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1.
J Ocul Pharmacol Ther ; 38(1): 43-55, 2022.
Article in English | MEDLINE | ID: mdl-34905402

ABSTRACT

The study objective was to investigate molecular thermodynamic properties of approved ophthalmic drugs and derive a framework outlining physicochemical design space for product development. Unlike the methodology used to obtain molecular descriptors for assessment of drug-like properties by Lipinski's Rule of 5 (Ro5), this work presents a retrospective approach based on in silico analysis of molecular thermodynamic properties beyond Ro5 parameters (ie, free energy of distribution/partitioning in octanol/water, dynamic polar surface area, distribution coefficient, and solubility at physiological pH) by using 145 marketed ophthalmic drugs. The study's focus was to delineate inherent molecular parameters explicitly important for ocular permeability and absorption from topical eye drops. A comprehensive parameter distribution analysis on ophthalmic drugs' molecular properties was performed. Frequencies in distribution analyses provided groundwork for physicochemical parameter limits of molecular thermodynamic properties having impact on corneal permeability and topical ophthalmic drug delivery. These parameters included free energy of partitioning (ΔGo/w) calculated based on thermodynamic free energy equation, distribution coefficient at physiological pH (clog DpH7.4), topological polar surface area (TPSA), and aqueous solubility (Sint, SpH7.4) with boundaries of clog DpH7.4 ≤4.0, TPSA ≤250 Å2, ΔGo/w ≤20 kJ/mol (4.8 kcal/mol), and solubility (Sint and SpH7.4) ≥1 µM, respectively. The theoretical free energy of partitioning model streamlined calculation of changes in the free energy of partitioning, Δ(ΔGo/w), as a measure of incremental improvements in corneal permeability for congeneric series. The above parameter limits are proposed as "rules of thumb" for topical ophthalmic drugs to assess risks in developability.


Subject(s)
Drug Design/methods , Ophthalmic Solutions/chemistry , Ophthalmology , Administration, Ophthalmic , Humans , Ocular Absorption , Ophthalmic Solutions/pharmacokinetics , Retrospective Studies , Solubility , Thermodynamics
2.
Drug Discov Today ; 24(8): 1587-1597, 2019 08.
Article in English | MEDLINE | ID: mdl-30959112

ABSTRACT

The estimation of ocular pharmacokinetics (PK) in various eye tissues is limited because of sampling challenges. Computational modeling and simulation (M&S) tools underpinning the elucidation of drug access routes and prediction of ocular exposure are essential for the mechanistic assessment of biopharmaceutics in the eye. Therefore, theoretical and experimental evaluation of ocular absorption and transit models is necessary. Biopharmaceutical parameter sensitivity analysis based on permeability and drug dose illustrates utility in ocular drug delivery assessment, which could have innovative and cost-saving impacts on ophthalmic product development and therapeutic bioequivalence (BE) evaluations.


Subject(s)
Eye/drug effects , Ophthalmic Solutions/administration & dosage , Ophthalmic Solutions/chemistry , Biopharmaceutics/methods , Chemistry, Pharmaceutical/methods , Computer Simulation , Drug Delivery Systems/methods , Humans , Permeability , Therapeutic Equivalency
4.
Pharm Res ; 36(2): 29, 2018 Dec 27.
Article in English | MEDLINE | ID: mdl-30591984

ABSTRACT

A resurgence of interest and investment in the field of gene therapy, driven in large part by advances in viral vector technology, has recently culminated in United States Food and Drug Administration approval of the first gene therapy product targeting a disease caused by mutations in a single gene. This product, LUXTURNA™ (voretigene neparvovec-rzyl; Spark Therapeutics, Inc., Philadelphia, PA), delivers a normal copy of the RPE65 gene to retinal cells for the treatment of biallelic RPE65 mutation-associated retinal dystrophy, a blinding disease. Many additional gene therapy programs targeting both inherited retinal diseases and other ocular diseases are in development, owing to an improved understanding of the genetic basis of ocular disease and the unique properties of the ocular compartment that make it amenable to local gene therapy. Here we review the growing body of literature that describes both the design and development of ocular gene therapy products, with a particular emphasis on target and vector selection, and chemistry, manufacturing, and controls.


Subject(s)
Dependovirus/chemistry , Drug Development/methods , Gene Transfer Techniques/standards , Genetic Therapy/methods , Retinal Diseases/therapy , Animals , Dependovirus/genetics , Dependovirus/isolation & purification , Drug Compounding , Genetic Vectors/administration & dosage , Humans , Macular Degeneration/drug therapy , Retinal Diseases/drug therapy , Retinal Diseases/genetics , Retinal Diseases/pathology
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