Transdermal Systems for Overactive Bladder: Principles and Practice

TREATMENT OF OVERACTIVE BLADDER Transdermal Systems for Overactive Bladder: Principles and Practice David R. Staskin, MD Section of Voiding Dysfunction, New York Presbyterian Hospital, and Departments of Urology and Obstetrics/Gynecology, Joan and Sanford I. Weill Medical College, Cornell University, New York, NY The transdermal system for delivery of medication to treat overactive bladder may provide an improved efficacy-to-tolerability ratio by regulating serum drug levels; avoiding gastrointestinal and hepatic metabolism, which is important when the metabolite has a lesser therapeutic index than the parent drug; and achieving clinical efficacy with a lower total drug burden. Additional advantages may include increased compliance and obviation of the need for oral drug administration, which is especially beneficial for the patient who is taking multiple oral medications or is caregiver-dependent. An efficient patch system must preserve the physical integrity of the drug layer, provide adequate adhesion, store and release the drug and permeation-enhancing agent in a predictable manner, promote consistent absorption through the skin regardless of location or skin or subcutaneous tissue differences, demonstrate dose proportionality, maintain skin integrity during product use and removal, and be cosmetically acceptable. A novel transdermal delivery system that incorporates an occlusive layer covering an acrylic adhesive containing the active agent oxybutynin and a skin permeation enhancer has been demonstrated in clinical trials to achieve these goals. [Rev Urol. 2003;5(suppl 8):S26-S30] © 2003 MedReviews, LLC Key words: Overactive bladder • Oxybutynin • Transdermal delivery system xybutynin is widely used for the treatment of overactive bladder as immediate-release (oxybutynin IR) and extended-release (oxybutynin ER) oral formulations and now as a transdermal patch (oxybutynin TDS).1-3 Oxybutynin has a molecular weight of 357 daltons and is a tertiary amine, produced as a 1:1 racemate of R- and S-isomers. It is soluble in alcohol but relatively O S26 VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY Transdermal Systems for OAB Immediate Release DEO OXY Extended Release DEO OXY 30 20 10 0 0 12 24 36 48 60 72 84 96 Time (h) Figure 1. The primary metabolite of oxybutynin (OXY), N-desethyloxybutynin (DEO), circulates in plasma concentrations approximately 4 and 10 times those of the parent compound after administration of oral extendedrelease and immediate-release OXY formulations, respectively. Transdermal administration results in a lower concentration of DEO relative to the parent compound. centage of the parent drug is converted to the metabolite before reaching the target site (the bladder) or other organs responsible for side effects—primarily, the salivary gland, bowel, eye, and brain.10 Transdermal administration essentially bypasses this initial pre-systemic metabolism.11 The extent of dermal metabolism of oxybutynin before it enters the As a molecule, oxybutynin has an excellent profile, based on size, charge, and lipophilicity, for use as a transdermal agent. TDS) avoiding intestinal and hepatic pre-systemic metabolism, the therapeutic index of the medication is improved. Pre-systemic metabolism of oxybutynin in the gastrointestinal system, before it enters the circulatory system, occurs intraluminally within the small intestine and then primarily through hepatic first-pass metabolism. A per- Transdermal System DEO OXY 40 Mean Plasma Concentration (ng/mL) insoluble in water. Oxybutynin has anticholinergic, spasmolytic, and local anesthetic properties. Because the compound is a weak base (pKa ≈ 8), the unionized free base form of the drug predominates at physiologic pH, enabling transdermal permeation.4 Therefore, as a molecule, oxybutynin has an excellent profile, based on size, charge, and lipophilicity, for use as a transdermal agent. Many patients discontinue oral anticholinergic therapy, especially with the immediate-release oral formulation and to a lesser extent with the extended-release formulation, because of unacceptable side effects, particularly dry mouth.5 These adverse effects have been associated in various clinical studies with relatively high plasma concentrations of oxybutynin’s primary metabolite, N-desethyloxybutynin (DEO), which circulates in concentrations approximately 4 (oxybutynin ER) to 10 (oxybutynin IR) times those of the parent compound (Figure 1).6-9 Simply stated, the proposed explanation for improved tolerability of oxybutynin ER and, more profoundly, oxybutynin TDS is that the metabolite DEO has a higher side effect-to-efficacy ratio than the parent compound, oxybutynin, and by partially (oxybutynin ER) or completely (oxybutynin venous system and circulates to the target organ is minimal in view of the low cytochrome P450 content of the epidermis (approximately 5% of that in the liver).12 Although many molecules can be delivered transdermally, the ideal candidate is a drug that is extensively metabolized by the cytochrome P450 system in the proximal gut and liver into a metabolite that exhibits a poor therapeutic profile compared with the parent compound. Topically applied patches and gels, as well as sublingual, intravesical, intraocular, intravenous, and intramuscular preparations, avoid the gut. The clinical observations on the differential activity of oxybutynin and DEO on bladder versus salivary gland are supported by radioligand binding studies assessing the ability of oxybutynin and DEO to displace 3H-quinuclidinyl benzilate from human detrusor and human salivary gland muscarinic receptors (12 cystectomy and 7 parotidectomy specimens removed for malignancy).13 In these studies, the average pKi for oxybutynin and DEO in bladder smooth muscle were identical (8.2 ± 0.1); however, salivary gland pKi for DEO was significantly greater than that of oxybutynin (8.7 ± 0.1 vs 8.5 ± 0.1, respectively; P < .05). Therefore, the greater affinity of DEO VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S27 Transdermal Systems for OAB continued Side view Occlusive backing film Adhesive layer with drug and triacetin Disposable release liner Top view 7.6 cm 5.7 cm Figure 2. The oxybutynin transdermal delivery system: The matrix system allows transdermal delivery of the active component, which is regulated by a penetration enhancer. for the muscarinic receptors of the salivary glands may contribute to the anticholinergic side effect of dry mouth in formulations that result in DEO levels that are relatively high compared with levels of the parent compound. Types of Transdermal Systems The 2 types of transdermal systems may be described as liquid reservoir and matrix-type systems. Liquid reservoir systems generally contain the drug and enhancers in a semisolid, alcoholic gel. These systems have an occlusive backing film and may or may not incorporate a rate-controlling membrane that holds the gel in place on the skin. Drugs that require relatively high doses or greater permeation enhancement, such as testosterone, use liquid reservoir systems. The application of new enhancer and adhesive technologies has allowed many drugs that were initially administered in liquid reservoirs to now use matrix-type systems (eg, estradiol, nitroglycerin, nicotine). The matrix system utilized for oxybutynin TDS is composed of a S28 VOL. 5 SUPPL. 8 2003 layer that is peeled off and disposed of by the patient before application and 2 layers that are applied—the occlusive layer or backing film (a thin layer of flexible polyester/ethylenevinyl acetate film) and the active component, a cast film of acrylic adhesive containing oxybutynin and triacetin (Figure 2).14 The oxybutynin TDS matrix design results in oxybutynin delivery through the skin, which is controlled by the stratum corneum (Figure 3).15-17 Upon application of oxybutynin TDS, skin hydration occurs, followed by diffusion of both oxybutynin and the triacetin permeation enhancer into the stratum corneum. The physiochemical interaction of the permeation enhancer with the lipids in the skin controls the rate of oxybutynin diffusion through the stratum corneum. Inter-person variability in skin penetration is approximately 20%. Oxybutynin plasma levels increase as the drug is absorbed into the bloodstream, with steady state reached during the first patch application.18 In some systems, the enhancer may diffuse out of the patch and into the skin faster than the drug, resulting in significantly uneven absorption. This does not occur to a significant degree in the currently available system. The 39 cm2 patch contains 36 mg of oxybutynin, and the osmotic gradient and enhancer provide an average absorption of 3.9 mg/d. After 84 Figure 3. Schematic of skin absorption: The delivery of oxybutynin through the skin is controlled by the stratum corneum. REVIEWS IN UROLOGY Dosage form Stratum corneum Permeation Epidermis Metabolism Capillary Dermis Absorption Hypodermis Transdermal Systems for OAB Mean Oxybutynin Plasma Concentration (ng/mL) 7 13 cm2 TDS 6 26 cm2 TDS 39 cm2 TDS 5 4 3 2 1 System Removal 0 0 12 24 36 48 60 72 84 96 108 120 Time Post 3rd TDS Application (h) Figure 4. As the size of the transdermal delivery system (TDS) increases, there is a dose-proportional increase in plasma oxybutynin concentration. hours of continuous patch application, 13.65 mg of oxybutynin has been absorbed into the skin and 22.35 mg remains in the patch; at 96 hours, 15.9 mg (44%) of oxybutynin has diffused, with 20.1 mg remaining in the patch. Because of a small depot of oxybutynin in the skin, there is a transient increase in oxybutynin level that occurs just after patch removal; however, within 1 hour, serum levels begin to decline. The “apparent” half-life (approximately 8 hours) after patch removal is somewhat longer than the half-life measured after intravenous administration of the drug (approximately 4 hours), again because of the depot of oxybutynin that is slowly released over a few hours following patch removal. Transdermal Systems and the Skin The ability of patients to apply the patch at different anatomical sites and achieve equivalent drug absorption was confirmed in a bioequivalence study involving healthy volunteers. Application of oxybutynin TDS to the hip or buttocks resulted in absorption equivalent to that with application on the abdomen, which was used as the reference site as it was the site used in clinical trials demonstrating the safety and efficacy of oxybutynin TDS. This absorption equivalence allows each patient to determine the best application sites for his or her convenience and comfort and to maintain appropriate site rotation.19 Single- and multiple-dose pharmacokinetic studies demonstrated mean peak plasma concentrations (Cmax) of oxybutynin to be 3.4 ± 1.1 ng/mL and 6.6 ± 2.4 ng/mL, respectively, with median times to reach peak plasma levels of 36 hours and 10 hours, respectively. Steady-state plas- size (Figure 4).20 The ability of the patch to adhere well to the skin for several days with minimal irritation and to preserve skin integrity requires unique adhesive properties. Although these properties can be tested in vitro in the laboratory and in vivo in animal and human models, the most important information comes from actual clinical use. Skin irritation may be caused by occlusion of the skin and decreased skin “breathing,” adhesive removal of the stratum corneum or deeper layers, the enhancer, or the drug. Occlusion of the skin with hydration under the patch may affect skin integrity. Removal of the patch will exfoliate the stratum corneum, which is replaced within 7 days (the reason for patch site rotation). The enhancer or drug may cause skin reaction secondary to a chemical irritation (eg, pH) or from a true allergic reaction. Testing various placebo and active formulations allows characterization of the contribution of each component of the transdermal system to observed dermal effects. Transdermal Delivery: The Future The successful development of a transdermal delivery system for overactive bladder medication Steady-state plasma concentrations are achieved during the second application. ma concentrations are achieved during the second application. Plasma oxybutynin and DEO concentrations decreased gradually following Cmax until patch removal.19 A series of pharmacokinetic studies supported the 3 to 4 day application period, the rapid attainment of steady-state conditions, and a doseproportional increase in plasma concentrations with increasing patch should stimulate further investigation of alternative delivery systems. Potential improvements in medication delivery systems include the use of improved adhesive and/or enhancer technologies; a purified enantiomer (eg, R-oxybutynin) or alternative molecule; and systems that utilize thermal, electrical, ultrasonic, or other forms of energy to “drive” molecules through the stratum VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S29 Transdermal Systems for OAB continued corneum or microneedles to bypass the occlusive nature of the stratum corneum in a controlled fashion. The science of drug delivery will have a profound impact on patient care. After consideration of the theories and data from in vitro and in vivo models and clinical studies, the ultimate choice will be the shared responsibility of clinicians and patients, each bringing their own preferences to the clinical decisionmaking process. 4. 5. 6. 7. 8. References 1. Yarker YE, Goa KL, Fitton A. Oxybutynin: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6:243-262. Appell RA, Sand P, Dmochowski R, et al, for the OBJECT Study Group. Prospective randomized controlled trial of extended release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc. 2001;76:358-363. Davila GW, Daugherty CA, Sanders SW. A shortterm, multicenter, randomized double-blind dose titration study of the efficacy and anticholinerigic side effects of transdermal compared to immediate release oral oxybutynin 2. 3. 9. 10. 11. treatment of patients with urge urinary incontinence. J Urol. 2001;166:140-145. Noronha-Blob L, Lowe VC, Peterson JS, Hanson RC. The anticholinergic activity of agents indicated for urinary incontinence is an important property for effective control of bladder dysfunction. J Pharmacol Exp Ther. 1989;251:586-593. Versi E, Appell R, Mobley D, et al, for the Ditropan XL Study Group. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. Obstet Gynecol. 2000;95:718-721. Madersbacher H, Jilg G. Control of detrusor hyperreflexia by the intravesical instillation of oxybutynin hydrochloride. Paraplegia. 1991; 29:84-90. Massad CA, Kogan BA, Trigo-Rocha FE. The pharmacokinetics of intravesical and oral oxybutynin chloride. J Urol. 1992;148:595-597. Gupta SK, Shah J, Sathyan JG. Evidence for site-specific pre-systemic metabolism of oxybutynin following oral administration [abstract]. Clin Pharmacol Ther. 1997;61:227. Buyse G, Waldeck K, Verpoorten C, et al. Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism. J Urol. 1998; 160:892-896. Douchamps J, Derenne F, Stockis A, et al. The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol. 1998;35:515-520. Zobrist RH, Schmid B, Feick A, et al. Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyloxybutynin following oral and transdermal administration of the racemate in healthy volunteers. Pharm Res. 2001;18:1029-1034. 12. 13. 14. 15. 16. 17. 18. 19. 20. Mukhtar H, Khan WA. Cutaneous cytochrome P-450. Drug Metab Rev. 1989;20:657-673. Waldeck K, Larsson B, Andersson KE. Comparison of oxybutynin and its active metabolite, N-desethyl-oxybutynin, in the human detrusor and parotid gland. J Urol. 1997;157:1093-1097. Quan D, Deshpanday NA, Venkateshwaran S, Ebert CD. Triacetin as a penetration enhancer for transdermal delivery of a basic drug. United States Patent 5,601,839. Feb 11,1997. Wester RC, Maibach HI. Perspectives of dermal and transdermal drug delivery. In: Breimer DD, Speiser P, eds. Topics in Pharmaceutical Sciences. Amsterdam: Elsevier Science Publishers; 1985: 359-364. Berner B, John VA. Pharmacokinetic characterization of transdermal delivery systems. Clin Pharmacokinet. 1994;26:121-134. Ranade VV, Hollinger MA. Drug Delivery Systems. Boca Raton, Fla: CRC Press; 1996:177-208. Davila GW, Daugherty CA, Sanders SW, for the Transdermal Oxybutynin Study Group. A shortterm, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol. 2001; 166:140-145. Oxytrol [prescribing information]. Corona, Calif: Watson Pharma, Inc; 2003. Zobrist RH, Quan D, Thomas HM, et al. Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo performance of a novel delivery system. Pharm Res. 2003;20:103-109. Main Points • Although oxybutynin is widely and successfully used to treat overactive bladder, many patients discontinue the oral form of therapy because of side effects (especially dry mouth). The new oxybutynin transdermal delivery system (TDS) may offer a better alternative. • Dry mouth associated with the use of oral oxybutynin may be explained by the greater affinity of its metabolite, N-desethyloxybutynin (DEO), for the muscarinic receptors of the salivary glands. Thus, when the drug is metabolized, DEO levels in the salivary glands are relatively high compared with levels of the parent compound. • In bypassing the pre-systemic metabolism that occurs in the gut, oxybutynin TDS causes fewer side effects than the oral form of the drug. • The matrix system of the oxybutynin patch includes an active layer of oxybutynin and triacetin, a permeation enhancer that controls oxybutynin’s diffusion into the stratum corneum. • The 39 cm2 oxybutynin patch contains 36 mg of the drug. Bioequivalence studies have demonstrated drug absorption to be equivalent whether oxybutynin TDS is applied to the abdomen, hip, or buttocks. S30 VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY