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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation and progressive joint damage, significantly affecting patients' quality of life worldwide. Despite the widespread use of ibuprofen as a non-steroidal anti-inflammatory drug (NSAID) for managing RA symptoms, its conventional oral administration is often associated with gastrointestinal irritation, poor patient compliance, and systemic side effects. In recent years, liposomal drug delivery systems have gained attention for enhancing topical therapeutic efficacy while minimizing systemic exposure. This review presents an in-depth analysis of ibuprofen-loaded liposomal gels as a promising alternative for topical treatment of RA. Key topics include the statistical prevalence of RA, the basic structure and function of liposomes, formulation components, and classifications. A detailed overview of various liposome preparation techniques is provided based on recent literature. Additionally, the advantages of liposomal incorporation over conventional ibuprofen formulations are critically discussed. The review also explores the formulation and significance of liposomal gels, common evaluation parameters (e.g., vesicle size, zeta potential, entrapment efficiency, in vitro drug release, and skin permeation), and their current and potential applications in topical therapy. This article aims to provide a consolidated understanding of liposomal gel systems and their role in improving the topical delivery of ibuprofen, offering new perspectives for effective and targeted management of inflammatory conditions.

Keywords

liposomes , ibuprofen ,liposomal gel, Rheumatic arthritis, Nanotechnology

Introduction

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Novel Drug Delivery Systems (NDDS) are advanced methods designed to deliver medications in a targeted, controlled, and efficient manner, aiming for better treatment outcomes. Traditional drug delivery often struggles with poor absorption, fast breakdown, or non-specific distribution in the body. NDDS help overcome these problems by boosting drug effectiveness, reducing side effects, and improving patient compliance1.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease that affects about 1.5% of people worldwide, with women being more commonly affected. The disease leads to ongoing joint inflammation, damage to joints, and eventually disability2. The primary site of damage is the synovial tissue. Research on early RA has shown that inflammation of the synovium involves infiltration of immune cells, along with increased levels of signaling molecules like cytokines, chemokines, granzymes, adhesion molecules, and enzymes that break down tissue, similar to what is seen in long-standing disease3-6.

In 2020, around 17.6 million people globally were living with RA. The age-adjusted global prevalence was 208.8 cases per 100,000 people, marking a 14.1% increase since 1990. Women are more affected than men. RA contributed to approximately 38,300 deaths worldwide, with most of the disease burden measured by disability-adjusted life years (DALYs) resulting from living with the condition. Smoking is estimated to be responsible for 7.1% of RA-related DALYs. Projections suggest that by 2050, nearly 31.7 million people worldwide will be affected7.

NSAIDs like ibuprofen play a key role in managing RA and other inflammatory conditions. They reduce pain and inflammation by blocking COX enzymes (COX-1 and COX-2), which are involved in the production of prostaglandins, key mediators of pain and inflammation8,9.

IBUPROFEN :

Ibuprofen is a widely used chiral non-steroidal anti-inflammatory drug (NSAID) known for its anti-inflammatory, pain-relieving, and fever-reducing effects. It is commonly prescribed to manage fever and mild to moderate pain, especially pain related to inflammation, surgery, and conditions like rheumatoid arthritis. Its therapeutic action is well understood—ibuprofen works by reversibly inhibiting the cyclooxygenase enzymes COX-1 and COX-2, which convert arachidonic acid into prostaglandins such as thromboxane and prostacyclin. These prostaglandins are key mediators of fever, inflammation, and pain. In particular, ibuprofen’s antipyretic and analgesic effects stem from the inhibition of prostaglandins PGE2 and PGI2 10.

Currently, ibuprofen is primarily taken orally in the form of tablets, capsules, suspensions, or oral solutions. Sustained-release formulations are also available. The typical oral dose ranges from 200 to 600 mg every six hours and can be increased up to 2.4 to 3.2 grams per day depending on clinical need. However, only a small portion (about 20–30 mg) of the administered dose is actually needed to produce a therapeutic effect. The high doses are necessary due to ibuprofen’s low solubility and poor absorption, which lead to significant first-pass metabolism and reduced bioavailability11,12.

This poor solubility slows the drug’s dissolution from oral dosage forms, limiting its effectiveness and increasing the risk of side effects13. Common gastrointestinal side effects of ibuprofen include gastritis, indigestion, stomach pain, heartburn, and even ulcers or bleeding. These side effects are closely linked to the amount of drug taken. Additionally, because prostaglandins produced by COX enzymes in the kidneys help regulate blood pressure, ibuprofen can also lead to hypertension. It may also cause bronchospasms, as the drug suppresses prostaglandins that help relax the airway muscles.To address these issues, injectable forms of ibuprofen have been developed for fast pain relief. However, their development is challenging due to the drug’s poor water solubility14. Topical formulations—such as creams, gels, sprays, and foams—have emerged as an alternative. These can be used to treat pain from muscle, joint, or soft tissue injuries while avoiding the gastrointestinal side effects of oral ibuprofen. That said, achieving therapeutic drug levels through the skin is difficult because of ibuprofen’s limited ability to penetrate the skin barrier.

Incorporating ibuprofen into liposomes presents an effective strategy for topical drug delivery :

Ibuprofen’s short half-life makes it a suitable candidate for controlled release systems, which can be effectively developed using polymeric nanoparticle technology15.

Topical administration of liposomal formulations presents a promising alternative to conventional, oral, and systemic delivery methods by potentially overcoming their associated limitations. Key advantages of using liposomes for topical drug delivery include:

  1. Minimized side effects and reduced risk of drug incompatibilities, as they help prevent excessive systemic absorption.
  2. Enhanced localization of the drug, leading to increased accumulation in target tissues.
  3. Versatility in encapsulating both hydrophilic and hydrophobic drugs, making them suitable for a wide range of therapeutic agents.
  4. improved penetration is primarily due to their phospholipid bilayer structure, which closely resembles the lipid composition of the skin, allowing them to fuse with the stratum corneum and facilitate deeper delivery of the drug into the epidermal and dermal layers16.
  5. Furthermore, liposomes can offer sustained or controlled drug release and improved cellular penetration, thereby increasing their effectiveness for topical applications.

LIPOSOMES : Liposomes have been one of the most widely explored drug carriers because of their versatile structure. These are small, spherical vesicles with a water-filled core surrounded by a membrane made of phospholipid bilayers. They were first described by Bangham and colleagues about 40 years ago as useful carrier for delivering various types of drugs17,18. the simplest methods to make liposomes. Lipids like egg lecithin, cholesterol, and phosphatidyl glycerol are dissolved in organic solvents like chloroform or a chloroform-methanol mix. After mixing, the solvent is removed using a nitrogen stream, and the lipid film is dried under vacuum for several hours19

Liposomes are particularly promising for topical drug delivery because they can:

  • Enhance drug penetration through the skin’s outer layer (stratum corneum)
  • Improve drug stability by protecting it from breakdown (oxidation, hydrolysis
  • Increase drug retention in the skin, improving local effects and reducing systemic exposure20,21,22.

Compared to other carriers like niosomes, liposomes made of natural phospholipids are better tolerated by the skin and integrate more easily with skin lipids, allowing for deeper, more effective drug delivery23,24.

Moreover, they provide sustained drug release, keeping therapeutic levels stable for longer periods. Their biocompatible and biodegradable nature makes them safer for long-term use25,26.

 

https://www.researchgate.net/publication/354432545/figure/fig1/AS:1078455454175236@1634135225856/The-basic-structure-of-a-liposome.jpg

 

Fig. 1 Structure of a Liposomes27

 

FORMULATION COMPONENT OF LIPOSOMES –

  1. LIPID COMPOSITION :

Phospholipids are special molecules with both water-attracting(hydrophilic) and water-repelling(hydrophobic) parts. They have a glycerol backbone, two fatty acid chains (which avoid water), and a phosphate-containing head group (which interacts with water). This unique structure allows them to naturally form bilayer membranes when placed in water, which is why they are vital components of biological membranes and liposome-based drug delivery systems28.

In liposomes, phospholipids create the bilayer structure that makes it possible to:

  • Encapsulate water-soluble (hydrophilic) drugs within the central aqueous core
  •  Integrate fat-soluble (lipophilic) drugs within the bilayer itself
  •  Ensure the system is biocompatible and biodegradable, making drug delivery safe

Additionally, the membrane’s characteristics, like fluidity and permeability, can be adjusted by changing the type and saturation level of the fatty acid chains present in the phospholipids29

Phospholipids:30

  1. Naturally derived phospholipids used in liposome:
  1. Phosphatidylethanolamine
  2. Phosphatidylcholine
  3. Phosphatidylserine
  1. Synthetically derived phospholipids used in the liposomes are:
  1. Dioleoyl phosphatidylcholine
  2. Disteroyl phosphatidylcholine
  3. Dioleoyl phosphatidylethanolamine
  1. CHOLESTEROL

Cholesterol is commonly incorporated into phospholipid membranes of liposomes, typically at a ratio of 1:1 or sometimes up to 1:2 with phospholipids like phosphatidylcholine. However, unlike phosphatidylcholine, cholesterol doesn’t form part of the bilayer structure in the same way. The hydroxyl group of cholesterol faces the water phase, while its acyl chain aligns parallel to the fatty acid chains within the phospholipid bilayer31,32.Adding cholesterol to liposomes helps modify the membrane structure. It reduces the leakage of the contents from inside the liposome and makes the membrane more compact and stable. Incorporating other lipids, like sphingomyelin, can also reduce leakage, especially when the membrane transitions from a fluid phase to a more solid-like structure32,33,34.

Overall, cholesterol plays an essential role in strengthening liposomal membranes by improving their stability, rigidity, and overall structural integrity35.

  1.  CHARGE INDUCER MOLECULES

Charge inducers are special additives used in liposome formulations to give the vesicles either a positive or negative surface charge. This surface charge plays a key role in determining the liposome's behavior, including its stability, interaction with cells, and how effectively it can encapsulate drugs.For example, Dicetylphosphate (DCP) imparts a negative charge to the liposome's surface. This negative charge increases the zeta potential, which helps stabilize the formulation by preventing the vesicles from clumping together36

Incorporating charge inducers such as stearylamine (for positive charge) or dicetylphosphate (for negative charge) is a deliberate strategy to fine-tune the surface charge. Doing so improves liposome stability, enhances drug loading efficiency, and can influence particle size. These modifications are essential for optimizing liposomal drug delivery systems to meet specific therapeutic requirements37.

  1.      HYDRATING MEDIUM

The ionic strength and composition of the hydration medium can significantly influence both the size and surface charge (zeta potential) of liposomes. For example, when the ionic strength is higher, it can create more compact ion layers around the liposomes, which can affect their stability and how they interact with biological environments38.The solubility of the drug in the chosen hydration medium also plays a major role in how effectively it gets encapsulated. Hydrophilic (water-soluble) drugs dissolved in the aqueous phase can be successfully trapped within the liposome's aqueous core, while the properties of the medium itself can impact the overall drug-loading capacity39.Using a phosphate buffer at pH 7.4 as the hydration medium has been shown to improve liposome stability over time. Studies report that liposomes prepared this way maintain their structural integrity and drug encapsulation efficiency even after being stored for 30 days at temperatures of 4?°C and 25?°C40 .

 

CLASSIFICATION OF LIPOSOMES 41,42,43

  • By Structure:
  • Multilamellar Vesicles (MLVs) – >0.5 µm
  • Oligolamellar Vesicles – 0.1-1 µm
  • Small Unilamellar Vesicles (SUVs) – 20-100 nm
  • Large Unilamellar Vesicles (LUVs) – >100 nm
  • Giant Unilamellar Vesicles – >1 µm
  • Multivesicular Vesicles – Larger, complex structures
  • By Preparation Method:
  • Reverse Phase Evaporation
  • Thin-Film Hydration
  • Extrusion Techniques
  • Freeze-Thaw Cycles
  • French Press or Fusion Methods
  • By Material and Application:
  • Conventional Liposomes – Phospholipids and cholesterol
  • Fusogenic Liposomes – Designed to merge with cell membranes
  • Cationic Liposomes – Positively charged for better cell interaction
  • Long-Circulating (Stealth) Liposomes – Modified with PEG for prolonged circulation
  • Immunoliposomes – Carry targeting antibodies for specific delivery

 

 

 

Fig.No.2 Schematic Diagram of liposomes

 

METHOD OF PREPARATION :

  1. lipid film hydration by hand shacking44:

Liposomes were prepared using the physical dispersion technique with varying ratios of lipids. Initially, the lipids were dissolved in chloroform and the solution was spread evenly on the inner surface of a  conical flask. The chloroform was then allowed to evaporate at room temperature without disturbing the solution, forming a thin lipid film.To hydrate the film, phosphate buffer (pH 7.4) containing the drug was gently added by tilting the flask slightly and introducing the buffer along the side. The flask was then slowly returned to its upright position, allowing the buffer to flow smoothly over the lipid layer. The flask was left undisturbed for 2 hours at 37?°C to allow complete swelling of the lipids. After swelling, the flask was gently swirled to form a milky white liposomal suspension.The resulting formulations were then subjected to centrifugation. Multiple batches were prepared using this method to determine the optimal formulation, each with different lipid compositions.

  1. Sonication 45,46

 is one of the most widely used methods for preparing small unilamellar vesicles (SUVs). In this method, multilamellar vesicles (MLVs) are sonicated using either a bath sonicator or a probe sonicator under an inert (passive) atmosphere.          However, this technique has several limitations, including:

  • Very low internal volume
  • Poor encapsulation efficiency
  • Possible degradation of phospholipids
  • Inability to encapsulate large molecules
  • Risk of metal contamination from the probe tip
  • Presence of residual MLVs along with SUVs

There are two main types of sonication techniques:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

       Probe Sonication

          Bath Sonication
  • In this method, the sonicator probe is directly inserted into the liposome dispersion.
  • It delivers a high amount of energy to the lipid mixture, which can cause local heating. To prevent overheating, the container is typically placed in a water or ice bath during the process.
  • Sonication may last up to an hour, during which more than 5% of lipids can undergo deesterification.
  • Here, the container holding the liposome dispersion is placed in a sonication bath with temperature control.
  • This method is generally easier and gentler than probe sonication.
  •  It also allows the sample to remain in a sterile, closed vessel, reducing the risk of contamination and making it suitable for use under an inert atmosphere.

 

  1. French pressure cell method 47

This method involves extruding multilamellar vesicles (MLVs) through a small orifice at a pressure of 20,000 psi and a temperature of 4°C. Compared to sonication, it offers several advantages: it is simple, fast, reproducible, and allows for gentle handling of temperature-sensitive or unstable materials (Hamilton and Guo, 1984). The liposomes produced using this technique are typically slightly larger than those obtained by sonication.However, the method has some limitations. Maintaining the low temperature (4°C) can be challenging, and the process is restricted to small working volumes, typically up to 50 mL.

  1. Macro-emulsification48

This technique used to produce small liposomal vesicles from a concentrated lipid suspension. In this method, large multilamellar vesicles (MLVs) are first prepared and then introduced into the microfluidizer.The equipment operates by pumping the lipid suspension at extremely high pressure through a narrow (5 mm) screen. The fluid is then directed through long microchannels where two fluid streams are forced to collide at right angles at very high velocity. This intense interaction breaks down the larger vesicles into smaller, more uniform ones.The output fluid can be recycled through the interaction chamber multiple times using a pump, continuing the process until liposomes of the desired spherical size are formed.

  1. Reverse phase evaporation method 49

In this method, a water-in-oil (W/O) emulsion is first created by briefly sonicating a two-phase system composed of phospholipids dissolved in an organic solvent (such as diethyl ether, isopropyl ether, ) and an aqueous buffer. The organic solvents are then removed under reduced pressure, which leads to the formation of a thick, gel-like substance.Liposomes are subsequently formed as the remaining solvent is eliminated through continued rotary evaporation under reduced pressure. This technique can achieve high encapsulation efficiency—up to 65%—especially when used in low ionic strength media.It is suitable for encapsulating both small molecules and large macromolecules.The main drawback of this method is that the materials being encapsulated are exposed to organic solvents and brief sonication, which may not be suitable for sensitive compounds.

  1. Ethanol injection method 50 :

When lipids dissolved in ethanol are injected into a large excess of buffer, multilamellar vesicles (MLVs) form instantly. However, this method has several drawbacks. The resulting liposomes are heterogeneous in size (ranging from 30 to 110 nm) and highly dilute, leading to low encapsulation efficiency. Additionally, complete removal of ethanol is difficult due to its azeotropic behavior with water. Even trace amounts of ethanol may cause inactivation of sensitive biological macromolecules, limiting the method’s suitability for certain therapeutic agents.

  1. Ether injection method :51,52

 In this technique, lipids are first dissolved in ether or a mixture of ether and methanol, then slowly injected into an aqueous solution containing the substance to be encapsulated. As the ether evaporates under reduced pressure, it leads to the spontaneous formation of liposomes due to the gradual dispersion of lipids in the aqueous phase.This method is relatively simple and can produce small unilamellar vesicles (SUVs) without the need for high shear forces. However, it has notable limitations: the resulting liposomes are often heterogeneous in size, and the process involves exposure of the active compounds to organic solvents and elevated temperatures, which may degrade sensitive drugs or biological materials. Additionally, complete removal of residual solvents is crucial to ensure safety, especially for pharmaceutical applications

  1. Proliposome method :53

Between 0.1–1 g of lipids are weighed into a small glass beaker. A mixture of 96% ethanol and water or buffer is then added, maintaining a lipid:ethanol:buffer ratio of 1:1:2 (w/w/w). The mixture is heated to 60?°C in a water bath for approximately 10 minutes while stirring at 600–800 rpm until a smooth, fine lipid paste is formed. After cooling to room temperature, additional water or buffer is added dropwise with continued stirring, leading to the formation of multilamellar vesicles (MLVs). These MLVs are further hydrated with stirring for 1 hour at room temperature, then sonicated in a bath sonicator for 3 minutes to reduce vesicle size. The resulting liposomes can be stored for up to 2 days at 4?°C or preserved long-term by transferring them into centrifuge tubes, flushing with nitrogen, freezing in liquid nitrogen, and storing at −80?°C. For encapsulation, lipophilic compounds can be added along with ethanol, while hydrophilic compounds are added with the aqueous buffer during liposome formation.

LIPOSOMAL GEL:

Topical liposomal formulations are considered potentially more effective and less toxic compared to traditional formulations54. These vesicles can also create a lipid-rich, moisturizing environment that helps retain the drug within the skin layers55. However, one key limitation of using liposomes on the skin is their naturally liquid consistency. To improve their viscosity and ease of application, liposomes can be blended with suitable carriers. Studies have shown that liposomes are generally compatible with viscosity enhancers like methylcellulose and acrylic acid-based polymers56. Therefore, incorporating liposomes into a gel base makes them more suitable and effective for topical application by enhancing their stability, spreadability, and skin retention.

 

Table No.1 . Showcase studies that use alternative teachniquesto prepare ibuprofen loaded liposomes .

Sr.No.

Article

Journal

Authors

Abstract

Methods used

1

Liposome and microemulsion loaded with ibuprofen: from preparation to mechanism of drug transport.

Microencapsulation,

Xu, Y., Cai, Y., Meng, Y., Wu, L., Chen, J., Cao, W., & Chu, X

A percutaneous study comparing liposomes (LP) and microemulsions (ME) for transdermal delivery of ibuprofen IBU (IBU-LP) showing superior effectiveness. The mechanisms behind this difference were also examined

Ethanol injection and spontaneous emulsification

2

Liposome formulation of poorly water soluble drugs: optimisation of drug loading and ESEM analysis of stability.

International journal of pharmaceutics

Mohammed, A. R., Weston, N., Coombes, A. G. A., Fitzgerald, M., & Perrie, Y.

The effect of liposomal composition and surface charge on the encapsulation and retention of ibuprofen, a model poorly water-soluble drug,wasexamined.

 

 

Film hydration method

3

Sterically Stabilized Liposomes Incorporating the Novel Anticancer Agent Phospho-Ibuprofen (MDC-917): Preparation, Characterization, and In Vitro/In Vivo Evaluation

 

Pharmaceutical research

. Mattheolabakis, G., Nie, T., Constantinides, P. P., & Rigas, B

Phospho-Ibuprofen (P-I) was efficiently loaded into liposomes, which remained stable after lyophilization with sucrose and storage. These liposomes showed greater tumor growth inhibition in mice than free P-I, supporting their further development.

 

Thin-film hydration method, lyophilization

4

Development of ibuprofen nanoliposome for transdermal delivery: Physical characterization, in vitro/in vivo studies, and anti-inflammatory activity

 

Artificial cells, nanomedicine, and biotechnology

 

Gaur, P. K., Bajpai, M., Mishra, S., & Verma, A.

A nanoliposomal ibuprofen gel, showed the smallest size, highest encapsulation, and superior drug permeation in vitro, ex vivo, and in vivo, confirming its advantage over non-vesicular formulations.

 

mechanical agitation , probe sonicator

5

Liposome delivery systems containing ibuprofen

 

Drug development and industrial pharmacy,

Bula, D., & Ghaly, E. S.

Multilamellar liposomes containing ibuprofen were prepared using organic solvent hydration. A 3:1 lipid-to-drug ratio gave the highest entrapment and complete drug release over 12 hours. Larger liposomes released more drug (65.7%) than smaller ones, and longer stirring during hydration further increased drug release.

Extrusion

6

Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment.

International journal of pharmaceutics

Lamprecht, A., Saumet, J. L., Roux, J., & Benoit, J. P.

Lipid nanocapsules (LNCs), due to their small size, offer potential for both injectable and oral drug delivery by enhancing drug solubility, preventing embolism during IV use, and improving absorption when taken orally.

Phase inversion method

7

DSC and Raman study of DMPC liposomes in presence of Ibuprofen at different pH.

Journal of Thermal Analysis and Calorimetry

Di Foggia, M., Bonora, S., Tinti, A., & Tugnoli, V.

In this study, the influence of varying concentrations of ibuprofen at both neutral and acidic pH on the properties of dimyristoylphosphatidylcholine (DMPC) liposomes was examined using Raman spectroscopy and differential scanning calorimetry (DSC) techniques.

Thin film hydration

8

Controlled release injectable liposomal gel of ibuprofen for epidural analgesia.

International journal of pharmaceutics,

Paavola, A., Kilpeläinen, I., Yliruusi, J., & Rosenberg, P.

The liposomal gel regulated the release and transdermal permeation of ibuprofen in vitro, demonstrating a permeation profile conducive to sustaining consistent drug concentrations.

Thin film hydration

9

Formulation and evaluation of ibuprofen loaded lipospheres for effective oral drug delivery

Dhaka University Journal of Pharmaceutical Sciences,

Momoh, M. A., Kenechukwu, F. C., Gwarzo, M. S., & Builders, P. F.

This study developed ibuprofen-loaded lipospheres using beeswax and phospholipid via hot emulsification, showing high encapsulation efficiency, sustained drug release, and significant analgesic and anti-inflammatory effects with prolonged plasma levels.

homogenization technique

10

Preparation, characterization and improved release profile of ibuprofen-phospholipid association.

Journal of drug delivery science and technology

. Amirinejad, M., Davoodi, J., Abbaspour, M. R., Akhgari, A., Hadizadeh, F., & Badiee, A

Ibuprofen–phosphatidylcholine associations (IPA) were prepared by refluxing the two compounds in molar ratios of 1:0.25, 1:0.5, and 1:1 to enhance ibuprofen's solubility by promoting its amorphous form.

Reflux method

 

11

Formulation, optimization and evaluation of ibuprofen loaded menthosomes for transdermal delivery

International Journal of Pharmaceutics,

Nayak, D., Shetty, M. M., Halagali, P., Rathnanand, M., Gopinathan, A., John, J., & Tippavajhala, V. K.

This study developed and optimized ibuprofen-loaded menthosomes to enhance transdermal delivery. The formulation showed improved drug release, skin permeation, and significant anti-inflammatory and analgesic effects in rat models, indicating its potential as an effective vesicular carrier for NSAIDs.

Thin film hydration

12

A novel ibuprofen derivative with anti-lung cancer properties: Synthesis, formulation, pharmacokinetic and efficacy studies.

International journal of pharmaceutics

Cheng, K. W., Nie, T., Ouyang, N., Alston, N., Wong, C. C., Mattheolabakis, G., & Rigas, B.

Phospho-ibuprofen amide (PIA), a stable analog of phospho-NSAIDs, was formulated in liposomes to enhance stability and anticancer efficacy. In preclinical lung cancer models, liposomal PIA showed over 95% tumor inhibition, superior to ibuprofen, with improved pharmacokinetics, lung targeting, and ROS-mediated antitumor effects.

Membrane extrusion

13

Long-Lasting, Antinociceptive Effects of pH-Sensitive Niosomes Loaded with Ibuprofen in Acute and Chronic Models of Pain.

Pharmaceutics.

. Marzoli, F., Marianecci, C., Rinaldi, F., Passeri, D., Rossi, M., & Minosi, P.

This study evaluated pH-sensitive niosomes  containing ibuprofen and Polysorbate 20–Glycine for pain relief. NioIbu showed significant,long lasting antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain, outperforming free ibuprofen and reducing side effects.

Thin film evaporation method

14

Improving ex vivo skin permeation of non-steroidal anti-inflammatory drugs: enhancing extemporaneous transformation of liposomes into planar lipid bilayers

International Journal of Pharmaceutics,

Vázquez-González, M. L., Bernad, R., Calpena, A. C., Domènech, O., Montero, M. T., & Hernández-Borrell, J

To enhance transdermal drug delivery, liposomes containing ibuprofen were prepared and characterized, and pharmaceutical formulations were developed by incorporating penetration enhancer (PE) surfactants just before use. Subsequently, drug release and permeation studies were conducted.

 

Thin film hydration , membrane extrusion

15

Fabrication and characterization of silk fibroin-coated liposomes for ocular drug delivery.

European Journal of Pharmaceutics and Biopharmaceutics,

Dong, Y., Dong, P., Huang, D., Mei, L., Xia, Y., Wang, Z., & Wu,

A silk fibroin-coated liposomal formulation was developed for topical ocular delivery of ibuprofen to improve drug bioavailability. The coated liposomes showed sustained release, enhanced corneal permeation, rapid cellular uptake, and no cytotoxicity, making them a promising ocular drug delivery system.

Ethanol injection method

16

Phospho?ibuprofen (MDC?917) incorporated in nanocarriers: anti?cancer activity in vitro and in vivo.

British journal of pharmacology

Nie, T., Wong, C. C., Alston, N., Aro, P., Constantinides, P. P., & Rigas, B.

The cellular uptake, cytotoxicity, and in vitro metabolic stability of Phospho –Ibuprofen(P-I) encapsulated in liposomes and micelles were assessed using human colon adenocarcinoma cell cultures. Additionally, the pharmacokinetics and anticancer efficacy of liposomal P-I were evaluated in mice and in a colon cancer xenograft model using nude mice.

Thin film hydration
 

Evaluation of Liposomes :

  1. Microscopy

The morphology of the prepared liposomes was examined using a Leica DMIL inverted fluorescence microscope. Each batch was analyzed to assess shape and lamellarity. For observation, the liposomal dispersion was appropriately diluted and placed on a glass slide, then viewed under 45x magnification73.

  1. Loading capacity, entrapment efficiency, and chemical stability of drug  were evaluated both in buffer solutions and within liposomal formulations.

The incorporation capacity, trapping efficiency, and chemical stability of drug  were evaluated in both buffer solutions and liposomal formulations. Given ibuprofen  known instability in aqueous media, its degradation in various buffers was assessed after saturation through shaking for 5 days. To understand the drug's behavior in liposomes, trapping efficiency (TE), total drug content, and unentrapped (free) drug were analyzed over time.For total content determination, a precisely weighed 500 mg sample of liposomal suspension was vigorously mixed with 250.0 ml methanol, followed by the gradual addition of 1.50 ml acetonitrile to precipitate lipids. The mixture was centrifuged for 15 minutes at 3000 rpm (1512 × g) using a refrigerated Mistral 400 centrifuge (Fisons, Onshore, UK). After suitable dilution, the supernatant was analyzed using HPLC. This same procedure was applied to study the stability of drug within the liposomal suspension.To determine the free (unentrapped)drug, about 1 ml of the suspension was centrifuged at 4000 rpm (2500 × g) for 20 minutes, and the drug present in the supernatant was analyzed by HPLC74,75,76.

  1. Particle size and particle size distribution

The average particle size and distribution of the optimized liposome batch were measured using a particle size analyzer (Sympatec HELOS, Germany, model H1004), which operates on the principle of laser diffraction. The system includes a 632.8 nm He-Ne laser with a minimum power output of 5 mW, focused through a Fourier lens (R-5) onto the center of a multi-element detector, along with a sample holding unit (Su cell). Before measurement, the sample was stirred to ensure uniformity. The vesicle dispersion was diluted 100-fold with deionized water and introduced into the dispersion unit, where it was stirred at high speed to minimize particle aggregation while the laser beam was focused for analysis77.

  1. Light microscopy

Light microscopy analysis was performed using an Olympus BX50 microscope connected to a Leica Q500IW computer system. Images were captured under phase contrast using the Ph 3 phase plate. A small drop of the liposome sample was placed on a pre-cleaned microscope slide, covered with a cover slip, and observed at 1000× magnification78.

  1. Differential scanning calorimetry (DSC) study

Differential scanning calorimetry (DSC) was carried out using a TA-60 DSC instrument (Shimadzu, Japan). Pure ketoconazole (KTZ), soya lecithin, cholesterol, and drug-loaded multilamellar liposomes were analyzed. Approximately 5 mg of each sample was sealed in standard aluminum pans for testing. The samples were scanned from 0°C to 200°C at a rate of 20°C per minute. The phase transition temperature was identified as the point of maximum excess heat capacity on the thermogram 79,80.

  1.  Determination of Lipid Content

Determining lipid content helps assess the efficiency of the liposome preparation method. For this, 100 ml of liposomal dispersion was used, and total phosphorus was quantified. Lipids were first extracted using methanol, and the methanol layer was separated, dried, and redissolved in a specific volume of chloroform. Then, 2 ml of ammonium ferrothiocyanate solution was added along with enough chloroform to reach a final volume of 2 ml. This biphasic mixture was vigorously shaken on a rotomixer for 1 minute. After phase separation, the lower chloroform layer was collected using a syringe, and if needed, clarified with a small amount of anhydrous Na?SO?. The optical density of the chloroform phase was then measured at 488 nm, using chloroform as the blank 81.

  1. In vitro Release Studies

In vitro release studies were conducted using a modified Franz diffusion cell. A dialysis membrane (HiMedia, molecular weight 5000) was positioned between the donor and receptor compartments. The donor compartment contained the dexibuprofen-loaded liposomal suspension, while the receptor compartment was filled with 18 ml of phosphate buffer (pH 7.4). The system was maintained at 37?±?0.5°C and stirred continuously at 200 rpm. At predetermined time intervals, 1 ml samples were withdrawn from the receptor compartment via a side tube and analyzed using a UV-Visible spectrophotometer at 224 nm. The release data were then applied to various kinetic models to determine the release mechanism of dexibuprofen from the liposomal formulation82.

  1. Stability study

To evaluate the stability of liposomes, the optimized liposomal dispersion was stored in airtight vials at different temperatures: 4–5?°C (in a refrigerator), room temperature, and 37, 45, and 55?°C (in stability ovens from Meta-Lab Scientific Industries). Samples were taken at regular intervals—0, 2, 4, 8, and 12 weeks—and examined for (i) any signs of sedimentation or creaming, and (ii) changes in the color of the dispersion at each storage condition83.

Applications of liposomes in drug delivery :

Liposome encapsulation can influence how and where drug molecules are distributed in the body over time, helping to lower toxic side effects and improve treatment efficiency.

  • Liposomes  used for drug targeting : It has been demonstrated that restricting the drug's distribution to a particular target site should boost efficacy at low doses while simultaneously lowering toxicity. It is true that administering a medication throughout the body is wasteful and, more importantly, increases adverse reactions. Therefore, lowering drug waste and delivering a medication to a tissue or cell area that is not typically accessible to the free or untargeted drug are two advantages of drug targeting [84]. Liposomes have been extensively used in targeted drug delivery, particularly for cancer therapy. One of the major challenges in chemotherapy is the severe toxicity associated with anticancer drugs. By encapsulating these drugs in liposomes, their distribution within the body can be controlled both spatially and temporally. This targeted delivery approach helps to significantly minimize harmful side effects and can enhance the overall effectiveness of the treatment 85.
  • Delivery of small molecule drugs by liposomes : In general, small-molecule drugs delivered via liposomes fall into two main categories: anti-infective agents and anti-cancer drugs. Hydrophilic (water-soluble) drugs are encapsulated within the aqueous core of liposomes, whereas lipophilic (fat-soluble) drugs are incorporated into the lipid bilayer. The first liposomal formulation approved for cancer therapy was Doxil®/Caelyx®, a PEGylated injectable liposome (approximately 100 nm in size) that carries the chemotherapy drug doxorubicin86.
  • Liposomes as vaccine carriers : Liposomes have become important carriers for vaccines, as antigens or adjuvants can be adsorbed or covalently attached to them. After intramuscular or subcutaneous injection, liposomes help deliver antigens to the lymphatic system, where they slowly release and preserve antigen structure. This promotes binding to B cell receptors and activates the immune response. Liposomes can also support cross-presentation to CD8? cells via MHC I. As immune adjuvants, liposomes enhance antigen exposure and prolong immune stimulation. Over the past two decades, liposome-based vaccine technologies have advanced, with several vaccines now approved or in late-stage trials. Virosomes—reconstituted influenza virus envelopes without genetic material—act as adjuvant systems. They incorporate viral proteins (hemagglutinin and neuraminidase) into liposomal membranes, aiding cell receptor binding and immune activation. For example, Inflexal® V is made of virosomes from three influenza strains 87,88,89.
  • Application of liposomes in cosmetics :Liposomes are widely used in cosmetics due to several benefits:They enhance skin hydration,Improve cell membrane fluidity for healthier-looking skin, andDeliver both oil- and water-soluble active ingredients deep into the dermis, creating a reservoir that prolongs their action.The first liposome-based cosmetic, “Capture,” was launched by Christian Dior in 1987, followed by L’Oreal’s “Nactosome” and Applied Genetics’ “Photosome” sunscreen. Later, Lee et al. developed silicified liposomes containing citrus unshiu extract, which showed strong antioxidant activity and effective controlled release.
  • liposomes may be useful as immunotherapeutic agents: Antigen-presenting liposomes offer a promising strategy for treating infectious diseases such as HIV and genital herpes. In 1994, the Swiss Serum Institute successfully introduced a liposomal hepatitis A vaccine. This formulation combines purified hepatitis A virions, viral phospholipids, and influenza virus envelope glycoproteins with phosphatidylcholine and phosphatidylethanolamine in the presence of excess detergent to form liposomes, which enhance the immune response. The same institute is also working on liposomal vaccines for influenza, hepatitis B, diphtheria, and tetanus90.
  • Topical Application of Liposomes :
  1. Drug Delivery Systems for RA Therapy : It has been discovered that a delivery system that delivers the medication straight to the synovial cavity works better than one that delivers it systemically . Nevertheless, the majority of RA treatments available today lack joint specificity. High systemic dosages of the medication must therefore be given in order to achieve enough drug concentrations in the afflicted joints, which could result in serious systemic adverse effects. While lowering medication dosages might decrease toxicity, it may also result in less effective treatment. Several strategies have been developed to balance side effects with efficacy91.
  2. Corticosteroids: Extensive corticosteroid therapy can affect the hypothalamic-pituitary-adrenal axis, but liposomal formulations help reduce this risk by lowering percutaneous absorption. Studies showed that liposomal triamcinolone increased drug concentration 4-fold in skin when applied as a lotion, and up to 5 times in the epidermis and 3 times in the dermis with a gel, allowing dose reduction while improving efficacy. This is especially beneficial for cortisol, which is safe long-term but often inadequate in acute skin conditions. In a clinical trial, Korting et al. found that a liposomal betamethasone dipropionate (0.039%) was slightly more effective in reducing inflammation in atopic eczema than a higher-dose conventional form (0.064%), likely due to enhanced skin penetration by liposomes 92.
  3. local anaesthatics : Recent studies have shown that liposomal formulations of local anesthetics like tetracaine and lidocaine offer superior skin anesthesia compared to conventional creams. Liposomal tetracaine (0.5%) is especially effective, providing up to 4 hours of anesthesia after a 1-hour occluded application, with deep anesthesia beginning within 30–60 minutes. It outperformed Pontocaine® cream and showed similar results with other anesthetics like lignocaine. Tetracaine is particularly well-suited for liposomal delivery due to its strong anesthetic effect and ability to anchor within liposome bilayers thanks to its hydrophobic structure 93,94.
  4. Wound treatment : Wound healing involves inflammation, cell proliferation, and migration. Povidone-iodine, a broad-spectrum antiseptic, is commonly used in wound care. A Phase II study evaluated a new liposomal hydrogel form (betasom) containing povidone-iodine in 36 patients with skin grafts, compared to 15 patients treated with chlorhexidine gauze. Betasom showed faster epithelialization (100% vs. 82.3% by day 13), earlier return to normal skin impedance (day 9 vs. 11), better antiseptic effect, and lower graft loss (5% vs. 35.7%). The improved results were attributed to sustained drug release, enhanced moisture, and targeted delivery. Another study confirmed that liposomal povidone-iodine hydrogel reduces inflammation and supports healing in burns, chronic wounds, and smokers95.

CONCLUSION

Ibuprofen-loaded liposomal gels offer a novel and efficient approach for the topical management of rheumatoid arthritis, addressing the limitations of conventional oral NSAID therapy. By leveraging the structural advantages of liposomes—such as their biocompatibility, controlled drug release, and enhanced skin permeability—these formulations significantly improve localized drug delivery while minimizing systemic exposure and associated side effects. This review consolidates recent advancements in liposomal design, formulation components, and preparation techniques, underscoring their potential to transform ibuprofen therapy into a safer and more patient-friendly alternative. With continued research and optimization, liposomal gels hold the promise to become a cornerstone in the topical treatment of chronic inflammatory conditions like RA, ultimately improving therapeutic outcomes and quality of life for affected individuals.

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Reference

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  9. Hernández?Díaz, S., Varas?Lorenzo, C., & García Rodríguez, L. A. (2006). Non?steroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic & clinical pharmacology & toxicology, 98(3), 266-274
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  12. Rashid A, White ET, Howes T, et al. Effect of Solvent Composition and Temperature on the Solubility of Ibuprofen in Aqueous Ethanol. J Chem Eng Data 2014;59(9):2699-2703
  13. Klueglich M, Ring A, Scheuerer S, et al. Ibuprofen extrudate, a novel, rapidly dissolving ibuprofen formulation: relative bioavailability compared to ibuprofen lysinate and regular ibuprofen, and food effect on all formulations. The Journal of Clinical Pharmacology 2005;45(9):1055-1061
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Manasi Mathkar
Corresponding author

Department of Pharmaceutics, Yashwantrao Bhonsale College of Pharmacy, Sawantwadi, dist – Sindhudurg, Maharashtra, India.

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Dr.Rohan barse
Co-author

Department of Pharmaceutics, Yashwantrao Bhonsale College of Pharmacy, Sawantwadi, dist – Sindhudurg, Maharashtra, India.

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Dr..vijay jagtap
Co-author

Department of Pharmaceutics, Yashwantrao Bhonsale College of Pharmacy, Sawantwadi, dist – Sindhudurg, Maharashtra, India.

Manasi Mathkar, Rohan Barse , Vijay Jagtap, A Review on Advanced Nsaid Delivery: Liposomal Ibuprofen For Targeted Skin Delivery, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 4482-4503, https://doi.org/10.5281/zenodo.19808457

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