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Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407

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Abstract

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12 h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1 h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

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REFERENCES

  1. Patil H, Kulkarni V, Majumdar S, et al. Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. Int J Pharm. 2014;471(1):153–6.

    Article  CAS  PubMed  Google Scholar 

  2. Baronsky-Probst J, Möltgen C-V, Kessler W, et al. Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production. Eur J Pharm Sci. 2016;87:14–21.

    Article  CAS  PubMed  Google Scholar 

  3. Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech. 2016;17(1):20–42.

    Article  CAS  PubMed  Google Scholar 

  4. Stanković M, Frijlink HW, Hinrichs WL. Polymeric formulations for drug release prepared by hot melt extrusion: application and characterization. Drug Discov Today. 2015;20(7):812–23.

    Article  PubMed  Google Scholar 

  5. Cossé A, König C, Lamprecht A, et al. Hot Melt Extrusion for Sustained Protein Release: Matrix Erosion and In Vitro Release of PLGA-Based Implants. AAPS PharmSciTech. 2016. doi:10.1208/s12249-016-0548-5.

  6. Repka MA, Shah S, Lu J, et al. Melt extrusion: process to product. Exp Opin Drug Deliv. 2012;9(1):105–25.

    Article  CAS  Google Scholar 

  7. Alsulays BB, Park J-B, Alshehri SM, et al. Influence of molecular weight of carriers and processing parameters on the extrudability, drug release, and stability of fenofibrate formulations processed by hot-melt extrusion. J Drug Deliv Sci Tech. 2015;29:189–98.

    Article  CAS  Google Scholar 

  8. Lu Z, Fassihi R. Influence of colloidal silicon dioxide on gel strength, robustness, and adhesive properties of diclofenac gel formulation for topical application. AAPS PharmSciTech. 2015;16(3):636–44.

    Article  CAS  PubMed  Google Scholar 

  9. Murphy DJ, Sankalia MG, Loughlin RG, et al. Physical characterisation and component release of poly (vinyl alcohol)–tetrahydroxyborate hydrogels and their applicability as potential topical drug delivery systems. Int J Pharm. 2012;423(2):326–34.

    Article  CAS  PubMed  Google Scholar 

  10. Heng P, Chan L, Chow K. Development of novel nonaqueous ethylcellulose gel matrices: rheological and mechanical characterization. Pharm Res. 2005;22(4):676–84.

    Article  CAS  PubMed  Google Scholar 

  11. Cevher E, Taha M, Orlu M, et al. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Deliv. 2008;15(1):57–67.

    Article  CAS  PubMed  Google Scholar 

  12. Islam MT, Rodriguez-Hornedo N, Ciotti S, et al. Rheological characterization of topical carbomer gels neutralized to different pH. Pharm Res. 2004;21(7):1192–9.

    Article  CAS  PubMed  Google Scholar 

  13. Nokhodchi A, Sharabiani K, Rashidi MR, et al. The effect of terpene concentrations on the skin penetration of diclofenac sodium. Int J Pharm. 2007;335(1):97–105.

    Article  CAS  PubMed  Google Scholar 

  14. Ho HO, Huang FC, Sokoloski TD, et al. The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system. J Pharm Pharmacol. 1994;46(8):636–42.

    Article  CAS  PubMed  Google Scholar 

  15. Ghanbarzadeh S, Arami S. Enhanced transdermal delivery of diclofenac sodium via conventional liposomes, ethosomes, and transfersomes. BioMed Res Int. 2013. doi:10.1155/2013/616810.

  16. Barakat NS. Evaluation of glycofurol-based gel as a new vehicle for topical application of naproxen. AAPS PharmSciTech. 2010;11(3):1138–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Park Y-J, Yong CS, Kim H-M, et al. Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. Int J Pharm. 2003;263(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  18. Ikeda S, Nishinari K. “Weak Gel”-type rheological properties of aqueous dispersions of nonaggregated κ-carrageenan helices. J Agric Food Chem. 2001;49(9):4436–41.

    Article  CAS  PubMed  Google Scholar 

  19. Cevher E, Sensoy D, Taha MA, et al. Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan. AAPS PharmSciTech. 2008;9(3):953–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Salerno C, Carlucci AM, Bregni C. Study of in vitro drug release and percutaneous absorption of fluconazole from topical dosage forms. AAPS PharmSciTech. 2010;11(2):986–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tai A, Bianchini R, Jachowicz J. Texture analysis of cosmetic/pharmaceutical raw materials and formulations. Int J Cosm Sci. 2014;36(4):291–304.

    Article  CAS  Google Scholar 

  22. Suwanpidokkul N, Thongnopnua P, Umprayn K. Transdermal delivery of zidovudine (AZT): the effects of vehicles, enhancers, and polymer membranes on permeation across cadaver pig skin. AAPS PharmSciTech. 2004;5(3):82–9.

    Article  PubMed Central  Google Scholar 

  23. Meidan VM, Al-Khalili M, Michniak BB. Enhanced iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers. Int J Pharm. 2003;264(1):73–83.

    Article  CAS  PubMed  Google Scholar 

  24. Patel SR, Zhong H, Sharma A, et al. In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate. Eur J Pharm Biopharm. 2007;66(2):296–301.

    Article  CAS  PubMed  Google Scholar 

  25. Maniruzzaman M, Boateng JS, Snowden MJ, et al. A review of hot-melt extrusion: process technology to pharmaceutical products. ISRN pharmaceutics. 2012. doi:10.5402/2012/436763

  26. Patil H, Feng X, Ye X, et al. Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach. AAPS J. 2015;17(1):194–205.

    Article  CAS  PubMed  Google Scholar 

  27. Bhagurkar AM, Angamuthu M, Patil H, et al. Development of an ointment formulation using hot-melt extrusion technology. AAPS PharmSciTech. 2016;17(1):158–66.

    Article  CAS  PubMed  Google Scholar 

  28. Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf B: Biointerfaces. 2014;113:330–7.

    Article  CAS  PubMed  Google Scholar 

  29. Jain K, Sood S, Gowthamarajan K. Optimization of artemether-loaded NLC for intranasal delivery using central composite design. Drug Deliv. 2015;22(7):940–54.

    Article  CAS  PubMed  Google Scholar 

  30. Pawar J, Tayade A, Gangurde A, et al. Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: a QbD approach. Eur J Pharm Sci. 2016;88:37–49.

    Article  CAS  PubMed  Google Scholar 

  31. Hurler J, Engesland A, Poorahmary Kermany B, et al. Improved texture analysis for hydrogel characterization: gel cohesiveness, adhesiveness, and hardness. J Appl Polym Sci. 2012;125(1):180–8.

    Article  CAS  Google Scholar 

  32. Chow KT, Chan LW, Heng PW. Characterization of spreadability of nonaqueous ethylcellulose gel matrices using dynamic contact angle. J Pharm Sci. 2008;97(8):3467–82.

    Article  CAS  PubMed  Google Scholar 

  33. Määttä J, Koponen H-K, Kuisma R, et al. Effect of plasticizer and surface topography on the cleanability of plasticized PVC materials. Appl Surf Sci. 2007;253(11):5003–10.

    Article  Google Scholar 

  34. Van Oss C, Good R, Chaudhury M. Additive and nonadditive surface tension components and the interpretation of contact angles. Langmuir. 1988;4(4):884–91.

    Article  Google Scholar 

  35. Puri V, Dantuluri AK, Kumar M, et al. Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug. Eur J Pharm Sci. 2010;40(2):84–93.

    Article  CAS  PubMed  Google Scholar 

  36. Chow D, Kaka I, Wang T. Concentration-dependent enhancement of 1-dodecylazacycloheptan-2-one on the percutaneous penetration kinetics of triamcinolone acetonide. J Pharm Sci. 1984;73(12):1794–9.

    Article  CAS  PubMed  Google Scholar 

  37. Takahashi A, Suzuki S, Kawasaki N, et al. Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats. Int J Pharm. 2002;246(1):179–86.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang L, Parsons DL, Navarre C, et al. Development and in-vitro evaluation of sustained release poloxamer 407 (P407) gel formulations of ceftiofur. J Control Release. 2002;85(1):73–81.

    Article  CAS  PubMed  Google Scholar 

  39. Forslind B, Engström S, Engblom J, et al. A novel approach to the understanding of human skin barrier function. J Dermatol Sci. 1997;14(2):115–25.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are thankful to the University Grants Commission India for providing the research fellowship no. UGC-SAP/ICT-DPST/2012-13/1115.

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Authors and Affiliations

  1. BASF India Ltd, Pharma Solutions, Plot No. 12, TTC Area, Thane Belapur Road, Turbhe, Navi Mumbai, 400705, India

    Jaywant Pawar, Rajkiran Narkhede & Vaishali Tawde

  2. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, University under Section-3 of UGC Act-1956, Elite Status & Centre of Excellence - Govt. of Maharashtra, N. P. Marg, Matunga, Mumbai, 400019, India

    Jaywant Pawar & Purnima Amin

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Correspondence to Jaywant Pawar.

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Pawar, J., Narkhede, R., Amin, P. et al. Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407. AAPS PharmSciTech 18, 2303–2315 (2017). https://doi.org/10.1208/s12249-017-0713-5

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