(M1430-07-46) Formulation of a Hydrophilic Transdermal Patch for Combined Delivery of Sumatriptan and Metoclopramide in Migraine Therapy

Purpose: Migraine is a common neurological disorder that severely affects quality of life and is often accompanied by nausea and vomiting, making oral drug administration challenging [1]. To overcome these limitations, we developed a novel hydrophilic transdermal patch for the combined delivery of sumatriptan succinate (logP 0.74, MW 413.5 Da) [2] and metoclopramide HCl (logP 1.79, MW 299.8 Da) [3]. This dual-therapy patch aims to provide both pain relief and antiemetic effects. Transdermal delivery offers several advantages over oral routes, including improved therapeutic efficacy, reduced side effects, avoidance of first-pass metabolism, lower dosing frequency, and bypassing the gastrointestinal tract, particularly beneficial during migraine-induced nausea [4]. This study explored various chemical enhancers and different polymers for patch formulations to optimize drug permeability and enhance transdermal delivery.

Methods: In vitro permeation testing (IVPT) was performed using vertical Franz diffusion cells with dermatomed porcine ear skin. Receptor samples (0.3 mL) were collected at predetermined time intervals over a 24-hour period and analyzed using a validated high-performance liquid chromatography (HPLC) method. Different chemical enhancers including 15% dimethyl isosorbide (DMI), 25% dimethyl sulfoxide (DMSO), 25% propylene glycol (PG), 25% N-methyl-2-pyrrolidone (NMP), 25% isopropyl myristate (IPM) and their combinations were used in phosphate-buffered saline (PBS) as the vehicle. Patch formulations were prepared using various concentrations of polyvinyl pyrrolidone (PVP), sodium carboxymethyl cellulose (CMC-Na), and hydroxypropyl methylcellulose (HPMC). Both drugs and liquid components, including chemical enhancers, glycerol, and polyethylene glycol (PEG), were first dissolved in water, followed by the addition of solid components such as polymers, mannitol, and gelatin. Various drying times were evaluated to optimize patch formation. After drying, a 15% solution of polyacrylic acid (PAA) in methanol was applied to the surface as an adhesive layer. Multiple release liners and backing membranes were tested to identify the most compatible materials for patch assembly. The optimized patches were characterized for their drug content uniformity, folding endurance, tack testing, and drug crystallization.

Results: Among enhancers, 15% DMI provided the highest delivery of both sumatriptan (27.47 ± 5.73 µg/cm²) and metoclopramide (35.55 ± 6.06 µg/cm²), over 24 hours. A combination of 25% PG and 10% DMI further enhanced permeation, delivering 641.29 ± 44.78 µg/cm² of sumatriptan and 886.57 ± 89.99 µg/cm² of metoclopramide across the skin. Among the four hydrophilic patch formulations, a matrix composed of a 1:3 ratio of PVP to HPMC (Patch D) demonstrated optimal delivery, with 110.64 ± 11.71 µg/cm² of sumatriptan and 232.81 ± 18.64 µg/cm² of metoclopramide delivered into the receptor. The patches were dried using a multistage drying process: initially at 65°C for 6 hours, followed by overnight drying at 55°C, and a final 2-hour drying cycle at 75°C. Patch D demonstrated uniform drug content (metoclopramide: 43.08 ± 0.51% w/w; sumatriptan: 33.26 ± 0.32% w/w), high tack strength (440.03 ± 21.46 g), acceptable flexibility ( >200 folding endurance), and the absence of crystallization, as confirmed via polarized light microscopy.

Conclusion: This study demonstrates the successful formulation of a hydrophilic transdermal patch for the dual delivery of sumatriptan and metoclopramide. Target therapeutic doses equivalent to 4 mg SC sumatriptan and 10 mg oral metoclopramide were successfully delivered within 8 hours using a 60 cm² patch. The developed patch offers a promising alternative to oral and injectable therapies, with potential to improve patient compliance, minimize nausea-related challenges, and enhance therapeutic outcomes in migraine management.

References: [1] J. Khan et al., “Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine,” Biomedicine & Pharmacotherapy, vol. 139, p. 111557, Jul. 2021, doi: 10.1016/J.BIOPHA.2021.111557.
[2] M. W. Pierce, “Transdermal Delivery of Sumatriptan for the Treatment of Acute Migraine,” Neurotherapeutics, vol. 7, no. 2, pp. 159–163, Apr. 2010, doi: 10.1016/J.NURT.2010.03.005.
[3] A. Dolgorukova, A. V. Osipchuk, A. A. Murzina, and A. Y. Sokolov, “The Influence of Metoclopramide on Trigeminovascular Nociception: Possible Anti-migraine Mechanism of Action,” Neuroscience, vol. 425, pp. 123–133, Jan. 2020, doi: 10.1016/J.NEUROSCIENCE.2019.11.026.
[4] O. Perumal, S. N. Murthy, and Y. N. Kalia, “Turning Theory into Practice: The Development of Modern Transdermal Drug Delivery Systems and Future Trends,” Skin Pharmacol Physiol, vol. 26, no. 4–6, pp. 331–342, Jul. 2013, doi: 10.1159/000351815.


Figure 1Results from penetration enhancers incorporated IVPT studies (n = 4). (a) Total amount of metoclopramide HCL delivered across the skin in 24 hours. (b) Permeation profile of metoclopramide HCL delivered across the skin in 24 hours. (c) Total amount of sumatriptan succinate delivered across the skin in 24 hours. (b) Permeation profile of sumatriptan succinate delivered across the skin in 24 hours. Statistical analysis performed with one-way ANOVA; ns indicates no significant difference between groups, ** and *** indicate significant difference between groups, p  < 0.05


Figure 2Results from penetration enhancer combination incorporated IVPT studies (n = 4). (a) Total amount of metoclopramide HCL delivered across the skin in 24 hours. (b) Permeation profile of metoclopramide HCL delivered across the skin in 24 hours. (c) Total amount of sumatriptan succinate delivered across the skin in 24 hours. (d) Permeation profile of sumatriptan succinate delivered across the skin in 24 hours. Statistical analysis performed with one-way ANOVA; ns indicates no significant difference between groups, *** and **** indicate significant difference between groups, p  < 0.05


Figure 3Results from IVPT studies with 3 different patch formulation. (a) Total amount of metoclopramide HCL delivered across the skin in 24 hours. (b) Permeation profile of metoclopramide HCL delivered across the skin in 24 hours. (c) Total amount of sumatriptan succinate delivered across the skin in 24 hours. (d) Permeation profile of sumatriptan succinate delivered across the skin in 24 hours. Statistical analysis performed with one-way ANOVA; *** and **** indicate significant difference between groups, p  < 0.05.