In Situ Forming Gels as Advanced Platforms for Nasal Drug Delivery

Intranasal drug delivery has been recognized as a therapeutic approach in the Ayurvedic system of Indian medicine since ancient times and has gained renewed interest in modern pharmaceutical research. The nasal route offers several advantages over conventional oral and parenteral administration, including rapid onset of action, improved systemic bioavailability, and avoidance of first-pass metabolism. The nasal mucosa provides a large, highly vascularized surface area with neutral pH and low enzymatic activity, which enhances drug permeability and absorption. Additionally, nasal administration minimizes the lag time associated with oral drug delivery and improves patient compliance due to its non-invasive nature and ease of self-administration. A significant advantage of this route is its potential for direct nose-to-brain drug delivery by bypassing the blood–brain barrier via the olfactory pathway, thereby increasing therapeutic efficacy while reducing systemic toxicity. Furthermore, intranasal delivery has emerged as a promising strategy for vaccination, as antigens administered to the nasal-associated lymphoid tissue can induce both humoral and cell-mediated immune responses, making it particularly suitable for rapid mass immunization programs, especially in developing countries [ Qian et.al 2025].^(1,2)

Figure 1 : Nasal Delivery Route

Nasal Drug Delivery System:         

1] Local (Topical) Delivery:

Intranasal route is mainly used for treatment of nasal disorders.

Common conditions treated:

• Rhinosinusitis
• Allergic rhinitis
• Common cold

Commonly used drugs:

• Antihistamines
• Corticosteroids
• Nasal decongestants

Advantages:

• Rapid onset of action
• Quick relief of nasal symptoms
• Reduced systemic side effects
• Intranasal route is the primary choice for local nasal therapy [Chand P et.al].⁽³⁾

2] Systemic Delivery

Acts as an alternative to:

• Oral route
• Injectable (intravascular) route

Advantages:

• Avoids first-pass metabolism
• Improved bioavailability
• Faster absorption

Examples of drugs administered intranasally for systemic action:

• Analgesics: Morphine
• Cardiovascular drugs: Propranolol, Carvedilol
• Hormones: Insulin, Levonorgestrel, Progesterone
• Anti-inflammatory drugs: Indomethacin, Ketorolac
• Antiviral drugs: Acyclovir [Karavasali C et.al].⁽⁴⁾

Anatomy And Physiology of Nose:

Anatomy of the Nose : Surrounds the nostrils

Includes about one-third of the nasal cavity.

Nasal cavity: Divided into two chambers

Approximate dimensions: Height: 5 cm Length: 10 cm

Total surface area: ~150 cm² Total volume: ~15 mL

Nasal valve (internal ostium): Located ~1.5 cm from the nares Narrowest part of the nasal airway

Cross-sectional area: ~30 mm² on each side responsible for ~50% of total nasal airflow resistance applied Physiology of the Nose.

Physiology of Nose:

• Olfaction (Smell)
• Sensory function
• Conditioning of Inspired Air
• Warming of air
• Humidification of air
• Filtration/cleaning of inhaled air
• Removal of dust
• Removal of microorganisms

• Pathology of Rhinitis [Nields Mygind et.al].⁽⁵⁾

Figure 2: Anatomy Physiology Nose

Advantages Of Intranasal Delivery :

• Rapid Onset Of Action
• Less Drug Degradation
• High Rate Of Absorption
• High Patient Compliance
• Self Administration By Patient
• Direct Nose To Brain Delivery
• Non-invasive Drug Delivery.
• Avoid 1st Pass Metabolism
• Avoid BBB

Limitations :

• High Chances Of Drug Elimination
• Low Bioavailability
• Irreversible Damage Of Nasal Mucosa
• Drug Dose Loss Due To Improper Use
• Mechanical Loss Of Dose Due To Unprpoer Administration Technique
• Mechanism Of Drug Transport Still Un Clear
• Drug Elimination Due To Mucocilliary
• Clearance [MDPI]. ⁽⁶⁾

Barriers For Intranasal Delivery :

1] Low Bioavailability of Nasal Drugs

• The nasal route shows low bioavailability, especially for polar drugs and peptides.
• Low molecular weight polar drugs show about 10% bioavailability.
• Peptides and proteins (e.g., insulin, calcitonin) show less than 1% bioavailability.
• High molecular weight drugs have poor nasal absorption.
• Drug Transport Pathways

Drugs cross the nasal membrane by:

• Transcellular route (through cells) paracellular route (between cells).
• Polar drugs with molecular weight below 1000 Da mainly use the paracellular route.
• Nasal absorption of polar drugs can be improved by using absorption enhancers.
• Effect of Polarity and Molecular Weight.
• Low molecular weight lipophilic drugs → ~100% bioavailability
• High molecular weight amphipathic drugs → ~10% bioavailability
• Peptides → < 1% bioavailability

Examples of Absorption Enhancers :

• Surfactants: Sodium lauryl sulfate, sodium dodecyl sulfate
• Bile salts: Sodium glycocholate, sodium taurocholate
• Fatty acids: Linoleic acid
• Phospholipids: Lysophosphatidylcholine
• Polymers: Chitosan, poly-L-arginine, poly-L-lysine
• Others: Fusidic acid derivatives

2] Mucocilliary Clearance :

• Mucocilliary clearance is the natural cleaning process of the nose.
• It removes foreign particles but also clears drugs quickly.
• Non-bioadhesive formulations are cleared within 15–30 minutes.
• This reduces drug absorption.

3] Enzymatic Degradation:

• Use bioadhesive excipients.
• Retain formulation in the anterior (less ciliated) part of the nasal cavity.
• Enzymatic Degradation
• Peptides and proteins may be broken down by enzymes in the nasal cavity.
• This leads to reduced bioavailability.

   Types of Enzymes :

• Exopeptidases: Break peptide ends (N and C terminals)
• Endopeptidases: Break internal peptide bonds
• Solutions
• Use enzyme inhibitors
• Use co-solvents
• Develop prodrugs[Kaur P et.al].⁽⁷⁾

Mechanism Of Drug Absorption [Y.B Chavan et.al].⁽⁸⁾ :

1] Transcellular Route (Through the cells)

Drugs pass through the epithelial cells by crossing the lipid membrane. Absorption mainly depends on lipid solubility and molecular size.

a) Passive Diffusion

• Most common transcellular mechanism
• Small, lipophilic drugs are absorbed easily
• Nasal absorption decreases sharply when molecular weight > 1000 Da
• Absorption depends on:
• Molecular size
• Degree of ionization
• Drug pKa and nasal pH (5.5–6.5)

b) Carrier-Mediated Transport

• Involves specific transport proteins
• First suggested by Kimura et al.
• Transporters present in nasal mucosa include:
• P-glycoprotein
• Organic cation transporter
• Dopamine transporter
• Amino acid transporters
• Mainly found in olfactory mucosa
• Important for transport of amino acids, amines, and cations

c) Endocytic Process

• Drug/particles taken into cells by vesicle formation
• Mostly occurs through M cells
• Useful for vaccine and gene delivery
• Naked DNA uptake is poor, so:
• Nanoparticles
• Hypotonic shock are used to improve uptake

2) Paracellular Route (Between the cells)

Drugs move between adjacent epithelial cells via tight junctions

Occurs by passive diffusion or solvent drag

Suitable for small, hydrophilic, polar, and charged drugs

Effective for drugs with molecular weight < 1000 Da

Transport follows Fick’s First Law of diffusion

Tight junctions are the main barrier limiting this route

Profile of an Ideal Drug Candidate for Nasal Delivery [Kundan A et.al]⁽⁹⁾

IN-SITU NASAL GEL :

 Intranasal delivery is one of the most interesting and challenging endeavors facing pharmaceutical scientists. The conventional nasal drug delivery systems including solutions, suspensions, and ointments show drawbacks such as short residence in the nasal cavity, highly variable efficiency, low permeability, and inconvenient administration. In situ gel-forming systems are an interesting polymeric system that exists as flowing aqueous solution before administration and undergoes phase transition to form a viscoelastic gel in a physiologic environment. Benefiting from the merits of both a solution and a gel, an impressive number of in situ gel-forming systems induced by temperature, pH, and ions have been prepared for use in nasal drug delivery in the past few years. In situ gel-forming systems increase the retention of drugs in the nasal cavity, and some of them also show permeation-enhancing capabilities. This article reviews the in situ gel-forming systems used for nasal drug delivery and introduces their gelling mechanisms and other favorable features for intranasal delivery. It also describes the release patterns and drug stability of in situ gels as well as their in vivo performances and local safety following nasal administration [Kothiyal P et.al].⁽¹⁰⁾

PROPERTIES OF NASAL IN- SITU GEL :

• It should have a long residence time.
• It should be low viscous.
• Free-flowing allows for reproducible administration to the nasal cavity.
• The nasal in-situ gel follows the phase transition mechanism and shear forces in nasal cavity wall.

APPROACHES OF IN-SITU GELLING SYSTEM :

 Various approaches for an in-situ gelling system:

 A) Stimuli Responsive In-Situ Gelling System

    1. Temperature induced in-situ gel system.

    2. pH induced in-situ gel systems.

 B) Osmotically Induced In-Situ Gelling System

 C) Chemically Induced In-Situ Gelling System

    1. Ionic cross linking.

    2. Enzymatic cross linking. 3. Photo- polymerization.

 D) In situ formation based on the physical mechanism.B [Ban MM et.al].⁽¹¹⁾

METHODS OF FORMULATION

1. Cold Method:

In this method, the drug is stirred with a sufficient quantity of double distilled water and kept overnight at 4°C in a refrigerator. The in situ gelling polymers are then added slowly with stirring. The dispersion is stored in a refrigerator till a clear solution is formed and finally volume is adjusted with distilled water. This method is chosen when poloxamer, chitosan or Carbopol is used as a gelling polymer. Considering the fact that polymeric dispersion of poloxamer is in solution at lower temperature and gets converted into a gel at higher nasal temperature because the solubility of polypropylene oxide chain of Poloxamer decreases at a high temperature which results in precipitation or salting-out of a polymer. Similarly, chitosan also requires the low temperature to remain as a solution at room temperature, its hydrophobicity increases temperature.

2. Hot Method:

 With an increase in Journal of Drug Delivery & Therapeutics. 2020; 10(2-s):183-197 B) Suspension Polymerization Spherical hydrogel microparticles with a size range of 1μm to 1mm are prepared by the suspension polymerization method. In the non-solvent solution, the monomer solution is dispersed to form fine droplets and a stabilizer is added in this solution to stabilize the fine droplets. Thermal decomposition of free radicals is used to initiate polymerization. Unreacted monomers, crosslinking agents and initiators are removed by washing from prepared microparticles. This method is used to prepare the hydrogel microparticles of polyvinyl alcohol.

3. Other methods of preparation:

 A) Solution polymerization/cross linking

 B) Suspension polymerization

 C) Polymerization by irradiation

 D) Chemically cross-linked hydrogel

 E) Physically cross-linked hydrogel [Nirmal HB et.al].⁽¹²⁾

DIFFERENT POLYMERS USED FOR THE PREPARATION OF IN-SITU GELLING SYSTEM [Xie H et.al]. ⁽¹³⁾