Selection of Active Pharmaceutical Ingredients …

1 JULY 2011 TransDermal20 Selection of Active PharmaceuticalIngredients (APIs) and Excipients forTopical Formulations Eugene Cooper, Cooper ConsultingGarry T. Gwozdz and Robert W. Lee, Particle Sciences, drug delivery (TDD) is a viable optionfor systemic delivery of select drugs. It providesadvantages, such as avoidance of first-passmeta bolism, patients improved compliance,con trolled or sustained release, and decreasedside effects. This article focuses on transdermaldelivery via application of a topical, semisolidformulation in the form of a gel, lotion, or authors discuss physicochemical criteria forselection of APIs and excipients for this type challenge in using TDD resides inthe issue of permeation of drugs through theskin.

2 Many researchers have written aboutchemical permeation enhancement and other methodsfor enhancing delivery. A recent review on advancedphysical techniques used for enhancing delivery ofdrugs includes discussions on structurally based, elec-trically based, velocity based and other physicallybased techniques that enhance permeation [1]. Another area of research focuses on transdermaldelivery of peptides and proteins. Since they havehigher molecular weights compared to chemicalAPIs and are hydrophilic in nature, they cannot pas-sively permeate across the skin because the stratumcorneum allows transport only of small lipophilicAPIs.

3 A recently published review of enhancementtechniques included chemical enhancers, ion-tophoresis, microneedles, electroporation, son -ophoresis, thermal ablation, laser ablation, radiofre-quency ablation, and noninvasive jet injectors thataid in the delivery of proteins by overcoming theskin barrier [2]. Kalluri and Banga s review describesvarious techniques and discusses mechanisms,sterility requirements, and commercial developmentassociated with these types of products. Nanotechnology also is an area of intense research andhas been applied successfully for transdermal deliv-ery.

4 For both dermal and transdermal delivery,approaches in the field of nanosized particulate sys-tems include nanosized microemulsions, vesicular sys-tems, solid lipid nanoparticles (SLN), nanostructuredlipid carriers (NLC), and polymeric nanoparticles [3].This article focuses on topical formulations fortransdermal delivery. The first section discussesphysicochemical criteria for Selection of APIs thatare suitable. A discussion of excipients follows,including design of experiments for formulationdevelopment and in-vitro release testing to evalu-ate the formulations.

5 Selection of APIsThis section provides general and simple guidelinesfor selecting APIs suitable to transdermal deliveryusing topical formulations. They are based on a sim-ple set of metrics derived from molecular properties,desired plasma levels, and pharmacokinetic parame-ters. The starting point for a simple pharmacokinetic(one compartment) system is a ratio of the steady-state transdermal input to the elimination steady-state transdermal input is the product ofA, the area of application, and Js, the steady stateflux.

6 The elimination output is the product of V, thevolume of distribution, and ke, an elimination-rateconstant. The steady-state transdermal input dividedby the elimination output gives the steady-stateplasma level C , as shown in Equation 1 [4]. Equation 1: C = AJs/VkeThus, if a formulation scientist knows the desiredplasma level and the pharmacokinetic parametersand can estimate Js, he or she can determine if Cpcan be achieved with a reasonable area of applica-TransDermal JULY 201121 Sfis the entropy of fusion of the permeant, whichfor a large number of permeants was about 16entropy unitsThus, the melting point of the permeant drives solu - bility .

7 Which decreases about ten-fold for every hun-dred-degree rise in melting researchers modeled the diffusion coefficient Dand fit it to human in-vitro skin-penetration data asfound through Equation 4 for molecular volume vand Equation 5 for molecular weight 4: D = D0exp (- v)Equation 5: D = D 0exp (- M)Figure 1 summarizes these considerations, showingconstant, maximum-flux (Jm) contours from saturatedvehicles for different melting points and molecularweights. The dashed lines represent the region of theexperimental data.

8 Although this figure represents agreat simplification of a very complex problem, it pro-vides a very simple way to obtain a ballpark estimateof the maximum flux based on two accessible molecu-lar parameters, the melting point and the molecularweight. Using Figure 1, the scientist needs only toknow the melting point and the molecular weight toestimate the maximum steady-state flux. tion on the skin surface. Cooper used Equation 1 anda Jsfrom in-vitro skin-penetration studies to predict,with reasonable accuracy, the surface area requiredto deliver systemic levels of indomethacin from top-ical application of a gel [5].

9 Assuming that the formulation scientist knows thedesired blood level and pharmacokinetic parame-ters, an estimate of Jsrequires use either of molecularparameters or results from in-vitro experiments. Theremainder of this section is devoted to estimating Jsfrom molecular simplicity, consider Jsto be the product of S, thesolubility of the drug in the lipids of the stratumcorneum, and Psc, the permeability of the stratumcorneum (Equation 2).Equation 2: Js= SPscWang, Kasting, and Nitsche have developed verysophisticated models for predicting permeability [6to 8].

10 Their models are beyond the scope of thisanalysis, which will employ a much simpler modelto determine if transdermal delivery is possible orout of the this simplest model, the formulation scientist canview permeability as the quotient of D, the diffusioncoefficient of the stratum corneum, divided by h, itseffective thickness. Kasting, Smith, and Cooperdeveloped a model for D based only on the molecu-lar volume of a drug (or on its molecular weightsince volume scales reasonably well with molecularweight) [9, 10].