Oral Fast and Topical Controlled Ketoprofen Release Through Supercritical Fluids Based Processes

  • Paola Franco
  • Iolanda De MarcoEmail author
Conference paper
Part of the Lecture Notes in Bioengineering book series (LNBE)


Ketoprofen (KET) is a non-steroidal anti-inflammatory drug (NSAID) widely used for different phlogistic diseases of rheumatoid and non-rheumatoid origin. When a fast release is required, KET is orally administered in form of capsules, tablets or granulates. In this case, due to KET poor solubility in water, large drug doses with consequent side effects, mainly gastrointestinal one are required. KET bioavailability can be enhanced through its coprecipitation with a hydrophilic carrier, such as polyvinylpyrrolidone (PVP). Another way to reduce the dosing frequency and avoid gastrointestinal irritation is the transdermal drug delivery with a controlled release. In this work, two different supercritical carbon dioxide (scCO2) based processes were used to modify KET dissolution rate: the supercritical antisolvent technique to coprecipitate PVP and KET in form of controlled dimensions microparticles for an oral delivery, and the supercritical adsorption to impregnate KET in alginate aerogel for a topical delivery. In the case of oral KET, composite spherical microparticles with controlled diameters were successfully produced, leading to a faster NSAID dissolution rate than unprocessed KET. In the case of topical KET, alginate aerogel was successfully impregnated with KET; it promotes a controlled release, suitable for transdermal anti-inflammatory patches, reducing frequency of administration and side effects. Supercritical techniques allow to obtain a fast or controlled release of the NSAID, according to the specific therapy desired.


Supercritical carbon dioxide Ketoprofen Oral fast release Topical controlled release 


  1. 1.
    Cabré, F., Fernández, M.F., Calvo, L., Ferrer, X., García, M.L., Mauleón, D.: Analgesic, antiinflammatory, and antipyretic effects of S(+)-ketoprofen in vivo. J. Clin. Pharmacol. 38, 3S–10S (1998)CrossRefGoogle Scholar
  2. 2.
    Scheiman, J.M.: NSAID-induced gastrointestinal injury: a focused update for clinicians. J. Clin. Gastroenterol. 50, 5–10 (2016)CrossRefGoogle Scholar
  3. 3.
    Yu, D.-G., Branford-White, C., Shen, X.-X., Zhang, X.-F., Zhu, L.-M.: Solid dispersions of ketoprofen in drug-loaded electrospun nanofibers. J. Dispers. Sci. Technol. 31, 902–908 (2010)CrossRefGoogle Scholar
  4. 4.
    Ivanov, I.T., Tsokeva, Z.: Effect of chirality on PVP/drug interaction within binary physical mixtures of ibuprofen, ketoprofen, and naproxen: a DSC study. Chirality 21, 719–727 (2009)CrossRefGoogle Scholar
  5. 5.
    Tita, B., Fuias, A., Bandur, G., Marian, E., Tita, D.: Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms. J. Pharm. Biomed. Anal. 56, 221–227 (2011)CrossRefGoogle Scholar
  6. 6.
    Prosapio, V., Reverchon, E., De Marco, I.: Formation of PVP/nimesulide microspheres by supercritical antisolvent coprecipitation. J. Supercrit. Fluids 118, 19–26 (2016)CrossRefGoogle Scholar
  7. 7.
    Manna, L., Banchero, M., Sola, D., Ferri, A., Ronchetti, S., Sicardi, S.: Impregnation of PVP microparticles with ketoprofen in the presence of supercritical CO2. J. Supercrit. Fluids 42, 378–384 (2007)CrossRefGoogle Scholar
  8. 8.
    Arunachalam, A., Karthikeyan, M., Vinay Kumar, D., Prathap, M., Sethuraman, S., Ashutoshkumar, S., Manidipa, S.: Transdermal drug delivery system: a review. Curr. Pharm. Res. 1, 70–81 (2010)CrossRefGoogle Scholar
  9. 9.
    Franco, P., Reverchon, E., De Marco, I.: Zein/diclofenac sodium coprecipitation at micrometric and nanometric range by supercritical antisolvent processing. J. CO2 Util. 27, 366–373 (2018)CrossRefGoogle Scholar
  10. 10.
    Kalogiannis, C.G., Michailof, C.M., Panayiotou, C.G.: Microencapsulation of amoxicillin in poly (l-lactic acid) by supercritical antisolvent precipitation. Ind. Eng. Chem. Res. 45, 8738–8743 (2006)CrossRefGoogle Scholar
  11. 11.
    Franco, P., Martino, M., Palma, V., Scarpellini, A., De Marco, I.: Pt on SAS-CeO2 nanopowder as catalyst for the CO-WGS reaction. Int. J. Hydrogen Energy 43, 19965–19975 (2018)CrossRefGoogle Scholar
  12. 12.
    Zhong, Q., Jin, M., Davidson, P.M., Zivanovic, S.: Sustained release of lysozyme from zein microcapsules produced by a supercritical anti-solvent process. Food Chem. 115, 697–700 (2009)CrossRefGoogle Scholar
  13. 13.
    Montes, A., Kin, N., Gordillo, M.D., Pereyra, C., Martínez de la Ossa, E.J.: Polymer–naproxen precipitation by supercritical antisolvent (SAS) process. J. Supercrit. Fluids 89, 58–67 (2014)Google Scholar
  14. 14.
    Montes, A., Wehner, L., Pereyra, C., Martínez de la Ossa, E.J.: Generation of microparticles of ellagic acid by supercritical antisolvent process. J. Supercrit. Fluids 116, 101–110 (2016)CrossRefGoogle Scholar
  15. 15.
    Prosapio, V., De Marco, I., Reverchon, E.: Supercritical antisolvent coprecipitation mechanisms. J. Supercrit. Fluids 138, 247–258 (2018)CrossRefGoogle Scholar
  16. 16.
    Franco, P., Aliakbarian, B., Perego, P., Reverchon, E., De Marco, I.: Supercritical adsorption of quercetin on aerogels for active packaging applications. Ind. Eng. Chem. Res. 57, 15105–15113 (2018)CrossRefGoogle Scholar
  17. 17.
    Smirnova, I., Suttiruengwong, S., Seiler, M., Arlt, W.: Dissolution rate enhancement by adsorption of poorly soluble drugs on hydrophilic silica aerogels. Pharm. Dev. Technol. 9, 443–452 (2005)CrossRefGoogle Scholar
  18. 18.
    Smirnova, I., Mamic, J., Arlt, W.: Adsorption of drugs on silica aerogels. Langmuir 19, 8521–8525 (2003)CrossRefGoogle Scholar
  19. 19.
    García-Casas, I., Crampon, C., Montes, A., Pereyra, C., Martínez de la Ossa, E.J., Badens, E.: Supercritical CO2 impregnation of silica microparticles with quercetin. J. Supercrit. Fluids 143, 157–161 (2019)CrossRefGoogle Scholar
  20. 20.
    Smirnova, I., Suttiruengwong, S., Arlt, W.: Aerogels: tailor-made carriers for immediate and prolonged drug release. KONA Powder Part. J. 23, 86–97 (2005)CrossRefGoogle Scholar
  21. 21.
    De Marco, I., Reverchon, E.: Starch aerogel loaded with poorly water-soluble vitamins through supercritical CO2 adsorption. Chem. Eng. Res. Des. 119, 221–230 (2017)CrossRefGoogle Scholar
  22. 22.
    Pantić, M., Knez, Ž., Novak, Z.: Supercritical impregnation as a feasible technique for entrapment of fat-soluble vitamins into alginate aerogels. J. Non Cryst. Solids 432, 519–526 (2016)CrossRefGoogle Scholar
  23. 23.
    Marin, M.A., Mallepally, R.R., McHugh, M.A.: Silk fibroin aerogels for drug delivery applications. J. Supercrit. Fluids 91, 84–89 (2014)CrossRefGoogle Scholar
  24. 24.
    Lovskaya, D.D., Lebedev, A.E., Menshutina, N.V.: Aerogels as drug delivery systems: in vitro and in vivo evaluations. J. Supercrit. Fluids 106, 115–121 (2015)CrossRefGoogle Scholar
  25. 25.
    Salgado, M., Santos, F., Rodríguez-Rojo, S., Reis, R.L., Duarte, A.R.C., Cocero, M.J.: Development of barley and yeast β-glucan aerogels for drug delivery by supercritical fluids. J. CO2 Util. 22, 262–269 (2017)CrossRefGoogle Scholar
  26. 26.
    Bouledjouidja, A., Masmoudi, Y., Sergent, M., Trivedi, V., Meniai, A., Badens, E.: Drug loading of foldable commercial intraocular lenses using supercritical impregnation. Int. J. Pharm. 500, 85–99 (2016)CrossRefGoogle Scholar
  27. 27.
    García-González, C.A., Jin, M., Gerth, J., Alvarez-Lorenzo, C., Smirnova, I.: Polysaccharide-based aerogel microspheres for oral drug delivery. Carbohydr. Polym. 117, 797–806 (2015)CrossRefGoogle Scholar
  28. 28.
    Baldino, L., Concilio, S., Cardea, S., Reverchon, E.: Interpenetration on natural polymer aerogels by supercritical drying. Polymers 8, 106–117 (2016)CrossRefGoogle Scholar
  29. 29.
    Andreatta, A.E., Florusse, L.J., Bottini, S.B., Peters, C.J.: Phase equilibria of dimethyl sulfoxide (DMSO) + carbon dioxide, and DMSO + carbon dioxide + water mixtures. J. Supercrit. Fluids 42, 60–68 (2007)CrossRefGoogle Scholar
  30. 30.
    Reverchon, E., De Marco, I.: Mechanisms controlling supercritical antisolvent precipitate morphology. Chem. Eng. J. 169, 358–370 (2011)CrossRefGoogle Scholar
  31. 31.
    Macnaughton, S.J., Kikic, I., Foster, N.R., Alessi, P., Cortesi, A., Colombo, I.: Solubility of anti-inflammatory drugs in supercritical carbon dioxide. J. Chem. Eng. Data 41, 1083–1086 (1996)CrossRefGoogle Scholar
  32. 32.
    Grimling, B., Górniak, A., Meler, J., Szcześniak, M.: Characterisation and dissolution properties of ketoprofen in binary solid dispersion with chitosan. Prog. Chem. Appl. Chitin Deriv. 19, 23–31 (2014)Google Scholar
  33. 33.
    Al-Tahami, K.: Preparation, characterization, and in vitro release of ketoprofen loaded alginate microspheres. Int. J. App. Pharm. 6, 9–12 (2014)Google Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Industrial EngineeringUniversity of SalernoFiscianoItaly

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