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Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: potential in glaucoma therapy.

Abstract

The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of Δ(9) -tetrahydrocannabinol (THC) through prodrug derivatization and formulation approaches. In vitro corneal permeability of THC and its hemisuccinate (THC-HS) and hemiglutarate (THC-HG) ester prodrugs and WIN 55-212-2 (WIN), a synthetic cannabinoid, was determined using isolated rabbit cornea. The formulations studied included hydroxypropyl beta cyclodextrin (HPβCD) or randomly methylated beta cyclodextrin (RMβCD), as well as prodrug-ion-pair complexes with l-arginine or tromethamine. Corneal permeability of WIN was found to be two-fold higher than THC in the presence of HPβCD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HPβCD, at pH 5 (donor solution pH), both prodrugs exhibited six-fold higher permeability compared with THC. However, permeability of the prodrugs was about three-fold lower than that of THC at pH 7.4. RMβCD, at pH 7.4, led to a significant improvement in permeability. Formation of ion-pair complexes markedly improved the solubility and permeability of THC-HG (sevenfold and threefold greater permeability compared with THC and WIN, respectively) at pH 7.4. The in vitro results demonstrate that the use of an ion-pair complex of THC-HG could be an effective strategy for topical delivery of THC.

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  • Authors+Show Affiliations

    ,

    Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.

    , , ,

    Source

    Journal of pharmaceutical sciences 101:2 2012 Feb pg 616-26

    MeSH

    Animals
    Cornea
    Dronabinol
    Glaucoma
    In Vitro Techniques
    Permeability
    Prodrugs
    Rabbits
    Solubility

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21989812

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: potential in glaucoma therapy. AU - Hingorani,Tushar, AU - Gul,Waseem, AU - Elsohly,Mahmoud, AU - Repka,Michael A, AU - Majumdar,Soumyajit, Y1 - 2011/10/11/ PY - 2011/02/21/received PY - 2011/08/10/revised PY - 2011/09/27/accepted PY - 2011/10/13/entrez PY - 2011/10/13/pubmed PY - 2012/5/12/medline SP - 616 EP - 26 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 101 IS - 2 N2 - The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of Δ(9) -tetrahydrocannabinol (THC) through prodrug derivatization and formulation approaches. In vitro corneal permeability of THC and its hemisuccinate (THC-HS) and hemiglutarate (THC-HG) ester prodrugs and WIN 55-212-2 (WIN), a synthetic cannabinoid, was determined using isolated rabbit cornea. The formulations studied included hydroxypropyl beta cyclodextrin (HPβCD) or randomly methylated beta cyclodextrin (RMβCD), as well as prodrug-ion-pair complexes with l-arginine or tromethamine. Corneal permeability of WIN was found to be two-fold higher than THC in the presence of HPβCD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HPβCD, at pH 5 (donor solution pH), both prodrugs exhibited six-fold higher permeability compared with THC. However, permeability of the prodrugs was about three-fold lower than that of THC at pH 7.4. RMβCD, at pH 7.4, led to a significant improvement in permeability. Formation of ion-pair complexes markedly improved the solubility and permeability of THC-HG (sevenfold and threefold greater permeability compared with THC and WIN, respectively) at pH 7.4. The in vitro results demonstrate that the use of an ion-pair complex of THC-HG could be an effective strategy for topical delivery of THC. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/21989812/abstract/Effect_of_ion_pairing_on_in_vitro_transcorneal_permeability_of_a_Δ_9___tetrahydrocannabinol_prodrug:_Potential_in_glaucoma_therapy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)31719-6 DB - PRIME DP - Unbound Medicine ER -