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Effect of surfactant concentration and sterilization process on intraocular pressure–lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (NB1111) nanoemulsions

Drug Delivery and Translational Research volume 11, pages 2096–2107 (2021)Cite this article

Abstract

The use of Δ9-tetrahydrocannabinol (THC) and Δ9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS; NB1111) has recently been investigated in the management of intraocular pressure (IOP). The current study was undertaken to develop an optimized THC-VHS-loaded nanoemulsion formulation (NE; THC-VHS-NE) that could improve the drug load and duration of activity. THC-VHS-NE formulation was prepared by homogenization followed by ultrasonication. Sesame oil, Tween®80, and Poloxamer®188 were used as the oil, surfactant, and cosurfactant, respectively. Stability of the optimized THC-VHS-NE formulation was observed at 4 °C. The IOP lowering effect of the lead formulations, commercial timolol, and latanoprost ophthalmic solutions, as well as an emulsion in Tocrisolve™ (THC-VHS-TOC), was studied in New Zealand White rabbits following topical administration. The effect of surfactant concentration and sterilization process on IOP-lowering activity was also studied. THC-VHS-NE formulations (0.5, 1.0, and 2.0% w/v) showed dose dependent duration of action. The 1.0%w/v THC-VHS-NE formulation was selected for further evaluation because of its desirable physical and chemical characteristics. THC-VHS-NE formulation prepared with 2% w/v Tween®80 exhibited a higher drop in IOP than the 0.75 and 4.0% w/v of Tween®80 containing formulations. The IOP-lowering duration was, however, similar for the formulations with 0.75 and 2.0% Tween®80, while that with 4.0% Tween®80 was shorter. THC-VHS-NE formulation produced a greater drop in IOP (p < 0.05) and a longer duration of activity compared to THC-VHS-TOC, latanoprost, and timolol. The formulation could be sterilized by filtration without impacting product attributes. Overall, the optimized THC-VHS-NE formulation demonstrated a significantly better IOP reduction profile in the test model compared to the commercial ophthalmic solutions evaluated.

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References

  1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311:1901.

    Article  Google Scholar 

  2. Taskar PS, Patil A, Lakhani P, Ashour E, Gul W, ElSohly MA, et al. Δ9-Tetrahydrocannabinol derivative-loaded nanoformulation lowers intraocular pressure in normotensive rabbits. Transl Vis Sci Technol. 2019;8:15–15.

    Article  Google Scholar 

  3. Parihar JKS. Glaucoma: the ‘Black hole’ of irreversible blindness. Med J Armed Forces India. 2016;72:3–4.

    CAS  Article  Google Scholar 

  4. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis. Lancet Glob Health. 2017;5:e1221–34.

    Article  Google Scholar 

  5. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52–9.

    CAS  Article  Google Scholar 

  6. Braunger BM, Fuchshofer R, Tamm ER. The aqueous humor outflow pathways in glaucoma: a unifying concept of disease mechanisms and causative treatment. Eur J Pharm Biopharm. 2015;95:173–81.

    Article  Google Scholar 

  7. Tham Y-C, Li X, Wong TY, Quigley HA, Aung T, Cheng C-Y. Global prevalence of glaucoma and projections of glaucoma burden through 2040. Ophthalmology. 2014;121:2081–90.

    Article  Google Scholar 

  8. Glaucoma Summary Benchmarks - 2018 [Internet]. AAO; 2017 Nov p. 6. Available from: https://www.aao.org/summary-benchmark-detail/glaucoma-summary-benchmarks-2018

  9. Glaucoma - Diagnosis and treatment - Mayo Clinic [Internet]. [cited 2019 Oct 15]. Available from: https://www.mayoclinic.org/diseases-conditions/glaucoma/diagnosis-treatment/drc-20372846

  10. Adelli GR, Bhagav P, Taskar P, Hingorani T, Pettaway S, Gul W, et al. Development of a Δ9-tetrahydrocannabinol amino acid-dicarboxylate prodrug with improved ocular bioavailability. Invest Ophthalmol Vis Sci. 2017;58:2167–79.

    CAS  Article  Google Scholar 

  11. Green K. Marijuana smoking vs cannabinoids for glaucoma therapy. Arch Ophthalmol. 1998;116:1433–7.

    CAS  Article  Google Scholar 

  12. Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. 1995;56:2097–102.

    CAS  Article  Google Scholar 

  13. Hepler RS, Frank IM, Ungerleider JT. Pupillary constriction after marijuana smoking. Am J Ophthalmol. 1972;74:1185–90.

    CAS  Article  Google Scholar 

  14. Marijuana and Medicine: Assessing the Science Base [Internet]. Washington, D.C.: National Academies Press; 1999 [cited 2020 Jan 23]. Available from: https://www.nap.edu/catalog/6376

  15. Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. 1980;87:222–8.

    CAS  Article  Google Scholar 

  16. Flach AJ. Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma. Trans Am Ophthalmol Soc. 2002;100:215–24.

    PubMed  PubMed Central  Google Scholar 

  17. Miller S, Daily L, Leishman E, Bradshaw H, Straiker A. Δ9-Tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Invest Ophthalmol Vis Sci. 2018;59(15):5904–11.

    CAS  Article  Google Scholar 

  18. Green K, Bigger JF, Kim K, Bowman K. Cannabinoid penetration and chronic effects in the eye. Exp Eye Res. 1977;24:197–205.

    CAS  Article  Google Scholar 

  19. Hingorani T, Gul W, ElSohly M, Repka MA, Majumdar S. Effect of ion-pairing on in vitro transcorneal permeability of a Δ9-tetrahydrocannabinol prodrug: potential in glaucoma therapy. J Pharm Sci. 2012;101:616–26.

    CAS  Article  Google Scholar 

  20. Elsohly MA, Gul W, Repka MA, Majumdar S, inventors; ElSohly Laboratories Inc, assignee. Compositions containing delta-9-thc-amino acid esters and process of preparation. United States patent US 8,809,261. 2014 Aug 19.

  21. Thumma S, Majumdar S, ElSohly MA, Gul W, Repka MA. Preformulation studies of a prodrug of Δ 9-tetrahydrocannabinol. AAPS PharmSciTech Sep 1. 2008;9(3):982–90.

    CAS  Article  Google Scholar 

  22. Urtti A, Salminen L. Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol. 1993;37:435–56.

    CAS  Article  Google Scholar 

  23. Kale SN, Deore SL. Emulsion micro emulsion and nano emulsion: A Review. 2016.

  24. Sharma N, Bansal M, Visht S, Sharma P, Kulkarni G. Nanoemulsion: a new concept of delivery system. Chron Young Sci. 2010;5.

  25. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2:47–64.

    CAS  Article  Google Scholar 

  26. Kumari B. Ocular drug delivery system: approaches to improve ocular bioavailability. GSC Biol Pharm Sci. 2019;6:001–10.

    Article  Google Scholar 

  27. Youssef A, Dudhipala N, Majumdar S. Ciprofloxacin loaded nanostructured lipid carriers incorporated into in-situ gels to improve management of bacterial endophthalmitis. Pharmaceutics Jun. 2020;12(6):572.

    CAS  Article  Google Scholar 

  28. Janga KY, Tatke A, Dudhipala N, Balguri SP, Ibrahim MM, Maria DN, Jablonski MM, Majumdar S. Gellan gum based sol-to-gel transforming system of natamycin transfersomes improves topical ocular delivery. J Pharmacol Exp Ther Sep 1. 2019;370(3):814–22.

    CAS  Article  Google Scholar 

  29. Inactive Ingredient Search for Approved Drug Products [Internet]. [cited 2020 Jan 28]. Available from: https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm?event=browseByLetter.page&Letter=P

  30. Abismaı̈l B, Canselier JP, Wilhelm AM, Delmas H, Gourdon C. Emulsification by ultrasound: drop size distribution and stability. Ultrason Sonochem. 1999;6:75–83.

  31. Delmas T, Piraux H, Couffin A-C, Texier I, Vinet F, Poulin P, et al. How to prepare and stabilize very small nanoemulsions. Langmuir American Chemical Society. 2011;27:1683–92.

    CAS  Google Scholar 

  32. Lovelyn C, Attama AA. Current state of nanoemulsions in drug delivery. J Biomater Nanobiotechnology. 2011;02:626–39.

    CAS  Article  Google Scholar 

  33. Tatke A, Dudhipala N, Janga KY, Balguri SP, Avula B, Jablonski MM, Majumdar S. In situ gel of triamcinolone acetonide-loaded solid lipid nanoparticles for improved topical ocular delivery: tear kinetics and ocular disposition studies. Nanomaterials. 2019;9(1):33.

    Article  Google Scholar 

  34. Guan Y, Wu J, Zhong Q. Eugenol improves physical and chemical stabilities of nanoemulsions loaded with β-carotene. Food Chem. 2016;194:787–96.

    CAS  Article  Google Scholar 

  35. Diebold Y, Calonge M. Applications of nanoparticles in ophthalmology. Prog Retin Eye Res. 2010;29:596–609.

    CAS  Article  Google Scholar 

  36. Ban J, Zhang Y, Huang X, Deng G, Hou D, Chen Y, et al. Corneal permeation properties of a charged lipid nanoparticle carrier containing dexamethasone. Int J Nanomedicine. 2017;12:1329–39.

    CAS  Article  Google Scholar 

  37. Chanana GD, Sheth BB. Particle size reduction of emulsions by formulation design-II: effect of oil and surfactant concentration. PDA J Pharm Sci Technol. 1995;49:71–6.

    CAS  PubMed  Google Scholar 

  38. Pepi I, Lovri J, Filipovi J. Polymeric micelles in ocular drug delivery: rationale, strategies and challenges. :14.

  39. Kiland JA, Gabelt BT, Kaufman PL. Studies on the mechanism of action of timolol and on the effects of suppression and redirection of aqueous flow on outflow facility. Exp Eye Res. 2004;78:639–51.

    CAS  Article  Google Scholar 

  40. Lim KS, Nau CB, O’Byrne MM, Hodge DO, Toris CB, McLaren JW, et al. Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects: a crossover study. Ophthalmology. 2008;115:790–5.

    Article  Google Scholar 

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Funding

This work has been supported by a research grant from Emerald Bioscience, INC.

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Authors and Affiliations

  1. Department of Pharmaceutics and Drug Delivery, University of Mississippi, Oxford, MS, 38677, USA

    Corinne Sweeney, Narendar Dudhipala, Ruchi Thakkar, Tabish Mehraj, Sushrut Marathe, Mahmoud. A. ElSohly & Soumyajit Majumdar

  2. ElSohly Laboratories Inc, 5-Industrial Park Drive, Oxford, MS, 38655, USA

    Waseem Gul & Mahmoud. A. ElSohly

  3. National Center for Natural Products Research, University of Mississippi, Oxford, MS, 38677, USA

    Waseem Gul & Mahmoud. A. ElSohly

  4. Emerald Bioscience Inc, Long Beach, CA, 90803, USA

    Brian Murphy

  5. Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS, 38677, USA

    Soumyajit Majumdar

Authors
  1. Corinne Sweeney
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  2. Narendar Dudhipala
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  3. Ruchi Thakkar
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  4. Tabish Mehraj
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  5. Sushrut Marathe
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  6. Waseem Gul
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  7. Mahmoud. A. ElSohly
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  9. Soumyajit Majumdar
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Correspondence to Soumyajit Majumdar.

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Ethics declarations

All animal experiments conformed to the tenets of the Association for Research in Vision and Ophthalmology statement on the Use of Animals in Ophthalmic and Vision Research and followed the University of Mississippi Institutional Animal Care and Use Committee approved protocols (18-029).

Conflict of interest

This research is sponsored by Emerald Bioscience, INC, and may lead to the development of products from which W.G., M.E., and S.M. may receive income as part of licensing fees and royalties paid to the University of Mississippi. M.E. is a scientific advisor to Emerald Bioscience. B.M. was the CMO of Emerald Bioscience, Inc. No competing financial interests exist for the other authors.

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Sweeney, C., Dudhipala, N., Thakkar, R. et al. Effect of surfactant concentration and sterilization process on intraocular pressure–lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (NB1111) nanoemulsions. Drug Deliv. and Transl. Res. 11, 2096–2107 (2021). https://doi.org/10.1007/s13346-020-00871-9

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  • DOI: https://doi.org/10.1007/s13346-020-00871-9

Keywords

  • Glaucoma
  • Tetrahydrocannabinol-valine-hemisuccinate
  • Nanoemulsion
  • Stability
  • Sterilization
  • IOP
  • Nonpigmented rabbits