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Transdermal Delivery of the Free Base of 3-Fluoroamphetamine: In Vitro Skin Permeation and Irritation Potential

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Abstract

This work aimed to continue our effort in establishing the feasibility of 3-fluoroamphetamine (also known as PAL-353) to be a transdermal drug candidate by studying the delivery of the base form through the human cadaver skin in lieu of the previously investigated salt form, and for the first time using an EPIDERM™–reconstructed human epidermal model to predict the skin irritation potential of PAL-353, in support of development for a matrix-type transdermal delivery system. Passive and enhanced (with chemical permeation enhancers) transdermal delivery were investigated via in vitro permeation studies that were performed on Franz diffusion cells with dermatomed human cadaver skin. After 24 h, PAL-353 free base revealed high passive permeation of 417.49 ± 30.12, 1577.68 ± 165.41, and 4295.16 ± 264.36 μg/cm2, with applied formulation concentrations of 5.5 (F1), 20 (F2), and 40 (F3) mg/mL, respectively. Oleyl alcohol produced an approximately threefold steady-state flux enhancement at 5% or 10% w/w but may not be needed as the free base alone provided therapeutically relevant permeation. Further, it was predicted that therapeutically relevant delivery would be unlikely to cause skin irritation using the EPIDERM™–reconstructed human epidermal model. In conclusion, the present study further supported the development of PAL-353 transdermal delivery systems.

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Abbreviations

HPLC:

High-performance liquid chromatography

UV:

Ultraviolet

FDA:

Food and Drug Administration

LOD:

Limit of detection

LOQ:

Limit of quantification

ICH:

The International Council for Harmonization

PBS:

Phosphate buffered saline

PG:

Propylene glycol

CPE:

Chemical permeation enhancer

MTT:

Methyl thiazolyl tetrazoilim

References

  1. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL. Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther. 2005;313(2):848–54.

    CAS  PubMed  Google Scholar 

  2. Wellman PJ, Davis KW, Clifford PS, Rothman RB, Blough BE. Changes in feeding and locomotion induced by amphetamine analogs in rats. Drug Alcohol Depend. 2009;100(3):234–9.

    CAS  PubMed  Google Scholar 

  3. Banks ML, Blough BE, Negus SS. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys. Behav Pharmacol. 2011;22(8):824–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Negus SS, Baumann MH, Rothman RB, Mello NK, Blough BE. Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine. J Pharmacol Exp Ther. 2009;329(1):272–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Negus SS, Mello NK. Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys. Drug Alcohol Depend. 2003;70(1):39–52.

    CAS  PubMed  Google Scholar 

  6. Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology. 2013;38(13):2698–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Grabowski J, Shearer J, Merrill J, Negus SS. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav. 2004;29(7):1439–64.

    PubMed  Google Scholar 

  8. Negus SS, Henningfield J. Agonist medications for the treatment of cocaine use disorder. Neuropsychopharmacology. 2015;40(8):1815–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jiang Y, Murnane KS, Bhattaccharjee SA, Blough BE, Banga AK. Skin delivery and irritation potential of phenmetrazine as a candidate transdermal formulation for repurposed indications. AAPS J. 2019;21(4):70.

    PubMed  Google Scholar 

  10. Ganti SS, Bhattaccharjee SA, Murnane KS, Blough BE, Banga AK. Formulation and evaluation of 4-benzylpiperidine drug-in-adhesive matrix type transdermal patch. Int J Pharm. 2018;550(1–2):71–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ganti SS, Nguyen HX, Murnane KS, Blough BE, Banga AK. Transdermal formulation of 4-benzylpiperidine for cocaine-use disorder. J Drug Deliv Sci Technol. 2018;47:299–308.

    CAS  Google Scholar 

  12. Isaac M, Holvey C. Transdermal patches: the emerging mode of drug delivery system in psychiatry. Ther Adv Psychopharmacol. 2012;2(6):255–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Volkow ND, Swanson JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry. 2003 Nov;160(11):1909–18.

    PubMed  Google Scholar 

  14. de Wit H, Bodker B, Ambre J. Rate of increase of plasma drug level influences subjective response in humans. Psychopharmacology. 1992;107(2–3):352–8.

    PubMed  Google Scholar 

  15. Ritz MC, Kuhar MJ. Relationship between self-administration of amphetamine and monoamine receptors in brain: comparison with cocaine. J Pharmacol Exp Ther. 1989;248(3):1010–7.

    CAS  PubMed  Google Scholar 

  16. Murnane KS, Winschel J, Schmidt KT, Stewart LM, Rose SJ, Cheng K, et al. Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates. J Neurosci. 2013;33(33):13367–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Murnane KS, Andersen ML, Rice KC, Howell LL. Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res. 2013;22(5):581–8.

    PubMed  Google Scholar 

  18. Howell LL, Murnane KS. Nonhuman primate neuroimaging and the neurobiology of psychostimulant addiction. Ann N Y Acad Sci 2008;1141(1):176–194.

  19. Puri A, Murnane KS, Blough BE, Banga AK. Effects of chemical and physical enhancement techniques on transdermal delivery of 3-fluoroamphetamine hydrochloride. Int J Pharm. 2017;528(1–2):452–62.

    CAS  PubMed  Google Scholar 

  20. Gasior M, Bond M, Malamut R. Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations. Postgrad Med. 2016;128(1):85–96.

    PubMed  Google Scholar 

  21. Mastropietro DJ, Omidian H. Current approaches in tamper-resistant and abuse-deterrent formulations. Drug Dev Ind Pharm. 2013;39(5):611–24.

    CAS  PubMed  Google Scholar 

  22. Song Y, Manian M, Fowler W, Korey A, Banga AK. Activated carbon-based system for the disposal of psychoactive medications. Pharmaceutics. 2016;8(4):31.

    PubMed Central  Google Scholar 

  23. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56(5):603–18.

    CAS  PubMed  Google Scholar 

  24. Ibrahim SA, Li SK. Efficiency of fatty acids as chemical penetration enhancers: mechanisms and structure enhancement relationship. Pharm Res. 2010;27(1):115–25.

    CAS  PubMed  Google Scholar 

  25. Naik A, Pechtold LARMRM, Potts RO, Guy RH. Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans. J Control Release. 1995;37(3):299–306.

    CAS  Google Scholar 

  26. Cooper ER. Increased skin permeability for lipophilic molecules. J Pharm Sci. 1984;73(8):1153–6.

    CAS  PubMed  Google Scholar 

  27. Gao S, Singh J. Effect of oleic acid/ethanol and oleic acid/propylene glycol on the in vitro percutaneous absorption of 5-fluorouracil and tamoxifen and the macroscopic barrier property of porcine epidermis. Int J Pharm. 1998;165(1):45–55.

    CAS  Google Scholar 

  28. Francoeur ML, Golden GM, Potts RO. Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery. Pharm Res An Off J Am Assoc Pharm Sci. 1990;7(6):621–7.

    CAS  Google Scholar 

  29. Kalluri H, Banga AK. Transdermal delivery of proteins. AAPS PharmSciTech. 2011;12(1):431–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Banga AK. Transdermal and intradermal delivery of therapeutic agents: application of physical technologies. Boca Raton, Florida: CRC press; 2011.

    Google Scholar 

  31. Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol. 1983;80(s6):44s–9s.

    CAS  PubMed  Google Scholar 

  32. Approved drug products with therapeutic equivalence evaluations (orange book) | FDA [Internet]. [cited 2019 Jun 16]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

  33. Bukstein OG. Transdermal methylphenidate system: old wine in a new bottle. Expert Opin Drug Metab Toxicol. 2009;5(6):661–5.

    CAS  PubMed  Google Scholar 

  34. Zakeri-Milani P, Islambulchilar Z, Majidpour F, Jannatabadi E, Lotfpour F, Valizadeh H. A study on enhanced intestinal permeability of clarithromycin nanoparticles. Brazilian J Pharm Sci. 2014;50(1):121–9.

    CAS  Google Scholar 

  35. Murthy SN, Sen A, Zhao Y-L, Hui SW. pH influences the postpulse permeability state of skin after electroporation. J Control Release. 2003;93(1):49–57.

    CAS  PubMed  Google Scholar 

  36. Bakshi P, Jiang Y, Nakata T, Akaki J, Matsuoka N, Banga AK. Formulation development and characterization of nanoemulsion-based formulation for topical delivery of heparinoid. J Pharm Sci. 2018;107(11):2883–90.

    CAS  PubMed  Google Scholar 

  37. Jiang Y, Ray A, Junaid MSA, Bhattaccharjee SA, Kelley K, Banga AK, et al. The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration. Drug Deliv Transl Res. 2019:1–11.

  38. Davies DJ, Ward RJ, Heylings JR. Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. Toxicol Vitr. 2004;18(3):351–8.

    CAS  Google Scholar 

  39. Southwell D, Barry BW, Woodford R. Variations in permeability of human skin within and between specimens. Int J Pharm. 1984;18(3):299–309.

    CAS  Google Scholar 

  40. Test No. 439: In vitro skin irritation - reconstructed human epidermis test method. OECD; 2013. (OECD Guidelines for the Testing of Chemicals, Section 4).

  41. Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, et al. Skin models for the testing of transdermal drugs. Clin Pharmacol Adv Appl. 2016;8:163–76.

    CAS  Google Scholar 

  42. Squillante E, Needham T, Maniar A, Kislalioglu S, Zia H. Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin. Baseline. 1998;46:265–71.

    CAS  Google Scholar 

  43. Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release. 2014;190:150–6.

    CAS  PubMed  Google Scholar 

  44. Johnson ME, Mitragotri S, Patel A, Blankschtein D, Langer R. Synergistic effects of chemical enhancers and therapeutic ultrasound on transdermal drug delivery. J Pharm Sci. 1996;85(7):670–9.

    CAS  PubMed  Google Scholar 

  45. Mitragotri S, Johnson ME, Blankschtein D, Langer R. An analysis of the size selectivity of solute partitioning, diffusion, and permeation across lipid bilayers. Biophys J. 1999;77(3):1268–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mitragotri S. Effect of bilayer disruption on transdermal transport of low-molecular weight hydrophobic solutes. Pharm Res. 2001;18(7):1018–23.

    CAS  PubMed  Google Scholar 

  47. Lee PJ, Ahmad N, Langer R, Mitragotri S, Prasad SV. Evaluation of chemical enhancers in the transdermal delivery of lidocaine. Int J Pharm. 2006;308(1–2):33–9.

    CAS  PubMed  Google Scholar 

  48. Transdermal drug delivery systems: the skinny on cutaneous reactions [Internet]. [cited 2019 Oct 14]. Available from: https://www.pharmacytimes.com/publications/issue/2013/may2013/transdermal-drug-delivery-systems-the-skinny-on-cutaneous-reactions

  49. Manian M, Madrasi K, Chaturvedula A, Banga AK. Investigation of the dermal absorption and irritation potential of sertaconazole nitrate anhydrous gel. Pharmaceutics. 2016;

  50. Sivaraman A, Ganti SS, Nguyen HX, Birk G, Wieber A, Lubda D, et al. Development and evaluation of a polyvinyl alcohol based topical gel. J Drug Deliv Sci Technol. 2017;39:210–6.

    CAS  Google Scholar 

  51. Gao X, Patel MG, Bakshi P, Sharma D, Banga AK. Enhancement in the transdermal and localized delivery of Honokiol through breast tissue. AAPS PharmSciTech. 2018;19(8):3501–11.

    CAS  PubMed  Google Scholar 

  52. Romita P, Foti C, Calogiuri G, Cantore S, Ballini A, Dipalma G, et al. Contact dermatitis due to transdermal therapeutic systems: a clinical update. Acta Bio Medica Atenei Parm. 2019;90(1):5–10.

    Google Scholar 

  53. Ananthapadmanabhan KP, Lips A, Vincent C, Meyer F, Caso S, Johnson A, et al. pH-induced alterations in stratum corneum properties. Int J Cosmet Sci. 2003;25(3):103–12.

    CAS  PubMed  Google Scholar 

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Funding

The current project was funded by grant # GRA.VL17.11 (Murnane and Banga—Multiple Principal Investigators) by Georgia Research Alliance based in Atlanta, Georgia, and by grant # DA12970 (Blough—Principal Investigator) by the National Institute on Drug Abuse.

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Authors and Affiliations

  1. Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, Georgia, USA

    Ying Jiang, Kevin S. Murnane & Ajay K. Banga

  2. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, Durham, North Carolina, USA

    Bruce E. Blough

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  1. Ying Jiang
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  2. Kevin S. Murnane
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  4. Ajay K. Banga
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Correspondence to Ajay K. Banga.

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Jiang, Y., Murnane, K.S., Blough, B.E. et al. Transdermal Delivery of the Free Base of 3-Fluoroamphetamine: In Vitro Skin Permeation and Irritation Potential. AAPS PharmSciTech 21, 109 (2020). https://doi.org/10.1208/s12249-020-01649-5

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