article · AAPS PharmSciTech
Verapamil hydrochloride is an antihypertensive drug with a short half-life and poor bioavailability when taken orally, though it is used off-label for cluster headaches. To overcome these limitations, a cubosome formulation was developed to deliver the drug directly to the brain through the nasal passage. Using a factorial design, the formulation was optimised with glyceryl monooleate and Poloxamer 407, successfully encapsulating the drug in an amorphous state. Ex vivo evaluation showed that the optimised nanocarriers significantly increased drug permeation across the nasal mucosa compared to a standard drug solution. Histopathological testing confirmed the safety of the carrier components on nasal tissue. Furthermore, pharmacokinetic and biodistribution assessments demonstrated enhanced systemic bioavailability, sustained drug release, and significantly superior brain-targeting efficiency and direct nose-to-brain transport percentages relative to a conventional intranasal solution.
Cluster headache treatments often face hurdles because oral medications struggle to reach the brain effectively and clear the body quickly. Delivering verapamil via nasal cubosomes allows the drug to bypass the digestive tract and travel directly into the brain. This approach could provide more potent, targeted relief at lower doses, potentially reducing systemic side effects while improving therapy outcomes for patients.
This research provides an applied and tested formulation that could enable pharmaceutical developers to create targeted intranasal therapeutics for cluster headaches. By reformulating an established drug into a lipid-based nanocarrier, it offers a direct nose-to-brain delivery platform. The technology currently appears to be at an early, preclinical stage, having established ex vivo permeation, tissue safety, and biodistribution profiles before advancing to formal clinical trials.
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Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high E<sub>r</sub> value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.
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DOI: 10.1208/s12249-024-02814-w
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