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Design for Optimized Topical Delivery: Prodrugs and a Paradigm Change

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Abstract

In theory, topical delivery has substantial potential to treat local and some systemic disease states more effectively than systemic delivery. Unfortunately many, if not most, drug candidates for topical delivery lack the requisite physicochemical properties that would allow them to permeate the skin to a clinically useful extent. One way to overcome this obstacle to effective topical delivery is to make a transient derivative of the drug, a prodrug, with the correct physicochemical properties. But what are those correct properties and can the directives for the design of prodrugs be applied to the design of new drugs, their analogs or homologs? For some time increasing the lipid solubility (S LIPID) or its surrogate, the partition coefficient between a lipid (LIPID) and water (AQ) (K LIPID:AQ), has been the standard working paradigm for increasing permeation of the skin, and the permeability coefficient (P = distance/time) has been the quantitative measure of the result. However, even the earliest reports on non-prodrugs such as alcohols showed that working paradigm was incorrect and that P should not be the relevant measure of permeation. The shorter chain and more water soluble alcohols exhibiting lower K LIPID:AQ values gave the greater flux values (J = amount/area × time; the more clinically relevant measure of permeation), regardless of whether they were applied neat or in an aqueous vehicle, while P showed opposite trends for the two applications. Subsequently a large volume of work has shown that, for prodrugs and non-prodrug homologs or analogs alike, S AQ (not solubility in the vehicle, S VEH) as well as S LIPID should be optimized to give maximum flux from any vehicle, J MVEH: a new working paradigm. The dependence of J MVEH on S AQ is independent of the vehicle so that S AQ as well as S LIPID are descriptors of the solubilizing capacity of the skin or S M1 in Fick’s law. The inverse dependence of J (or P) on molecular weight (MW) or volume (MV) remains. Here we review the literature that leads to the conclusion that a new working paradigm is necessary to explain the experimental data, and argue for its use in the design of new prodrugs or in the selection of candidate analogs or homologs for commercialization.

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Abbreviations

Δ log J :

absolute difference between experimental and calculated fluxes

AQ:

water

C 7.4 :

concentration in pH 7.4 buffer

C AQ :

concentration in water

C LIPID :

concentration in a lipid

C M1 :

concentration in the first few layers of membrane

C Mn :

concentration in last layer of membrane

C OCT :

concentration in octanol

C VEH :

concentration in a nonspecified vehicle

D :

diffusion coefficient

D 0 :

diffusion coefficient of a molecule with zero volume

IPM:

isopropyl myristate

J :

flux

J M :

maximum flux

J M4.0 :

maximum flux from pH 4.0 buffer

J M5.0 :

maximum flux from pH 5.0 buffer

J M5.5 :

maximum flux from pH 5.5 buffer

J M6.4 :

maximum flux from pH 6.4 buffer

J M7.4 :

maximum flux from pH 7.4 buffer

J MAQ :

maximum flux from water

J MIPM :

maximum flux from isopropyl myristate

J MLIPID :

maximum flux from a lipid

J MMO :

maximum flux from mineral oil

J MOCT :

maximum flux from octanol

J MVEH :

maximum flux from a nonspecified vehicle

J VEH :

flux from a nonspecified vehicle

K AQ:MO :

partition coefficient between water and mineral oil

K IPM:AQ :

partition coefficient between IPM and water

K LIPID:AQ :

partition coefficient between a lipid and water

K LIPID:VEH :

partition coefficient between a lipid and a nonspecified vehicle

K MEM:AQ :

partition coefficient between a membrane and water

K MEM:LIPID :

partition coefficient between a membrane and lipid

K MEM:VEH :

partition coefficient between a membrane and a nonspecified vehicle

K OCT:4.0 :

partition coefficient between octanol and pH 4.0 buffer

K OCT:5.0 :

partition coefficient between octanol and pH 5.0 buffer

K OCT:7.0 :

partition coefficient between octanol and pH 7.0 buffer

K OCT:7.4 :

partition coefficient between octanol and pH 7.4 buffer

K OCT:AQ :

partition coefficient between octanol and water

K SO:AQ :

partition coefficient between silicone oil and water

L :

effective thickness of membrane

MEM:

membrane

MO:

mineral oil

MV:

molecular volume

MW:

molecular weight

OCT:

octanol

P 4.0 :

permeability coefficient for delivery from pH 4.0 buffer

P 5.0 :

permeability coefficient for delivery from pH 5.0 buffer

P 5.5 :

permeability coefficient for delivery from pH 5.5 buffer

P 7.0 :

permeability coefficient for delivery from pH 7.0 buffer

P 7.4 :

permeability coefficient for delivery from pH 7.4 buffer

P AQ :

permeability coefficient for delivery from water

PG:

Potts–Guy model

P IPM :

permeability coefficient for delivery from IPM

P LIPID :

permeability coefficient for delivery from a lipid

P MO :

permeability coefficient for delivery from mineral oil

P OCT :

permeability coefficient for delivery from octanol

P VEH :

permeability coefficient for delivery from a nonspecified vehicle

RS:

Roberts–Sloan model

S 4.0 :

solubility in pH 4.0 buffer

S 5.0 :

solubility in pH 5.0 buffer

S 6.4 :

solubility in pH 6.4 buffer

S 7.0 :

solubility in pH 7.0 buffer

S 7.4 :

solubility in pH 7.4 buffer

S AQ :

solubility in water

SC:

stratum corneum

S IPM :

solubility in isopropyl myristate

S LIPID :

solubility in a lipid

S M1 :

solubility in the first few layers of membrane

S MO :

solubility in mineral oil

S OCT :

solubility in octanol

S SO :

solubility in silicone oil

S VEH :

solubility in a nonspecified vehicle

VEH:

vehicle

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Authors and Affiliations

  1. Department of Medicine Chemistry, University of Florida, P.O. Box 100485, Gainesville, Florida, 32610, USA

    Kenneth B. Sloan & Scott C. Wasdo

  2. Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, F1-70211, Kuopio, Finland

    Jarkko Rautio

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  1. Kenneth B. Sloan
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Correspondence to Kenneth B. Sloan.

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Sloan, K.B., Wasdo, S.C. & Rautio, J. Design for Optimized Topical Delivery: Prodrugs and a Paradigm Change. Pharm Res 23, 2729–2747 (2006). https://doi.org/10.1007/s11095-006-9108-0

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