Skip to main content

Advertisement

SpringerLink
Log in

QbD based development and evaluation of topical microemulsion-based hydrogel against superficial fungal infections

  • Original Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

Even though quality by design is becoming an essential method for a development of pharmaceutical product, limited studies have been performed to develop topical drug delivery systems. The aim of this study was to apply a quality by design approach to achieve predictable critical quality attributes of a microemulsion-based hydrogel formulation (MBH) contained itraconazole (ITZ). The control and response factors were determined based on a risk assessment with primary knowledge. Benzyl alcohol (x1), Cremophor® EL (x2), and Transcutol® P (x3) were screened out and selected as oil, surfactant, and co-surfactant, respectively. A D-optimal mixture design was used for optimizing the formulation with desirable characteristics. To obtain an optimal formulation, globule size was minimized, while viscosity and pH were in the range of 500–700 cps × 103 and pH 5–7, respectively. The optimal formulation was characterized by globule size, pH, rheological properties, in vitro permeability, and drug release simulation with a mathematical model. The optimal formulation was stable when stored at 40 °C/75% relative humidity and at ambient temperature for 6 months. Therefore, this study suggests that the optimized MBH formulation may present a better alternative over conventional ITZ delivery systems against superficial fungal infections.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Alam S, Iqbal Z, Ali A, Khar R, Ahmad F, Akhter S, Talegaonkar S (2009) Microemulsion as a potential transdermal carrier for poorly water soluble antifungal drug itraconazole. J Dispers Sci Technol 31:84–94

    Article  CAS  Google Scholar 

  • Basalious EB, Shawky N, Badr-Eldin SM (2010) SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: development and optimization. Int J Pharm 391:203–211

    Article  CAS  PubMed  Google Scholar 

  • Berner B, Wilson DR, Guy RH, Mazzenga GC, Clarke FH, Maibach HI (1988) The relationship of pK a and acute skin irritation in man. Pharm Res 5:660–663

    Article  CAS  PubMed  Google Scholar 

  • Berner B, Wilson DR, Steffens RJ, Mazzenga GC, Hinz R, Guy RH, Maibach HI (1990) The relationship between pKa and skin irritation for a series of basic penetrants in man. Toxicol Sci 15:760–766

    Article  CAS  Google Scholar 

  • Boddé HE, Joosten JG (1985) A mathematical model for drug release from a two-phase system to a perfect sink. Int J Pharm 26:57–76

    Article  Google Scholar 

  • Chamkha AJ, Rashad M, Subba Reddy Gorla R (2014) Non-similar solutions for mixed convection along a wedge embedded in a porous medium saturated by a non-Newtonian nanofluid: natural convection dominated regime. Int J Numer Methods Heat Fluid Flow 24:1471–1486

    Article  Google Scholar 

  • Charoo NA, Ali AA (2013) Quality risk management in pharmaceutical development. Drug Dev Ind Pharm 39:947–960

    Article  CAS  PubMed  Google Scholar 

  • Choi DH, Shin S, Viet Truong NK, Jeong SH (2012a) A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets. Drug Dev Ind Pharm 38:1117–1127

    Article  CAS  Google Scholar 

  • Choi YK, Poudel BK, Marasini N, Yang KY, Kim JW, Kim JO, Choi H-G, Yong CS (2012b) Enhanced solubility and oral bioavailability of itraconazole by combining membrane emulsification and spray drying technique. Int J Pharm 434:264–271

    Article  CAS  PubMed  Google Scholar 

  • Chudasama A, Patel V, Nivsarkar M, Vasu K, Shishoo C (2011) Investigation of microemulsion system for transdermal delivery of itraconazole. J Adv Pharm Technol Res 2:30–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Beule K, Van Gestel J (2001) Pharmacology of itraconazole. Drugs 61:27–37

    Article  PubMed  Google Scholar 

  • Fang JY, Tsai MJ, Huang YB, Wu PC, Tsai YH (1997) Percutaneous absorption and skin erythema: quantification of capsaicin and its synthetic derivatives from gels incorporated with benzalkonium chloride by using non-invasive bioengineering methods. Drug Dev Res 40:56–67

    Article  CAS  Google Scholar 

  • Fouad SA, Basalious EB, El-Nabarawi MA, Tayel SA (2013) Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: in vitro/in vivo evaluation. Int J Pharm 453:569–578

    Article  CAS  PubMed  Google Scholar 

  • Friedman D, Benita S (1987) A mathematical morel for drug release from 0/W emulsions: application to controlled release morphine emulsions. Drug Dev Ind Pharm 13:2067–2085

    Article  CAS  Google Scholar 

  • Gelderblom H, Verweij J, Nooter K, Sparreboom A (2001) Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 37:1590–1598

    Article  CAS  PubMed  Google Scholar 

  • Grassi M, Coceani N, Magarotto L (2000) Mathematical modeling of drug release from microemulsions: theory in comparison with experiments. J Colloid Interface Sci 228:141–150

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Jhawat V (2017) Quality by design (QbD) approach of pharmacogenomics in drug designing and formulation development for optimization of drug delivery systems. J Control Release 245:15–26

    Article  CAS  PubMed  Google Scholar 

  • Guy RH, Hadgraft J (1992) Rate control in transdermal drug delivery? Int J Pharm 82:R1–R6

    Article  Google Scholar 

  • Guy RH, Hadgraft J, Kellaway IW, Taylor M (1982) Calculations of drug release rates from particles. Int J Pharm 11:199–207

    Article  CAS  Google Scholar 

  • Hashiguchi T, Kodama A, Ryu A, Otagiri M (1998) Retention capacity of topical imidazole antifungal agents in the skin. Int J Pharm 161:195–204

    Article  CAS  Google Scholar 

  • Huang YB, Tsai YH, Yang WC, Chang JS, Wu PC, Takayama K (2004) Once-daily propranolol extended-release tablet dosage form: formulation design and in vitro/in vivo investigation. Eur J Pharm Biopharm 58:607–614

    Article  CAS  PubMed  Google Scholar 

  • Huang YB, Tsai YH, Lee SH, Chang JS, Wu PC (2005) Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology. Int J Pharm 289:87–95

    Article  CAS  PubMed  Google Scholar 

  • Hulbert MH, Feely LC, Inman EL, Johnson AD, Kearney AS, Michaels J, Mitchell M, Zour E (2008) Risk management in the pharmaceutical product development process. J Pharm Innov 3:227–248

    Article  Google Scholar 

  • Idrees M, Rahman N, Ahmad S, Ali M, Ahmad I (2011) Enhance transdermal delivery of flurbiprofen via microemulsions: effects of different types of surfactants and cosurfactants. DARU 19:433–439

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kincl M, Turk S, Vrečer F (2005) Application of experimental design methodology in development and optimization of drug release method. Int J Pharm 291:39–49

    Article  CAS  PubMed  Google Scholar 

  • Kumar N, Shishu (2015) D-optimal experimental approach for designing topical microemulsion of itraconazole: characterization and evaluation of antifungal efficacy against a standardized Tinea pedis infection model in Wistar rats. Eur J Pharm Sci 67:97–112

    Article  CAS  PubMed  Google Scholar 

  • Lambers H, Piessens S, Bloem A, Pronk H, Finkel P (2006) Natural skin surface pH is on average below 5, which is beneficial for its resident flora. Int J Cosmet Sci 28:359–370

    Article  CAS  PubMed  Google Scholar 

  • Lapasin R, Grassi M, Coceani N (2001) Effects of polymer addition on the rheology of o/w microemulsions. Rheol Acta 40:185–192

    Article  CAS  Google Scholar 

  • Lawrence MJ, Rees GD (2000) Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 45:89–121

    Article  CAS  PubMed  Google Scholar 

  • Le Dévédec F, Strandman S, Hildgen P, Leclair G, Zhu JX (2013) Pegylated bile acids for use in drug delivery systems: enhanced solubility and bioavailability of itraconazole. Mol Pharm 10:3057–3066

    Article  CAS  PubMed  Google Scholar 

  • Lestner JM, Roberts SA, Moore CB, Howard SJ, Denning DW, Hope WW (2009) Toxicodynamics of itraconazole: implications for therapeutic drug monitoring. Clin Infect Dis 49:928–930

    Article  CAS  PubMed  Google Scholar 

  • Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W (2005) Reduced oral itraconazole bioavailability by antacid suspension. J Clin Pharm Ther 30:201–206

    Article  CAS  PubMed  Google Scholar 

  • Murphy M, Carmichael AJ (2000) Transdermal drug delivery systems and skin sensitivity reactions. Am J Clin Dermatol 1:361–368

    Article  CAS  PubMed  Google Scholar 

  • Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen T, Urtti A (2003) Microemulsions for topical delivery of estradiol. Int J Pharm 254:99–107

    Article  CAS  PubMed  Google Scholar 

  • Pena LE, Lee BL, Stearns JF (1994) Structural rheology of a model ointment. Pharm Res 11:875–881

    Article  CAS  PubMed  Google Scholar 

  • Pereira-Lachataignerais J, Pons R, Panizza P, Courbin L, Rouch J, Lopez O (2006) Study and formation of vesicle systems with low polydispersity index by ultrasound method. Chem Phys Lipids 140:88–97

    Article  CAS  PubMed  Google Scholar 

  • Rambali B, Verreck G, Baert L, Massart D (2003) Itraconazole formulation studies of the melt-extrusion process with mixture design. Drug Dev Ind Pharm 29:641–652

    Article  CAS  PubMed  Google Scholar 

  • Rhee YS, Park CW, Nam TY, Shin YS, Chi SC, Park ES (2007) Formulation of parenteral microemulsion containing itraconazole. Arch Pharmacal Res 30:114–123

    Article  CAS  Google Scholar 

  • Saari TI, Grönlund J, Hagelberg NM, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT (2010) Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 66:387–397

    Article  CAS  PubMed  Google Scholar 

  • Shah RR, Magdum CS, Wadkar KA, Naikwade NS (2009) Fluconazole topical microemulsion: preparation and evaluation. Res J Pharm Technol 2:353–357

    CAS  Google Scholar 

  • Sirotti C, Coceani N, Colombo I, Lapasin R, Grassi M (2002) Modeling of drug release from microemulsions: a peculiar case. J Membr Sci 204:401–412

    Article  CAS  Google Scholar 

  • Tang J, Wei H, Liu H, Ji H, Dong D, Zhu D, Wu L (2010) Pharmacokinetics and biodistribution of itraconazole in rats and mice following intravenous administration in a novel liposome formulation. Drug Deliv 17:223–230

    Article  CAS  PubMed  Google Scholar 

  • Tenjarla S (1999) Microemulsions: an overview and pharmaceutical applications. Crit Rev Ther Drug Carr Syst 16:62

    Article  Google Scholar 

  • Trey SM, Wicks DA, Mididoddi PK, Repka MA (2007) Delivery of itraconazole from extruded HPC films. Drug Dev Ind Pharm 33:727–735

    Article  CAS  PubMed  Google Scholar 

  • Valenta C, Schultz K (2004) Influence of carrageenan on the rheology and skin permeation of microemulsion formulations. J Control Release 95:257–265

    Article  CAS  PubMed  Google Scholar 

  • Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA (2008) Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Intect Dis 46:327–360

    Article  CAS  Google Scholar 

  • Walters KA, Walker M, Olejnik O (1988) Non-ionic surfactant effects on hairless mouse skin permeability characteristics. J Pharm Pharmacol 40:525–529

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Xue M, Gu J, Fang X, Sha X (2012) Transdermal microemulsion drug delivery system for impairing male reproductive toxicity and enhancing efficacy of Tripterygium Wilfordii Hook f. Fitoterapia 83:690–698

    Article  CAS  PubMed  Google Scholar 

  • Washington C (1990) Drug release from microdisperse systems: a critical review. Int J Pharm 58:1–12

    Article  CAS  Google Scholar 

  • Washington C, Evans K (1995) Release rate measurements of model hydrophobic solutes from submicron triglyceride emulsions. J Control Release 33:383–390

    Article  CAS  Google Scholar 

  • Xi J, Chang Q, Chan CK, Meng ZY, Wang GN, Sun JB, Wang YT, Tong HH, Zheng Y (2009) Formulation development and bioavailability evaluation of a self-nanoemulsified drug delivery system of oleanolic acid. AAPS PharmSciTech 10:172–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu LX (2008) Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res 25:781–791

    Article  CAS  Google Scholar 

  • Zhu W, Yu A, Wang W, Dong R, Wu J, Zhai G (2008) Formulation design of microemulsion for dermal delivery of penciclovir. Int J Pharm 360:184–190

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Guo C, Yu A, Gao Y, Cao F, Zhai G (2009) Microemulsion-based hydrogel formulation of penciclovir for topical delivery. Int J Pharm 378:152–158

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors report no conflicts of interest. This work was supported by the Technology Innovation Program (Project No. SA112810) funded by the Small & Medium Business Administration (SMBA), Korea and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03931513).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Engineering, Inje University, Gimhae, 621-749, Republic of Korea

    Du Hyung Choi

  2. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi, Republic of Korea

    Yun-Sik Kim

  3. College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea

    Dae-Duk Kim

  4. College of Pharmacy, Dongguk University-Seoul, Donggukro 32, Ilsandonggu, Goyang, Gyeonggi, 410-820, Republic of Korea

    Seong Hoon Jeong

Authors
  1. Du Hyung Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Sik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dae-Duk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seong Hoon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seong Hoon Jeong.

Additional information

Du Hyung Choi and Yun-Sik Kim have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, D.H., Kim, YS., Kim, DD. et al. QbD based development and evaluation of topical microemulsion-based hydrogel against superficial fungal infections. J. Pharm. Investig. 49, 87–103 (2019). https://doi.org/10.1007/s40005-018-0386-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-018-0386-4

Keywords

Search

Navigation