Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of Dose-Response Relationship of Permeation Enhancer Isopropyl Myristate Release on Drug Release: Release Enhancement Efficiency and Molecular Mechanism

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The objective of this study is to investigate the dose-response relationship between various concentrations of permeation enhancers (PEs) and their ability to enhance drug release from a polymer matrix, utilizing an innovative parameter known as release enhancement efficiency (K). Additionally, the molecular mechanism underlying dynamic enhancement was also examined. Isopropyl myristate (IPM) was used as model enhancer and zolmitriptan (ZOL) was used as model drug to investigate dose-effect relationship in pressure sensitive adhesives (PSA). The release behavior of the PEs was determined by LC-MS/MS and verified by confocal laser scanning microscopy (CLSM). The enhancing effect of the PE on ZOL release was evaluated through in vitro release experiments and further validated by pharmacokinetics study. And the molecular mechanism was characterized with thermal analysis (DSC), Fourier transform infrared spectroscopy (FT-IR) and molecular dynamics simulation. K was 0.156, 0.286 and 0.279 at 3%, 6% and 9% IPM concentrations, indicating that the enhancement efficiency reached the maximum when the 6% IPM was applied. According to the mechanism research results, the fluidity of PSA increased linearly with the increase of IPM concentrations, but the interaction between IPM and ZOL reached its strongest point at 6%. In summary, the increase of K value (from 0 to 6% IPM content) was caused by the synergy of increased mobility of PSA and interaction (dipole-dipole and hydrogen-bond) among three components, and when the above two actions were in antagonistic, K no longer increased (6–9% IPM content).

Graphical abstract

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

PEs:

Permeation enhancers

K :

Release enhancement efficiency

IPM:

Isopropyl myristate

ZOL:

Zolmitriptan

PSA:

Pressure sensitive adhesive

CLSM:

Confocal laser scanning microscopy

FT-IR:

Fourier transform infrared spectroscopy

DSC:

Differential scanning calorimetry

MD:

Molecular dynamic

References

  1. Chen W, Li H, Shi D, Liu Z, Yuan W. Microneedles as a delivery system for gene therapy. Front Pharmacol. 2016;7:137.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wu HW, Liu C, Wang X, Zhang L, Yuan W, Zheng JW, Su LX, Fan XD. Topical application of 0.5% timolol maleate hydrogel for the treatment of superficial infantile hemangioma. Front. Oncol. 2017;7:137.

    Google Scholar 

  3. Alfrd MGA, Tagumirwa MC. Asiatic acid-pectin hydrogel matrix patch transdermal delivery system influences parasitaemia suppression and inflammation reduction in P berghei murine malaria infected Sprague-Dawley rats. Asian Pac J Trop Med. 2016;9:1172–80.

    Article  Google Scholar 

  4. Phatale V, Vaiphei KK, Jha S, Patil D, Agrawal M, Alexander A. Overcoming skin barriers through advanced transdermal drug delivery approaches. J Control Release. 2022;351:361–80.

    Article  CAS  PubMed  Google Scholar 

  5. Kováčik A, Kopečná M, Vávrová K. Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin Drug Deliv. 2020;17:145–55.

    Article  PubMed  Google Scholar 

  6. Maurya A, Rangappa S, Bae J, Dhawan T, Ajjarapu SS, Murthy SN. Evaluation of soluble fentanyl microneedles for loco-regional anti-nociceptive activity. Int J Pharm. 2019;564:485–91.

    Article  CAS  PubMed  Google Scholar 

  7. Haque T, Talukder MMU. Chemical enhancer: a simplistic way to modulate barrier function of the stratum corneum. Adv Pharm Bull. 2018;8:169–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ibrahim SA, Li SK. Effects of chemical enhancers on human epidermal membrane: structure-enhancement relationship based on maximum enhancement (E(max)). J Pharm Sci. 2009;98:926–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang Z, Xue Y, Zhu Z, Hu Y, Zeng Q, Wu Y, Wang Y, Shen C, Jiang C, Liu L, Zhu H, Liu Q. Quantitative structure-activity relationship of enhancers of Licochalcone A and Glabridin release and permeation enhancement from carbomer hydrogel. Pharmaceutics. 2022;14:262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ruan S, Wang Z, Xiang S, et al. Mechanisms of white mustard seed (Sinapis alba L.) volatile oils as transdermal penetration enhancers. Fitoterapia. 2019;138:104195.

    Article  CAS  PubMed  Google Scholar 

  11. Patel NA, Patel NJ, Patel RP. Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug. Drug Dev Ind Pharm. 2009;35:234–42.

    Article  CAS  PubMed  Google Scholar 

  12. Liu C, Guan Y, Tian Q, Shi X, Fang L. Transdermal enhancement strategy of ketoprofen and teriflunomide: the effect of enhanced drug-drug intermolecular interaction by permeation enhancer on drug release of compound transdermal patch. Int J Pharm. 2019;572:118800.

    Article  CAS  PubMed  Google Scholar 

  13. Xu W, Liu C, Zhang Y, Quan P, Yang D, Fang L. An investigation on the effect of drug physicochemical properties on the enhancement strength of enhancer: the role of drug-skin-enhancer interactions. Int J Pharm. 2021;607:120945.

    Article  CAS  PubMed  Google Scholar 

  14. Kaushik D, Batheja P, Kilfoyle B, Rai V, Michniak-Kohn B. Percutaneous permeation modifiers: enhancement versus retardation. Expert Opin Drug Deliv. 2008;5:517–29.

    Article  CAS  PubMed  Google Scholar 

  15. Ibrahim SA, Li SK. Efficiency of fatty acids as chemical penetration enhancers: mechanisms and structure enhancement relationship. Pharm Res. 2010;27:115–25.

    Article  CAS  PubMed  Google Scholar 

  16. Romero EL, Morilla MJ. Highly deformable and highly fluid vesicles as potential drug delivery systems: theoretical and practical considerations. Int J Nanomedicine. 2013;8:3171–86.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Shen M, Liu C, Wan X, Farah N, Fang L. Development of a daphnetin transdermal patch using chemical enhancer strategy: insights of the enhancement effect of Transcutol P and the assessment of pharmacodynamics. Drug Dev Ind Pharm. 2018;44:1642–9.

    Article  CAS  PubMed  Google Scholar 

  18. Song W, Quan P, Li S, Liu C, Lv S, Zhao Y, Fang L. Probing the role of chemical enhancers in facilitating drug release from patches: mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis. J Control Release. 2016;227:13–22.

    Article  CAS  PubMed  Google Scholar 

  19. Budd PM, Mckeown NB, Fritsch D. Free volume and intrinsic microporosity in polymers. J. Mater Chem. 2005;15(20):1977–86.

    Article  CAS  Google Scholar 

  20. Li N, Quan P, Wan X, Liu C, Liu X, Fang L. Mechanistic insights of the enhancement effect of sorbitan monooleate on olanzapine transdermal patch both in release and percutaneous absorption processes. Eur J Pharm Sci. 2017;107:138–47.

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Wang W, Liu C, Luo Z, Wan X, Fang L. Investigation of molecular mobility of pressure-sensitive-adhesive in oxybutynin patch in vitro and in vivo: effect of sorbitan monooleate on drug release and patch mechanical property. Eur J Pharm Sci. 2018;122:116–24.

    Article  CAS  PubMed  Google Scholar 

  22. Arun G, Shweta P, Upendra KJ. Formulation and evaluation of ternary solid dispersion of curcumin. Int. J. Pharm. Pharm. Sci. 2012;4:360–5.

    CAS  Google Scholar 

  23. Sarode AL, Sandhu H, Shah N, Malick W, Zia H. Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation. Eur J Pharm Sci. 2013;48:371–84.

    Article  CAS  PubMed  Google Scholar 

  24. Xiang TX, Anderson BD. Effects of molecular interactions on miscibility and mobility of ibuprofen in amorphous solid dispersions with various polymers. J Pharm Sci. 2019;108:178–86.

    Article  CAS  PubMed  Google Scholar 

  25. Liu C, Fang L. Drug in adhesive patch of zolmitriptan: formulation and in vitro/in vivo correlation. AAPS PharmSciTech. 2015;16:1245-1253.

  26. Luo Z, Liu C, Quan P, Zhang Y, Fang L. Effect of chemical penetration enhancer-adhesive interaction on drug release from transdermal patch: mechanism study based on FT-IR spectroscopy, 13C NMR spectroscopy, and molecular simulation. AAPS PharmSciTech. 2021;22:198.

    Article  CAS  PubMed  Google Scholar 

  27. Shteinikov VY, Barygin OI, Gmiro VE, Tikhonov DB. Multiple modes of action of hydrophobic amines and their guanidine analogues on ASIC1a. Eur J Pharmacol. 2019;844:183–94.

    Article  CAS  PubMed  Google Scholar 

  28. Evlanenkov KK, Komarova MS, Dron MY, Nikolaev MV, Zhukovskaya ON, Gurova NA, Tikhonov DB. Derivatives of 2-aminobenzimidazole potentiate ASIC open state with slow kinetics of activation and desensitization. Front Physiol. 2023;14:1018551.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Al Sulaiman D, Chang JYH, Bennett NR, et al. Hydrogel-coated microneedle arrays for minimally invasive sampling and sensing of specific circulating nucleic acids from skin interstitial fluid. ACS Nano. 2019;13:9620–8.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bhujbal SS, Hadawale SS, Kulkarni PA, Bidkar JS, Thatte VA, Providencia CA, Yeola RR. A novel herbal formulation in the management of diabetes. Int J Pharm Investig. 2011;1:222–6.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Srinivasu MK, Rao BM, Sridhar G, Kumar PR, Chandrasekhar KB, Islam A. A validated chiral LC method for the determination of zolmitriptan and its potential impurities. J Pharm Biomed Anal. 2005;37:453–60.

    Article  CAS  PubMed  Google Scholar 

  32. Chen J, Jiang XG, Jiang WM, Mei N, Gao XL, Zhang QZ. High-performance liquid chromatographic analysis of zolmitriptan in human plasma using fluorescence detection. J Pharm Biomed Anal. 2004;35:639–45.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang ZJ, Osmałek T, Michniak-Kohn B. Deformable liposomal hydrogel for dermal and transdermal delivery of Meloxicam. Int J Nanomedicine. 2020;15:9319–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dai X, Gu Y, Guo J, Huang L, Cheng G, Peng D, Hao H. Clinical breakpoint of apramycin to swine Salmonella and its effect on Ileum Flora. Int J Mol Sci. 2022;23:1424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang D, Liu C, Quan P, Fang L. A systematic approach to determination of permeation enhancer action efficacy and sites: molecular mechanism investigated by quantitative structure-activity relationship. J Control Release. 2020;322:1–12.

    Article  CAS  PubMed  Google Scholar 

  36. Lv C, Wang Z, Wang P, Tang X. Photodegradable polyesters for triggered release. Int J Mol Sci. 2012;13:16387–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Youssouf L, Bhaw-Luximon A, Diotel N, Catan A, Giraud P, Gimié F, Koshel D, Casale S, Bénard S, Meneyrol V, Lallemand L, Meilhac O, Lefebvre D'Hellencourt C, Jhurry D, Couprie J. Enhanced effects of curcumin encapsulated in polycaprolactone-grafted oligocarrageenan nanomicelles, a novel nanoparticle drug delivery system. Carbohydr Polym. 2019;217:35–45.

    Article  CAS  PubMed  Google Scholar 

  38. Barth JH, Field HP, Yasmin E, Balen AH. Defining hyperandrogenism in polycystic ovary syndrome: measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots. Eur J Endocrinol. 2010;162:611–5.

    Article  CAS  PubMed  Google Scholar 

  39. Dei Cas M, Zulueta A, Mingione A, Caretti A, Ghidoni R, Signorelli P, Paroni R. An innovative lipidomic workflow to investigate the lipid profile in a cystic fibrosis cell line. Cells. 2020;9:1197.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Chen J, Jiang XG, Jiang WM, Mei N, Gao XL, Zhang QZ. High-performance liquid chromatographic analysis of zolmitriptan in human plasma using fluorescence detection. J Pharm Biomed Anal. 2004;35:639–45.

    Article  CAS  PubMed  Google Scholar 

  41. Ma Y, Zhu J, He H, Yuan P, Shen W, Liu D. Infrared investigation of organo-montmorillonites prepared from different surfactants. Spectrochim Acta A Mol Biomol Spectrosc. 2010;76(2):122–9.

    Article  ADS  PubMed  Google Scholar 

  42. Plazzer MB, Henry DJ, Yiapanis G, Yarovsky I. Comparative study of commonly used molecular dynamics force fields for modeling organic monolayers on water. J Phys Chem B. 2011;115:3964–71.

    Article  CAS  PubMed  Google Scholar 

  43. Kowsari MH, Alavi S, Ashrafizaadeh M, Najafi B. Molecular dynamics simulation of imidazolium-based ionic liquids. I. Dynamics and diffusion coefficient. J Chem Phys. 2008;129(22):224508.

    Article  ADS  CAS  PubMed  Google Scholar 

  44. Siepmann J, Siepmann F. Mathematical modeling of drug delivery. Int J Pharm. 2008;364(2):328–43.

    Article  CAS  PubMed  Google Scholar 

  45. Guy RH, Hadgraft J. Rate control in transdermal drug delivery? Int. J. Pharm. 1992;82:R1–6.

    Article  Google Scholar 

  46. Drogoń A, Skotnicki M, Skotnicka A, Pyda M. Physical ageing of amorphous indapamide characterised by differential scanning calorimetry. Pharmaceutics. 2020;12(9):800.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Jeong YI, Kim DH, Chung CW, Yoo JJ, Choi KH, Kim CH, Ha SH, Kang DH. Doxorubicin-incorporated polymeric micelles composed of dextran-b-poly(DL-lactide-co-glycolide) copolymer. Int J Nanomedicine. 2011;6:1415–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang Y, Snee RD, Keyvan G, Muzzio FJ. Statistical comparison of dissolution profiles. Drug Dev Ind Pharm. 2016;42:796–807.

    Article  PubMed  Google Scholar 

  49. Zhang H, Du X, Tang Y, Lu X, Zhou L, Zheng C, Lin H, Tao S. Introducing trifluoromethyl to strengthen hydrogen bond for high efficiency organic solar cells. Front Chem. 2020 Mar;24(8):190.

    Article  ADS  Google Scholar 

  50. Li C, Stracha A. Cohesive energy density and solubility parameter evolution during the curing of thermoset. Polymer. 2018;135:162–70.

    Article  CAS  Google Scholar 

  51. Lu Y, Shu Y, Liu N, Lu X, Xu M. Molecular dynamics simulations on ε-CL-20-based PBXs with added GAP and its derivative polymers. RSC Adv. 2018;8:4955–62.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bae JH, Won JC, Lim WB, Kim BJ, Lee JH, Min JG, Seo MJ, Mo YH, Huh PH. Tacky-free polyurethanes pressure-sensitive adhesives by molecular-weight and HDI trimer design. Materials (Basel). 2021;14:2164.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wolff HM, Irsan DK. Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films. Pharm Res. 2014;31:2186–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yasunori M, Takemasa K, Kenji S. Diffusion of drugs in acrylic-type pressure-sensitive adhesive matrix. II. Influence of interaction. J. Control. Release. 1992;18:113–21.

    Article  Google Scholar 

Download references

Funding

This work was financially supported by the Guangzhou Municipal Science and Technology Bureau, The Project of Basic and Applied Basic Research Jointly Funded by Municipality and University (Hospital) (Fund No. 2023A03J0345).

Author information

Authors and Affiliations

  1. School of Pharmacy, Chengdu Medical College, 783 Xindu Avenue, Chengdu, 610500, Sichuan, China

    Jiuheng Ruan & Jinye Tang

  2. The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Sida Liao

  3. Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, China

    Liang Fang

Authors
  1. Jiuheng Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sida Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinye Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jiuheng Ruan: Conceptualization, Methodology, Writing—review & editing, Supervision, Project administration. Sida Liao: Writing original draft, Formal analysis, Validation. Jinye Tang: Project administration. Liang Fang: Writing—review & editing.

Corresponding author

Correspondence to Jiuheng Ruan.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 1300 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruan, J., Liao, S., Tang, J. et al. Evaluation of Dose-Response Relationship of Permeation Enhancer Isopropyl Myristate Release on Drug Release: Release Enhancement Efficiency and Molecular Mechanism. AAPS PharmSciTech 25, 1 (2024). https://doi.org/10.1208/s12249-023-02713-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02713-6

Keywords

Search

Navigation