Deformable Vesicles with Edge Activators for the Transdermal Delivery of Non-Psychoactive Cannabinoids


Cite item

Full Text

Abstract

Background:Transdermal delivery of highly lipophilic molecules is challenging due to the strong barrier function of the skin. Vesicles with penetration enhancers are safe and efficient systems that could improve the transdermal delivery of non-psychoactive cannabinoids such as cannabidiol and desoxy-cannabidiol. In the last decades, research interest in desoxy-cannabidiol as a potent drug with anti-nociceptive properties has risen. Still, its scarce market availability poses a limit for both research and clinical applications. Therefore, it is necessary to improve the synthesis to produce sufficient amounts of desoxy-cannabidiol. Moreover, also the formulation aspects for this drug are challenging and require to be addressed to meet an efficient delivery to the patients.

Objective:This work aimed to develop innovative phospholipid-based vesicles with propylene glycol (PG), oleic acid (OA), or limonene as edge activators, for the transdermal delivery of highly lipophilic drugs such as non-psychoactive cannabinoids. In particular, desoxy-cannabidiol was selected thanks to its anti-nociceptive activity, and its synthesis was improved enhancing the stereoselectivity of its synthon's production.

Methods:Desoxy-cannabidiol was synthesized by Lewis acid-mediated condensation of p-mentha-2,8-dien- 1-ol and m-pentylphenol, improving the stereoselectivity of the first synthon's production. Transethosomes containing 20-50% w/w PG, 0.4-0.8% w/w OA, or 0.1-1% w/w limonene were optimized and loaded with cannabidiol or desoxy-cannabidiol (0.07-0.8% w/w, 0.6-7.0 mg/mL). Ex-vivo studies were performed to assess both the skin permeation and accumulation of the cannabinoids, as well as the penetration depth of fluorescein- loaded systems used as models.

Results:An enantioselective bromination was added to the pathway, thus raising the production yield of pmentha- 2,8-dien-1-ol to 81% against 35%, and the overall yield of desoxy-cannabidiol synthesis from 12% to 48%. Optimized transethosomes containing 0.6 mg/mL cannabinoids were prepared with 1:10 PG:lipid weight ratio, 0.54 OA:lipid molar ratio, and 0.3 limonene:lipid molar ratio, showing good nanometric size (208 ± 20.8 nm - 321 ± 26.3 nm) and entrapment efficiency (> 80%). Ex-vivo tests showed both improved skin permeation rates of cannabinoids (up to 21.32 ± 4.27 µg/cm2 cannabidiol), and skin penetration (depth of fluorescein up to 240 µm, with PG).

Conclusion:Desoxy-cannabidiol was successfully produced at high yields, and formulated into transethosomes optimized for transdermal delivery. Loaded vesicles showed improved skin penetration of desoxy-cannabidiol, cannabidiol and a lipophilic probe. These results suggest the potential of these carriers for the transdermal delivery of highly lipophilic drugs.

About the authors

Elisa Vettorato

Department of Pharmaceutical and Pharmacological Science, University of Padova

Author for correspondence.
Email: info@benthamscience.net

Marisa Fiordelisi

Department of Pharmaceutical and Pharmacological Sciences, University of Padova

Email: info@benthamscience.net

Silvia Ferro

Department of Pharmaceutical and Pharmacological Sciences,, University of Padova

Email: info@benthamscience.net

Desirè Zanin

Department of Pharmaceutical and Pharmacological Sciences,, University of Padova

Email: info@benthamscience.net

Erica Franceschinis

Department of Pharmaceutical and Pharmacological Sciences,, University of Padova,

Email: info@benthamscience.net

Giovanni Marzaro

Department of Pharmaceutical and Pharmacological Sciences,, University of Padova,

Email: info@benthamscience.net

Nicola Realdon

epartment of Pharmaceutical and Pharmacological Sciences,, University of Padova

Email: info@benthamscience.net

References

  1. Parnham MJ. Liposome dermatics. In: Braun-Falco O, Korting HC, Maibach HI, Eds. Drug News Perspect. 1991; 4: pp. 567-70. doi: 10.1007/978-3-642-48391-2
  2. Korting HC, Zienicke H, Schäfer-Korting M, Braun-Falco O. Liposome encapsulation improves efficacy of betamethasone dipropionate in atopic eczema but not in Psoriasis vulgaris. Eur J Clin Pharmacol 1990; 39(4): 349-51. doi: 10.1007/BF00315408 PMID: 2076716
  3. Mujoriya R, Bodla RB, Dhamande K, Singh D, Patle L. Niosomal drug delivery system: The magic bullet. J Appl Pharm Sci 2011; 1: 20-3.
  4. Souto EB, Macedo AS, Dias-Ferreira J, Cano A, Zielińska A, Matos CM. Elastic and ultradeformable liposomes for transdermal delivery of active pharmaceutical ingredients (Apis). Int J Mol Sci 2021; 22(18): 9743. doi: 10.3390/ijms22189743 PMID: 34575907
  5. El Maghraby GMM, Williams AC, Barry BW. Skin delivery of oestradiol from deformable and traditional liposomes: Mechanistic studies. J Pharm Pharmacol 2010; 51(10): 1123-34. doi: 10.1211/0022357991776813 PMID: 10579683
  6. Trotta M, Peira E, Debernardi F, Gallarate M. Elastic liposomes for skin delivery of dipotassium glycyrrhizinate. Int J Pharm 2002; 241(2): 319-27. doi: 10.1016/S0378-5173(02)00266-1 PMID: 12100859
  7. Trotta M, Peira E, Carlotti ME, Gallarate M. Deformable liposomes for dermal administration of methotrexate. Int J Pharm 2004; 270(1-2): 119-25. doi: 10.1016/j.ijpharm.2003.10.006 PMID: 14726128
  8. Boinpally RR, Zhou SL, Poondru S, Devraj G, Jasti BR. Lecithin vesicles for topical delivery of diclofenac. Eur J Pharm Biopharm 2003; 56(3): 389-92. doi: 10.1016/S0939-6411(03)00143-7 PMID: 14602181
  9. Dragicevic-Curic N, Scheglmann D, Albrecht V, Fahr A. Development of liposomes containing ethanol for skin delivery of temoporfin: Characterization and in vitro penetration studies. Colloids Surf B Biointerfaces 2009; 74(1): 114-22. doi: 10.1016/j.colsurfb.2009.07.005 PMID: 19651496
  10. Qadri GR, Ahad A, Aqil M, Imam SS, Ali A. Invasomes of isradipine for enhanced transdermal delivery against hypertension: Formulation, characterization, and in vivo pharmacodynamic study. Artif Cells Nanomed Biotechnol 2017; 45(1): 139-45. doi: 10.3109/21691401.2016.1138486 PMID: 26829018
  11. Opatha SAT, Titapiwatanakun V, Chutoprapat R. Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics 2020; 12(9): 855. doi: 10.3390/pharmaceutics12090855 PMID: 32916782
  12. Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes - novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. J Control Release 2000; 65(3): 403-18. doi: 10.1016/S0168-3659(99)00222-9 PMID: 10699298
  13. Touitou E. Composition for applying substances to or through the skin. US Patent 5540934A, 1998.
  14. Song CK, Balakrishnan P, Shim CK, Chung SJ, Chong S, Kim DD. A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: Characterization and in vitro/in vivo evaluation. Colloids Surf B Biointerfaces 2012; 92: 299-304. doi: 10.1016/j.colsurfb.2011.12.004 PMID: 22205066
  15. Ainbinder D, Touitou E. A new approach for skin tumor treatment: From delivery system characterization to in vivo evaluation. Drug Deliv Transl Res 2011; 1(1): 53-65. doi: 10.1007/s13346-010-0006-y PMID: 25787889
  16. Verma S, Utreja P. Vesicular nanocarrier based treatment of skin fungal infections: Potential and emerging trends in nanoscale pharmacotherapy. Asian J Pharm Sci 2019; 14(2): 117-29. doi: 10.1016/j.ajps.2018.05.007 PMID: 32104444
  17. Manconi M, Mura S, Sinico C, Fadda AM, Vila AO, Molina F. Development and characterization of liposomes containing glycols as carriers for diclofenac. Colloids Surf A Physicochem Eng Asp 2009; 342(1-3): 53-8. doi: 10.1016/j.colsurfa.2009.04.006
  18. Abdulbaqi IM, Darwis Y, Khan NAK, Assi RA, Khan AA. Ethosomal nanocarriers: The impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials. Int J Nanomedicine 2016; 11: 2279-304. doi: 10.2147/IJN.S105016 PMID: 27307730
  19. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev 2012; 64: 128-37. doi: 10.1016/j.addr.2012.09.032 PMID: 15019749
  20. Touitou E, Fabin B. Altered skin permeation of a highly lipophilic molecule: Tetrahydrocannabinol. Int J Pharm 1988; 43(1-2): 17-22. doi: 10.1016/0378-5173(88)90053-1
  21. Goodman M, Barry BW. Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique. J Invest Dermatol 1988; 91(4): 323-7. doi: 10.1111/1523-1747.ep12475655 PMID: 3171212
  22. Ptak M, Egret-Charlier M, Sanson A, Bouloussa O. A NMR study of the ionization of fatty acids, fatty amines and N-acylamino acids incorporated in phosphatidylcholine vesicles. Biochim Biophys Acta Biomembr 1980; 600(2): 387-97. doi: 10.1016/0005-2736(80)90442-3 PMID: 7407120
  23. Zakir F, Vaidya B, Goyal AK, Malik B, Vyas SP. Development and characterization of oleic acid vesicles for the topical delivery of fluconazole. Drug Deliv 2010; 17(4): 238-48. doi: 10.3109/10717541003680981 PMID: 20235758
  24. Cistola DP, Hamilton JA, Jackson D, Small DM. Ionization and phase behavior of fatty acids in water: Application of the Gibbs phase rule. Biochemistry 1988; 27(6): 1881-8. doi: 10.1021/bi00406a013 PMID: 3378036
  25. El Maghraby GMM, Williams AC, Barry BW. Oestradiol skin delivery from ultradeformable liposomes: Refinement of surfactant concentration. Int J Pharm 2000; 196(1): 63-74. doi: 10.1016/S0378-5173(99)00441-X PMID: 10675708
  26. El Maghraby GMM, Williams AC, Barry BW. Interactions of surfactants (edge activators) and skin penetration enhancers with liposomes. Int J Pharm 2004; 276(1-2): 143-61. doi: 10.1016/j.ijpharm.2004.02.024 PMID: 15113622
  27. Shamma RN, Elsayed I. Transfersomal lyophilized gel of buspirone HCl: Formulation, evaluation and statistical optimization. J Liposome Res 2013; 23(3): 244-54. doi: 10.3109/08982104.2013.801489 PMID: 23713516
  28. Srisuk P, Thongnopnua P, Raktanonchai U, Kanokpanont S. Physico-chemical characteristics of methotrexate-entrapped oleic acid- containing deformable liposomes for in vitro transepidermal delivery targeting psoriasis treatment. Int J Pharm 2012; 427(2): 426-34. doi: 10.1016/j.ijpharm.2012.01.045 PMID: 22310459
  29. Choi J, Choi MK, Chong S, Chung SJ, Shim CK, Kim DD. Effect of fatty acids on the transdermal delivery of donepezil: In vitro and in vivo evaluation. Int J Pharm 2012; 422(1-2): 83-90. doi: 10.1016/j.ijpharm.2011.10.031 PMID: 22037444
  30. Witzke S, Duelund L, Kongsted J, Petersen M, Mouritsen OG, Khandelia H. Inclusion of terpenoid plant extracts in lipid bilayers investigated by molecular dynamics simulations. J Phys Chem B 2010; 114(48): 15825-31. doi: 10.1021/jp108675b PMID: 21070035
  31. Šturm L, Poklar Ulrih N. Propolis flavonoids and terpenes, and their interactions with model lipid membranes: A review. Adv Biomembr Lipid Self-Assem 2020; 32: 25-52. doi: 10.1016/bs.abl.2020.04.003
  32. Cornwell PA, Barry BW, Bouwstra JA, Gooris GS. Modes of action of terpene penetration enhancers in human skin; Differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies. Int J Pharm 1996; 127(1): 9-26. doi: 10.1016/0378-5173(95)04108-7
  33. Touitou E, Natsheh H. Topical administration of drugs incorporated in carriers containing phospholipid soft vesicles for the treatment of skin medical conditions. Pharmaceutics 2021; 13(12): 2129. doi: 10.3390/pharmaceutics13122129 PMID: 34959410
  34. Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release 2003; 93(3): 377-87. doi: 10.1016/j.jconrel.2003.09.001 PMID: 14644587
  35. Natsheh H, Vettorato E, Touitou E. Ethosomes for dermal administration of natural active molecules. Curr Pharm Des 2019; 25(21): 2338-48. doi: 10.2174/1381612825666190716095826 PMID: 31333087
  36. Abrams DI. The therapeutic effects of cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med 2018; 49: 7-11. doi: 10.1016/j.ejim.2018.01.003 PMID: 29325791
  37. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N Engl J Med 2017; 376(21): 2011-20. doi: 10.1056/NEJMoa1611618 PMID: 28538134
  38. Upadhya D, Castro OW, Upadhya R, Shetty AK. Prospects of cannabidiol for easing status epilepticus-induced epileptogenesis and related comorbidities. Mol Neurobiol 2018; 55(8): 6956-64. doi: 10.1007/s12035-018-0898-y PMID: 29372545
  39. Xiong W, Cheng K, Cui T, et al. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol 2011; 7(5): 296-303. doi: 10.1038/nchembio.552 PMID: 21460829
  40. Hejazi N, Zhou C, Oz M, Sun H, Ye JH, Zhang L. Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol 2006; 69(3): 991-7. doi: 10.1124/mol.105.019174 PMID: 16332990
  41. Ahrens J, Demir R, Leuwer M, et al. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 2009; 83(4): 217-22. doi: 10.1159/000201556 PMID: 19204413
  42. Xiong W, Wu X, Lovinger DM, et al. A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci 2012; 32(15): 5200-8. doi: 10.1523/JNEUROSCI.6347-11.2012 PMID: 22496565
  43. Xiong W, Cui T, Cheng K, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012; 209(6): 1121-34. doi: 10.1084/jem.20120242 PMID: 22585736
  44. Petrzilka T, Haefliger W, Sikemeier C. Synthese von Haschisch-Inhaltsstoffen. 4. Mitteilung. Helv Chim Acta 1969; 52(4): 1102-34. doi: 10.1002/hlca.19690520427
  45. Reggio PH, Bramblett RD, Yuknavich H, et al. The design, synthesis and testing of desoxy-CBD: Further evidence for a region of steric interference at the cannabinoid receptor. Life Sci 1995; 56(23-24): 2025-32. doi: 10.1016/0024-3205(95)00185-9 PMID: 7776828
  46. Schenck GO, Neumüller OA, Ohloff G, Schroeter S. Zur Autoxydation des (+)-Limonens. Justus Liebigs Ann Chem 1965; 687(1): 26-39. doi: 10.1002/jlac.19656870105
  47. Rickards RW, Watson WP. Conversion of (+)-(R)-Limonene into (+)-(1S,4R)-p-mentha-2,8-dien-1-ol, an intermediate in the synthesis of tetrahydrocannabinoids. Aust J Chem 1980; 33(2): 451-4. doi: 10.1071/CH9800451
  48. Wilkinson SM, Price J, Kassiou M. Improved accessibility to the desoxy analogues of Δ9-tetrahydrocannabinol and cannabidiol. Tetrahedron Lett 2013; 54(1): 52-4. doi: 10.1016/j.tetlet.2012.10.080
  49. Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it’s been. Headache 2015; 55(6): 885-916. doi: 10.1111/head.12570 PMID: 26015168
  50. National Academies of Sciences, Medicine Division, Board on Population Health, Public Health Practice, Committee on the Health Effects of Marijuana, An Evidence Review, Research Agenda. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. 2017; pp. 440. doi: 10.17226/24625
  51. National Center for Biotechnology Information. Pubchem compound summary for CID 50919314, 5-Desoxy-delta9-tetrahydrocannabinol. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/5-Desoxy-delta9-tetrahydrocannabinol (Accessed March 13, 2022).
  52. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci 2001; 14(2): 101-14. doi: 10.1016/S0928-0987(01)00167-1
  53. Lazzari P, Fadda P, Marchese G, Casu GL, Pani L. Antinociceptive activity of Δ9-tetrahydrocannabinol non-ionic microemulsions. Int J Pharm 2010; 393(1-2): 239-44. doi: 10.1016/j.ijpharm.2010.04.010 PMID: 20399844
  54. Murgia S, Fadda P, Colafemmina G, et al. Characterization of the Solutol® HS15/water phase diagram and the impact of the Δ9-tetrahydrocannabinol solubilization. J Colloid Interface Sci 2013; 390(1): 129-36. doi: 10.1016/j.jcis.2012.08.068 PMID: 23099249
  55. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain 2016; 20(6): 936-48. doi: 10.1002/ejp.818 PMID: 26517407
  56. Tai K, Rappolt M, He X, et al. Effect of β-sitosterol on the curcumin-loaded liposomes: Vesicle characteristics, physicochemical stability, in vitro release and bioavailability. Food Chem 2019; 293: 92-102. doi: 10.1016/j.foodchem.2019.04.077 PMID: 31151654
  57. Abd El-Alim SH, Kassem AA, Basha M, Salama A. Comparative study of liposomes, ethosomes and transfersomes as carriers for enhancing the transdermal delivery of diflunisal: In vitro and in vivo evaluation. Int J Pharm 2019; 563: 293-303. doi: 10.1016/j.ijpharm.2019.04.001 PMID: 30951860
  58. Zhang Y, Huo M, Zhou J, et al. DDSolver: An add-in program for modeling and comparison of drug dissolution profiles. AAPS J 2010; 12(3): 263-71. doi: 10.1208/s12248-010-9185-1 PMID: 20373062
  59. Godin B, Touitou E. Transdermal skin delivery: Predictions for humans from in vivo, ex vivo and animal models. Adv Drug Deliv Rev 2007; 59(11): 1152-61. doi: 10.1016/j.addr.2007.07.004 PMID: 17889400
  60. Casiraghi A, Musazzi UM, Centin G, Franzè S, Minghetti P. Topical administration of cannabidiol: Influence of vehicle-related aspects on skin permeation process. Pharmaceuticals 2020; 13(11): 337. doi: 10.3390/ph13110337 PMID: 33114270
  61. Burnier C, Esseiva P, Roussel C. Quantification of THC in cannabis plants by fast-HPLC-DAD: A promising method for routine analyses. Talanta 2019; 192: 135-41. doi: 10.1016/j.talanta.2018.09.012 PMID: 30348368
  62. Hauenstein O, Reiter M, Agarwal S, Rieger B, Greiner A. Bio-based polycarbonate from limonene oxide and CO2 with high molecular weight, excellent thermal resistance, hardness and transparency. Green Chem 2016; 18(3): 760-70. doi: 10.1039/C5GC01694K
  63. Elmoslemany RM, Abdallah OY, El-Khordagui LK, Khalafallah NM. Propylene glycol liposomes as a topical delivery system for miconazole nitrate: Comparison with conventional liposomes. AAPS PharmSciTech 2012; 13(2): 723-31. doi: 10.1208/s12249-012-9783-6 PMID: 22566173
  64. Zhang JP, Wei YH, Zhou Y, Li YQ, Wu XA. Ethosomes, binary ethosomes and transfersomes of terbinafine hydrochloride: A comparative study. Arch Pharm Res 2012; 35(1): 109-17. doi: 10.1007/s12272-012-0112-0 PMID: 22297749
  65. Natsheh H, Touitou E. Phospholipid vesicles for dermal/transdermal and nasal administration of active molecules: The effect of surfactants and alcohols on the fluidity of their lipid bilayers and penetration enhancement properties. Molecules 2020; 25(13): 2959. doi: 10.3390/molecules25132959 PMID: 32605117
  66. Mabrey S, Sturtevant JM. Incorporation of saturated fatty acids into phosphatidylcholine bilayers. Biochim Biophys Acta Lipids Lipid Metab 1977; 486(3): 444-50. doi: 10.1016/0005-2760(77)90094-7 PMID: 856286
  67. Cistola DP, Small DM, Hamilton JA. Ionization behavior of aqueous short-chain carboxylic acids: A carbon-13 NMR study. J Lipid Res 1982; 23(5): 795-9. doi: 10.1016/S0022-2275(20)38114-1 PMID: 7119577
  68. Cistola DP, Small DM, Hamilton JA. Carbon 13NMR studies of saturated fatty acids bound to bovine serum albumin. II. Electrostatic interactions in individual fatty acid binding sites. J Biol Chem 1987; 262(23): 10980-5. doi: 10.1016/S0021-9258(18)60914-7 PMID: 3611100
  69. Bruno MC, Gagliardi A, Mancuso A, et al. Oleic acid-based vesicular nanocarriers for topical delivery of the natural drug thymoquinone: Improvement of anti-inflammatory activity. J Control Release 2022; 352: 74-86. doi: 10.1016/j.jconrel.2022.10.011 PMID: 36228953
  70. Schaefer H, Redelmeier TE. Skin barrier: Principles of percutaneous absorption. Basel, New York: Karger 1996.
  71. Maibach H. Dermatological formulations: Percutaneous absorption. By Brian W. Barry. Marcel Dekker, 270 Madison Avenue, New York, NY 10016. 1983. 479pp. 16 × 23.5cm. Price $55.00 (2070 higher outside the US. and Canada). J Pharm Sci 1984; 73(4): 573. doi: 10.1002/jps.2600730442
  72. Touitou E. Drug delivery across the skin. Expert Opin Biol Ther 2002; 2(7): 723-33. doi: 10.1517/14712598.2.7.723 PMID: 12387671

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers