This route is slow and passive • It is suitable for hydrophilic drugs • There is an inverse log–log correlation between intranasal absorption and the molecular weight of water-soluble compounds • Poor bio-availability was observed for drugs with a molecular weight greater than 1000 Daltons

• It has a lipoidal route of transport • By an active transport route, drugs also cross cell membranes via carrier-mediated transport through the openings of tight junctions • It is a means of the transport of lipophilic drugs that show a rate-dependency on their lipophilicity • For example, chitosan, a natural biopolymer, opens tight junctions between epithelial cells to facilitate drug transport

Factors influencing nasal drug absorption

Factors related to drug

Molecular weight

Fisher et al. concluded that the permeation of drugs less than 300 Da is not significantly influenced by the physicochemical properties of the drug (like molecular weight, size, formulation pH, and pKa of molecule). As molecular weight increases, nasal absorption of drug increases (Fisher et al. 1992).

Chemical form

The chemical form of the drug is an important factor for absorption. Conversion of the drug into a salt or an ester form can change its absorption; for example in situ absorption of carboxylic acid esters of L-tyrosine was significantly greater than that of unmodified L-Tyrosine (Garg et al. 2012b).

Polymorphism

Polymorphism affects the rate of drug dissolution, solubility, and absorption through biological membranes (Garg et al. 2013).

Solubility & dissolution rate

Both are important factors in determining nasal absorption of drugs from powders and suspensions. In the nasal cavity, the deposited particles need to be dissolved prior to absorption. No absorption takes place if particles remain in the nasal cavity. The mucosa in nasal cavity is insufficient for dissolution of drug particles, when compared to gastrointestinal fluid available in the case of oral drug delivery (Goyal et al. 2013a).

Lipophilicity

On increasing lipophilicity, 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 membranes through the transcellular route, since they are fit to partition into the lipid (bilayer) of the cell membrane and diffuse into and traverse the cell in the cell cytoplasm. Systemic bioavailability is decreased due to the hydrophilic nature of many drugs (Goyal et al. 2013b).

Partition coefficient and pKa

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 a study of the constant relationship between the physicochemical properties of drugs and their nasal absorption, the results showed that a quantitative relationship existed between the partition coefficient and the nasal absorption constant.

• In biological tissues, drug concentration increases with increase in the lipophilicity or partition coefficient of the drug (Goyal et al. 2014a).

Factors related to formulation

Physicochemical properties of formulation

pH and mucosal irritation

In addition to the properties of the nasal surface, the pH of the formulation can affect a drug's permeation. Both the pH and pKa of drug are considered to rationalize systemic absorption. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5. Avoiding irritation results in obtaining efficient drug permeation and prevents the growth of bacteria. Nasal secretions contain lysozyme, which, at acidic pH, destroys certain bacteria. Under alkaline conditions, lysozyme is inactivated and the nasal tissue is susceptible to microbial infection (Goyal et al. 2014b).

Osmolarity

Isotonic solutions are administered for shrinkage of the nasal epithelial mucosa, because of the effect of osmolarity on the absorption. This results in increased permeation of the compound because of structural changes. Isotonic solutions also known to inhibit or cease ciliary activity (Hussain et al. 2014).

Viscosity

A higher viscosity of the formulation increases contact time between the drug and the nasal mucosa, thereby increasing permeation time. At the same time, highly viscous formulations interfere with the normal functions like ciliary beating or muco-ciliary clearance, and thus alter the permeability of drugs (Johal et al. 2014).

Buffer capacity

Nasal formulations are administered in small volumes ranging from 25 to 200 μL. Therefore, nasal secretions may alter the pH of the administrated dose, which can affect the concentration of nonionized drug available for absorption. Hence, an adequate formulation buffer capacity may be required to maintain the pH in situ (Joshi et al. 2014a).

Drug concentration, dose, & dose volume

These are three interrelated parameters that impact the performance of the nasal delivery.

• Therapeutic dose: upper limit 25 mg/dose

• Higher the drug concentration, higher the permeation

• Dose volume: 0.05–0.15 ml/dose (Joshi et al. 2014b)

Physiological factors

Effect of deposition on absorption

Deposition of the formulation in the anterior portion of the nose provides a longer nasal residence time and better absorption, and this is an area of low permeability, whereas in the posterior portion of the nose, where the drug permeability is generally higher, the deposited drug is eliminated by muco-ciliary clearance and therefore has a shorter residence time. (Kalia et al. 2014).

Nasal blood flow

The nasal mucosal membrane is very rich in vasculature and plays an important role in thermal regulation and humidification of the inhaled air, and therefore the drug absorption will depend upon the vasoconstriction and vasodilatation of the blood vessels (Kataria et al. 2014).

Effect of enzymatic activity

Many enzymes might affect the stability of drugs which are present on the nasal mucosa. For example, proteins and peptides are subjected to degradation by proteases and amino-peptidases at the mucosal membrane (Kaur et al. 2014a).

Effect of muco-ciliary clearance

The muco-ciliary clearance is inversely related to the residence time, and therefore inversely proportional to the absorption of drugs administered. It is important to maintain the nasal clearance mechanism to perform normal physiological functions like removal of dirt, allergens, and bacteria (Kaur et al. 2014b).

Effect of pathological conditions

Intranasal pathologies such as infections, nasal surgery, cold, and allergic rhinitis may affect the nasal muco-ciliary transport process and/or capacity for nasal absorption. Nasal pathology also alters mucosal pH, and thus affects the absorption of drugs (Kaur et al. 2014c).

Strategy to overcome these factors

Different methods to improve nasal absorption

Permeation enhancers

A variety of permeation enhancers have been investigated to improve the nasal absorption, like fatty acids, bile salts, phospholipids, surfactants, cyclodextrin, etc., which act via different mechanisms such as inhibition of enzyme activity, reduction of mucus viscosity, decreasing muco-ciliary clearance, opening tight junctions, and solubilizing or stabilizing the drug (Kaur et al. 2014d).

Prodrug approach

Prodrugs are the inactive chemical moiety which become active at the target site. This approach is mainly used to improve the physicochemical properties such as taste, solubility, and stability of formulation. This approach includes derivatization of C and N termini, esters, and cyclic prodrugs (Kaur et al. 2014f).

In situ gel

The conversion into gel by the influence of stimuli including temperature, pH, and ionic concentration, is possible with substances like Carbopol, cellulose derivatives, lecithin, chitosan, etc. (Kaur et al. 2014e). These formulations generally control the problems of administration.

Nasal enzyme inhibitors

Enzyme inhibitors like protease and peptidase are used as inhibitors for the formulation of peptide and protein molecules. Other examples are bile salts, amastatin, bestatin, boroleucine, fusidic acids, etc. (Kaur et al. 2014g).

Structural modification

Drug structure can be modified without changing the pharmacologic activity, to improve nasal absorption. Chemical modifications are mainly used to modify the physiochemical properties of the drug such that they lead to improved nasal absorption of drug (Kaur et al. 2014h).

Mucoadhesion

Mucoadhesion can be defined as the state in which two materials are held together for a long period. Mucoadhesive polymers make intimate contact with the biological membrane, and after the establishment of contact, they penetrate into the tissue surface. Natural polymers can be easily obtained from natural sources, and require an environmentally-friendly method of processing with low cost. Some examples include potato starch, rice starch, maize starch, wheat starch, guar gum, tragacanth, xanthan gum, etc. Synthetic polymers produce environmental pollution during synthesis, and have a high cost of production. These polymers include poly ethylene oxide, poly vinyl alcohol, methyl cellulose, ethyl cellulose, hydroxyl propyl methyl cellulose, etc. (Kaur et al. 2014i).

Nasal formulations

Various nasal formulations such as nasal drops, nasal sprays, nasal gels, nasal powders, nasal inserts, nasal ointments, and so on, are used to deliver the drug into the target site that is brain (Figure 1) (Kaur et al. 2014j). Among these formulations, in situ gelling systems are widely used for brain targeting.

Figure 1. Various forms of nasal formulations.

In situ gelling system

For the past 30 years, greater attention has been directed towards the development of controlled and sustained drug delivery systems. A vast amount of research has been carried out in designing polymeric systems such as in situ gels (Kaur et al. 2014k). This system has received significant attention over the past few years. In Latin, in situ means ‘in position’ or ‘in its original place’ (Malik et al. 2014). The routes of administration for in situ gel could be oral, ocular, rectal, vaginal, injectable and intra-peritoneal. “Gel” is the state between liquid and solid, which consists of physically crosslinked networks of long polymer molecules, with liquid molecules trapped within a three dimensional polymeric network swollen by a solvent (Marwah et al. 2014). Many numbers of in situ gel-forming systems have been investigated, and many copyrights for their use in different biomedical applications, including drug delivery, have been reported (Peppas and Langer 1994). This system is a liquid aqueous solution before the administration, and a gel at physiological conditions. Prolonged and sustained release of the drug is reproducible, and the in situ gel is biocompatible, with magnificent stability and reliable quantities of medication, making it more accurate (Modgill et al. 2014a). There are various routes for in situ gel drug delivery, for example, oral, ocular, vaginal, rectal, intravenous, intraperitoneal, etc. (Modgill et al. 2014b). This new idea of making a gel in situ was proposed for the first time in the early 1980s. Gelation happens through crosslinking of the polymer chain, which can be attained through covalent bond formation (chemical crosslinking) or non-covalent bond formation (physical crosslinking) (Carlfors et al. 1998). The major advantages of in situ gel systems are the ease of administration, improved local bioavailability, reduced dose concentration, reduced dosing frequency, improved patient compliance and comfort, and simple formulation and manufacturing, involving less investment and cost (Morie et al. 2014). Different mechanisms exist which provoke the formulation of in situ gels, such as those based on physiologic stimuli (e.g. temperature modifications, pH-triggered systems) (Pabreja et al. 2014), those based on physical changes in biomaterials (e.g. solvent exchange and swelling) (Rohilla et al. 2014a), and those based on chemical reactions (e.g. UV radiation, ionic crosslinking, and ion-activated systems) (Rohilla et al. 2014b). In this approach, there is no need for any organic solvents, copolymerization agents, or a directly applied trigger for gelation (Cho et al. 2003). In situ gel formulation is executed for targeted delivery through the vaginal and rectal routes, and the nasal mucosa, circumventing the hepatic first pass metabolism, which is basically important for the delivery of proteins and peptides that are usually administered via the intravenous route because of their susceptibility to the gastrointestinal proteases (Illum 2003).

Mechanisms of in situ gelling systems

Physiological stimulus-based in situ formulation

Thermally triggered systems

In drug delivery research, the temperature-responsive hydrogels are probably the most usually studied class of environment-responsive polymer systems, because they are easy to control and have practical advantages, both in vitro and in vivo. Gelling can be achieved by means of a polymer that is a solution at room temperature (< 25°C) and undergoes gelation when it comes in contact with the site of application due to an increase in temperature (35–37°C) (Wei et al. 2002). The ambient and physiologic temperature is the best significant temperature range for such a system, such that experimental management is facilitated and no external source of heat is required to cause gelation. A temperature-sensitive in situ gel undergoes a volume phase-transition or sol-gel phase-transition at a critical temperature, specifically at the lower critical solution temperature (LCST) or upper critical solution temperature (UCST). LCST polymers reveal a hydrophilic-to-hydrophobic transition with increasing temperature. LCST polymers include poly (N-isopropylacrylamide) (PNIPAM), poly (N,N-diethylacrylamide) (PDEAM), poly(vinyl ether) (PVE), poly(N-vinylalkylamide) (PNVAAM), polyphosphazene derivatives, and poly(ethylene oxide)-b-poly(propylene oxide) (PEO-b-PPO). UCST polymers exhibit a hydrophobic-to-hydrophilic transition with increasing temperature. UCST polymers include polyacrylamide/poly acrylic acid interpenetrating polymer networks (PAAm/PAAcIPN) (Sharma et al. 2014a).

They are classified into:

1. Positively thermosensitive gels

2. Negatively thermosensitive gels

3. Thermally reversible gels (Table IV)

Table IV. Characteristics of different thermosensitive gels.

Types	Characteristics of different thermosensitive gels
Positively thermosensitive	A positive temperature-sensitive hydrogel has an upper critical solution temperature (UCST), such hydrogels contract upon cooling below this UCST Ex. Poly(acrylic acid), Poly(acrylamide-co-butyl methacrylate)
Negatively thermosensitive	These gels have a lower critical solution temperature (LCST), and contract upon heating above LCST. Most investigated polymers exhibit useful LCST transition, for example Poly(N-isopropylacrylamide), which is a water-soluble polymer at low LCST, but hydrophobic above LCST, which results in precipitation of PNIPAAm from the solution at the LCST
Thermo reversible gels	They are prepared from Pluronics and Tetronics, and also from naturally occurring polymers and cellulose derivatives (methyl cellulose, HPMC, and ethyl (hydroxyl ethyl) cellulose (EHEC). Pluronics are poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock co-polymers that are fluid at low temperature, but thermoresponsive gels when heated, as a consequence of a disorder-order transition in micelle packing, which makes these polymers appropriate for in situ gelation For example natural polymers such as gelatin and carrageen show sol-gel transition. Before cooling, a continuous network is formed by partial helix formation (Qiu and Park 2001).

These three principal mechanisms have been proposed to explain the sol-to-gel transition after an increase in temperature.

• Gradual dissolution of the polymer,

• Increased micellar aggregation, and

• The improved embarrassment of the polymeric network.

pH-Triggered systems

The pH is another important environment-sensitive parameter for drug delivery, because the pH change occurs at many specific or pathologic body sites, for example stomach, intestine, endosome, vagina, blood vessels, lysosome, and tumor extracellular sites. All pH-responsive polymers contain suspended acidic or basic groups that also accept or release protons in response to changes in environmental pH. Polyelectrolytes are known as the polymers with a large number of ionizable groups (Sharma et al. 2014b).

• As the external pH increases, swelling of the hydrogel increases in the case of weakly anionic (acidic) groups, but decreases when the polymer contains weakly cationic (basic) groups. Examples: Anionic pH-responsive polymers are based on

  	–	Poly (acrylic acid) (PAA), (Carbopol)
  	–	Polyvinyl acetal diethylaminoacetate solutions form hydrogels at a neutral pH condition at pH 4, with a low viscosity.
  	–	Other examples are Polymethacrylic acid (PMMA), Polyethylene glycol (PEG), Cellulose acetate phthalate (CAP) latex, Pseudolatexes, etc. (Ron and Bromberg 1998).

In situ gel formation based on physical mechanism

In situ gel formation (physical mechanism) is based mainly on swelling and diffusion.

Swelling

In situ gel development occurs when the substance absorbs water from the surrounding environment and swells to cover the desired space. An example is Myverol 18–99 (glycerol mono-oleate), which is a polar lipid that swells in water to form lyotropic liquid crystalline phase structures that have some bioadhesive properties and can be degraded in vivo by enzymatic action (Sharma et al. 2014c).

Diffusion

Solvent exchange diffusion: In this method, the solvent diffuses from the polymer solution into surrounding tissue, and the outcome is precipitation or solidification of the polymer matrix. N- methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran, and triacetin have been shown to be useful solvents (Singh et al. 2014a).

In situ gel formation based on chemical reactions

Ionic crosslinking, enzymatic crosslinking, and photo polymerization chemical reactions mainly cause gelation.

Ionic crosslinking

In this class of in situ gels, the sol-to-gel transition is induced by the presence of various ions (mono or divalent cations such as Na+, K+, Ca++, and Mg++ ions) (84). Naturally occurring anionic polymers such as gellan gum, sodium alginate, carrageenan, and xyloglucan have the characteristic property of cationic-induced gelation.

• K-carrageenan forms stiff, delicate gels in response to small amounts of K⁺, i-carrageenan forms elastic gels mainly in the presence of Ca²⁺.

• Gellan gum, commercially available as Gelrite^® or Kelcogel^®, is an anionic deacetylated exo cellular polysaccharide secreted by Pseudomonas elodea that undergoes in situ gelling in the presence of mono- and divalent cations, including Ca²⁺, Mg²⁺, K⁺ and Na⁺, involving a three-dimensional network by complexation and hydrogen bonding with water.

• Low-methoxy pectin (degree of esterification < 50%) gelation can be caused by divalent cations, particularly in the presence of free Ca²⁺ ions which crosslink the galacturonic acid chains in a manner described by the egg-box model. Gelation of pectin also occurs in the presence of H⁺ ions (divalent ions). The main advantage is that pectin is water soluble, and therefore organic solvents are not needed.

• Similarly, alginic acid undergoes gelation in the presence of divalent/polyvalent cations. It is a linear block copolymer polysaccharide, for example Ca²⁺ due to the interaction with guluronic acid block in alginate chains (Singh et al. 2014b).

Xyloglucan is a polysaccharide derived from tamarind seeds. When xyloglucan is partially degraded by B- galactosidase, the resultant product exhibits thermally reversible gelation by the lateral stacking of the rod shaped chains. The sol-gel transition temperature varies with the degree of galactose elimination, and warming on body temperature, it forms thermally reversible gels (Kawasaki et al. 1999).

Enzymatic crosslinking

In this group of in situ gels, the sol-to-gel transition is catalyzed by natural enzymes. They have not been investigated broadly but seem to have some advantages over chemical and photochemical approaches. For example,

• An enzymatic process operates capably under physiologic conditions without the need for potentially harmful chemicals such as monomers and initiators.

• Intelligent stimuli-approachable delivery systems using in situ gels that can discharge insulin have been investigated.

• Cationic pH-responsive polymers containing immobilized insulin and glucose oxidase can swell, releasing the entrapped insulin in a pulsatile fashion in response to blood glucose level. A convenient mechanism for controlling the rate of gel formation is provided by adjusting the amount of enzyme, which allows the mixtures to be injected before gel formation (Podual et al. 2000).

Photo-polymerization

For over more than decade, in situ photo-polymerization has been used in biomedical applications. Monomers (reactive macromeres) and initiator solution can be injected into a tissue site. The application of electromagnetic radiation is used to form a gel.

• Acrylate or similar functional groups are typically used as the polymerizable groups on the individual monomers and macromere because they rapidly go through photo polymerization in the presence of a suitable photo initiator.

• Classically long wavelength UV and visible wavelengths are used; short UV wavelength is not used because of incomplete penetration of tissue and biological risk. For example, the initiator ketone, such as 2,2 dimethoxy-2-phenyl acetophenone, is used for UV photo-polymerization. Other initiators, camphorquinone and ethyl eosin, are used in visible light systems.

• Photo polymerizable systems, when introduced to the desired site via injection, get photo-cured in situ with the help of fiber optic cables and then discharge the drug for a prolonged period of time.

• At physiologic temperature, photo reactions provide rapid polymerization rates.

Moreover, the systems are easily placed in complex-shaped volumes leading to an implant formation (Burkoth and Anseth 2000).

Application of intranasal in situ gel delivery

Intranasal delivery is an economic, convenient, simple, and noninvasive method of delivery to target the brain. Through this system, various molecules, such as peptides, proteins, vaccines, analgesics, antidepressants, and antimalarial, antiepileptic, antimigraine, antiemetic, and anticonvulsant drugs etc., are successfully administered to the target site (Singh et al. 2012, Singh et al. 2014c). Table V gives an overview of reported studies related to drug delivery by in situ gel systems to the targeted site (brain).

Table V. Overview of studies reported related to in-situ gel.

Therapeutic molecules	Category	Polymer	Inferences	References
Artemether (Containing hydroxy propyl B- cyclodextrin) inclusion complex	Antimalarial	Pluronic, HPMC K4M	Showed good mucoadhesion strength and good stability at accelerated conditions over a period of 90 days.	Iguchi et al. (2014)
Bromohexine Hydrochloride	Oral mucolytic agent	Poloxamer (PLX), HPMC	Controlled release, increased permeation studied.	Hoffler et al. (1972)
Curcumin	Anti inflammatory	Capryol 90, Solutol HS 15, Transcutol HP	Compared to the IV route, the nasal route is better for direct drug transport to brain.	Wang et al. (2012)
Metoclopramide HCL	Antiemetic	Gellan gum, Xanthan gum	Sustained release of drug, improved drug absorption.	Kasirer et al. (2014)
Metoprolol Succinate	Antihypertensive	Pluronic F127, Sodium alginate	Bioavailability improved, avoid first pass effect.	Whayne (2014)
Midazolam HCL	Anticonvulsant	Pluronic F127, Carbopol 934P, HPMC	Increased bioavailability	Basu and Bandyopadhyay (2010)
Midazolam	Anticonvulsant	Ficus carica mucilage (0.5%,0.1%&1.5%) and synthetic polymers (HPMC and Carbopol 934)	Higher bioavailability, higher permeation through Ficus carica mucilage rather than synthetic polymers.	Basu and Bandyopadhyay (2010)
Mometasone furoate	Antiinflammatory	Gellan gum	Effective for allergic rhinitis.	Cao et al. (2009)
Ondansetron Hydrochloride	Antiemetic	PF 127 as thermosensitive HPMC as mucoadhesive	Increase in bioadhesive strength, diffusion-controlled release of drug.	Singh et al. (2013)
Ondansetron Hydrochloride	Cancer chemotherapy	Pluronics 127 P, HPMC	Diffusion-controlled release.	Chen et al. (2010)
Radix Bupleuri	Antipyretic	20% Poloxamer as gel base 6% PEG 4000	Longer residence and release time.	Chen et al. (2010)
Radix Bupleuri	Antipyretic	Gellan gum	Longer antipyretic effect through in situ gel rather than in situ solution.	Cao et al. (2007)
Sumatriptan Succinate	Antimigraine	Pluronic F127, Carbopol 974	Controlled drug release with higher permeability rate by using permeation enhancer, fulvic acid.	Zhao et al. (2014)
Sumatriptan succinate	Antimigraine	Pluronic F127 as mucoadhesive polymer (18%w/v) Carbopol 934P (0.3 w/v)	Higher permeation rate because of good mucoadhesive strength and gelation temperature	Majithiya et al. (2006)
Zolmitriptan	Antimigraine	Sterculia foetida gum	Improved bioadhesion, increased permeation, and increased bioavailability of drug.	Bird et al. (2014)
Zolmitriptan	Antimigraine	Pluronic (F127), Pluronic (F68)	Gelation temperature Decreased, with Mucoadhesive content increased.	Doring et al. (2014)

Conclusions

This study has been conducted in view of prevalent interest in intranasal mucosal delivery, which provides a needle-free, non- invasive method of targeting the brain by passing the BBB and avoiding hepatic first-pass metabolism in delivering the drug to the brain. This method 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. It is predictable that intranasal formulations will go on to achieve market potential. The nasal mucosa offers controlled-release drug delivery, but due to certain limitations, the use of the intranasal route for administration of drugs is limited. To decrease these limitations, the mucoadhesive polymeric system is used. The first requirement for controlled drug delivery is to focus on patient comfort, which is offered here by the in situ gelling system. In situ gels also offer a number of other advantages, such as prolonged or sustained release of drug. For the past few decades, extraordinary and novel research on pH-induced, temperature-sensitive, and ion-induced gel-forming formulations have been described in literature. Use of good biodegradable biocompatible, and water-soluble polymers to formulate in situ nasal gels can make them further suitable and excellent as drug delivery systems.

Acknowledgements

The author Dr. Amit K Goyal is thankful to Department of Biotechnology (DBT), New Delhi (under IYBA scheme; BT/01/IYBA/2009 dated May 24, 2010).

Declaration of interest

The authors confirm that the content of this article has no conflicts of interest.