JP7602732B2 - Method for rapidly achieving therapeutic concentrations of zolmitriptan suitable for the treatment of migraine and cluster headaches - Patents.com - Google Patents

Description

Application of Article 30, paragraph 2 of the Patent Act 1. Certificate (A) for application of the provisions of exceptions to loss of novelty of invention Website posting date: June 1, 2017 Website address: http://ir.zosanopharma.com/releasedetail.cfm?ReleaseID=1028620 2. Certificate (B) Website posting date: June 12, 2017 Website address: http://ir.zosanopharma.com/releasedetail.cfm?ReleaseID=1029861 3. Certificate (C) Website posting date: June 16, 2017 Website address: http://www. zosanopharma.com/file.cfm/18/docs/ADAM_Zolmitriptan_06.16.17.pdf 4. Certificate (C') Date held: June 10, 2017 Name of the conference: 59th Annual Scientific Meeting of the American Headache Society 5. Certificate (D) Date of website posting: June 26, 2017 Website address: http://ir.zosanopharma.com/releasedetail.cfm?ReleaseID=1031284 6. Certificate (E) Website publication date: July 31, 2017 Website address: http://ir.zosanopharma.com/news-releases/news-release-details/zosano-announcements-publication-positive-phase-1-data-zolmitoriptan? ReleaseID=1035098 7. Certificate (F) Issue date: July 25, 2017 Publication information: Pain Management, Vol. 7, No. 6, pp. 559-567 Publisher name: Future Medicine Limited

The present invention relates to the field of transdermal or intradermal delivery of pharmaceuticals, and more particularly to the delivery of triptans, including zolmitriptan.

According to the Migraine Research Foundation, 30 million people in the United States suffer from migraines, regardless of gender or age. Migraines usually last between 4 and 24 hours, but can last as long as 3 days. Published studies show that 63% of migraine sufferers experience 1-4 migraines per month. The prevalence in women (about 18%) is comparable to the number of people with asthma and diabetes combined. It is reported that about one-third of migraine sufferers suffer from 3 or more migraines per month, and more than half are severely disabled or require bed rest. Migraines are most common in people in their 30s, affecting productivity and quality of life. When surveyed about desired factors in migraine treatment, rapid pain relief consistently ranks at the top as one of the most important factors in migraine treatment.

Acute migraine is a disabling headache disorder characterized by sudden attacks of moderate to severe headache accompanied by various combinations of neurological, gastrointestinal, and autonomic symptoms. Migraine without aura is usually accompanied by nausea, vomiting, and sensitivity to light, sound, or motion, and can last from 4 to 72 hours if untreated. Migraine without aura, formerly known as "common migraine," is experienced by approximately 65% of patients. Migraine with aura is experienced by approximately 15% to 20% of patients and is characterized by a discrete, transient focal neurological symptom, usually a visual symptom, known as an aura. The remaining migraine patients experience both types of migraine.

About one-quarter of migraine sufferers experience one or more episodes per week. The most unpleasant symptoms associated with acute migraine are nausea and vomiting. The vast majority of patients (about 90%) experience nausea, about 70% experience vomiting, and typically one-third experience both symptoms with each attack.

Cluster headaches are extremely severe headaches that occur repeatedly in cycles ("clusters"), usually daily, for periods of one week or more, typically six to twelve weeks. Chronic cluster headaches can last for a year or more without remission. Cluster headaches are considered to be one of the most debilitating headaches known to medicine and have been shown to cause more severe pain than migraines. Cluster headache attacks occur repeatedly during the day or night, especially during sleep, in approximately 47% of cases. Cluster periods may begin at the same time and last for a similar length of time for years. The primary cause of this recurrent pattern is unknown, but is thought to involve the hypothalamus (the body's internal clock).

Cluster headache pain is typically one-sided (unilateral) or localized, occurring around or above the eye. During attacks, patients may become agitated and restless and have difficulty remaining still in one place. Patients may feel the need to move about, rocking, sitting, pacing, crawling, screaming in pain, or even banging their head on hard surfaces. For some patients, the severity and recurrence of cluster headaches puts them at high risk for alcohol and drug abuse, self-harm, and even suicide. In fact, cluster headaches are sometimes referred to as "suicide headaches."

Treatment options for cluster headaches are very limited, and there is a dire need for treatments that provide rapid and effective responses. See, for example, Epidemiology and Clinical Neuropathy, 1999, 144: 1111-1123. Although migraine is distinct from cluster headaches, it is believed that certain treatments for migraine, including triptans, may also be effective for cluster headaches. However, oral and nasal routes of administration are not particularly effective due to slow absorption rates and the short duration of headaches. Triptan injections have shown some efficacy, but their use is limited by needle phobia, lack of portability, complex preparation, the need to dispose of needles, and safety issues related to infection from punctures, cuts, and cross-contamination.

Acute treatment of migraine headaches changed dramatically in 1991 with the introduction of the triptan group, including sumatriptan and zolmitriptan. Triptans are serotonin derivatives that exhibit highly selective and potent agonist activity at vascular and neuronal 5-HT _1B and 5-HT _1D receptors, respectively. Triptans are believed to have three mechanisms of action: (1) stimulating vasoconstriction of meningeal vessels by binding to postsynaptic vascular 5-HT _1B receptors, (2) inhibiting the release of proinflammatory neuropeptides by binding to presynaptic neuronal 5-HT _{1D receptors, and (3) reducing firing rate in the trigeminal nerve and trigeminal nucleus caudalis (central action) by binding to presynaptic neuronal 5-HT 1D} receptors. _Triptans have also shown greater efficacy than placebo in the treatment of cluster headaches.

Currently available methods of triptan administration, including oral, nasal spray, subcutaneous injection, and iontophoretic intradermal patch (a device that delivers the drug through the skin with a low electrical current), each have significant drawbacks. Some migraine patients do not respond to oral triptans, and patients who suffer from the nausea, vomiting, or gastric stasis that can accompany migraine may find oral treatment ineffective and/or uncomfortable. In addition, oral, nasal, and iontophoretic patch triptan preparations are characterized by slow absorption and a relatively slow onset of action, resulting in incomplete relief, especially early in the episode. This delay is a fatal flaw in cluster headaches, because cluster headache episodes often last 30 minutes or less, making oral triptans completely ineffective, and nasal triptans may be significantly less effective than subcutaneously delivered triptans. Cluster headaches are often accompanied by nasal congestion and runny nose, which may affect absorption after nasal delivery. Nasal sprays can have an unpleasant taste, and using injections can be painful.

Sumatriptan (IMITREX®) is available in a variety of dosage forms, including tablets, subcutaneous (SC) injections, nasal sprays, and transdermal electrophoresis. Oral administration (as the succinate salt) results in low bioavailability (approximately 15%) due to low absorption and presystemic metabolism. The time to reach peak concentration in the bloodstream (T _max ) after oral tablet administration is approximately 2 hours. Rapid-release tablet formulations have a T _max that is on average 10-15 minutes earlier than conventional tablets, but have roughly similar bioavailability. When injected, sumatriptan is fast acting (usually within 10 minutes), but has a short duration of action. Despite the faster SC delivery, tablet formulations of sumatriptan are prescribed much more frequently than injectable formulations, due to the reluctance of many patients to self-inject.

Triptans have an excellent safety profile when used appropriately, with an adverse effect profile similar to that seen with placebo in clinical trials. Zolmitriptan, like other members of the triptan class, has demonstrated efficacy and good tolerability in placebo-controlled clinical trials. It is available in a number of commercial formulations (ZOMIG®), including: (a) normal release tablets (2.5 mg and 5.0 mg); (b) "fast-dissolve" orally disintegrating tablets (2.5 mg and 5.0 mg); and (c) a nasal spray (5.0 mg).

Zolmitriptan normal release tablets have been found to have a bioavailability of 41%-48%, with a 13%-16% decrease in _Cmax and AUC when administered with food (J. J. Med. 2002, 144: 1111-1112, and J. Med. 2002, 144: 1111-1112, 2002). Conventional tablets have a _Tmax of approximately 1.5 hours. In fact, it has been reported that absorption is reduced during a migraine attack, and _Tmax values can be increased during a migraine headache. Zolmitriptan is converted to an active N-desmethyl metabolite, whose concentration is approximately two-thirds that of zolmitriptan. The 5HT _1B/1D potency of the metabolite is two- to six-fold that of the parent compound, and thus the metabolite may be responsible for a significant portion of the overall effect of zolmitriptan after administration.

The bioavailability of the orally disintegrating tablet is similar to that of the conventional tablet, but the _Tmax is (somewhat unexpectedly) greater: approximately 3 hours for the disintegrating tablet compared to 1.5 hours for the conventional tablet. Disintegrating tablets may also exacerbate the nausea that often accompanies a migraine attack.

Zolmitriptan has significant advantages over other triptans when alternative delivery routes and methods are considered. Zolmitriptan, naratriptan, and frovatriptan are the only three triptans with the lowest oral doses, less than 5 mg, but at this low dose, zolmitriptan is significantly more effective than naratriptan, with 62% vs. 49% pain relief at 2 hours and 29% vs. 18% pain relief at 2 hours (Non-Patent Document 4). Frovatriptan is also "the least effective compared to other triptans in terms of response at 2 hours and pain relief at 2 hours" (Non-Patent Document 5).

To overcome the drawbacks of oral delivery, nasal administration of zolmitriptan has been attempted, with doses of 2.5 mg and 5.0 mg being commercially available, but this only slightly improves the _Tmax of zolmitriptan (to about 1.5 hours), and most of the dose is swallowed and undergoes first-pass metabolism.

Other parenteral routes of administration, such as transdermal iontophoresis, patches, and liquid injections, have disadvantages including skin irritation and scarring, pain, and inability to deliver therapeutically effective amounts. Subcutaneous sumatriptan has been available for many years but has not been widely used because of difficulties in preparation and problems with needle phobia, needle disposal, and accidental pricks, cuts, and cross-contamination associated with needle delivery.

It has been found that the efficacy of triptan treatments for migraine depends more on the rate of absorption than on the dose or plasma concentration. Rapid absorption and shorter _Tmax provide better pain relief not only early in the migraine episode, but also, unexpectedly, later, when slower absorbing treatments provide higher plasma concentrations. In addition to the above effects, rapid absorption is necessary in cluster headaches simply because of the short duration of the headache event. Rapid absorption also shortens the time required for application of the transdermal patch, allowing for efficient delivery of the packaged dose. This, for example, reduces variability and facilitates reproducibility due to variability in patch wear time.

Law et al, Triptans for acute cluster headache, Cochrane Database of Systematic Reviews (2013), Issue 7 Seaber et al. “The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)” Br. J. Clin. Pharmacol. 1997; 43(6): 579-87 Seaber et al. “The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers” Br. J. Clin. Pharmacol. 1998; 46: 433-439 C. Asseburg, P. Peura, T. Oksanen, J. Turunen, T. Purmonen and J. Martikainen (2012); Cost-effectiveness of oral triptans for acute migraine: Mixed treatment comparison. International Journal of Technology Assessment in Health Care, 28, pp 382-389 Neuropsychiatr Dis Treat. 2008 Feb; 4(1): 49-54

The objective of the present invention is to provide a method for rapidly obtaining a therapeutic concentration of zolmitriptan suitable for the treatment of migraine and cluster headaches.

Thus, advantages would be offered by an alternative to currently available migraine and cluster headache treatments that (a) has an onset of action faster than oral and as good as SC preparations and does not have needle-related issues; (b) does not use the oral route, where absorption may be limited by the gastric effects of migraine (gastric stasis, nausea, and vomiting); (c) reduces the potential for food interactions, avoids first-pass metabolism, and reduces the potential for drug-drug interactions; (d) is preferred by patients (rapid acting but not injected and has no unpleasant taste or odor, e.g., nasal spray); (e) has reduced absorption to reduce triptan side effects (e.g., chest tightness), yet is still effective enough to relieve migraine headache and nausea; (f) is easily carried by patients for use at the first sign of a migraine or cluster headache; and (g) can be quickly, conveniently, and safely self-administered. Furthermore, because nausea accompanies 60% to 70% of migraine attacks, physicians and patients would benefit from a formulation that can be administered without using the gastrointestinal system and without the absorption-blocking effects of vomiting. Similarly, the nasal congestion and runny nose that accompany cluster headaches can also affect the effectiveness of medications delivered nasally.

Therefore, there is a need in the art for a route of administration that can provide triptans, such as zolmitriptan, at the relatively large doses typical of oral administration, but without the side effects associated with orally delivered administration. The present disclosure specifically meets these challenges and needs. For example, Applicants have surprisingly found that transdermal delivery of triptans, such as zolmitriptan described herein, can rapidly deliver zolmitriptan at the relatively large doses typical of oral administration, resulting in plasma concentrations in or above the range found following oral administration, despite the extremely low permeability nature of the skin.

There is also a need for a route of triptan administration that is highly effective by having an absorption rate similar to that of injection, is portable, and is easily prepared, but does not pose the problems of needle phobia, needle disposal, and accidental punctures, cuts, and cross-contamination associated with needle-based delivery.

Furthermore, there is a need in the art for an effective method of administering triptans using transdermal delivery that can precisely and uniformly coat the patch and avoid problems of residual drug on the array or manufacturing variability, such as unevenly coated formulation or poor adherence of the formulation to the patch. Many attempts have been made to use transdermal microneedle patches to effectively deliver drugs, but it has been difficult to achieve rapid release of drug from and rapid treatment with a microneedle system, while optimizing and constructing an effective microneedle shape and size, and containing a sufficient dose of drug. Through extensive development, applicants have constructed an effective triptan delivery system by addressing the challenges of viscosity, drug loading, surface tension, microneedle shape and size, and general manufacturing defects.

The present disclosure relates to compositions, devices, methods of treatment, kits, and methods of manufacture of pharmaceutical formulations useful for the treatment of migraine and other conditions, including cluster headaches. More specifically, the disclosure relates to administering a triptan, such as zolmitriptan, as an active pharmaceutical ingredient to a subject in need thereof. In particular, the disclosure is directed to administering a therapeutically effective amount of the active ingredient transdermally, intradermally, or through the skin in an easy-to-use and portable form suitable for rapid administration, where the effective amount becomes available in the subject's bloodstream more rapidly than if the therapeutically effective amount of the active ingredient were administered orally. In one embodiment, a means for transdermal delivery of a triptan, such as zolmitriptan, typically includes a patch assembly having a microprojection portion with a plurality of microprojections (i.e., "needles" or "microneedles" or "arrays"), the plurality of microprojections being coated with a drug, in fluid communication with a reservoir of the drug, or containing the drug. The patch assembly further includes an adhesive portion, and in a preferred embodiment, the microprojections and adhesive portion are attached with a retaining ring. These microprojections are adapted to be applied to the skin to deliver the drug to the bloodstream, or more specifically, to penetrate or pierce the stratum corneum to a depth sufficient to deliver a therapeutically effective amount to the bloodstream. In one embodiment, the insertion of the drug-coated microneedles into the skin is controlled by a hand-held applicator that provides sufficient impact energy density within less than about 10 milliseconds.

Preferably, the microprojections include a biocompatible coating formulation that includes a drug, such as zolmitriptan, in a dose sufficient to provide a therapeutic effect. The coating may further include one or more excipients or carriers that facilitate administration of the drug through the skin. For example, the biocompatible coating formulation may include zolmitriptan and a water-soluble carrier that is first applied to the microprojections in liquid form and then dried to form a solid biocompatible coating.

In a preferred embodiment, the zolmitriptan, excipients, and coating and drying process result in a non-crystalline (amorphous) drug coating with a surprisingly fast dissolution rate. In this embodiment, the coating dissolves at a rate sufficient to allow rapid uptake of the drug into the epidermis and bloodstream when applied to the skin via microneedles. In one embodiment, the rate is less than 20 minutes, or less than 15 minutes, or less than 10 minutes, or less than 5 minutes, or less than 2.5 minutes, or less than 1 minute. This fast rate provides rapid migraine relief and cluster headache relief. Preferably, this fast uptake results in pain relief in more than about 10% of patients within 1 hour of administration, more preferably in more than about 20% of patients, and most preferably in more than about 25% of patients. In another embodiment, this fast uptake results in pain relief in more than 40% of patients within 1 hour of administration, or pain relief in more than 50% of patients, or more than about 65% of patients at 1 hour of administration. Preferably, the drug coating remains amorphous for one year, and more preferably for two years, after exposure to gamma or electron beam radiation.

Such an intradermal delivery system may be in the form of a device adapted for easy direct use by a patient. For example, the system may be a drug-device combination product that includes (a) a disposable microprojection having titanium microneedles coated and dried with a pharmaceutical formulation, the microprojections being centered on an adhesive surface to form a patch, and (b) a reusable handheld applicator that presses the microneedles against the stratum corneum to ensure that the patch is applied to the skin with a specific application energy sufficient to absorb the drug. In one embodiment, the delivery system comprises a patch containing about 0.2 mg to about 10 mg of zolmitriptan, or about 1 mg to about 4 mg, or about 1 mg, or about 1.9 mg, or about 2 mg, or about 3 mg, or about 3.8 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg of zolmitriptan. In one embodiment, the delivery system is designed to deliver about 0.2 mg to about 10 mg of zolmitriptan intradermally, or about 1 mg to about 4 mg, or about 1 mg, or about 1.9 mg, or about 2 mg, or about 3 mg, or about 3.8 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or more than about 1 mg, or more than about 1.9 mg, or more than about 2 mg, or more than about 3 mg, or more than about 3.8 mg, or more than about 4 mg, or more than about 5 mg, or more than about 6 mg, or more than about 7 mg, or more than about 8 mg, or more than about 9 mg of zolmitriptan.

In another embodiment, the disclosure relates to a method of transdermally or intradermally administering a triptan to a patient in need thereof, comprising: (a) providing a transdermal patch adapted to deliver a triptan intradermally, the transdermal patch comprising a microprotrusion portion having a plurality of microprotrusions adapted to pierce or pierce the stratum corneum of a patient, the microprotrusions having a biocompatible coating disposed over a portion or all of the microprotrusions, the coating comprising a therapeutically effective amount of the triptan; and (b) applying the microprotrusion portion of the device to the patient's skin, wherein the plurality of microprotrusions pierce or pierce the stratum corneum to deliver the triptan to the patient's bloodstream. In one embodiment, the triptan is zolmitriptan and is coated onto the microprojections in a total amount of about 0.2 mg to 10 mg, with about 50%, or 60%, or 65%, or 75%, or 80%, or 85%, or 90%, or 95%, or 100% of this dose reaching the patient's bloodstream after administration, and preferably more than about 50%, or more than 60%, or more than 65%, or more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95% of this dose reaching the patient's bloodstream after administration.

The present disclosure encompasses a method of treating migraine or cluster headache in a human patient in need of such treatment or relief, comprising administering a therapeutically effective amount of zolmitriptan transdermally or intradermally, which administration results in a therapeutic concentration of zolmitriptan in the blood more rapidly than a therapeutically effective amount administered orally, intranasally, sublingually, or iontophoretically. In one aspect, the method of treating or relieving migraine or cluster headache in a patient results in a rapid plasma _Tmax , from about 2 minutes to about 30-40 minutes or less in many subjects. In another aspect, the method results in a maximum plasma concentration ( _Cmax ) of zolmitriptan of less than 50 ng/ml.

In one embodiment, a microneedle patch coated with zolmitriptan disclosed herein is applied during a migraine or cluster headache attack to achieve rapid plasma concentrations. Such a patch results in relief of pain and relief of bothersome migraine or cluster headache symptoms at least 45 minutes after administration. In addition to pain, the most bothersome migraine symptoms for patients are typically selected from sensitivity to light, especially bright light (photophobia), sensitivity to sound, especially loud sounds (phonophobia), and nausea, although migraines may also be accompanied by vomiting, sensitivity to smells, aura, vision changes, numbness, tingling, weakness, dizziness, dizziness or lightheadedness, eyelid edema, lack of concentration, fatigue, diarrhea, constipation, mood swings, binge eating, hives, and/or fever. Common symptoms of cluster headaches include severe pain on one side of the head, usually felt in or around one eye, but which can spread to other areas such as the face, head, neck, and shoulders, restlessness, excessive tearing and redness of the eye on the affected side, stuffy or runny nose, forehead or facial sweating, pale skin (pallor), facial flushing, swelling around the eye on the affected side, and/or ptosis.

Further embodiments of the devices, compositions, methods, and the like will become apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and following description, any feature described herein, and any combination of two or more of such features, are included within the scope of the present disclosure, provided that the characteristics of such combinations are not mutually inconsistent. Furthermore, any feature or combination of features may be specifically excluded from any of the embodiments or aspects. Further aspects and embodiments are described in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.
Color drawing reference

This application contains at least one drawing executed in color. Copies of this publication with color drawing(s) will be provided by the Patent Office upon request and payment of the appropriate fee.

That is, the gist of the present invention relates to the following.
[1] An intradermal delivery system comprising a plurality of microprojections adapted to penetrate or pierce the stratum corneum of a human patient, said microprojections comprising a solid formulation coating covering from about 10% to about 80% of the length of each microprojection measured from the tip to the base, said coating comprising zolmitriptan or a pharma- ceutically acceptable salt thereof in an amount of from about 1 mg to about 5 mg per system, and wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes as measured by the paddle-over-disk method (Apparatus 5) of the United States Pharmacopeia (USP).
[2] The system described in [1], wherein at least 95% of the zolmitriptan is released within about 1 minute.
[3] The system described in [1], wherein approximately 100% of the zolmitriptan is released within approximately 1 minute.
[4] The system of [1], wherein when the system is applied to a selected area of the patient's skin, a therapeutically effective plasma concentration T _max occurs within about 45 minutes of application, a C _max is about 5 ng/ml to about 25 ng/ml, and an AUC _{0-2 hours} is about 5 ng/ml-hour to about 20 ng/ml-hour.
[5] The system described in [1], wherein when the system is applied to a selected area of the patient's skin, the T _max of a therapeutically effective serum concentration occurs within about 30 minutes of the application.
[6] The system of [1], wherein the formulation coating has a viscosity before drying of about 150 cP to about 350 cP and a surface tension of about 50 mNm ^-1 to about 72 mNm ^-1 .
[7] The system of [6], wherein the coating covers about 20% to about 70% of the length of each microprojection.
[8] The system of [7], wherein the coating covers about 30% to about 60% of the length of each microprojection.
[9] The system of [1], wherein the formulation coating has a viscosity before drying of about 200 cP to about 300 cP and a surface tension of about 55 mNm ^-1 to about 65 mNm ^-1 .
[10] The system of [1], wherein the formulation coating on each microprojection has an approximate American football shape with a thickness tapering from a maximum of about 270 μm.

The present invention provides a method for rapidly achieving therapeutic concentrations of zolmitriptan suitable for the treatment of migraine and cluster headaches.

The features of the foregoing embodiments will be more readily understood by reference to the following detailed description taken in conjunction with the accompanying drawings, in which:
1A-1B are scanning electron micrographs (SEM) of the MF1663 array design coated with 1.9 mg of zolmitriptan. 2A-2B show the structure of a patch and a retaining ring: (A) a top view of the patch and the retaining ring, and (B) a bottom perspective view of the patch attached to the retaining ring. 3A-3B show a patch assembly comprised of a patch assembled to a retaining ring, (A) a side view of the patch assembly, and (B) an exploded view of the patch assembly. 4A-4B show how to remove the used plastic retaining ring from the applicator and discard it. Use your fingers to remove the used retaining ring from the applicator. (A) A side view of the retaining ring attached to the applicator. (B) A side view of the retaining ring removed from the applicator. 5A-5E are photographs showing the steps of applying a patch of the present invention. (A) Shows step 1 of fitting the patch assembly onto the applicator. (B) Also shows a bottom front perspective image of the patch assembly integrated with the applicator in step 1. (C) Shows step 2 of turning the applicator cap clockwise from position 1 to position 2 to unlock for applying the patch. (D) Shows step 3 of pressing the applicator downward to apply the patch to the skin. (E) Shows step 4 where the patch has been applied to the patient's skin and the retaining ring remains attached to the applicator. 6A-6C show in vitro release profiles of ZP-zolmitriptan M207 1.9 mg patch. (A) Top left: In vitro release profile of ZP-zolmitriptan M207 1.9 mg patch (L/N0164004) irradiated with e-beam and stored at room temperature for 10 months. (B) Top right: In vitro release profile of ZP-zolmitriptan M207 1.9 mg patch (L/N0203149-NI) not irradiated and stored at 40° C. and 75% relative humidity for 10 months. (C) Bottom left: In vitro release profile of ZP-zolmitriptan M207 1.9 mg patch (L/N0203149-IR) irradiated with e-beam and stored at 40° C. and 75% relative humidity for 10 months. 7 is a line graph showing the mean plasma concentrations of zolmitriptan and sumatriptan over time (0 hr to 24 hr) in normal human volunteers: Treatment A, M207 system (0.48 mg); Treatment B, M207 system (0.48 mg x 2); Treatment C, M207 system (1.9 mg); Treatment D, zolmitriptan (2.5 mg oral tablet); Treatment E, sumatriptan (6.0 mg SC using autoinjector pen); Treatment F, zolmitriptan system (1.9 mg x 2); Treatment G, zolmitriptan system (3.8 mg). For sumatriptan, the graph is scaled to 6/90 to show the sumatriptan concentration-time profile in comparison to the other treatments. 8 is a line graph depicting the mean plasma concentrations of zolmitriptan and sumatriptan over time (0 hr to 2 hr) for treatment A=M207 system (0.48 mg), treatment B=M207 system (0.48 mg×2), treatment C=M207 system (1.9 mg), treatment D=zolmitriptan (2.5 mg oral tablet), treatment E=sumatriptan (6.0 mg SC using autoinjector pen), treatment F=zolmitriptan system (1.9 mg×2), and treatment G=zolmitriptan system (3.8 mg). In this graph, sumatriptan is scaled to 6/90 to show the sumatriptan concentration-time profile in comparison to the other treatments. FIG. 9 is a line graph showing the C _max dose linearity of M207 (excluding 3.8 mg) for single and multiple patches. FIG. 10 is a line graph showing the AUC _t dose linearity of M207 (excluding 3.8 mg) for single and multiple patches. FIG. 11 is a line graph of mean plasma zolmitriptan concentrations in women from 0 hours to 2 hours. FIG. 12 is a line graph of mean plasma zolmitriptan concentrations in men from 0 hours to 2 hours. FIG. 13 is a line graph of mean plasma N-desmethylzolmitriptan concentrations from 0 hours to 2 hours. FIG. 14 is a line graph of mean plasma N-desmethylzolmitriptan concentrations from 0 hours to 24 hours. FIG. 15 is a line graph showing the C _max dose linearity of M207 for single and multiple patches. FIG. 16 is a line graph showing the AUC _t dose linearity of M207 for single and multiple patches. FIG. 17 is a line graph showing the AUC _inf dose linearity of M207 for single and multiple patches. FIG. 18 is a line graph showing the AUC _inf dose linearity of M207 for single and multiple patches (excluding the 3.8 mg patch). FIG. 19 is a line graph showing the C _max dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. FIG. 20 is a line graph showing the AUC _t dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. FIG. 21 is a line graph showing the AUC _inf dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. FIG. 22 is a line graph showing the C _max dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. FIG. 23 is a line graph showing the AUC _t dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. FIG. 24 is a line graph showing the AUC _inf dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. FIG. 25 is a graphical comparison of the % Pain Relief at 1, 2, and 4 hours after treatment. FIG. 26 is a graphical comparison of the % Pain Relief at 1, 2, and 4 hours after treatment. FIG. 27 is a graphical comparison of the "Percentage of Pain Relief" 1, 2, and 4 hours after treatment. FIG. 28 is a graphical comparison of the % Pain Relief at 1, 2, and 4 hours after treatment. FIG. 29 is a graphical comparison of the % of subjects who were pain free for up to 4 hours after treatment. FIG. 30 is a graphical representation of average flux results from ex vivo human skin samples. FIG. 31 illustrates the interaction of the microprojections with the skin, specifically, how the microprojections penetrate the stratum corneum for effective drug delivery. FIG. 32 shows an embodiment of microprojections of one shape and size before they are bent outward from the substrate and coated with a drug.

Various aspects and embodiments are described in detail below. However, these aspects and embodiments may be embodied in various different forms and should not be construed as limiting. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present subject matter to those skilled in the art. All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

I. Introduction Applicants have surprisingly found that doses of zolmitriptan, particularly those typical for oral delivery, are well tolerated by routes of delivery other than oral delivery, such as intradermal or transdermal delivery of zolmitriptan as described herein. In accordance with the present disclosure, a means of delivery of zolmitriptan generally includes a delivery system comprising a microprojection (or system) having a plurality of microprojections (or an array thereof) adapted to penetrate or pierce the stratum corneum into the underlying epidermal layer or epidermal and dermal layers. Applicants have modified the transdermal delivery of zolmitriptan through considerable trial and error and diligent investigation. In one embodiment, the microprojections comprise a biocompatible coating that includes zolmitriptan. This system provides better pharmacokinetics and pharmacodynamics than existing therapies and can be expanded to other triptans useful for treating migraine, cluster headaches, and other diseases or conditions.

II. Definitions Unless otherwise defined, all terms and phrases used herein include the meaning that the term and phrase has acquired in the art, unless a contrary meaning is expressly stated or is apparent from the context in which the term or phrase is used. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, certain methods and materials are described below.

Unless otherwise expressly stated, each numerical value is used as an approximation as if the value were preceded by the word "about" or "approximately". Similarly, the numerical values in the various ranges set forth in this application are shown as approximations as if the minimum and maximum values in the range were preceded by "about" or "approximately" unless otherwise expressly stated. In this manner, variable values above and below the stated range can be used to obtain substantially the same results as the values within the range. The terms "about" and "approximately", when used herein, when attached to numerical values, will have their obvious and ordinary meaning to those skilled in the art of the art most closely related to the disclosed subject matter or to the range or element at issue. The amount beyond a specific numerical boundary will depend on many factors. For example, possible factors include the importance of the element and/or the effect of a particular variable amount on the implementation of the claimed subject matter, as well as other considerations known to those skilled in the art. Even with the use of various significant figures for the various numerical values, the use of the word "about" or "approximately" as used herein is not intended to limit the extent to which a particular numerical value or range extends. Thus, in general terms, "about" or "approximately" broadens the numerical range. Moreover, the disclosure of a range is intended to indicate a continuous range including every value between the minimum and maximum values, as well as the breadth of the range permitted by the use of the terms "about" or "approximately." Thus, the description of a range of values herein is merely intended to serve as a shorthand method of referring to each individual value within the range, and each individual value is incorporated herein as if each were set forth herein.

The term "amorphous" refers to a non-crystalline solid, i.e., a solid that does not have the long-range order characteristic of a crystalline solid.

The term "area under the curve" or "AUC" refers to the area under the curve (mathematically known as the definite integral) in a plot of drug concentration in plasma against time. The area is typically calculated starting from the time the drug is administered and ending when the concentration in plasma is negligible. In practice, drug concentrations are measured at specific time points and the trapezoidal rule is used to estimate the AUC.

The term "biocompatible coating," as used herein, means and includes a coating formed from a "coating formulation" that has sufficient adhesive properties and has no (or minimal) adverse interactions with biologically active agents (also known as active pharmaceutical ingredients, therapeutic agents, or drugs).

The term "bioequivalence" as used herein refers to the scientific basis for comparing two or more pharmaceutical formulations, compositions, or methods containing the same active ingredient with each other. "Bioequivalence" means that there is no significant difference in the rate and extent to which the active agent in the pharmaceutical equivalents or substitutes is available at the site of action when administered in a properly designed study. Bioequivalence can be determined by in vivo studies comparing pharmacokinetic parameters for the two compositions. Parameters often used in bioequivalence studies are T _max , C _max , AUC _0-inf , AUC _0-t . In the present context, substantial bioequivalence of two compositions or two formulations is established by 90% confidence intervals (CI) of 0.80 to 1.25 for AUC and C _max .

The term "cluster" as used herein means a series of recurring cluster headache attacks. The duration of a cluster attack is usually from one week to one year, although chronic cluster headaches last longer than one year. A cluster attack is considered ended by at least one month of remission.

The term "cluster headache", as used herein, refers to a condition characterized by recurrent, severe headaches, usually daily (attacks may occur up to eight times per day) for a week or more. The pain of a cluster headache is typically localized to one side of the head ("unilateral"), usually on the same side, although the side affected may vary from patient to patient. The pain usually reaches maximum intensity in less than 10 minutes and lasts between 15 minutes and 3 hours (usually 30 to 60 minutes). The rapid onset and short duration of symptoms dictate the need for treatment via routes that allow rapid absorption of medication.

The term "coating formulation" as used herein means and includes a free-flowing composition or mixture used to coat a delivery surface, including one or more microprojections and/or arrays thereof.

The term "degradation," as used herein, means a decrease in the purity of a biological agent from its original point in time.

The term "desiccant" as used herein means an agent, usually a chemical agent, that absorbs water.

The term "degrade" as used herein means that the quality, properties, or effectiveness of a biologically active agent is diminished or impaired.

The term "electrotransport" generally refers to the permeation of a beneficial agent, such as a drug or drug precursor, through a body surface, such as the skin, mucous membrane, nails, etc. Application of an electrical potential, and therefore an electrical current, induces or increases transport of the drug, thereby delivering or facilitating delivery of the drug, or, in the case of "reverse" electrotransport, sampling or facilitating sampling of the drug. Electrotransport of drugs into or out of the body can be accomplished in a variety of ways.

The term "half-life" as used herein means the time required for the blood or plasma concentration of a drug to decrease by half. This decrease in drug concentration is the result of elimination or excretion after absorption is complete and distribution has reached equilibrium or quasi-equilibrium. The blood half-life of a drug can be calculated from a pharmacokinetic plot, which is a plot of the blood concentration of the drug over time, typically after intravenous administration to a sample population. Half-life can also be calculated using mathematical calculation methods well known in the art. Additionally, as used herein, the term "half-life" also includes the "apparent half-life" of a drug. The apparent half-life may be a multi-component number that takes into account contributions from other processes, such as absorption, reuptake, or enterohepatic recirculation, in addition to excretion.

The term "headache scale" as used herein means a scale used to allow a patient to quantify their level of pain. Preferably, a scale of 0 to 3 is used, with severe pain being a headache score of 3, moderate pain being a score of 2, mild pain being a score of 1, and no pain (also referred to as "pain absence") being a score of 0.

The term "intradermal," as used herein, is a generic term meaning delivery of an active agent (e.g., a therapeutic agent such as a drug, medicament, peptide, polypeptide, or protein) through the skin to local tissue or the systemic circulatory system without substantially cutting or penetrating the skin, such as by cutting with a scalpel or piercing the skin with a hypodermic needle. Intradermal drug delivery includes delivery via passive diffusion, as well as delivery based on external energy sources such as electricity (e.g., iontophoresis) and ultrasound (e.g., phonophoresis).

The term "intradermal flux" as used herein means the intradermal delivery rate of a drug.

Terms such as "microprojections" or "microneedle array" as used herein generally refer to a group of microprojections, preferably arranged in an array, that include a plurality of microprojections for penetrating or piercing the stratum corneum. The microprojections can be formed by etching or punching a plurality of microprojections from a thin sheet of metal or other hard material and then folding or bending the microprojections away from the sheet to create a three-dimensional shape. Alternatively, the microprojections can be formed from other materials, including plastics or polymers such as polyetheretherketone (PEEK). The microprojections can be formed by other known methods such as injection molding or micromolding, microelectromechanical systems (MEMS), or by constructing one or more strips with microprojections along each end of the strip. These are described in U.S. Pat. Nos. 6,083,196, 6,091,975, 6,050,988, 6,855,131, 8,753,318, 9,387,315, 9,192,749, 7,963,935, 7,556,821, 9,295,714, 8,361,022, 8,633,159, 7,419,481, 7,131,960, 7,798,987, 7,097, 631, 9,421,351, 6,953,589, 6,322,808, 6,083,196, 6,855,372, 7,435,299, 7,087,035, 7,184,826, 7,537,795, 8,663,155, and U.S. Patent Application Publication Nos. 20080039775, 20150038897, 20160074644, and 20020016562. As will be appreciated by those skilled in the art, when using microprojection arrays, the dose of therapeutic agent delivered can also be varied or altered by changing the size, density, etc. of the microprojection array.

The terms "microprojections" and "microneedles" are used interchangeably herein and refer to piercing elements adapted to penetrate, pierce, or cut into the skin of an animal, particularly mammalian, and more particularly human, into the stratum corneum and/or through the stratum corneum into the underlying epidermal or epidermal and dermal layers. In one embodiment of the invention, the piercing elements have a projection length of less than 1000 micrometers. In a further embodiment, the piercing elements have a projection length of less than 500 micrometers, more preferably less than 400 micrometers. Additionally, the width of the microprojections ranges from about 25 micrometers to 500 micrometers, and the thickness ranges from about 10 micrometers to 100 micrometers. The microprojections may be formed in a variety of shapes, such as needles, blades, pins, perforations, and combinations thereof.

The terms "minimize" or "mitigate" as used herein mean to reduce.

"Very bothersome other symptoms" means symptoms that are very bothersome to the patient in addition to pain, typically migraine symptoms. Preferably, the very bothersome other symptoms are identified by the patient at the start of the clinical trial. Very bothersome other symptoms are typically selected from nausea, photophobia, and phonophobia.

"Release of very bothersome other symptoms" means that the patient reports no very bothersome other symptoms at one or more predetermined time points after drug administration. For migraine patients, the preferred time points are 1 hour, 2 hours, and 4 hours. For cluster headache patients, the preferred time points are 15 minutes and 30 minutes.

"Relief of nausea" means that the patient reports no nausea for a predefined period of time after administration of the drug.

"Optional" or "optionally" means that the subsequently described element, component, or circumstance may or may not be present, and thus the description includes instances in which the element, component, or circumstance is present and instances in which it is not present.

"Pain relief" means that the patient reports no headache (headache score = 0) at one or more pre-determined time points after drug administration. Preferred time points for migraine patients are 1 hour, 2 hours, and 4 hours. Preferred time points for cluster headache patients are 15 minutes and 30 minutes.

"Pain relief" means that at one or more pre-determined time points after drug administration, the patient reports that their headache has decreased, i.e., their headache has decreased from moderate or severe pain (headache score = 3 or 2) to mild pain or no pain (headache score = 1 or 0). For migraine patients, the preferred time points are 1 hour, 2 hours, and 4 hours. For cluster headache patients, the preferred time points are 15 minutes and 30 minutes.

Phonophobia means the fear or aversion of sound, especially loud sounds.

"Relief of phonophobia" means that the patient reports no phonophobia for a predefined period of time after drug administration.

"Photophobia" means heightened, often painful, sensitivity to light, especially bright light.

"Absence of photophobia" means that the patient reports no photophobia for a predefined period of time after drug administration.

"Partial AUC" refers to the area under the drug concentration-time curve (AUC) calculated using linear trapezoidal summation method for a particular time period, e.g., AUC(0-1 hr), AUC(0-2 hr), AUC(0-4 hr), AUC(0-6 hr), AUC(0-8 hr), etc.

Drug "release rate", as used herein, means the amount of drug released from a dosage form or pharmaceutical composition per unit time, e.g., milligrams of drug released per hour (mg/hr). The drug release rate of a drug dosage form is typically measured as the in vitro dissolution rate, i.e., the amount of drug released from a dosage form or pharmaceutical composition per unit time, measured under the right conditions and in the right fluid.

The term "stable" as used herein, in relation to a drug formulation, means that the drug formulation is not prone to undue chemical or physical changes, e.g., decomposition, disintegration, or inactivation. As used herein, in relation to a coating, "stable" means that the drug formulation is mechanically stable, i.e., not prone to undue displacement or loss of the surface to which it is coated.

The terms "subject" and "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.

The term "therapeutic effectiveness" or "therapeutically effective amount," as used herein, refers to the amount of biologically active agent required to promote or elicit a desired beneficial result. The amount of biologically active agent used in the coatings of the present invention is that amount necessary to deliver the amount of biologically active agent required to achieve the desired result. In practice, this amount will vary widely depending on the particular biologically active agent being delivered, the site of delivery, and the dissolution and release kinetics for delivery of the biologically active agent into skin tissue.

The term "transdermal," as used herein, refers to the delivery of a drug into and/or through the skin for local or systemic therapy.

The term "transdermal flux" as used herein means the rate of transdermal delivery.

The term "T _max " refers to the time from the start of delivery to reaching C _max , i.e., the maximum plasma concentration of a biologically active agent.

It will be understood that the term "package" or "packaging" also includes the meaning of "storage" or "storing."

The term "zolmitriptan" includes, but is not limited to, zolmitriptan salts, simple derivatives of zolmitriptan, and closely related molecules.

III. Intradermal Delivery System In one embodiment, the intradermal delivery system is a transdermal or intradermal drug delivery system with a disposable patch consisting of microprojections in the center of an adhesive surface. The microprojections comprise titanium (or other hard materials, including plastic or polymeric materials such as polyetheretherketone (PEEK)) microneedles coated with a dry drug formulation. The patch is attached to a retaining ring to form a patch assembly. The patch assembly is removably attached to a handheld applicator to form an intradermal delivery system. The applicator ensures that the patch is applied to the intradermal administration site at a predetermined application rate and energy. The applicator may be designed for single use or may be reusable.

More specifically, the patch may comprise a titanium microneedle array of about 3 cm ² to 6 cm ² , with the microneedles having a length of about 200 micrometers to 350 micrometers, coated with a suitable hydrophilic formulation of the drug, and attached to an adhesive surface. The maximum amount of active drug that can be coated on the microneedle array of the patch varies depending on the active portion of the drug formulation, the weight of the excipients of the drug formulation, and the coatable surface area of the microneedle array. For example, patches with microneedle arrays of about 1 cm ² , 2 cm ² , 3 cm ² , 4 cm ² , 5 cm ² , and 6 cm ² can be used. The patch is applied in conjunction with a hand-held applicator that presses the microneedles into the skin to a substantially uniform depth adjacent to the capillary bed with each application, allowing the drug coating to dissolve and absorb, but not to reach the nerve endings in the skin. Typical patch wear times are about 15 to 45 minutes or less to reduce the possibility of skin irritation. A nominal applicator energy of about 0.20 Joules to 0.60 Joules will generally provide a good balance between impact perception and array penetration. The actual kinetic energy at the moment of impact is likely to be less than these nominal values due to incomplete extension of the applicator spring, energy losses due to the patch detaching from the retaining ring, and other losses, which may total about 25% of the nominal amount.
A. Array Design

A variety of variables influence the type of array utilized for a particular active agent. For example, different shapes (e.g., arrowhead, hook, cone, or shapes similar to the Washington Monument shape (FIGS. 1A-1B)) can provide high drug loading while increasing the length of the microprojections can increase the driving force for penetration. The stratum corneum is approximately 10 μm to 40 μm thick, and the microprojections must be of an appropriate size, thickness, and shape to penetrate through the stratum corneum and provide drug delivery. FIG. 31, not to scale, shows that the array has interacted with the skin resulting in the microprojections penetrating the stratum corneum and the substrate contacting the surface of the skin. It is advantageous to apply a thicker coating to the microprojections that will penetrate the stratum corneum and not to the substrate or base of the array ("streets") that do not penetrate the stratum corneum. The larger the surface area, the thicker the coating can be without spilling over onto the base or streets of the array. The coating is applied only to the microprojections. Additionally, increasing the thickness of projections in a coating requires greater penetration force, but this can be offset by increasing projection length and decreasing projection density per ^cm2 .

Examples of intradermal delivery systems that can be used in the present disclosure include those described in U.S. Patent Nos. 6,083,196, 6,091,975, 6,050,988, 6,855,131, 8,753,318, 9,387,315, 9,192,749, 7,963,935, 7,556,821, 9,295,714, 8,361,022, 8,633,159, 7,419,481, 7,131,960, 7,798,987, 7,09 These include the drug delivery techniques described in U.S. Pat. Nos. 7,631, 9,421,351, 6,953,589, 6,322,808, 6,083,196, 6,855,372, 7,435,299, 7,087,035, 7,184,826, 7,537,795, 8,663,155, and U.S. Patent Application Publication Nos. 20080039775, 20150038897, 20160074644, and 20020016562. The disclosed systems and devices use piercing elements of various shapes and sizes to pierce the outermost layer of the skin (i.e., the stratum corneum) to increase the flux of the drug. The piercing elements typically extend perpendicularly from a thin, flat substrate portion such as a pad or sheet. The piercing elements are typically small, some having a microprojection length of only about 25 micrometers to 400 micrometers and a microprojection thickness of about 5 micrometers to 50 micrometers. These small piercing/cutting elements, depending on their shape, create small microslits/microfabrications in the stratum corneum to enhance transdermal/intradermal drug delivery. The active agent to be delivered is provided on one or more of the microprojections, preferably by coating the microprojections with a triptan- or zolmitriptan-based formulation to form a solid dry coating, or by using a reservoir, optionally in communication with the stratum corneum after forming the microslits, or by forming the microprojections from a solid triptan-based formulation that dissolves after application. The microprojections may be solid or hollow and may further include device structures such as openings, grooves, surface irregularities, or similar modifications adapted to support and/or increase the coating volume, increasing the surface area and allowing greater amounts of coating to be applied. The microneedles may be formed from similar biocompatible materials such as stainless steel, titanium, nickel-titanium alloys, or polymeric materials.

The present disclosure therefore encompasses patches and microneedle arrays having the following features:
Patch size: about 1 cm ² to 20 cm ² , or about 2 cm ² to 15 cm ² , or about 4 cm ² to 11 cm ² , or about 5 cm ² , or about 10 cm ² .
Substrate size: about 0.5 cm ² to 10 cm ² , or about 2 cm ² to 8 cm ² , or about 3 cm ² to 6 cm ² , or about 3 cm ² , or about 3.13 cm ² , or about 6 cm ² .
Array size: about 0.5 cm ² to 10 cm ² , or about 2 cm ² to 8 cm ² , or about 2.5 cm ² to 6 cm ² , or about 2.7 cm ² , or about 5.5 cm ² , or about 2.74 cm ² , or about 5.48 cm ² .
Density (microprotrusions/ ^cm2 ): at least about 10 microprotrusions/ ^cm2 , or in the range of about 200 to about 2000 microprotrusions/ ^cm2 , or in the range of about 500 to about 1000 microprotrusions/ ^cm2 , or in the range of about 650 to about 800 microprotrusions/ ^cm2 , or about 725 microprotrusions/ ^cm2 .
Number of microprojections per array: about 100 to 4000, or about 1000 to 3000, or about 1500 to 2500, or about 1900 to 2100, or about 2000, or about 1987, or about 200 to 8000, or about 3000 to 5000, or about 3500 to 4500, or about 4100 to 4900, or about 4000, or about 3974.
- Microprojection length: about 25 micrometers to 600 micrometers, or about 100 micrometers to 500 micrometers, or about 300 micrometers to 450 micrometers, or about 320 micrometers to 410 micrometers, or about 340 micrometers, or about 390 micrometers, or about 387 micrometers. In other embodiments, the length is less than 1000 micrometers, or less than 700 micrometers, or less than 500 micrometers. Thus, the microneedles penetrate the skin about 25 micrometers to 1000 micrometers.
Tip length: about 100 micrometers to 250 micrometers, or about 130 micrometers to 200 micrometers, or about 150 micrometers to 180 micrometers, or about 160 micrometers to 170 micrometers, or about 165 micrometers.
Microprojection width: about 10 micrometers to 500 micrometers, or about 50 micrometers to 300 micrometers, or about 75 micrometers to 200 micrometers, or about 90 micrometers to 160 micrometers, or about 250 micrometers to 400 micrometers, or about 300 micrometers, or about 100 micrometers, or about 110 micrometers, or about 120 micrometers, or about 130 micrometers, or about 140 micrometers, or about 150 micrometers.
Microprojection thickness: from about 1 micrometer to about 500 micrometers, or from about 5 micrometers to 300 micrometers, or from about 10 micrometers to 100 micrometers, or from about 10 micrometers to 50 micrometers, or from about 20 micrometers to 30 micrometers, or about 25 micrometers.
Tip angle: about 10 degrees to 70 degrees, or about 20 degrees to 60 degrees, or about 30 degrees to 50 degrees, or about 35 degrees to 45 degrees, or about 40 degrees.
Total active agent per array: about 0.1 mg to 10 mg, or about 0.5 mg to 5 mg, or about 1 mg to 4 mg, or about 1 mg, or about 1.9 mg, or about 3.8 mg.
Amount of non-active ingredients per array: about 0.1 mg to 10 mg, or about 0.2 mg to 4 mg, or about 0.3 mg to 2 mg, or about 0.6 mg, or about 0.63 mg, or about 1.3 mg, or about 1.26 mg. Alternatively, the amount of non-active ingredients is at most 1/3 to 1 times the amount of active agent, or about 0.033 mg to about 3.33 mg.
Coating thickness: from about 100 μm to about 500 μm, or from about 200 μm to about 350 μm, or from about 250 μm to about 290 μm, or about 270 μm.
Active agent per microprojection: from about 0.01 μg to about 100 μg, or from about 0.1 μg to about 10 μg, or from about 0.5 μg to about 2 μg, or about 1 μg, or about 0.96 μg.

In a particularly preferred embodiment, the patch has an area of about 5 ^cm2 and is attached to a titanium substrate having an area of about 3.1 ^cm2 and a thickness of about 25 μm. The substrate is composed of a microprojection array having an area of about 2.74 ^cm2 with about 1987 microprojections at a density of about 725 microprojections/ ^cm2 . The dry formulation contained within each microprojection may have a rough football shape with a tapered thickness from a maximum of about 270 μm and comprises about 0.96 μg zolmitriptan and about 0.32 tartaric acid, or about 1.9 mg zolmitriptan and about 0.63 mg tartaric acid per patch.

32 shows the shape of the microprojections before bending (molding) in a preferred embodiment. Array molding is a process in which individual microprojections are bent at the appropriate angle relative to the substrate surface. The array is first placed on a mold with a mold that mimics the microprojections. An elastomer molded disk is placed on top of the array and pressure is applied to the mold of the molded device. The elastomer enters the mold and bends the microprojections to the desired angle. The use of elastomer has the advantage that the molded disk does not need to be precisely aligned with the microprojections and mold for effective array molding. As shown in FIG. 32, the microprojections can be substantially rectangular with a width of about 120±13 μm and a thickness of about 25.4±2.5 μm. The microprojections end in triangular tips to facilitate penetration. The tip angle is 40±5 degrees and the length is about 165±25 micrometers. Before bending (molding) from the substrate, the microprojections have a length of 387±13 μm, and after bending, the microprojections protrude perpendicularly from the substrate by about 340 μm.

In another preferred embodiment, the patch has an area of about 5 ^cm2 and is attached to a titanium substrate with an area of about 6 ^cm2 and a thickness of about 25 μm. The substrate is composed of an array with an area of about 5.5 ^cm2 with about 4000 microprojections at a density of about 725 microprojections/ ^cm2 . The dry formulation contained in each microprojection is roughly football-shaped with a thickness tapering from a maximum of about 270 μm, and consists of about 0.96 μg zolmitriptan and about 0.32 tartaric acid or about 3.8 mg zolmitriptan and about 1.3 mg tartaric acid per patch. The length of the microprojections is about 387±13 μm, the width is about 120±13 μm, and the thickness is about 25.4±2.5 μm. The microprojections are rectangular with triangular tips to facilitate penetration. The tip angle is 40±5 degrees and the length is about 165±25 micrometers.

The exact combination of size, length, and density that results in the desired penetration can vary and depend on the drug, the drug dose, the disease or condition being treated, and the frequency of administration. Thus, the drug delivery efficiency (i.e., the amount of drug delivered to the bloodstream) of a particular array can vary from about 40% to 100%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 100%.
B. Impact Applicator

As shown in Figures 4A-4B and 5A-5E, the intradermal drug delivery system of the present disclosure may further include an impact applicator having a body and a piston movable within the body, where a surface of the piston presses the patch against the skin and causes the microprotrusions to pierce the stratum corneum, the applicator adapted to press the microneedle array against the stratum corneum with an impact energy density of at least 0.05 Joules ^{per cm2} within 10 milliseconds or less, or about 0.26 Joules per cm2 within 10 milliseconds or less, or about 0.52 Joules per ^cm2 within 10 milliseconds or less.

As shown in Figures 2A-2B, the intradermal delivery system includes a patch with an adhesive surface on one side and a shiny metal surface on the other side composed of an array of drug-coated microneedles. The patch can be applied to the skin by pressing the shiny metal surface against the skin, either manually or preferably with an applicator. Preferably, the applicator presses the patch against the skin with an impact energy density of 0.26 Joules per ^cm2 within 10 milliseconds or less. As shown in Figures 2A, 2B, 3A, and 3B, the patch can be connected to and supported by a retaining ring structure to form a patch assembly. The retaining ring is adjusted to fit over an impact adapter, removably attaching the patch to the applicator. The retaining ring structure may include an inner ring and an outer ring, which are designed to fit the adhesive patch and the microneedle array. Figures 5A-5E show one embodiment of the claimed invention, in which a user connects an impact applicator to a retaining ring that already has a patch and a microneedle array attached. As shown, once the retaining ring and impulse applicator are connected, the user can unlock the impulse applicator by twisting the applicator cap. Figure 5C shows that the user can then press the applicator downwards onto the skin to release the patch and apply it to the skin. The patch removably adheres to the patient's skin, and the retaining ring remains attached to the applicator. As shown in Figures 4A and 4B, the retaining ring is reversibly attached to the impulse applicator, allowing the impulse applicator to be reused for subsequent administrations with additional patch assemblies and potentially for other active ingredients or medical conditions.

In another embodiment, the patch and applicator are provided as a single, integrated unit in packaging that ensures stability and sterility of the formulation. The user removes the system from the packaging and applies the patch as described above. The used applicator is then disposed of. This embodiment provides a system that is uncomplicated, small, lightweight, and easy to use, at a slightly higher cost per dose.

The present disclosure may also be used in conjunction with a variety of active transdermal systems (as opposed to the passive manual intradermal delivery devices described herein), and the present disclosure is not limited in this respect.

Some active transdermal systems use electrotransport. Electrotransport drug delivery systems are illustratively disclosed in U.S. Patent Nos. 5,147,296, 5,080,646, 5,169,382, and 5,169,383, the disclosures of which are incorporated herein by reference in their entirety. One widely used electrotransport process is iontophoresis, which involves the electrically induced transport of charged ions. Electroosmosis is another type of electrotransport process involved in the transdermal transport of uncharged or charge-neutral molecules (e.g., transdermal sampling of glucose) and involves the movement of a solvent containing the drug through a membrane under the influence of an electric field. Electroporation is yet another type of electrotransport and involves the passage of a drug through pores formed by the application of an electric or high voltage pulse to a membrane. In many cases, one or more of the described processes may be occurring simultaneously to varying degrees. Thus, the term "electrotransport" is used herein in its broadest reasonable interpretation to include electrically induced or enhanced transport of at least one charged or uncharged drug, or mixtures thereof, regardless of the particular mechanism by which the drug is actually transported.

Additionally, any other transport enhancement method may be used in conjunction with the disclosure herein, including, but not limited to, chemical penetration enhancement, laser ablation, heat, ultrasound, or piezoelectric elements.

IV. Active Agents and Biocompatible Coatings The coating formulation applied to the microprojections to form a solid coating is a liquid, preferably an aqueous formulation that contains at least one biologically active agent that can be dissolved or suspended in a biocompatible carrier.The biologically active agent may be a triptan, including zolmitriptan, sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan, avitriptan, and donitriptan, as well as pharmaceutically acceptable salts, fragments, analogs, or prodrugs thereof.Preferably, the biologically active agent is zolmitriptan.

Examples of pharma- ceutically acceptable salts include, but are not limited to, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarballyl salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconic acid, citramalate, dimethylolpropionate, tiglate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydroacrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzenesulfonate, methanesulfonate, sulfate, and sulfonate.

The concentrations of biologically active ingredients and excipients must be carefully controlled to obtain the desired amount of active ingredient at a reasonable coating thickness, to avoid wicking of the coating formulation at the base of the microneedle array, to maintain coating uniformity, and to ensure stability. In one embodiment, the active agent is included in the coating formulation at a concentration of about 1% to about 60% w/w, preferably about 15% to 60%, or more preferably 35% to 45%. The formulation may further include an acid at a concentration of about 0.1% to about 20% w/w. Such acids may be selected from tartaric acid, citric acid, succinic acid, malic acid, maleic acid, ascorbic acid, lactic acid, and hydrochloric acid, either individually or in combination. In another embodiment, the ratio of active agent to acid in the coating formulation is about 1:1, about 2:1, about 3:1, about 4:1, or about 5:1. The present disclosure further encompasses a coating formulation comprising about 33% w/w zolmitriptan base and about 11% w/w tartaric acid. In some embodiments, the acid is one of tartaric acid, citric acid, succinic acid, malic acid, or maleic acid, and is included in an amount of about 0.33% w/w to 10% w/w, or about 8.33% w/w to 16.67% w/w, or about 13.33% w/w, or about 15% w/w, or about 6.67% w/w. In some embodiments, the coating formulation comprises 45% w/w active agent, 15% w/w acid, and 40% w/w water.

Surfactants may be included in the coating formulation. Suitable surfactants for addition to the coating formulation include, but are not limited to, polysorbate 20 and polysorbate 80. Surfactants are commonly used to enhance drug delivery as penetration enhancers. However, applicants have found that surfactants result in undulating coating formulations that exhibit non-uniform films and are highly undesirable. Applicants have found that by using the claimed invention, and in particular by using the claimed zolmitriptan transdermal delivery patch, the need for surfactants and other penetration enhancers can be eliminated. Furthermore, applicants have surprisingly found that despite the absence of surfactants, the microneedle coating was free of wicking and the coating was firmly attached to the microprojections during the manufacturing process of the microneedle array.

Antioxidants may be included in the coating formulation. Suitable antioxidants for addition to the coating formulation include, but are not limited to, methionine, ascorbic acid, and EDTA.

The coating formulation further comprises a liquid, preferably water, in an amount sufficient to make the formulation 100% before drying on the microneedles. The pH of the liquid coating formulation may be less than about pH 8. In other cases, the pH is about pH 3-7.4, or about pH 3.5-4.5.

Representative examples of liquid coating formulations according to the present disclosure are set forth below in Table 1. The coatings typically include at least one acid.

The present disclosure contemplates that sumatriptan or other triptans may be substituted for zolmitriptan in amounts or ratios similar to those set forth above.

The liquid coating formulations according to the present disclosure generally contain less than 5% water, preferably less than 3% water, and are capable of coating the microneedles with the correct amount and morphology consistently, thus resulting in a stable solid (dry) formulation. The liquid formulation is applied to the microneedle array and its microprojection tips using an industrial application device that can precisely control the depth to which the microprojection tips are immersed in the liquid film. An example of a suitable coating technique is described in U.S. Patent No. 6,855,372, which is incorporated herein by reference in its entirety. Thus, as already mentioned, the viscosity of the liquid will affect the coating process of the microprojections. See Ameri, M.; Fan, SC.; Maa, YF (2010); "Parathyroid hormone PTH(l-34) formulation that enables uniform coating on a novel transdermal microprojection delivery system;" Pharmaceutical Research, 27, pp. 303-313; also see Ameri M, Wang X, Maa YF (2010); "Effect of irradiation on parathyroid hormone PTH(l-34) coated on a novel transdermal microprojection delivery system to produce a sterile product-adhesive compatibility;" Journal of Pharmaceutical Sciences, 99, 2123-34.

The viscosity of the coating formulation containing zolmitriptan is less than about 500 centipoise (cP) and more than 3 cP, or less than about 400 cP and more than 10 cP, or less than about 300 cP and more than 50 cP, or less than about 250 cP and more than 100 cP. In some embodiments, the viscosity of the liquid formulation prior to coating is at least 20 cP. In other embodiments, the viscosity is about 25 cP, or about 30 cP, or about 35 cP, or about 40 cP, or about 45 cP, or about 50 cP, or about 55 cP, or about 60 cP, or about 65 cP, or about 70 cP, or about 75 cP, or about 80 cP, or about 85 cP, or about 90 cP, or about 95 cP, or about 100 cP, or about 150 cP, or about 200 cP, or about 300 cP, or about 400 cP, or about 500 cP. In other embodiments, the viscosity is greater than about 25 cP, or greater than about 30 cP, or greater than about 35 cP, or greater than about 40 cP, or greater than about 45 cP, or greater than about 50 cP, or greater than about 55 cP, or greater than about 60 cP, or greater than about 65 cP, or greater than about 70 cP, or greater than about 75 cP, or greater than about 80 cP, or greater than about 85 cP, or greater than about 90 cP, or greater than about 95 cP, or greater than about 100 cP, or greater than about 150 cP, or greater than about 200 cP, or greater than about 300 cP, or greater than about 400 cP, or less than about 500 cP. In a preferred embodiment, the viscosity of the coating formulation is greater than about 80 cP and less than about 350 cP, in another preferred embodiment, the viscosity is greater than about 100 cP and less than about 350 cP, and in another preferred embodiment, the viscosity is greater than about 100 cP and less than about 250 cP.

After application to the microprojections, the average thickness of the coating formulation, as measured from the microprojection surface, may be about 10 micrometers to about 400 micrometers, or about 30 micrometers to about 300 micrometers, or about 100 micrometers to about 175 micrometers, or about 115 micrometers to about 150 micrometers, or about 135 micrometers. The thickness of the coating formulation covering the microprojections is preferably uniform, but there may be some variation in the formulation as a result of the manufacturing process. As shown in FIG. 31, the microprojections are typically coated uniformly to penetrate the stratum corneum. In some embodiments, the entire length of the microprojections from tip to base is not coated, but instead a portion of the length of the microprojections is coated with the coating, and that portion of the length is at least about 10% to about 80%, or 20% to 70%, or about 30% to about 60%, or about 40% to about 50% of the length of the microprojections, as measured from tip to base.

The liquid coating formulation is applied to the microprojection array to deliver an active agent dose in an amount of about 0.1 mg to 10 mg per array. In the case of zolmitriptan, the dose delivered to the stratum corneum (delivered via a patch or other form) per array is about 0.25 mg to about 10 mg, or about 1 mg or more, or about 1.9 mg or more, or about 2 mg or more, or about 3 mg or more, or about 3.8 mg or more, or about 4 mg or more, or about 5 mg or more. In one embodiment, the amount of zolmitriptan contained in the coating formulation is 1 μg to 1000 μg or 10 μg to 100 μg. In one embodiment, the array size is about 5.5 ^cm2 and contains a dose of about 3.8 mg of zolmitriptan, or the array size is about 3 ^cm2 and contains a dose of about 3.8 mg, or the array size is about 3 ^cm2 and contains a dose of about 1.9 mg. The amount of zolmitriptan or a similar active agent per microprojection may range from about 0.001 μg to about 1000 μg, or from about 0.01 μg to about 100 μg, or from about 0.1 μg to about 10 μg, or from about 0.5 μg to about 2 μg. In one embodiment, the amount of zolmitriptan or a similar active agent per microprojection is about 1 μg. The shape and size of the microprojections play a large role in the drug loading capacity and drug delivery efficiency.

It is important to note that the formulations of the present disclosure do not rely primarily on penetration enhancers to facilitate absorption of the active agent into the bloodstream. Penetration enhancers such as Azone® and fatty acids often cause skin irritation and have other disadvantages. Thus, the systems of the present disclosure are completely free of penetration enhancers or are substantially free of penetration enhancers. In other embodiments, the dry formulation contains less than 15% w/w, or less than 10% w/w, or less than 5% w/w, or less than 2.5% w/w, or less than 1% w/w.

The biologically active agent formulation is typically prepared as a solid coating by drying the coating formulation on the microprojections as described in U.S. Patent Application Publication No. 2002/0128599. The coating formulation is typically an aqueous formulation. During the drying process, virtually all volatile materials, including water, are removed, but the final solid coating may still contain about 1% water, or about 2% water, or about 3% water, or about 4% water, or about 5% water by weight. The oxygen and/or water content of the formulation is reduced by using a dry inert atmosphere and/or reduced pressure. In the solid coating on the microprojection array, the agent may be present in an amount of less than about 10 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg per unit dose. With the addition of excipients, the total mass of the solid coating may be less than about 15 mg per unit dose.

The microprojections are typically on an adhesive surface and attached to a disposable polymeric retaining ring. The assembly is individually packaged in a sachet or polymeric container. The package contains, in addition to the assembly, a dead volume of at least 3 mL of dose. A portion of this large volume (compared to the volume of the coating) acts as a water absorber. For example, at 20° C., the amount of water contained as a result of vapor pressure in 3 mL of air is about 0.05 mg at saturation, which typically results in the amount of residual water contained in the solid coating after drying. It is therefore believed that storage in a dry, inert atmosphere and/or under reduced pressure will further reduce the water content of the coating, thereby improving its stability.

According to the present disclosure, the coating can be applied to the microprojections using various known methods. For example, the coating can be applied only to the microprojections or to the locations of the microprojections that pierce the skin (e.g., the tips). The coating is then dried to form a solid coating. Such coating methods include dip coating. Dip coating can be described as a method of coating the microprojections by partially or completely immersing the microprojections in a coating solution. The use of partial immersion techniques allows for the coating to be limited to only the tips of the microprojections.

A further coating method is roller coating, which also uses a roller coating mechanism that limits the coating to only the tips of the microprojections. A roller coating method is disclosed in U.S. Patent Application Publication No. 2002/0132054. As discussed in detail therein, the disclosed roller coating method provides a smooth coating that does not easily peel off from the microprojections during skin penetration.

A further coating method that may be used within the scope of the present invention is spray coating. Spray coating may involve forming an aerosol suspension of the coating composition. In one embodiment, an aerosol suspension having a droplet size of about 10 picoliters to 200 picoliters is sprayed onto the microprojections and then dried.

Pattern coating can also be used to coat the microprojections. A dispensing system can be used to coat the microprojection surface with liquid at specific locations. The amount of coating liquid is preferably in the range of 0.1 nanoliters to 20 nanoliters per microprojection. Examples of suitable precision metered liquid dispensing devices are disclosed in U.S. Pat. Nos. 5,916,524, 5,743,960, 5,741,554, and 5,738,728, which are incorporated herein by reference in their entireties.

The microprojection coating formulation or solution can also be applied using inkjet technology with known solenoid valve dispensers and optional liquid transport and positioning means that are typically controlled using an electric field. Other liquid ejection techniques from the printing industry or similar liquid ejection techniques known in the art can also be used to apply the pattern coating of the present invention.

In one embodiment of the present disclosure, the thickness of the dry coating formulation containing zolmitriptan ranges from about 10 micrometers to 100 micrometers, or about 20 micrometers to 80 micrometers, or about 30 micrometers to 60 micrometers, or about 40 micrometers to 50 micrometers, as measured from the microprojection surface. The desired coating thickness depends on several factors, including the desired dose and therefore the coating thickness required to deliver that dose, the density of microprojections per unit area of the sheet, the viscosity, solubility and concentration of the coating composition, and the coating method selected. The thickness of the coating applied to the microprojections can also be adjusted to optimize the stability of the zolmitriptan. Known formulation adjuvants can be added to the coating formulation as long as they do not adversely affect the solubility or viscosity characteristics required for the coating formulation or the physical integrity of the dry coating.

The coating is applied to the base or microneedles protruding from the streets of the microneedle array. The coating is applied to the tips of the microneedles and is not intended to cover the surfaces of the microneedles and microneedle array. This results in a reduced amount of drug per transdermal patch. This is advantageous in view of FDA guidelines regarding residual drug hazards in transdermal delivery systems, which suggest that the amount of residual drug in the system should be minimized. See FDA Guidance for Industry, "Residual Drug in Transdermal and Related Drug Delivery Systems" (August 2011). It has been the applicant's strategy to maximize the drug release per unit area into the skin without using excess drug in the coating.

After the coating is applied, the coating formulation is dried on the microprojections using a variety of methods. The coated microprojections can be dried at ambient room conditions. However, various temperatures and humidity levels can also be used to dry the coating formulation on the microprojections. Additionally, the coating can be heated, stored under vacuum or over a desiccant, lyophilized, freeze-dried, or similar techniques to remove residual moisture from the coating.

Coating was performed at ambient temperature by rotating a roller drum of a drug formulation reservoir (volume 2 mL) at 50 rpm to form a film with a controlled thickness of approximately 270 μm. Further information regarding the coating process can be found in U.S. Pat. No. 6,855,372, which is incorporated herein by reference in its entirety. The microprojection array is dipped into the drug film and the amount of coating is controlled by the number of dips (passes) through the drug film.

During the drying process, problems may occur with uniformly coating the microprojections with a controlled and uniform thickness. One common problem in transdermal patch coating, also called "dripping" or "teardrop" formation, occurs when the coating dries and pools in a "teardrop" shape at the end of the microprojection. This teardrop shape can blunt the tip of the microneedle and can affect the effectiveness and uniformity of penetration. If the formulation is in an uneven layer on the microprojections, it will result in uneven and sometimes inadequate drug delivery. Furthermore, this problem in the drying process causes problems with the quality control of the formulation coating. A preferred liquid coating formulation comprises zolmitriptan in an amount of 30% w/w to about 60% w/w, preferably about 40% w/w to about 50% w/w, more preferably about 45% w/w, and tartaric acid in an amount of about 5% w/w to about 25% w/w, preferably about 10% w/w to about 20% w/w, more preferably about 15% w/w, in a liquid carrier, preferably in water, more preferably in ion-exchanged water. In such liquid coating formulations, applicants have surprisingly found that dripping can be avoided by maintaining a viscosity of about 150 cP to about 350 cP, preferably about 200 cP to about 300 cP, more preferably about 250 centipoise, and a surface tension of about 50 mNm ^-1 to about 72 mNm ^-1 , preferably about 55 mNm ^-1 to about 65 mNm ^-1 , more preferably about 62.5 mNm ^-1 . While avoiding teardrop formation, a sufficient volume of the liquid coating formulation can be applied each time the microprojections are dipped into the liquid coating formulation, and the desired drug dose can be achieved with a minimum number of dippings. If the viscosity and surface tension of the coating solution are high enough, the coating liquid will not immediately retract or form a teardrop shape after dipping and before drying.

The formulations and methods described herein are directed to delivering zolmitriptan in a manner that rapidly achieves therapeutic concentrations of zolmitriptan suitable for the treatment of migraine or cluster headaches, but are also applicable to other triptans, including sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan, avitriptan, and donitriptan.

In one aspect, the route of administration of zolmitriptan is intramuscular, intradermal, subcutaneous, intranasal, oral inhalation, transdermal, buccal, pulmonary, or sublingual. For example, a formulation designed for intramuscular or subcutaneous delivery contains 1 mg zolmitriptan (base) and 0.3 mg tartaric acid in 1 mL of 0.9% w/v saline. Additionally, formulations designed for pulmonary delivery may be in the form of a zolmitriptan salt dissolved or suspended in water, or in the form of a zolmitriptan powder for inhalation delivery made using milling, supercritical fluid processing, spray drying, or spray freeze drying, and may be respirable fine particles with a controlled particle size of about 0.5 μm to 5.8 μm mass median aerodynamic diameter (MMAD) to ensure that a significant proportion of zolmitriptan is taken up into the lungs. The process resulting in zolmitriptan powder can be used directly by metering or pre-metering from a powder reservoir into a dry powder inhaler (DPI) configuration, or in a metered dose inhaler (MDI) configuration, the microparticles can be directly suspended/dispersed in a suspension medium such as a pharma- ceutically acceptable propellant such as hydrofluoroalkanes (selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, and mixtures of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoro-n-propane, or mixtures thereof). The particles produced can be crystalline or amorphous, depending on the process that produces the zolmitriptan powder. In one embodiment, the zolmitriptan dose ranges from 0.5 mg to 4 mg and is administered at the onset of a migraine or cluster headache.

V. Packaging Sterilization The increased physical stability of the dry coated formulation not only has the advantage of increasing the shelf life or storage life of the therapeutic agent itself, but also enhances efficacy, as the therapeutic agent stabilized in accordance with the compositions and formulation and delivery methods of the present invention renders the therapeutic agent useful in a broader range of potential formulations and a wider variety of therapeutic agent delivery means.

The present disclosure includes activator formulations in which degradation by oxygen and/or water is minimized and/or controlled by manufacturing and/or packaging the activator formulation in a dry, inert atmosphere. The formulation may be held in a dry, inert atmosphere in the presence of a desiccant, optionally in a chamber or package including a foil layer.

The desiccant may be any known to one of skill in the art. Some common desiccants include, but are not limited to, molecular sieves, calcium oxide, clay desiccants, calcium sulfate, and silica gel. The desiccant may be combined with the biologically active agent-containing formulation in a package that includes a foil layer under an inert atmosphere.

In another aspect, the active agent formulation is packaged in a chamber containing a foil layer after the formulation is coated onto the microprojection array delivery device. In this embodiment, a desiccant is placed into the chamber, preferably attached to a chamber lid containing a foil layer, and the foil lid is sealed over the foil chamber containing the delivery device after the chamber is purged with dry nitrogen or other inert gas such as a noble gas. Any suitable inert gas can be used herein to create a dry, inert atmosphere.

In one embodiment, the zolmitriptan composition suitable for intradermal delivery and the zolmitriptan formulation and delivery methods utilize a patch assembly. The patch assembly is manufactured and/or packaged in a dry inert atmosphere and in the presence of a desiccant. In one embodiment, the patch assembly is manufactured in a dry inert atmosphere and/or packaged in a chamber that includes a foil layer and has a dry inert atmosphere and a desiccant. In one embodiment, the patch assembly is manufactured and/or packaged under reduced pressure. In one embodiment, the patch assembly is manufactured and/or packaged in a dry inert atmosphere and under reduced pressure. In one embodiment, the patch assembly is manufactured in a dry inert atmosphere under reduced pressure and/or packaged in a chamber that includes a foil layer and has a dry inert atmosphere, reduced pressure and a desiccant.

In the described embodiments of the invention, the inert atmosphere typically has a substantially zero water content. For example, nitrogen gas with a substantially zero water content (dry nitrogen gas) can be prepared by electrically controlled boiling of liquid nitrogen. A purge system can also be used to reduce the water or oxygen content. The reduced pressure ranges from about 0.01 atmospheres to about 0.3 atmospheres.

In one aspect of this embodiment, the zolmitriptan formulation further comprises a biocompatible carrier. In another embodiment, there is an intradermal delivery system adapted to deliver zolmitriptan, comprising: (a) a microprojection portion having a plurality of microprojections adapted to pierce the stratum corneum of a patient; (b) a hydrogel formulation comprising zolmitriptan, the hydrogel formulation being in communication with the microprojection portion; and (c) packaging adapted to control a sealed environmental condition around the microprojection portion that is purged with an inert gas, the sealed packaging being exposed to radiation to sterilize the microprojection portion.

In another embodiment, there is an intradermal delivery system adapted to deliver zolmitriptan, comprising: (a) a microprojection region having a plurality of microprojections adapted to pierce the stratum corneum of a patient; (b) a solid membrane disposed proximate the microprojections, the solid membrane being formed by casting a liquid formulation comprising zolmitriptan, a polymeric material, a plasticizer, a surfactant, and a volatile solvent; and (c) packaging adapted to control a sealed environmental condition around the microprojections, purged with an inert gas, the sealed packaging being exposed to radiation to sterilize the microprojections.

The present disclosure also relates to a method of terminally sterilizing a patch assembly adapted to deliver zolmitriptan, comprising the steps of: (a) providing a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, the microprojections having a biocompatible coating thereon comprising zolmitriptan; and (b) exposing the microprojections to radiation selected from the group consisting of gamma radiation and electron beam radiation, the radiation being sufficient to achieve a desired sterility assurance level. The sterility assurance level may be between ^10-6 and ^10-5 . The method may further comprise sealing the microprojections and desiccant together in inert gas purged packaging, and exposing the packaged microprojections to radiation selected from the group consisting of gamma radiation and electron beam radiation, the radiation being sufficient to achieve a desired sterility assurance level.

In one aspect of this embodiment, the method further comprises attaching the patch with the microprojections affixed to the adhesive surface to a pre-dried retaining ring to form a patch assembly, and then sealing the microprojections in packaging. In one aspect of this embodiment, the system further comprises a desiccant sealed with the patch assembly in the packaging, and/or the packaging is purged with nitrogen, and/or the packaging comprises a pouch with a foil layer. Preferably, the foil layer comprises aluminum.

The step of exposing the microprojections to radiation can be performed at about -78.5°C to 25°C, although the microprojections can be exposed to radiation at room temperature. The radiation can be in the range of about 5 kGy to 50 kGy, or in the range of about 10 kGy to 30 kGy, or in the range of about 15 kGy to 25 kGy, or about 21 kGy, or about 7 kGy. In one aspect of this embodiment, radiation is administered to the microprojections at a dose of at least about 3.0 kGy/hr.

As described herein, the applicant has developed a zolmitriptan formulation which, when coated onto the microneedle portion of the present disclosure, is stable and maintains its amorphous character for at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months after exposure to the radiation described above.

In one embodiment, the dried zolmitriptan formulation on the microneedles retains about 100% of its original purity, or about 99% of its original purity, or about 98% of its original purity, or about 97% of its original purity, or about 96% of its original purity, or about 95% of its original purity, or about 90% of its original purity for at least 6 months. In other aspects, such purity is retained for at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months after packaging. In further embodiments, the zolmitriptan coated on the microneedles retains its purity as described in this paragraph and also maintains its substantially amorphous character for at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months after packaging.

In one embodiment, a method for manufacturing a patch assembly for an intradermal delivery system adapted for delivery of zolmitriptan includes providing a microneedle portion having a plurality of microneedles adapted to pierce or pierce the stratum corneum of a patient, the microneedle portion having a biocompatible coating formed and coated on a surface of the microneedle portion, the coating being formed from a coating formulation comprising zolmitriptan; sealing the microneedle portion with a desiccant in packaging adapted for controlling environmental conditions around the microneedle, the packaging being purged with nitrogen; and exposing the microneedle portion to radiation selected from the group consisting of gamma radiation, electron beam, and x-ray radiation, the radiation being sufficient to achieve a desired sterility assurance level.

According to another embodiment of the present invention, a method of delivering a stable biologically active agent formulation includes the steps of: (i) providing a microprojection section having a plurality of microprojections; (ii) providing a stabilized formulation of a biologically active agent; (iii) producing a biocompatible coating formulation comprising the stabilized biologically active agent formulation; (iv) coating the microprojections with the biocompatible coating formulation to form a biocompatible coating; (v) stabilizing the biocompatible coating by drying; and (vi) applying the coated microprojections to the skin of a subject.

Furthermore, optimal stability and shelf life of the drug is achieved with a solid and substantially dry biocompatible coating. However, the kinetics of coating dissolution and the kinetics of drug release may vary appreciably depending on a variety of factors. It will be appreciated that the biocompatible coating is storage stable while still providing the desired release of the therapeutic agent.

Included herein is a method of terminally sterilizing a transdermal device adapted for delivery of zolmitriptan, comprising the steps of providing a microprojection having a plurality of microprojections adapted to pierce or pierce the stratum corneum of a patient, the microprojections having a biocompatible coating formed and coated on the microprojection surface, the coating being formed from a coating formulation comprising at least one triptan, preferably zolmitriptan, and exposing the microprojections to radiation selected from the group consisting of gamma radiation and electron beam radiation, the radiation being sufficient to achieve a desired sterility assurance level. A further aspect of the method further comprises sealing the microprojections in packaging adapted to control environmental conditions around the microprojections. In one aspect, the packaging comprises a foil pouch. A further aspect of the method further comprises sealing a desiccant in the packaging. The method also comprises attaching the microprojections to a pre-dried retaining ring prior to sealing the microprojections in the packaging. A further aspect of the method includes purging the packaging with an inert gas prior to sealing the packaging. In one embodiment, the inert gas comprises nitrogen.

VI. In vivo Pharmacokinetics (PK)
The intradermal/transdermal systems of the present invention provide more rapid serum concentrations in the bloodstream and reduce total drug exposure compared to oral administration of the same drug. For example, absorption of zolmitriptan administered intradermally using the disclosed system results in a _Cmax of less than 50 mg/mL and a _Tmax of about 2 to 30 minutes. In another embodiment, the plasma zolmitriptan AUC over the first 2 hours is greater than that seen after oral administration, but the plasma zolmitriptan AUC _{(0 to 24 hours)} is less than that seen after oral administration.

In another aspect, absorption of zolmitriptan increases peak plasma zolmitriptan levels, but reduces N-desmethylzolmitriptan products (AUC _{0-24 hours} ), reducing the potential for metabolic product accumulation. Intradermal administration of triptans, including zolmitriptan, avoids the first-pass hepatic metabolism seen with oral administration, resulting in increased bioavailability. Specifically, significant reduction in metabolism results in serum concentrations of N-desmethylzolmitriptan that are at least about 20% less than those seen with oral formulations at each time point following application (e.g., 1.5 hours, 2 hours, 5 hours, 10 hours). Additionally, zolmitriptan plasma levels may be increased, but N-desmethylzolmitriptan products are reduced compared to those that would occur with an equivalent oral dose of zolmitriptan. Thus, reducing the potential for metabolic product accumulation. However, N-desmethylzolmitriptan is more active at the target site than zolmitriptan, making the present invention highly effective in treating migraine or cluster headaches, as described in more detail below. Additionally, the apparent half-life of zolmitriptan is decreased compared to oral administration, thereby reducing the duration of side effects.

In another embodiment, the plasma concentration of N-desmethylzolmitriptan is about 0.05 ng/ml to 0.9 ng/ml at about 15 minutes, or about 0.1 ng/ml to 1.4 ng/ml at about 30 minutes, or about 0.1 ng/ml to 1.6 ng/ml at about 1 hour, or about 0.1 ng/ml to 1.4 ng/ml at about 1.5 hours, or about 0.1 ng/ml to 1.3 ng/ml at about 2 hours, or less than about 0.7 ng/ml at about 5 hours, or less than about 0.2 ng/ml at about 10 hours after application.

Further, the intradermally delivered biocompatible coating comprises a dose of zolmitriptan of about 0.2 mg to 10 mg, preferably 1 mg to 5 mg, more preferably about 1.9 mg or 3.8 mg, after one application or after two applications, and the intradermal delivery of zolmitriptan results in a plasma C _max of at least 2 ng/mL zolmitriptan, at least 3.6 ng/mL zolmitriptan, at least 4 ng/mL zolmitriptan, at least 6 ng/mL zolmitriptan, at least 9 ng/mL zolmitriptan, at least 10 ng/mL zolmitriptan, at least 12 ng/mL zolmitriptan, at least 14 ng/mL zolmitriptan, at least 16 ng/mL zolmitriptan, at least 18 ng/mL zolmitriptan, at least 20 ng/mL zolmitriptan, at least 25 ng/mL zolmitriptan, at least 30 ng/mL zolmitriptan, at least 40 ng/mL zolmitriptan, at least 45 ng/mL zolmitriptan, at least 50 ng/mL zolmitriptan, less than 50 ng/mL zolmitriptan, at least 55 ng/mL zolmitriptan, at least 60 ng/mL zolmitriptan, or at least 65 ng/mL zolmitriptan.

Intradermal delivery of zolmitriptan also results in a plasma T _max of 1 minute or less, 2 minutes or less, 3 minutes or less, 4 minutes or less, 5 minutes or less, 8 minutes or less, 10 minutes or less, 12 minutes or less, 15 minutes or less, 20 minutes or less, 30 minutes or less, 35 minutes or less, 40 minutes or less, 45 minutes or less, 50 minutes or less, 55 minutes or less, 2 minutes to 30 minutes, or 60 minutes or less after a single application.

In one embodiment, the _Tmax of zolmitriptan administered intradermally using the system of the present invention is at least about 2 hours before a normal release oral zolmitriptan tablet, or at least about 1.8 hours before such tablet, or at least about 1.6 hours before such tablet, or at least about 1.4 hours before such tablet, or at least about 1.2 hours before such tablet, or at least about 1.0 hour before such tablet, or at least about 0.8 hours before such tablet, or at least about 0.6 hours before such tablet, or at least about 0.4 hours before such tablet, or at least about 0.2 hours before such tablet.

In another embodiment, the _Tmax of zolmitriptan administered intradermally using a system of the present invention is about 3 hours or more before the ZOMIG® (zolmitriptan) orally disintegrating tablet, or about 2.5 hours or more before such tablet, or about 2.0 hours or more before such tablet, or about 1.5 hours or more before such tablet, or about 1.0 hour or more before such tablet, or about 0.5 hour or more before such tablet.

In further embodiments, the _Tmax of zolmitriptan administered intradermally using the system of the present invention is about 3 hours or more prior to the zolmitriptan nasal spray, or about 2.5 hours or more prior to such spray, or about 2.0 hours or more prior to such spray, or about 1.5 hours or more prior to such spray, or about 1.0 hour or more prior to such spray, or about 0.5 hour or more prior to such spray.

In another embodiment, the excretion rate (t _1/2 ) of zolmitriptan administered intradermally using the system of the present invention is about 0.75 hours, or 1.0 hours, or 1.1 hours, or 1.2 hours, or 1.3 hours, or 1.4 hours, or 1.5 hours, or 1.6 hours, or 1.7 hours, or 1.8 hours, or 1.9 hours, or 2.0 hours. Such an excretion rate (t _1/2 ) is about three times the rate of conventional zolmitriptan tablets, or about twice the rate of conventional zolmitriptan tablets.

In further embodiments, the _Cmax of zolmitriptan administered intradermally using the system of the present invention is about 1-8 times, or about 1.5-7 times, or about 2-6 times, or about 3-5 times, or about 4 times higher than the _Cmax of a conventional oral zolmitriptan tablet 2.5 mg.

Additionally, the mean maximum exposure (C _max ) is about 2-fold to about 5-fold higher for intradermal zolmitriptan compared to oral tablets. In further aspects, the mean maximum exposure (C _max ) for intradermal zolmitriptan of the present invention is from about 1.0 mg/mL to about 40.0 mg/mL, or from about 5.0 mg/mL to about 35.0 mg/mL, or from about 10.0 mg/mL to about 30.0 mg/mL, or from about 15.0 mg/mL to about 25.0 mg/mL, or from about 20.0 mg/mL to about 30.0 mg/mL, or about 25 mg/mL.

In addition, compared to conventional oral zolmitriptan at a dose of about 0.5 mg to about 4.0 mg, the intradermal zolmitriptan of the present invention has a bioavailability that is about 50% to about 100% of the oral bioavailability. In other embodiments, the intradermal bioavailability is about 55% to about 95%, or about 60% to about 90%, or about 65% to about 85%, or about 70% to about 80%, or about 75% of the oral bioavailability.

Finally, the present invention encompasses formulations and devices that are bioequivalent to the M207 intradermal delivery system described herein. Thus, the disclosure encompasses products with bioequivalence that: (i) have a 90% confidence interval (CI) for AUC of 0.80 to 1.25; and (ii) have a 90% CI for _Cmax of 0.80 to 1.25.

VII. Methods of Treatment The drug-device combination of the present invention can be used to treat a variety of diseases and conditions, including migraine and cluster headaches. In one embodiment of the present invention, there is a method of treating or alleviating migraine or cluster headache to an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based drug, where absorption of the zolmitriptan-based drug results in a plasma _Cmax of less than 50 ng/mL. Doses include about 0.2 mg to about 10 mg of zolmitriptan. Doses may be 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mg of zolmitriptan. Doses also include a single patch administration of 1.0 mg, 1.9 mg, or 3.8 mg, or two patch administrations of 1.9 mg. These doses can be delivered using a patch as described herein and can be applied to the skin of any part of the body. In a preferred embodiment, a dose of zolmitriptan is delivered via a patch to the upper arm to treat a single attack of migraine or cluster headache.

In certain embodiments, the methods of treating migraine or cluster headache described herein provide improvements in the following treatment endpoints: absence of migraine pain at 1 hour, 2 hours, or 4 hours after administration, absence of cluster headache pain at 15 minutes or 30 minutes after administration, absence of other very bothersome migraine symptoms at 1 hour or 2 hours after administration, absence of other cluster headache symptoms previously identified by the patient at 15 minutes or 30 minutes after administration, migraine pain relief at 1 hour, 2 hours, or 4 hours, cluster headache pain relief at 15 minutes or 30 minutes after administration, pain relief at 30 minutes, absence of photophobia at 2 hours, absence of phonophobia at 2 hours, pain relief at 15 minutes, pain relief at 3 hours, pain relief at 4 hours, absence of nausea at 2 hours, absence of pain at 30 minutes, absence of pain at 24 hours, and absence of pain at 48 hours. Additionally, improvements are provided for treated patients requiring rescue administration. Continued improvements have been seen in routine sequential testing for pain, other very bothersome symptoms, photophobia, phonophobia, nausea, and other bothersome symptoms.

Tables 45-48 show the effectiveness of the claimed invention in reducing or eliminating pain from migraine or cluster headaches compared to triptans and other forms of zolmitriptan. These results are based on one embodiment of the claimed invention, but are not limited thereto.

As can be seen in Table 45, the method described herein demonstrates a significant improvement over zolmitriptan tablets in one embodiment of the claimed invention in providing patients with no pain at one hour after administration. The results shown in Table 45 are merely an example showing that the claimed invention is significantly more effective than known methods for treating migraine or cluster headaches with zolmitriptan. In one embodiment of the claimed invention, at a 1 mg zolmitriptan dose, more than 15% of patients were pain free at one hour after treatment. In another embodiment (1.9 mg), more than 20% of patients were pain free at one hour. In a third embodiment (3.8 mg), more than 25% of patients were pain free at one hour. This demonstrates improved efficacy over nasal zolmitriptan treatment, which showed that only about 10% of patients were pain free at one hour. The present invention is much more effective than the 2.5 mg, 5 mg, and 10 mg tablets, and the 2.5 mg orally disintegrating tablet, which each provide less than 10% pain relief after 1 hour. The claimed invention also provides significantly improved pain relief results after 2 and 4 hours of treatment. In one embodiment, more than 30% of patients were pain free at 2 hours after treatment. In another embodiment, more than 40% of patients were pain free at 2 hours. In a third embodiment, more than 50% of patients were pain free at 4 hours after treatment. These are improvements over intranasal treatment with zolmitriptan, where less than 25% and less than 40% of patients were pain free at 2 and 4 hours after treatment, respectively. These results can also be compared to other zolmitriptan dosage forms and delivery routes, with 40% pain relief at 2 hours being a better result than all other zolmitriptan dosage forms and delivery routes. These results are also shown graphically in FIG. 25.

Table 46 compares the pain relief results of the claimed inventive method and current methods for treating migraine or cluster headaches with zolmitriptan. The 1 mg, 1.9 mg, and 3.8 mg embodiments provided greater than 45%, 55%, and 65%, respectively, pain relief just 1 hour after administration. 65%, 68%, and 80%, respectively, experienced pain relief 2 hours after administration. The 3.8 mg embodiment provided greater than 80% of patients with pain relief 4 hours after administration. All three embodiments provided significant improvement in pain relief at 1 hour when compared to other zolmitriptan dosage forms and delivery routes, with the 3.8 mg embodiment also being more effective than other zolmitriptan dosage forms at 2 and 4 hours. These results are also shown graphically in FIG. 26.

Tables 47 and 48 show that the claimed invention shows a significant improvement in reducing or reducing headache or cluster headache pain compared to other triptans used to treat migraine or cluster headache. As shown in Table 47, the claimed invention shows a significant improvement in pain relief results compared to other triptans currently used in the art. The 1 mg, 1.9 mg, and 3.8 mg embodiments resulted in 17.7%, 20.5%, and 26.8% pain relief at 1 hour, respectively, all three values being higher levels of pain relief than any of the other triptans. The 3.8 mg embodiment resulted in 41.5% and 54.9% pain relief at 2 and 4 hours, respectively, still higher than all of the other triptans. These results are also shown graphically in Figure 27. As shown in Table 48, the claimed invention shows a significant improvement in pain relief results compared to other triptans currently used in the art. The 1 mg, 1.9 mg, and 3.8 mg embodiments provided 46.8%, 55.4%, and 68.3% pain relief at 1 hour, respectively, all three values being higher levels of pain relief than any of the other triptans. The 3.8 mg embodiment provided 80.5% and 82.9% pain relief at 2 and 4 hours, respectively, still higher than all of the other triptans. These results are also shown graphically in FIG. 28. In another aspect, the plasma T _max of the administered zolmitriptan-based drug is about 2 to 30 minutes. In one embodiment, administration of the zolmitriptan-based drug is by transdermal or intradermal administration. Alternatively, the route of administration of the zolmitriptan-based drug is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal, or sublingual.

In another embodiment, there is a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administration of a therapeutically effective amount of a zolmitriptan based drug, wherein the plasma zolmitriptan AUC in the first two hours is greater than the plasma zolmitriptan AUC following oral administration of an equivalent dose of zolmitriptan, but the plasma zolmitriptan AUC _0-inf following intradermal administration of a therapeutically effective amount of the zolmitriptan based drug is less than the plasma zolmitriptan AUC _0-inf seen following oral administration of an equivalent dose of zolmitriptan. In one aspect of this embodiment, administration of the zolmitriptan based drug is transdermal or intradermal. In one aspect of this embodiment, the route of administration of the zolmitriptan based drug is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal, or sublingual.

In another embodiment, there is a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based drug that increases zolmitriptan plasma levels but reduces N-desmethylzolmitriptan production compared to oral administration of an equivalent dose of zolmitriptan, thus reducing the likelihood of metabolic product accumulation. In one aspect of this embodiment, administration of the zolmitriptan-based drug is transdermal or intradermal. In one aspect of this embodiment, administration of the zolmitriptan-based drug is intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal, or sublingual.

In another embodiment, there is a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administration of a therapeutically effective amount of a zolmitriptan-based drug, which reduces the apparent half-life of zolmitriptan compared to oral administration of an equivalent dose of zolmitriptan, thus offering the potential for reducing the duration of side effects. In one aspect of this embodiment, administration of the zolmitriptan-based drug is transdermal or intradermal. In one aspect of this embodiment, administration of the zolmitriptan-based drug is intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal, or sublingual.

In any of the embodiments disclosed herein, the route of administration of the zolmitriptan-based drug is selected from the group consisting of intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal, and sublingual.

In one aspect of this embodiment, the zolmitriptan-based drug administered intradermally provides a pharmacokinetic profile similar to that obtained with subcutaneous administration of an equivalent dose of the sumatriptan-based drug administered intradermally.

In one embodiment of the method of administering zolmitriptan, administration of zolmitriptan does not have a greater effect on blood pressure than that seen with oral zolmitriptan, despite faster absorption.

In one embodiment, there is a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administration of a therapeutically effective amount of a zolmitriptan-based drug, the time to reach maximum plasma concentration ( _Tmax ) being equal to or less than _{the Tmax} when an equivalent dose of zolmitriptan is administered orally. In one aspect of this embodiment, the administration of the zolmitriptan-based drug is transdermal or intradermal. In one aspect of this embodiment, the route of administration of the zolmitriptan-based drug is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal, or sublingual. In one aspect of these embodiments, the amount of N-desmethylzolmitriptan produced is reduced compared to the amount of N-desmethylzolmitriptan produced when an equivalent amount of the zolmitriptan-based drug is administered orally. In another aspect of these embodiments, absorption of the intradermally administered zolmitriptan-based drug results in a C _max of less than 50 ng/mL.

VIII. EXAMPLES The following examples are included to demonstrate certain embodiments of the present invention. However, those skilled in the art should understand in light of this disclosure that modifications can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present invention. Accordingly, all matters set forth should be construed as illustrative and not limiting.

In the following examples, unless otherwise stated, the microprojection arrays were fabricated by photo/chemical etching and formed using a controlled manufacturing process. The method is substantially similar to that described in M. Cormier et al., "Device for enhancing transdermal agent delivery or sampling", EP 0914178 B1, which is incorporated herein by reference in its entirety. Drug formulation coating onto the microprojection arrays was carried out at ambient temperature using a roller drum rotating at 50 rpm in a drug formulation reservoir (volume 2 mL) to produce a drug-coated formulation film of controlled thickness. The method is similar to that described in J. C. Trautman et al. The method is substantially similar to that described in J. C. Trautman et al., "Method and apparatus for coating skin piercing microprojections," U.S. Patent No. 6,855,372; J. C. Trautman et al., "Method and apparatus for coating skin piercing microprojections," U.S. Patent No. 7,435,299, which are incorporated herein by reference in their entireties. The microprojections are dipped into the film. The amount of coating is controlled by the drug coating formulation properties as well as the number of dips (passes) through the drug film. The time between each dip was a few seconds, which was sufficient to allow the coated liquid formulation to dry under ambient conditions. A cooling liquid was circulated through the reservoir to maintain a film temperature of 1°C. The coating apparatus was placed in a dew point control system since the reservoir was open to the ambient air. Dew point control minimizes water condensation into or evaporation from the liquid formulation during coating. The zolmitriptan-coated microneedle array was assembled with an adhesive backing to form a patch and attached to a retaining ring to form a patch assembly. The patch assembly was packaged in an aluminum pouch (Mangar, New Britain, PA, USA), purged with dry nitrogen, and heat sealed using a Multivac heat sealer (model C400) (Multivac, Kansas City, MO, USA).

Example 1 - Zolmitriptan Coating Formulation, Characterization, Physical Properties Zolmitriptan is a weak base with a pKa of 9.6. Solubility measurements were performed by adding excess zolmitriptan base to 0.5 ml of 0.1 M acid and rotating the suspension overnight at 2-8°C. The suspension was then centrifuged. The supernatant was then collected and the concentration of dissolved zolmitriptan was determined. Table 2 shows the solubility results of zolmitriptan in various acids.

Zolmitriptan exhibits good solubility in a variety of acids. It was observed that the rheological behavior of zolmitriptan solutions was affected by the counterion in the formulation for pH control. Several weak acid buffers were tested, including one triacid (citric acid) and two diacids (maleic acid and tartaric acid). Zolmitriptan formulations prepared with citric acid, maleic acid and tartaric acid had pH 5.2, 4.3 and 6.2 at the pKa of the acid, respectively. The viscosity profiles of the formulations containing these acids were measured as a function of time. The citric acid and maleic acid buffered formulations exhibited rheopectic behavior, i.e., an increase in viscosity as a function of time, whereas the formulation buffered with tartaric acid maintained a relatively uniform viscosity with time. Considering the overall rheological effects, tartaric acid was selected as the counterion for pH adjustment.

A liquid coating formulation of 33% w/w zolmitriptan, 11% w/w tartaric acid and 56% w/w deionized water formulation was prepared at pH 4.5 and the contact angle on titanium substrate was determined to be 65.8 degrees indicating a poorly wettable formulation. To improve the wettability of the formulation on titanium, polysorbate 20 at a concentration of 0.2% w/w was added to the zolmitriptan formulation. The contact angle decreased to 51.6 degrees.

The static contact angle of the drug solution formulation on titanium surface was determined using an FDS contact angle meter (Model OCA15) using an optical contact angle method called the "sessile drop method". For static contact angle measurements, a snapshot photograph is taken when a drop of solution (5 μL) is dispensed from a syringe and placed on a clean titanium foil surface. The angle between the baseline of the drop and the tangent of the drop boundary is measured on both sides. A complete measurement was obtained by averaging the two counts. At least five readings were recorded for each sample.

Coating tests were performed with 33% w/w zolmitriptan, 11% w/w tartaric acid, 0.2% w/w polysorbate 20, and sufficient deionized water. Drug formulation coating onto the microprojection array was performed at ambient temperature using a roller drum rotating at 50 rpm in a drug formulation reservoir (2 mL volume) to produce a drug formulation film of controlled thickness. The microprojections were dipped into the drug film. The amount of coating was controlled by the number of dips (passes) through the drug coating formulation film. The time between each dip was only a few seconds, which was sufficient to allow the coated liquid formulation to dry under ambient conditions. The reservoir was open to the ambient air, so the coating equipment was placed in a dew point control system. The process was designed to match the drug film temperature to the dew point of the air, which prevents evaporation of the coating formulation over the duration of the manufacturing run. However, undulations were visually observed in the zolmitriptan liquid formulation, which is an indication of an uneven film. The concentration of zolmitriptan in the liquid formulation was increased to 51% w/w (17% w/w tartaric acid in the formulation, and 0.2% w/w polysorbate 20). Ripples in the film were still observed in the higher solids content formulation. The polysorbate 20 was then removed, and it was observed that the ripples were no longer present. This is a surprising and unobvious result, since conventional teaching in pharmacology supports the use of surfactants to facilitate the production of smooth, uniform coatings.

In another coating embodiment, a 33% w/w zolmitriptan, 11% w/w tartaric acid, and 56% w/w deionized water formulation caused a high incidence of wicking for the particular microprojection array utilized, such that the drug did not stick to the microprojections. The viscosity of the formulation was 22 cP, but the design of the microprojections (120 μm wide, 340 μm long) and thick drug film (calculated film thickness 270 μm) was such that at each dip in the drug film, the microprojections picked up a volume of liquid that could not dry quickly enough, leading to the drug film spreading over the base of the microprojections. For a formulation with a higher solids content, 40% w/w zolmitriptan, 13.3% w/w tartaric acid, and 46.7% w/w deionized water (M207), with a viscosity of 85 cP, the microprojections were evenly coated and no wicking was observed. This formulation was utilized for further evaluation. Representative batch formulations for two strengths of microneedle array patches (internal product name M207) based on a nominal batch size of 45 g (zolmitriptan base) are provided in Tables 3 and 4.

Viscoelastic Properties A 40% w/w zolmitriptan liquid formulation was evaluated for viscoelastic properties. Characterization of the viscoelasticity of a liquid can be a useful tool for predicting the gelling tendency of a liquid. H. A. Barnes, J. F. Hutton, and K. Walters, An Introduction to Rheology (Elsevier, New York, 1989). Measurement of viscoelasticity (i.e., elastic and viscous components) in a viscometer is based on a complex theoretical model. Briefly, a material is subjected to an oscillatory stress or strain, the value of which is small enough to disrupt the structure of the material and produce a phase angle output. The phase angle is the ratio of the viscous and elastic moduli. A phase angle of 0 degrees corresponds to a totally elastic material according to Hooke's law of elasticity, thus suggesting a more rigid and ordered structure. A phase angle of 90 degrees corresponds to a material with entirely viscous behavior, indicating a less ordered structure with less tendency to gel. The 40% w/w zolmitriptan liquid formulation exhibited a high phase angle of about 83 degrees, indicating that the formulation was less likely to gel.

Characterization of Mechanical Properties of ZP-Zolmitriptan Patches by Nanoindentation Mechanical properties of zolmitriptan coating such as hardness and toughness were evaluated by nanoindentation on M207 1.9 mg patches. Nanoindentation tests were performed on individual microprojections coated with zolmitriptan after breaking the microprojections at the base of a titanium array. For hardness measurements, coated microprojections were sampled from the center and two edge locations of the array and 10 indentation measurements were performed for each of the three locations. Hardness and reduced modulus of elasticity were determined using a Berkovich indenter from Nanomechanical Test System, TriboIndenter. Toughness was determined by fracture toughness using a TriboIndenter with a cube corner indenter. Five indentations were made for each patch sample.

Dynamic Vapor Sorption Water sorption and desorption isotherms of M207 1.9 mg patches at 25°C were determined by DVS Intrinsic (Surface Measurement Systems, Ltd.). Each patch was exposed to controlled relative humidity (RH) cycles with ramping steps from 0% to 65% and then 65% to 0%. Mass change was continuously measured by a microbalance with 0.1 μg resolution. At each RH step, the sample was allowed to reach equilibrium at a 0.0004 dm/dt criterion before moving to the next RH step. Uncoated patches were analyzed under the same conditions to determine background water uptake by patch components other than the coated drug formulation.

Crystallinity X-ray diffraction (XRD) analysis was performed to characterize the solid state phase of the dried zolmitriptan coating on the patches for the M207 1.9 mg system. Non-irradiated and gamma irradiated M207 patches were analyzed and compared to uncoated patches of the same array design. For each patch sample analyzed, approximately 45-50 microprojections with zolmitriptan coating were broken at the base of the titanium array and analyzed as bulk by XRD. XRD data was collected on a coupled Theta: 2 theta scan on a Bruker D8 Vantec diffractometer equipped with a microfocus copper X-ray tube with a Montel optics monochromator, a 0.5 mm collimator, a Vantec 500 2-D area detector and a laser alignment system. The XRD patterns of the zolmitriptan coated microprojections were compared to the XRD patterns of the uncoated microprojections. All sharp peaks present in the zolmitriptan coated patch samples matched those in the uncoated patch samples. The sharp peaks were identified as titanium (Ti) metal based on reference XRD data from the ICDD/ICSD database, indicating a crystalline phase result from the Ti microprojection substrate. The zolmitriptan coated patch showed a broad peak centered at about 18° 2-theta, which was absent in the uncoated patch sample, indicating that the drug coating was an amorphous material for both the non-irradiated and gamma-irradiated patches. The percent crystallinity was calculated using peak profile fitting and the results are summarized in Table 6, and stability was monitored as described below.

The mechanical properties of the zolmitriptan coating were evaluated as a function of time and storage conditions. Mechanical properties such as hardness, which is a measure of a material's resistance to localized plastic deformation, elastic modulus, which is a measure of a material's resistance to elastic deformation when a force is applied (a measure of the stiffness of the material), and fracture toughness, which describes the material's ability to contain cracks and resist fracture, were evaluated. Multiple coated microprojections from different regions of individual ZP-zolmitriptan patches were sampled for testing. Table 5 summarizes the nanohardness (H), reduced modulus elastic modulus (E _r ), and fracture toughness (K _c ) results for gamma irradiated M207 1.9 mg patches stored at 25° C./60% RH for up to 12 months and at 40° C./75% RH for up to 3 months. Stability results suggest a decreasing trend in hardness and fracture toughness, and an increasing trend in elastic modulus.

Quantification of Zolmitriptan Purity and Content Zolmitriptan purity was determined by a reversed phase high performance liquid chromatography (RPHPLC) method (TM-601) at a wavelength of 225 nm. Chromatography for the assay was performed using a Phenomenex Kinetex EVO C18, (4.6 mm ID x 150 mm, 5 μm) maintained at 30°C. The mobile phase was solvent A: ammonium dihydrogen phosphate buffer: MeOH: acetonitrile, 70:20:10 (v/v) and solvent B: ammonium dihydrogen phosphate buffer: acetonitrile, 30:70 (v/v) with gradient elution, pumped at a flow rate of 0.6 ml/min on a HPLC system (Water Alliance 2695) equipped with a binary pump, a thermostated autosampler, a column compartment, and a PDA detector. Data were collected and analyzed using Empower Pro (Empower 2 software, Waters Corporation).

In Vitro Dissolution The in vitro dissolution of M207 1.9 mg patches was evaluated using a standard USP paddle-over-disk apparatus (USP apparatus 5) using a Distek 2100C 6-position dissolution tester. The paddle height was set at 25 mm above the patch and rotated at 50 RPM. The USP container was filled with 500 mL of degassed PBS dissolution medium and the temperature was controlled at 32°C. The entire patch assembly, containing the coated patch adhered to the center of the inner ring and then attached to the outer ring, was inserted into the container along the container wall with the coated microprojections facing up. The release of zolmitriptan from the coated patch was continuously monitored via quantification of the zolmitriptan concentration of the dissolution medium by UV absorbance using a Pion Rainbow 6-Ch Fiber Optic System with a 14 cm dip probe and 10 mm path length.

M207 patches stored at room temperature and at 40°C/75% relative humidity for 10 months were evaluated. The results, shown in Figures 6(A)-(C) and Table 7, demonstrated immediate release of zolmitriptan for all patches tested, with steep slopes that reached a concentration plateau for complete dissolution in less than 1 minute.

Example 2 - Ex vivo human skin The in vitro Franz human skin finite dose model is a tool for the study of percutaneous absorption of topically applied drugs. The model uses ex vivo human torso skin mounted in a specially designed diffusion cell that allows the skin to be maintained at a temperature and humidity that matches typical in vivo conditions. A finite dose (e.g., ² mg/cm2 to 10 mg/ ^cm2 of a semi-solid, or transdermal delivery system) formulation is applied to the outer surface of the skin, and drug absorption is measured by monitoring the rate at which it appears in a receptor solution bathing the inner surface of the skin. Data defining skin content, as well as total absorption and absorption rate, can be determined in this model.

Administration. Zolmitriptan patches were applied to the ex vivo skin using an applicator. After administration, the patch and skin were immediately mounted in a Franz diffusion cell.

Skin receptor medium. Normal phosphate buffered saline (pH 7.4±0.1) containing 0.008% gentamicin sulfate (PBSg) solution was used when the diffusion cells were first set up.

Diffusion Cell and Skin Preparation. Percutaneous absorption was measured using the in vitro human skin Franz finite dose technique. Ex vivo dermatomal excised human torso skin with no obvious signs of skin disease or damage was used for this study. The skin was provided to the testing facility as excised, cryopreserved, and sealed in water-impermeable bags with continuous storage at approximately -70°C. Before use, it was thawed in water at approximately 37°C and then rinsed with distilled deionized water (ddH2O) to remove any adhering blood or other material from the surface.

Skin from each donor was cut into multiple smaller sections large enough to fit into a nominal 7 cm2 static Franz diffusion cell. The actual thickness of each skin section was measured in triplicate using a Digital Pocket Thickness Gauge (results in Table 2). Each skin section was then mounted into a diffusion cell.

The volume of the skin receptor compartment was filled with PBSg. The epidermal chamber (also known as the chimney or donor compartment) was left unblocked and exposed to the ambient laboratory environment. The cell was then placed in a rack system and attached to a water circulation system from which the receptor solution was magnetically stirred at approximately 600 RPM and the temperature was maintained to achieve a skin surface temperature of 32±1°C (in-house data). The skin was allowed to equilibrate for a minimum of 1 hour prior to barrier integrity testing.

One additional skin section per donor was prepared for all testing procedures but was dosed with a placebo patch to serve as a negative sample control.

Barrier Integrity Testing. To ensure the barrier integrity of each skin section, water desorption was measured for transepidermal water loss (TEWL). The Delfin Vapometer probe was activated and placed on the skin surface, and the TEWL value was recorded. Skin mounted in the diffusion cell with a TEWL less than 25 g/m2/h was considered acceptable. Skin sections determined to be unacceptable for dosing could be used as undosed negative sample control cells, if desired. After completing the barrier integrity test, the receptor solution was replaced with the designated stock receptor solution in 0.1x PBSg.

Donor Demographics. Skin donor demographics are summarized in Table 8.

Dose Administration and Sample Collection. Prior to administration of the patch to the skin sections, the entire receptor solution volume was removed to collect a pre-dose (0 hour) sample, and an approximately 5 mL aliquot of the collected sample was kept for subsequent analysis. The receptor solution was replaced with the designated stock receptor solution in 0.1x PBSg. The chimney was then temporarily removed from the Franz diffusion cell to allow full access to the epidermal surface of the skin.

Immediately after patch application, the skin-patch combination and the donor compartment (chimney) were replaced and placed into the receptor compartment of the Franz diffusion cell.

At scheduled sampling time points (3, 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min), the entire receptor solution was removed and refilled with stock receptor solution, and approximately 5 mL aliquots of collected samples were stored for subsequent analysis. For sample analysis, 5 mL aliquots were lyophilized using a vacuum centrifuge and reconstituted in 0.25 mL _ddH2O .

After the final receptor sample was collected, the patch was removed for subsequent extraction and analysis. Skin surface washing was performed using two successive reflux washes of ddH2O. Each washing cycle consisted of at least 10 refluxes. The two wash volumes from each donor cell were pooled to generate a single surface wash sample for the diffusion cell.

After superficial cleaning, the skin was allowed to dry for 10 minutes or more. The skin was then tape stripped using up to 10 sequential tapes (e.g., 3M Transpore® tape) to remove and collect the stratum corneum. Tape strips were extracted overnight in ddH2O. The skin was then removed from the cell and manually dissected into epidermis and dermis for subsequent extraction and analysis. Skin sections were extracted overnight in ddH2O.

Sample analysis. Quantification of zolmitriptan in collected samples was achieved using a validated HPLC method.

Samples were analyzed by a Shimadzu Series LC System. The HPLC UV/Vis method used a solvent system consisting of a mobile phase gradient using (solvent A) 0.1% ammonium acetate with 0.1% acetic acid in H2O and (solvent B) methanol run through a Phenomenex Luna C18(2) column, (100 x 4.6 mm, 3μ) at a flow rate of 0.5 mL/min for the analysis of zolmitriptan. The column was maintained at 40°C.

Mean Flux Results. Percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application (mean ± SE). Mean flux (μg/ ^cm2 /hr) is summarized in Table 9 and plotted in Figure 30, which summarizes across donors the results of percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application (mean, N=3 donors).

Total Absorption and Mass Balance Results. The results of percutaneous absorption of zolmitriptan into and through ex vivo human torso skin over 300 minutes from a single application are summarized in Table 10. Means ± SE as percent (%) of applied dose and total mass (μg).

Conclusions and Discussion. Total absorbed zolmitriptan through the skin to the receptor solution was 83.41±1.33% for the 1.9 mg patch. Peak flux occurred approximately 4 minutes after application with a peak flux of 849.4±42.1 μg/ ^cm2 /hr. Less than 1% of zolmitriptan was recovered from the three skin layers at the end of the dosing period. Mass balance was approximately 90% of the applied dose.

Example 3 - Stability of M207 Patches M207 patch assemblies were irradiated with e-beam and gamma radiation at doses up to 25 kGy. The irradiated patch assemblies were then placed in stable storage conditions of 25°C/60% RH and 40°C/75% RH. The results for the e-beam and gamma irradiated M207 patches are shown in Tables 11-17.

Solid state physical stability was evaluated by XRD. Amorphous vs. crystalline phase change for zolmitriptan coating was examined by XRD analysis. M207 1.9 mg patches were analyzed at initial time point (T0), 6 months and 12 months of storage. Drug coating was amorphous for both non-irradiated and gamma irradiated patches at T0. Gamma irradiated zolmitriptan patches stored at 25°C/60% RH for 12 months and 40°C/75% RH showed similar XRD patterns as T0 patches. Percent crystallinity was calculated using peak profile fitting and the results are summarized in Table 16 below. No crystalline phase was detected for zolmitriptan formulation solids coated on gamma irradiated patches stored under both intended (25°C/60% RH) and accelerated storage conditions (40°C/75% RH) for 12 months and 6 months, respectively.

As described herein, zolmitriptan coated microneedles were exposed to a dose of radiation in the range of about 7-30 kGy, more preferably in the range of 15-30 kGy for a sterility assurance level of ^10-5 to ^10-6 . Table 17 shows the 12 month stability results of irradiated and non-irradiated zolmitriptan patches stored at 25°C and 40°C.

Example 4 - Drug-Device Combination Product A novel drug-device combination product (M207) was manufactured according to the present disclosure. M207 is an intradermal delivery system that includes a disposable titanium microprojection member centered around an adhesive backing to form a patch. The patch was mounted into a plastic retaining ring to form a patch assembly. The patch includes dry microneedles coated with a drug product formulation. The retaining ring facilitates attachment of the patch to the base of a hand-held applicator. The applicator ensures that the patch is applied to the site of administration with a defined application energy. The combination of the patch assembly and applicator constitutes an intradermal delivery system. The applicator is held in the hand to apply the patch. The applicator cap is twisted to unlock the applicator. When the applicator is pressed against the skin, a plunger pushes the patch out of the retaining ring and applies it to the skin.

When the patch is applied to the skin, it remains on the skin and the plastic ring remains on the applicator, which is later detached and discarded. The delivery system was designed to rapidly deliver 1 mg, 1.9 mg, or 3.8 mg doses of zolmitriptan intradermally. The unit composition of the M207 drug product is provided in Table 18.

The zolmitriptan coated titanium microneedle array is a 3 ^cm2 array of about 1987 or about 997 titanium microneedles for 1.9 mg or 1 mg of drug product, respectively. It is attached to an adhesive patch of about 5 ^cm2 . The patch may be mounted in a polycarbonate plastic retaining ring with a co-molded desiccant. Alternatively, the desiccant may be attached to the lid of the foil pouch. The completed patch assembly is packaged in a foil pouch that is purged with dry nitrogen. The user prepares the patch for application by pressing a hand-held applicator onto the patch assembly. The applicator includes a spring-loaded piston for applying the patch to the user's skin (Figures 4(A), 4(B), and 5(A)-(E)). The applicator is released by twisting the outer grip against the base from position #1 to position #2 (Figure 5(C)). The user applies the patch by pressing the patch assembly with the applicator attached against the skin site. The applicator releases its piston with sufficient impact energy, for example, about 0.26 Joules. The piston releases the patch from the retaining ring and applies the patch to the skin with a predetermined impact energy density to ensure reproducible patch application. The applicator is designed to ensure that the same force is applied for each delivery and across different users.

The drug-coated microneedles penetrate or pierce the stratum corneum of the skin, allowing drug delivery. Upon administration, the solid zolmitriptan coating rapidly dissolves from the microneedles into the interstitial fluid of the skin to form a solution that is available for absorption. The patch is removed after approximately 30 minutes.

The components of the M207 system are listed in Table 19.

Example 5 - Human PK Clinical Trials The M207 product was evaluated in humans. This Phase 1 study included commercially available oral zolmitriptan tablets 2.5 mg and subcutaneous sumatriptan 6.0 mg as comparators. As described in the examples above, M207 is administered intradermally via a patch consisting of a titanium array of microneedles coated with zolmitriptan and applied by a specialized applicator. The purpose of this study was to provide information on the pharmacokinetics and tolerability of the M207 system. An evaluation of the tolerability of various doses of intradermal zolmitriptan versus a standard oral dose (2.5 mg) of zolmitriptan was also completed along with an evaluation of reactions at the application site.

Specifically, the study compared a single dose of 2.5 mg oral zolmitriptan tablets and 6.0 mg subcutaneous sumatriptan in addition to five regimens of M207 in a seven-way crossover design in 20 healthy volunteers. Analysis of plasma samples for zolmitriptan, N-desmethylzolmitriptan and sumatriptan concentrations was performed at Quest Pharmaceutical Services, Groningen, Holland by assays known in the art. In this study, administration of the M207 system resulted in a rapid time to maximum concentration (T _max ) equivalent to exposure to orally administered zolmitriptan, but showed reduced exposure to the major metabolite N-desmethylzolmitriptan. The doses evaluated in this study using the M207 system were 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mg.

The first four doses of zolmitriptan utilized a 5 ^cm2 patch and a 0.26 Joule applicator in the intradermal microneedle system described herein. The final treatment administered was 3.8 mg in a 10 ^cm2 patch using an applicator with an applied energy of 0.52 Joules in the intradermal microneedle system described herein. The products tested were:

M207 0.48 mg Patch Assembly: The zolmitriptan 0.48 mg patch consisted of a 3 ^cm2 titanium array of nominally 340 μm long microprojections coated with 0.48 mg zolmitriptan. The array was applied to the center of a 5 cm2 ^tan adhesive backing to form the patch. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with desiccant, and the patch assembly was packaged in a foil pouch.

M207 1.9 mg Patch Assembly: The zolmitriptan 1.9 mg patch consisted of a 3 ^cm2 titanium array of nominally 340 μm long microprojections coated with 1.9 mg of zolmitriptan. The array was applied to the center of a 5 cm2 ^tan adhesive backing to form the patch. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with desiccant, and the patch assembly was packaged in a foil pouch.

M207 3.8 mg Patch Assembly: The zolmitriptan 3.8 mg patch consisted of a 5.5 ^cm2 titanium array of nominally 340 μm long microprojections coated with 3.8 mg of zolmitriptan. The array was applied to the center of a 10 cm2 ^tan adhesive backing to form the patch. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with desiccant, and the patch assembly was packaged in a foil pouch.

Study Design This was a single-center, open-label, randomized, five-way crossover study (Part 1) followed by sequential testing of two additional treatments (Parts 2 and 3). After obtaining informed consent and establishing eligibility, each subject received one dose of each of the seven study treatments, followed by extensive blood sample collection for in-hospital monitoring and pharmacokinetic analysis. Dosing days in Part 1 were spaced 48-120 hours apart until dosing of Treatments A-E (see Table 20) was completed in the randomized order according to the treatment flow table. Plasma samples from the initial dosing day were sent to an analytical laboratory for analysis, and tolerability for each dose level was summarized. Tolerability was deemed acceptable, and subjects returned for Part 2. During Part 2, subjects received intradermal zolmitriptan in 1.9 mg x 2 patches (applied with the same 0.26 J applicator used in Part 1) and completed procedures identical to Part 1. During Part 3, subjects received a single 3.8 mg patch (applied using a 0.52 J applicator) and completed the same procedures as on the preceding dosing day. After completing the seven dosing days, subjects were evaluated one final time and discharged from the study.

The treatments used in the study were as listed in Table 20 below.

Twenty subjects participated in the study, 10 males and 10 females. The mean age of the subjects was 29 ± 3.5 years, and the mean BMI was 24.4 ± 3.5. All subjects completed all seven treatment visits of the study and received all seven study treatments, except for one subject who missed one treatment visit. In two subjects (#1010 in Treatment A and #2010 in Treatment D), very small pre-dose blood samples were collected at one visit due to difficulty in accessing the vein, but for all other subjects, virtually all of the scheduled pharmacokinetic blood samples (14 per visit) were collected for analysis.

Tolerability was deemed acceptable in Part 1, and following review of safety and pharmacokinetic data from the first five dosing periods and discussions with the sponsor and principal investigator, subjects progressed to and completed visits in Parts 2 and 3. Serum collected was analyzed for zolmitriptan and N-desmethylzolmitriptan using methods well known in the art, such as the use of liquid chromatography-mass spectrometry (LC-MS-MS) methods.

Pharmacokinetics The M207 patch was well tolerated and rapid absorption was observed, which may translate to rapid pain relief for migraine or cluster headache sufferers. Phase 1 results are presented below, demonstrating the rapid absorption of M207 characteristic of Zosano's microneedle patch and applicator system.

Mean plasma concentration versus time data for each of the six zolmitriptan regimens administered are shown in Figures 7 and 8. Figure 7 shows results for the full 24-hour sampling period, while Figure 8 shows results for only the first 2 hours after study drug administration. Both figures include subcutaneous sumatriptan concentration versus time data (scaled for presentation purposes to illustrate the time course). Results after SC sumatriptan were similar to several published studies of this dose and route of administration.

Based on the results presented in Figures 7 and 8, the plasma levels of zolmitriptan following intradermal application were dose-dependent, with absorption following patch application being much faster than that seen following administration of the 2.5 mg tablet. The plasma levels seen following the single larger 3.8 mg patch were higher than those seen following 2 x 1.9 mg patches. Dose linearity plots for zolmitriptan Cmax _{, AUCt} , and _AUCinf are shown in Figures 9, 10, and 18 (excluding the larger 3.8 mg patch). Dose linearity plots for N-desmethylzolmitriptan Cmax _{, AUCt} , and _AUCinf are shown in Figures 22-24 (excluding the larger 3.8 mg patch). Excellent dose linearity was observed over the range of doses evaluated. The calculated key mean (median _Tmax ) pharmacokinetic parameters for the zolmitriptan regimens and subcutaneous sumatriptan are shown below in Table 22.

Perhaps most relevant to the potential utility of this product for the treatment of migraine or cluster headaches is the _Tmax for intradermal administration of the zolmitriptan regimen, which indicates a much more rapid absorption of zolmitriptan from intradermal administration than from oral administration.

The pharmacokinetic parameters following intradermal administration of zolmitriptan were, on average, very similar when comparing the results in male subjects with those seen in female subjects, as shown in Figures 11 and 12.

The active metabolite N-desmethylzolmitriptan was detectable in all subjects receiving the five higher dose regimens. N-desmethylzolmitriptan pharmacokinetic parameters for each zolmitriptan regimen are shown in Table 23 below.

N-desmethylzolmitriptan levels were significantly lower after intradermal administration of M207 zolmitriptan than were seen after oral administration (Treatment D).

PK parameters were summarized by treatment group using descriptive statistics (arithmetic mean, standard deviation, coefficient of variation, sample size, minimum, maximum, and median). In addition, geometric means and 95% confidence intervals (CI) were calculated for _AUC2h , _AUCt , _AUCinf , and _Cmax . For each zolmitriptan treatment, the ratio of _AUCinf N-desmethylzolmitriptan/ _AUCinf zolmitriptan was calculated for each subject and group means were determined.

Dose proportionality was evaluated for the three doses of M207, and dose proportionality was not based solely on strict statistical rules. The relationship between zolmitriptan dose and PK parameters was examined using graphical approaches and by descriptive statistics. Graphs of apparent dose linearity and proportionality of PK parameters ( _AUCt , _AUCinf , and _Cmax ) were compiled.

Rapid absorption of zolmitriptan was observed after intradermal patch application, with mean peak plasma concentrations (T _max ) ranging from 16.1 to 18.4 minutes, which was similar to that of sumatriptan SC injection (12.5±4.4 minutes) and significantly faster than that of zolmitriptan tablets (107.4±76.4 minutes [1.8±1.27 hours]).

The mean (±SD) elimination half-life (t _1/2 ) of the M207 system was 1.15±0.27 hours to 1.53±0.31 hours over the dose range of 0.48 mg to 3.8 mg, respectively. Elimination of zolmitriptan after zolmitriptan tablets (3.27±0.8 hours) was nearly twice as slow as M207.

The mean (±SD) maximum plasma concentration (C _max ) of the zolmitriptan tablets was 3.77±1.51 ng/mL. Administration of 2×0.48 mg patches provided nearly equivalent maximum concentrations of 3.70±1.05 ng/mL, with Group C (1.9 mg) administered as a single patch having nearly double the C _max (6.76±2.75 ng/mL). Groups F and G produced maximum plasma concentrations 3.9-fold (14.61±4.46 ng/mL) and 6-fold (22.56±14.0 ng/mL) higher than the zolmitriptan tablets, respectively.

The mean (±SD) total exposure (AUC _inf ) was 3.81±1.46 ng.H/mL for M207 0.48 mg and 33.81±7.95 ng.H/mL for M207 3.8 mg applied as a single patch. Treatment with M207 patches in groups F and G produced similar exposures (AUC _inf ) to zolmitriptan tablets (30.12 and 33.81 ng.H/mL, respectively). The mean exposure (AUC _inf ) for M207 was proportional to dose for single patch administration (y=8.31). Concentration-time curves over 0-2 hours for all treatments are shown in FIG. 8 and for 0-24 hours in FIG. 7.

At the higher doses of Group F (2 × 1.9 mg) and Group G (3.8 mg), plasma concentrations were slightly higher in men than in women. At the lower doses (Group A [0.48 mg] to Group C [1.9 mg]), there did not appear to be any gender differences.

を使用してＭ２０７システムの相対バイオアベイラビリティをゾルミトリプタン錠剤と比較した。 The formula:

was used to compare the relative bioavailability of the M207 system with that of zolmitriptan tablets.

The mean total exposure for the M207 intradermal microneedle system was lower compared to zolmitriptan tablets (range: 0.70-0.86). However, the mean peak exposure was 2.35-3.73 times higher for intradermal zolmitriptan compared to zolmitriptan tablets.

A summary of the key calculated pharmacokinetic parameters from the study is shown in Table 24.

Approximately twice the amount of the active metabolite N-desmethylzolmitriptan was formed after oral administration of zolmitriptan compared to that seen after M207 (mean 59.8±16%) (Table 25).

を使用して、Ｍ２０７パッチについて生じた活性代謝物Ｎ－デスメチルゾルミトリプタンの相対バイオアベイラビリティをゾルミトリプタン錠剤と比較した。 The formula:

was used to compare the relative bioavailability of the resulting active metabolite N-desmethylzolmitriptan with the M207 patch compared with the zolmitriptan tablet.

There was lower conversion to the N-desmethylzolmitriptan metabolite for the M207 patch compared to the zolmitriptan tablet (F _rel AUC range: 0.32-0.46), with an approximately 50% lower exposure rate for the M207 patch compared to the zolmitriptan tablet based on the relative bioavailability of C _max .

Maximal plasma concentrations of the N-desmethyl metabolites were reached at approximately 1 hour (range: 54.7-65.0 min) for M207 administered via the intradermal route compared to zolmitriptan tablets (162.6 min [2.71 H]) (FIG. 13). Elimination half-lives (t _1/2 ) for the metabolites were similar for all treatments, including oral administration (range 2.7 H-3.31 H]). Concentration-time curves from 0 to 24 hours for N-desmethylzolmitriptan are shown in FIG. 14.

The mean maximum plasma concentration (C _max ) for the M207 0.48 mg dose was 0.22 ng/mL, 1.77 ng/mL for the 3.8 mg strength compared to 2.08 ng/mL for the zolmitriptan tablet. The mean AUC _inf ranged from 1.38 ng.H/mL for the 0.48 mg strength to 8.17 ng.H/mL for the 3.8 mg strength versus 14.55 ng.H/mL for the zolmitriptan tablet. The amount of N-desmethyl metabolite (C _max and AUC _inf ) for the M207 patch was directly proportional to dose (y=0.4127 and 2.022, respectively) and was significantly lower than that for the zolmitriptan tablet. See Figures 19 and 21.

A summary of the mean pharmacokinetic parameters for N-desmethylzolmitriptan is detailed in Table 26.

M207 also tended to have lower within-group variability (as indicated by CV%) for the AUC _inf parameter compared to zolmitriptan tablet.

Dose Linearity of Administration of the M207 System Positive linear relationships were found for C _max (y=4.81), AUC _t (y=7.61) and AUC _inf (y=8.31) for both single (0.48 mg, 1.9 mg and 3.8 mg) and multiple (0.48 mg×2 and 1.9 mg×2) administrations of the system. See Figures 15-17. At the low end of the dosing range (0.48 mg×2), concentrations of both zolmitriptan and the N-desmethylzolmitriptan metabolite were very similar. However, at the highest dose (1.9 mg×2), plasma concentrations achieved with multiple patch administrations were slightly lower than those with a single patch (and administration force of 0.52 J) for both zolmitriptan and N-desmethylzolmitriptan. See Figures 19-21 for N-desmethylzolmitriptan.

Administration of the M207 patch resulted in rapid peak plasma concentrations (T _max ) occurring within 20 minutes of patch application. This compares favorably to 12.5 minutes for SC sumatriptan and represents a considerable improvement over conventional release oral zolmitriptan tablets (1.8 hours). The elimination rate (t _1/2 ) for M207 was shorter, approximately two-fold shorter than that of the zolmitriptan tablet (1.2-1.5 hours vs. 3.3 hours).

_Cmax for zolmitriptan tablets was 3.77 ng/mL. Treatment with M207 patches in Groups C (1.9 mg), F (1.9 mg x 2) and G (3.8 mg) produced mean peak plasma concentrations 1.8-, 3.9- and 6-fold higher than zolmitriptan 2.5 mg tablets. Multiple patch administration with 2 x 0.48 mg M207 produced a _Cmax (3.70 ng/mL) equivalent to oral zolmitriptan tablets.

Treatment with the M207 patch in Groups F and G produced similar exposures (AUC _inf ) to oral zolmitriptan tablets (30.12, 33.81, and 27.19 ng.H/mL, respectively). However, the mean total exposures (AUC _inf ) for the M207 patch were lower (0.700-0.86) and the mean peak exposures (C _max ) were 2.35-3.73-fold higher compared to oral zolmitriptan tablets.

The time to peak plasma concentration of the N-desmethyl metabolite from M207 was significantly faster at approximately 1 hour versus 2.7 hours for oral zolmitriptan. However, the amount of metabolite generated from M207 was approximately 50% lower than the oral zolmitriptan tablet. Key PK findings are summarized below in Table 27.

Perhaps most relevant to the potential utility of this product for the treatment of migraine or cluster headaches is the _Tmax for the M207 regimen, which indicates a much more rapid absorption of zolmitriptan from intradermal administration than from oral administration.

Exposure comparisons are provided in Table 28 below.

Excellent dose linearity was observed for high and low doses for _Cmax and _AUCinf . M207 was well tolerated. Adverse events (AEs) were primarily mild (87%) of short duration (<24 hours) and mostly consistent with events previously reported with zolmitriptan (88%). There were no serious or serious AEs. Transient changes in both systolic and diastolic blood pressure occurred, with pressure values returning to pretreatment levels 1-2 hours after drug administration for both systolic and diastolic blood pressure. No significant ECG changes occurred. Patch application was well tolerated with mostly mild to moderate reactions that resolved after 24 hours. Local tolerability of the 3.8 mg patch applied with greater force (0.52 J) was less favorable than the other regimens.

The M207 intradermal delivery system should provide a pharmacokinetic advantage over zolmitriptan tablets, resulting in a faster onset of action, comparable exposure, and reduced first-pass metabolism with reduced potential for drug interactions and adverse events. Importantly, delivery is via a method that does not involve the gastrointestinal route or injection. Further comparisons of zolmitriptan with conventional oral tablets are provided below in Tables 29 and 30.

Example 5 - In vivo pig testing The M207 patch was tested in pigs.

Determination of zolmitriptan by LC/MS/MS method Analysis of zolmitriptan from used patch skin swabs and plasma PK samples was performed using an established in-house LC/MS/MS method. The lower limit of quantification (LLOQ) and upper limit of quantification (HLOQ) were 0.1 and 1000 ng/mL, respectively. A 4-minute method utilizing high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) was developed for the quantification of zolmitriptan and its two main metabolites in HGP plasma. The instrumentation consisted of an Agilent® 1200 pump, a CTC PAL® Autosampler with a cooled stack, an AB Sciex® TurboV® ESI source, and an API 4000® mass spectrometer.

All plasma samples and standards were first protein precipitated using 100% methanol, then diluted with a 30% solution of acetonitrile in a 1:2 ratio (plasma:30% ACN) and 20 μL of this solution was injected into the autosampler. The autosampler was equipped with a 100 μL syringe and a 100 μL loop. The syringe and loop were washed twice between each injection with solvent 1 (0.2% formic acid) and solvent 2 (0.2% formic acid in acetonitrile).

A 10-port, two-position Valco® valve was placed in-line with the mass spectrometer equipped with a protective cartridge (Zorbax 300SB-C8, 12.5 x 4.6 mm) used for online solid-phase extraction (SPE). The valve was set up such that in the "load" position, the sample was injected into the cartridge and washed with 10% mobile phase B for 30 seconds, then the valve was switched to the "inject" position where the washed sample was eluted in the reverse direction from the SPE cartridge into an analytical column (Luna PFP(2), 100A, 5 μm, 50 x 2 mm) and the mass spectrometer.

The HPLC method used was a reversed-phase gradient method (0.0 min, 10% B; 0.5 min, 10% B; 1.0 min, 40% B; 1.7 min, 40% B; 2.1 min, 10% B; 4.0 min, 10% B). The HPLC mobile phase consisted of 80% acetonitrile in 20% 20 mM ammonium acetate as mobile phase A and 20% 20 mM ammonium acetate as mobile phase B. The source settings for all analyses were as follows: collision gas (CAD) = 12; curtain gas (CUR) = 25; ion source gas 1 (GS1) = 60; ion source gas 2 (GS2) = 60; ion spray voltage (IS) = 5500; temperature (TEM) = 600; interface heater (ihe) = on. Eleven MRM transitions were monitored during mass spectrometer acquisition. All 11 MRM transitions were used for data processing. The peak areas under each corresponding MRM transition were added together and compared to those of spiked standard plasma samples to calculate the concentration for each sample. Quadratic (1/x) fitting was used for all calculations.

Anesthesia Animals were induced with Telazol intramuscularly and maintained with Isoflurane on a ventilator.

Blood Sample Collection for Pharmacokinetic Studies Blood samples were collected from one or more of the following blood vessels in the animals: ear marginal vein/artery (left/right), saphenous vein (left/right), mammary vein (left/right), and femoral artery (left/right). An indwelling catheter/sheath was placed to access the preferred vessel and secured in place for the blood collection period. All procedures were performed by trained staff following approved protocols and SOPs at the study facility. A 5 mL blank blood collection was obtained from each animal prior to the first dose. A 1 mL blood sample was collected up to 5 hours after patch application administration. Heparinized microtiter tubes were used to collect all blood samples. The collected blood volume was replaced with an equal volume of heparinized saline, taking into account the dead volume of the catheter. In general, daily blood collection did not exceed 3-5% of the animal's total blood volume.

Intravenous Administration of Zolmitriptan Zolmitriptan solution for IV administration was prepared in-house with a maximum zolmitriptan concentration of 3 mg/mL. Dose volumes of less than 3 mL were injected into the marginal ear vein of the animals using a 28-30 G needle. Pressure was applied momentarily and gauze was used immediately after injection to prevent bleeding at the site of injection.

Determination of Patch Delivery Performance Determination of ZP-zolmitriptan Delivery Using Residual Drug Analysis Zolmitriptan residues were determined from used patches and swabs from treated skin sites. Once the skin was peeled, the used patch was removed from the adhesive band outside the microprojection array section and stored for analysis of zolmitriptan residues. Three synthetic fiber swabs were used to collect residual zolmitriptan from the treated skin sites. The first swab was pre-moistened by inserting it into a vial containing 1 mL of swab buffer. The first swab was applied across the patch-treated skin site with slight pressure (using a rotational motion) in several directions to the periphery of the treatment site. The second and third swabs were dried and used to capture any residual buffer from the skin site moistened by the first swab. All three swabs were placed into the original vial containing swab buffer. The amount of zolmitriptan remaining on the microprojection array and skin surface after each application was compared to the amount originally coated on the array, allowing for the determination of the total amount of zolmitriptan delivered and the delivery efficiency. The equations for determining the total drug delivered and the drug delivery efficiency are shown below as (1) and (2), respectively.
Total Residual Amount = Patch Residual Amount + Skin Residual Amount Total Drug Delivery = Nominal Coating Amount - Total Residual Amount (1)

Study Design Three pre-estrus female Yorkshire pigs were used in the study. Naïve animals were purchased from an approved vendor following the study facility's approved protocols and SOPs and were quarantined for up to 7 days. Animals in each group were administered up to five treatments (crossover) with a recovery/washout period of up to 5 days between treatments. At the first dose, animals had body weights ranging from 18-25 kg and at the last dose, animals had body weights ranging from 25-41 kg. In general, treatments per group included 1-2 control and 1-3 ZP-zolmitriptan administrations. Controls included IV zolmitriptan. When more than one patching treatment was performed, the location of the ZP-zolmitriptan patch was rotated from the left and right ventral thighs of the hind legs in each group of animals.
result

The average delivery was greater than 1.7 mg for all coatings in both in vivo studies. Delivery efficiency was greater than 85% and consistent for both studies. Pharmacokinetic studies were then performed using the MF1663 array design with a 1.9 mg coating. Table 32 summarizes the patch and IV results.

In vivo evaluation demonstrated rapid systemic absorption of zolmitriptan using patch administration. Plasma levels were maintained over 5 hours with a median _Tmax of 15 minutes. The zolmitriptan patch had an absolute bioavailability of 77%. The ZP-zolmitriptan patch demonstrated that the required amount of drug could be coated, high delivery efficiency was consistently achieved, and coated zolmitriptan could be well absorbed with a fast time to _Cmax .

Example 6 - Human Efficacy Clinical Trials The ZOTRIP core efficacy study was a multicenter, double-blind, randomized, placebo-controlled study comparing three doses of M207 (1.0 mg, 1.9 mg, and 3.8 mg) to placebo for the treatment of a single migraine attack. Subjects participated in the ZOTRIP study at 36 sites in the United States. Those recruited into the study had at least a one-year history of migraine attacks with or without aura. At recruitment, subjects were placed into a run-in period that ensured they met the key eligibility criteria of 2-8 migraine attacks per month, which they recorded using an electronic diary or cell phone app. Subjects also identified the most bothersome other symptom selected from nausea, photophobia, and phonophobia, and indicated the presence or absence of nausea, phonophobia, or photophobia during attacks during the run-in period. Subjects who successfully screened were then randomized into a treatment/administration period during which subjects were given 8 weeks to confirm and receive blinded treatment for a single migraine attack, referred to as a "qualifying migraine," in which their previously identified most bothersome other symptoms were present.

During qualifying migraines, subjects scored pain severity on a 4-point headache scale and the presence or absence of migraine-related symptoms (photophobia, phonophobia, or nausea) at intervals beginning before dosing and continuing for 48 hours after dosing. The coprimary endpoint of the study was relief of pain and other symptoms that were most bothersome as defined in the October 2014 FDA Draft Guidance "Migraine: Developing Drugs for Acute Treatment." Subjects recorded migraine symptoms in a patient diary before treatment and at various intervals up to 48 hours after treatment. Safety was assessed by reported adverse events and other standard safety measures.

589 subjects were enrolled in the study, of which 365 were randomized. Of the randomized subjects, 333 subjects were treated and included in the safety analysis, and 321 were eligible for the modified intention to treat (mITT) population. 51% of randomized subjects had severe migraines before treatment. Even at the time of treatment, 70% reported nausea, 37% aura, and 51% waking up with a migraine (morning migraine). With multiple doses and multiple endpoints in the study, a sequential study procedure was used, starting with the maximum dose and coprimary endpoint. Statistical significance was not achieved for the most bothersome other symptoms in the 1.9 mg group, so the p-values for the secondary endpoints should be considered nominal p-values.

All three doses of M207 (1 mg, 1.9 mg, and 3.8 mg) achieved statistically significant relief of pain at 2 hours. The 3.8 mg dose achieved both coprimary endpoints of relief of pain and relief of most bothersome other symptoms at 2 hours. The 3.8 mg dose also achieved significance in the secondary endpoints of relief of pain at 45 minutes and 1 hour, demonstrating durability of effect on relief of pain at 24 and 48 hours. Additionally, M207 was not associated with any serious adverse events (SAEs).

The 3.8 mg dose of M207 achieved statistical significance for both co-primary endpoints at 2 hours, as shown in Table 33.

Furthermore, the secondary endpoint of relief of pain at additional time points for the 3.8 mg dose of M207 showed that M207 was superior to placebo with a nominal p-value of less than 0.05, as shown in Table 34.

Overall, only 13 subjects (3.9%) reported pain at the application site, with all but three subjects reporting the pain at the application site as mild. The most frequently reported adverse event was erythema at the application site (18.3% of subjects). All cases of erythema resolved. Additionally, five patients (1.5%) in the M207 treatment group reported dizziness, compared with 0% in the placebo group.

Additional data from the clinical trial results are presented in the table below.

In Table 35 above, the 3.8 mg dose group met both co-primary endpoints with a p-value of <0.05. The 1.9 mg dose group met the endpoint of relief of pain with a p-value of <0.05. For the endpoint of relief of most bothersome other symptom at 2 hours, the 1.9 mg dose group had a p-value of 0.05 or greater. The 1 mg dose group met the endpoint of relief of pain with a p-value of <0.05. For the 1 mg dose group, the endpoint of relief of most bothersome other symptom at 2 hours had a p-value of 0.05 or greater.

Table 36 above is matched to the co-primary endpoint analysis (mITT LOCF). Table 35 below provides a fixed order for testing each of the multiple endpoints described for migraine to assess whether the study was successful. For doses of 3.8 mg, 1.9 mg, and 1.0 mg, the efficacy of treatment was tested for the co-primary and secondary endpoints in Table 35. As shown, all endpoints in or after the study in Order 4 are not significant under the MCP methodology.

Tables 38-46 provide the results of a clinical trial of treatment with one embodiment of the claimed invention. In this embodiment, endpoints including pain relief, pain relief, photophobia relief, phonophobia relief, and nausea relief for 1 mg, 1.9 mg, and 3.8 mg treatments at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 12 hours, 24 hours, and 48 hours after treatment were assessed sequentially as described in Table 35, as shown in Tables 36-40. The investigator also performed a visual assessment of the skin after patch removal for adverse events such as purpura, edema, and erythema, as shown in Tables 41-44.

Tables 47-50 and Figures 25-28 demonstrate the effectiveness of one embodiment of the claimed invention against published results of treatments currently used in the art. The state of the art up to the claimed invention included intranasal treatments and standard and orally dissolving tablets.

The embodiments of the invention described above are intended to be merely illustrative, and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the invention as defined in any accompanying claims.

Claims (32)

An intradermal delivery system , comprising: a disposable patch assembly including a substrate comprising an array of microprojections, said microprojections extending perpendicularly from said substrate and adapted to pierce or pierce the stratum corneum of a human patient, said microprojections having thereon a solid coating formulation comprising zolmitriptan or a pharma- ceutically acceptable salt thereof in an amount of about 0.5 mg to about 5 mg per array;
(i) the array has an area of about 0.5 to 10 ^cm2 ;
(ii) the array has a density of about 500 to 1000 microprojections/ ^cm2 ;
(iii) the microprojections are rectangular with triangular tips and have a length of about 300 to about 450 μm, a thickness of about 10 μm to about 50 μm, and a width of about 90 μm to about 160 μm;
(iv) the tips of the microprojections have a length of about 130 μm to about 200 μm and an angle of about 30 to about 50 degrees;
(v) the coating on each microprojection has an approximate shape of an American football;
system. The system of claim 1, wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes as measured by the paddle-over-disk method (Apparatus 5) of the United States Pharmacopeia (USP). The system of claim 1 or 2, wherein at least 95% of the zolmitriptan is released within about 1 minute. When the system is applied to a selected area of a patient's skin,
4. The system of any one of claims 1 to 3, wherein (i) the _T of a therapeutically effective plasma concentration occurs within about 45 minutes of said application, the _C is about 5 to about 25 ng/ml, and the AUC _0-2hr is about 5 to about 20 ng/ml·hr, and/or (ii) the _T of a therapeutically effective serum concentration occurs within about 30 minutes of said application. The system of any one of claims 1 to 4, wherein the coating covers approximately 10% to 80% of the length of each microprojection measured from the tip to the base. The system of claim 5, wherein the coating covers about 20% to about 70% of the length of each microprojection. The system of claim 6, wherein the coating covers about 30% to about 60% of the length of each microprojection. A solid coating formulation is obtained by applying a liquid coating formulation to the microprojections and drying, the liquid coating formulation having a viscosity of greater than about 3 centipoise (cP) and less than about 500 cP, less than about 400 cP and more than about 10 cP, less than 300 cP and more than about 50 cP, less than about 250 cP and more than about 100 cP, greater than about 80 cP and less than about 350 cP, greater than about 100 cP and less than about 350 cP, greater than about 100 cP and less than about 250 cP, at least 20 cP, at least 25 cP, at least about 30 cP, at least about 35 cP, at least about 40 cP, at least about 50 cP, at least about 60 cP, at least about 70 cP, at least about 80 cP, at least about 90 cP, at least about 100 cP, at least about 100 cP, at least about 15 ... The system according to any one of claims 1 to 7, having a viscosity selected from the group consisting of at least about 40 cP, at least about 45 cP, at least about 50 cP, at least about 55 cP, at least about 60 cP, at least about 65 cP, at least about 70 cP, at least about 75 cP, at least about 80 cP, at least about 85 cP, at least about 90 cP, at least about 95 cP, at least about 100 cP, at least about 150 cP, at least about 200 cP, at least about 300 cP, at least about 400 cP, and less than about 500 cP. The system of any of claims 1 to 8, wherein the formulation coating has a viscosity before drying of about 150 cP to about 350 cP and a surface tension of about 50 mNm ^-1 to about 72 mNm ^-1 . 10. The system of claim 9, wherein the formulation coating has a viscosity before drying of about 200 cP to about 300 cP and a surface tension of about 55 mNm ^-1 to about 65 mNm ^-1 . The system of any one of claims 1 to 10, wherein the microprojections are made of a thin sheet of metal or a hard material. The system of claim 11, wherein the microprojections are made of a material selected from the group consisting of plastic, stainless steel, titanium, and nickel-titanium alloys. The system of claim 12, wherein the microprojections are made of titanium. The system according to any one of claims 1 to 13, wherein the solid coating formulation further comprises at least one inactive ingredient. The system of claim 14, wherein the inactive ingredient is tartaric acid. The system of any one of claims 1 to 15, wherein the system includes a patch affixed to a substrate, and the microprojections are arranged in an array on the substrate. Features:
(a) a patch size selected from the group consisting of about 1-20 cm ² , about 2-15 cm ² , about 4-11 cm ² , about 5 cm ² , and about 10 cm ² ;
(b) a substrate size selected from the group consisting of about 0.5-10 cm ² , about 2-8 cm ² , about 3-6 cm ² , about 3 cm ² , about 3.1 cm ² , about 3.13 cm ² , and about 6 cm ² ;
(c) an array size selected from the group consisting of about 2-8 cm ² , about 2.5-6 cm ² , about 2.7 cm ² , about 5.5 cm ² , about 2.74 cm ² , and about 5.48 cm ² ;
(d ) an array density selected from the group consisting of about 650-800 microprojections/cm ² and about 725 microprojections/cm ² ;
(e) a number of microprojections/arrays selected from the group consisting of about 100-4000, about 1000-3000, about 1500-2500, about 1900-2100, about 2000, about 1987, about 200-8000, about 3000-5000, about 3500-4500, about 4900-4100, about 4000, and about 3974;
(f ) a microprojection length selected from the group consisting of about 320-410 μm, about 340 μm, about 390 μm, about 387 μm, less than 700 μm, and less than 500 μm;
(g ) a tip length selected from the group consisting of about 150-180 μm, about 160-170 μm, and about 165 μm;
(h ) a microprojection width selected from the group consisting of about 100 μm, about 110 μm, about 120 μm, about 130 μm, about 140 μm, and about 150 μm;
(i ) a microprojection thickness selected from the group consisting of about 20 μm to 30 μm, and about 25 μm;
(j ) a microprojection tip angle selected from the group consisting of about 35-45 degrees, and about 40 degrees;
(k) a total amount of zolmitriptan or a pharma- ceutically acceptable salt thereof per array selected from the group consisting of about 1 mg to 5 mg, about 1 mg to 4 mg, about 1 mg, about 1.9 mg, and about 3.8 mg;
(l) an amount of non-active ingredient per array selected from the group consisting of about 0.1-10 mg, about 0.2-4 mg, about 0.3 mg-2 mg, about 0.6 mg, about 0.63 mg, about 1.3 mg, about 1.26 mg, 1× to 1/3× the amount of active agent, and about 0.033 mg to about 3.33 mg;
(m) a coating thickness selected from the group consisting of about 100 μm to about 500 μm, about 200 μm to about 350 μm, about 250 μm to about 290 μm, and about 270 μm;
17. The system of claim 16, having at least one of the following amounts of zolmitriptan or a pharma- ceutically acceptable salt thereof per microprojection selected from the group consisting of about 0.001 to about 1000 μg, about 0.01 to about 100 μg, about 0.1 to 10 μg, about 0.5 to 2 μg, about 1 μg, and about 0.96 μg. 20. The system of claim 17 having a patch area of about 5 ^cm2 attached to a titanium substrate having an area of about 3.1 ^cm2 and a microprojection thickness of about 25 μm. 19. The system of claim 17 or 18, wherein the microprojection array has an area of about 2.74 ^cm2 and comprises about 1987 microprojections at a density of about 725 microprojections/ ^cm2 . 20. The system of claim 18 or 19, wherein the formulation contained on each microprojection comprises about 0.96 μg zolmitriptan and about 0.32 μg tartaric acid or about 1.9 mg zolmitriptan and about 0.63 mg tartaric acid per patch. 20. The system of claim 17 having a patch area of about 5 ^cm2 attached to a titanium substrate having an area of about 6 ^cm2 and a thickness of about 25 μm. 22. The system of claim 17 or 21, wherein the microprojection array has an area of about 5.5 ^cm2 and comprises about 4000 microprojections at a density of about 725 microprojections/ ^cm2 . The system of claim 21 or 22, wherein the formulation contained on each microprojection comprises about 0.96 μg zolmitriptan and about 0.32 μg tartaric acid or about 3.8 mg zolmitriptan and about 1.3 mg tartaric acid per patch. 24. The system of any of claims 1 to 23, wherein the microprojections have a length of about 387±13 μm, a width of about 120±13 μm, and a thickness of about 25.4±2.5 μm , and the tips of the microprojections have a length of about 165±25 μm and an angle of 40±5 degrees . The system of claim 1 , wherein the microprojections are bent perpendicular to the surface of the substrate. The microprotrusions include:
a. Before bending, it has a length of about 387±13 μm;
b) The system of claim 25 , wherein after bending, the system protrudes approximately 340 μm in a direction perpendicular to the substrate. The system of any one of claims 1 to 26 , wherein the coating formulation does not include surfactants or other penetration enhancers. 10. The liquid coating formulation, prior to drying:
(a) zolmitriptan in an amount selected from the group consisting of about 30% w/w to about 60% w/w, about 40% w/w to about 50% w/w, and about 45% w/w;
28. The system of any one of claims 1 to 27, comprising: (b) tartaric acid in an amount selected from the group consisting of about 5% w/w to about 25% w/w, about 10% w/w to about 20% w/w, and about 15 % w/w; and (c) a liquid carrier. 30. The system of claim 28 , wherein the liquid carrier is water. The system of any one of claims 1 to 29 , wherein the coating on each microprojection has a thickness that tapers from a maximum of about 270 μm. 31. The system of any of claims 1 to 30, wherein the coating has an average thickness, measured from the microprojection surface, selected from the group consisting of about 10 to about 400 microns, about 30 to about 300 microns, about 100 microns to about 175 microns, about 115 to about 150 microns, and about 135 microns. The system according to any one of claims 1 to 31 , wherein the system is an adhesive dermally-applied microarray (ADAM).