(T0930-04-23) Put a Ring on It: 2-Hydroxypropyl-β-cyclodextrin-Complex-Cabotegravir Sodium with Hydrogel-Forming Microarray Patches for Minimally Invasive HIV- Pre-exposure Prophylaxis

Purpose: Currently, there are an estimated 1.5 million new HIV infections each year and, in 2020 alone, approximately 680,000 deaths were attributed to HIV-related illnesses [1,2]. Current antiretroviral therapy (ART) strategies can be costly, which limits the accessibility of ART for those living in lower- and middle-income areas within the region of Sub-Saharan Africa [3,4]. Pre-exposure prophylaxis (PrEP) is a highly effective pharmacological tool used for HIV prevention among high-risk groups [3]. Effective use of PrEP has previously demonstrated a significant reduction in new HIV infections among high-risk individuals from 86% to 44% [5]. However, in this region, the availability of trained healthcare staff for application of parenteral treatment (who are required for ART in its current form) is low, which negatively impacts the rate of successful treatment [2]. In this context, HF-MAPs are promising devices, offering minimally invasive, pain-free and prolonged drug delivery. These devices are designed to be self-administered and self-disabling, avoiding contaminated sharps waste generation. Cabotegravir sodium (CAB-Na) is a poorly soluble anti-HIV drug for the treatment and PrEP of HIV infection that lends itself to depot formation following intradermal delivery but presents significant challenges when delivered via HF-MAPs, whose nature is aqueous. Specifically, CAB-Na, in combination with 2- HP-β-CD, was formulated into a suitable tablet reservoir that dissolved rapidly and completely when placed atop a swollen HF-MAP. Intradermal delivery of this anti-HIV therapeutic was achieved over 24 hours in rats in vivo, and drug pharmacokinetics were studied over the following 28 days.

Methods: Compressed tablet reservoirs containing CAB-Na and HP-β-CD (4:96 w/w) were formulated from freeze-dried inclusion complexes (Figure 1 (A)). The CAB-Na/HP-β-CD complex was then characterized for NMR and FTIR. These novel reservoirs were combined with two different HF-MAP formulations [MAP1 (Gantrez S97® + poly (ethylene glycol) 10,000 + Na₂CO₃), which was crosslinked at 80°C for 24h ((Figure 1 (B)); and MAP2 (poly (vinyl pyrrolidone) 58 kDa + poly (vinyl alcohol) 85-120 kDa + citric acid)), crosslinked at 130°C for 1h] to form fully integrated MAP devices (Figure 1 (C)). The CAB-Na/ HP-β-CD tablet reservoirs with MAPs and then applied to full-thickness neonatal porcine skin on Franz-diffusion cells (n = 6) to evaluate drug deposition and permeation in the skin (ex-vivo). After 24h, the integrated patches were removed, and the drug deposited in skin samples extracted and analysed by the validated HPLC-UV method. The MAP2 integrated with CAB-Na/HP-β-CD was evaluated in vivo and pharmacokinetic studies in rats were performed using CAB LA-IM injection as a control, over 28 days [6].

Results: The drug complexation into the HP-β-CD ring was confirmed by NMR, observing the Δδ (proton chemical shift) that had occurred for H-3 and H-5. The FITR results were represented at the 3363 cm^-1 bands and confirmed at the 1371 cm-1 stretching, suggesting a hydrogen bond interaction between CAB-Na and HP-β-CD occurred. Ex vivo skin deposition with integrated MAPs and drug reservoir (Figure 2 (C)) shows that MAP1 (Figure 2 (A)) and MAP2 (Figure 2 (B)) were able to deliver 141 ± 40 μg and 342 ± 34 μg of CAB-Na into 0.5 cm² of excised neonatal porcine skin after 24h, respectively. Subsequent in vivo pharmacokinetics of MAP2 was demonstrated an extended drug release profile and an observed Cmax of 53.4 ± 10.16 µg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (Cmax of 43.6 ± 5.3 µg/mL) (Figure 3 (A, B and C)).

Conclusion: This work describes, for the first time, the successful delivery of a poorly soluble anti-HIV drug-using HF-MAPs. The utilisation of effective cyclodextrin complexation teamed with the rate-controlled delivery of high drug loads provided by the HF-MAP platform facilitated the delivery of clinically relevant doses of CAB-Na in an in vivo setting over 28 days following a single administration. The long-acting release was achieved by forming intradermal micro-depots in the skin using HF-MAPs. Furthermore, MAPs are designed to be self-administered by the patient, thus relieving the burden placed on healthcare professionals in terms of treatment delivery. The findings within demonstrate that the current delivery profile of the formulated MAP device is similar to that of an FDA-approved therapeutic marketed for PrEP and HIV treatment. Alternative delivery systems such as HF-MAPs have the potential to unlock benefits for those who are affected by HIV infection. The realisation of this potential will surely improve the quality of life of millions across the globe.

References:
[1] W. World Health Organization, HIV/AIDS, 30 Novemb. 2021. (2021). https://www.who.int/news-room/fact-sheets/detail/hiv-aids (accessed December 1, 2021).
[2] A.J. Paredes, I.K. Ramöller, P.E. McKenna, M.T.A. Abbate, F. Volpe-Zanutto, L.K. Vora, M. Kilbourne-Brook, C. Jarrahian, K. Moffatt, C. Zhang, I.A. Tekko, R.F. Donnelly, Microarray patches: Breaking down the barriers to contraceptive care and HIV prevention for women across the globe, Adv. Drug Deliv. Rev. 173 (2021) 331–348. https://doi.org/https://doi.org/10.1016/j.addr.2021.04.002.
[3] J. Ghosn, B. Taiwo, S. Seedat, B. Autran, C. Katlama, Seminar HIV, Lancet. 392 (2018). https://doi.org/10.1016/S0140-6736(18)31311-4.
[4] J.M. Molina, I. Charreau, B. Spire, L. Cotte, J. Chas, C. Capitant, C. Tremblay, D. Rojas-Castro, E. Cua, A. Pasquet, C. Bernaud, C. Pintado, C. Delaugerre, L. Sagaon-Teyssier, S. Le Mestre, C. Chidiac, G. Pialoux, D. Ponscarme, J. Fonsart, D. Thompson, M.A. Wainberg, V. Doré, L. Meyer, Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study, Lancet HIV. 4 (2017) e402–e410. https://doi.org/10.1016/S2352-3018(17)30089-9.
[5] W. World Health Organization, HIV/AIDS, 30 Novemb. 2021. (2021).

Acknowledgements: The authors would like to thank the United States Agency for International Development (USAID) and the United States President’s Emergency Plan for AIDS Relief (PEPFAR) (Cooperative Agreement #AID-OAA-A-17-00015) for supporting this project. The contents are the responsibility of QUB and do not necessarily reflect the views of USAID, PEPFAR, or the United States government. This work was also supported in part by the EPSRC grant EP 15028919/1. The authors would also like to thank the PATH team for revising this work, especially Jessica Mistilis and Courtney Jarrahian.


Figure 1: (A) CAB-Na (8 mg/mL) was dissolved in an aqueous solution containing 20% (w/w) of HP-β-CD (Cavitron®W7/HP7) and then lyophilised. The dried CAB-Na/CD complex was compressed (2 tonnes for 20 s) to form a 250 mg tablet containing 8 mg of CAB Na. Regarding MAPs preparation, two different HFMNs (0.5 cm2 array consist of 11x11 microneedles measuring 900 µm in height) were prepared from an aqueous blend (MAP1) of (B)“super-swelling” Gantrez-S97®:20%(w/w) Gantrez-S97®, 3%(w/w) Na2CO3 and 7.5%(w/w) PEG 10,000 with 24h of cross-linking/80°C and (C) (MAP2) poly(vinylalcohol)-poly(vinylpyrrolidone) (PVA-PVP): 25%(w/w) PVA 85- 120,000K, 4%(w/w) PVP 58,000K, 1.5%(w/w) citric acid, with 1h of cross-linking/130°C.


Figure 2: Digital light microscope images of HF-MAPs: (A1) MAP1 x35 and (B1) MAP2 x35 magnification. Scanning electron microscope images of HF-MAPs: (A2) MAP1 x180 and (B2) MAP2 x200. (C) Integrated microarray patch with drug reservoir before and after skin application. (D) 1 Microscopic image of CAB-Na/HP-β-CD tablet upper surface and (D) 2 Microscopic images of CAB-Na/HP-β-CD tablet lateral surface. (E) Amount of CAB-Na present in lyophilised CAB-Na/HP-β-CD inclusion complex powder (100 mg) and in formulated CAB-Na/HP-β-CD tablets (250 mg) (means ± S.D., n= 12). (F) 1 Concentration of CAB-Na deposited into full-thickness skin after 24 h (F) 2 Concentration of CAB-Na permeated through the skin after 24 h. (Means ± S.D., n = 6) ND* = drug was not detected


Figure 3: (A) Schematic representation of pharmacokinetic studies in rats comparing two groups: Integrated MAP2 with CAB-NA/HP-β-CD drug reservoir and the CAB-LA IM injection. (B) Pharmacokinetic profiles following the administration of CAB-LA administered via IM injection and CAB-Na delivered via MAPs (MAP2 + CAB-Na/HP-β-CD) (Means ± S.D., n = 6). Statistical analysis using an unpaired t-test was used to compare groups at each time point. Accordingly, ns denoted no significant difference (p > 0.05), * denoted p ≤ 0.05; ** denoted p ≤ 0.01 and **** denoted p ≤ 0.0001). (C) CAB pharmacokinetic parameters in animals and their corresponding dose based on the body weight-normalised, following administration of CAB-Na, delivered via MAPs (MAP2 formulation) and CAB-LA administered via IM injection (Means ± S.D., n = 6).