Scott Wasdo

Design for Optimized Topical Delivery: Prodrugs and a Paradigm Change

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.

Topical delivery of 5-fluorouracil and 6-mercaptopurine by their alkylcarbonyloxymethyl prodrugs from water: vehicle effects on design of prodrugs.

AbstractPurpose. To determine whether the fluxes through hairless mouse skin for three homologous series of prodrugs of 5-fluorouracil (5-FU, 1) and 6-mercaptopurine (6-MP, 2) from saturated aqueous suspensions show dependencies on aqueous (SAQ) and isopropyl myristate (SIPM) solubilities similar to those shown by the identical compounds delivered from IPM. Methods. Flux through hairless mouse skin from water (JMAQ) and solubility data were measured for a homologous series of six 3-alkylcarbonyloxymethyl (ACOM) prodrugs of 5-FU (3-ACOM-5-FU), and five 6-ACOM-6-MP prodrugs, then combined with literature data for five bis-6,9-ACOM-6-MP prodrugs to give a data base. Multiple linear regression using SPSS 7.5 was performed on log SIPM, log SAQ, molecular weight and log JMAQ data to determine the best fit coefficients to the transformed Potts-Guy equation: log JMAQ = x + y log SIPM + (1 - y) log SAQ + z MW. Permeability coefficients (PMAQ) were calculated from JMAQ/SAQ. Results. The best fit coefficients for the flux from AQ(JMAQ)were x = -1.497, y = 0.660 and z = -0.00469 (r2 = 0.765) with an average error of prediction equal to 0.193 log units. The best fit coefficients for the flux from IPM (JMIPM) were x = -0.557, y = 0.536 and z = -0.00261 (r2 = 0.941) with an average error of prediction equal to 0.109 log units. For all three series, log PMAQ increased whereas log PMIPM decreased with increasing alkyl chain lengths in the promoiety and with decreasing solubility parameter values. Conclusions. The transformed Potts-Guy equation can be used to predict JMAQ but with less certainty than JMIPM. SIPM and SAQ have consistently been shown to have a positive influence on JMIPM, and now on JMAQ, with a balance between the two solubilities being obviously important. The previous observation that log PMAQ increased with lipophilicity is an artifact of normalizing JMAQ by SAQ.

Topical Delivery of a Model Phenolic Drug: Alkyloxycarbonyl Prodrugs of Acetaminophen

AbstractPurpose. To determine whether the delivery of a phenolic parent drug by its alkyloxycarbonyl (AOC) prodrugs through hairless mouse skin would show similar dependencies on water and lipid solubilities that similar prodrugs of more polar heterocyclic amide and imide parent drugs have shown. Methods. Flux through hairless mouse skin from suspensions in isopropyl myristate (JMIPM), solubilities in IPM (SIPM) and water (SAQ), and partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (KIPM:4.0) were measured for two series of AOC derivatives of acetaminophen (APAP); their solubilities in pH 4.0 buffer (S4.0) were estimated from SIPM/KIPM: 4.0. Log JMIPM values were calculated from the n = 43 coefficients for the parameters in the transformed Potts-Guy (Roberts-Sloan) equation, and the average error of prediction (Δ log J`IPM) was calculated. The JMIPM, SIPM, S4.0, and molecular weight (MW) data for this series and two other series were combined with the n = 43 database to give a n = 61 database, and new best fit coefficients were determined for the Roberts-Sloan equation: log JMIPM = x + y log SIPM + (1 - y) log S4.0 - z MW. Results. All of the 4-AOC-APAP derivatives underperformed based on their predicted log JMIPM (Δ log J`MIPM = 0.275 ± 0.147 log units) and, although the two more water soluble members of this more lipid soluble series were more effective than APAP, they were only marginally so: <2 times. Addition of three new series to the n = 43 database for the Roberts-Sloan equation did not substantially change the coefficients to the parameters: x, y, z, and r2 = -0.322, 0.530, 0.00337 and 0.92, respectively. Conclusions. The topical delivery of a model phenolic drug by its AOC prodrugs through hairless mouse skin from IPM shows the same dependence on SIPM, S4.0, and MW as the delivery of polar heterocycles by their similar prodrugs.

Differential binding of serum proteins to nanoparticles

In the physiological environment, endogenous proteins readily adsorb to the surface of foreign materials. These proteins facilitate recognition by phagocytic cells and strongly influence the nature of the immune and inflammatory responses. Properly anticipating the potential adverse effects caused by nanomaterials requires a fundamental understanding of the physical properties that govern this process. The large number of adherent proteins and the competitive nature of adsorption in multicomponent solutions have made quantifying protein adsorption to nanomaterials from native physiological fluids a challenging analytical prospect. In this paper, we report the use of an isotope coded affinity tag (ICAT) based dual-label method to identify the proteins that adsorb to aluminium, nickel and diamond nanoparticles following their exposure to human serum. With this method, we were able to identify 69 unique proteins that exhibited adsorption to the various nanoparticles and quantify the relative affinities with which these proteins bind.

Feasibility of a Breath Test for Monitoring Adherence to Vaginal Administration of Antiretroviral Microbicide Gels

Adherence to microbicide gel use is critical to optimizing effectiveness in preventing human immunodeficiency virus transmission. The authors hypothesized that ester taggants added to vaginal gels would generate exhaled alcohol and ketone metabolites and provide a “breath test” for vaginal gel use. This 2‐arm (vaginal and dermal), randomized, participant‐blinded, pilot study tested this hypothesis. On 8 visits, healthy women (n = 8) received intravaginal taggant (2‐butyl acetate, 2‐pentyl acetate, isopropyl butyrate, or 2‐pentyl butyrate; 30 mg) formulated in hydroxyethylcellulose or tenofovir placebo gel. A second group (n = 4) of women received the same formulations administered dermally on the forearm to determine if skin administration might confound the system. Breath samples were collected using bags before and after taggant administration for 1 hour. Samples were measured using a miniature gas chromatograph and/or gas chromatography–mass spectroscopy for ester taggant, alcohol, and ketone concentrations. After vaginal administration, 2‐butyl acetate, 2‐pentyl acetate, and metabolites were observed in breath, whereas isopropyl butyrate, 2‐pentyl butyrate, and metabolites were not. Some women reported self‐resolving, mild burning (24/64 visits) with vaginal administration or a “bubblegum” taste (7/64 visits). No taggants or metabolites were detected following dermal application. A “breath test” for adherence to antiretroviral vaginal gel application appears physiologically and technically feasible.

A correlation of flux through a silicone membrane with flux through hairless mouse skin and human skin in vitro.

The maximum fluxes of 32 prodrugs and parabens through polydimethylsiloxane membranes from water (EXP log J(MPAQ)) have been correlated with the maximum flux of the same prodrugs and parabens through hairless mouse skin from water (EXP log J(MMAQ)): EXP log J(MMAQ)=0.608 EXP log J(MPAQ)-0.636, r(2)=0.743. The average of the absolute values for the differences between the EXP log J(MMAQ) and the log J(MMAQ) calculated from EXP log J(MPAQ) (Delta log J(MMAQ)) was 0.227 log units. Similarly the maximum fluxes of 11 unrelated permeants through human skin from water (EXP log J(MHAQ)) was correlated with the EXP log J(MPAQ) for the same permeants: EXP log J(MHAQ)=0.516 EXP log J(MPAQ)-0.922, r(2)=0.82 and Delta log J(MHAQ)=0.252 log units. Since the best fit of the databases for EXP log J(MPAQ), log J(MMAQ) and log J(MHAQ) was to the Roberts-Sloan (RS) model, and the dependency of RS on a balance in lipid and aqueous solubility for optimization of topical delivery has been established, the present correlation suggests that the flux through a silicone can be used to predict flux through mouse or human and that the physicochemical properties that lead to optimized flux through one membrane will lead to optimized flux through the others.

Modeling of flux through silicone membranes from water

Do the Roberts-Sloan (RS) or modified Kasting-Smith-Cooper (KSC) equations that provide good fit to data for maximum flux, from water through mouse or human skin also provide a good fit to data for maximum fluxes through silicone membranes (polydimethylsiloxane, PDMS). The maximum fluxes through silicone membranes from water (J(MPAQ)), molecular weights (MW), solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) of 31 prodrugs and one parent drug have been fitted to the RS equation, which includes a parameter for dependence on S(AQ), and the KSC equation, which does not, to determine which equation gave the better fit. In addition, the J(MPAQ), MW, S(AQ) and solubilities in octanol (S(OCT)) of 26 diverse molecules from other laboratories were collected and fitted to the RS and KSC equations to determine if the choice of lipid parameter (S(IPM) or S(OCT)) had an effect on which equation gave the better fit. RS gave the better fit to the present prodrug database where: logJ(MPAQ)=-2.454+0.716 logS(IPM)+0.284 logS(AQ)+0.00208 MW, r(2)=0.77. RS also gave the better fit to the database from other laboratories where: logJ(MPAQ)=-2.046+0.667 logS(OCT)+0.333 logS(AQ)-0.00374 MW, r(2)=0.878 after four obvious outliers were removed to give n=22. Thus, data for J(MPAQ) can be fitted to the RS equation, which also provides the best fit to maximum flux from water through mouse or human skin and includes a dependence on S(AQ).

A comparison of the fit of flux through hairless mouse skin from water data to three model equations

Data for the delivery of total species containing parent drugs from water through hairless mouse skin by prodrugs, logJ(MMAQ), has been fitted to the Roberts-Sloan, RS, the Kasting-Smith-Cooper, KSC, and Magnusson-Anissimov-Cross-Roberts, MACR, equations. The RS model which contains a parameter for the dependence of flux on solubility in water, S(AQ), as well as solubility in the lipid isopropyl myristate, S(IPM), gave the best fit: logJ(MMAQ)=-2.30+0.575 logS(IPM)+0.425 logS(AQ)-0.0016MW, r(2)=0.903. The values for the coefficients to the parameters are quite similar to those obtained when the RS model was fit to flux of solutes from water through human skin, logJ(MHAQ). There was no trend in predicting the under or over-performance of prodrugs based on their fit to the RS model and whether they were more or less soluble than their parent drugs. There was an inverse dependence of logJ(MMAQ) on partition coefficients or permeability coefficients similar to that observed for logJ(MHAQ). The similarities in trends for results for logJ(MMAQ) and logJ(MHAQ) suggests that design directives obtained from mouse skin can be extended to design new prodrugs or select new drugs for delivery through human skin.

The effect of lipid and aqueous solubilities on flux of nicotinic acid esters from water through silicone membrane

Objective: The maximum fluxes (JM) of nicotinic acid esters (NAE) across silicone membranes from water (JMPAQ) have been measured to determine how well they correlate with JM of NAE across human skin from water in vitro (JMHAQ) and in vivo (JMHAQ1) and with JM of NAE across hairless mouse skin from water (JMMAQ). Materials and methods: The NAE were all commercially available. Solubilities in water (SAQ), isopropyl myristate (SIPM) and octanol (SOCT) were obtained from literature sources. JMPAQ were measured at saturation for all the esters except the methyl ester. In that case, flux was measured at a concentration (C) less than saturation (JPAQ) and converted to JMPAQ = (JPAQ)(SAQ/CAQ). Results and discussion: JMPAQ values predicted from the previously reported coefficients to the parameters in the Roberts-Sloan (RS) equation (PRE JMPAQ) were substantially lower than the experimental JMPAQ values (EXP JMPAQ) values obtained here. The EXP JMPAQ were incorporated into the previous JMPAQ database and new coefficients were obtained: x = −1.837; y = 0.742; z = 0.00435; r2 = 0.86. Correlation of JMPAQ values with JMHAQ, JMHAQ1, and JMMAQ values show the same trend as the JMPAQ values. Conclusions: The inclusion of the NAE n = 6 data into the previous n = 32 database for the permeation of the prodrugs through a silicone membrane from water (JMPAQ) greatly improved the fit of the n = 38 database to the RS equation: r2 = 0.86 vs r2 = 0.77. The correlation between log JMHAQ and log JMPAQ gave r2 = 0.98. This suggests that JMPAQ values are good predictors of JMHAQ values.

Topical Delivery Using Prodrugs

The objective of any prodrug approach is to transiently mask a particular functional group in a drug and thus change its physicochemical properties (solubility profile, degree of ionization), protect it from premature chemical or biological metabolism, or facilitate its active or passive transport across a biological barrier, to name only a few of the more obvious applications. In the example of the use of a prodrug approach to enhance topical delivery, a change in the physicochemical properties of the drug is the objective. That change is designed to facilitate the passive absorption across the stratum corneum (SC)—wherein lies the major barrier to permeation—into the viable epidermis and beyond, if necessary. More complete descriptions of the skin can be found in other references (Barry, 1983). Here, we use the term “topical delivery” to include dermal delivery (delivery into the skin) and transdermal delivery (delivery through the skin into systemic circulation).