A Review on Nasal In-Situ Gels: A Novel Approach for Dry Eye Relief

The human eye is perhaps the most complex organ of the human body. Of all our senses, the eye is the most used. Most information we receive about the world we live in is in the form of what we can see using our eyes. The eye is a camera in the sense that it absorbs light and transmits it into images.

1.1 Anatomy and Physiology of The Eye

They can be approximately divided into two halves—the anterior and the posterior. The anterior includes the cornea, the conjunctiva, the aqueous humor, the iris and ciliary body, and finally the lens. All these structures together weigh one-third of the front half of the organ. The posterior half includes sclera, choroid layer, retinal pigment epithelium, and finally the neural retina. Under the subject 'Anatomy of the Eye,' anatomy and physiology of the eye is given below. ^[1]

Anterior segment

Conjunctive

It is thin, richly vascular, semi-clear, mucus-secreting tissue which covers the inner surface of the upper and lower eyelids. It appears on the eye as thin, transparent tissue over the sclera and extending as far forward as the limbus of the cornea. The tissue is richly innervated with efferent, afferent, and sensory nerves and also provided with lymphoid tissue. It can be stated that the entire conjunctiva covers an area 17 times greater than the entire corneal area. Moreover, its elasticity allows unimpeded movement of eyeballs and eyelids. ^[1]

Cornea

The cornea is the anterior portion of the outer coat of the eye and is distinguished by its transparency. It smoothly blends into the opaque sclera, which constitutes the rest of the outer coat. The transitional area of the cornea blending into the sclera is called the limbus or the corneoscleral junction ^[2]. The mean horizontal corneal diameter of the human eye is approximately 11.5 mm, whereas the vertical diameter is 10.5 mm ^[3]. There are five distinct layers in the human cornea: the epithelium, Bowman's membrane, the lamellar stroma, Decrement's membrane, and the endothelium. ^[2]

Aqueous humour

Aqueous humor is a clear fluid filling the anterior and posterior chamber of the eye and supplies nutrition to avascular tissues such as the cornea, which needs to be kept transparent for light transmission. It acts as a blood substitute, clearing the products of metabolism, carrying neurotransmitters, giving ocular structure stability, and in maintaining tissue homeostasis epithelium. Aqueous humor plays a very significant role in the optical system of the eye. Its composition includes organic and inorganic ions, carbohydrates, glutathione, urea, amino acids, proteins, oxygen, carbon dioxide, and water. (Goel et al., 2010; Sires, 1997). ^[4]. The aqueous humor leaves the eye by two pathways at the anterior chamber angle close to the limbus. The traditional pathway goes through the trabecular meshwork, Schlemm's canal, and to episcleral veins. The non-traditional (uveoscleral) pathway drains through the uveal meshwork, ciliary muscle, and suprachoroidal space and leaves through the sclera. ^[5]

Ciliary body

Ciliary body is a component of the uveal tract that takes part in the production of aqueous humor and aqueous humor dynamics. Is between choroid and iris. Triangular cross-section, roughly 6 mm long. Apex is attached to the choroid, and its base is adjacent to the iris. Its extrinsic fixation is to the scleral spur and creates the supraciliary space, and its internal surface adheres to the vitreous and continues with the retina. Its anterior aspect is referred to as the pars plicata or corona ciliaris. Possesses about 70 large ciliary processes and minute intermediate processes. This part, in contact with the posterior iris, is roughly 2 mm long ^[6]. The ciliary epithelium's inner non-pigmented layer continues with the neural retinal tissue. The ciliary epithelium's outer layer, on the other hand, is quite pigmented and continues with the retinal pigmented epithelium (RPE). ^[7]

Lens

The lens is a clear, biconvex organ with a thickness of 4 mm and a diameter of 9 mm, lying behind the iris and suspended by the zonule, which is attached to the ciliary body. It lies between the aqueous humor (anteriorly) and the vitreous humor (posteriorly). Its semipermeable capsule allows water and electrolytes to pass. The lens supplies about 20 diopters of the eye's 60 D power of accommodation. Its equatorial diameter is 6.5 mm at birth and becomes 9–10 mm in adulthood, while its anteroposterior width goes up from 3 mm at birth to about 6 mm at 80 years of age. It consists of 65% water and 35% protein and is the most proteinaceous tissue. ^[8]

Posterior segment

Sclera

The sclera constitutes five-sixths of the external tunic of the eye, from the corneal limbus to the optic foramen, and it is perforated by the optic nerve. It is almost spherical, measuring a mean vertical diameter of 24 mm. The thickness of the sclera is variable, being maximal at the posterior pole (1–1.35 mm) and diminishing to 0.4–0.6 mm at the equator and 0.3 mm beneath the recti muscles. Thickness is increased to 0.6 mm close to the insertions of the extra ocular muscles and to 0.8 mm at the limbus, blending with the cornea. Scleral thickness is thinner in women than in men, and scleral thickness and opacity rise with age ^[9]. The sclera overlying the optic nerve is perforated by the long and short posterior ciliary arteries and the long and short ciliary nerves. The long posterior ciliary arteries and long ciliary nerves follow a shallow groove on the inner aspect of the sclera at the 3 and 9 o'clock. ^[10]

Retina

The retina is a thin, transparent, and delicate neuroectodermal tissue containing sensory neurons to initiate the process of vision. The neural retina or neuroretina consists of nine distinct layers: outer and inner segments of photoreceptors (rods and cones), external limiting membrane, outer plexiform layer, outer nuclear layer, inner plexiform layer, inner nuclear layer, ganglion cell layer, nerve fiber layer, and internal limiting membrane. The light has to pass through all these layers in order to enter the photoreceptors, where it initiates signal transduction, the start of the visual process ^[11]. The eyes of most vertebrates have two types of photoreceptors: rods and cones. Rods are present in approximately 20 times as many numbers as cones in human beings. ^[12]

Choroid

The choroid invests the inner surface of the fibrous tunic of the eye and constitutes the posterior half of the uvea, the anterior half being the thicker zone of ciliary bodies. These two areas are demarcated from each other at the equator of the eye by the ora serrata, a scalloped-line formed structure. The choroid contains two surfaces: an outer, convex surface fixed to the sclera by vessels, ciliary nerves, and loose connective tissue (lamina fusca), and an inner, concave surface lying against the retina without fixation to it. The choroid contains two apertures: an anterior aperture lined by the ora serrata and a posterior aperture containing the optic nerve ^[13]. Choroidal ganglion cells or intrinsic choroidal neurons (ICNs) are the neurons present in the choroid, whose sole function is to regulate choroidal circulation. There are about 2,000 ICNs present in each eye, and most of them are present in the temporal and central parts of the submacular area.^14]

Dry eye (DE) is a multifactorial disease characterized by ocular surface symptoms like dryness, pain, poor or fluctuating vision and signs of reduced tear break-up time. The decreased tear production and corneal staining often leads to aqueous tear deficiency, evaporative dry eye, anatomical abnormalities and nerve dysfunction. Various environmental factors and constant   usage of visual displays like TV, mobile, laptops causes DE diseases. Worldwide, 5-50% of people are suffering from DE disease. ^[15]

DE treatment aims to improve tear-film stability and reverse ocular surface damage. Artificial tear supplements are the most common therapy, effective for mild to moderate dry eye patients. ^[16]

2.1 PATHOLOGY OF Dry Eye

2.1.1 Etiology and classification ^[17]    

Aqueous-Deficient Dry Eye (ADDE) – Caused by impaired tear production because of lacrimal gland malfunction.

• Primary: Sjögren's syndrome (autoimmune disease).

• Secondary: Lacrimal gland insufficiency (with age, radiation, or disease such as sarcoidosis), lacrimal duct obstruction, or decreased reflex tear secretion (e.g., with LASIK, diabetes, or nerve damage).

Evaporative Dry Eye (EDE) – Caused by abnormal tear evaporation due to meibomian gland dysfunction or environmental conditions.

•Causes: Meibomian gland disease, eyelid disease, infrequent blinking (e.g., Parkinson's disease), contact lens wear, and vitamin A deficiency.

2.1.2 Classification of Dry Eye ^[18]

Chart no. 1 Classification of Dry eye

Chart no.2 Etiopathogenesis of dry eye

2.3 Risk factor ^[20]

Fig No.2 Risk Factors for Dry Eye Disease Discussed in The Present Review, Including Demographic, Systemic, Ocular and Modifiable Risk Factors, As Reported in The Literature.

2.3.1 Demographic Factors

• Age: Higher risk after 40 years.
• Gender: Women are more prone due to hormonal changes.
• Ethnicity: East Asians have a higher prevalence.

Systemic Conditions

• Autoimmune diseases: Sjögren’s syndrome, lupus, rheumatoid arthritis.
• Diabetes: Poor blood sugar control affects tear production.
• Mental health disorders: Anxiety, depression, and chronic stres

Medications

• Antidepressants, antihistamines, hormone replacement therapy, isotretinoin reduce tear secretion.

 2.3.2 Ocular Factors

• Contact lens wear: Leads to tear film instability.
• Ocular surgeries: Can damage corneal nerves.

 2.3.3 Lifestyle & Environmental Factors

• Prolonged screen time: Reduces blinking.
• Low humidity, wind, pollution: Increase tear evaporation.
• Poor diet: Low Omega-3 and Vitamin A deficiency worsen symptoms.

2.4 Signs and symptoms of Dry Eye ^[21]

DE leads to ocular discomfort in the form of dryness, irritation and foreign-body sensation. Symptoms may include burning pain, light sensitivity (photophobia), and fluctuating vision because of instability of the tear film. Symptoms usually worsen with windy, air-conditioned, or dry conditions. The key signs include instability of the tear film, hyperosmolarity, inflammation of the ocular surface and dysfunction of the meibomian glands leading to rapid tear evaporation.

2.5 Drugs used in the treatment of Dry Eye ^[22]

Table No: 1 Drugs Used in The Treatment of DE And Their Mechanism

3. Complication of Dry eye

Dry eye disease (DED) can lead to a range of complications affecting both ocular and systemic health. These complications vary in severity, from mild discomfort to serious vision-threatening conditions.

3.1 Ocular Complications ^{[23, 24, 25, 26, 27].}

3.1.1 Ocular Irritation and Visual Disturbances

• Persistent dryness, burning, itching, and foreign body sensation in the eyes.
• Fluctuating vision, blurriness, and difficulty focusing, especially during prolonged screen use or reading.

3.1.2 Corneal Complications

• Infectious Keratitis: Chronic dryness weakens the corneal surface, making it more vulnerable to infections caused by bacteria, viruses, or fungi. This can lead to pain, redness, and vision impairment.

• Corneal Ulceration: Severe cases of DED can cause corneal epithelial breakdown, leading to open sores or ulcers on the cornea, increasing the risk of scarring and vision loss.
• Corneal Scarring: Prolonged inflammation and damage can result in scarring of the cornea, leading to permanent visual impairment.     

c. Vision Loss

• In severe cases, corneal damage due to chronic dryness, ulceration, and scarring can lead to irreversible vision loss, significantly affecting a person’s quality of life.

3.2 Non-ocular Associations

While a direct cause-and-effect relationship has not been confirmed, research suggests that DED is linked to several systemic conditions, including

a. Depression and Mood Disorders

• Chronic discomfort and impaired vision from DED can negatively impact mental health, contributing to anxiety, stress, and depression.
• The persistent irritation and difficulty performing daily tasks such as reading or driving can reduce overall well-being.

b. Sleep disorders

• Studies indicate that individuals with DED often have poor sleep quality, possibly due to night-time eye discomfort or underlying inflammatory processes affecting both sleep regulation and tear production.

c. Dyslipidaemia (Abnormal Lipid Levels)

• Some research suggests a potential link between DED and dyslipidaemia, a condition characterized by high or abnormal levels of cholesterol and triglycerides, which may contribute to meibomian gland dysfunction (MGD), a key factor in evaporative dry eye.

d. Migraine Headaches

Many DED patients report frequent migraines, possibly due to shared underlying inflammatory mechanisms, nerve dysfunction, or heightened sensitivity to environmental triggers like bright lights and screen exposure.

4. Ocular complication via nasal route ^{[28 29 30 31 32]}

5. Anatomy and Physiology of the Nose

Nasal cavity is separated into symmetrical halves by nasal septum and continues posteriorly up to nasopharynx. Nasal vestibule, i.e., anterior part of nasal cavity, is in communication with the face through the nostril. Atrium is an area between vestibule and respiratory area. Respiratory area or nasal turbinates occupy majority of nasal cavity. It is characterized by lateral walls which divide it into three parts: superior nasal turbinate at the superior end, middle nasal turbinate below and inferior nasal turbinate at the inferior chamber ^[33].The total surface area of nasal cavity in man is approximately 180 cm² and 2-4mm mucosal thickness with the total volume of approximately 20ml. ^[34]  Each of the two nasal cavities is subdivided into three regions: the nasal vestibule, the olfactory region and the respiratory region.

The Respiratory region

The respiratory zone is the most perfused and largest zone to be influenced by systemic drug absorption. The respiratory epithelial lining consists of four cell populations: non-ciliated cells, ciliated columnar cells, basal cells and goblet cells. They are responsible for active transport functions like water and ion transport between cells and ciliary movement. They also avoid drying of the nasal mucosa. ^[35]

Nasal vestibule

The most anterior part of the nasal cavity is the nasal vestibule, which lies immediately inside the nostrils, with an area of approximately 0.6 cm². Nasal hairs or vibrissae, which are located inside the area, serve to filter the particles entering the respiratory tract. Histologically, the vestibule is covered with stratified squamous keratinized epithelium and contains sebaceous glands. ^[36]

The olfactory area

The human olfactory surface, which has a surface area of approximately 10 cm², is of utmost importance in drug transport to CSF and brain. It is made up of the lamina propria, where the olfactory epithelium is housed consisting of basal, olfactory receptor, and supporting cells. They are bipolar neurons that extend dendrites to the apical surface, which terminate in olfactory knobs with non-motile cilia. A mucus layer captures particles and is replaced every 10–15 minutes. The nasal cavity, with an adult pH of 5.5–6.5, harbors enzymes such as Cytochrome P-450, Carboxylesterases, and Glutathione S-transferase for metabolic purposes. ^[37]

 5.2 Physiology of Nose

Olfaction: What is the role of the nose? We take in around 12 to 24 breaths a minute, taking in some 10 000 litres a day of varying temperature, humidity and which includes dust and organisms ^[38]. We can smell over 10,000 different odours and distinguish between 5,000. The olfactory epithelium houses several million olfactory sensory neurons. Odorant-binding proteins (OBPs) bind and dissolve hydrophobic molecules, concentrating them up to 10,000 times that in the ambient air. OBPs can also strip odorant molecules following transduction, which is achieved through specific binding between the odorant molecules and receptor proteins on the olfactory cilia surface ^[39]. Odorants are of biological importance, with a child preferring the smell of its mother within 6 to 10 days, which is also responsible for mediating attachment during ages 3 to 5 years. Smell can have various other impacts, with pheromones having a deep psycho-sexual impact. ^[40]

Turbinate: The three, sometimes four, scroll-shaped projections of the lateral nasal wall, most important being the inferior and middle turbinates. Each is composed of a bony skeleton lined by respiratory epithelium, expanding the mucosal surface of the nasal cavity to 100–200 cm² ^[41]. The inferior turbinate maintains lung defense and nasal physiology. Reducing its anterior part is less likely to decrease nasal resistance but should never precede examination of enlargement reasons ^[42]. Function preservation in turbinate surgery is important because gland distribution changes, and a cancellous bony layer covering main arteries needs to be conserved to safeguard vascular integrity. ^[43]

Nasal cycle: In an adult man, global nasal airway resistance is more or less constant, whereas airflow in each nasal passage is reciprocally variable—whereas one increases, the other will diminish. This condition is referred to as the nasal cycle ^[44]. Due to fluctuations in vascular engorgement of the turbinates and septal tuberculum. Under normal circumstances, people are unaware of this cycle because overall nasal resistance is stable. Also, the cycling does not influence the level of water vapour saturation in breathing air ^[45]. The nasal cycle is controlled by a pacemaker in the hypothalamus. ^[46]

Fig No.3 Physiology of Nose

Solutions and Sprays: Nasal drug solutions are given as sprays, drops, or nebulizers. Dosage varies with drug volume and concentration. Intrapulmonary delivery of 0.8 mg/ml nitro-glycerine in saline produced therapeutic blood levels in two minutes ^[47]. Formulation considerations such as dose, pH, and osmolality have a strong influence on nasal absorption and drug effect ^[48]. Nasal sprays may be formulated as solutions or suspensions. Metered-dose pumps guarantee exact delivery (25–200 µm). Particle size, shape, and formulation viscosity determine particle size, shape, and choice of pump and actuator in the case of suspensions. ^[49]

Nasal drops: Nasal drops represent a simple and easy-to-use system for delivery by the nasal route. However, their prime disadvantage lies in the absence of dose accuracy and, as a consequence, in a relatively less ideal prescription application. Nasal drops have been said to deliver human serum into the nostrils more effectively than nasal sprays ^[50]. When technetium-99m-labeled human serum albumin was given as a nasal spray or drop, about 40% of the dose cleared within short half-times with mean half-times between 6 and 9 min. ^[51]

Nasal Gels: Nasal gels are thickened suspensions or solutions of high viscosity. Demand for this system has increased due to the recent development of exact dosing systems. Their merits are decreased posterior drip from high viscosity, diminished taste effect by reduced swallowing, decreased anterior leakage, decreased irritation with calming excipients, and mucosal-specific delivery for better absorption ^[52]. Recently a first nasal gel with vitamin B12 for systemic treatment has appeared on the market. ^[53]

Powder Dosage Forms:

Nasal powder dosage forms are prepared with active pharmaceutical ingredients along with fillers. Spray drying and freeze-drying are the two methods of drying. Insulin is mixed with water-insoluble derivatives like cellulose and Carbopol 934P and delivered nasally. On exposure to water, the formulation swells and releases its pharmacological effect. ^[54]

Dry powder inhalers (DPIs): Dry powder inhalers (DPIs) administer dry powder drugs through the pulmonary route for local or systemic action. Applied in respiratory disorders and diabetes. DPIs contain medication in capsules or proprietary forms. During inhalation, the drug is fluidized, and patients must inhale and hold their breath for 5–10 seconds. Doses are restricted to a few tens of milligrams to avoid coughing. ^[55]

Nanoparticles: Nanoparticles have various benefits because of their small size; however, only the tiniest of nanoparticles can pass through the mucosal membrane through the par cellular pathway, and even that in negligible amounts, since tight junctions are between 3.9 to 8.4 Å. Research on the application of nanoparticles in intranasal drug delivery has produced conflicting findings (Simon et al., 2005). ^[56]

Liposomes: Liposomes are phospholipid vesicles in the form of lipid bilayers that contain one or more aqueous compartments with the ability to include drugs and other materials. Liposomal nasal products have the drug alone or in combination with other excipients. They are delivered to the respiratory tract in the form of an aerosol. ^[57]

Microsphere: Microspheres play a crucial role in nasal drug delivery by enhancing absorption, providing sustained release and protecting the drug from enzymatic degradation. ^[57]

7. In-Situ Gel

Gel- gel is a state between solid and liquid phases where a three-dimensional network of interlinked molecules in the solid component immobilizes the liquid phase. ^[58]

In-Situ Gel Delivery System -In-gel formulation systems are drug delivery systems that remain in solution before administration but undergo gelation in situ upon injection. This gelation is triggered by external factors such as temperature or pH, allowing for continuous or controlled drug release. ^[59]

1. 1. Mechanisms of In Situ Gel Formation

7.1.1 In-situ gelation induced by physiological stimuli

1. Temperature-sensitive in situ gel systems
2. pH-responsive in situ gelling systems
   1. 2. Ion-Activated In Situ Gelation
      3. In-Situ Gel Formation via Physical Mechanisms:

1. Polymer swelling
2. Solvent diffusion                                                                   
   1. 4. In-Situ Gel Formation via Chemical Reactions:

1. Ionic interactions and cross-linking
2. Enzyme-mediated cross-linking
3. Light-induced photo polymerization.

7.1.1 A) Temperature-sensitive in situ gel systems ^{[60 61]}

Temperature-sensitive in situ gel systems are a well-researched group of drug delivery since they make use of thermo sensitive polymers. Temperature regulation is easy and usable both in vitro and in vivo. These hydrogels are liquid at room temperature (20–25°C) and gel when they come into contact with body fluids (35–37°C), thereby enabling controlled drug release. The change from sol to gel is brought about by a rise in temperature, thereby eliminating the requirement for external heating. Poloxamers, Pluronic, cellulose derivatives (HPMC, EHEC, and methylcellulose), xyloglucan, and tetronics are examples. They are categorized as negatively thermo sensitive (contract when heated), positively thermo sensitive (contract when cooled), and thermo reversible gel.

In this system, pH variation results in gel transition. This method relies on the use of pH-responsive or pH-sensitive polymers. Polymers containing pendant basic or acidic groups absorb or release protons based on their pH environment variations ^[62]. Polyelectrolytes are ionisable groups consisting of large-scale polymers. Here, as the formulation consists of polyelectrolytes, an increase in external pH causes swelling of the hydrogel to create an in situ gel. The most suitable polymers for this approach are anionic polymers. Some of the most commonly employed anionic polymers are polyethylene glycol (PEG), pseudo-latexes, carbomer and its derivatives, cellulose acetate phthalate (CAP), polymethacrylic acid (PMA), and more ^[63]. A blend of polymethacrylic acid (PMA) and polyethylene glycol (PEG) has also been used as a pH-sensitive system to trigger gelation ^[64]. Polyacrylic acid is another widely known polymer that also shows pH-responsive behaviour. Carbopol is the term used for this polymer, which is soluble in acidic pH values and is a low-viscosity gel at alkaline pH values. ^[65]

Fig No: 5 Mechanism Involved in The Ph-Sensitive System

7.1.3 In-Situ Gel Formation via Physical Mechanisms:

Swelling: It forms in place when a substance picks up moisture from its environment and swells to form the necessary space. One substance like that is Myverol 18-99 (glycerol mono-oleate), a polar lipid that swells upon contact with water to form liquid crystalline phase structures. ^[66]

Diffusion: This kind of process consolidates the polymer matrix by permitting the solvent from the polymer solution to diffuse into the tissue. Research has indicated that N-methyl pyrrolidone (NMP) is a suitable solvent for the system. ^[67]

7.1.4 In-Situ Gel Formation via Chemical Reactions:

Ion cross-linking: Ions can induce phase transitions in polymers. Certain ion-sensitive polysaccharides include κ-carrageenan, which forms brittle gels with K?, and ι-carrageenan, which forms elastic gels with Ca²?. Gellan gum (Gel rite®) gelifies in situ in the presence of mono- and divalent cations such as Ca²?, Mg²?, K?, and Na?. Low-methoxy pectins and alginic acid also gel in the presence of divalent cations, especially Ca²?, by association with their polymer chains. ^[68]

Enzymatic cross-linking: Here, the gelation occurs due to cross-linking with enzymes in body fluids, which has benefits over photochemical and chemical methods. ^{[69, 70]}

Photo-polymerization: In situ photo-polymerization has been used in biomedical applications for more than a decade. A solution containing the monomers or reactive macromers along with an initiator may be injected into the tissue site and then applied with electromagnetic radiation to create the gel. Use of acrylate or analogous polymerizable functional groups on macromeres and monomers is also very frequent due to their easy photo polymerization in the presence of a compatible photo initiator. Upon injection to the site, fiber optic cables lead to in situ photo curing of photopolymerizable systems to induce sustained drug release for a prolonged duration. ^[71]

Fig No: 6 Mechanism of Ion Responsive In Situ Gelation