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Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels

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Abstract

Purpose

In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed.

Methods

KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed.

Results

HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation.

Conclusions

KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

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Abbreviations

C940:

Carbopol® 940

HG:

Hydrogel

HPLC:

High performance liquid chromatography

KT:

Ketorolac tromethamine

P:

Porosity

P407:

Pluronic® F-127

PBS:

Phosphate buffer solution

PEO:

Poly(ethylene oxide)

PPO:

Poly(propylene oxide)

SC:

Stratum corneum

SCH:

Stratum corneum hydration

SR:

Swelling ratio

TEWL:

Trans epidermal water loss

TPA:

12-O-detradecanoylphorbol-13-acetate

WL:

Weight loss

References

  1. De Oliveira Jr GS, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: ameta-analysis of randomized trials. Anesth Analg. 2012;114(2):424–33.

    Article  Google Scholar 

  2. El-Setouhy DA, El-Ashmony SM. Ketorolac trometamol topical formulations: release behaviour, physical characterization, skin permeation, efficacy and gastric safety. J Pharm Pharmacol. 2010;62(1):25–34.

    Article  Google Scholar 

  3. Ting WW, Vest CD, Sontheimer RD. Review of traditional and novel modalities that enhance the permeability of local therapeutics across the stratum corneum. Int J Dermatol. 2004;43(7):538–47.

    Article  CAS  Google Scholar 

  4. Vega E, Egea MA, Garduño-Ramírez ML, García ML, Sánchez E, Espina M, Calpena AC. Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-β-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy. Colloids Surf B: Biointerfaces. 2013;110:339–46.

    Article  CAS  Google Scholar 

  5. Koop HS, de Freitas RA, de Souza MM, Savi-Jr R, Silveira JL. Topical curcumin-loaded hydrogels obtained using galactomannan from Schizolobium Parahybae and xanthan. Carbohydr Polym. 2015;116:229–36.

    Article  CAS  Google Scholar 

  6. Guvendiren M, Lu HD, Burdick JA. Shear-thinning hydrogels for biomedical applications. Soft Matter. 2012;8:260e272.

    Article  Google Scholar 

  7. Ahmed EM. Hydrogel: preparation, characterization, and applications: a review. J Adv Res. 2015;6(2):105–21.

    Article  CAS  Google Scholar 

  8. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49:1993–2007.

    Article  CAS  Google Scholar 

  9. Miguel SP, Ribeiro MP, Brancal H, Coutinho P, Correia IJ. Thermoresponsive chitosan-agarose hydrogel for skin regeneration. Carbohydr Polym. 2014;111:366–73.

    Article  CAS  Google Scholar 

  10. de Araújo DR, da Silva DC, Barbosa RM, Franz-Montan M, Cereda CM, Padula C, et al. Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches. Expert Opin Drug Deliv. 2013;10(11):1551–63.

    Article  Google Scholar 

  11. Brugués AP, Naveros BC, Calpena Campmany AC, Pastor PH, Saladrigas RF, Lizandra CR. Developing cutaneous applications of paromomycin entrapped in stimuli-sensitive block copolymer nanogel dispersions. Nanomedicine (London). 2015;10(2):227–40.

    Article  Google Scholar 

  12. Chawla V, Saraf SA. Rheological studies on solid lipid nanoparticle based carbopol gels of aceclofenac. Colloids Surf B: Biointerfaces. 2012;92:293–8.

    Article  CAS  Google Scholar 

  13. Das B, Nayak AK, Nanda U. Topical gels of lidocaine HCl using cashew gum and Carbopol 940: preparation and in vitro skin permeation. Int J Biol Macromol. 2013;62:514–7.

    Article  CAS  Google Scholar 

  14. ICH harmonised tripartite guideline. Validation of analytical procedures: text and methodology Q2(R1). Geneva: ICH; 2005.

  15. Guidance document for the conduct of skin absorption studies. OECD series on testing and assessment No.28. Paris: OECD; 2004.

  16. Skin absorption: in vitro Method. OECD guideline for the testing of chemicals. Guideline 428.Paris: OECD; 2004.

  17. Basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients. SCCS/1358. Brussels: Scientific Committee on Consumer Safety; 2010.

  18. Williams AC. Transdermal and topical drug delivery. London: Pharmaceutical Press; 2003.

    Google Scholar 

  19. Flo A, Calpena AC, Halbaut L, Araya EI, Fernández F, Clares B. Melatonin delivery: transdermal and transbuccal evaluation in different vehicles. Pharm Res. 2016;33(7):1615–27.

    Article  CAS  Google Scholar 

  20. Alonso C, Lucas R, Barba C, Marti M, Rubio L, Comelles F, et al. Skin delivery of antioxidant surfactants based on gallic acid and hydroxytyrosol. J Pharm Pharmacol. 2015;67(7):900–8.

    Article  CAS  Google Scholar 

  21. Domínguez-Villegas V, Clares-Naveros B, García-López ML, Calpena-Campmany AC, Bustos-Zagal P, Garduño-Ramírez ML. Development and characterization of two nano-structured systems for topical application of flavanones isolated from Eysenhardtia Platycarpa. Colloids Surf B: Biointerfaces. 2014;116:183–92.

    Article  Google Scholar 

  22. World medical association. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.

    Article  Google Scholar 

  23. Clarys P, Clijsen R, Taeymans J, Barel AO. Hydration measurements of the stratum corneum: comparison between the capacitance method (digital version of the Corneometer CM 825(R)) and the impedance method (Skicon-200EX(R)). Skin Res Technol. 2012;18(3):316–23.

    Article  Google Scholar 

  24. Lee SG, Kim SR, Cho HI, Kang MH, Yeom DW, Lee SH, Lee S, Choi YW. Hydrogel-based ultra-moisturizing cream formulation for skin hydration and enhanced dermal drug delivery. Biol Pharm Bull. 2014;37(10):1674–82.

    Article  CAS  Google Scholar 

  25. Cordero JA, Alarcon L, Escribano E, Obach R, Domenech J. A comparative study of the transdermal penetration of a series of nonsteroidal antiinflammatory drugs. J Pharm Sci. 1997;86(4):503–8.

    Article  CAS  Google Scholar 

  26. Escobar-Chávez JJ, López-Cervantes M, Naïk A, Kalia YN, Quintanar-Guerrero D, Ganem-Quintanar A. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J Pharm Pharm Sci. 2006;9(3):339–58.

    PubMed  Google Scholar 

  27. Sierra AF, Ramirez ML, Campmany AC, Martinez AR, Naveros BC. In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation. J Dermatol Sci. 2013;69(3):202–14.

    Article  CAS  Google Scholar 

  28. Tang C, Yin L, Pei Y, Zhang M, Wu L. New superporous hydrogels composites based on aqueous carbopol® solution (SPHCcs): synthesis, characterization and in vitro bioadhesive force studies. Eur Polym J. 2005;4(3):557–62.

    Article  Google Scholar 

  29. Dong L, Liu C, Cun D, Fang L. The effect of rheological behavior and microstructure of the emulgels on the release and permeation profiles of Terpinen-4-ol. Eur J Pharm Sci. 2015;78:140–50.

    Article  CAS  Google Scholar 

  30. Dewan M, Bhowmick B, Sarkar G, Rana D, Bain MK, Bhowmik M, et al. Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations. Int J Biol Macromol. 2015;72:706–10.

    Article  CAS  Google Scholar 

  31. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23(12):2709–28.

    Article  CAS  Google Scholar 

  32. Almeida H, Amaral MH, Lobão P, Lobo JM. Pluronic F-127 and pluronic lecithin organogel (PLO): main features and their applications in topical and transdermal administration of drugs. J Pharm Pharm Sci. 2012;15(4):592–605.

    Article  Google Scholar 

  33. Cevc G, Blume G. Biological activity and characteristics of triamcinolone-acetonide formulated with the self-regulating drug carriers. Transfersomes Biochim Biophys Acta. 2003;1614(2):156–64.

    Article  CAS  Google Scholar 

  34. Mohammed D, Hirata K, Hadgraft J, Lane ME. Influence of skin penetration enhancers on skin barrier function and skin protease activity. Eur J Pharm Sci. 2014;51:118–22.

    Article  CAS  Google Scholar 

  35. del Pozo A, Viscasillas A. Efficacy evaluation. In: Salvador A, Chisvert A, editors. Analysis of cosmetic products. Amsterdam: Elsevier; 2007. p. 462–74.

    Chapter  Google Scholar 

  36. Shin SC, Cho CW, Oh IJ. Effects of non-ionic surfactants as permeation enhancers towards piroxicam from the poloxamer gel through rat skins. Int J Pharm 2001;222(2):199–203.

    Article  CAS  Google Scholar 

  37. Erukova VY, Krylova OO, Antonenko YN, Melik-Nubarov NS. Effect of ethylene oxide and propylene oxide block copolymers on the permeability of bilayer lipid membranes to small solutes including doxorubicin. Biochim Biophys Acta. 2000;1468(1–2):73–86.

    Article  CAS  Google Scholar 

  38. Demina T, Grozdova I, Krylova O, Zhirnov A, Istratov V, Frey H, et al. Relationship between the structure of amphiphilic copolymers and their ability to disturb lipid bilayers. Biochemistry. 2005;44(10):4042–54.

    Article  CAS  Google Scholar 

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Acknowledgments and Disclosures

This work was supported by the Ministry of Science and Innovation of Spain for the financial (MAT2014-59134R). Prof. Juan Blasi and Inmaculada Gómez de Aranda from the Department of Pathology and Experimental Therapeutics are also acknowledged for their excellent technical support in histological studies. The authors report no conflict of interests, financial or otherwise. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Authors and Affiliations

  1. Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, 27-31 Joan XXIII Av,, 08028, Barcelona,, Spain

    Mireia Mallandrich, Francisco Fernández-Campos, Lyda Halbaut, Alfonso del Pozo & Ana C. Calpena

  2. Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, 27-31 Joan XXIII Av, 08028, Barcelona, Spain

    Mireia Mallandrich, Beatriz Clares, Lyda Halbaut & Ana C. Calpena

  3. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja s/n,, 18071, Granada,, Spain

    Beatriz Clares

  4. Institute of Advanced Chemistry of Catalonia, 18-26 Jordi Girona St, 08034, Barcelona, Spain

    Cristina Alonso & Luisa Coderch

  5. Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001,, 62209, Cuernavaca, Morelos, Mexico

    Maria L. Garduño-Ramírez & Berenice Andrade

  6. Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square,, London,, WC1N 1AX, UK

    Majella E. Lane

Authors
  1. Mireia Mallandrich
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  2. Francisco Fernández-Campos
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  3. Beatriz Clares
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  4. Lyda Halbaut
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  5. Cristina Alonso
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  6. Luisa Coderch
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  7. Maria L. Garduño-Ramírez
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  8. Berenice Andrade
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  9. Alfonso del Pozo
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  10. Majella E. Lane
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  11. Ana C. Calpena
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Corresponding author

Correspondence to Beatriz Clares.

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Mallandrich, M., Fernández-Campos, F., Clares, B. et al. Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels. Pharm Res 34, 1728–1740 (2017). https://doi.org/10.1007/s11095-017-2181-8

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  • DOI: https://doi.org/10.1007/s11095-017-2181-8

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