Elsevier

Journal of Controlled Release

Volume 268, 28 December 2017, Pages 159-165
Journal of Controlled Release

Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy

https://doi.org/10.1016/j.jconrel.2017.10.021Get rights and content

Abstract

Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108 ± 9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2 min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259 ± 917 ng/mL min) was not significantly different (p > 0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5 min for both delivery methods and tmax value of MNPs (38 ± 23 min) showed no significant difference (p > 0.05) compared to subcutaneous injection (24 ± 13 min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability.

Introduction

Approximately 50% of adults worldwide suffer from an active headache disorder, and according to a World Health Organization's survey, headaches rank 19th among the most disabling conditions [1]. This sometimes-incapacitating health issue is among the top five most disabling conditions for women [2]. Migraine headaches are the 3rd most prevalent illness in the world and affect about 11% of adults worldwide [3]. Attacks are often accompanied by one or more disabling symptoms, and migraineurs consistently report reduced quality of life between attacks [4]. The direct and indirect management of migraine therapy has an annual economic cost of approximately $13 billion just in the USA [5].

There have been many encouraging developments in antimigraine medications over the past few decades, but currently available medical therapies are still far from optimal. The introduction of the “triptans” in the 1990s drastically changed prescribing patterns. Members of this antimigraine drug family are considered the first choice for moderate to severe attacks in migraine therapy unless there are contraindications [6]. However, nearly one-third of patients taking triptans for acute migraine therapy discontinue this therapy because of lack of efficacy, migraine recurrence, cost, and/or side effects [7]. Thus, this subgroup has dificulties managing acute migraine attacks and often seeks alternative drugs, such as dihydroergotamine mesylate (DHE) [8].

DHE is an ergot derivative that has been extensively utilized and studied in the treatment of episodic and chronic migraine. The mechanism of action is most likely vasoconstriction by stimulating α-adrenergic and 5-HT receptors [9]. Two pharmaceutical dosage forms of DHE, namely parenteral and nasal spray, were approved in United States in 1945 and 1990, respectively. An orally inhalable form of DHE was submitted to FDA for approval in 2013, but is not yet approved [10]. Nasal administration of DHE exhibits inconsistent pharmacokinetic (PK) profiles, resulting in poor acceptance among patients and prescribers, whereas the parenteral route has the disadvantage of pain, needle phobia, risk of infections at the injection site, and requirement of specialized personnel for administration, which leads to poor patience compliance [11]. Thus, there is a need for a new formulation design of DHE that enables easy self-administration, safe and effective delivery mimicking the parenteral (especially SC) PK profile. Such a new formulation could offer convenience as well as therapeutic advantages for migraineurs [12].

In the last decade, advances in the field of transdermal delivery using microneedle patches (MNPs) have shown that the barrier function of stratum corneum can be overcome while retaining the advantages of patch-based delivery. Microneedles are typically a few hundred microns in width and up to 1 mm in length, and they are arranged as an array on a patch that is applied to the skin. The microneedles painlessly puncture the stratum corneum and deliver drugs and vaccines to viable epidermis and dermis below [13], [14]. MNPs can be self-administered and are strongly preferred over injection [15], [16], [17]. Among the different types of microneedles, water-soluble polymer ones that dissolve in the skin have received great attention because they do not generated sharps waste and cannot be reused after removal from a patient's skin [18], [19]. Prior studies have investigated the delivery of triptans using microneedle patches for possible treatment of migraine, including sumatriptan [20], [21], [22], [23], zolmitriptan [24] and rizatriptan [25].

It is desirable to have rapid uptake of anti-migraine drugs for fast onset of relief to the patient. Rapid uptake is facilitated by the dense capillary bed in the superficial dermis where microneedle patches deliver drug and by formulation with suitable polymeric excipients that dissolve quickly, such as polyvinylpyrolidone (PVP) [26], fibroin [27], maltose [28] and chondroitin sulphate [29].

The aim of this study is to formulate dissolving MNPs for rapid release and capillary uptake of DHE in the skin. We therefore used highly water-soluble PVP as the microneedle matrix material to enable rapid delivery to treat acute migraine therapy and used DHE as the active pharmaceutical ingredient to provide relief to patients who suffer from unsufficient medication with triptan derivatives. We carried out in vitro tests measure content uniformity, mechanical strength of microneedle needles for complete insertion into skin, solubility and delivery efficiency of DHE from the MNPs, and optical microscopy imaging of MNPs. We also conducted in vivo studies of bioavailability of DHE delivered by MNPs in hairless rats. In this way, we introduce this alternative therapy approach to acute migraine therapy with DHE-loaded MNPs.

Section snippets

Materials

DHE (Tocris, Minneapolis, MN, USA), caroverine HCI (Sigma-Aldrich, St. Louis, MO, USA), PVP (10 kDa, Sigma-Aldrich) polyvinylalcohol (6 kDa, 78% hydrolyzed, Acros Organics, New Jersey, USA), Sucrose (Fluka Analytical, St. Louis, MO, USA), Gentian violet (Good Neighbor Pharma, Brawley, CA, USA), Optical Microscope (Olympus SZX16, Shinjuku, Tokyo, Japan). All reagents were of analytical grade and used as received.

Fabrication of DHE-loaded MNPs

MNPs were prepared using two separate solutions. A stock solution of DHE was prepared

Characterization of DHE-loaded MNPs

MNPs were formulated using PVP as microneedle matrix material because of its suitable properties, such as biocompatibility, water solubility and rapid release of encapsulated drug after insertion into the skin. A two-step casting process under vacum was used to localize the drug in the tips of the needles, where the first cast was used to create the drug-loaded microneedles and the second cast, which contained no drug, was used to create the drug-free base of the microneedle array. MNPs were

Discussion

Migraine can cause significant negative effects on social activities and relationships, including decreased school and work attainment and productivity [5]. There is a need for effective and acceptable migraine treatments to decrease impact and disability associated with the disease. The formulation of DHE in MNPs can have a significant effect on migraine therapy as a patient-friendly delivery method that serves as an alternative approach for migraneurs, especially triptan non-responders [31],

Conclusion

DHE delivery using MNPs had a pharmacokinetic profile similar to SC injection, as determined by the lack of statistically significant difference in tmax and AUC and with comparable Cmax values. DHE delivery was facilitated by formulation with PVP, which is believed to enable rapid dissolution of microneedles due to the high water solubility of PVP and to increase DHE solubility in a manner similar to solid dispersions used in other types of dosage forms. These findings suggest that DHE-loaded

Acknowledgements

Mark Prausnitz is an inventor of patents licensed to companies developing microneedle-based products, is a paid advisor to companies developing microneedle-based products, and is a founder/shareholder of companies developing microneedle-based products (Micron Biomedical). This potential conflict of interest has been disclosed and is managed by Georgia Tech and Emory University. Jessica Joyce was funded through the NIH/NIGMS-sponsored Cell and Tissue Engineering (CTEng) Biotechnology Training

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