Skip to main content

Advertisement

SpringerLink
Log in

Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Phenmetrazine, a selective dopamine and norepinephrine releaser, previously available as an oral anorectic, is prone to be abused. This study aimed to assess the feasibility of delivering phenmetrazine via the transdermal route for a new indication, while also minimizing its abuse potential. The passive permeation of phenmetrazine through dermatomed human cadaver skin was evaluated using static Franz diffusion cells at 10 mg/mL for the fumarate salt, and at 20, 40, and 80 mg/mL for the free base in propylene glycol for 24 h. Further, oleic acid (5% w/w), oleyl alcohol (5% and 10% w/w), and lauric acid (10% w/w) were investigated as chemical permeation enhancers to enhance the delivery. Skin irritation potential was assessed using EpiDerm™ in vitro reconstructed human epidermal model. The free base showed superior 24-h delivery (8.13 ± 4.07%, 10.6 ± 2.5%, and 10.4 ± 1.4% for groups with 20, 40, and 80 mg/mL of the free base, respectively) to phenmetrazine fumarate salt (undetectable). The successful screening of effective chemical enhancers, oleyl alcohol (5% and 10% w/w), oleic acid (5% w/w), and lauric acid (10% w/w) resulted in significant enhancement of delivery. The calculated therapeutic relevant flux for the potential indication, attention deficit hyperactivity disorder, 20 μg/cm2/h was met, where a 24-mg daily dose from a 50-cm2 patch was projected to be delivered to a 60-kg individual. Irritation study results suggest that formulations with therapeutically relevant delivery are likely to be non-irritant. In conclusion, it is feasible to deliver therapeutically relevant amounts of phenmetrazine via the transdermal route.

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

References

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

    Article  CAS  Google Scholar 

  2. McColl S, Sellers EM. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Depend. 2006;83(SUPPL. 1):52–62.

    Article  Google Scholar 

  3. Rothman R, Baumann M. Therapeutic potential of monoamine transporter substrates. Curr Top Med Chem. 2006;6(17):1845–59.

    Article  CAS  Google Scholar 

  4. Malenka RC, Nestler EJ, Hyman SE. Higher cognitive function and behavioral control. In: Sydor A, Brown RY, editors. Molecular neuropharmacology: A foundation for clinical neuroscience, 2nd ed. New York: McGraw-Hill Medical; 2009. p. 318. 

  5. Ressler C. Treatment of obesity with phenmetrazine hydrochloride, a new anorexiant. J Am Med Assoc. 1957;165(2):135–8.

    Article  CAS  Google Scholar 

  6. Evans J. Psychosis and addiction to phenmetrazine (preludin). Lancet. 1959;2(7095):152–5.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present - a pharmacological and clinical perspective. J Psychopharmacol. 2013;27(6):479–96.

    Article  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. Bolin BL, Stoops WW, Sites JP, Rush CR. Abuse potential of oral phendimetrazine in cocaine-dependent individuals: implications for agonist-like replacement therapy. J Addict Med. 2016;10(3):156–65.

    Article  CAS  Google Scholar 

  11. 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. 

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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. 

    Article  CAS  Google Scholar 

  14. Yener G, Gönüllü Ü, Üner M, Deǧim T, Araman A. Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of celecoxib through human skin. Pharmazie. 2003;58(5):330–3.

    CAS  PubMed  Google Scholar 

  15. Funke AP, Schiller R, Motzkus HW, Ginther C, Miller RH, Lipp R. Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations. Pharm Res. 2002;19(5):661–8.

    Article  CAS  Google Scholar 

  16. Larrucea E, Arellano A, Santoyo S, Ygartua P. Combined effect of oleic acid and propylene glycol on the percutaneous penetration of tenoxicam and its retention in the skin. Eur J Pharm Biopharm. 2001;52(2):113–9.

    Article  CAS  Google Scholar 

  17. Perkins M, Osborne R, Rana FR, Ghassemi A, Robinson MK. Comparison of in vitro and in vivo human skin responses to consumer products and ingredients with a range of irritancy potential. Toxicol Sci. 1999;48(2):218–29.

    Article  CAS  Google Scholar 

  18. Test No. 439: In vitro skin irritation - reconstructed human epidermis test method. OECD; 2013. (OECD Guidelines for the testing of chemicals, section 4).

  19. Lee M, Hwang JH, Lim KM. Alternatives to in vivo Draize rabbit eye and skin irritation tests with a focus on 3D reconstructed human cornea-like epithelium and epidermis models. Toxicol Res. 2017;33(3):191–203.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. In vitro EpiDerm™ skin irritation test (EPI-200-SIT) for use with MatTek corporation’s reconstructed human epidermal model EpiDerm ™ (EPI-200-SIT). 2017.

  22. FDA. Inactive Ingredient Search for Approved Drug Products Inactive Ingredient Search for Approved Drug Products Page 2 of 2. 2013;5–6.

  23. Squillante E, Needham T, Maniar A, Kislalioglu S, Zia H. Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin. Eur J Pharm Biopharm. 1998;46(3):265–71.

    Article  CAS  Google Scholar 

  24. ChemAxon. Chemicalize - instant cheminformatics solutions [Internet]. Chemicalize. 2018 [cited 2018 Sep 30]. Available from: https://chemicalize.com/#/calculation

  25. Altman R, Bosch B, Brune K, Patrignani P, Young C. Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology. Drugs. 2015;75(8):859–77.

    Article  CAS  Google Scholar 

  26. Müller TD, Clemmensen C, Finan B, DiMarchi RD, Tschöp MH. Anti-obesity therapy: from rainbow pills to polyagonists. Pharmacol Rev. 2018;70(4):712–46.

    Article  Google Scholar 

  27. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64(SUPPL):128–37.

    Article  Google Scholar 

  28. Aungst BJ, J. Rogers N, Shefter E. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int J Pharm. 1986;33(1–3):225–234.

    Article  CAS  Google Scholar 

  29. Aungst BJ. Structure/effect studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm Res. 1989;6(3):244–7.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Osborne JL, Nelson M, Enscore DJ, Yum SI, Gale RM, inventors; Alza Corporation, assignee. Subsaturated nicotine transdermal therapeutic system. United States patent US 6165497A. 2000 Dec 26. 

Download references

Funding

These studies were supported by the Georgia Research Alliance based in Atlanta, Georgia, by grant number GRA.VL17.11 (Murnane and Banga—Multiple Principal Investigators) as well as by the National Institute on Drug Abuse by grant number DA12970 (Blough—Principal Investigator).

Author information

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, Sonalika A. Bhattaccharjee & Ajay K. Banga

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

    Bruce E. Blough

Authors
  1. Ying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin S. Murnane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonalika A. Bhattaccharjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruce E. Blough
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ajay K. Banga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ajay K. Banga.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Y., Murnane, K.S., Bhattaccharjee, S.A. et al. Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications. AAPS J 21, 70 (2019). https://doi.org/10.1208/s12248-019-0335-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-019-0335-9

KEY WORDS

Search

Navigation