Update on transcutaneous microneedles for ARV drug delivery

Speaker: Ryan Donnelly, Professor of Pharmaceutical Technology at Queen's University Belfast

Ryan Donnelly

Microneedles (MNs) are a minimally invasive alternative to conventional needle and syringe for long-acting antiretroviral drug delivery.

  • MNs offer the potential for sustained drug delivery and co-administration of several drugs (potentially suitable for HIV treatment and prevention). 
  • Advantages of MNs: enhanced patient and healthcare worker safety (avoids risks and disposal issues associated with convention injection), enhanced patient acceptability (painless drug delivery and avoids needle phobia), and self-administration via microarray patch (MAP).

Formation and application of MAP for LA ARV delivery. 

  • A high concentration of a nano-formulated ARV (typically a water-soluble nanocrystal form) is loaded into an aqueous gel, cast into a mould and dried to form MNs. A border adhesive and occlusive backing layer is added to MNs, so patch will stick to the skin when MNs are inserted. 
  • MNs painlessly penetrate the outermost skin barrier, deposit drug in viable skin layers for prolonged, sustained release, and the drug depot is absorbed into the dermal microcirculation.
  • Ideally, the baseplate should detach upon MN dissolution in the skin (affords short patch wear time and optimizes drug delivered vs removing residual drug within MNs along with the patch) 

Pre-clinical studies in rats suggest that sustained mono- and co-delivery of CAB and RPV is possible using MNs, repeated MAP application is safe and translation to a weekly patch is most likely for adult human HIV treatment. 

  • Single RPV MAP or CAB MAP application yielded sustained plasma concentrations above therapeutic targets, but efficiency of MN delivery was lower than IM or ID injection. 
    • RPV MAP (nanocrystal) vs RPV IM – MAP performed as well as IM; plasma RPV levels remained above IC90 (12ng/mL) for 56 days.
    • CAB MAP (nanocrystal vs micronized sodium salt vs FA) vs CAB IM vs CAB ID – all MAP formulations yielded plasma levels below IM/ID, but above 4x IC90 (664ng/mL) for 28 days (micronized sodium salt performed as well as IM/ID over 7 days).  
    • Efficiency of MN drug delivery was lower than IM (30% vs 80%) – allometric scaling and basic PKPB modeling suggest that a patch size of 25-30 cm2 for RPV and 30-40 cm2 for CAB would provide 7-day coverage for an adult human (patch size would be smaller for smaller children, making a monthly patch feasible). 
  • Single-dose co-delivery of RPV and CAB via MAP sustained plasma levels above the therapeutic targets for both drugs.
    • RPV MAP (19x19 vs 16x16) vs RPV IM vs RPV ID – MAP outperformed IM/ID delivery, regardless of patch density; plasma RPV remained above IC90 (12ng/mL) for 70 days.
    • CAB MAP (19x19 vs 16x16) vs CAB IM vs CAB ID – MAP yielded CAB plasma levels below IM/ID, but above 4x IC90 (664ng/mL) for 28 days.  
  • Repeated CAB/RPV MAP application every 14 days with and without an initial IM bolus. 
    •  RPV plasma levels were similar among cohorts after 14 days, CAB plasma levels were similar among cohorts after 28 days, and no adverse events were observed.

in-vivo animal studies suggest that sustained delivery of Etravirine (ETR), Bictegravir (BIC) and Tenofovir Alafenamide (TAF) is possible using MNs, and a weekly patch is most likely for adult human HIV treatment.

  • ETR and BIC are hydrophobic (can use micro-suspension or engineered nanosuspension).
    • ETR dissolving MNs outperformed IV delivery (ETR micro-suspension MAP vs ETR nanosuspension MAP vs ETR IV); both MAP formulations sustained plasma levels over one month, whereas IV concentrations decreased over 10 days. 
    • BIC MNs outperformed IM delivery (BIC micro-suspension MAP vs BIC nanosuspension MAP vs BIC IM), but efficiency of delivery was similar to CAB and RPV, suggesting weekly delivery is most likely for adult humans using a “reasonably sized” patch.   
  • TAF is more hydrophilic (can use prodrug-loaded dissolving MNs [make a high-density hydro-form as the MN tips] or implantable PGLA tips to control drug release).
    • Both approaches yielded sustained plasma concentrations longer than IM (dissolvable TAF prodrug MAP vs implantable PGLA TAF MAP vs TAF IM), but concentrations fell below the therapeutic target after 7 days, even with PGLA system.
    • Translation to a weekly TAF patch for adult human dosing may be possible with potential for co-administration with BIC MAP for HIV treatment (Currently working with Univ of Liverpool to combine TAF and BIC).

Summary and Next Steps.

  • Mono- and co-delivery of ARVs is feasible using MN technology.
  • The ARVs studied to date are suitable for a weekly patch in adults/older children and potentially a monthly patch in smaller children.
  • More potent drugs could accomplish longer duration of action or smaller patch size. 
  • Next steps include Macaque studies and clinical trials. 
  • Scalable manufacturing is needed for this work to have real-world benefit for patients. 
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