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

Abstract

To provide a method for rapidly achieving a therapeutic concentration of zolmitriptan suitable for the treatment of migraine and cluster headache. [Solution] An intradermal delivery system comprising a plurality of microprojections adapted to penetrate or pierce the stratum corneum of a human patient, the microprojections having a solid formulation coating covering about 10% to about 80% of the length of each microprojection measured from the tip to the base, the coating containing zolmitriptan or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 5 mg per system, and at least 95% of the zolmitriptan being released from the system within about 5 minutes as measured by the paddle-over-disk method (Apparatus 5) listed in the United States Pharmacopeia (USP).

Description

[Technical field]

[0001] The present invention relates to the field of transdermal or intradermal delivery of pharmaceutical agents, and more particularly to the delivery of triptans, including zolmitriptan. [Background technology]

[0002] 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 one to four 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 three 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 their 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.

[0003] 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. The visual symptom is known as an aura. The remaining migraine patients experience both types of migraine.

[0004] About a 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.

[0005] Cluster headaches are extremely severe headaches that occur repeatedly in cycles ("clusters"), usually daily, for periods of one or more weeks, typically six to twelve weeks. Chronic cluster headaches can last for more than a year 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 of day 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).

[0006] 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 urge 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 higher risk for alcohol and drug abuse, self-harm, and even suicide. In fact, cluster headaches are sometimes referred to as "suicide headaches."

[0007] 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, Non-Patent Document 1. Although migraine headaches are different from cluster headaches, it is believed that certain treatments for migraine headaches, 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 short-term headaches. Triptan injections have shown some efficacy, but their use is limited by needle phobia, lack of portability, complex preparation, the need to discard needles, and safety issues related to infections from punctures, cuts, and cross-contamination.

[0008] Acute treatment of migraine underwent a dramatic change in 1991 with the introduction of the triptans, including sumatriptan and zolmitriptan. Triptans inhibit vascular 5-HT 1B Receptors and neuronal 5-HT 1D They are serotonin derivatives that exhibit highly selective and strong agonist activity at the receptor. The mechanism of action of triptans is thought to consist of the following three mechanisms: (1) inhibition of 5-HT in postsynaptic blood vessels; 1B (2) stimulate vasoconstriction of meningeal blood vessels by binding to 5-HT receptors in presynaptic neurons; 1D (3) inhibiting the release of pro-inflammatory neuropeptides by binding to the presynaptic 5-HT 1D Receptor binding reduces firing rate in the trigeminal nerve and trigeminal nucleus caudalis (central action). Triptans have also shown greater efficacy than placebo in treating cluster headaches.

[0009] Currently available methods of triptan administration, including oral, nasal spray, subcutaneous injection, and iontophoretic intradermal patch (a device that delivers drugs through the skin with a low electrical current), each have significant drawbacks. Some migraine patients do not respond to oral triptans, and oral treatments may be ineffective and / or uncomfortable for patients who suffer from the nausea, vomiting, or gastric stasis that can accompany migraine. 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 also affect absorption after nasal delivery. Nasal sprays can have an unpleasant taste and the use of injections can be painful.

[0010] 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) is associated with low bioavailability (approximately 15%) due to low absorption and presystemic metabolism. The time to reach peak concentrations in the bloodstream after oral tablet administration (T max ) is about 2 hours. For immediate release tablet formulations, T max On average, SC delivers 10 to 15 minutes faster than conventional tablets, but has roughly similar bioavailability. Sumatriptan is fast acting when injected (usually within 10 minutes), but has a short duration of action. Despite the faster delivery of SC, tablet formulations of sumatriptan are prescribed much more frequently than injectables, as many patients are reluctant to self-inject.

[0011] 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).

[0012] Zolmitriptan normal release tablets have been shown to have a bioavailability of 41%-48% and, when administered with food, C max and AUC decreased by 13% to 16% (Non-Patent Documents 2 and 3). max It has been reported that absorption is actually reduced during a migraine attack, and T max Zolmitriptan is converted to an active N-desmethyl metabolite, the concentration of which is approximately two-thirds that of zolmitriptan. 1B / 1D With potencies ranging from 2- to 6-fold that of the parent compound, metabolites may be responsible for a significant portion of the overall effects of zolmitriptan following administration.

[0013] The bioavailability of the orally disintegrating tablets is similar to that of conventional tablets, but T max The values ​​are (somewhat unexpectedly) greater: about 3 hours for the disintegrating tablets compared to 1.5 hours for the conventional tablets. Disintegrating tablets may also worsen the nausea that often accompanies a migraine attack.

[0014] Zolmitriptan has significant advantages over other triptans when other delivery routes and methods are considered. Zolmitriptan, naratriptan, and frovatriptan are the only 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).

[0015] In order to overcome the above-mentioned drawbacks of oral delivery, nasal administration of zolmitriptan has been attempted, and administration of 2.5 mg and 5.0 mg has been put to practical use. However, the T max however, the time to ingestion is only slightly improved (to approximately 1.5 hours) and most of the administered dose is swallowed and undergoes first-pass metabolism.

[0016] Other parenteral routes of administration, such as transdermal iontophoresis, patches, and liquid injections, have disadvantages such as skin irritation and scarring, pain, and the 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.

[0017] When migraine is treated with triptans, it has been shown that their effectiveness depends more on the rate of absorption than on the dose or plasma concentration. maxShorter absorption time provides better pain relief not only early in a migraine episode, but also, unexpectedly, later, when the slower absorbing treatments have 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, resulting in efficient delivery of the packaged dose. This, for example, reduces variability and improves reproducibility due to variability in patch wear time. [Prior art documents] [Non-patent literature]

[0018] [Non-Patent Document 1] Law et al, Triptans for acute cluster headache, Cochrane Database of Systematic Reviews (2013), Issue 7 [Non-Patent Document 2] 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 [Non-Patent Document 3] 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 [Non-Patent Document 4] 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 [Non-Patent Document 5] Neuropsychiatr Dis Treat. 2008 Feb; 4(1): 49-54 Summary of the Invention [Problem to be solved by the invention]

[0019] It is an object of the present invention to provide a method for rapidly obtaining therapeutic concentrations of zolmitriptan suitable for the treatment of migraine and cluster headaches. [Means for solving the problem]

[0020] Therefore, 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 formulations and does not have the issues associated with needles; (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 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%-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 may affect the efficacy of medications delivered nasally.

[0021] Thus, 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.

[0022] 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 suffer from the problems of needle phobia, needle disposal, and accidental punctures, cuts, and cross-contamination associated with needle-based delivery.

[0023] Furthermore, there is a need in the art for an effective method of administering triptans using transdermal delivery, which can precisely and uniformly coat the patch, and can avoid problems of residual drug on the array or manufacturing variability, such as unevenly coating the formulation on the patch or poor adhesion of the formulation to the patch. Although many attempts have been made to use transdermal microneedle patches to effectively deliver drugs, it has been difficult to achieve rapid release of drugs from the microneedle system and rapid treatment with the system, while optimizing and constructing effective microneedle shapes and sizes, and containing sufficient dosage of drug. Through intensive development, the applicants have constructed an effective triptan delivery system by addressing the issues of viscosity, drug loading, surface tension, microneedle shapes and sizes, and general manufacturing defects.

[0024] 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 present disclosure relates to administering a triptan, such as zolmitriptan, as an active pharmaceutical ingredient to a subject in need thereof. In particular, the present disclosure is directed to administering a therapeutically effective amount of the active ingredient transdermally or 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 quickly 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 the adhesive portion are attached by a retaining ring. These microprojections are adapted to be applied to the skin to deliver drugs to the bloodstream, or more specifically, to penetrate or pierce the stratum corneum to a depth sufficient to provide a therapeutically effective amount to the bloodstream. In one embodiment, the insertion of 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.

[0025] Preferably, the microprojections are provided with 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.

[0026] 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, more preferably for two years, after exposure to gamma or electron beam radiation.

[0027] 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 comprising: (a) a disposable microprojection having titanium microneedles coated with a pharmaceutical formulation and dried, 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 for the drug to be absorbed. In one embodiment, the delivery system comprises a patch comprising 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.

[0028] In another embodiment, the disclosure relates to a method of transdermally or intradermally administering a triptan to a patient in need thereof, the method comprising: (a) providing a transdermal patch adapted to deliver a triptan intradermally, the transdermal patch comprising a microprojection portion having a plurality of microprojections adapted to pierce or pierce the stratum corneum of a patient, the microprojections having a biocompatible coating disposed over a portion or all of the microprojections, the coating comprising a therapeutically effective amount of the triptan; and (b) applying the microprojection portion of the device to the patient's skin, wherein the plurality of microprojections 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 greater than about 50%, or greater than 60%, or greater than 65%, or greater than 75%, or greater than 80%, or greater than 85%, or greater than 90%, or greater than 95% of this dose reaching the patient's bloodstream after administration.

[0029] The present disclosure encompasses a method of treating migraine or cluster headache in a human patient in need thereof, comprising administering a therapeutically effective amount of zolmitriptan transdermally or intradermally, which administration results in a therapeutic blood concentration of zolmitriptan more rapidly than a therapeutically effective amount administered orally, intranasally, sublingually, or iontophoretically. In one embodiment, the present method of treating or alleviating migraine or cluster headache in a patient includes administering a therapeutically effective amount of zolmitriptan transdermally or intradermally, which ... max In another embodiment, the method provides a rapid phasic response of zolmitriptan to a maximum plasma concentration (C max ) is less than 50ng / ml.

[0030] In one embodiment, the microneedle patch coated with zolmitriptan disclosed herein is applied during a migraine or cluster headache attack, and then obtains rapid plasma concentration.These patches eliminate pain and troublesome migraine or cluster headache symptoms at least 45 minutes after administration.The migraine symptoms that are most troublesome to patients are generally selected from light sensitivity, especially bright light (photophobia), sound sensitivity, especially loud sound (phonophobia), and nausea, in addition to pain, but migraine may also be accompanied by vomiting, smell sensitivity, aura, vision changes, numbness, tingling, weakness, dizziness, dizziness or vertigo, eyelid edema, lack of concentration, fatigue, diarrhea, constipation, mood swings, hyperphagia, hives, and / or fever. Common symptoms of cluster headaches include severe pain on one side of the head and 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.

[0031] Further embodiments of the devices, compositions, methods, etc. will become apparent from the following description, drawings, examples, and claims. As can be understood from the above 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

[0032] This application contains at least one drawing executed in color. Copies of this publication with color drawing(s) will be provided by the Office upon request and payment of the appropriate fee.

[0033] 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, 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 about 1 minute. [4] 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 said application, max is about 5 ng / ml to about 25 ng / ml, and AUC 0時間~2時間 The system according to [1], wherein the concentration of IL-1 in the blood is about 5 ng / ml·hour to about 20 ng / ml·hour. [5] determining a therapeutically effective serum concentration, T, of the patient when the system is applied to a selected area of ​​the patient's skin; max occurs within about 30 minutes of said application. [6] The viscosity of the formulation coating before drying is about 150 cP to about 350 cP and the surface tension is about 50 mNm -1 ~about 72mNm -1 The system according to [1], [7] The system described in [6], wherein the coating covers about 20% to about 70% of the length of each microprojection. [8] The system described in [7], wherein the coating covers about 30% to about 60% of the length of each microprojection. [9] The viscosity of the formulation coating before drying is about 200 cP to about 300 cP and the surface tension is about 55 mNm -1~about 65mNm -1 The system according to [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. Effect of the Invention

[0034] The present invention may provide a method for rapidly achieving therapeutic concentrations of zolmitriptan suitable for the treatment of migraine and cluster headaches. [Brief description of the drawings]

[0035] 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: [Figure 1] 1A-1B are scanning electron micrographs (SEM) of the MF1663 array design coated with 1.9 mg of zolmitriptan. [Diagram 2] 2A and 2B are diagrams showing 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. [Diagram 3] 3A-3B show a patch assembly comprised of a patch assembled into a retaining ring, (A) a side view of the patch assembly, and (B) an exploded view of the patch assembly. [Figure 4] 4A-4B show how to remove a 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. [Diagram 5]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. [Figure 6] 6A-6C are diagrams showing in vitro release profiles of 1.9 mg patches of ZP-zolmitriptan M207. (A) Top left: In vitro release profile of 1.9 mg patch of ZP-zolmitriptan M207 (L / N0164004) irradiated with electron beam and stored at room temperature for 10 months. (B) Top right: In vitro release profile of 1.9 mg patch of ZP-zolmitriptan M207 (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 1.9 mg patch of ZP-zolmitriptan M207 (L / N0203149-IR) irradiated with electron beam and stored at 40° C. and 75% relative humidity for 10 months. [Figure 7] FIG. 7 is a line graph showing the time course (0-24 hours) of mean plasma concentrations of zolmitriptan and sumatriptan in normal human volunteers, where treatment A is the M207 system (0.48 mg), treatment B is the M207 system (0.48 mg x 2), treatment C is the M207 system (1.9 mg), treatment D is zolmitriptan (2.5 mg oral tablet), treatment E is sumatriptan (6.0 mg SC, using an autoinjector pen), treatment F is the zolmitriptan system (1.9 mg x 2), and treatment G is the zolmitriptan system (3.8 mg). For sumatriptan, the graphs are scaled to 6 / 90 to show the sumatriptan concentration-time profile compared to the other treatments. [Figure 8]Figure 8 is a line graph showing the mean plasma concentrations of zolmitriptan and sumatriptan over time (0-2 hours) for 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), and treatment G, zolmitriptan system (3.8 mg). In this graph, sumatriptan is scaled to 6 / 90 to show the sumatriptan concentration-time profile compared to the other treatments. [Figure 9] FIG. 9 is a line graph showing the Cmax dose linearity of M207 (excluding 3.8 mg) for single and multiple patches. [Figure 10] FIG. 10 is a line graph showing the AUCt dose linearity of M207 (excluding 3.8 mg) for single and multiple patches. [Figure 11] FIG. 11 is a line graph of the mean plasma zolmitriptan concentrations in women from 0 hours to 2 hours. [Figure 12] FIG. 12 is a line graph of mean plasma zolmitriptan concentrations in men from 0 hours to 2 hours. [Figure 13] FIG. 13 is a line graph of mean plasma N-desmethylzolmitriptan concentrations from 0 hours to 2 hours. [Figure 14] FIG. 14 is a line graph of mean plasma N-desmethylzolmitriptan concentrations from 0 hours to 24 hours. [Figure 15] FIG. 15 is a line graph showing the Cmax dose linearity of M207 for single and multiple patches. [Figure 16] FIG. 16 is a line graph showing the AUCt dose linearity of M207 for single and multiple patches. [Figure 17] FIG. 17 is a line graph showing the AUCinf dose linearity of M207 for single and multiple patches. [Figure 18]FIG. 18 is a line graph showing the AUCinf dose linearity of M207 for single and multiple patches (excluding the 3.8 mg patch). [Figure 19] FIG. 19 is a line graph showing the Cmax dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. [Figure 20] FIG. 20 is a line graph showing the AUCt dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. [Figure 21] FIG. 21 is a line graph showing the AUCinf dose linearity of N-desmethylzolmitriptan as a function of M207 dose for single and multiple patches. [Figure 22] FIG. 22 is a line graph showing the Cmax dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. [Diagram 23] FIG. 23 is a line graph showing the AUCt dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. [Figure 24] FIG. 24 is a line graph showing the AUCinf dose linearity of N-desmethylzolmitriptan as a function of M207 dose (excluding 3.8 mg) for single and multiple patches. [Diagram 25] FIG. 25 is a graphical comparison of the "Percentage of Pain Relief (%)" 1 hour, 2 hours, and 4 hours after treatment. [Figure 26] FIG. 26 is a graphical comparison of the % Pain Relief at 1, 2, and 4 hours after treatment. [Figure 27] FIG. 27 is a graphical comparison of the "Percentage of Pain Relief (%)" 1, 2, and 4 hours after treatment. [Figure 28] FIG. 28 is a graphical comparison of the % Pain Relief at 1, 2, and 4 hours after treatment. [Figure 29] FIG. 29 is a graphical comparison of the percentage of subjects who were pain free up to 4 hours after treatment. [Diagram 30] FIG. 30 is a graphical representation of average flux results from ex vivo human skin samples. [Diagram 31] FIG. 31 illustrates the interaction of the microprojections with the skin, specifically, how the microprojections penetrate the stratum corneum for effective drug delivery. [Diagram 32] 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] 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 in this specification, whether supra or sub, are incorporated herein by reference in their entirety.

[0037] I. Introduction Applicant has 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. Applicant has 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.

[0038] II. Definition Unless otherwise defined, all terms and phrases used herein include the meaning that such terms and phrases have 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.

[0039] 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 indicated 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 in conjunction with numerical values ​​shall 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 ranges 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 recitation of ranges 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 individually set forth herein.

[0040] The term "amorphous" refers to a non-crystalline solid, i.e., a solid that does not possess the long-range order characteristic of a crystal.

[0041] 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 versus 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.

[0042] The term "biocompatible coating," as used herein, means and includes a coating formed from a "coating formulation" that has sufficient adhesion properties and has no (or minimal) adverse interactions with biologically active agents (also known as active pharmaceutical ingredients, therapeutic agents, or drugs).

[0043] 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 that compare pharmacokinetic parameters for the two compositions. Parameters often used in bioequivalence studies are T max , C max , AUC 0~inf , AUC 0~t In this context, substantial bioequivalence of two compositions or two formulations is determined by the AUC and C max This is confirmed by a 90% confidence interval (CI) of 0.80 to 1.25.

[0044] The term "cluster" as used herein means a series of recurring cluster headaches. Clusters usually last from one week to one year, although chronic cluster headaches last longer than one year. A cluster is considered ended by at least one month of remission.

[0045] The term "cluster headache" as used herein means a condition characterized by repeated 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"), and usually occurs on the same side, although which side 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.

[0046] 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.

[0047] The term "degradation" as used herein means a decrease in the purity of a biological agent from its original point in time.

[0048] The term "desiccant" as used herein means an agent, usually a chemical agent, that absorbs water.

[0049] The term "degrade" as used herein means that the quality, properties, or effectiveness of a biologically active agent is diminished or impaired.

[0050] 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 thus application of an electric current, induces or increases the transport of the drug, thereby delivering or facilitating the delivery of the drug, or, in the case of "reverse" electrotransport, sampling or facilitating the sampling of the drug. Electrotransport of drugs into or out of the body can be accomplished in a variety of ways.

[0051] 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 excretion or elimination after absorption is complete and distribution reaches 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. Furthermore, 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.

[0052] The term "headache scale" as used herein refers to 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 receiving a headache score of 3, moderate pain receiving a score of 2, mild pain receiving a score of 1, and no pain (also referred to as "pain absence") receiving a score of 0.

[0053] 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 a 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 an external energy source, such as electricity (e.g., iontophoresis) and ultrasound (e.g., phonophoresis).

[0054] The term "intradermal flux," as used herein, refers to the intradermal delivery rate of a drug.

[0055] Terms such as "microprojection" or "microneedle array" as used herein generally refer to a group of microprojections, preferably arranged in an array, that includes a plurality of microprojections for penetrating or piercing the stratum corneum.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 from the sheet surface to create a three-dimensional shape.Alternatively, microprojections can be formed from other materials, including plastics or polymers such as polyetheretherketone (PEEK).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 include 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, 7,097, 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.

[0056] 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, more particularly human, skin, into the stratum corneum and / or through the stratum corneum into the underlying epidermis or epidermis and dermis 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 various shapes, such as needles, blades, pins, perforations, and combinations thereof.

[0057] The terms "minimize" or "mitigate" as used herein mean to reduce.

[0058] "Very bothersome other symptoms" means symptoms that are very bothersome to the patient in addition to pain, usually migraine symptoms. Preferably, the very bothersome other symptoms are identified by the patient at the start of the clinical trial. The very bothersome other symptoms are usually selected from nausea, photophobia, and phonophobia.

[0059] "Absence of other symptoms that are very bothersome" means that the patient reports that there are no other symptoms that are very bothersome at one or more predetermined time points after administration of the drug. 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.

[0060] "Absolution of nausea" means that the patient reports no nausea for a predefined period of time after drug administration.

[0061] "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.

[0062] "Pain relief" means that the patient reports no headache (headache score = 0) at one or more pre-determined 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.

[0063] "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.

[0064] Phonophobia refers to the fear or aversion of sound, especially loud sounds.

[0065] "Relief of phonophobia" means that the patient reports an absence of phonophobia for a predefined period of time after drug administration.

[0066] "Photophobia" means heightened, often painful, sensitivity to light, especially bright light.

[0067] "Absence of photophobia" means that the patient reports an absence of photophobia for a predefined period of time after drug administration.

[0068] "Partial AUC" refers to the area under the drug concentration-time curve (AUC) calculated using linear trapezoidal addition method during a particular time period, e.g., AUC(0 hr-1 hr), AUC(0 hr-2 hr), AUC(0 hr-4 hr), AUC(0 hr-6 hr), AUC(0 hr-8 hr), etc.

[0069] Drug "release rate", as used herein, refers to 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 the dosage form or pharmaceutical composition per unit time, measured under the right conditions and in the right fluid.

[0070] 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, such as, for example, 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.

[0071] The terms "subject" and "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, a human.

[0072] 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.

[0073] The term "transdermal," as used herein, refers to the delivery of agents into and / or through the skin for local or systemic therapy.

[0074] The term "transdermal flux," as used herein, refers to the rate of transdermal delivery.

[0075] "T max " The term "C max i.e., the time until the maximum plasma concentration of the biologically active agent is reached.

[0076] It will be understood that the term "package" or "packaging" also includes the meaning of "storage" or "storing."

[0077] The term "zolmitriptan" includes, but is not limited to, zolmitriptan salts, simple derivatives of zolmitriptan, and closely related molecules.

[0078] III. Intradermal Delivery Systems 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 rigid 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 the 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.

[0079] More specifically, the patch is approximately 3 cm 2 ~6cm 2The patch may comprise a titanium microneedle array of about 200-350 micrometers in length, coated with a hydrophilic formulation of a suitable drug, and attached to an adhesive surface. The maximum amount of active drug that can be coated onto the microneedle array of the patch will vary depending on the active portion of the drug formulation, the weight of the excipients in the drug formulation, and the coatable surface area of ​​the microneedle array. For example, a microneedle array of about 1 cm 2 , 2cm 2 , 3cm 2 , 4cm 2 , 5cm 2 , and 6 cm 2 A patch with a microneedle array of 1000 μm to 1500 μm may be used. The patch is applied in conjunction with a handheld applicator that presses the microneedles into the skin to a substantially uniform depth in close proximity to the capillary bed for each application to dissolve and absorb the drug coating, but not to the nerve endings in the skin. A typical patch wear time is about 15 to 45 minutes or less to reduce the possibility of skin irritation. A nominal energy of the applicator of about 0.20 to 0.60 joules generally provides a good balance between the perception of impact and the penetration of the array. The actual kinetic energy at the moment of impact is likely to be less than these nominal values ​​due to the applicator spring not fully extending, energy losses due to the patch separating from the retaining ring, and other losses, which may total about 25% of the nominal amount. A. Array Design

[0080] Various variables influence the type of array utilized for a particular active agent. For example, different shapes (e.g., arrowhead, hook, cone, or Washington Monument-like shapes (FIGS. 1A-1B) as shown in FIG. 31) can provide high drug loading, while the length of the microprojections can be increased to increase the driving force for penetration. The stratum corneum is approximately 10 μm to 40 μm thick, and the microprojections must be of the appropriate size, thickness, and shape to penetrate through the stratum corneum and provide drug delivery. In FIG. 31, although not drawn to scale, it can be seen that the array interacts 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. Furthermore, if the thickness of the projections increases with the coating, a greater penetration force is required, but the projections can be lengthened to 1 cm. 2 This can be offset by lowering the density of the protrusions.

[0081] 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 The drug delivery techniques include those described in US Patent Publication 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 US Patent 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) and 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-based 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 modified shapes adapted to support and / or increase the coating volume, increasing the surface area and allowing for 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.

[0082] The present disclosure therefore encompasses patches and microneedle arrays having the following features: Patch size: Approx. 1cm 2 ~20cm 2 , or about 2 cm 2 ~15cm 2 , or about 4 cm 2 ~11cm 2 , or about 5 cm 2 , or about 10 cm 2 . Board size: approx. 0.5cm 2 ~10cm 2 , or about 2 cm 2 ~8cm 2 , or about 3 cm 2 ~6cm 2 , or about 3 cm 2 , or about 3.13 cm 2 , or about 6 cm 2 . Array size: approx. 0.5cm 2 ~10cm 2 , or about 2 cm 2 ~8cm 2 , or about 2.5 cm 2 ~6cm 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 / cm 2 ): at least about 10 microprojections / cm 2 or about 200 to about 2000 microprojections / cm 2or about 500 to about 1000 microprojections / cm 2 or about 650 to 800 microprojections / cm 2 or approximately 725 microprojections / cm 2 . 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 by 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. Microprotrusion 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: about 1 micrometer to about 500 micrometers, or about 5 micrometers to 300 micrometers, or about 10 micrometers to 100 micrometers, or about 10 micrometers to 50 micrometers, or about 20 micrometers to 30 micrometers, or about 25 micrometers. Tip angle: Approximately 10 degrees to 70 degrees, or approximately 20 degrees to 60 degrees, or approximately 30 degrees to 50 degrees, or approximately 35 degrees to 45 degrees, or approximately 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 inactive 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 inactive 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: about 100 μm to about 500 μm, or about 200 μm to about 350 μm, or 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.

[0083] A particularly preferred embodiment is a patch having an area of ​​about 5 cm 2 is about 3.1 cm 2 The microprojections are attached to a titanium substrate with an area of ​​about 1987 microprojections and a thickness of about 25 μm. The substrate has about 725 microprojections / cm 2 With a density of approx. 2.74 cm 2The dry formulation contained in each microprojection may have a shape roughly like an American football with a tapered thickness from a maximum of about 270 μm, and 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.

[0084] FIG. 32 shows the shape of the microprojections before bending (molding) in a preferred embodiment. Array molding is a process of bending individual microprojections at an appropriate angle relative to the substrate surface. The array is first placed on a former with a mold that mimics the microprojections. An elastomer molding disk is placed on top of the array and pressure is applied to the mold of the former. The elastomer enters the mold and bends the microprojections to the desired angle. The use of an elastomer has the advantage that the molding 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.

[0085] Another preferred embodiment is a patch having an area of ​​about 5 cm 2 and is about 6 cm 2 The microprojections are attached to a titanium substrate with an area of ​​about 100 μm and a thickness of about 25 μm. The substrate has about 4000 microprojections with a density of about 725 microprojections / cm. 2 With a density of about 5.5 cm 2Each microprojection is approximately football shaped with a tapered thickness of about 270 μm and contains 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. 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.

[0086] The proper combination of size, length, and density that results in the desired penetration can vary and depend on the drug, the dose of drug, 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

[0087] As shown in Figures 4A-4B and 5A-5E, the intradermal drug delivery system of the present disclosure can further include an impingement applicator having a body and a piston movable within the body, the surface of the piston pressing the patch against the skin so that the microprotrusions pierce the stratum corneum. The applicator can be moved 1 cm within 10 milliseconds or less. 2 At least 0.05 Joules per second, or 1 cm within 10 milliseconds 2 Approximately 0.26 Joules per second, or 1 cm in less than 10 milliseconds 2 The microneedle array is adapted to press against the stratum corneum with a collision energy density of about 0.52 Joules per impact.

[0088] As shown in Figures 2A-2B, the intradermal delivery system comprises a patch with an adhesive surface on one side and a shiny metal surface on the other side comprised 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 is capable of dispersing 1 cm within 10 milliseconds or less. 2 The patch is pressed against the skin with an impact energy density of 0.26 Joules per impact. 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 the impact adapter and removably attach the patch to the applicator. The retaining ring structure may include an inner ring and an outer ring that 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 microneedle array attached. As shown, once the retaining ring and impact applicator are connected, the user can unlock the impact applicator by turning the applicator cap. Figure 5C shows that the user can then press the applicator downwards against 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 impingement applicator, allowing the impingement applicator to be reused for subsequent administrations with additional patch assemblies and potentially for other active ingredients or medical conditions.

[0089] In another embodiment, the patch and applicator are provided as a single integral 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 less complicated, smaller, lighter, and easier to use system at a slightly higher cost per dose.

[0090] The present disclosure may also be used in conjunction with a variety of active transdermal systems (other than the passive, manual intradermal delivery devices described herein), and the present disclosure is not limited in any way in this regard.

[0091] 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 glucose sampling), 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, which involves the passage of a drug through pores formed by applying an electric pulse, i.e., a high-voltage pulse, to a membrane. In many cases, one or more of the described processes may be occurring simultaneously to various 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.

[0092] Additionally, any other transport enhancement method may be used in conjunction with the disclosure herein, including but not limited to chemiosmotic enhancement, laser ablation, heat, ultrasound, or piezoelectric elements.

[0093] IV. Active Agents and Biocompatible Coatings The coating formulation applied to the microprotrusions to form a solid coating is a liquid, preferably an aqueous formulation, containing 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.

[0094] 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, tricarballylate, malonate, adipate, citraconate, glutarate, itaconate, mesaconicate, 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 salts.

[0095] 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 the coating formulation wicking 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% w / w 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% w / w 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 of zolmitriptan base and about 11% w / w of tartaric acid. In some embodiments, the acid is one of tartaric acid, citric acid, succinic acid, malic acid, or maleic acid, and is present 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 of active agent, 15% w / w of acid, and 40% w / w of water.

[0096] Surfactants may be included in the coating formulation. Suitable surfactants for adding to the coating formulation include, but are not limited to, polysorbate 20 and polysorbate 80. Surfactants are commonly used as permeation enhancers to enhance drug delivery. However, applicants have found that surfactants cause the coating formulation to undulate, which exhibits non-uniform film and is highly unfavorable. Applicants have found that the use of the claimed invention, particularly the claimed zolmitriptan transdermal delivery patch, can eliminate the need to use surfactants and other permeation enhancers. Furthermore, applicants have surprisingly found that, despite the absence of surfactants, the microneedle coating is free of wicking and the coating is firmly attached to the microprojections during the manufacturing process of the microneedle array.

[0097] 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.

[0098] 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.

[0099] 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. [Table 1]

[0100] The present disclosure contemplates that sumatriptan or other triptans may be substituted for zolmitriptan in amounts or ratios similar to those set forth above.

[0101] The liquid coating formulation according to the present disclosure generally contains less than 5% water, preferably less than 3% water, and can coat the microneedles with consistent and correct amount and morphology, thus resulting in a stable solid (dry) formulation. The liquid formulation is applied to the microneedle array and its microprojection tips using an industrial coating device that can precisely control the depth of the microprojection tips that 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, S. C.; 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.

[0102] 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 before 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.

[0103] After application to the microprojections, the average thickness of the coating formulation, as measured from the microprojection surface, can 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.

[0104] 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 cm 2 and containing a dose of about 3.8 mg of zolmitriptan or an array size of about 3 cm 2 and containing a dose of about 3.8 mg or an array size of about 3 cm 2and contains a dose of about 1.9 mg. The amount of zolmitriptan or a similar active agent per microprojection can 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 microprojection are greatly related to the drug loading capacity and drug delivery efficiency.

[0105] It is important to note that the formulations of the present disclosure do not rely on penetration enhancers to facilitate the absorption of active agents 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 or 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.

[0106] The biologically active agent formulation is generally prepared as a solid coating by drying the coating formulation on the microprojections as described in US Patent Application Publication No. 2002 / 0128599. The coating formulation is usually an aqueous formulation. During the drying process, almost all volatile materials, including water, are removed, but the final solid coating may still contain about 1% water w / w, or about 2% water w / w, or about 3% water w / w, or about 4% water w / w, or about 5% water w / w. 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 drug 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. When excipients are added, the total mass of the solid coating may be less than about 15 mg per unit dose.

[0107] 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 a dead volume in addition to the assembly, which is at least 3 mL of the 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 is typically 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.

[0108] 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 points 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.

[0109] A further coating method includes 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.

[0110] A further coating method that can be used within the scope of the present invention is spray coating. Spray coating can include forming an aerosol suspension of the coating composition. In one embodiment, the aerosol suspension having a droplet size of about 10 picoliters to 200 picoliters is sprayed onto the microprojections and then dried.

[0111] 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 precise metered liquid dispensing devices are disclosed in U.S. Patent Nos. 5,916,524, 5,743,960, 5,741,554, and 5,738,728, which are fully incorporated herein by reference.

[0112] The microprojection coating formulation or solution can also be applied using inkjet technology with known solenoid valve dispensers, optional liquid transport means, 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.

[0113] 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 the microprojections per unit area of ​​the sheet, the viscosity, the 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.

[0114] The coating is applied to the microneedles protruding from the base or street of the microneedle array. The coating is applied to the tip of the microneedle and is not intended to cover the surface of the microneedle and the microneedle array. This results in a reduced amount of drug per transdermal patch. This is advantageous in terms of FDA guidelines regarding the risk of residual drug 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 into the skin per unit area without using excess drug in the coating.

[0115] After coating, the coating formulation is dried on the microprojections using various 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.

[0116] 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 thin film with a controlled thickness of about 270 μm. Further information regarding the coating process can be found in U.S. Patent 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 times it is dipped into (passed through) the drug film.

[0117] During the drying process, problems can arise with uniformly coating the microprojections with a controlled, uniform thickness. One common challenge 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, which 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 challenge in the drying process creates problems with 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 they have 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 viscosity of about 50 mNm -1 ~about 72mNm -1 , preferably about 55 mNm -1 ~about 65mNm -1 , more preferably about 62.5 mNm -1 It has been found that dripping can be avoided by maintaining a surface tension of 0.01 mm to 0.05 mm. While avoiding teardrop formation, a sufficient volume of 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.

[0118] 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.

[0119] In one embodiment, 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. Furthermore, a formulation 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 also be a respirable fine particle 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 for producing 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 for producing 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.

[0120] 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 therapeutic agents stabilized in accordance with the compositions and formulation and delivery methods of the present invention render the therapeutic agents useful in a broader range of potential formulations and with a wider variety of therapeutic agent delivery means.

[0121] 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 within a chamber or package including a foil layer.

[0122] The desiccant may be any known to those skilled 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 and placed in a package that includes a foil layer under an inert atmosphere.

[0123] In another aspect, the active agent formulation is packaged in a chamber that comprises a foil layer after the formulation is coated on the microprojection array delivery device.In this embodiment, a desiccant is placed in the chamber, and is preferably attached to a chamber cover that comprises a foil layer, and the chamber is purged with dry nitrogen or other inert gas such as noble gas, and then the foil chamber that contains the delivery device is sealed with the foil cover.Any suitable inert gas can be used herein to create a dry inert atmosphere.

[0124] In one embodiment, the composition of zolmitriptan suitable for intradermal delivery and the method of formulating and delivering zolmitriptan utilizes 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.

[0125] Typically, in the described embodiments of the invention, the inert atmosphere has a substantially zero water content. For example, nitrogen gas having 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 content or oxygen content. The reduced pressure ranges from about 0.01 atm to about 0.3 atm.

[0126] 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 having a plurality of microprojections adapted to pierce the stratum corneum of a patient, (b) a hydrogel formulation comprising zolmitriptan, the hydrogel formulation in communication with the microprojections, and (c) packaging adapted to control a sealed environmental condition around the microprojections that is purged with an inert gas, the sealed packaging being exposed to radiation to sterilize the microprojections.

[0127] In another embodiment, there is an intradermal delivery system adapted to deliver zolmitriptan, the intradermal delivery system including: (a) a microprojection portion having a plurality of microprojections adapted to pierce the stratum corneum of a patient; (b) a solid membrane disposed proximate to the microprojections, the solid membrane being formed by casting a liquid formulation including 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.

[0128] The present disclosure also relates to a method of terminally sterilizing a patch assembly adapted to deliver zolmitriptan, the method 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 is 10. -6 ~10 -5 The method may further include 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, wherein the radiation is sufficient to achieve a desired sterility assurance level.

[0129] 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, followed by 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.

[0130] The step of exposing the microprojections to radiation can be carried out at about -78.5°C to 25°C, although the microprojections may 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.

[0131] As described herein, applicants have developed a zolmitriptan formulation which, when coated onto the microneedle portions 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.

[0132] 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.

[0133] In one embodiment, a method of manufacturing a patch assembly for an intradermal delivery system adapted for delivery of zolmitriptan includes the steps of 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 on a surface of the microneedle portion, the coating being formed and coated from a coating formulation comprising zolmitriptan; sealing the microneedle portion with a desiccant in packaging that is purged with nitrogen and adapted to control the environmental conditions around the microneedle; 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.

[0134] 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) generating 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.

[0135] 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 can 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.

[0136] A method for terminally sterilizing a transdermal device adapted for delivery of zolmitriptan is included herein, comprising: providing a microprojection having a plurality of microprojections adapted to pierce or pierce the stratum corneum of a patient, the microprojections being provided with a biocompatible coating on the microprojection surface, the coating being formed and coated with 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 embodiment of the method further comprises sealing the microprojections in a packaging adapted to control the environmental conditions around the microprojections. In one embodiment, the packaging comprises a foil pouch. A further embodiment of the method further comprises sealing a desiccant in the packaging. The method also comprises attaching the microprojections to a pre-dried retaining ring before sealing the microprojections in the packaging. A further embodiment of the method further comprises purging the packaging with an inert gas before sealing the packaging. In one embodiment, the inert gas comprises nitrogen.

[0137] 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, the absorption of zolmitriptan administered intradermally using the disclosed system is C max is less than 50 mg / mL, and T max In another embodiment, the plasma zolmitriptan AUC during the first 2 hours is greater than that seen after oral administration, but is about 2 to 30 minutes. (0時間~24時間) is less than that seen after oral dosing.

[0138] In another aspect, absorption of zolmitriptan increases the maximum plasma zolmitriptan level, but the N-desmethylzolmitriptan product (AUC 0時間~24時間) is reduced, reducing the possibility of metabolic product accumulation. Intradermal administration of triptans, including zolmitriptan, avoids the first-pass hepatic metabolism seen with oral administration, resulting in increased bioavailability. Specifically, the 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 after application (e.g., 1.5 hours, 2 hours, 5 hours, 10 hours). Furthermore, although zolmitriptan plasma levels may be increased, N-desmethylzolmitriptan products are reduced compared to those that would result from the same amount of zolmitriptan administered orally. Thus, there is less possibility of metabolic product accumulation. Meanwhile, 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. Furthermore, the apparent half-life of zolmitriptan is reduced compared to oral administration, reducing the duration of side effects.

[0139] 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.

[0140] Further, the intradermally delivered biocompatible coating contains 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 increases plasma C maxis 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.

[0141] Intradermal delivery of zolmitriptan also increased plasma T after a single application. max is 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.

[0142] In one embodiment, the T of zolmitriptan administered intradermally using the system of the present invention max is at least about 2 hours before the 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.

[0143] In another embodiment, the T of zolmitriptan administered intradermally using the system of the present invention is maxmay be administered at least about 3 hours prior to ZOMIG® (zolmitriptan) orally disintegrating tablet, or at least about 2.5 hours prior to such tablet, or at least about 2.0 hours prior to such tablet, or at least about 1.5 hours prior to such tablet, or at least about 1.0 hour prior to such tablet, or at least about 0.5 hour prior to such tablet.

[0144] In a further embodiment, the T of zolmitriptan administered intradermally using the system of the present invention is max is about 3 hours or more prior to 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 hours or more prior to such spray.

[0145] In another embodiment, the excretion rate (t 1 / 2 ) 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. 1 / 2 ) is about three times the rate of conventional zolmitriptan tablets, or about twice the rate of conventional zolmitriptan tablets.

[0146] In a further embodiment, the C of zolmitriptan administered intradermally using the system of the present invention is max The C of conventional oral zolmitriptan tablets 2.5 mg max about 1 to 8 times, or about 1.5 to 7 times, or about 2 to 6 times, or about 3 to 5 times, or about 4 times higher.

[0147] In addition, the maximum exposure (C max ) is about 2- to about 5-fold higher for intradermal zolmitriptan compared to oral tablets. In a further embodiment, the mean maximum exposure (C max) is about 1.0 mg / mL to about 40.0 mg / mL, or about 5.0 mg / mL to about 35.0 mg / mL, or about 10.0 mg / mL to about 30.0 mg / mL, or about 15.0 mg / mL to about 25.0 mg / mL, or about 20.0 mg / mL to about 30.0 mg / mL, or about 25 mg / mL.

[0148] Additionally, compared to conventional oral zolmitriptan at a dose of 2.5 mg, the intradermal zolmitriptan of the present invention at a dose of about 0.5 mg to about 4.0 mg 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.

[0149] Finally, the present invention encompasses formulations and devices that are bioequivalent to the M207 intradermal delivery system described herein. Thus, the present disclosure provides that bioequivalence is achieved with (i) a 90% confidence interval (CI) for AUC of 0.80 to 1.25, and (ii) a C max This covers products with a 90% CI of 0.80 to 1.25.

[0150] VII. Treatment method The drug-device combination of the present invention can be used to treat a variety of diseases and conditions, including migraine and cluster headache. In one embodiment of the present invention, a method for treating or alleviating migraine or cluster headache to an individual in need thereof comprises administering a therapeutically effective amount of a zolmitriptan-based drug, and increasing plasma C by absorption of the zolmitriptan-based drug. maxThere are methods of treatment or palliative care in which the pulmonary circulation is less than 50 ng / mL. Doses include about 0.2 mg to about 10 mg of zolmitriptan. The doses may be 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mg of zolmitriptan. Doses also include single patch doses of 1.0 mg, 1.9 mg, or 3.8 mg, or two patch doses of 1.9 mg. These doses can be delivered using the patches 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.

[0151] In certain embodiments, the method of treating migraine or cluster headache described herein provides improvements in the following treatment endpoints: absence of migraine pain 1 hour, 2 hours, or 4 hours after administration, absence of cluster headache pain 15 minutes or 30 minutes after administration, absence of other very bothersome migraine symptoms 1 hour or 2 hours after administration, absence of other very bothersome cluster headache symptoms previously identified by the patient 15 minutes or 30 minutes after administration, migraine pain relief 1 hour, 2 hours, or 4 hours, cluster headache pain relief 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, pain relief at 30 minutes, pain relief at 24 hours, and pain relief at 48 hours. Additionally, improvements are provided for treated patients who require rescue administration. Continued improvements have been seen with routine sequential testing procedures with regard to pain, other symptoms that are very bothersome, photophobia, phonophobia, nausea, and other bothersome symptoms.

[0152] 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.

[0153] As seen in Table 45, the method described herein demonstrates that one embodiment of the claimed invention provides a significant improvement over zolmitriptan tablets 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.

[0154] 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% pain relief, respectively, just 1 hour after administration. 65%, 68%, and 80% experienced pain relief, respectively, 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 graphically depicted in FIG. 26.

[0155] Tables 47 and 48 show that the claimed invention shows a significant improvement in reducing or diminishing 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 Figure 28. In another aspect, plasma T max The time is about 2 to 30 minutes. In one embodiment, the zolmitriptan-based drug is administered transdermally or intradermally. Alternatively, the route of administration of the zolmitriptan-based drug is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal, or sublingual.

[0156] In another embodiment, there is provided a method for treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based drug, wherein the plasma zolmitriptan AUC in the first 2 hours is greater than the plasma zolmitriptan AUC following oral administration of an equivalent dose of zolmitriptan, but is greater than the plasma zolmitriptan AUC following intradermal administration of a therapeutically effective amount of the zolmitriptan-based drug. 0~inf is the plasma zolmitriptan AUC observed after oral administration of equal doses of zolmitriptan. 0~inf 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.

[0157] In another embodiment, there is a method for treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based drug, which 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, the administration of the zolmitriptan-based drug is transdermal or intradermal. In one aspect of this embodiment, the administration route of the zolmitriptan-based drug is intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal, or sublingual.

[0158] In another embodiment, there is a method for treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based drug, which reduces the apparent half-life of zolmitriptan compared to an equivalent dose of zolmitriptan administered orally, thus offering the potential for reducing the duration of side effects. 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, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal, or sublingual.

[0159] 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.

[0160] In one aspect of this embodiment, the zolmitriptan-based drug administered intradermally results in a pharmacokinetic profile similar to that obtained with subcutaneous administration of an equivalent dose of the sumatriptan-based drug administered intradermally.

[0161] In one embodiment of the method of administering zolmitriptan, administration of zolmitriptan, despite faster absorption, does not have a greater effect on blood pressure than that seen with oral zolmitriptan.

[0162] In one embodiment, a method for treating or alleviating migraine or cluster headache in an individual in need thereof is provided, comprising administering a therapeutically effective amount of a zolmitriptan-based drug, comprising administering to the individual a dose that is sufficient to achieve a peak plasma concentration (T max ) is the time to reach T max or equivalent to T maxIn 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 zolmitriptan-based drug administered intradermally reduces C max is less than 50 ng / mL. EXAMPLES

[0163] VIII. Examples The following examples are included to demonstrate certain specific 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 interpreted as illustrative and not in a limiting sense.

[0164] 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", EP0914178B1, 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 (2 mL volume) to produce a drug coated formulation film of controlled thickness. The method is substantially similar to that described in JC Trautman et al., "Method and apparatus for coating skin piercing microprojections", U.S. Pat. No. 6,855,372; JC Trautman et al., "Method and apparatus for coating skin piercing microprojections", U.S. Pat. No. 7,435,299, which is incorporated herein by reference in its entirety. The microprojections are immersed in the film. The amount of coating is controlled by the number of dips (passes) through the drug film as well as the drug coating formulation properties. The time between each dip was a few seconds, which was sufficient to allow the coated liquid formulation to dry under ambient conditions. A film temperature of 1°C was maintained by circulating a cooling liquid through the reservoir. Since the reservoir is open to the ambient air, the coating apparatus was placed in a dew point control system. 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 the patch assembly.The patch assemblies were packaged in aluminum pouches (Mangar, New Britain, PA, USA), purged with dry nitrogen, and heat sealed using a Multivac heat sealer (model C400) (Multivac, Kansas City, MO, USA).

[0165] Example 1 - Zolmitriptan coated formulations, characterization and 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. [Table 2]

[0166] Zolmitriptan exhibits good solubility in a variety of acids. It was observed that the rheological behavior of zolmitriptan solutions was affected by the counter ions 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 were at pH 5.2, 4.3 and 6.2, respectively, at the pKa of the acid. 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 effect, tartaric acid was selected as the counter ion for pH adjustment.

[0167] 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.

[0168] 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.

[0169] 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 arrays was performed at ambient temperature using a roller drum rotating at 50 rpm in a drug formulation reservoir (volume 2 mL) 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). Undulations in the film were still observed in the higher solids content formulation. The polysorbate 20 was then removed, and it was observed that the undulations 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.

[0170] 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. In 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 patch (internal product name M207) based on a nominal batch size of 45 g (zolmitriptan base) are provided in Tables 3 and 4. [Table 3] [Table 4]

[0171] 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 the liquid. HA Barnes, JF 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 complex theoretical models. 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 give rise to a phase angle output. The phase angle is the ratio of the viscous and elastic coefficients. A phase angle of 0 degrees corresponds to a material that is totally elastic 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 totally viscous behavior and indicates 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 not prone to gelation.

[0172] Characterization of the 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 zolmitriptan coated microprojections after breaking the microprojections at the base of a titanium array. For hardness measurements, the 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 elastic modulus were determined using a Berkovich indenter by 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. [Table 5]

[0173] 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 in incremental steps from 0% to 65% and then 65% to 0%. Mass change was measured continuously by a microbalance with 0.1 μg resolution. At each RH step, samples were allowed to reach equilibrium at a dm / dt criterion of 0.0004 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.

[0174] Crystallinity X-ray diffraction (XRD) analysis was performed to characterize the solid state phase of the dried zolmitriptan coating on the patch 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 were collected by coupled Theta:2 Theta scan on a Bruker D8 Vantec diffractometer equipped with a microfocus copper X-ray tube with a Montel optical 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 resulting 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. Percent crystallinity was calculated using peak profile fitting, and the results are summarized in Table 6, and stability was monitored as described below. [Table 6]

[0175] 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 (a measure of a material's stiffness), which is a measure of a material's resistance to elastic deformation when a force is applied, and fracture toughness, which describes a 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 shows the nanohardness (H), conversion factor elastic modulus (E) 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. r ), and fracture toughness (K c ) The stability results suggest a decreasing trend in hardness and fracture toughness, and an increasing trend in elastic modulus.

[0176] Determination of purity and content of zolmitriptan The purity of zolmitriptan 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 was collected and analyzed using Empower Pro (Empower 2 software, Waters Corporation).

[0177] In vitro lysis The in vitro dissolution of M207 1.9 mg patch was evaluated using a standard USP paddle-over-disk apparatus (USP apparatus 5) with 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.

[0178] 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.

[0179] [Table 7]

[0180] 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) is used to study the percutaneous absorption of topically applied drugs. 2 ~10mg / cm 2A formulation of the drug (semi-solid, or transdermal delivery system) is applied to the outer surface of the skin and drug absorption is measured by monitoring the rate at which it appears in the receptor solution bathing the inner surface of the skin. In addition to total absorption and absorption rate, data defining skin content can be determined in this model.

[0181] 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.

[0182] Skin receptor medium. When the diffusion cells were first set up, normal phosphate buffered saline (pH 7.4±0.1) containing 0.008% gentamicin sulfate (PBSg) solution was utilized.

[0183] 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.

[0184] 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.

[0185] 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 before barrier integrity testing.

[0186] One additional skin section per donor was prepared for all test procedures but was dosed with a placebo patch to serve as a negative sample control.

[0187] 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 below 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 necessary. After completing the barrier integrity test, the receptor solution was replaced with the specified stock receptor solution in 0.1x PBSg.

[0188] Donor Demographics. Skin donor demographics are summarized in Table 8. [Table 8]

[0189] Dose Administration and Sample Collection. Prior to application 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 PBS. The chimney was then temporarily removed from the Franz diffusion cell to allow full access to the epidermal surface of the skin.

[0190] Immediately after patch application, the skin-patch combination and the donor compartment (chimney) were replaced and placed into the receptor compartment of a Franz diffusion cell.

[0191] 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 resuspended in 0.25 mL of ddHO. 2 Reconstituted in O.

[0192] 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.

[0193] After surface cleaning, the skin was allowed to dry for 10 minutes or more.The skin was then tape stripped with up to 10 successive tapes (e.g., 3M Transpore® tape) to remove and collect the stratum corneum.The 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.The skin sections were extracted overnight in ddH2O.

[0194] Sample analysis. Quantification of zolmitriptan in collected samples was achieved using a validated HPLC method.

[0195] 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.

[0196] Mean flux results. Percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 min from a single application (mean ± SE). Mean flux (μg / cm 2 / hr) are summarized in Table 9 and plotted in Figure 30, which summarizes across donors and shows the results of percutaneous absorption of zolmitriptan through ex vivo human torso skin over 300 minutes from a single application (average, N=3 donors). [Table 9]

[0197] 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). [Table 10]

[0198] Conclusions and Discussion: Total absorption of zolmitriptan through the skin into the receptor solution was 83.41 ± 1.33% for the 1.9 mg patch. Peak flux occurred approximately 4 minutes after application and was 849.4 ± 42.1 μg / cm 2 / hr. Less than 1% of zolmitriptan was recovered from the three skin layers at the end of the treatment period. Mass balance was approximately 90% of the applied dose.

[0199] Example 3 - Stability of M207 Patch The M207 patch assemblies were irradiated with electron 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 electron beam and gamma irradiated M207 patches are shown in Tables 11-17. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0200] 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 at 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. [Table 17]

[0201] As described herein, the zolmitriptan coated microneedles are exposed to a dose of radiation in the range of about 7 to 30 kGy. More preferably, the dose is 10 -5 ~10 -6 The sterility assurance level for irradiated and non-irradiated zolmitriptan patches is in the range of 15-30 kGy. Table 17 shows the 12-month stability results of irradiated and non-irradiated zolmitriptan patches stored at 25°C and 40°C.

[0202] Example 4 - Drug-Device Combination Products 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 attached 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 bottom 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 the 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.

[0203] 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. [Table 18]

[0204] The zolmitriptan coated titanium microneedle arrays were 3 cm2 each consisting of approximately 1987 or approximately 997 titanium microneedles for 1.9 mg or 1 mg of drug product, respectively. 2 It is an array of about 5cm 2 The patch assembly is attached to an adhesive patch of 1000 μm diameter. 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 (FIGS. 4(A), 4(B), and 5(A)-(E)). The applicator is released by twisting the outer grip relative to the base from position #1 to position #2 (FIG. 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, e.g., about 0.26 Joules. The piston releases the patch from the retaining ring and applies the patch to the skin at 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.

[0205] 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.

[0206] The components of the M207 system are listed in Table 19. [Table 19-1] [Table 19-2]

[0207] 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 dedicated 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.

[0208] Specifically, the study compared five regimens of M207 along with a single dose of 2.5 mg oral zolmitriptan tablet and 6.0 mg subcutaneous sumatriptan 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) comparable to exposure to orally administered zolmitriptan. max ), 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.

[0209] The first four doses of zolmitriptan were administered at 5 cm 2A patch and 0.26 Joule applicator were utilized. The final treatment administered was a 10 cm patch using an applicator with 0.52 Joules of applied energy in the intradermal microneedle system described herein. 2 The patch dose was 3.8 mg. The products tested were:

[0210] M207 0.48mg Patch Assembly: The zolmitriptan 0.48mg patch is comprised of 3cm of nominally 340μm long microprojections coated with 0.48mg of zolmitriptan. 2 The array consisted of a 5 cm 2 The patch was formed by applying it to the center of a tan adhesive backing. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with a desiccant, and the patch assembly was packaged in a foil pouch.

[0211] M207 1.9mg Patch Assembly: The zolmitriptan 1.9mg patch is comprised of 3cm of nominally 340μm long microprojections coated with 1.9mg of zolmitriptan. 2 The array consisted of a 5 cm 2 The patch was then applied to the center of a tan adhesive backing to form a patch. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with a desiccant, and the patch assembly was packaged in a foil pouch.

[0212] M207 3.8mg Patch Assembly: The zolmitriptan 3.8mg patch is comprised of 5.5cm of nominally 340μm long microprojections coated with 3.8mg of zolmitriptan. 2 The array consisted of a 10 cm 2 The patch was then applied to the center of a tan adhesive backing to form a patch. The patch was attached to the inside of a white to off-white polycarbonate ring co-molded with a desiccant, and the patch assembly was packaged in a foil pouch.

[0213] Study Design This was a single-center, open-label, randomized, five-way crossover study (Part 1) followed by a sequential study 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 administration 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 was summarized for each dose level. 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 procedures identical to the preceding dosing day. After completing the seven dosing days, subjects were evaluated one final time and released from the study.

[0214] The treatments used in the study were as listed in Table 20 below. [Table 20]

[0215] Twenty subjects participated in the study, 10 males and 10 females. The mean age of the subjects was 29 years ± 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.

[0216] 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. Collected serum was analyzed for zolmitriptan and N-desmethylzolmitriptan using methods well known in the art, such as using liquid chromatography-mass spectrometry (LC-MS-MS) methods.

[0217] 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 demonstrating the rapid absorption of M207 characteristic of Zosano's microneedle patch and applicator system are shown below. [Table 21]

[0218] Mean plasma concentration versus time data for each of the six zolmitriptan regimens administered are shown in Figures 7 and 8. Figure 7 shows the results for the entire 24 hour sampling period, while Figure 8 shows the 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.

[0219] Based on the results presented in Figures 7 and 8, the plasma levels of zolmitriptan after intradermal application were dose-dependent, and absorption after patch application was much faster than that seen after administration of a 2.5 mg tablet. The plasma levels seen after a single larger 3.8 mg patch were higher than those seen after 2 x 1.9 mg patches. max、 AUC t , and AUC infDose linearity plots for N-desmethylzolmitriptan C are shown in Figures 9, 10, and 18 (excluding the larger 3.8 mg patch). max、 AUC t , and AUC inf Plots of dose linearity for the zolmitriptan regimen and subcutaneous sumatriptan are shown in Figures 22-24 (excluding the larger 3.8 mg patch). Excellent dose linearity was observed over the range of doses evaluated. Calculated key means (T max The pharmacokinetic parameters (median of 100 mg / kg / day) are shown in Table 22 below. [Table 22-1] [Table 22-2] [Table 22-3]

[0220] Perhaps most relevant to the potential utility of this product for the treatment of migraine or cluster headaches is the T max , indicating a much more rapid absorption of zolmitriptan from intradermal administration than from oral administration.

[0221] 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.

[0222] 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. [Table 23-1] [Table 23-2]

[0223] N-desmethylzolmitriptan levels were significantly lower after intradermal administration of M207 zolmitriptan than were seen after oral administration (Treatment D).

[0224] 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, AUC 2時間 , AUC t , AUC inf and C max Geometric means and 95% confidence intervals (CIs) were calculated for each zolmitriptan treatment. inf N-desmethylzolmitriptan / AUC inf Zolmitriptan ratios were calculated for each subject and group means determined.

[0225] 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. PK parameters (AUC t , AUC inf and C max ) were plotted to show apparent dose linearity and proportionality.

[0226] Rapid absorption of zolmitriptan was observed after intradermal patch application, with mean peak plasma concentrations (T max ) ranged 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]).

[0227] The mean (±SD) elimination half-life (t 1 / 2) ranged from 1.15 ± 0.27 hours to 1.53 ± 0.31 hours, respectively, over the dose range of 0.48 mg to 3.8 mg. Elimination of zolmitriptan after zolmitriptan tablets (3.27 ± 0.8 hours) was nearly twice as slow as that of M207.

[0228] Mean (±SD) maximum plasma concentration (C max ) was 3.77 ± 1.51 ng / mL. Administration of 2 × 0.48 mg patches provided a similar maximum concentration of 3.70 ± 1.05 ng / mL, compared with C of group C (1.9 mg) administered as a single patch. max Groups F and G produced maximum plasma concentrations that were 3.9-fold (14.61 ± 4.46 ng / mL) and 6-fold (22.56 ± 14.0 ng / mL) higher than those of zolmitriptan tablets, respectively.

[0229] 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 the M207 patch in groups F and G provided similar exposure (AUC inf ) (30.12 and 33.81 ng.H / mL, respectively). inf ) was proportional to dose for single patch administration (y=8.31). Concentration-time curves for all treatments over 0-2 hours are shown in FIG. 8 and for 0-24 hours in FIG.

[0230] For the higher doses of Groups F (2 × 1.9 mg) and G (3.8 mg), plasma concentrations were slightly higher in men than in women. For the lower doses (Groups A [0.48 mg] to C [1.9 mg]), there did not appear to be any gender differences.

[0231] The following formula:

number

[0232] 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.

[0233] A summary of the key calculated pharmacokinetic parameters from the study is shown in Table 24. [Table 24-1] [Table 24-2]

[0234] 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). [Table 25]

[0235] The following formula:

number

[0236] There was lower conversion to the N-desmethylzolmitriptan metabolite for the M207 patch compared with the zolmitriptan tablet (F rel AUC range: 0.32-0.46), C max Based on the relative bioavailability of the two, there was an approximately 50% lower exposure rate for the M207 patch compared to the zolmitriptan tablet.

[0237] The plasma concentration of the N-desmethyl metabolite reached a maximum 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]) (Figure 13). The elimination half-life (t 1 / 2 ) were comparable for all treatments, including oral administration (range 2.7H to 3.31H). Concentration-time curves from 0 to 24 hours for N-desmethylzolmitriptan are shown in FIG.

[0238] Mean maximum plasma concentration (C) for the 0.48 mg dose of M207 max ) was 0.22 ng / mL for the 3.8 mg strength and 1.77 ng / mL for the 3.8 mg strength, compared with 2.08 ng / mL for the zolmitriptan tablet. inf The amount of N-desmethyl metabolite (C) for the M207 patch 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. max and AUC inf ) were directly proportional to dose (y=0.4127 and 2.022, respectively) and significantly lower than those for the zolmitriptan tablets. See Figures 19 and 21.

[0239] A summary of the mean pharmacokinetic parameters for N-desmethylzolmitriptan is detailed in Table 26. [Table 26]

[0240] M207 also demonstrated a significantly improved AUC inf There was a trend towards lower within-group variability (as indicated by CV%) for the parameters.

[0241] Dose Linearity of Administration of the M207 System C for both single (0.48 mg, 1.9 mg and 3.8 mg) and multiple (0.48 mg x 2 and 1.9 mg x 2) doses of the system. max (y=4.81), AUC t (y=7.61) and AUC inf A positive linear relationship was observed for (y=8.31). See Figures 15-17. At the lower end of the dosing range (0.48 mg x 2), concentrations of both zolmitriptan and N-desmethylzolmitriptan metabolites were very similar. However, at the highest dose (1.9 mg x 2), plasma concentrations achieved using multiple patch administration were slightly lower than those using a single patch (and dosing force of 0.52 J) for both zolmitriptan and N-desmethylzolmitriptan. For N-desmethylzolmitriptan, see Figures 19-21.

[0242] Administration of the M207 patch resulted in rapid peak plasma concentrations (T max ) which compares favorably with 12.5 minutes for SC sumatriptan and represents a considerable improvement over conventional release oral zolmitriptan tablets (1.8 hours). 1 / 2 ) was shorter, approximately twice as fast as the rate for zolmitriptan tablets (1.2-1.5 hours vs. 3.3 hours).

[0243] C for Zolmitriptan Tablets max The mean peak plasma concentration was 3.77 ng / mL. Treatment with the M207 patch in Groups C (1.9 mg), F (1.9 mg × 2), and G (3.8 mg) produced mean peak plasma concentrations 1.8-, 3.9-, and 6-fold higher than the zolmitriptan 2.5 mg tablet. Multiple patch administrations with 2 × 0.48 mg M207 produced mean peak plasma concentrations equivalent to oral zolmitriptan tablets. max (3.70 ng / mL).

[0244] Treatment with the M207 patch in groups F and G resulted in similar exposure (AUC inf) (30.12, 33.81, and 27.19 ng.H / mL, respectively). However, the mean total exposure (AUC inf ) was lower (0.700–0.86) compared with oral zolmitriptan tablets, and the mean peak exposure (C max ) was 2.35 to 3.73 times higher.

[0245] 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. [Table 27]

[0246] Perhaps most relevant to the potential utility of this product for the treatment of migraine or cluster headaches is the T max , indicating a much more rapid absorption of zolmitriptan from intradermal administration than from oral administration.

[0247] A comparison of exposures is provided in Table 28 below. [Table 28]

[0248] C max and AUC infExcellent dose linearity was observed for high and low doses of M207. M207 was well tolerated. Adverse events (AEs) were primarily mild (87%) of short (<24 hours) duration and mostly consistent with events previously reported with zolmitriptan (88%). There were no serious or critical 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.

[0249] 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. [Table 29] [Table 30]

[0250] Example 5 - In vivo pig test The M207 patch was tested in pigs.

[0251] 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 quantification of zolmitriptan and its two main metabolites in HGP plasma. The instrumentation consisted of an Agilent® 1200 pump, a CTC PAL® Autosampler with cooling stack, an AB Sciex® TurboV® ESI source, and an API 4000® mass spectrometer.

[0252] 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).

[0253] A 10-port, 2-position Valco® valve was placed in-line with the mass spectrometer equipped with a guard cartridge (Zorbax 300SB-C8, 12.5×4.6 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, 50×2 mm) and the mass spectrometer.

[0254] 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 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 eleven 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 concentrations for each sample. A quadratic (1 / x) fit was used for all calculations.

[0255] anesthesia Animals were induced with Telazol intramuscularly and maintained on a ventilator with isoflurane.

[0256] 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 according to approved protocols and SOPs at the testing 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 dosing. All blood samples were collected using heparinized microtiter tubes. 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 collections did not exceed 3-5% of the animal's total blood volume.

[0257] Intravenous 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.

[0258] Determination of patch delivery performance Determining ZP-zolmitriptan Delivery Using Residual Drug Analysis Zolmitriptan residues were determined from the used patch and swabs from the treated skin site. 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 site. 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 dry and used to capture all 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 the determination of the total amount of zolmitriptan delivered and the delivery efficiency. The equations for determining the total drug delivered and drug delivery efficiency are shown below as (1) and (2), respectively. Total Residual Amount = Patch Residual Amount + Skin Residual Amount Total drug delivered = nominal coating amount - total residual amount (1)

number

[0259] Study Design Three pre-estrus female Yorkshire pigs were used in the study. Naïve animals were purchased from an approved vendor following the approved protocols and SOPs of the study facility 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 to 25 kg, and at the last dose, animals had body weights ranging from 25 to 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 animals in each group. result [Table 31]

[0260] 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. [Table 32]

[0261] In vivo evaluation demonstrated rapid systemic absorption of zolmitriptan using patch administration. Plasma levels were measured at 15 min median T max The zolmitriptan patch had an absolute bioavailability of 77%. The ZP-zolmitriptan patch was able to coat the required amount of drug, and high delivery efficiency was consistently achieved, and the coated zolmitriptan was C max It was shown that the drug could be well absorbed with a short time to

[0262] 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 1-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 criterion of 2 to 8 migraine attacks per month, which they recorded using an electronic diary or mobile 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 between 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.

[0263] During the qualifying migraine, subjects scored the severity of their pain 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 the elimination 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 their 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.

[0264] 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% reported aura, and 51% reported 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.

[0265] 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 co-primary 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, and demonstrated durability of effect on relief of pain at 24 and 48 hours. Additionally, M207 was not associated with any serious adverse events (SAEs).

[0266] The 3.8 mg dose of M207 achieved statistical significance for both co-primary endpoints at 2 hours, as shown in Table 33. [Table 33]

[0267] 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. [Table 34]

[0268] 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.

[0269] Additional data from the clinical trial results are presented in the table below. [Table 35]

[0270] In Table 35 above, the 3.8 mg dose group met both co-primary endpoints with a p-value <0.05. The 1.9 mg dose group met the endpoint of freedom from pain with a p-value <0.05. For the endpoint of freedom from most bothersome other symptom at 2 hours, the 1.9 mg dose group had a p-value ≥0.05. The 1 mg dose group met the endpoint of freedom from pain with a p-value <0.05. For the 1 mg dose group, the endpoint of freedom from most bothersome other symptom at 2 hours had a p-value ≥0.05. [Table 36]

[0271] 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 evaluate 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. [Table 37]

[0272] 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 were assessed sequentially as described in Table 35 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, as shown in Tables 36-40. The investigators 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. [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46]

[0273] Tables 47-50 and Figures 25-28 demonstrate the effectiveness of one embodiment of the claimed invention against published results of procedures currently used in the art. The state of the art up to the claimed invention included intranasal procedures and standard and orally dissolving tablets. [Table 47] [Table 48] [Table 49] [Table 50]

[0274] 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

1. 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 is about 0.5 to 10 cm ２ and has an area of (ii) the array has about 500 to 1000 microprojections / cm ２ and having a density of (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.

2. 2. 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 United States Pharmacopeia (USP) Paddle-over-Disk Method (Apparatus 5).

3. 3. The system of claim 1 or 2, wherein at least 95% of the zolmitriptan is released within about 1 minute.

4. When the system is applied to a selected area of ​​a patient's skin, (i) Therapeutic Effective Plasma Concentration T ｍａｘ occurs within about 45 minutes of said application, C ｍａｘ is about 5 to about 25 ng / ml, and AUC ０～２時間 is about 5 to about 20 ng / ml·hr; and / or (ii) the T of therapeutically effective serum concentration ｍａｘ The system of any one of claims 1 to 3, wherein occurs within about 30 minutes of said application.

5. The system of any one of claims 1 to 4, wherein the coating covers between about 10% and 80% of the length of each microprojection measured from the tip to the base.

6. The system of claim 5, wherein the coating covers from about 20% to about 70% of the length of each microprojection.

7. The system of claim 6, wherein the coating covers about 30% to about 60% of the length of each microprojection.

8. 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 greater than about 10 cP, less than 300 cP and greater than about 50 cP, less than about 250 cP and greater 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 The system of any one of claims 1 to 7, wherein the viscosity is selected from the group consisting of 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.

9. 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 ~Approx. 72mNm －１ The system according to any one of claims 1 to 8,

10. 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 ~Approx. 65mNm －１ The system of claim 9 .

11. The system according to any one of claims 1 to 10, wherein the microprojections are made of a thin sheet of metal or a hard material.

12. 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 alloy.

13. The system of claim 12 , wherein the microprojections are made of titanium.

14. The system according to any one of claims 1 to 13, wherein the solid coating formulation further comprises at least one inactive ingredient.

15. The system of claim 14, wherein the inactive ingredient is tartaric acid.

16. The system according to any one of claims 1 to 15, wherein the system comprises a patch affixed to a substrate, and the microprojections are arranged in an array on the substrate.

17. Features: (a) Approximately 1-20cm ２ , about 2-15cm ２ , about 4-11cm ２ , about 5cm ２ , and about 10 cm ２ A patch size selected from the group consisting of: (b) Approximately 0.5-10cm ２ , about 2-8cm ２ , about 3 to 6 cm ２ , about 3cm ２ , about 3.1cm ２ , about 3.13cm ２ , and about 6 cm ２ A substrate size selected from the group consisting of: (c) Approximately 2-8cm ２ , about 2.5 to 6 cm ２ , about 2.7cm ２ , about 5.5cm ２ , approx. 2.74cm ２ , and about 5.48 cm ２ an array size selected from the group consisting of: (d) Approximately 650 to 800 microprotrusions / cm ２ , and about 725 microprojections / cm ２ an array density selected from the group consisting of: (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; (n) an amount 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; The system of claim 16, comprising at least one of:

18. Approximately 3.1cm ２ and a microprojection thickness of about 25 μm. ２ 20. The system of claim 17, having a patch area of

19. The area of ​​the microprojection array is about 2.74 cm ２ and approximately 1987 microprojections, or approximately 725 microprojections / cm ２ 19. The system of claim 17 or 18, comprising at a density of

20. 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.

21. Approximately 6 cm ２ and a thickness of about 25 μm. ２ 20. The system of claim 17, having a patch area of

22. The area of ​​the microprojection array is about 5.5 cm ２ and about 4000 microprojections at about 725 microprojections / cm ２ 22. The system of claim 17 or 21, comprising at a density of

23. 23. 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. 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.

25. The system of any one of claims 1 to 24, wherein the microprojections are bent perpendicular to the surface of the substrate.

26. 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.

27. The system of any one of claims 1 to 26, wherein the coating formulation does not include surfactants or other penetration enhancers.

28. 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; (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) Liquid carrier The system according to any one of claims 1 to 27, comprising:

29. 30. The system of claim 28, wherein the liquid carrier is water.

30. The system of any of claims 1 to 29, wherein the coating on each microprojection has a thickness that tapers from a maximum of about 270 μm.

31. 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.

32. The system according to any one of claims 1 to 31, wherein the system is an adhesive dermally-applied microarray (ADAM).

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