(M1230-09-49) Microneedle-Based Co-Delivery System for Naproxen Sodium and Caffeine in Migraine Therapy

Purpose: Conventional migraine treatments are often delayed and inefficient. Nausea associated with the migraine makes oral drug delivery challenging, and patients have a strong reluctance towards injectables. A microneedle (MN) patch would offer a patient-friendly solution that would allow both rapid and sustained relief. This work aims to develop an MN patch to co-deliver caffeine (CAF) and naproxen (NAP) to improve migraine therapy. A delivery profile with both rapid and sustained delivery will be targeted, achieved from dissolving microneedles (dMNs) and a topically applied gel, respectively. In the current work, we fabricated dMNs and tested release and permeation profiles of sustained release gels when applied to skin pre-treated with solid MNs (as proof of concept).

Methods: Dissolving microneedles (dMNs) of 600 μm and 800 μm length, containing 1% w/w each of NAP and CAF in 45% w/w polyvinylpyrrolidone (PVP, 55 kDa molecular weight) were fabricated through a two-step process. First, a drug-PVP solution was prepared and filled into PDMS templates¹. After drying, the dMNs were carefully ejected for further characterization. Mechanical strength was evaluated by measuring height reduction under a continuous 0.2N force for 30 seconds using a rotational rheometer². Drug-polymer compatibility was assessed using FTIR. An HPLC method was developed and validated for simultaneous quantification of NAP and CAF. Sustained release gels containing NAP and CAF, alone and in combination, were prepared in 45% PVP. Drug release studies were performed using Franz diffusion cells with cellulose membranes. Permeation studies were performed on flow-through cells, using porcine skin dermatomed to a thickness of 0.8 mm. The receiver solution was HEPES buffer, pH 7.4, maintained at 32 ±1°C. The skin was pre-treated with 500 μM length solid MNs to create 100 microchannels, and drug-containing PVP gel was applied. Intact skin was used as a control. All experiments were conducted in triplicate. Steady-state flux (Jss) was calculated from the linear portion of the cumulative permeation vs time graph; the lag time to reach steady-state was extrapolated from the line back to the time axis.

Results: The dMNs demonstrated robust mechanical strength, which will facilitate effective skin penetration. dMNs of 600 μm and 800 μm length experienced less than 15% height reduction. FTIR analysis revealed no interaction between the drugs and the polymer (Fig 1A &1B). The 45% PVP gel formulations exhibited controlled release profiles, with over 60% of both NAP and CAF released within the initial 8 hours. The release mechanism for CAF followed Fickian diffusion (n value = 0.378), suggesting controlled release via diffusion through the polymer matrix. In contrast, NAP demonstrated a non-Fickian mechanism (n value = 0.716), indicating a combination of diffusion and gel matrix erosion. The combined drug formulation showed a higher release rate compared to the individual drugs. This suggests that CAF in the combined formulation enhanced the release of NAP. The increased release can be attributed to NAP's higher solubility and compatibility with the gel matrix, which was further improved by the presence of CAF, likely enhancing NAP's diffusion rate. (Fig 2A). Permeation studies using 500 μM solid MN-treated skin showed increased drug flux compared to untreated skin when both drugs were combined in the gel. Steady-state flux Jss values for NAP and CAF were 11.2 ± 1.01 μg/cm²/h and 10.78 ± 0.81 μg/cm²/h, respectively, significantly higher than those observed in untreated skin (NAP: 6.24 ± 0.31 μg/cm²/h; CAF: 6.11 ± 1.37 μg/cm²/h). Therefore, NAP and CAF showed approximately a 1.76 to 1.79-fold increase in flux through 500 μM solid MN-treated skin compared to untreated skin. This indicates enhanced drug delivery efficiency through MN-treated skin compared to intact skin.

Conclusion: The dMNs demonstrated excellent mechanical robustness, which will be necessary for enhancing permeation of NAP and CAF through the skin. FTIR analysis confirmed no drug-excipient interactions, ensuring formulation stability. The 45% PVP gel formulations provided controlled drug release, with over 60% of both drugs released within the first 8 hours. Permeation studies showed a 1.76 to 1.79-fold increase in drug flux through MN-treated skin compared to untreated skin. These results validate the proof of concept that MN skin treatment enhances permeation of CAP and CAF. Next steps will focus on combining dMNs and the sustained release gel in order to produce rapid and sustained delivery of NAP and CAF from one treatment.

References: 1. Duan X, Ma J, Ning M, Gao Y. Dissolving Microneedles Loaded with Gestodene: Fabrication and Characterization In Vitro and In Vivo. Iran J Pharm Res. 2023 May 19;22(1):e131819. doi: 10.5812/ijpr-131819.
2. Ando D, Miyatsuji M, Sakoda H, Yamamoto E, Miyazaki T, Koide T, Sato Y, Izutsu K-i. Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles. Pharmaceutics. 2024; 16(2):200. https://doi.org/10.3390/pharmaceutics16020200

Acknowledgements: We extend our thanks to Krishna Kumar Patel for his valuable contributions and insights during this research.

Funding: This work was funded by NIH R35GM149337.
Conflict of Interest Statements: The authors declare no conflict of interest.

Fig 1. (A) FTIR Interaction Study

Fig 2. (A) In vitro release of caffeine and naproxen from 45% PVP gel (n=3); (B) cumulative amount of naproxen sodium and caffeine permeated through intact porcine skin vs skin treated with solid MNs.