(W1130-03-14) Microarray Patches with Cyclodextrin-Carvedilol Complex for Heart Failure Treatment

Purpose: Heart failure is a progressive multi-faceted cardiovascular condition characterized by reduced cardiac output [1]. This reduction in the heart's efficiency to pump or fill with blood may stem from various factors, including myocardial infarction, hypertension, or, rarely, cardiac amyloidosis [2]. Carvedilol (CAR), a third-generation β-blocker, is widely prescribed for chronic heart failure management [3]. However, its oral bioavailability is limited (25-35%) with significant interpatient variability [4]. This variability arises from its narrow absorption window in the upper gastrointestinal tract, slow dissolution profile, and significant hepatic first-pass metabolism [4]. To address these limitations, we present, for the first time, the development of tip microarray patches (MAPs) made from ternary cyclodextrin (CD) complexes of CAR for transdermal delivery, aiming to enhance its bioavailability for heart failure management.

Methods: The ternary complex of CAR with hydroxypropyl γ-CD (HPγCD) and poly(vinyl pyrrolidone) (PVP) was prepared as the first layer of MAPs by mixing the powder with deionized water (powder-to-water ratio 1:2). The aqueous mixtures were cast into silicone molds (16 x 16 pyramidal needle density on a 0.36 cm² area with 850 µm height). All MAP formulations were visualized using a digital microscope and scanning electron microscope (SEM). A Texture Analyzer evaluated the mechanical properties of the MAPs under a compressive force of 32 N, akin to manual thumb pressure ^[5]. The insertion capability of the MAPs into the skin simulant Parafilm^® M and ex vivo full-thickness neonatal porcine skin were evaluated using optical coherence tomography (OCT). In vitro permeation studies were conducted using modified Franz diffusion cells to quantify the amount of drug deposited into the skin and the amount that permeated through the neonatal porcine skin. Biocompatibility of dissolving MAPs loaded with carvedilol/CD/PVP and CD/PVP alone with fibroblast cells (ATCC CL-173) was evaluated through a series of biocompatibility assays. Pharmacokinetics of the formulation were assessed over 7 days compared to oral gavage using male Sprague Dawley rats. To determine the effect of the formulation on the lumen diameter of the aorta, hearts of the rats were collected post-mortem and stained with haematoxylin and eosin for evaluation.

Results: Prior to fabricating the MAPs, we developed, optimized, and characterized ternary complexes of carvedilol/HPγCD/PVP. The results indicate the formation of CD complexes (Figure 1). The optimized formulation of these ternary complexes was then incorporated into the MAPs using a double casting technique. The resulting MAPs formed homogeneous arrays successfully, as depicted in Figure 2. Application of a force of 32N/array reduced needle height by less than 10% in all cases (Figure 2). Insertion studies revealed that MAP formulations effectively breached ex vivo neonatal porcine skin to a depth of approximately 600 µm. Upon insertion, the needles dissolved within 2 hours, facilitating CAR deposition and transdermal delivery. Evaluation with fibroblast cells confirmed minimal toxicity and acceptable biocompatibility of the MAPs. During the in vivo study, upon removal of the MAPs after 24 hours, we observed complete dissolution of the needle layers. Additionally, there were no indications of skin irritation on any of the rats post-MAP removal, corroborating the biocompatibility data. Moreover, transdermal administration of carvedilol via MAPs did not induce noticeable signs of hepatotoxicity relative to the oral group or the positive and negative control. Administration of carvedilol as a dissolving MAP resulted in a significant shift (p < 0.05) in T_max from 3 hours to 41 hours (Figure 3). Additionally, we observed an increase in C_max from 43.2 ng/mL to 59.4 ng/mL. Furthermore, the AUC for the MAP-treated group was 7-fold higher than that of the oral treatment group. In this instance, the AUC indicates that delivery of CAR via dissolving MAP resulted in enhanced bioavailability relative to oral administration. Moreover, administration of CAR via dissolving MAP loaded with CD complexes resulted in a statistically significant (p < 0.05) dilation in the aorta relative to both the untreated and oral treatment group.

Conclusion: This study demonstrates for the first time that ternary cyclodextrin complexes generated in the tip of MAPs can serve as intradermal depots for sustained release of poorly soluble drugs, such as carvedilol, over several days upon skin application. This novel approach offers a patient-friendly and painless method to improve the bioavailability of carvedilol, ultimately contributing to effective heart failure management.

References: [1] R.H.G. Schwinger, Pathophysiology of heart failure, Cardiovasc Diagn Ther 11 (2021) 263–276. https://doi.org/10.21037/CDT-20-302.
[2] M. Grogan, A. Dispenzieri, Natural history and therapy of AL cardiac amyloidosis, Heart Fail Rev 20 (2015) 155–162. https://doi.org/10.1007/s10741-014-9464-5.
[3] National Institute for Health and Care Excellence, Chronic heart failure in adults: diagnosis and management, NICE Clinical Guideline (2018) 1–36. https://www.nice.org.uk/guidance/ng106/chapter/Recommendations.
[4] M. Sharma, R. Sharma, D. Kumar, A. Saraf, International Journal of Biological Macromolecules Enhancement of oral bioavailability of poorly water soluble carvedilol by chitosan nanoparticles : Optimization and pharmacokinetic study, Int J Biol Macromol 135 (2019) 246–260. https://doi.org/10.1016/j.ijbiomac.2019.05.162.
[5] E. Larrañeta, J. Moore, E.M. Vicente-Pérez, P. González-Vázquez, R. Lutton, A.D. Woolfson, R.F. Donnelly, A proposed model membrane and test method for microneedle insertion studies, Int J Pharm 472 (2014) 65–73. https://doi.org/10.1016/J.IJPHARM.2014.05.042.

Acknowledgements: The animal experiments were conducted following the guidelines of the Committee on Animal Research & Ethics (CARE) of the Faculty of Pharmacy, UiTM.


Figure 1. (A) Formation of carvedilol/HPγCD/PVP ternary complex via lyophilisation. Characterisation of carvedilol (CAR): (B) Response surface plots detailing the effect HPγCD and PVP on the solubility of CAR, (C) DSC thermograms, (D) FTIR spectra (E) XRD diffractograms, and (F) SEM images of pure CAR, pure excipients, physical mixture, binary and ternary complex of the CAR.


Figure 2. (A,B) Optical microscopy and (C) SEM images of different MAPs that are tip prepared with carvedilol/CD/PVP complexes. (D) Needle height reduction (%) for MAP loaded with CD-complexes upon being compressed with a 32 N force for 30 s (means + SD, n = 20). (E) Percentage of microneedle pores generated per Parafilm® layer following the insertion of carvedilol/CD/PVP loaded MAPs (means ± SD, n = 3). OCT images of MAP insertion (F) ex vivo neonatal porcine skin and (G) Parafilm®M. (H) Amount of drug permeated across the skin of the Franz cell following 24 h permeation study (means ± SD, n = 3). (I) Amount of carvedilol extracted from the skin (means + SD, n = 3).


Figure 3. (A) Schematic illustrating the delivery of carvedilol in vivo using dissolving MAPs with CD ternary complex tips. (B) Plasma level of carvedilol over time for rats treated with either dissolving MAPs or oral gavage (means ± SEM, n=6). (C) Pharmacokinetic parameters, AUC, Cmax, Tmax following dose administration (means ± SEM, n=6). (D) Aorta diameter of rats from different treatment group (means + SEM, n=6). (E) Representative histological analysis of the aorta of rats that were untreated or those that were either treated with oral administration of carvedilol or via dissolving MAPs.