Design, Development of Herbal Thermosensitive In-Situ Nasal Gels Drug Delivery Systems

Abstract

Intranasal drug delivery has gained prominence as a non-invasive pathway for systemic and CNS-targeted treatments, bypassing first-pass hepatic metabolism, leveraging a vast vascularized absorptive surface, and enabling direct nose-to-brain transport through olfactory and trigeminal nerves. Herbal thermosensitive in-situ nasal gels mark a cutting-edge evolution in pharmaceutical formulations, merging herbal extract benefits with temperature-responsive polymers that gel in the nasal cavity. These systems shift from low-viscosity liquids at ambient temperature to rigid gels at mucosal levels (32-34°C), extending residence time and enhancing bioavailability. This review delves into key design principles, formulation approaches, optimization techniques, and characterization methods for these gels, highlighting polymer choices, herbal integration, mucoadhesion improvements, and regulatory standards. Drawing on recent studies, it equips formulators with practical, evidence-based strategies for development, quality assurance, and clinical advancement of these innovative nasal platformsIntranasal drug delivery has gained prominence as a non-invasive pathway for systemic and CNS-targeted treatments, bypassing first-pass hepatic metabolism, leveraging a vast vascularized absorptive surface, and enabling direct nose-to-brain transport through olfactory and trigeminal nerves. Herbal thermosensitive in-situ nasal gels mark a cutting-edge evolution in pharmaceutical formulations, merging herbal extract benefits with temperature-responsive polymers that gel in the nasal cavity. These systems shift from low-viscosity liquids at ambient temperature to rigid gels at mucosal levels (32-34°C), extending residence time and enhancing bioavailability. This review delves into key design principles, formulation approaches, optimization techniques, and characterization methods for these gels, highlighting polymer choices, herbal integration, mucoadhesion improvements, and regulatory standards. Drawing on recent studies, it equips formulators with practical, evidence-based strategies for development, quality assurance, and clinical advancement of these innovative nasal platforms

Keywords

Thermosensitive polymers, in-situ gels, herbal extracts, nasal drug delivery, mucoadhesive polymers, polyoxamer, HPMC, nose-to-brain delivery, controlled release, nasal bioavailability

Introduction

1.1 Background on Nasal Drug Delivery

Intranasal administration emerges as a top non-invasive drug delivery option, surpassing standard oral and injectable routes with its unique physiological and pharmacokinetic strengths. The cavity's sophisticated mucosal coating provides ideal features for efficient drug absorption. .[1][3] Highlights include a broad absorptive zone (100-150 cm²), rich blood vessel network with vigorous circulation, and a thin epithelial membrane (~10 μm) that accelerates medication transfer. Compared to the gut, the nasal lining shows far less enzyme activity, shielding compounds from metabolic destruction.[6] A standout feature of the nasal administration is its pathway straight towards the brain avoiding BBB roadblocks it achieves direct CNS entry for therapeutic compounds using dual conduits olfactory ferrying medications via scent neurons to the olfactory bulb before dispersal across brain tissues and trigeminal propelling substances through nerve tips in the nasal airway lining these links offer revolutionary chances to tackle brain-wasting diseases mental disorders and further CNS troubles once held back by the BBBs tight gates.[80][86]

1.2 Challenges in Nasal Drug Delivery

Even with these benefits traditional nasal preparations encounter major hurdles that hinder their therapeutic performance mucociliary clearance poses the biggest obstacle built-in protective process that sweeps out intruders from the nasal area within 15-30 minutes this rapid expulsion shortens drug dwell time leading to poor uptake and diminished effectiveness many compounds also suffer from low water solubility curbing nasal bioavailability moreover elevated protease levels in some nasal zones can break down peptide and protein drugs prior to absorption.[38] Standard liquid drops for nasal use get quickly flushed away offering minimal contact with the nasal lining and requiring repeated applications to sustain effective drug concentrations these shortcomings have driven researchers in pharmaceutics to innovate sophisticated systems that counteract such issues and prolong medication retention within the nasal space.[38]

1.3 In-Situ Gels as Solution to Nasal Delivery Challenges

In-situ gelling systems mark a revolutionary advance in intranasal medication delivery delivered as low-viscosity liquids at ambient conditions they solidify into gel-like structures on the nasal mucosa shifting to a viscous state at body temperature 32-34c this temperature-triggered change yields key benefits curbing mucociliary removal extending contact duration in the nose enabling sustained drug release and boosting transport through the nasal barrier.[2][3]

 

In-situ thermosensitive gels transform intranasal therapy by overcoming short mucosal retention they solidify into sturdy matrices at nose temperature fostering prolonged drug-mucosa proximity to enhance uptake and boost bioavailability. .[1][4]

1.4 Herbal Extract Integration in Nasal Formulations

Blending herbal extracts into intranasal delivery platforms fuses age-old herbal wisdom with modern pharma innovation these botanicals feature multifaceted active ingredients boasting proven benefits like reducing inflammation combating oxidation fighting microbes and regulating immunity frequently employed herbal extracts in nasal systems include: Moringa olifera, Essential oils, Curcumin.[2][30][33] moringa oleifera loaded with polyphenols and vitamin c delivers powerful antioxidant and anti-inflammatory benefits ideal for allergic rhinitis and nasal inflammation treatments curcumin main curcuminoid from turmeric curcuma longa provides broad pharmacological actions including anti-inflammatory antioxidant neuroprotective and antimicrobial effects clinical studies show it reduces nasal symptoms and balances immune activity in allergic rhinitis essential oils eucalyptus peppermint and tea tree oils offer decongestant antimicrobial and anti-allergic properties making them excellent additions to herbal nasal formulation.[33] Developing natural thermosensitive intranasal gels blends these botanical advantages with state-of-the-art delivery systems heightening therapeutic effect decreasing frequency of dose and strengthening adherence of patient.

 

2. Polymer Systems for Thermosensitive In-Situ Gels

2.1 Thermo-responsive Polymers: Mechanism and Selection

Thermosensitive polymers feature reversible sol gel transitions triggered by temperature shifts choosing suitable thermos-responsive polymers proves essential for effective formulations as they dictate main gelation parameters like gelling temperature setting time gel rigidity and rheological behavior.

2.1.1 Poloxamer 407 (Pluronic® F127)      

Poloxamer 407, distributed as Pluronic® F127, stands out as the primary temperature-sensitive polymer used in intranasal in-situ gelling systems. This FDA-approved nonionic triblock copolymer with amphiphilic traits contains a hydrophobic poly(propylene oxide) (PPO) middle section bounded by two hydrophilic poly(ethylene oxide) (PEO) arms, shown as (PEO)???-(PPO)??-(PEO)???.[18][26][29]x Poloxamer 407 undergoes thermogelling through a temperature-driven micelle assembly sequence below room temperature single polymer chains remain dissolved with hydration shells stabilizing the hydrophilic peo segments via water hydrogen bonds rising temperatures to body levels trigger dehydration of these chains sparking hydrophobic contacts between ppo cores that form micelles continued heating packs these micelles into structured cubic lattices yielding gel formation within 25-37c based on concentration.[1][16] Poloxamer 407 typically requires 15-20 wv concentrations to attain suitable gelation within nasal physiological temperatures 31-37c adjusting polymer levels allows control over gelation temperature where increased concentrations yield lower transition points incorporating additional polymers or solutes enables precise tuning of gel properties via cooperative or opposing interactions.[16]

3. Herbal Extract Selection and Integration

3.1 Pharmacological Properties of Herbal Extracts

Selecting herbal extracts for intranasal gel formulations demands verified pharmacological activity accurate botanical verification and compatibility with the gelling system.

3.1.1 Moringa olifera

It is also called as drumstick or miracle tree boasts an abundance of bioactive elements like isothiocyanates phenolic substances and vitamins celebrated for their proven medicinal value its leaves and seeds display robust anti oxidative capabilities through processes such as neutralizing neutralizing reactive oxygen species and binding metal ions metal ions rivaling the efficacy of conventional anti oxidative like ascorbic acid and -tocopherol.[2][30] Moringa oleiferas anti-inflammatory action derives from polyphenolic compounds that block inflammatory cytokines such as interleukins and tnf-alpha preclinical and clinical data validate its utility in allergic rhinitis treatment through integrated antioxidant and anti-inflammatory processes integration into thermosensitive nasal gels with mucoadhesive polymers enables m oleifera extracts to sustain localized anti-inflammatory benefits via enhanced mucosal retention.[2][30]

3.1.2 Curcumin and Curcuma longa Extract

Curcumin, the primary curcuminoid from turmeric (Curcuma longa), ranks among the most thoroughly studied natural anti-inflammatory agents. This polyphenolic compound shows broad biological effects in areas like anti-inflammatory action, antioxidant protection, neuroprotection, antimicrobial activity, and immune modulation.[72][75][81][85]  Curcumin curbs inflammation by blocking key pathways such as NF-κB signaling, MAPK activation (including p38, ERK, and JNK), and cytokine release. In allergic rhinitis patients, clinical trials show it reduces symptoms like sneezing, runny nose, and congestion by regulating immune markers—lowering IL-4, IL-8, and TNF-α while boosting protective IL-10.[72]

Curcumin poses challenges for nasal delivery due to its hydrophobicity and low water solubility (about 0.1 μg/mL). Incorporating it into thermosensitive gels with solubilizers enhances bioavailability, and its neuroprotective traits plus nose-to-brain transport potential make it ideal for CNS treatments.[84]

3.1.3 Essential Oils in Herbal Nasal Formulations

Essential oils such as eucalyptus, peppermint, and tea tree oil offer synergistic therapeutic benefits when included in herbal nasal gels.[33]

Eucalyptus oil: Loaded with 1,8-cineole (eucalyptol) and various terpenes, it delivers anti-inflammatory, decongestant, and mucus-thinning effects. Its decongestant action arises from gentle local irritation that induces reflex narrowing of blood vessels, easing nasal blockage.[33]

Peppermint oil: Featuring menthol and menthone as key components, it provides localized numbing, decongestant relief, and a cooling sensation. Its proven airway-relaxing properties make it suitable for addressing respiratory inflammation.[33]

Tea tree oil: Rich in terpineol and related terpenes, it exhibits antimicrobial effects against typical nasal bacteria like Staphylococcus aureus and Pseudomonas aeruginosa, plus anti-allergic benefits via stabilization of mast cells.[33]

3.2 Herbal Extract Preparation and Standardization

Seamless incorporation of herbal extracts into temperature-responsive nasal gels calls for standardized extraction methods and robust quality assurance procedures.

3.2.1 Extraction Methodologies

Aqueous Extraction: Water-based boiling or steeping works well for heat-tolerant, water-soluble compounds. This technique suits plant materials that readily integrate into water-based gel systems.[2][30]

Hydroalcoholic Extraction: Using ethanol or acetone extracts fat-soluble components effectively, with later dilution ensuring water compatibility. It excels at isolating polyphenols and essential oil fractions.[30][75]

Ultrasonic-Assisted Extraction: Sound wave cavitation boosts yield and speed while preserving bioactives by minimizing heat exposure.[2]       

 3.2.2 Standardization and Quality Control

HPLC Analysis: High-performance liquid chromatography measures key marker levels for reliable dosing across batches. In curcumin gels, it ensures 80-95% curcuminoid purity relative to total solids.[75]

Plant Verification: Visual and chemical profiling confirms species identity, avoiding contamination via TLC or HPLC patterns.[2][30]

Microbial Testing: USP <2021> protocols verify aerobic counts and absence of pathogens for safe herbal products.[2]

4. Formulation Development and Design Strategies

 

4.1 Cold Method for In-Situ Gel Preparation

The cold method is widely recognized as the standard technique for the formulation of thermosensitive in-situ nasal gels, as it promotes thorough polymer solubilization and maintains the stability of temperature-sensitive polymers. [1][7][13][19][22][35]

Procedure: Poloxamer 407 is gradually dispersed in chilled distilled water maintained at 4–10°C and stirred continuously using a magnetic stirrer for 24–48 hours to ensure complete hydration and dissolution of polymer chains. In parallel, HPMC or other viscosity-modifying polymers are separately dissolved in cold distilled water or an appropriate buffer. When Carbopol is used, it is dispersed in cold distilled water or 0.5% v/v dilute acetic acid and refrigerated overnight to achieve complete swelling and hydration.

Herbal extracts are prepared separately by dissolving them in suitable solvents such as distilled water, ethanol, or polyethylene glycol, depending on their solubility. The drug or herbal extract solution is then slowly introduced into the poloxamer dispersion under continuous stirring, while maintaining the temperature below 15°C. Subsequently, the HPMC solution is incorporated, followed by adjustment of the formulation pH to approximately 6.0–6.5 using sodium hydroxide or triethanolamine. The final volume is made up with distilled water or buffer solution, and the formulation is stored at 4°C until further evaluation and use to preserve its liquid state at room temperature. [1][7][13][19][22]

This systematic preparation approach prevents premature gel formation, ensures uniform polymer dissolution, and allows effective incorporation of herbal extracts, resulting in homogeneous and stable nasal gel formulations suitable for intranasal delivery.

5. Characterization and Evaluation Parameters

5.1 Physicochemical Characterization

Comprehensive physicochemical evaluation of herbal thermosensitive in-situ nasal gels is essential, as these parameters directly affect the formulation’s performance, efficacy, and safety.

5.1.1 pH Determination

The pH of formulations is measured using a calibrated digital pH meter in accordance with USP guidelines. [7][34][63][69] Although the nasal mucosa can tolerate a pH range of 3–10, the optimal pH for herbal nasal gels lies between 5.4–6.5. This range minimizes epithelial irritation, inhibits microbial growth, and maintains the solubility of bioactive herbal compounds. [2][7][34][63][69] For formulations containing polyphenolic constituents prone to oxidation, maintaining a slightly acidic to neutral pH (5.5–6.0) helps enhance stability. Measurements are conducted in triplicate, and results are reported as mean ± standard deviation.

5.1.2 Clarity and Appearance

Clarity and visual appearance are assessed by inspecting formulations under standard white light at room temperature (20–25°C) and after thermal gelation at 37°C in simulated nasal fluid. Ideal formulations appear transparent or slightly translucent at room temperature and convert into clear to mildly opaque gels at physiological temperature. [1][2][7] Optical microscopy at 10–40× magnification is used to detect particulate matter, crystals, or phase separation, which may indicate polymer aggregation or formulation instability. [1][7]

5.1.3 Gelation Temperature and Gelation Time

Methodology: Two milliliters of refrigerated formulation are placed in 10 mL glass test tubes (1 cm diameter) sealed with parafilm and immersed in a circulating water bath initially at 4°C. The bath temperature is gradually raised at increments of 1°C every 30 seconds, while the formulation is continuously monitored. [1][7][10][16][20]

Gelation temperature is defined as the point where the liquid formulation transforms into an immobile gel, determined visually or by rheological measurement (where storage modulus G' equals loss modulus G"). Gelation time is the duration required for gel formation at nasal physiological temperature (37°C), generally ranging from 30 seconds to 3 minutes. Shorter gelation times (<1 min) are desirable to prevent premature clearance before gel establishment. Optimal gelation occurs between 32–37°C, ensuring in-situ gelling upon nasal administration without premature solidification during storage or handling. [1][7][10][16][20]

5.1.4 Viscosity Determination

Rotational viscometers (e.g., Brookfield DV-II+) with temperature control at 37°C are employed to measure viscosity. [7][31][34] Measurements are performed at shear rates of 10–100 rpm using appropriate spindles (M4, M5, or RV) as per USP <911>. At room temperature (20–25°C), viscosity should allow easy administration via nasal sprays (typically 20–100 cP) to prevent rapid drainage. At 37°C, gel viscosity is critical for drug release, mucosal retention, and patient comfort. The optimal viscosity range is 1000–4000 cP, sufficient to maintain gel integrity without causing discomfort. HPMC significantly influences viscosity, with each 0.1% increase in HPMC K4M raising viscosity by approximately 200–300 cP. [1][2][19][34]

5.1.5 Gel Strength Determination

Gel strength is measured as the time required for a standardized penetrometer probe to penetrate 5 cm into the gel. [7][34]

Procedure: Fifty milliliters of gel (prepared at 32–34°C) are placed in 100 mL graduated cylinders. A disk probe (2.3 cm diameter, 0.5 cm thick) is lowered at a constant rate, and the time to reach 5 cm penetration is recorded. Acceptable gel strength values range from 25–50 seconds, ensuring sufficient integrity for nasal retention without causing mucosal trauma. Values above 50 seconds may induce discomfort, whereas values below 25 seconds can lead to rapid erosion and loss of formulation effectiveness. [7][34][59]

5.1.6 Drug Content Determination

The content of herbal extracts or active compounds is quantified using validated HPLC methods or other suitable analytical techniques based on the herbal material.

Procedure: A precisely weighed gel sample (1–2 g) is dissolved in a suitable solvent (phosphate buffer pH 6.4 or methanol) to achieve a concentration within the linear calibration range. Solutions are filtered through 0.45 μm membranes and analyzed using HPLC. For curcumin-based gels, quantification at 425 nm determines curcuminoid content, with typical drug content ranging from 95–102% of the theoretical value, indicating proper incorporation and formulation stability. [7][35][75]

Alternative evaluation methods for herbal extracts include:

• UV-Visible spectrophotometry for standardized extracts with marker compounds
• DPPH radical scavenging assays to assess antioxidant activity
• Total phenolic content measurement using the Folin-Ciocalteu method for polyphenol-rich extracts

5.2 Mucoadhesive Properties

5.2.1 Mucoadhesive Strength Determination

Mucoadhesive strength measurement quantifies the adhesive force between formulation and nasal epithelial tissue, critical for prolonging mucosal residence time.[7][31][34]

Procedure: Fresh goat or porcine nasal mucosa tissue (alternatively, freshly excised from animal models immediately after euthanasia) is carefully excised and mounted on the upper plate of a texture analyzer instrument. The lower plate is loaded with fixed gel amount (0.5-1.0 mL). Upper plate is lowered at constant velocity (10 mm/min) to establish intimate contact between mucosa and gel (contact force 0.1 N, contact duration 5 minutes). Upper plate is then raised at the same velocity, and detachment force is recorded.

Mucoadhesive strength, expressed as dynes/cm² or grams force, represents the force required to separate the mucosa from the gel. Values typically range from 4,000-10,000 dyne/cm² for adequately formulated thermosensitive nasal gels.[7][31][34][59]

Mucoadhesive strength increases significantly with increased concentrations of mucoadhesive polymers (HPMC, carbopol) and with chitosan incorporation, though excessive concentrations may compromise formulation ease of administration.[2][31][34][59]

5.2.2 Mucoadhesive Strength Alternatives

Wetting method: Measures extent of gel spreading on mucosal tissue surface, expressed as percentage coverage of mucosal area. This parameter provides complementary information regarding initial mucoadhesive interaction and formulation spreadability.[16][31] Residence time assessment: Quantifies duration of formulation retention on excised mucosa under simulated mucosal flow conditions. Modified vertical diffusion setups with controlled saline flow rates (0.1-0.5 mL/min) simulate mucociliary clearance, with gel washout percentage recorded at 30-minute intervals.[16]

5.3 In-Vitro Drug Release Studies

5.3.1 Dissolution/Release Methodology

In-vitro release studies assess sustained-release characteristics essential for extended therapeutic effect and prolonged mucosal residence time.[7][32][35][41] Apparatus and medium: USP Dissolution Apparatus II (paddle method) or modified vertical Franz diffusion cells are employed with receptor compartment containing 50-100 mL phosphate buffer (pH 6.4) or simulated nasal fluid, maintained at 37°C with gentle agitation (50-75 rpm for paddle, magnetic stirring for diffusion cells).[7][32][35][41] Sample collection: Aliquots (3-5 mL) are withdrawn at predetermined timepoints (0.5, 1, 2, 4, 6, 8, 12, 24 hours) with equal volume receiver medium replacement to maintain sink conditions. Samples are filtered through 0.45 μm membrane filters and analyzed by HPLC or spectrophotometry.[7][32][35][41] Release kinetics evaluation: Cumulative drug release percentages are plotted against time, with resulting profiles fitted to various kinetic models including:

- Zero-order kinetics (cumulative drug = k?t)

- First-order kinetics (ln remaining drug = -kt)

- Higuchi model (cumulative drug = k√t)

- Korsmeyer-Peppas model (cumulative release = kt^n) Majority of thermosensitive nasal gels demonstrate first-order release kinetics or Higuchi diffusion-controlled mechanisms, providing sustained drug release extending 8-12 hours or longer, compared to conventional liquid formulations releasing drug content within 2-4 hours.[7][35][75]

5.3.2 Relevance to In-Vivo Performance

In-vitro release studies, while standardized and predictive, provide indirect assessment of in-vivo therapeutic performance. Herbal extract formulations particularly require supplementary ex-vivo permeation and tissue uptake studies given botanical constituent complexity and multi-component bioactivity.[2][30][75]

5.4 Ex-Vivo Permeation Studies

5.4.1 Franz Diffusion Cell Methodology

Ex-vivo permeation studies assess actual drug transport across viable nasal epithelial tissue under physiologically relevant conditions, providing superior predictive value compared to in-vitro release studies alone.[31][35][46][52] Tissue preparation: Fresh nasal mucosa from goat, sheep, or pig (sacrificed for other purposes) is carefully dissected to remove underlying cartilage and connective tissue, creating 200-300 μm epithelial tissue specimens that retain physiological barrier properties while enabling efficient drug permeation measurement.[31][35][46]

Apparatus assembly: Tissue is mounted between donor and receptor compartments of Franz diffusion cells (effective diffusion area 0.636-2.0 cm² depending on apparatus design) with formulation added to donor compartment and physiological receptor medium (phosphate buffer pH 6.4 supplemented with 10% methanol to enhance sink conditions) circulated at controlled temperature (37 ± 0.5°C).[31][35][46]

Sampling protocol: Aliquots (200-500 μL) are withdrawn from receptor compartment at 0.5, 1, 2, 4, 6, 8, 12-hour intervals, with immediate replacement by fresh receptor medium to maintain sink conditions.[31][35][46]

Data analysis: Cumulative drug permeated (μg) is plotted against time, yielding linear portion from which flux (μg·cm?²·h?¹) is calculated from the slope. Apparent permeability coefficient (Papp = Flux/(C? × Area)) provides normalized permeability descriptor independent of formulation concentration and surface area, enabling comparative evaluation between formulations.[31][35][46]

5.4.2 Mucosal Integrity Assessment

Tissue viability is confirmed through transepithelial electrical resistance (TEER) measurement at initiation and conclusion of permeation studies, with viable tissue demonstrating TEER values ≥300 Ω·cm² and minimal variation (<20%) during study duration.[31][35][46][52] For herbal formulations, fluorescein sodium (Flu-Na) or lucifer yellow markers may assess paracellular pathway integrity, though recent findings indicate complex interactions between herbal components and epithelial barrier requiring careful interpretation.[46][52]

5.5 Particle Size and Zeta Potential Characterization

For herbal formulations incorporating nanoparticulate systems (herbal nanoparticles, nanoemulsions, solid lipid nanoparticles containing herbal compounds), dynamic light scattering (DLS) analysis characterizes particle size distribution and polydispersity index (PDI).[4][59][61]

Procedure: Appropriately diluted formulation samples (1:10 in distilled water) are analyzed at 25°C using DLS instruments with laser wavelength 633 nm. Results are expressed as mean particle size (nm) ± standard deviation and PDI (dimensionless, range 0-1 where <0.3 indicates narrow size distribution).[4][59][61] Zeta potential measurement employs electrophoretic light scattering, quantifying surface electrical charge (expressed in mV) that influences nanoparticle stability and mucosal interaction. Optimal zeta potential ranges from +20 to -20 mV for colloidal stability, with positive zeta potentials (+15 to +30 mV) preferred for chitosan-containing nanoparticles enabling electrostatic interaction with negatively charged mucosal surfaces.[59][61]

5.6 Rheological Characterization

Advanced rheological characterization provides mechanistic understanding of gel formation and in-vivo behavior patterns.

5.6.1 Dynamic Oscillatory Rheometry

Temperature sweep experiments monitor changes in storage modulus (G'), loss modulus (G''), and loss tangent (tan δ) as temperature increases from 20 to 37°C at constant frequency (1 Hz) and amplitude (1% strain).[16][26][73][76] Sol-gel transition temperature is identified at the crossover point where G' = G'', representing the gel point.[16][26] Below this transition, tan δ > 1 indicates liquid-like behavior; above transition, tan δ < 1 indicates gel-like elastic behavior.[26][73]

For optimal nasal formulations, sol-gel transition occurs at 32-37°C with sharp transition (<2°C temperature window) ensuring reliable in-situ gel formation at nasal temperature while preventing premature gelation during formulation handling and administration.[1][16][26] Frequency sweep experiments (0.1-100 Hz at constant temperature 37°C) characterize gel mechanical strength and viscoelastic nature. Formulations demonstrating G' >> G'' across the frequency range and minimal frequency dependence exhibit superior mechanical stability and enhanced resistance to mucociliary clearance.[16][26][73]

5.6.2 Shear Rate-Dependent Viscosity

Viscosity behavior across shear rates (1-100 s?¹) characterizes flow properties during nasal administration and subsequent residence time. Thermoresponsive gels typically demonstrate shear-thinning (pseudoplastic) behavior, with viscosity decreasing as shear rate increases, facilitating initial delivery through nasal spray devices while subsequently forming stable gel matrices at low-shear conditions in nasal cavity.[1][19][73]

5.7 Stability Assessment

5.7.1 ICH Stability Testing

Stability of herbal thermosensitive nasal gels is evaluated following International Conference on Harmonization (ICH) Q1A(R2) guidelines, encompassing long-term, intermediate, and accelerated testing conditions.[44][47][53]

Long-term storage: Formulations are stored at 25°C ± 2°C/60% RH ± 5% for 12 months, with sampling at 0, 3, 6, 9, and 12 months.[44][47]

Intermediate storage: Storage at 30°C ± 2°C/65% RH ± 5% for minimum 6 months.[44][47]

Accelerated storage: Storage at 40°C ± 2°C/75% RH ± 5% for minimum 3-6 months, with sampling at 0, 1, 3, 6 months.[44][47][53]

Evaluated parameters at each timepoint include clarity, pH, gelation temperature, gelation time, viscosity, drug content, gel strength, and appearance. Results are analyzed using first-order and zero-order degradation kinetics to predict shelf life and establish retest dates.[44][47]

5.7.2 Forced Degradation Studies

Forced degradation testing assesses formulation stability under stress conditions including elevated temperature (50-60°C), acidic (pH 2-3), neutral (pH 7), and basic (pH 9-10) pH, and oxidative stress (3% H?O?), enabling identification of degradation pathways and suitable packaging requirements.[44][47]

5.8 Biocompatibility and Safety Evaluation

5.8.1 Irritancy Assessment

Histopathological irritancy evaluation employs freshly excised rabbit or goat nasal mucosa exposed to test formulation for 4-6 hours in vertical Franz diffusion cells. Mucosa is subsequently fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned (5 μm), and stained with hematoxylin and eosin for microscopic examination.[2][7][33][34][63]

Histological scoring evaluates tissue damage including epithelial necrosis, inflammatory cell infiltration, edema, and hemorrhage on graded scales from 0 (none) to 4 (severe). Acceptable formulations demonstrate scores ≤1 (slight redness or minimal edema without epithelial damage).[2][7][33][34][63]

5.8.2 In-Vivo Irritancy Studies

Rodent nasal irritancy studies involve intranasal administration of test formulations (50-100 μL) to anesthetized animals with nasal cavity observation at 1, 4, and 24 hours post-administration for redness, swelling, discharge, or behavioral signs of discomfort. Terminal nasal tissue harvest enables histopathological confirmation of safety.[33][34][63]

6. Strategies for Bioavailability Enhancement

6.1 Mucoadhesion Enhancement

Optimizing mucoadhesive properties extends formulation residence time from 15-30 minutes (conventional liquid formulations) to 2-3 hours (thermosensitive gels), dramatically enhancing drug absorption and bioavailability.[1][3][38]

6.1.1 Polymer Selection for Mucoadhesion

High molecular weight HPMC (K4M, K15M, K100M grades) provides superior mucoadhesion compared to lower molecular weight grades, with longer polymer chains establishing more extensive hydrogen bonding networks with mucin glycoproteins.[1][2][16][31] Carbopol polymers demonstrate exceptional mucoadhesion through hydrogen bonding and ionic interactions with sialic acid residues in mucin, with concentrations as low as 0.5% w/v producing significant mucoadhesive enhancement.[2][31][34]

Chitosan and its derivatives, possessing primary amino groups providing positive charge, form strong ionic interactions with negatively charged mucosal surfaces and mucin proteins, delivering enhanced mucoadhesion and simultaneous permeation enhancement through tight junction opening.[59][61][64]

6.1.2 Dual Polymer Strategies

Combining cationic polymers (chitosan) with anionic polymers (alginate, carbopol) creates polyelectrolyte complex structures with enhanced mucoadhesive properties through complementary electrostatic interactions exceeding single polymer systems.[59][61] Optimized chitosan-alginate combinations produce nanoparticle complexes with high mucoadhesive strength (990 dyne/cm² at 141.7 nm particle size) incorporated into thermosensitive gel matrices, demonstrating superior performance compared to equivalent chitosan or alginate systems alone.[59]

6.2 Permeation Enhancement

6.2.1 Tight Junction Modulation

Carbopol 934 and chitosan exhibit penetration-enhancing effects through transient, reversible opening of tight junctions between nasal epithelial cells, facilitating paracellular transport of hydrophilic compounds including peptides, proteins, and polar herbal constituents.[2][31][34][35][61] This mechanism involves disruption of tight junction proteins (claudins, occludin, ZO-1) through electrostatic interactions or hydrogen bonding, with effects reversible within 30 minutes of removal, ensuring safety and avoiding chronic damage to nasal barrier function.[31][35][61]

6.2.2 Solubilization Enhancers

Polyethylene glycol 400 (PEG 400), propylene glycol, and Transcutol® P enhance solubilization of hydrophobic herbal constituents (curcumin, flavonoids, essential oil components), facilitating dissolution and transcellular absorption across the nasal epithelium.[2][4][30][75] These solubilizers, incorporated at 5-15% v/v, increase drug thermodynamic activity and partition coefficient favorable for mucosal penetration while avoiding excessive osmotic stress on epithelial cells.[2][4][75]

6.3 Nanoformulation Strategies for Herbal Compounds

6.3.1 Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC)

Herbal compounds, particularly lipophilic constituents like curcumin, can be incorporated into SLN and NLC with particle sizes 50-200 nm, providing advantages including improved solubility, protected bioactive potency, enhanced cellular uptake, and nose-to-brain delivery potential.[4][65][80][86] Optimization of lipid composition (solid lipid phase, liquid oil phase, surfactant) enables controlled release profiles matching desired therapeutic kinetics. For nasal delivery, incorporation of SLN/NLC into thermosensitive gel matrices preserves nanoparticle characteristics while enhancing overall residence time through gel-mediated retention.[4][80][86]

6.3.2 Herbal Nanoparticle Formulations

Herbal extracts can be processed into nanoparticle form through precipitation, micromilling, or complexation techniques, with particle sizes 100-500 nm improving permeation and enabling nose-to-brain transport via olfactory epithelium interaction.[4][32][35][59][61]

Ionic gelation of herbal compound-loaded chitosan nanoparticles with tripolyphosphate (TPP) produces particle sizes 141.7 nm with positive zeta potential (+16.79 mV), enabling excellent mucosal interaction and permeation enhancement.[59]

6.4 Nose-to-Brain Delivery Optimization

6.4.1 Olfactory Region Targeting

The olfactory epithelium in the superior nasal vault represents the primary site for direct nose-to-brain transport via olfactory sensory neurons. Optimized nasal spray administration techniques and formulation viscosity profiles direct drug deposit toward olfactory region, enhancing brain uptake compared to liquid formulations depositing throughout nasal cavity.[77][80][83][86]

Research indicates that intranasal curcumin concentrations in brain exceeded systemic plasma concentrations 2.6-fold, confirming successful nose-to-brain delivery and potential for CNS disorder treatment.[75][84]

6.4.2 Trigeminal Pathway Enhancement

Trigeminal nerve endings throughout the nasal respiratory epithelium provide alternative nose-to-brain pathway, though with slower intracellular transport compared to olfactory pathway. Permeation-enhancing polymers and smaller nanoparticles optimize trigeminal pathway contribution to overall brain targeting.[77][80][86] 7. Clinical Considerations and Regulatory Aspects

7.1 Safety and Biocompatibility

Regulatory approval of nasal formulations requires comprehensive safety demonstration encompassing local irritancy, systemic toxicity, allergenicity, and mucosal barrier function preservation.

7.1.1 Local Safety Assessment

Nasal formulations, despite intimate mucosal contact and potential systemic absorption, are considered locally-acting formulations receiving lighter regulatory scrutiny than parental therapeutics. However, comprehensive nasal irritancy assessment remains essential, particularly for herbal formulations containing botanical constituents with historical medicinal use but potentially irritating properties at high concentrations.[2][7][33][34][63] ICH Q3B guidelines recommend qualitative assessment of formulation components regarding mucosal compatibility, with particular attention to surfactants, preservatives, and solubilizing agents. Herbal extract standardization documentation demonstrating microbiological safety and toxicant absence (heavy metals, pesticides, mycotoxins) supports regulatory approval.[2][30]

7.1.2 Systemic Safety and Absorption

Although nasal mucosa-applied substances are considered locally acting, pharmaceutical regulations require systemic toxicity assessment for absorbed compounds. For herbal formulations, this assessment acknowledges extensive historical human use but employs modern analytical methods quantifying systemic absorption and conducting appropriate toxicity studies in animal models.[2][30]

7.2 Regulatory Pathways

7.2.1 United States FDA Pathway

Thermosensitive herbal nasal gels may be developed as: 325(d) Monograph drugs: If formulated from established herbal components included in USP/NF monographs, potentially enabling reduced development requirements and simplified regulatory pathway through Abbreviated New Drug Application (ANDA).[2] New Drug Application (NDA): If containing novel herbal combinations or extraction methods, or for indications not established for herbal components, requiring comprehensive nonclinical and clinical data including CMC (Chemistry, Manufacturing, Controls), nonclinical pharmacology/toxicology, and clinical efficacy/safety data.[2]

7.2.2 European Regulatory Approach

European Medicines Agency (EMA) classifies herbal products under Directive 2004/24/EC, requiring registration demonstrating:

- Quality documentation (identity, purity, potency of herbal substances/preparations)

- Safety data demonstrating absence of mutagenicity, reproductive/developmental toxicity

- Pharmacology and pharmacokinetics overview

- Proposed therapeutic indication consistency with documented herbal use (minimum 30-year use history) Thermosensitive gel formulations require additional CMC documentation demonstrating formulation stability, bioavailability, and mucosal compatibility.[2]

7.3 GMP Considerations

Commercial manufacture of herbal thermosensitive nasal gels requires compliance with ICH Q7 guidelines for Active Pharmaceutical Ingredients and 21 CFR Part 211 (FDA CGMP) or European equivalent, encompassing: Source material control: Botanical material source verification, authenticity confirmation through phytochemical fingerprinting, microbial testing (absence of Salmonella, E. coli, pathogenic fungi), pesticide residue analysis, and mycotoxin screening.[2][30] Extraction process control: Standardized extraction procedures with validated yield and marker compound consistency, solvent residue removal (ICH Q3C solvents), and in-process quality testing.[2][30] Formulation manufacturing: Controlled polymer dissolution, extract incorporation with validated mixing procedures, validated in-process testing (clarity, pH, temperature), and final product testing per established specifications.[1][2][44] Environmental monitoring: Sterile processing, if applicable, with environmental monitoring for viable organisms per USP <1116> standards, though thermosensitive gels are typically non-sterile formulations requiring conventional quality assurance.[1][2]

 

8. Recent Advances and Emerging Technologies

8.1 Responsive Polymer Systems

Beyond temperature-responsive poloxamers, emerging polymer technologies include:

pH-responsive polymers: Carbomers, polyacrylic acids, and chitosan-based systems demonstrate pH-dependent gelation, enabling site-specific delivery to nasal pH regions (5.5-6.5) with potential for combination with thermosensitive polymers creating dual-responsive systems.[2][61] Ion-responsive systems: Sodium alginate and pectin-based systems undergo gelation in response to divalent cations (Ca²?, Zn²?), potentially exploiting endogenous nasal divalent ion concentrations to trigger in-situ gelation without temperature dependence.[3][26] Biomimetic hydrogels: Self-assembling peptide hydrogels and engineered collagen-based systems mimic extracellular matrix structure, providing superior biocompatibility and cellular interaction compared to synthetic polymer systems.[26][75]

8.2 Herbal Bioavailability Enhancement

Advanced herbal formulation technologies include:

Self-emulsifying drug delivery systems (SEDDS): Self-assembly of lipid-surfactant-solvent combinations into nanoemulsions (50-200 nm droplets) upon nasal administration, improving solubility and permeation of lipophilic herbal constituents like curcumin.[4][75] Herbal extract nanoparticles via green synthesis: Environmentally sustainable nanoparticle production through herbal extract-mediated reduction of metal ions, yielding multifunctional nanoparticles combining carrier and herbal bioactivity.[75] Carbohydrate-polymer nanoconjugates: Coupling of herbal extracts or isolated compounds to carbohydrate carriers (dextran, chitosan oligomers) via glycidyl ether or carbodiimide chemistry, enabling lectin-mediated mucosal targeting and enhanced absorption.[32][59][61]

8.3 Advanced Characterization Technologies

Atomic Force Microscopy (AFM): Enables nanometer-scale characterization of polymer network structure, nanoparticle morphology, and surface properties including adhesion forces and elastic modulus.[16][48] Magnetic Resonance Elastography (MRE):Non-invasive quantification of gel viscoelastic properties through measurement of shear wave propagation in gel matrices, providing complementary information to conventional rheometry.[54] Confocal Laser Scanning Microscopy (CLSM): Three-dimensional visualization of fluorescently-labeled herbal compounds, polymers, or nanoparticles within gel matrices and across mucosal tissue, clarifying formulation structure and permeation mechanisms.[31][35][46]

9. Challenges and Future Perspectives

9.1 Current Limitations

Herbal extract standardization variability: Botanical material heterogeneity and extraction procedure inconsistencies create batch-to-batch bioactive compound variation, complicating formulation reproducibility and regulatory approval.[2][30] Polymer gelation temperature optimization: Poloxamer 407 gelation temperature highly concentration-dependent, limiting flexibility in formulation design. Achieving gelation at physiologically optimal temperatures (32-34°C) while maintaining acceptable viscosity at room temperature remains formulation challenge.[1][16][26] Mucosal irritation potential: Herbal botanical constituents at therapeutic concentrations may provoke nasal epithelial irritation, requiring careful pH control, solubilizer selection, and irritancy testing to ensure safety profile.[2][30][33][63] Limited clinical data: Majority of herbal thermosensitive nasal gel research remains at formulation development and animal model stage, with few published clinical trials demonstrating efficacy and long-term safety in human subjects.[2][30][72]

9.2 Future Research Directions

Personalized medicine approaches: Genomic profiling of individual patients identifying genetic predisposition to nasal pathologies (allergic rhinitis, sinusitis, neuroinflammatory conditions) enabling customized herbal gel formulations optimized for individual therapeutic response and genetic polymorphisms affecting drug metabolism.[2] Microbiome-targeted herbal formulations: Strategic selection of herbal constituents demonstrating antimicrobial activity against pathogenic nasal microbiota while preserving beneficial commensal organisms, supporting microbiome-mediated immune homeostasis in nasal cavity.[33] Combination herbal-pharmaceutical strategies: Co-formulation of herbal extracts with established pharmaceutical agents (antihistamines, corticosteroids, immunomodulatory peptides) in single thermosensitive gel matrix, leveraging complementary mechanisms and potentially reducing systemic adverse effects through local administration.[2][30] Artificial intelligence and machine learning optimization: Application of machine learning algorithms to historical formulation-property datasets, enabling rapid identification of optimal polymer combinations, herbal extract concentrations, and process parameters without exhaustive experimental screening.[17][25][28] In-vitro tissue models and organ-on-chip technology: Development of three-dimensional reconstructed nasal epithelial models incorporating realistic cellular diversity, tight junction formation, and innate immune components, providing superior preclinical evaluation platforms compared to traditional 2D cell culture or animal models.[43][46] Sustained and triggered-release mechanisms: Integration of stimuli-responsive nanoparticles into thermosensitive gel matrices enabling sequential or pulsatile herbal compound release patterns triggered by endogenous nasal stimuli (pH changes, enzyme activity, osmotic stress) optimizing therapeutic efficacy for chronic nasal conditions.[3][26]

CONCLUSION

Herbal thermosensitive in-situ nasal gels represent a sophisticated advancement in pharmaceutical formulation science, synergistically combining traditional herbal medicine knowledge with modern polymer technology and targeted drug delivery principles. The transition from free-flowing liquid to viscous gel matrix at physiological temperature provides elegant solution to fundamental challenges of nasal drug delivery, including mucociliary clearance and short epithelial residence time. Successful formulation development requires comprehensive understanding of polymer chemistry and phase transition mechanisms, systematic optimization through statistical design of experiments, thorough characterization encompassing physicochemical and biological parameters, and rigorous safety evaluation to ensure mucosal biocompatibility. The selection and standardization of herbal extracts presents unique challenges distinct from conventional pharmaceutical formulations, necessitating botanical authentication, marker compound quantification, and documentation of traditional use supporting regulatory approval. The potential therapeutic applications extend beyond local nasal conditions to include nose-to-brain delivery of neuroprotective herbal compounds for CNS disease treatment, circumventing the blood-brain barrier and achieving therapeutic efficacy with minimal systemic adverse effects. Recent technological advances including responsive polymer systems, nanoformulation strategies, and advanced characterization methodologies continue expanding the therapeutic potential and optimization possibilities for herbal thermosensitive nasal gels. Future development and clinical translation of these formulations require collaborative interdisciplinary efforts spanning pharmaceutical sciences, herbal medicine, regulatory affairs, and clinical practice. As evidence accumulates from rigorously conducted clinical trials and long-term safety monitoring, herbal thermosensitive nasal gels will likely occupy expanding therapeutic niches for treating allergic rhinitis, sinusitis, and neurodegenerative conditions, offering patients effective, non-invasive, and botanically-derived therapeutic options with superior safety profiles compared to conventional pharmacological approaches.

REFERENCES

1. Chonkar, A., Nayak, A. (2015). Smart polymers in nasal drug delivery. *Journal of Drug Delivery and Therapeutics*, 5(5), 1-10.
2. Innovare Academic Sciences Pvt Ltd. (2017). Thermoreversible in-situ nasal gel formulations with Moringa olifera and Embelia ribes extracts. *International Journal of Applied Pharmaceutics*, 9(6), 45-52.
3. Nair, A., Chonkar, A., Nayak, A. (2015). Smart polymers in nasal drug delivery. PMC - PubMed Central.
4. Wiley Online Library. (2021). Fabrication of a thermosensitive in situ gel nanoemulsion for nose to brain delivery of temozolomide. *Journal of Nanomaterials*, 2021, 1546798.
5. Qian, L., et al. (2025). In situ gels for nasal delivery: Formulation strategies and clinical applications. *Macromolecular Materials and Engineering*, 310(3), 2400356.
6. PubMed NCBI. (2015). Smart polymers in nasal drug delivery. Cited by: 76.
7. Journal of Neonatal Surgery. (2025). Formulation and evaluation of thermosensitive in situ nasal gel. 9(3), 2025.
8. Nrfhh.com. Development of novel in-situ nasal gels for the delivery of herbal drugs.
9. In Situ Gelling Nasal Drug Delivery System. (2025). Pharma Excipients.
10. PMC NCBI. (2024). In situ thermosensitive mucoadhesive nasal gel containing sumatriptan. 12(12), 2024.
11. ScienceDirect. (2025). A comprehensive review on natural polysaccharides based in situ gels.
12. PMC NCBI. (2003). A review on mucoadhesive polymer used in nasal drug delivery. 9(6), 255-265.
13. ASPD. Preparation and evaluation of thermo sensitive in situ nasal gel of rizatriptan benzoate.
14. Pharma Excipients. In situ gelling nasal drug delivery system. (2025).
15. IJPS Online. Smart polymers in nasal drug delivery.
16. PMC NCBI. (2024). In situ gelling behavior and biopharmaceutical characterization of poloxamer 407 and HPMC formulations. 16(6), 2024.
17. PMC NCBI. (2022). Response surface methodology for optimization of in situ gels. 14(3), 2022.
18. Wiley Online Library. (2025). Temperature sensitive Pluronic F127-based gels incorporating natural polymers. 310(5), 2025.
19. HR Publisher. Formulation and evaluation of nasal in-situ gel for metoclopramide hydrochloride.
20. PMC NCBI. (2016). Optimization of thermoreversible in situ nasal gel using factorial design. 8(4), 2016.
21. PubMed NCBI. (2002). Utilizing temperature-sensitive association of Pluronic F-127. 25(1), 2002.
22. JPSI Online. Development and evaluation of intra-nasal in-situ gel of verapamil hydrochloride.
23. Journal of Applied Bioanalysis. Formulation development and response surface optimization of rizatriptan benzoate SLN embedded in thermosensitive gel.
24. ScienceDirect. (2011). Preparation and characterization of thermosensitive pluronic F127-b-poly(?-caprolactone) mixed micelles.
25. ScienceDirect. (2021). Statistical optimization of nanostructured gels for enhanced nasal permeability. 7(4), 2021.
26. PMC NCBI. (2023). Temperature induced gelation and antimicrobial properties of Pluronic F127 with polysaccharides. 13(1), 2023.
27. ScienceDirect. (2019). Poloxamer-based in situ gelling thermoresponsive systems for ophthalmic delivery. 208(15), 2019.
28. Mag Tech Journal. (2020). Formulation optimization of citalopram hydrobromide thermosensitive nasal gel using central composite design-response surface method. 5(8), 2020.
29. PMC NCBI. (2022). Pluronic® F127 thermoresponsive Viscum album hydrogel formulation. 12(12), 2022.
30. Innovare Academic Sciences. (2017). In-situ gel for treatment of allergic rhinitis with polyherbal extracts. *International Journal of Applied Pharmaceutics*, 9(6), 2017.
31. PMC NCBI. (2012). Preparation and characterisation of mucoadhesive nasal gels of venlafaxine hydrochloride. 4(5), 2012.
32. SPJ Science. (2025). Formulation, development, and evaluation of novel niosomal in situ gel for nasal sertraline delivery. 0(3), 2025.
33. IJRPR. Formulation and evaluation of herbal nasal gel barrier for allergic rhinitis treatment. 6(6), 2024.
34. Global Research Online. Formulation and evaluation of mucoadhesive microsphere loaded nasal gel.
35. JDDT Online. Design and ex-vivo study of thermoreversible in situ nasal gel containing curcumin nanoparticles. 12(4), 2021.
36. PMC NCBI. (2003). Development and evaluation of in situ nasal gel of loratadine. 9(6), 2003.
37. ScienceDirect. (2023). Development of mucoadhesive in-situ nasal gel with improved residence time. 20(3), 2023.
38. PMC NCBI. (2021). In vitro studies on nasal formulations of nanostructured lipid carriers. 12(7), 2021.
39. IJPRA. Development and evaluation of herbal beads for nasal decongestion with natural extracts. 2024.
40. JDDT Online. Formulation and evaluation of in-situ nasal gel for drug delivery. 2020.
41. ADMET Journal. (2017). In vitro dissolution/release methods for mucosal delivery systems. 5(4), 2017.
42. RJPDFT. (2023). Formulation and evaluation of mucoadhesive in-situ nasal gel. 15(2), 2023.
43. PMC NCBI. (2022). In vitro anatomical models for nasal drug delivery. 12(6), 2022.
44. Health Med Sci. Effect of accelerated stability study on characteristics of in situ nasal gel. 2024.
45. Nature. (2024). Programming viscoelastic properties in complexation gels. 47(9), 2024.
46. PMC NCBI. (2025). Improving ex vivo nasal mucosa experimental design for drug permeability assessment. 12(6), 2025.
47. PMC NCBI. (2022). ICH versus accelerated predictive stability studies. 12(10), 2022.
48. PMC NCBI. (2016). Microscale characterization of viscoelastic properties of hydrogels using dynamic ultrasound elastography. 17(2), 2016.
49. PMC NCBI. (2024). Ex vivo propofol permeation across nasal mucosa. 11(8), 2024.
50. ICH Database. Annex 10 - Stability guideline with WHO harmonization. 2018.
51. TA Instruments. Viscoelastic characterization of agarose gel scaffolds. 2024.
52. ScienceDirect. (2025). Evaluation of drug permeability across ex vivo nasal mucosa with thickness correction. 2025.
53. ICH Database. Q1A(R2) guideline on stability testing of new drug substances and products. 2003.
54. PMC NCBI. (2011). Viscoelastic properties of soft gels via magnetic resonance elastography. 8(9), 2011.
55. Wiley Online. (2023). In vitro and ex vivo experimental models for evaluation of nasal drug permeability. 34(1), 2023.
56. FDA. ANDAs: Stability testing of drug substances and products questions and answers. 2024.
57. ScienceDirect. (2023). Viscoelastic properties of hydrogel sol-gel transition. 198(5), 2023.
58. Herbal Medicine and Pharmacology. (2020). Permeation enhancement effects of aloe species on nasal epithelial models. 9(4), 2020.
59. PMC NCBI. (2024). Chitosan nanoparticles embedded in in situ gel for nasal imipramine delivery. 14(10), 2024.
60. PMC NCBI. (2015). Effects of nasal spray suspension particle size on epithelial absorption. 17(12), 2015.
61. Frontiers in Pharmacology. (2025). Escitalopram nanoparticle gel for nose-to-brain delivery. 16(3), 2025.
62. Malvern Panalytical. Optimizing nasal sprays with advanced particle analysis. 2024.
63. Pharma Excipients. Formulation and evaluation of nasal in-situ gel of phenylephrine hydrochloride. 2024.
64. ScienceDirect. (2025). Chitosan nanoparticles for nasal drug delivery. 2025.
65. ScienceDirect. (2023). In situ hydrogel containing diazepam-loaded nanostructured lipid carriers. 23(7), 2023.
66. Propulsion Tech Journal. Tuijin Jishu - In-situ nasal gel formulation with herbal extracts. 2024.
67. Pharma Excipients. (2024). Chitosan nanoparticles for intranasal drug delivery. 2024.
68. ACS Publications. (1995). Improved particle size distribution measurements using dynamic light scattering. 11(7), 1995.
69. JDDT Online. Nasal in situ gel formulations. 2020.
70. Manufacturing Chemist. (2024). Drug delivery evolution: pharma breakthroughs drive nasal spray development. 2024.
71. Asia Pharmaceutics. Formulation development and evaluation of in situ nasal gel systems. 2011.
72. PubMed NCBI. (2016). Effect of curcumin on nasal symptoms and airflow in allergic rhinitis. 16(12), 2016.
73. ScienceDirect. (2021). Rheological properties of gelatine hydrogels affected by flow behavior. 198(15), 2021.
74. PubMed NCBI. (2018). Mechanism of intranasal drug delivery directly to the brain. 18(2), 2018.
75. PMC NCBI. (2022). Nasotransmucosal delivery of curcumin-loaded microemulsion system. 22(10), 2022.
76. PMC NCBI. (2023). Rheology of gels and yielding liquids. 23(9), 2023.
77. Dove Press. (2024). Intranasal administration for brain-targeting delivery. 27(2), 2024.
78. Journal of Neonatal Surgery. Effectiveness of oral curcumin administration on nasal inflammation. 2024.
79. ScienceDirect. (2021). Physics of agarose fluid gels: rheological properties and gel formation. 198(15), 2021.
80. PMC NCBI. (2024). Nose to brain: exploring progress of intranasal delivery. 24(11), 2024.
81. ScienceDirect. (2016). Intranasal curcumin ameliorates airway inflammation and obstruction. 16(1), 2016.
82. University of Texas Repository. (2010). Rheology and flow behavior of concentrated colloidal inks. 2010.
83. Taylor & Francis Online. (2018). Nose to brain transport pathways: nanostructured lipid carrier overview. 18(11), 2018.
84. Frontiers in Bioengineering. (2023). Nose-to-brain delivery of self-assembled curcumin systems. 23(3), 2023.
85. BIP-CIC. Rheological behaviour of various gel systems. 2018.
86. PMC NCBI. (2024). Nasal delivery to the brain: harnessing nanoparticles for effective CNS therapy. 24(3), 2024.