Pharmaceutical Research

, Volume 23, Issue 12, pp 2729–2747

Design for Optimized Topical Delivery: Prodrugs and a Paradigm Change

  • Kenneth B. Sloan
  • Scott C. Wasdo
  • Jarkko Rautio
Review Article

DOI: 10.1007/s11095-006-9108-0

Cite this article as:
Sloan, K.B., Wasdo, S.C. & Rautio, J. Pharm Res (2006) 23: 2729. doi:10.1007/s11095-006-9108-0

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 (SLIPID) or its surrogate, the partition coefficient between a lipid (LIPID) and water (AQ) (KLIPID: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 KLIPID: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, SAQ (not solubility in the vehicle, SVEH) as well as SLIPID should be optimized to give maximum flux from any vehicle, JMVEH: a new working paradigm. The dependence of JMVEH on SAQ is independent of the vehicle so that SAQ as well as SLIPID are descriptors of the solubilizing capacity of the skin or SM1 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.

Key words

lipid solubility partition coefficient Potts–Guy equation prodrugs Roberts–Sloan equation water solubility 

Abbreviations

Δ log J

absolute difference between experimental and calculated fluxes

AQ

water

C7.4

concentration in pH 7.4 buffer

CAQ

concentration in water

CLIPID

concentration in a lipid

CM1

concentration in the first few layers of membrane

CMn

concentration in last layer of membrane

COCT

concentration in octanol

CVEH

concentration in a nonspecified vehicle

D

diffusion coefficient

D0

diffusion coefficient of a molecule with zero volume

IPM

isopropyl myristate

J

flux

JM

maximum flux

JM4.0

maximum flux from pH 4.0 buffer

JM5.0

maximum flux from pH 5.0 buffer

JM5.5

maximum flux from pH 5.5 buffer

JM6.4

maximum flux from pH 6.4 buffer

JM7.4

maximum flux from pH 7.4 buffer

JMAQ

maximum flux from water

JMIPM

maximum flux from isopropyl myristate

JMLIPID

maximum flux from a lipid

JMMO

maximum flux from mineral oil

JMOCT

maximum flux from octanol

JMVEH

maximum flux from a nonspecified vehicle

JVEH

flux from a nonspecified vehicle

KAQ:MO

partition coefficient between water and mineral oil

KIPM:AQ

partition coefficient between IPM and water

KLIPID:AQ

partition coefficient between a lipid and water

KLIPID:VEH

partition coefficient between a lipid and a nonspecified vehicle

KMEM:AQ

partition coefficient between a membrane and water

KMEM:LIPID

partition coefficient between a membrane and lipid

KMEM:VEH

partition coefficient between a membrane and a nonspecified vehicle

KOCT:4.0

partition coefficient between octanol and pH 4.0 buffer

KOCT:5.0

partition coefficient between octanol and pH 5.0 buffer

KOCT:7.0

partition coefficient between octanol and pH 7.0 buffer

KOCT:7.4

partition coefficient between octanol and pH 7.4 buffer

KOCT:AQ

partition coefficient between octanol and water

KSO: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

P4.0

permeability coefficient for delivery from pH 4.0 buffer

P5.0

permeability coefficient for delivery from pH 5.0 buffer

P5.5

permeability coefficient for delivery from pH 5.5 buffer

P7.0

permeability coefficient for delivery from pH 7.0 buffer

P7.4

permeability coefficient for delivery from pH 7.4 buffer

PAQ

permeability coefficient for delivery from water

PG

Potts–Guy model

PIPM

permeability coefficient for delivery from IPM

PLIPID

permeability coefficient for delivery from a lipid

PMO

permeability coefficient for delivery from mineral oil

POCT

permeability coefficient for delivery from octanol

PVEH

permeability coefficient for delivery from a nonspecified vehicle

RS

Roberts–Sloan model

S4.0

solubility in pH 4.0 buffer

S5.0

solubility in pH 5.0 buffer

S6.4

solubility in pH 6.4 buffer

S7.0

solubility in pH 7.0 buffer

S7.4

solubility in pH 7.4 buffer

SAQ

solubility in water

SC

stratum corneum

SIPM

solubility in isopropyl myristate

SLIPID

solubility in a lipid

SM1

solubility in the first few layers of membrane

SMO

solubility in mineral oil

SOCT

solubility in octanol

SSO

solubility in silicone oil

SVEH

solubility in a nonspecified vehicle

VEH

vehicle

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Kenneth B. Sloan
    • 1
  • Scott C. Wasdo
    • 1
  • Jarkko Rautio
    • 2
  1. 1.Department of Medicine ChemistryUniversity of FloridaGainesvilleUSA
  2. 2.Department of Pharmaceutical ChemistryUniversity of KuopioKuopioFinland

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