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Abstract

Depression remains a global health challenge, often inadequately managed due to the poor bioavailability and limited brain penetration of conventional antidepressants. Intranasal drug delivery offers a non-invasive route to bypass the blood-brain barrier (BBB), enabling rapid and targeted drug delivery to the brain. Liposomal in situ gel formulations have emerged as a promising strategy, combining the advantages of liposomes for enhanced drug encapsulation and nasal mucosal permeation with the sustained release properties of in situ gels. These formulations utilize thermosensitive or pH-sensitive polymers, ensuring sol-to-gel transitions upon administration, prolonging nasal residence time, and enhancing drug transport via the olfactory and trigeminal pathways. Factors such as liposome composition, polymer type, and drug loading play a critical role in optimizing drug release and therapeutic efficacy. By reducing systemic side effects, improving drug retention, and increasing patient compliance, liposomal in situ gels offer a novel, effective approach for intranasal antidepressant delivery, with the potential to revolutionize depression management.

Keywords

Depression, Antidepressants, Liposomes, In Situ Gel, Intranasal Delivery.

Introduction

Depression is a state of low mood and aversion to activity that can affect a person’s thoughts, behavior, feelings, physical well-being, and circadian rhythm. Depression has become the leading cause of disability worldwide and is a significant global health burden[1].  one of the major reasons patients fail in their treatment course is the existence of the blood-brain barrier (BBB), which is the bottleneck of drug delivery for the central nervous system (CNS). BBB, which is mainly composed of cerebra endothelial cells (CECs) that constitute a selective barrier covering the inner surface of cerebral capillaries, is the majorsite of blood–CNS exchange, maintaining the homeostasis of the CNS [2][3]. To compare the effectiveness of two active medications, assess the effectiveness of antidepressants in combination with other treatment modalities such as electroconvulsive therapy or psychiatric treatment, and assess the effectiveness of antidepressants using a placebo as a comparator. Serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors are examples of antidepressants that have been produced [4]. The proper use of antidepressant medication should be emphasized for patients who are more likely to struggle with adherence. These patients usually have other major psychiatric diagnoses, than affectiveor anxiety disorders,  have low incomes, are on other medications for coexisting medical conditions, and/orlive in rural areas where access to specialized care is limited. For such patients,it is important to emphasize the link between adherence to proper treatmentand therapeutic outcomes, while giving them personalized information and making sure they follow up regularly as much as possible. Psychiatrists and general practitioners should assess whether their patients fully understand and follow instructions, and offer the opportunity to collaborate in addressingany challenges that may arise during antidepressant treatment [5]. Liposomes was firstly discovered in the 1960’s by Bengham and later became among the most expansive drug delivery systems [6]. Liposomes are widely used in nano-medicine mainly due to their biocompatibility, stability, easy to synthesize, and high drug loading efficiency, high bioavailability [7][8].

Signs and Symptoms:[9]

Chart No 1: Signs and symptoms for depression.

Pathology:

Neurotransmitter Systems: Alterations in Serotonergic and Noradrenergic functions in the central nervous system are commonly observed in patients with depression. These neurotransmitters play crucial roles in mood regulation[10].

Hypothalamic-pituitary-adrenal(HPA) Axis: Dysregulation of the HPA axis, often characterized by hyper activity and increased cortisol production is associated with depression. High cortisol levels have been linked to the severity of depressive symptoms, particularly in melancholic depression[11].

Neurotrophic factors: Brain-delivered neurotrophic factor(BDNF) is significant in the pathophysiology in depression. Reduced levels of BDNF are associated with decreased neuroplasticity and neurogenesis, particularly in the hippocampus which is often found to be volumetrically reduced in depressed patients[11,10].

Inflammation: The inflammatory hypothesis suggests that elevated levels of inflammatory cytokines may contribute to the development of depression. This is supported by findings that show a correlation between inflammation and depressive symptoms[10].

Oxidative Stress and Mitochondrial Dysfunction: Imbalances in oxidant-antioxidant systems and mitochondrial dysfunction are also implicated in the pathology of depression, These factors can affect energy metabolism and neuronal health[12].

Mechanism of action:

The primary mechanism of action of selective serotonin reuptake inhibitors (SSRIs) involves inhibiting the presynaptic reuptake of serotonin at the serotonin transporter. This inhibition leads to increased levels of serotonin in the synaptic cleft, enhancing its availability at the postsynaptic membrane. As a result, SSRIs effectively increase serotonergic neurotransmission, which is associated with their therapeutic effects in treating depression and anxiety disorders[13].

Antidepressant drugs, mechanisms of action, and their adverse effects [14].

Table No 1: Antidepressant Drugs, Mechanisms of Action, And Their Adverse Effects

 

Group

Mechanism of action

Common side effects

SSRIs

Inhibition of SERT

Nausea, diarrhea, drymouth, sexual dysfunction, initial anxiety.

SNIRs

Inhibition of SERT and NAT

Headache, insomnia, nausea, increased blood pressure.

NDIRs

Inhibition of NAT and DAT

Anorexia, Constipation, dry mouth, Headache.

NRIs

Inhibition of NAT

Anorexia, insomnia, dizziness, anxiety, drymouth.

MTAs

Agonism of MT1/MT2

Drowsiness and headache.

Α2-Antagonists

Α2 Antagonism

 

Increased appitate, dry mouth, sedation and hypotension.

SARIs

Inhibition of SERT and 5HT2A/2C Antagonism

Edema, blurred vision.

TCAs

Inhibition of SERT and NAT

Fatigue, sedation.

MM

Inhibition of SERT, 5-HT1A/1B/1D Agonist and 5-HT7 Antagonist

Dizziness and dry mouth.

            Serotonin reuptake inhibitors: SSRIs inhibit serotonin reuptake by blocking the serotonin transporter (SERT), increasing serotonin levels in the synaptic left to enhance neurotransmission. Drugs like Fluoxetine, Sertraline, citaloporam, paroxetine[13].

  1. Serotonin-Norepinephrine Reuptake Inhibitors: SNRIs work by blocking the reuptake of serotonin (5-HT) and norepinephrine (NE) at the presynaptic neuron, increasing their levels in the synaptic cleft. This leads to enhanced neurotransmission and improved mood regulation, making SNRIs effective in treating depression, anxiety, and chronic pain.Common SNRIs include duloxetine, venlafaxine, and desvenlafaxine[15].
  2. Norepinephrine-Dopamine Reuptake Inhibitors: NDRIs block the reuptake of norepinephrine (NE) and dopamine (DA), increasing their levels and enhancing neurotransmission. Bupropion (used for depression, ADHD, smoking cessation) and Methylphenidate (used for ADHD, narcolepsy) are common NDRIs. They boost focus, mood, and energy, but may cause insomnia, anxiety, and seizures[16].
  3. Norepinephrine Reuptake Inhibitors:  NRIs block the reuptake of norepinephrine (NE) at the presynaptic neuron, increasing NE levels in the synaptic cleft and enhancing adrenergic neurotransmission. This leads to improved alertness, focus, and mood regulation. Common NRIs include Atomoxetine (ADHD), Reboxetine (depression), and Maprotiline (major depressive disorder). Side effects include insomnia, increased heart rate, and hypertension[17].
  4. Serotonin Antagonist and Reuptake Inhibitors:  SARIs block serotonin (5-HT) reuptake while antagonizing specific serotonin receptors (5-HT2A/5-HT2C). This dual action enhances serotonergic neurotransmission while reducing side effects like insomnia, anxiety, and sexual dysfunction. Common SARIs include Trazodone (used for depression, insomnia) and Nefazodone (depression). Side effects include sedation, dizziness, and orthostatic hypotension[18].

Types of Depression [19].

Chart no 2: Types of Depression

Nasal Anatomy and Physiology:

Researchers are interested in the nasal route for systemic drug delivery due to the high vascularization and permeability of the nasal mucosa, allowing for rapid absorption and onset of action. This route bypasses first-pass metabolism, improving bioavailability. It is useful for drugs with poor oral absorption and CNS-targeted therapies via the olfactory pathway [20]. The nasal cavity in humans and other animal species serves several key functions, primarily breathing and olfaction. It plays an essential protective role by filtering, heating, and humidifying inhaled air before it reaches the lower airways. The nasal cavity extends approximately 12-14 cm from the nasal vestibule to the nasopharynx, with a total surface area of about 150 cm² and a volume of around 15 ml in adult humans [21].  The viscosity of nasal secretions affects mucociliary clearance and drug permeation. If the sol layer is too thin, ciliary function is impaired; if too thick, drug contact decreases. Drug solubility in nasal secretions is crucial for absorption, requiring appropriate physicochemical properties for effective dissolution and permeation.[22]. Each nasal cavity is divided into various regions, including the nasal vestibule, inferior turbinate, middle turbinate, superior turbinate, olfactory region, frontal sinus, sphenoidal sinus, and the cribriform plate of the ethmoid bone. The nasal cavity contains nasal-associated lymphoid tissue (NALT), primarily located in the nasopharynx. It is lined with a mucus layer and hairs that trap inhaled particles and pathogens. Additionally, the nasal structures perform essential functions such as mucociliary clearance, immunological activities, and the metabolism of endogenous substances.[23]. The nasal cavity is divided by the middle septum into two symmetrical halves, each opening at the face through the nostrils and extending posteriorly to the nasopharynx. Each half consists of four distinct areas: the nasal vestibule, atrium, respiratory region, and olfactory region. These areas are differentiated based on their anatomical and histological characteristics[23].

Atrium: The atrium is the intermediate area between the nasal vestibule and the respiratory region. Its anterior section is lined with stratified squamous epithelium, while the posterior area is composed of pseudostratified columnar cells that feature microvilli[24,25].

Respiratory region: The respiratory region, also known as the conchae, is the largest part of the nasal cavity and is divided into superior, middle, and inferior turbinates that project from the lateral wall. This area is vital for systemic drug delivery and is composed of nasal respiratory mucosa, which includes the epithelium, basement membrane, and lamina propria. The epithelial lining consists of pseudostratified columnar cells, goblet cells, basal cells, and mucous and serous glands[8]. Many epithelial cells have microvilli on their apical surfaces, and most are equipped with fine projections called cilia [26]Mucus membrane of nose and its composition: The nasal mucus layer is approximately 5 μm thick and is organized into two distinct layers: an outer viscous and dense layer, and an inner fluid and serous layer. The composition of the nasal mucus consists of about 95% water, 2.5-3% mucin, and 2% various components such as electrolytes, proteins, lipids, enzymes, antibodies, sloughed epithelial cells, and bacterial products.[22]

Epithelial cells: Epithelial cells in the nasal cavity serve two main functions: they provide a physical barrier against infectious microorganisms and allergens, and they work alongside mucus glands and cilia to secrete and remove mucus, along with trapped foreign particles, thus ensuring respiratory health and clear nasal passages[23].

Figure no 1: Nasal Cavity

Advantages of Nasal Route:[27, 28]

  • Higher bioavailability allowing lower doses.
  • Fast onset of therapeutic action.
  • Avoidance of gastric irritation.
  • Ease of self medication.
  • Reduced risk of infectious disease transmission.

Limitations of Nasal Route:[29, 30]

  • There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa.
  • Certain compounds when used as absorption enhancers may disrupt and even dissolve the nasal membrane in the high concentration.
  • There could be mechanical loss of the dosage form into the other parts of the respiratory tract like lungs.

Anatomy from Nose to Brain pathway:

Chart no 3: Pathways for brain targeting after intranasal administration

Pathways and mechanisms:

Although the exact mechanisms of intranasal drug delivery to the CNS are not yet fully understood, growing evidence suggests that neural pathways connecting the nasal passages to the brain and spinal cord play a significant role. Vascular, cerebrospinal fluid (CSF), and lymphatic pathways have also been implicated in transporting molecules from the nasal cavity to the CNS, indicating that a combination of these routes may be involved. Pathway is responsible, although one pathway may predominate, depending on the properties of neurotherapeutics, the characterstics of formulations and delivery device used.[31]

Olfactory nerve pathway:

In order to gain access to the cerebrospinal fluid or brain parenchyma from the olfactory region in the nasal cavity, a drug must penetrate the nasal olfactory epithelium and, depending on the route, the arachnoid membrane surrounding the subarachnoid space. Three major routes of transport across the olfactory epithelium have been identified. The first of these is the transcellular route, by which drugs pass through sustentacular cells, primarily by receptor-mediated endocytosis, fluid-phase endocytosis, or passive diffusion. The most common pathway for lipophilic drugs is passive diffusion. It is quick and fast the transport rate relies on the lipophilicity of the drug. The paracellular pathway refers to the drug molecule passing through tight junctions between sustentacular cells or between clefts between sustentacular cells and olfactory neurons. Hydrophilic drugs rely on this pathway, where drugs diffuse in an aqueous channel or pores through a slow, passive route. This pathway is dependent on the drug's molecular weight; good bioavailability has been observed for up to 1000 Da and, with the use of absorption enhancers, has been extended to 6000 Da. The third pathway involves the olfactory nerve pathway where drugs are taken up by neuronal cells through endocytosis or pinocytosis and then transported intracellularly through axonal transport to the olfactory bulb.[32,33]

Trigeminal nerve pathway:

A important pathway connecting the nasal passages to the CNS is that of the trigeminal nerve, the largest cranial nerve, which innervates the respiratory and olfactory epithelium of the nasal passages and enters the CNS at the pons. A small portion of the trigeminal nerve also terminates in the olfactory bulbs. It conveys sensory information from the nasal cavity, oral cavity, eyelids, and cornea to the CNS through its three divisions: the ophthalmic division (V1), the maxillary division (V2), and the mandibular division (V3).[34] The former two have only sensory function while later have both sensory as well motor function.  The ophthalmic and maxillary branches of the trigeminal nerve play an important role in nose-to-brain drug delivery since the neurons of these branches pass directly across the nasal mucosa. A characteristic feature of the trigeminal nerve is its dual entry into the brain from the respiratory epithelium of the nasal passages: first, through the anterior lacerated foramen near the pons, and second, via the cribriform plate near the olfactory bulb, thus allowing access to both caudal and rostral brain regions after intranasal administration. Although there are no reports of detailed description about ensheathing cells and channels related to the trigeminal nerve, comparable to those observed with olfactory nerves, such anatomical features might exist.[34] Other nerves that innervate the face and head, like the facial nerve, or sensory structures in the nasal cavity, such as the Grueneberg ganglion, may also be used as potential entry points for intranasal delivery of neurotherapeutics into the CNS. Thorne and colleagues were the first to demonstrate CNS delivery of insulin-like growth factor-I (125I-IGF-I), a neurotropic protein, after intranasal administration, observing high levels of radioactivity in trigeminal nerve branches, the trigeminal ganglion, the pons, and the olfactory bulbs, suggesting delivery via both olfactory and trigeminal pathways. Since one component of the trigeminal neural pathway traverses through the cribriform plate into the brain via the olfactory route, it is difficult to differentiate between intranasally administered drugs entering the olfactory bulbs and rostral brain areas like the anterior olfactory nucleus and frontal cortex via the olfactory route, the brain stem and spinal cord areas via the trigeminal pathway, or both, since these pathways avoid passing through the BBB.[35]

Advantages:

  • It is a rapid, safe, non-invasive and convenient method of drug delivery.
  • It avoids drug degradation in gastrointestinal tract, particularly peptide drugs.
  • It avoids hepatic first-pass metabolism and gut-wall metabolism of drugs, allowing enhanced bioavailability.[31]

Limitations:

  • Rapid elimination of drug substances from nasal cavity due to mucocilliary clearance.
  • Absorption enhancers used in formulation may create mucosal toxicity.
  • High molecular weight of drugs may result in decreased permeability across nasal mucosa.[31]

Factors Affecting for nasal drug absorption:

Chart no 4: Factors Affecting for nasal drug absorption[31]

Liposomes: [36]

Liposomes are spherical vesicles comprised of lipid bilayer shells surrounding aqueous interior cores and are formed spontaneously when amphiphillic lipids are dispersed in water. Among different types of nanoparticles of drug delivery, liposomes are the most developed and established drug delivery system available clinically.[37] Liposome is colloidal carriers, which range in size from 0.01-5.0µm diameter. The capability makes liposomes an attractive carrier system with uses in a variety of industries, including food, cosmetics, agriculture and pharmaceutics.[38, 39]

Advantages [40, 41]

  1. Amphiphatic in nature so entrap both kind of drugs either water soluble or insoluble.
  2. Increased efficacy and therapeutic index of drug.
  3. Liposomes are biodegradable.
  4. Non ionic.
  5. Liposome increases stability of drug.
  6. Improve protein stabilization.
  7. Provides selective passive targeting to tumor tissues.
  8. Provide sustained release.

Disadvantages: [42, 43]

  1. Low solubility.
  2. Short half-life.
  3. Production cost is high.
  4. Less stable.

Structure and main components of liposomes:

Structure of liposomes

Liposomes can be classified as unilamellar vesicles(ULVs), oligolamellar vesicles(OLVs), multilamellar vesicles(MLVs), and multivesicular liposomes(MLVs), depending on compartment structure and lamellarity. OLVs and MLVs show anonion like structure but present 2-5 and >5 concentric lipid bilayers, respectively. Different from MLVs, MVLs include hundreds of non- concentric aqueous chambers bounded by a single bilayer lipid membrane and display a honeycomb-like structure. Based on the particle size, ULVs further divided into small unilamellar vesicles(SUVs, 30-100nm), large unilamellar vesicles(LUVs, >100nm), and giant unilamellar vesicles(GUVs, >1000nm). Different size range of ULVs was report, i.e., SUVs with a size of less than 200nm and LUVs with a size of 200-500nm.[44,45,46,47]

Figure no 3: Liposomes

Mechanism of liposome formation

Liposomes are mainly composed of phospholipids, which are amphiphilic molecules with a hydrophilic head and a hydrophobic tail. The hydrophilic part mainly consists of phosphoric acid bound to a water-soluble molecule, while The hydrophobic part consists of two fatty acid chains, each containing between 10 to 24 carbon atoms and 0 to 6 double bonds. When phospholipids are dispersed in an aqueous medium, they organize themselves into lamellar sheets, where polar head groups face the aqueous region, while fatty acid tails point inward toward each other. This structure gives rise to spherical vesicle-like structures termed as liposomes in which the polar portion is in contact with the aqueous region, thus protecting the non-polar part by protecting it from the outer aqueous environment.[48]

Classification of liposomes: Small unilamellar vesicles, These vesicles have a low aqueous volume to lipids ratio and are made up of a single bilayer. Sizes range from 10-1nm. Large unilamellar vesicles, These vesicles are are ideal for carrying hydrophilic drugs. Since they are composed of a single bilayer and have a high-water volume to lipid ratio. The ramge of sizes is 100nm-1µm. Multilamellar vesicles, These are several bilayers, the lipid-to water ratio is roughly more lipid water. It can range in size from 100nm-20µm. Oligolamellar vesicles, A middle ground between LUV and MUV. The size of these spans from 0.1-1µm, and there are more than one of them but less than MUV.[48]

Multilamellar Vesicles: Multilamellar vesicles (MLVs) are liposomes larger than 0.1 μm with multiple bilayers, formed using simple methods like thin-film hydration. They are mechanically stable but rapidly cleared by the reticuloendothelial system (RES), making them useful for RES-targeted drug delivery. Their moderate aqueous-to-lipid ratio allows for enhanced drug entrapment through slow hydration and gentle mixing. Lyophilization and rehydration further improve encapsulation efficiency up to 40%.[49]

Large Unilamellar Vesicles: Large unilamellar vesicles (LUVs) are single-bilayer liposomes larger than 0.1 μm, known for their high encapsulation efficiency, making them ideal for hydrophilic drug delivery. They require less lipid to encapsulate large drug quantities and, like MLVs, are rapidly cleared by RES cells due to their size. Various methods, including ether injection, detergent dialysis, and reverse-phase evaporation, can formulate LUVs. Additional techniques like freeze-thawing, dehydration/rehydration of SUVs, and slow lipid swelling in non-electrolyte solutions also aid in their preparation. Their high trapped volume makes them efficient carriers for drug delivery applications.[50]

Small Unilamellar Vesicles: Small unilamellar vesicles (SUVs) are liposomes smaller than 0.1 μm with a single bilayer and a low aqueous volume-to-lipid ratio. They have a long circulation half-life but are prone to aggregation and fusion if they have low or no charge. SUVs can be prepared via solvent injection (ethanol or ether injection) or by reducing the size of MLVs or LUVs through sonication (bath or probe) or extrusion under inert gases like nitrogen or argon. Additionally, passing MLVs through a narrow orifice under high pressure can produce SUVs, making them useful for drug delivery applications.[51]

Strutcural components:

Lipids and Phospholipids:  Liposomes are spherical or multilayered vesicles formed by the self-assembly of diacyl-chain phospholipids into a lipid bilayer in aqueous solutions.[52]. Liposomes have an amphiphilic structure due to their bilayer phospholipid membrane, which consists of hydrophobic tails and hydrophilic heads. They can be synthesized using both natural and synthetic phospholipids.[53][54]. Lipid composition plays a crucial role in determining liposome properties, including particle size, rigidity, fluidity, stability, and electrical charge, all of which impact their performance and effectiveness in drug delivery systems.[55,]. Lipids have hydrophilic groups that can be negatively, positively, or zwitterionically charged, enhancing stability through electrostatic repulsion. Their hydrophobic groups differ in acyl chain length, symmetry, and saturation, influencing the structural and functional properties of liposomes in drug delivery systems.[56].

Steroid: Steroids are hydrophobic lipids with a four-ring structure, with their diversity arising from various functional groups attached to these rings. Cholesterol, a key steroid, is commonly used in liposome preparation at a concentration of less than 30% of the total lipids. It enhances liposomal rigidity and stability by integrating into the lipid bilayer.58. A comparative study on cholesterol and β-sitosterol effects on liposome membranes showed that both steroids reduce membrane fluidity, increase absolute zeta potential, alter particle size, and lower the DPPC phase transition temperature (Tm) and enthalpy.[57].

Surfactants: Surfactants were incorporated into liposome formulations to enhance encapsulation and control drug release by reducing surface tension between immiscible phases, thereby improving stability and permeability [58]. Surfactants are single acyl-chain amphiphiles that destabilize the liposomal lipid bilayer, increasing nanoparticle deformability. This enhances drug encapsulation, release, and permeability by reducing surface tension between immiscible phases.[59,60]. Common surfactants used in liposome formulations include sodium cholate, Span 60, Span 80, Tween 60, and Tween 80.[61]. These surfactants enhance liposomal properties by modifying bilayer stability, improving drug encapsulation, and controlling release through surface tension reduction and increased deformability.[62].

Method of preparation:

  • Thin film hydration method:

This is one of the most widely used methods for liposomes preparation.

Steps:

  • Dissolve lipids in an organic solvent like chloroform or methanol to create a lipid solution.
  • Evaporate the solvent under reduced pressure to form a thin lipid film on the walls of a round bottom flask.
  • Hydrate the lipid film by adding an aqueous solution and sonicating to form multilamellar vesicles.
  • Optionally, you can reduce the size of MLVs to smaller unilamellar vesicles through sonication.[63]

Thin film hydration method for empty liposome preparation. The liposomes produced from this method are often polydisperse; however, there is a correlation between the duration spent during the rotary evaporation step and the quality of thin film produced. Factors such as mixing speed and temperature after the hydration will also effect the quality of the liposomes so this must be monitored.

Figure no 3: Thin film hydration

Reverse phase evaporation method:

This method is used for preparing liposomes with high encapsulation efficiency.

Steps:

  • Dissolve lipids in an organic solvent with an aqueous solution containing the substance to the encapsulated.
  • Evaporate the organic solvent under reduced pressure to form a water-in-oil emulsion.
  • Remove the organic phase, leaving behind liposomes containing the encapsulated substance.[64]
  • Extrusion method:

This method is used to prepare liposomes with uniform size and narrow size distribution.

Steps:

  • Prepare liposomes using thin film hydration method to create MLV s.
  • Pass the liposome suspension through a series of polycarbonate membrane filters with defined pore sizes using a hand-held extruder.
  • This process results in smaller liposomes with a consistent size.[65]
  • Sonication method

Steps:

  • This method is used to downsize liposomes or to prepare small unilamellar vesicles.
  • Subject the liposome suspension to high-frequency ultrasound to reduce the size of the liposomes.[66]
  • Detergent Removal Method:

Steps:

  • Dissolve lipids and the hydrophobic substance in a detergent solution.
  • Remove the detergent using techniques like dialysis or chromatography to obtain liposomes with the encapsulated substance.[67]

Marketed formulation of liposomes:[68]

Table no 2: Marketed formulation of liposomes

 

Product

Drug

Company

AmbisomeTM

Amphotericin B

Nexstar pharmaceuticalsbInc., CO

AbelcetTM

Amphotericin B

The Liposome, NJ

AmphocilTM

Amphotericin B

Sequus pharmaceuticals, Inc., C.A,

DoxilTM

Doxorubicin

Sequus pharmaceuticals, Inc., C.A,

DaunoXomeTM

Daunorubicin

Nexstar pharmaceuticalsbInc., CO

MikasomeTM

Amikacin

Nexstar pharmaceuticalsbInc., CO

DC99TM

Doxorubicin

Liposome CO., NJ, USA

EpaxelTM

Hepatitis A Vaccine

Swiss Serum institute, Switzerland.

ELA-MaxTM

Lidocaine

Biozone Labs, CA, USA.

Characterization and Evaluation of liposomes:

Size and Size distribution: The manufacturing process and the lipid content significantly affect the mean size of liposomes. Dynamic Light Scattering (DLS) method is employed to determine the average size of liposomes in aqueous dispersion. DLS is noted for its capability to provide size distribution data. Electron microscopy techniques such as transmission and scanning electron microscopy allow for direct imaging of liposomes, offering qualitative insights into their size, shape, and the presence of any fusion or aggregation. This imaging can provide valuable information regarding bilayer thickness and interlayer distance. The size of liposomes typically ranges from 0.1 to 0.2 µm following processing techniques. Size is critical as it can affect the circulation time in the bloodstream, tissue penetration, and cellular uptake, ultimately influencing therapeutic efficacy.[69]

Surface charge: The surface charge of liposomes is crucial for their stability, encapsulation efficiency, and interaction with biological tissues. Liposomes can be neutral, negative, or positive depending on the lipids used, which influences their stability and drug entrapment capabilities. Zeta potential, a measure of electrostatic repulsion between like-charged particles, is essential for determining liposomal stability, with higher values indicating reduced aggregation. Manipulating surface charge is vital for optimizing liposomes in drug delivery systems, enhancing therapeutic efficacy while minimizing side effects.[70]

Zeta Potential: Zeta potential depends on the surface charge of lipid vesicles, the suspension medium, and any adsorbed layers. While it cannot be measured directly, it is calculated using theoretical models and experimental electrophoretic mobility. A high zeta potential prevents vesicle aggregation, ensuring liposomal stability by reducing coalescence, fusion, and precipitation. Stability can be enhanced through electrostatic or steric repulsion. Liposome surface charge also affects circulation time in the bloodstream. Lipid composition influences zeta potential values. Filion and Phillips measured zeta potential in cationic liposomes using Doppler electrophoretic light scattering with laser Doppler electrophoresis (LDE) and a zetasizer.[71]

Morphology: Transmission electron microscopy (TEM) and cryogenic transmission electron

Microscopy (cryo-TEM) are powerful imaging techniques used to visualize the morphology and internal structure of liposomes at the nanoscale level. TEM provides high-resolution images of liposome morphology. These techniques help to characterize liposome size, shape, lamellarity, and vesicle intergrity.[72]

Determination of Lamellarity: Lamellarity in liposomes is determined using spectroscopic methods or electron microscopy to assess the number of lipid bilayers. Encapsulation efficiency measurements with hydrophilic markers also aid in verifying layers. Understanding lamellarity is crucial for evaluating the drug delivery capabilities and stability of liposomal formulations liposomes.[73]

Entrapped volume: Entrapped volume in liposomes refers to the total amount of solute contained within the lipid vesicles. It is typically quantified by measuring the concentration of a hydrophilic marker inside the liposomes compared to the surrounding medium. Methods include separation techniques to isolate the liposomes and ensure accurate volume determination for effective drug delivery.[74]

Entrapment efficiency and Drug loading: HPLC and UV-Visible spectroscopy are commonly used techniques for quantifying drug encapsulation efficiency and loading in liposomal formulations. HPLC enables accurate and selective analysis of drug concentrations in liposome suspensions. UV-Visible spectroscopy allows for rapid and sensitive detection of encapsulated drugs based on their absorbance spectra. These methods are essential for optimizing drug loading conditions and assessing the efficiency of drug encapsulation within liposomes.[75,76]

Stability of liposomes

The stability of liposomes controls the therapeutic effectiveness of medicinal molecules. Two forms of stability exist.

Physical Stability: Physical stability of liposomes refers to their ability to maintain structure and integrity over time, influenced by factors like fusion, aggregation, and leakage of drug components. Key considerations include maintaining optimal size and morphology, preventing excessive unsaturation, and storing liposomes correctly, typically at 4°C, away from light.[77]

Chemical Stability: Chemical stability of liposomes involves the resistance of their phospholipid components to degradation, particularly hydrolysis and oxidation. Unsaturated fatty acids in phospholipids can undergo hydrolysis, impacting drug stability. To enhance chemical stability, antioxidants like butylated hydroxy anisole may be added to prevent oxidative degradation of the liposomal formulation.[77]

Approaches for Insitu gel: In-situ gelation involves gel formation at the application site, enabling drug delivery in liquid form with sustained release. Introduced in the 1980s, it uses natural or synthetic polymers for localized drug delivery, offering controlled plasma profiles and advantages for topical, surgical, and other medical applications in humans and animals.[78]

Over the last 30 years, research on controlled drug delivery has focused on polymeric systems like in situ gels. These systems, transitioning to gels via stimuli like temperature or pH, enable sustained, site-specific drug release, enhancing efficacy, reducing side effects, and improving patient compliance across applications like intranasal, ocular, and injectable delivery.[79]

Thermally triggered systems:  A thermally triggered in situ gel system transitions from a liquid to a gel state upon exposure to physiological temperatures (35–37°C). These systems typically utilize polymers with a Lower Critical Solution Temperature (LCST), like Poly(N-isopropylacrylamide) (PNIPAAm), which become hydrophobic and precipitate as gels when heated. Alternatively, some polymers exhibit Upper Critical Solution Temperature (UCST) behavior. Thermally responsive gels are advantageous in drug delivery as they allow for easy administration and precise control over gelation without requiring external heat sources, making them practical for clinical applications.[80, 81]

pH Triggered systems:  pH-triggered systems are drug delivery methods that respond to changes in environmental pH, useful for targeting specific body sites such as the stomach and tumors. These systems typically use polymers containing ionizable groups that swell or shrink in response to pH changes. For instance, anionic polymers like Poly(acrylic acid) swell and form gels at higher pH levels, enabling sustained drug release. This mechanism enhances drug efficacy while minimizing systemic side effects, making pH-responsive systems a valuable approach in targeted drug delivery applications.[82]

Swelling: Swelling in in situ gel systems involves the absorption of water by the polymer network, causing the gel to expand and transition from a liquid to a gel-like state. This process is essential for controlled drug release, as it creates a three-dimensional structure capable of retaining and gradually releasing the drug over time. Swelling can be triggered by environmental factors such as temperature, pH changes, or ionic conditions. This property enhances the therapeutic efficacy of drug delivery systems while ensuring better patient compliance and comfort.[83]

Diffusion: Diffusion in drug delivery refers to the movement of drug molecules from an area of higher concentration to one of lower concentration across biological membranes. In the context of in situ gel systems, once the gel is formed and swells, the drug becomes available for release as it diffuses out from the gel matrix into the surrounding tissue. This process is of the surrounding environment. Controlled diffusion ensures a steady release of the drug, optimizing therapeutic effects while minimizing side effects.[84]

Ionic crosslinking: Ionic crosslinking is a method used in the formulation of in situ gels, where the gelation process is induced by the presence of specific ions, such as mono or divalent cations (e.g., Na?, K?, Ca²?, and Mg²?). In this system, naturally occurring anionic polymers (like gellan gum and sodium alginate) undergo a sol-to-gel transition when exposed to these ions. This type of crosslinking enhances the stability and mechanical properties of the gel, allowing for effective drug encapsulation and controlled release, making it a valuable strategy in drug delivery applications.[85]

Photo-polymerization: Photopolymerization is a technique used in the formation of in situ gels through the application of light to initiate the polymerization process. In this method, monomers or macromers mixed with a photoinitiator are injected into the desired tissue site. When exposed to specific wavelengths of light, the photoinitiator activates and triggers the polymerization reaction, resulting in gel formation. This technique allows for precise control over the timing and location of gelation, leading to the creation of a stable hydrogel that can effectively encapsulate and release drugs over time.[86]

Enzymatic crosslinking: Enzymatic crosslinking is a method used in the formation of in situ gels where enzymes catalyze the crosslinking process of polymers. This technique typically involves the incorporation of specific enzymes that react with functional groups in natural or synthetic polymers, leading to the formation of a stable gel network. For example, certain enzymes can act on polysaccharides or proteins to create crosslinks between polymer chains, enhancing the gel's mechanical stability and bioadhesive properties. This approach is particularly beneficial for creating smart drug delivery systems that can respond to physiological conditions and release therapeutic agents in a controlled manner.[87]

Safety Profile:

  • The safety profile of in situ nasal gels is critical due to their prolonged retention, which may interfere with mucociliary clearance. This extended contact with nasal mucosa can lead to irritation, tissue damage, ciliotoxicity, or epithelial toxicity, depending on the formulation's polymers and drugs, unlike conventional nasal solutions.[88]
  • Studies evaluating the safety of stimuli-responsive in situ gels highlight that poloxamer and chitosan exhibit excellent safety profiles. Chitosan, in particular, enhances drug permeation by opening tight junctions without causing damage or swelling to epithelial tissues, making it a safe and effective gelling agent.[89]
  • Some studies reported that certain stimuli-responsive in situ gels may cause reversible damage and mild irritation to the nasal epithelium, highlighting the need for careful formulation to minimize adverse effects.[90]
  • Poloxamer-based thermoresponsive gels are generally safe, showing no or minimal local irritation, ciliotoxicity, or nasal tissue damage.[91, 92]
  • Carbopol and gellan gum, including ion-activated DGG, are also preferred for in situ nasal gels. Galgatte et al. demonstrated that DGG-based gels cause no necrosis or damage to the nasal epithelium.[93]

Applications for liposomes:

  1. Liposomes in medicines: Liposomes are crucial in medicine as targeted drug delivery systems. They encapsulate therapeutic agents, enabling delivery to specific tissues while minimizing side effects. Notably, liposomal formulations are used in anticancer therapy, exhibiting reduced toxicity compared to conventional drugs, although challenges with bioavailability remain. They also facilitate treatment for respiratory disorders and can cross the blood-brain barrier for neurological conditions. Liposomes can be administered through various routes, such as intravenous and inhalation, enhancing their versatility in therapeutic applications and improving drug effectiveness and safety.[94,95]
  2. Liposomes in Infectious and Parasitic diseases: Liposomes are potent carriers in managing parasitic and infectious diseases due to their ability to be engulfed by phagocytic cells. This "Trojan horse" mechanism allows liposomes to deliver drugs directly to infected cells, enhancing therapeutic efficacy against parasites and pathogens. They improve the stability and bioavailability of therapeutic agents while minimizing toxicity, making liposomal formulations valuable for treating diseases like leishmaniasis and tuberculosis. By targeting the immune system's mononuclear phagocytic system, liposomes significantly optimize drug delivery in infectious diseases.[96,97,98,99,100]
  3. Liposomes in Anticancer therapy: Liposomes are crucial in anticancer therapy, providing targeted drug delivery that enhances the effectiveness of chemotherapeutic agents. By encapsulating drugs, liposomes minimize toxicity and improve stability, allowing higher drug concentrations to reach tumor sites while sparing healthy tissues. This targeted approach can lead to improved patient tolerability and reduced side effects. Several liposomal formulations, such as Doxil, are already on the market, exhibiting better therapeutic profiles than traditional chemotherapy. Despite their benefits, challenges regarding drug bioavailability and efficacy persist, necessitating continued research in this area.[101,102]
  4. Liposomes for Respiratory Drug Delivery System: Liposomes are increasingly recognized as an effective respiratory drug delivery system. They can be aerosolized for inhalation, allowing targeted delivery of medications directly to the lungs. This method enhances drug stability and provides sustained release, minimizing local irritation and systemic side effects. Additionally, liposomes can encapsulate both hydrophobic and hydrophilic drugs, making them versatile for various respiratory therapies. Their ability to improve drug deposition in lung tissues makes liposomal formulations particularly promising for managing respiratory diseases such as asthma and pulmonary infections.[103]
  5. Liposomes are Brain Targeted Drug Delivery: Liposomes are emerging as a promising method for brain-targeted drug delivery, particularly due to their ability to cross the blood-brain barrier (BBB). By encapsulating therapeutic agents within liposomes, drugs can be delivered more effectively to brain tissues while minimizing systemic side effects. Modifying the surfaces of liposomes with specific ligands enhances targeting to brain cells, making this approach particularly valuable for treating neurological disorders and brain tumors. This innovative delivery system improves drug efficacy and reduces toxicity, paving the way for advanced therapies in neuropharmacology.[104]
  6. Other Applications:
  • Liposomes are used for the treatment of heavy metal poisoning.
  • Liposomes act as a carrier for the drug invivo and invitro.
  • Liposomes are used as a pulmonary drug delivery system.
  • Used in recombinant DNA technology.
  • The most important use of liposomes in cell biology is to manipulate the status of membrane lipids.[105]

Recent Approaches:

Liposomes on chips:  Microfluidic technologies enable precise control of fluids in microscale volumes, enhancing reproducibility and manufacturability. Operating at low Reynolds numbers, these systems improve reaction efficiency, reduce reagent costs, and increase throughput. By controlling vesicle size and encapsulation, microfluidics optimizes liposome formation for drug delivery. This approach ensures high analytical performance, making it ideal for applications like targeted therapies, nucleic acid delivery, and controlled-release formulations, including intranasal liposomal in situ gels[106]. Membrane lamellarity (number of bilayers) and size distribution are crucial for liposome function. Manufacturing techniques significantly impact these properties. Most applications require monodisperse vesicle populations to ensure uniform drug delivery, stability, and efficiency. Precise control over these factors enhances the performance of liposomal formulations in targeted therapies and controlled-release applications[107]. The key advantage of this method is its ability to produce monodisperse vesicles. Vesicle stability depends on membrane composition, size, osmolarity, salinity, pH, and temperature, all of which influence drug delivery efficiency and shelf life[108,109].

Flow focusing: Jahn et al. developed a technique where a phospholipid-alcohol solution is flanked by aqueous streams in a microchannel. As alcohol diffuses, lipids self-assemble into monodisperse liposomes (50–150 nm). The vesicle size depends on flow rates, making this method highly controllable for drug delivery application[110]. Microfluidic tweezing uses fluid flow within microchannels to precisely manipulate particles or vesicles. Similar to flow focusing, it generates membrane tubes that can be adapted for vesicle formation. The technique provides controlled shear forces, allowing for the precise formation of vesicles, useful in drug delivery and biomedical applications[111].

Pulsed jetting: This method mimics blowing soap bubbles through a loop. A micro-nozzle ejects an aqueous solution into a planar lipid membrane, where the momentum from the jets stretches and pinches the membrane, forming a vesicle. This technique is useful for creating vesicles in various biomedical and drug delivery applications[112].

Droplet Emulsion Transfer: This method forms vesicles by evaporating the oil phase from a lipid-stabilized water-in-oil-in-water emulsion. A mixture of organic solvents, such as toluene and chloroform, is used to remove the oil, leaving behind vesicles suitable for drug delivery and other biomedical applications[113,114]. The use of ethanol to remove oleic acid enhances biocompatibility in double emulsion methods. Deshpande et al. introduced Octanol-Assisted Liposome Assembly (OLA), a technique using 1-octanol as a lipid carrier. OLA efficiently forms unilamellar, monodisperse, cell-sized liposomes through a rapid transformation of double emulsion droplets. The lipid bilayer zips fully, separating the octanol pocket, making this method efficient, biocompatible, and user-friendly compared to traditional techniques[115].

Future Perspectives: The analysis of Scopus data (1970–2020) reveals key trends in liposome and nanomedicine research. Liposomes as drug carriers emerged earlier (1970) than nanomedicine (1990). Their medical applications increased significantly, reaching 74% of total liposomal publications by 2020. Nanomedicine publications showed exponential growth, but only 7% involved nanoliposomes, possibly due to terminology differences. The FDA reported over 500 liposome applications by 2016. These findings highlight the evolving role of liposomes and nanotechnology in drug delivery[116]. Many smart liposomal systems are in development or clinical trials, including active targeting liposomes like anti-EGFR immunoliposomes and MBP-426 (both in Phase II) and stimuli-sensitive liposomes like ThermoDox. These advancements highlight the potential of liposomes for targeted and responsive drug delivery in various therapeutic applications[117].

CONCLUSION:

Liposomal in situ gel formulations for intranasal delivery provide an effective strategy for depression management by enhancing drug bioavailability and targeting the brain directly. Combining the advantages of liposomes and in situ gels ensures sustained drug release, prolonged nasal residence time, and reduced systemic side effects. Optimized formulation parameters, confirmed by comprehensive characterization and stability studies, contribute to their efficacy. These formulations offer a non-invasive, patient-friendly alternative with the potential to improve therapeutic outcomes and patient compliance in depression treatment.

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        105. Manish Kumar, Arpita Singh, Swarnima Pandey, Mohd. Aqil Siddiqui, Nitish Kumar. Liposomes: Type, Preapration and Evaluation. Int J Indig Herbs Drugs. 2021;(April):17–22.
        106. Weibel DB, Whitesides GM. Applications of microfluidics in chemical biology. Curr Opin Chem Biol. 2006;10(6):584–91.
        107. Jesorka A, Orwar O. Liposomes: Technologies and analytical applications. Annu Rev Anal Chem. 2008;1(1):801–32.
        108. Armengol X, Estelrich J. Physical stability of different liposome compositions obtained by extrusion method. J Microencapsul. 1995;12(5):525–35.
        109. Gliozzi A, Relini A, Chong PLG. Structure and permeability properties of biomimetic membranes of bolaform archaeal tetraether lipids. J Memb Sci. 2002;206(1–2):131–47.
        110. Jahn A, Vreeland WN, Gaitan M, Locascio LE. Controlled Vesicle Self-Assembly in Microfluidic Channels with Hydrodynamic Focusing. J Am Chem Soc. 2004;126(9):2674–5.
        111. West J, Manz A, Dittrich PS. Massively parallel production of lipid microstructures. Lab Chip. 2008;8(11):1852–5.
        112. Funakoshi K, Suzuki H, Takeuchi S. Lipid bilayer formation by contacting monolayers in a microfluidic device for membrane protein analysis. Anal Chem. 2006;78(24):8169–74.
        113. Shum HC, Lee D, Yoon I, Kodger T, Weitz DA. Double emulsion templated monodisperse phospholipid vesicles. Langmuir. 2008;24(15):7651–3.
        114. Foster T, Dorfman KD, Ted Davis H. Giant biocompatible and biodegradable PEG-PMCL vesicles and microcapsules by solvent evaporation from double emulsion droplets. J Colloid Interface Sci [Internet]. 2010;351(1):140–50. Available from: http://dx.doi.org/10.1016/j.jcis.2010.05.020
        115. Deshpande S, Caspi Y, Meijering AEC, Dekker C. Octanol-assisted liposome assembly on chip. Nat Commun [Internet]. 2016;7:1–9. Available from: http://dx.doi.org/10.1038/ncomms10447
        116. Kapoor M, Lee SL, Tyner KM. Liposomal Drug Product Development and Quality: Current US Experience and Perspective. AAPS J. 2017;19(3):632–41.
        117. Abri Aghdam M, Bagheri R, Mosafer J, Baradaran B, Hashemzaei M, Baghbanzadeh A, et al. Recent advances on thermosensitive and pH-sensitive liposomes employed in controlled release. J Control Release [Internet]. 2019;315:1–22. Available from: https://doi.org/10.1016/j.jconrel.2019.09.018.

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Gagan K. S.
Corresponding author

Department of Pharmaceutics, Karnataka College of Pharmacy.

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S. Swetha Malika Devi
Co-author

Department of Pharmaceutics, Karnataka College of Pharmacy.

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Beny Baby
Co-author

Department of Pharmaceutics, Karnataka College of Pharmacy.

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S Rajarajan
Co-author

Department of Pharmaceutics, Karnataka College of Pharmacy.

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Yallappa
Co-author

Department of Pharmaceutics, Karnataka College of Pharmacy.

Gagan K. S.*, S. Swetha Malika Devi, Beny Baby, S. Rajarajan, Yallappa, A Review on Liposomal Insitu Gel Formulations for Intranasal Delivery of Antidepressants, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 1242-1266 https://doi.org/10.5281/zenodo.15189478

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