A Review on Nanohydrogel of Ketoprofen for the Management of Inflammation

Abstract

Ketoprofen-loaded nanohydrogels, when used in transdermal drug delivery systems, provide a new and effective way to treat inflammation. These formulations use biocompatible materials like hyaluronan, chitosan, and other hydrogels to wrap ketoprofen, a type of nonsteroidal anti-inflammatory drug (NSAID) that stops the COX-1 and COX-2 enzymes from working. These enzymes help make prostaglandins, which are part of the body's inflammatory response. By applying the nanohydrogel through the skin, the drug slowly and directly reaches the affected area, making it more effective at targeting the right tissues and keeping a steady level of the drug in the body without causing widespread side effects. Studies show that these systems help reduce levels of several inflammatory markers, including nitric oxide, PGE2, IL-12 p40, TNF-?, and IL-6. The nanohydrogels are stable, safe, and work well over a long time without causing skin irritation or breaking down quickly. In short, transdermal systems using ketoprofen-loaded nanohydrogels are a promising and safe alternative to traditional NSAID use, especially for managing long-term chronic inflammation that needs ongoing treatment.

Keywords

Introduction

Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) commonly prescribed for the management of inflammatory and painful conditions such as rheumatoid arthritis, osteoarthritis, and musculoskeletal disorders.[1] It exerts its action primarily through the inhibition of cyclooxygenase (COX) enzymes, thereby reducing the production of prostaglandins responsible for inflammation, pain, and fever. Despite its proven therapeutic benefits, the clinical application of ketoprofen is significantly restricted by its poor water solubility and limited bioavailability when administered orally.[2] Moreover, oral administration is associated with gastrointestinal disturbances such as ulcers, bleeding, and discomfort, which affect 10 to 30 percent of patients and can lead to poor treatment adherence in chronic therapy. Transdermal drug delivery provides a promising alternative route to overcome these limitations. Unlike oral or injectable routes, transdermal systems allow drugs to be absorbed through the skin into systemic circulation in a controlled and sustained manner. This approach bypasses hepatic first-pass metabolism, thereby improving bioavailability, reducing systemic toxicity, and minimizing the risk of gastrointestinal side effects. Additionally, transdermal systems enable localized delivery to target tissues, making them particularly advantageous for treating inflammatory conditions affecting joints and muscles. The ease of application, patient compliance, and potential for controlled drug release further contribute to the growing preference for transdermal drug delivery systems (TDDS) in modern therapeutics. However, the human stratum corneum, which serves as the primary barrier to drug penetration, poses a major challenge for transdermal delivery, especially for hydrophobic drugs such as ketoprofen. To enhance the efficiency of skin permeation, several strategies have been explored, including the use of chemical permeation enhancers, liposomes, microemulsions, iontophoresis, and microneedle arrays. Among emerging technologies, nanocarrier-based systems have demonstrated considerable potential due to their ability to encapsulate drugs at the nanoscale level, resulting in improved solubility, enhanced penetration through the skin layers, and sustained release of the therapeutic agent. Nanohydrogels, as novel polymer-based nanocarriers, represent a hybrid system that combines the advantages of traditional hydrogels with the functional benefits of nanoparticles.[3] These structures are composed of three-dimensional polymeric networks with high water content, allowing for excellent biocompatibility, flexibility, and the ability to mimic the natural extracellular environment. The nanoscale size of these hydrogels facilitates deeper skin penetration, while their tunable crosslinking density ensures controlled and prolonged drug release. Moreover, nanohydrogels can be engineered using biocompatible and biodegradable polymers such as N-vinylpyrrolidone (NVP) and acrylic acid (AA), which provide excellent mechanical strength, stability, and low toxicity suitable for dermal applications. The formulation of ketoprofen-loaded nanohydrogels for transdermal delivery is expected to improve the therapeutic potential of this drug by enhancing its solubility, prolonging its residence time in skin tissues, and enabling sustained anti-inflammatory effects.[4] Incorporating ketoprofen into nanohydrogel systems not only improves the drug’s pharmacokinetic profile but also reduces the dosage frequency and systemic exposure, thereby minimizing adverse effects. Furthermore, the use of these nanohydrogels as pressure-sensitive adhesives or incorporated within transdermal patches can ensure intimate contact with the skin surface, optimizing drug diffusion and overall therapeutic efficacy.[5]

Drug profile

Ketoprofen is a strong nonsteroidal anti-inflammatory drug (NSAID) that mainly stops the enzyme cyclooxygenase-2. It helps reduce pain and inflammation. According to the Biopharmaceutics Classification Scheme, ketoprofen is a class II drug, meaning it has low solubility in water but can pass through the body's membranes easily.  Ketoprofen is a type of nonsteroidal anti-inflammatory drug (NSAID) that belongs to the propionic acid group. It works in a similar way to other NSAIDs like ibuprofen and naproxen, both in terms of its chemical structure and how it affects the body. It is commonly used to help with pain, reduce inflammation, and bring down fever in various health conditions.[6]

Chemical and Structural Profile

The chemical formula for ketoprofen is C16H14O3, and its molecular weight is 254.28 g/mol. This drug is also known as 2-(3-benzoylphenyl) propionic acid. It is available in several forms, including tablets, creams, injections, and suppositories. It is sometimes sold as a sodium salt to help the body absorb it more effectively.

Fig. No. 1: Structure of Ketoprofen

Mechanism of Action

Ketoprofen works by stopping the activity of enzymes called cyclooxygenase (COX), specifically COX-1 and COX-2.

These enzymes are responsible for making prostaglandins, which are involved in causing pain, swelling, and fever. In addition to this, ketoprofen also helps to protect certain cell structures and has a small effect on a substance called bradykinin, which further helps in reducing inflammation.[7]

Pharmacokinetics

Absorption: When taken by mouth or given by injection, ketoprofen is quickly absorbed into the bloodstream.

The highest levels in the blood are usually reached between half an hour to three hours after taking the drug.[8]

Distribution: A large portion of the drug, about 99%, becomes attached to proteins in the blood.[9]

Metabolism: Ketoprofen is mainly processed by the liver through processes such as glucuronidation and hydroxylation. These processes involve several enzymes, including UGT and CYP isoenzymes like CYP2C9 and CYP3A4.[10]

Elimination: The main way the drug leaves the body is through the urine, in a form called a conjugated glucuronide. The half-life of ketoprofen is usually between two to four hours in adults. This means that it takes that amount of time for the body to get rid of half the dose.[11]

Therapeutic Uses [12]

Ketoprofen is used to treat several conditions, including:

• Osteoarthritis and rheumatoid arthritis
• Ankylosing spondylitis
• Dysmenorrhea (pain during menstruation)
• Mild to moderate pain from surgery, injuries to muscles or joints, dental procedures, or childbirth
• Reducing fever

Dosage [13-14]

For oral use:

• For pain or menstrual pain: 25 to 50 mg every 6 to 8 hours, with a maximum daily dose of 300 mg.
• For arthritis conditions: Up to 300 mg per day, taken in smaller doses throughout the day.

A single dose of 25 to 50 mg of ketoprofen is about the same as 400 mg of ibuprofen in terms of pain relief.

Adverse Effects [15-16]

Common side effects may include:

• Stomach problems like nausea, stomach lining irritation, or ulcers
• Dizziness, tiredness, and headaches
• Fluid retention and swelling

In rare cases, the drug can cause issues with the kidneys or liver.

Long-term use or use in people at higher risk may lead to serious problems like stomach bleeding or ulcers.

Contraindications and Precautions [17-18]

Ketoprofen should not be used in patients who:

• Have a peptic ulcer or a history of stomach bleeding
• Have serious kidney, liver, or heart disease
• Are allergic to NSAIDs
• Are pregnant, especially after the 20th week, as it can harm the baby's kidneys.

Nanohydrogel [19-21]

Hydrogels are three-dimensional structures made from polymers that can hold a lot of water but won't dissolve in it because the chemical bonds keep them from breaking apart. These materials have been studied and changed at the nanoscale to be used in many different ways. Nanohydrogels have several benefits compared to other nanomaterials, like being flexible, adaptable, and safe for the body. These nanohydrogels are generally grouped based on how they are made, their physical features, where they come from, their charge, how they break down in the body, and the type of chemical connections that hold them together. Based on these categories, many polymers have been found that come from natural sources. These natural polymers are further divided based on their building blocks, how they are formed, how they react to their environment, and how their molecular chains interact. Recently, scientists have discovered new natural sources for making nanohydrogels, and earlier research used materials like DNA and other naturally occurring polymers. Natural-based polymers are widely studied because they can move through the body, not hurt cells, break down safely, and be easily removed. Studies have also shown that the structure, breakdown, and ability to release drugs from natural polymers can be changed by creating synthetic or mixed networks that connect the polymer chains. Both synthetic and hybrid polymers are used to build nanohydrogels, and these include materials like polyamides, polyethylene glycol, polypeptides, polyesters, and poly-phosphazenes. Synthetic polymers are known for being stable, having clear structures, and behaving predictably when releasing drugs. But they don't match the body's natural proteins as well as natural polymers do. A ketoprofen nanohydrogel is a modern drug delivery system that uses ketoprofen nanoparticles mixed with a hydrogel base. This helps the drug pass through the skin better and makes it work longer to reduce inflammation and pain.

Structure and Composition: [22-24]

Ketoprofen nanohydrogels are made by putting ketoprofen nanoparticles into a biocompatible hydrogel, like hyaluronan/collagen, Carbopol, or chitosan. These nanoparticles are usually smaller than 100 nanometers and are created using methods such as bead milling, emulsification, or solvent evaporation. They often include things like surfactants (for example, Tween 80), oils (like oleic acid), and co-surfactants (such as ethanol) to help keep them stable before they form a gel.

ADVANTAGES: [25-29]

Enhanced Skin Penetration: The tiny size of the nanoparticles helps them move through the skin more effectively, getting more of the drug to where it's needed.

Improved Bioavailability: The nanoscale structure releases the drug slowly and steadily, offering longer-lasting treatment and needing less frequent use.

Reduced Side Effects: By delivering the drug through the skin, this method lowers the chance of stomach irritation that often happens with oral ketoprofen.

Therapeutic Efficacy: Research shows that ketoprofen nanohydrogels can lower levels of inflammatory substances like nitric oxide, TNF-α, and IL-6, and they have better anti-inflammatory effects in animal studies.

Preparation and Evaluation

Making a ketoprofen nanohydrogel starts with creating a nanoemulsion, which is then turned into a gel using a polymer such as chitosan or Carbopol. Pseudo-ternary phase diagrams are used to find the best mix of oil, surfactant, and co-surfactant for stable nanoparticles. The final product is tested through several checks, including physical properties, particle size, gel thickness, how the drug is released, and how well it gets into the skin, using lab techniques and in vitro models.[30]

Applications [31-36]

Ketoprofen nanohydrogels are mainly used for:

• Relieving pain and inflammation through skin application
• Treating specific conditions like rheumatoid arthritis
• Creating advanced wound dressings that offer anti-inflammatory support for long-term wound care.

CONCLUSION: Ketoprofen-loaded nanohydrogels are a big step forward in delivering medicines through the skin and managing inflammation. By mixing the healing power of ketoprofen with the flexible and safe structure of nanohydrogels, this method overcomes many of the problems with traditional ways of taking NSAIDs, like pills or creams. These include issues like not dissolving well in water, not lasting long enough, and causing stomach problems. The tiny size and flexible nature of nanohydrogels help the medicine get deeper into the skin, release slowly over time, and reach exactly where the inflammation is. Research shows that ketoprofen nanohydrogels lower levels of key inflammation markers like nitric oxide, TNF-α, IL-6, and PGE2, showing they are very good at fighting inflammation. These nanohydrogels are also stable, safe, and don't cause much irritation, so they can be used for a long time. Using natural or combined materials like chitosan and hyaluronan makes them work well with the body and respond to changes in their surroundings, making them useful for dealing with ongoing inflammation. In short, ketoprofen-loaded nanohydrogels provide a reliable, easy, and effective way to deliver NSAIDs through the skin. Future work should focus on improving the formula, making it easier to produce on a larger scale, and doing detailed clinical tests to confirm their long-term benefits and safety.

Conflict Of Interest:

Regarding this investigation, the authors have no conflicts of interest.

ACKNOWLEDGMENTS:

For the literature review, the authors are grateful to the Shraddha Institute of Pharmacy, Library in Kondala Zambre, Washim.

REFERENCES

1. Gallelli, L., Colosimo, M., Pirritano, D., Ferraro, M., De Fazio, S., Marigliano, N. M., et al. (2007). Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs. Clinical Drug Investigation, 27(2), 115–122.
2. Gruppo Italiano Farmacovigilanza (GIF). (2009). Retrieved June 15, 2013, from http://www.gruppogif.org/
3. Gallelli, L., Ferraro, M., Mauro, G. F., De Fazio, S., & De Sarro, G. (2005). Nimesulide-induced hepatotoxicity in a previously healthy woman. Clinical Drug Investigation, 25(7), 421–424.
4. Kokki, H. (2010). Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients. Paediatric Drugs, 12(5), 313–329.
5. Kokki, H., Nikanne, E., & Tuovinen, K. (1998). Intravenous intraoperative ketoprofen in small children during adenoidectomy: A dose-finding study. British Journal of Anaesthesia, 81(6), 870–874.
6. Celebi, S., Hacimustafaoglu, M., Aygun, D., Arisoy, E. S., Karali, Y., Akgoz, S., et al. (2009). Antipyretic effect of ketoprofen. Indian Journal of Pediatrics, 76, 287–291.
7. Kokki, H., Tuomilehto, H., & Tuovinen, K. (2000). Pain management after adenoidectomy with ketoprofen: Comparison of rectal and intravenous routes. British Journal of Anaesthesia, 85, 836–840.
8. Salonen, A., Kokki, H., & Nuutinen, J. (2002). The effect of ketoprofen on recovery after tonsillectomy in children: A 3-week follow-up study. International Journal of Pediatric Otorhinolaryngology, 62, 143–150.
9. Ghlichloo, I., & Gerriets, V. (2023). Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. PMID: 31613522.
10. Heo, S. K., Cho, J., Cheon, J. W., Choi, M. K., Im, D. S., Kim, J. J., Choi, Y. G., Jeon, D. Y., Chung, S. J., Shim, C. K., & Kim, D. D. (2008). Pharmacokinetics and pharmacodynamics of ketoprofen plasters. Biopharmaceutics & Drug Disposition, 29(1), 37–44. https://doi.org/10.1002/bdd.587
11. Herwadkar, A., Sachdeva, V., Taylor, L. F., Silver, H., & Banga, A. K. (2012). Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen. International Journal of Pharmaceutics, 423(2), 289–296. https://doi.org/10.1016/j.ijpharm.2011.11.041
12. Jadhav, P., Sinha, R., Uppada, U. K., Tiwari, P. K., & Subramanya Kumar, A. V. S. S. (2018). Pre-emptive diclofenac versus ketoprofen as a transdermal drug delivery system: How they face. Journal of Maxillofacial and Oral Surgery, 17(4), 488–494. https://doi.org/10.1007/s12663-017-1048-1
13. Jang, S., Lee, K., & Ju, J. H. (2021). Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. International Journal of Molecular Sciences, 22(5), 1–15. https://doi.org/10.3390/ijms22052619
14. Aboofazeli, R., Barlow, D. J., & Lawrence, M. J. (2000). Particle size analysis of concentrated phospholipid microemulsions: I. Total-intensity light scattering. AAPS PharmSci, 2(2), 1–13.
15. Jiao, J., & Burgess, D. J. (2003). Rheology and stability of water-in-oil-in-water multiple emulsions containing span 83 and tween 80. AAPS PharmSci, 5(1), 62–73.
16. Kaushik, D., Batheja, P., Kilfoyle, B., Rai, V., & Michniak-Kohn, B. (2008). Percutaneous permeation modifiers: Enhancement versus retardation. Expert Opinion on Drug Delivery, 5(5), 517–529.
17. Shinoda, K., & Lindman, B. (1987). Organized surfactant systems: Microemulsions. Langmuir, 3(2), 135–149.
18. Azeem, A., Rizwan, M., Ahmad, F. J., et al. (2009). Nanoemulsion components screening and selection: A technical note. AAPS PharmSciTech, 10(1), 69–76.
19. Lee, C. H., Moturi, V., & Lee, Y. (2009). Thixotropic property in pharmaceutical formulations. Journal of Controlled Release, 136(2), 88–98.
20. Zhao, J. H., Ji, L., Wang, H., Chen, Z. Q., Zhang, Y. T., Liu, Y., et al. (2011). Microemulsion-based novel transdermal delivery system of tetramethylpyrazine: Preparation and evaluation in vitro and in vivo. International Journal of Nanomedicine, 6, 1611–1619.
21. Swarbrick, J., & Boylan, J. C. (1996). Encyclopedia of pharmaceutical technology (Vol. 20, pp. 23–24). New York: Pharmaceutical Technology.
22. Lawrence, M. J., & Rees, G. D. (2012). Microemulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews, 64, 175–193.
23. Muxika, A., Etxabide, A., Uranga, J., Guerrero, P., & De la Caba, K. (2017). Chitosan as a bioactive polymer: Processing, properties and applications. International Journal of Biological Macromolecules, 105, 1358–1368. https://doi.org/10.1016/j.ijbiomac.2017.07.087
24. S. A., & S. I. (2015). Chitosan and its derivatives: A review in recent innovations. International Journal of Pharmaceutical Sciences and Research, 6(1), 14–30.
25. Azuma, K., Izumi, R., Osaki, T., Ifuku, S., Morimoto, M., Saimoto, H., et al. (2015). Chitin, chitosan, and its derivatives for wound healing: Old and new materials. Journal of Functional Biomaterials, 6(1), 104–142.
26. Okamoto, Y., Kawakami, K., Miyatake, K., Morimoto, M., Shigemasa, Y., & Minami, S. (2002). Analgesic effects of chitin and chitosan. Carbohydrate Polymers, 49(3), 249–252.
27. Pathan, I. B., & Mallikarjuna Setty, C. (2012). Nanoemulsion system for transdermal delivery of tamoxifen citrate: Design, characterization, effect of penetration enhancers and in vivo studies. Digest Journal of Nanomaterials and Biostructures, 7(4), 1373–1387.
28. Jiménez-Rosado, P., & Romero, M. (2022). Drug transport pathways across skin. Polymers, 2022, 3023.
29. Shah, P., & Singh, M. (2012). Enhanced skin permeation using polyarginine modified nanostructured lipid carriers. Journal of Controlled Release, 161(3), 735–745. https://doi.org/10.1016/j.jconrel.2012.05.011
30. Shah, P. P., Desai, P. R., Patel, A. R., & Singh, M. S. (2012). Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs. Biomaterials, 33(5), 1607–1617. https://doi.org/10.1016/j.biomaterials.2011.11.011
31. Somagoni, J., Boakye, C. H. A., Godugu, C., et al. (2014). Nanomiemgel – A novel drug delivery system for topical application: In vitro and in vivo evaluation. PLoS One, 9(12). https://doi.org/10.1371/journal.pone.0115952
32. Chouhan, C., Rajput, R. P. S., Sahu, R., Verma, P., & Sahu, S. (2020). An updated review on nanoparticle-based approach for nanogel drug delivery system. Journal of Drug Delivery and Therapeutics, 10(5–S), 254–266. https://doi.org/10.22270/jddt.v10i5-s.4465
33. Joglekar, M., & Trewyn, B. G. (2013). Polymer-based stimuli-responsive nanosystems for biomedical applications. Biotechnology Journal, 8(8), 931–945. https://doi.org/10.1002/biot.201300073
34. Parhi, R., Sahoo, S. K., & Das, A. (2023). Applications of polysaccharides in topical and transdermal drug delivery: A recent update of literature. Brazilian Journal of Pharmaceutical Sciences, 58, e20802. https://doi.org/10.1590/s2175-97902022e20802
35. Wang, W., Lu, K. J., Yu, C. H., Huang, Q. L., & Du, Y. Z. (2019). Nano-DDS in wound treatment and skin regeneration. Journal of Nanobiotechnology, 17(1). https://doi.org/10.1186/s12951-019-0514-y
36. Bashir, M. H., Korany, N. S., Farag, D. B. E., et al. (2023). Polymeric nanocomposite hydrogel scaffolds in craniofacial bone regeneration: A comprehensive review. Biomolecules, 13(2). https://doi.org/10.3390/biom13020205.