Lyophilized drug reservoir-integrated hydrogel-forming microarray patches for transdermal delivery of isoniazid and pyridoxine hydrochloride as a strategy to treat latent tuberculosis

Tuberculosis (TB), recognized for decades as a global health priority, remains one of the most lethal infectious diseases worldwide, causing approximately 1.6 million deaths each year (1). A significant portion of the TB burden is due to latent TB infection (LTBI): a dormant form of the disease that can activate. The Centers for Disease and Control and Prevention (CDC) estimates that over 80% of TB cases in the United States result from the activation of a LTBI (2). While significant strides have been made in diagnosing and treating TB, strategies for managing LTBI remain constrained due to limitations of current oral regimens, including long treatment durations [daily isoniazid (INH) for 6–9 months], hepatotoxicity, and poor patient adherence (3,4). Many individuals with latent TB feel healthy and are reluctant to undergo months of pill-taking, leading to low completion rates. Even newer, shorter-course regimens (e.g., 3–4 months of rifamycin-based therapy) face challenges with side effects and ensuring patients complete therapy. Therefore, alternative routes like transdermal drug delivery (TDD) using microarray patches (MAPs) or microneedle (MN) patches have been studied for the administration of medications, in addition to vaccines, peptides, hormones, and cosmetic agents (5-8). Unlike oral pills or intramuscular injections, MAPs can painlessly bypass the skin barrier and deliver medications directly into the systemic circulation, avoiding the gastrointestinal tract and first-pass liver metabolism. Various types of MAPs exist (solid, coated, hollow, dissolvable, and hydrogel-forming MNs), each suited for different applications (9,10). Given their versatility, MAP technologies are being explored for a range of uses in both animals and humans (11-14). In the context of LTBI treatment, a transdermal patch could potentially improve patient compliance (no daily pills) and further encourage adherence by simplifying the regimen. In this landscape, Anjani and collaborators have presented multiple studies in the past addressing the usage of hydrogel-forming MAPs for the transdermal delivery of multiple antibiotics (rifampicin, ethambutol dihydrochloride, pyrazinamide) for the treatment of TB disease (15). Following up on their previous findings, the authors currently present a timely and highly innovative approach for LTBI treatment (16). They describe the design, optimization, and evaluation of a hydrogel-forming MN array patch coupled with a lyophilized drug reservoir for transdermal delivery of INH and pyridoxine hydrochloride (16). This study, recently published in Biomaterials Advances, offers both a technological leap and a potential shift in how LTBI treatment may be administered in the future.

Anjani and colleagues took advantage of a key intrinsic property of hydrogels: the ability to swell with water (17,18). Once their MNs painlessly pierce through the stratum corneum (outer skin layer) and reach the dermis, they absorb interstitial fluid (ISF) and swell, transforming into microporous channels (Figure 1). Initially, the authors focused on achieving optimal swelling behavior for the hydrogel-forming MAP composed of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), one of the polymers blends previously studied by the team (15). In this research, they focused the hydrogel optimization on (I) multiple crosslinkers: citric, adipic, tartaric, fumaric, and succinic acid and (II) different osmolytes: sodium chloride, maltose, and sorbitol. The authors then fabricated the hydrogel-forming MAP by casting 500 mg of an aqueous blend that consisted of 15% weight-to-weight (w/w) PVA, 10% w/w PVP, 1.5% w/w crosslinker, and 5% w/w osmolyte in water. The blend was placed in a pre-formed silicon mold (11×11 conical MNs array with 600 µm height, 300 µm base, and 300 µm pitch). The filled molds were centrifuged to drive the solution into the needle tips, then allowed to dry at room temperature for 48 h. After drying, the solidified patch was peeled out of the mold and further heat treated at 130 ℃ for 3 h to strengthen the polymer network via crosslinking. This production method yields a patch with 121 stiff hydrogel-forming MNs capable of piercing the skin. The researchers verified that the MNs had sufficient mechanical strength and sharpness by measuring the reduction in MN height under compression and assessing insertion efficiency (using layers of parafilm to simulate skin) as well as penetration depth in excised pig skin.

Figure 1 Schematic representation of the hydrogel-forming MAP with lyophilized reservoir for transdermal delivery of INH and pyridoxine HCl via MN swelling. HCl, hydrochloric acid; INH, isoniazid; MAP, microarray patch; MN, microneedle.

The optimized formulation of the hydrogel-forming MAP included adipic acid and sorbitol as the crosslinker and osmolyte, respectively, as they resulted in the highest MN swelling capacity. Furthermore, to improve the mechanical properties of the MAP associated with its gel fraction, the authors varied the concentration of the crosslinker and the osmolyte. Results showed that a composition of 15% w/w PVA, 10% w/w PVP, 1.5% w/w adipic acid, 5% w/w sorbitol, and 68.5% w/w water led to a high swelling capacity (>1,000% from the initial size). However, the final optimized MAP formulation selected was 3% w/w adipic acid, 1% w/w sorbitol, and 71% w/w water, which resulted in a significant increase in the MAP gel fraction (over ~20% increment) while retaining a high swelling capacity.

After finalizing the MN matrix, Anjani and colleagues continued with the fabrication of the lyophilised drug reservoir, which in their previous studies showed the highest cumulative drug permeability of INH in comparison to directly compressed tablets and polyethylene glycol (PEG)-based solid tablets (15). In the current study, the lyophilised reservoir was optimized using a central composite design, by evaluating concentrations between 6% and 54% w/w of INH or pyridoxine hydrochloric acid (HCl), and 0–11% w/w of sorbitol and gelatin dissolved in deionized water. Approximately 100 mg of the mixtures were poured into a cylindrical mold (8 mm in diameter and 4 mm depth), frozen at −80 ℃ for 3 h and subsequently lyophilised in a freeze-dryer. The complete dissolution of the reservoir was visually assessed by submerging the samples in phosphate-buffered saline (PBS) at 37 ℃. The results indicated that the optimal formulation consisted of 50% w/w drugs, 1% w/w sorbitol, and 1% w/w gelatin, demonstrating the fastest dissolution times (2 s for INH and 3 s for pyridoxine HCl).

The integrated MAP-reservoir system was then evaluated in an in vitro permeation study to assess the drugs release profiles in neonatal porcine skin adapted to a Franz cell. Their results showed that 8 mg of INH and 5 mg of pyridoxine HCl permeated the skin after 24 h, while 1 and 2 mg of INH and pyridoxine HCl, respectively, were retained in the skin. Finally, the team conducted an in vivo pharmacokinetic study in female Sprague-Dawley rats. The MAP system containing a dose of 50 mg of INH and pyridoxine HCl was placed on the back of the rat and left for 5 days, and oral administration (50 mg dose) was established as a control. Administration of INH via the MAP system produced a peak plasma concentration of 9,489±1,517 ng/mL, vs. 393±141 ng/mL from a single 50 mg oral dose, reaching well into the therapeutic range of 3,000–6,000 ng/mL. Pyridoxine delivered via MAP similarly reached 750±366 ng/mL at peak, compared to 313±152 ng/mL orally, far exceeding the target plasma range of 5–50 ng/mL.

From our perspective, this MAP system offers multiple benefits. Among these, the MAP bypasses the first-pass metabolism (liver metabolism before systemic circulation), resulting in the delivery of a greater fraction of the drugs directly into the bloodstream for systemic circulation. Consequently, a 50 mg MAP dose achieved therapeutic plasma levels of INH, while oral delivery would require a significantly higher dose to achieve the desirable plasma concentration of the drug.

Another advantage that we highlight from this platform is its modularity. Because the MN array and drug reservoir are separate components, each can be optimized or replaced independently, allowing flexibility to tailor treatments or to combine drugs as needed. Moreover, since the hydrogel-forming MNs act as fluid conduits rather than being fully loaded with drug, the system’s drug loading capacity is not limited by the physical volume of the needles. This means far larger doses can be delivered from the external reservoir than would be possible with traditional dissolving or coated MAP designs.

Although the MAP system offers relevant advantages, this technology presents limitations related to the system’s ability to deliver significant amounts of drug for long periods of time, since it plateaus after 24 hours, potentially due to clogging of the microchannels or partial dissolution of the swollen needles. This implies that a fresh patch might need to be applied daily for prolonged therapy, which could affect patient adherence. Additionally, the MAP delivered INH at concentrations above the desired therapeutic window for several hours, raising concerns about transient hepatotoxicity (liver damage caused with the accumulation of metabolites from phase I and II reactions, not first-pass metabolism) or peripheral neuropathy (19). The pyridoxine levels raised additional concerns: transdermal delivery kept plasma pyridoxine above the upper therapeutic limit for over 12 hours, even exceeding concentrations reported clinically as extremely elevated (300 ng/mL) (20), which could induce sensory neuropathy, photosensitivity, and ataxia (21). To mitigate these risks, future studies should explore using substantially lower pyridoxine doses in the reservoir (well below 50 mg) to maintain plasma levels within the safe therapeutic range.

From a translational perspective, several considerations must be addressed to confirm safety, efficacy, and reproducibility of the MAP system. Although in general MAPs are painless systems for TDD, it could be relevant to assess whether the hydrogel-forming MNs generate stress, pain, or skin irritation after swelling, or during removal. Also, overswelling could cause ejection from the skin. On the other hand, since the MNs are composed of PVA and PVP, materials that are fully and partially biodegradable, respectively (22,23), their degradation profile in the body should be assessed over time. If the MNs break down or detach prematurely, the drug conduct could be lost, limiting delivery beyond the first day. Detailed studies of the needles’ integrity and biodegradation profile in living tissue will therefore be necessary.

Another concern regarding the MAP system is the stability of the drug reservoir under elevated humidity conditions or exposure to sweat. Considering the drug reservoir contains highly hygroscopic excipients (gelatin and sorbitol) (24,25), there is a risk that the reservoir uptakes moisture that could alter its stability. Therefore, the drug could potentially spread on the skin rather than diffuse through the swollen MN, reducing the systems’ therapeutical efficacy. It will be important to evaluate the reservoir’s performance under different humidity levels and in the presence of sweat to ensure that it remains robust. Furthermore, inter-individual variability in skin properties (e.g., stratum corneum thickness, hydration, permeability, and age-related changes) could influence transdermal drug uptake, so these factors should be considered in future evaluations.

Future advances on this MAP technology could incorporate a multi-drug reservoir to allow the co-delivery of INH and pyridoxine HCl (or other drug combinations) using a single MAP. This could be achieved either by designing a stacked reservoir (one drug layered above the other) for sequential delivery (the drug located at the top of the reservoir is released after the component contained in the bottom is completely administered) or by a sectioned reservoir for a co-delivery in which each drug will be released through a specific part of the MAP if co-formulation is not feasible.

In parallel, innovations in hydrogel formulation chemistry offer promising opportunities to fine-tune release kinetics through more deliberate control over network dynamics. The performance of hydrogel-forming MAPs is tightly linked to the polymer matrix architecture, which dictates both mechanical integrity and drug diffusion. In this system, the PVA/PVP hydrogel crosslinked with adipic acid provides rapid swelling and structural robustness. However, the system’s fast release suggests a need for greater modulation. Future iterations could explore strategies to slow or delay channel formation and expansion (such as incorporating slowly hydrating domains or reversible crosslinks that resist immediate swelling), thereby prolonging conduit functionality and sustaining drug delivery over time.

In conclusion, Anjani and colleagues present an innovative contribution to the landscape of TDD for the treatment of LTBI. Their hydrogel-forming MAP platform, enhanced by an external lyophilized drug reservoir, offers a pharmacologically feasible alternative to traditional LTBI therapy with INH and pyridoxine HCl. Their MAP system achieved substantially higher drug bioavailability than oral administration and enabled much larger drug doses to be administered. This approach could improve LTBI treatment by reducing dosing frequency and potentially enhancing patient adherence. Nevertheless, further optimization and rigorous evaluation are needed to ensure that drug levels remain within safe therapeutic ranges and that the system is reliable and safe for clinical use. Before translation to the clinic, additional studies should confirm the absence of significant skin irritation, characterize the post-swelling behavior and biodegradation of the MNs, determine whether the patch can be used for multi-day delivery, and verify the reservoir’s stability under conditions of high humidity or direct contact with sweat. If optimized successfully, this platform could represent a major step forward in global TB prevention strategies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-120/coif). The authors have no conflicts of interest to declare.

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