Excipients in topical drug formulations

The penetration of active substances through the skin in transdermal and topical preparations can be improved by the use of suitable penetration enhancers. Johann Wiechers of Unichema* describes how excipients can play a big role in creating a successful formulation

A good topical formulation is one that exerts the desired pharmacological activity without the occurrence of negative side-effects such as skin irritation, while being pleasant and easy to use for the patient ensuring patient compliance. A good topical formulation is therefore a lot more than just the intrinsic activity of its drug. Excipients are those chemicals in formulations that do not exert a pharmacological activity themselves, but that have an impact on many other aspects including those mentioned above. Not only do they affect the clinical effectiveness, skin irritation potential and product feel of topical formulations, but they also influence formulation structure and manufacturing. In this paper, I will primarily focus on the skin penetration enhancing aspects of excipients and provide some general recommendations of suitable skin penetration enhancers.

The importance of skin delivery

The overall pharmacological activity of a finalised formulation can be characterised by the equation:

Clinical activity of formulation = Intrinsic activity of drug V Delivery

The multiplication sign in this formula indicates that both the intrinsic activity of the drug and its delivery need to be optimised to obtain a truly active formulation. It is quite common in pharmaceutical companies to concentrate their activities in their drug design/discovery, pharmacology and toxicology departments rather than their formulation department. Once a positive pharmacological activity and toxicological profile has been established, the desire to go into clinical trials is tremendous as in vivo evidence for the clinical activity of the formulation is the ultimate goal and patents run out relatively fast. However, this approach bears the risk of failure in clinical trials. If more time and effort would be spent the selection of the proper excipients, these disappointments may be overcome.

What could excipients do to ensure that the clinical activity of the formulation is optimised? Enhancing skin delivery is useful when the concentration of drug at its site of action is below the minimal effective concentration (MEC), or if high levels of drug are needed in the formulation to reach the MEC. Fig. 1 shows a typical concentration-delivery profile in which the concentration at the site of action continues to increase at increasing drug concentrations in the formulation until a certain value when a plateau is reached.

When incorporating a skin penetration enhancer, the concentration-delivery profile will shift towards higher levels in the skin at the same concentration of drug in the formulation. Two scenarios can be envisaged: Firstly, it may be possible to achieve the same concentration of drug at the site of action using a lower concentration of drug in the formulation. Secondly, it may lift the concentration at the target site above the minimal effective concentration, thereby creating an efficacious topical product. The first scenario may have major advantages for the systemic toxicological profile of the product as well as the production cost, whereas the benefits for the second scenario are too obvious to spell out.

It will always be very useful to know the Minimal Effective Concentration (MEC). From this, one can calculate the minimally required skin penetration rate to obtain clinical effect. For transdermal drug delivery, where pharmacokinetic parameters like the volume of distribution and clearance may be known, this is quite easy to do, but this approach is not common for dermal delivery. By realising that at steady-state the input rate of drug into the skin equals the output rate influenced by the clearance of the drug from the dermis, the following equations can be derived:

Input = JSS = kP . DC

Output = Cl . CT

in which JSS is the flux at steady state, kp the permeability coefficient, DC the drug concentration difference between formulation and plasma levels, normally equal to C, Cl the clearance, ie estimated to be equal to the cutaneous blood flow, and CT the skin tissue concentration; and therefore:

CT = kP . DC

Cl

Clinical efficacy might be expected, if CT equals or is greater than the MEC. Excipients can influence both the permeability coefficient and the drug concentration in the formulation both positively and negatively, and therefore the choice of excipients becomes very important. Unfortunately, it is quite common in formulation development studies that the formulation scientist has the precise knowledge of the active ingredients that are to be formulated into the dosage form and yet still needs to know which excipients to select.

Skin penetration enhancers

The ideal properties of chemical skin penetration enhancers were listed by Barry in 1983,1 and have not changed since. Apart from enhancing the skin penetration of a wide variety of drugs, they should be pharmacologically inert, non-toxic, non-irritating, non-allergenic; their onset of action should be immediate, reversible and unidirectional; they should be compatible with a wide range of ingredients in various dosage forms; they should be an excellent solvent for the drug, spread well and possess suitable skin sensory properties and finally, they should be inexpensive, odourless, tasteless and colourless. It is not surprising that the ideal skin penetration enhancer has not yet been identified. In addition, these molecules should ideally be Pharmacopoeia-listed, or sufficient safety data should be available in case they are not.

New chemical skin penetration enhancers appear quite regularly in the scientific literature, a process probably facilitated by the elucidation of their mechanism of action. However, hardly any of these purpose-made enhancers are incorporated in marketed formulations. For example, 1-dodecylazacycloheptan-2-one (Azone) was developed specifically as a pharmaceutical vehicle for incorporation into both topical and transdermal drug delivery systems to facilitate and control delivery of drugs across the stratum corneum. It was patented in 1976 and described for the first time in the scientific literature in 19822 and has become a benchmark for skin penetration enhancement. In 1996, it was still only used in no more than two marketed products. This does not mean that there are no skin penetration enhancers used in modern topical formulations, but it is generally recognised that there is a direct correlation between the extent of skin penetration enhancement and the amount of regulatory difficulties one is likely to encounter due to incorporating purpose-made skin penetration enhancers as excipients in one's formulation.

Good skin penetration enhancers, i.e. those enhancing skin penetration 50 to 100-fold or more, are often prone to skin irritation although there are exceptions to this rule. This can be understood by realising that they work by influencing bilayers not too dissimilar from those comprising the biological membranes. Therefore, skin permeation enhancers with an enhancement ratio of about 10 are preferred. They are active enough to rectify their role in the formulation, but not active enough to cause additional skin irritancy problems. One class of enhancers showing only moderate enhancement and on average lacking prominent skin irritancy are the fatty acids and alcohols and esters thereof. These common ingredients in pharmaceutical formulations have the advantage of being one of the endogenous compounds in human skin lipids, including the stratum corneum.3

Structure-activity relationships

Aungst investigated many fatty acids and alcohols for their capacity to enhance skin penetration of naloxone4,5 and these investigations were recently complemented by Tanojo for p-aminobenzoic acid.6 It demonstrated that saturated fatty acids and alcohols showed a parabolic pattern of enhancement, with a maximum around C12. For unsaturated fatty acids and alcohols, the maximum chain length is around C18, whilst the effects of introducing more than one double bond and the position of the bonds are relatively small. The configuration of the bonds, however, is important. The cis-isomers demonstrate on average more skin penetration enhancement than their corresponding trans-isomers.

Mechanism of action

There are three main modes of action for skin penetration enhancers as summarised by Barry in his lipid-protein-partition (LPP) theory. Enhancers can be classified according to whether their primary effect is by disruption of the stratum corneum lipids, interaction with intracellular proteins, and improved partitioning of the drug into the stratum corneum.7

Disruption of the stratum corneum lipids: In the skin lipid domain, enhancers may perturb the polar head groups of the lipid bilayer (site A, see Fig. 2), the aqueous regions between the polar lipid head groups (site B) and/or the rigid packing of the lipophilic bilayers (site C). It has been proposed that oleic acid disrupts the packed structure of the intercellular lipids because of the incorporation of its kinked structure (the kink being due to the cis double bond).8

Another recently proposed mechanism is that oleic acid penetrates the skin but does not homogenously mix with the stratum corneum lipids. It would exist as pools of fluid within the stratum corneum, thus forming defects in the barrier function by providing an alternative penetration route.9 Rigidly packed lipid structures of long, saturated hydrocarbon chains are also disrupted by the incorporation of shorter, saturated hydrocarbon chains or those with branched side chains. Assuming this also to be the case for intercellular lipids in the stratum corneum, this would explain the optimum for skin penetration enhancement for the C10-12 unsaturated fatty acids and alcohols and why isostearic acid is a better skin penetration enhancer than stearic acid.5

Interaction with intracellular proteins: The interaction of skin penetration enhancers in the proteinaceous domain results in the swelling of the protein matrix and changes in the keratin helices. There is no evidence in the literature that fatty acids and alcohols work by this mechanism.

Increased partitioning of the drug into the stratum corneum: The vehicle/stratum corneum partition coefficient of the drug decides whether the drug will preferentially remain in the vehicle or penetrate the skin. If the main solvent of the vehicle were to penetrate the skin rapidly and the drug has a high affinity for this solvent, then the partitioning into and permeation through the skin can be increased by a solvent drag mechanism in which drug and vehicle permeate together. This has been demonstrated to be the case for mixtures of fatty acids or alcohols and propylene glycol for a variety of penetrants.5 However, ion-pair formation with fatty acids has also been mentioned as a mechanism to contribute to the skin penetration enhancement of cationic drugs.10

Secondary enhancers

The vehicle in which putative enhancers are tested is very important. Especially for the more lipophilic enhancers like Azone, fatty acids like oleic acid and terpenes, it was noticed that skin penetration enhancement was increased manyfold when combined with propylene glycol.11 This widely used constituent of dermatological formulations seems to be the best vehicle for the fatty acids and alcohols as compared to isopropanol, polyethylene glycol 400, mineral oil or isopropyl myristate.4

Propylene glycol works in two different ways. Firstly, the solubilising capacity of the aqueous sites of the stratum corneum is increased. The accumulation of propylene glycol may cause the establishment of a drug reservoir. On the other hand, only drugs that are highly soluble in propylene glycol offer enhanced penetration behaviour. Therefore, it seems likely that the sorption promoting effect is mainly related to a solvent drag effect.11 It has been argued that it is this solvent drag that allows the primary enhancer to reach its site of action, and therefore to reach its full potential.

General recommendations

Based on the information above, a few general recommendations can be extracted for the use of skin penetration enhancers in dermal and transdermal drug delivery. Firstly, identify whether the molecule of interest has the right physico-chemical, pharmacological and pharmacokinetic characteristics to be delivered via the topical route. Obtain predicted permeability coefficient values from the equations provided by Barratt12 or Potts and Guy.13 Secondly, estimate the gap that needs to be bridged between predicted CT and MEC.

Thirdly, use mild to moderate skin penetration enhancers with a proven track record for skin safety, paying special attention to skin irritation. Combine suitable enhancers (especially the lipophilic ones) with secondary enhancers such as propylene glycol, optimising the drug concentration in the vehicle (close to the maximum solubility of the drug in the formulation, and enough drug in absolute terms to reach the minimal effective concentrations). Measure skin delivery and estimate whether minimal effective concentrations could be reached prior to performing clinical studies. Re-test the skin irritation potential of the finalised formulation before finally going into clinical trials.

References

1. B.W. Barry, `Dermatological formulations: percutaneous absorption', Marcel Dekker, New York, 1983.

2. R.B. Stoughton, Arch Dermatol., 1982, 118, 474.

3. M.A. Lampe, A.L .Burlingame, J.A. Whitney, M.L. Williams, B.E. Brown, E. Roitman and P.M. Elias, J. Lipid Res., 1983, 24, 120.

4. B.J. Aungst, N.J. Rogers and E. Shefter, Int. J. Pharm., 33 (1986) 225.

5. B.J. Aungst, Fatty Acids as Skin Permeation Enhancers, in: E.W. Smith and H.I. Maibach, (Eds), `Percutaneous penetration enhancers', CRC Press, Boca Raton, FL, US, 1995, Chapter 9.1.

6. H. Tanojo, J.A. Bouwstra, H.E. Junginger and H.E. Bodd, Pharm. Res., 14 (1997) 42.

7. B.W. Barry, J. Contol. Rel., 1991, 15, 237.

8. B.W. Barry, J. Control. Rel., 1987, 6, 85.

9. B. Ongpipattanakul, R.R. Burnette, R.O. Potts and M.L. Francoeur, Pharm. Res., 1991, 8, 350.

10. P.G. Green, R.H. Guy and J. Hadgraft, Int. J. Pharm., 1988, 48, 103.

11. B. Bendas, R. Neubert and W. Wohlrab, `Propylene glycol', in: E.W. Smith and H.I. Maibach, (Eds), `Percutaneous penetration enhancers', CRC Press, Boca Raton, FL, US, 1995, Chapter 3.2.

12. M.D. Barratt, Toxicol. in Vitro, 1995, 9, 27.

13. R.O. Potts, and R.H. Guy, Pharm. Res., 1992, 9, 663.

*Dr. Johann Wiechers is at Unichema International, PO Box 2, NL-2800 AA Gouda, The Netherlands.

This is an edited version of a paper given at the 1997 CPhI Conference. Full proceedings are available from Manufacturing Chemist at the address on p3