(T0930-04-23) Poly(Acrylic Acid)/Poly(Vinyl Alcohol) Microarray Patches for Continuous Transdermal Delivery of Levodopa and Carbidopa: In Vitro and In Vivo Studies

Purpose: Parkinson’s disease (PD) is one of the most prevalent neurological disorders, affecting 10 million people across the globe (1). Among the various treatment options, levodopa (LD) is the most efficacious and the gold standard therapy for decades. While effective, one major issue is the ‘off’ period complications such as rapid fluctuation between good and poor symptom management, which is believed to be the result of the fluctuating pharmacokinetics of LD following oral administration (2). Once orally administered, LD undergoes extensive first-pass metabolism and rapid distribution into the skeletal muscles. The competence of transport carriers from other amino acids, which varies upon daily food uptake, and the delayed gastric emptying time in PD patients, results in a frequent treatment ‘off-state’ and, more importantly, an insufficient amount of LD delivered to the brain (3). It is also challenging for a PD patient to adhere to a treatment regimen that requires administration at several time points within a single day (4). Duodopa® is the most effective option currently to offer a continuous delivery of LD and its decarboxylase inhibitor carbidopa (CD), whereas the administration involves invasive surgical procedures, which could potentially lead to lifelong complications, such as infection. Therefore, we proposed, for the first time, the concept of using dissolving microarray patch (MAP) for the continuous delivery of LD and CD as a minimally-invasive alternative approach.

Methods: Poly(acrylic acid) (PAA) was selected to maintain an acidic pH during the MAP casting. A ‘two-layered’ dissolving MAP design as illustrated in Figure 1(a), was utilised to ensure the majority of the ‘drug-containing’ shaft of each needle could be inserted beneath the skin’s physiological barrier, the stratum corneum, to deliver the incorporated drug cargo into the viable skin layers for absorption into the systemic circulation. The ex vivo skin permeation profiles of LD and CD were evaluated via a Franz cell apparatus, using dermatomed porcine skin (~ 350 μm) obtained from stillborn piglets. Healthy female Sprague Dawley^® rats were used to understand the in vivo pharmacokinetic profiles of LD/CD dissolving MAPs in comparison to the oral suspension.

Results: The formulated dissolving MAPs illustrated a clear separation between the ‘drug-containing’ needle and the transparent ‘drug-free’ supporting baseplate as shown in Figure 1(b) and (c), indicating a successful fabrication of the ‘two-layered’ dissolving MAPs. Based on the ex vivo permeation profiles of the LD/CD dissolving MAPs illustrated in Figure 1(d), there was 1.49 ± 0.10 mg of LD (~ 82% of LD content) and 0.28 ± 0.02 mg of CD (~ 60% of CD content) delivered over a period of 24 h. Moving forward to the in vivo pharmacokinetics study (22 mg/kg LD and 6 mg/kg CD), as depicted in Figure 1(e) and (f) both drugs were detected in the plasma just 1 h after application of the dissolving MAPs. Some pharmacokinetic parameters are listed in Table 1. There was no significant difference in the LD AUC values obtained from the MAP and oral cohorts (p > 0.05), indicating a comparable drug exposure between the two formulations. However, a continuous release behavior of LD and CD was observed with the dissolving MAPs, whereas the plasma levels of LD and CD from the rats treated with oral suspension rapidly rose and then declined after 30 h and 6 h, respectively. There is no available data for the minimum effective concentration of CD while the therapeutic level of LD has been reported as 3-12 nmol/ml (approximately 394-1577 ng/ml) (5). The plasma levels of LD of rats treated with the dissolving MAPs stayed within the therapeutic range for at least 4 days, whereas those of the orally administered LD/CD were above the therapeutic range from 24 h to 48 h, highlighting the benefits of using the dissolving MAPs to avoid having unnecessarily high plasma concentrations, thereby reducing the risks of having side effects.

Conclusion: This work, for the first time, describes the concept of using dissolving MAPs fabricated from an acidic polymer to continuously deliver LD and CD transdermally. The in vitro and in vivo results demonstrate that the formulated MAPs can continuously deliver LD and CD upon a single application of 24 h. Not only could this work highlight the promising role of MAPs in transdermal drug delivery, but also provide a novel insight into the practical benefits of using MAP as an alternative to the current LD controlled release formulations.

References: 1. Beitz JM. Parkinson's disease: a review. Frontiers in Bioscience (Scholar Edition). 2014;6(1):65-74.
2. Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's disease: current status and future developments. Current Neuropharmacology. 2018;16(8):1239-52.
3. Contin M, Martinelli P. Pharmacokinetics of levodopa. Journal of Neurology. 2010;257(2):253-61.
4. Reichmann H. Transdermal delivery of dopamine receptor agonists. Parkinsonism & Related Disorders. 2009;15:S93-S6.
5. Nutt JG, Woodward WR. Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology. 1986;36(6):739-744.


Figure 1. (a) A schematic illustration of the dissolving MAP casting process. Representative digital microscopic images of (b) morphology of the dissolving MAPs and (c) drug distribution in the dissolving MAPs. (d) Ex vivo permeation profiles of the dissolving MAPs (means  S.D., n = 3). In vivo pharmacokinetic profiles of (e) LD and (f) CD following dissolving MAP administration and oral gavage (means  S.D., n = 5).


Table 1. In vivo pharmacokinetic parameters of the LD/CD dissolving MAPs.