(W1030-11-72) Formulation and Evaluation of Carvedilol Loaded Niosomes Encapsulated in Polymeric Microneedle

Purpose: To develop and evaluate a novel drug delivery system for carvedilol using niosomal encapsulation and polymeric microneedles that can overcome the limitations of conventional drug delivery methods for carvedilol, improve the bioavailability of carvedilol, and sustain its release.

Methods: The methodology involved fabrication various niosomes formulations utilizing a nonionic surfactant (span 60) and cholesterol at different concentrations. The particle size, polydispersity index (PDI), and zeta potential (ZP) of the formulations were then analyzed utilizing a particle Zetasizer analyzer. The entrapment efficiency of carvedilol-loaded niosomes was determined by isolating the unencapsulated drug via ultracentrifugation. An in vitro release experiment was conducted using a Franz cell diffusion system. The study involved preparing aqueous gels using different biocompatible polymers such as PVA and PVP at varying concentrations. To prepare the MNs, the selected polymer formulations were mixed with niosomes containing carvedilol until they were evenly mixed. The resulting mixture was then dispensed into MN molds with a needle density of 15 × 15, pyramidal needles, and 600μm height and 300 μm width at the base and 300 μm interspacing. The mechanical and insertion properties of the MNs were characterized, and ex vivo permeation studies were conducted using Franz diffusion cells. An HPLC method was used for the quantification of tested samples.

Results: The method of ether injection was employed to fabricate different niosomal formulations loaded with carvedilol. The spherical shape of the niosomes was confirmed by Transmission electron microscopy (TEM ) imaging. The size of the niosomes ranged from 170 to 612 nm. The study revealed that the niosomes produced using a 4:1 ratio of Span 60 to cholesterol (N-1) had the smallest vesicle sizes with a diameter of 170.80 ± 9.30 nm, followed by N-2 with a diameter of 249.30 ± 3.60 nm which has a surfactant to cholesterol ratio of 2:1. N-4 had a slightly larger particle size than N-1 and N-2, with a diameter of 259.10 ± 5.60 nm which has a surfactant to cholesterol ratio of 1:1. Vesicles with a PS greater than 600 nm are typically unable to deliver the encapsulated drug to the deeper skin layers [1]. Accordingly, they tend to remain on or in the SC and form a lipid layer on the skin. In contrast, vesicles with a diameter of 300 nm or less are able to reach the deeper skin layers to some extent. Therefore, vesicles with a PS larger than 300 nm were excluded from this study. It can be observed that N-1 formulation has the highest EE% of 98.33 ± 0.43 and the EE% for N-4 was 90%. Formulation N-1 and N-4 show the most favorable characteristics among the studied formulations. As a result, they were chosen for further analysis and evaluation. Cumulative carvedilol release from N-1 and N-4 was approximately 95% and 64%, respectively, within 24 hours. All release profiles were biphasic, with an initial fast release phase lasting roughly 2-3 hours, followed by slower, and more controlled release pattern as shown in Figure 1. The primary and secondary release phases may be caused by drug molecule diffusion distances in the outer and inner vesicle membranes, respectively. After the first hour, the release percentage results from N-1 and N-4 were 8.5% ± 0.3, and 27.7% ± 4.3 respectively. As a result, N-4 was chosen to be used in polymeric MNs formulations. To prepare the MNs, the selected polymer formulations were mixed with niosomes containing carvedilol until they were evenly mixed. The resulting formulations had excellent physical properties upon removal from the mold, being firm but not brittle, with a smooth, and uniform texture. We observed that within 20 minutes, the microneedles had completely dissolved as shown in Figure 2. This can improve the safety of microneedle-based drug delivery systems and avoid the need for needle disposal [2]. MNs inserted up to 510 µm which is approximately 85% of the MN height. For MNs loaded with raw carvedilol, the cumulative amount (Q) was found to be 36.21±6.50 µg/cm², flux (Jss) was 1.70±0.424 µg/cm²/hr, and P was 0.002±0.0005 cm/hr. On the other hand, for MNs loaded with niosomal carvedilol, the Q was found to be significantly higher (P < 0.05) at 303.59±2.81 µg/cm², Jss was 14.00±0.916 µg/cm²/hr, and P was 0.018±0.0012 cm/hr. These results suggest that the use of niosomal carvedilol in MNs can significantly enhance drug permeation compared to MNs loaded carvedilol without niosomes.

Conclusion: In conclusion, the development of a novel drug delivery system for carvedilol using niosomal encapsulation and polymeric microneedles has shown promising results. The use of niosomes as a drug carrier has enabled a controlled release of the drug, and the most effective formulation was selected to fabricate polymeric MNs as an alternative method of drug administration.

References: 1. Opatha, S.A.T., Titapiwatanakun, V. , and Chutoprapat, R., Transfersomes: A Promising Nanoencapsulation Technique for Transdermal Drug Delivery. 2020. 12(9).
2. Alkilani, A. Z., Nasereddin, J., Hamed, R., Nimrawi, S., Hussein, G., Abo-Zour, H., & Donnelly, R. F. Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems. Pharmaceutics, 2022. 14(6), 1152.

Acknowledgements: This work received financial support from the Zarqa University.

Table 1: Size, PDI and Entrapment efficiency of CAR-loaded niosomes.

Figure 1: In vitro release studies of carvedilol from N-1 and N-4 niosome (n= 3).

Figure 2: Morphological changes of the MN-2 after insertion into the rat skin at (A), 5 (B), 10 (C), and 20 (D) min.