KR20200032170A - How to quickly achieve therapeutic concentrations of zolmitriptan for the treatment of migraine and cluster headaches - Google Patents

Abstract

Compositions, devices and methods using therapeutic concentrations of trytan for the treatment of migraine are described. In addition, methods and devices for delivery of zolmitriptan to achieve T _max as fast as 2 minutes and up to 30 minutes at the latest in a large number of subjects are also described.

Description

How to quickly achieve therapeutic concentrations of zolmitriptan for the treatment of migraine and cluster headaches

The present invention relates to the field of transdermal or intradermal delivery of pharmaceutical preparations, and more particularly to delivery of tryptans, including zolmitriptan.

According to the Migraine Research Foundation, migraine headaches affect 30 million men, women and children in the United States. Most migraine headaches last 4 to 24 hours, while some last 3 degrees. According to a published study, 63% of migraine sufferers experience migraine 1 to 4 times a month. The prevalence of women (about 18%) is a combination of asthma and diabetes. About one third of people with migraine headaches have three or more migraine headaches per month, and more than half report severe dysfunction or need for bed rest. Migraines are most prevalent in life's twenties, affecting both productivity and quality of life. In the investigation of desirable properties for migraine treatment, rapid relief as one of the most important elements for migraine treatment consistently scores very high.

Acute migraine is an incapacitating headache disorder characterized by episodic seizures of moderate to severe headache with various combinations of neurological, gastrointestinal and autonomic nervous system symptoms. Migraine without aura is usually associated with sensitivity to nausea, vomiting, light, sound or movement and can last for 4 to 72 hours if not treated. Asymptomatic migraine, previously referred to as "common migraine," is experienced by approximately 65% of patients. Symptoms Migraines are experienced by about 15 to 20% of patients; The subject suffers from temporary focal neurological symptoms, usually visual. This visual symptom is known as a symptom. The rest of the migraine sufferers experience both types of migraine headaches.

About a quarter of migraine sufferers experience at least one episode a week. The most unpleasant symptoms associated with acute migraine are nausea and vomiting. The majority of patients (about 90%) experience nausea; About 70% experience vomiting; And, 1/3 typically experience both symptoms in every seizure.

Cluster headaches are severe headaches ("clusters") that recur in a cyclical pattern, usually daily, for a week or longer, usually for 6 to 12 weeks. In chronic cluster headaches, clusters last more than a year without remission. Cluster headaches are considered to be among the worst headaches known to the medical community and are known to cause more pain than migraine headaches. In approximately 47% of cases, cluster headache attacks recur at the same time of day or night, especially during sleep. Clusters can start at the same time and have a similar duration each year. Although the exact cause is unknown, these recurrence patterns suggest a hypothalamic role (body's biological clock).

The pain of a cluster headache is typically on one side (one side) or localized and is around or on the eye. During seizures, the patient may be restless and unsettled, and they may have difficulty resting in one place. Patients may prefer to wander around, so they can shake, sit, pace, crawl, scream with pain, or even bump their heads against hard surfaces . In some patients, the severity and recurrence of cluster headaches increases the risk of alcohol and drug abuse, self-harm, and even suicide. In particular, cluster headaches are sometimes referred to as "suicide headaches."

Treatment options for cluster headaches are extremely limited and there is a strong need for treatments that provide a rapid and effective response. See, eg, Law et al., Triptan for acute cluster headache , Cochrane Database of Systematic Reviews (2013), Issue 7. Migraine headaches are different from cluster headaches, but it is believed that some treatments for migraine headaches, including tryptan, may also be effective for cluster headaches. However, oral and nasal routes of administration are not very effective due to the slow absorption rate and short headache duration. The injected trytans showed some efficacy, but are limited by needle phobia, lack of portability, complex preparation, the need for sharp object disposal, and safety issues associated with needle prick, amputation and cross-contamination infections. .

The acute treatment of migraine headaches was transformed in 1991 by the introduction of tryptan types such as sumatriptan and zolmitriptan. The trytan is a serotonin derivative that exhibits highly selective and potent agonist activity at the vascular 5-HT _IB receptor and neuron 5-HT _ID receptor. The mode of action of the tryptan is assumed to be triple: (1) binding of the post-synaptic vascular 5-HT _IB receptor to stimulate vasoconstriction of meningeal vessels; (2) binding of a pre-synaptic neuron 5-HT _ID receptor to inhibit the release of a pro-inflammatory neuropeptide; And (3) binding of a pre-synaptic neuron 5-HT _ID receptor to reduce firing rates in tertiary neurons and trigeminal nucleus caudalis (central action). Trytan similarly showed improved efficacy over placebo in treating cluster headaches.

Each of the currently available methods of administration of tryptan, including oral, nasal sprays, subcutaneous injections, and iontophoretic intradermal patches (which are devices that deliver medication through the skin by low current), has significant drawbacks. Some migraine sufferers do not respond consistently to oral trytans, and oral treatment may be ineffective and / or unpleasant to patients suffering from nausea, vomiting, or stomach congestion that may be associated with migraine headaches. Oral, nasal and iontophoretic patch tryptan products are also characterized by delayed absorption and relatively slow onset of action, leading to insufficient relief, especially early in the episode. The delay is clustered because the fact that cluster headache episodes often persist for up to 30 minutes or less means a completely insufficient treatment with oral trytans and a markedly reduced efficacy by nasal passages compared to subcutaneously delivered trytans. It is a major failure in headaches. Cluster headaches are often accompanied by choking or runny nose, which can affect absorption after nasal delivery. Nasal sprays can have an unpleasant taste and can cause discomfort using the injector.

Sumatriptan (IMITREX®) is commercially available by numerous dosage forms such as tablets, subcutaneous (SC) injections, nasal sprays, and transdermal electrophoresis. Oral administration (as succinate) has poor bioavailability (about 15%) due to poor absorption and pre-systemic metabolism. The time to reach the maximum concentration in the bloodstream (T _max ) after oral tablet administration is about 2 hours. The immediate release tablet formulation has an average of 10 to 15 minutes earlier than the conventional T _max , but has approximately the same bioavailability. It acts faster when sumatriptan is injected (usually within 10 minutes) but has a shorter duration of action. Subcutaneous (SC) is faster, but since many patients do not like to inject themselves, tablet formulations of sumatriptan have been prescribed much more widely than injection.

The triptans have a good safety profile when used properly, and their side effects profile is similar to that observed in placebos in clinical trials. Like other compounds of the tryptan class, zolmitriptan has been shown to be effective and tolerable in placebo-controlled clinical trials. Multiple commercial formulations (ZOMIG®): (a) conventional release tablets (2.5 mg and 5.0 mg); (b) “quick melting” oral disintegrating tablets (2.5 mg and 5.0 mg); And (c) nasal spray (5.0 mg).

The bioavailability of zolmitriptan conventional release tablets was found to be 41-48%, and administration with food reduced C _max and AUC 13-16% (Seaber et al., "The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90), "Br. J. Clin. Pharmacol. 1997; 43 (6): 579-87; Seaber et al.," The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers, "Br. J. Clin. Pharmacol. 1998; 46: 433-439]). The T _max of conventional tablets is about 1.5 hours. In actual migraine triggering, absorption is reported to be lower, so the T _max may be higher during migraine headaches. The zolmitriptan is converted to an active N-desmethyl metabolite so that the metabolite concentration is about 2/3 of the zolmitriptan concentration. Since the 5HT _{1B / 1D} efficacy of the metabolite is 2 to 6 times that of the parent, the metabolite can provide a significant portion of the overall effect after administration of zolmitriptan.

The bioavailability of the orally disintegrating tablets is similar to that of the conventional tablets, but the T _max is about 3 hours (somewhat surprisingly) higher than the conventional tablets, which is about 1.5 hours. The disintegrating tablets can also exacerbate the nausea that often accompanies migraine attacks.

Zolmitriptan has significant advantages over other trytans when considering alternative delivery routes and methods. Only three triptans, zolmitriptan, naratriptan and pro bartriptan have the lowest oral dosage of less than 5 mg. However, at this lowest dose, zolmitriptan significantly outperformed naratriptan in terms of pain relief at 2 hours (62% vs. 49%) and no pain at 2 hours (29% vs. 18%). (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), provatriptan has "lowest efficacy in 2-hour response, 2-hour pain-free compared to other trytans" (Neuropsychiatr Dis Treat. 2008 Feb; 4 (1 ): 49-54]).

Nasal administration of zolmitriptan has been used as an attempt to overcome the disadvantages of oral delivery described above, and dosages of 2.5 mg and 5.0 mg are commercially available. However, the T _max of zolmitriptan is only slightly improved (to about 1.5 hours), much of this dose is swallowed and still undergoes first pass metabolism.

Other non-oral routes of administration, such as transdermal iontophoresis, patches and liquid syringes, have the disadvantage of being unable to deliver skin irritation and scarring, pain, and therapeutically effective dosages. Subcutaneous injectable sumatriptan has been available for many years, but it has been difficult to manufacture and has not been widely used due to problems associated with needle phobia, sharp tip disposal, and accidental fricks associated with delivery by the needle, cutting and cross contamination.

The effectiveness of migraine treatment with tryptan has been shown to be more dependent on absorption rate than dose or plasma concentration. Not only in the early stages of migraine episodes, but also in surprisingly late when the plasma concentration is higher from a more slowly absorbed therapy, faster absorption and earlier T _max lead to better pain relief. In cluster headaches, in addition to the above effects, there is a need for rapid absorption due to the short duration of the headache phenomenon. Rapid absorption can further reduce the required application time of transdermal patches and can lead to more efficient delivery of packaged doses, which facilitates reproducibility, for example by reducing the variability caused by variations in patch wear time. .

Thus, benefits can be achieved by therapeutic alternatives to currently available migraine and cluster headache treatments: (a) faster than the oral and comparable in SC formulations but with an onset of action that does not have needle-related problems; (b) avoiding oral routes that may limit absorption, caused by gastric effects of the migraine (stomach retention, nausea and vomiting); (c) reducing the likelihood of food interactions, avoiding first-pass metabolism, and reducing the likelihood of drug interactions; (d) preferred by the patient (rapid onset without injection or unpleasant taste / smell, eg nasal spray); (e) while still effective in reducing migraine-related headaches and nausea, having lower absorption to reduce side effects of tryptans such as chest contractions; (f) the patient can conveniently carry it for use in the first sign of a migraine or cluster headache; And, (g) can be self-administered quickly, conveniently and safely. Additionally, since nausea is present in 60-70% of migraine attacks, it would be advantageous for doctors and patients to have products that can be administered without using the gastrointestinal system and not easily affected by lack of absorption due to vomiting. Similarly, choking and runny nose in cluster headaches can affect the efficacy of the drug delivered to the nasal cavity.

Accordingly, there is a need in the art for a route of administration that can accommodate relatively large doses of tryptan, such as zolmitriptan, which is representative of oral administration, but does not have the side effects of oral delivered administration. The present disclosure specifically meets these challenges and needs. For example, Applicants have the transdermal delivery of tryptans, such as zolmitriptan, as described herein, can rapidly deliver a relatively large dosage of zolmitriptan, which is representative of oral dosing, and the difficulty of the high impermeability properties of the skin Nevertheless, it was surprisingly found to have a plasma concentration in the range seen or higher after oral administration.

In addition, a triptan administration route that avoids the problem of needle phobia, sharp tip disposal, and accidental tricks associated with delivery by the needle, cutting and cross-contamination, while having improved efficacy and portability and ease of preparation due to absorption similar to injection. Is necessary.

In addition, the patch can be accurately and uniformly coated without causing problems of residual drug on the array or problems of inconsistent manufacturing, such as non-uniform formulation coating on the patch or difficulty in adhering the formulation to the patch. There is a need in the art for effective methods of administering tryptan via transdermal delivery. Many attempts have been made to use transdermal microneedle patches for effective drug delivery; However, it has proven difficult to find a drug containing sufficient dose of drug while achieving rapid release of the drug from the micron system and rapid treatment with the microneedle system and optimizing and developing effective microneedle shape and size. Applicants have developed an effective triptan delivery system through significant development efforts to address viscosity, drug loading, surface tension, microneedle shape and size, and conventional manufacturing defects.

The present disclosure relates to methods of making compositions, devices, methods of treatment, kits and pharmaceutical products useful for the treatment of migraine, and other diseases including cluster headaches. More specifically, the present disclosure relates to the administration of trytans such as zolmitriptan as an active pharmaceutical ingredient to a subject in need thereof. In particular, the present disclosure is transduced to a therapeutically effective dosage of an active ingredient that is more readily available in the subject's bloodstream when compared to the therapeutically effective oral dosage of the active ingredient, in an easy-to-use and portable form for rapid administration. Or intradermal or otherwise administered through the skin. In one embodiment, transdermal delivery of tryptans such as zolmitriptan is generally a plurality of microprotuberances (or “needles”) coated with the drug or in fluid communication with the reservoir of the drug, or otherwise comprising the drug. Or "microneedle" or "array"). The patch assembly further includes an adhesive component, and in a preferred embodiment, the microprotrusion member and the adhesive component are mounted to a retainer ring. The microprotrusion is adapted to be applied to the skin to deliver the drug to the bloodstream, or more specifically, to penetrate or pierce the stratum corneum to a depth sufficient to provide a therapeutically effective amount to the bloodstream. In one embodiment, the insertion of the drug-coated microneedle into the skin is controlled by a hand-held applicator that imparts sufficient impact energy density in less than about 10 milliseconds.

Preferably, the microprotrusion member comprises a biocompatible coating formulation comprising a drug such as zolmitriptan in a dosage 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 includes zolmitriptan and a water-soluble carrier, which is first applied to the microprotrusions in liquid form, and then dried to form a solid biocompatible coating.

In a preferred embodiment, the zolmitriptan, excipients, coating and drying process surprisingly leads to a non-crystalline (amorphous) drug coating with a rapid dissolution rate. In this embodiment, the coating dissolves at a rate sufficient to rapidly absorb the drug into the epidermis and bloodstream when applied to the skin through a microneedle. In one embodiment, this 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 rate leads to rapid migraine and cluster headache relief. Preferably, this rapid absorption renders more than about 10% of the patients painless after 1 hour of administration, more preferably more than about 20% of the patients, and most preferably more than about 25% of the patients are painless. In another embodiment, such rapid absorption causes more than 40% of patients to achieve pain relief after 1 hour of administration, or more than 50% of patients, or at least about 65% of patients achieve pain relief after 1 hour of administration To do. Preferably, the drug coating is amorphous for 1 year, more preferably 2 years after gamma or e-beam irradiation.

Such an intradermal delivery system may be in the form of a device suitable for easy and direct use by the patient. For example, the system can be a drug-device combination product comprising: (a) a disposable microprotrusion member having a titanium microneedle coated and dried in a pharmaceutical formulation, wherein the microprotrusion member is on an adhesive backing. A disposable microprotrusion member that forms a patch at the center, and (b) a reusable hand that ensures that the patch is applied to the skin with limited applied energy sufficient to press the microneedle into the stratum corneum to cause drug absorption. Held applicator. In one embodiment, the delivery system comprises about 0.2 mg to about 10 mg 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 about 0.2 mg to about 10 mg zolmitriptan intradermally, or about 1 mg to about 4 mg, or about 1 mg, or 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 about 1 mg or more, or about 1.9 mg or more, or about Greater than 2 mg, or greater than about 3 mg, or greater than about 3.8 mg, or greater than about 4 mg, or greater than about 5 mg, or greater than about 6 mg, or greater than about 7 mg, or greater than about 8 mg or greater than about 9 mg It is designed to deliver zolmitriptan.

In another embodiment, the present disclosure relates to a method comprising administering tryptan to a patient in need thereof, transdermally or intradermally, comprising the following steps: (a) suitable to penetrate or pierce the stratum corneum of the patient. A biocompatible coating comprising a microprotrusion member having a plurality of microprotrusions, wherein the microprotrusions are partially or wholly disposed on the microprotrusions, the coating comprising a therapeutically effective amount of tryptan, Providing a transdermal patch suitable for delivery of tryptan intradermally; And (b) applying a microprotrusion member of the device to the patient's skin, such that a plurality of microprotrusions penetrate or penetrate the stratum corneum and deliver the tryptan to the patient's bloodstream. In one embodiment, the triptan is zolmitriptan, coated on the microprotuberance in a total amount of approximately 0.2 to 10 mg, approximately 50%, or 60%, or 65%, or 75%, or 80, or 80 of the dose %, Or 85%, or 90%, or 95%, or 100% reaches the patient's bloodstream after administration, preferably approximately 50%, or 60%, or 65%, or 75% of the dose , Or more than 80%, or 85%, or 90%, or 95%, reaches the patient's bloodstream.

The present disclosure is a method of treating or alleviating a migraine or cluster headache in a human patient in need of treatment or alleviation of a migraine or cluster headache, which is less than a therapeutically effective dosage administered orally, intranasally, sublingually or iontophorically. And a method comprising transdermal or intradermal administration of a therapeutically effective amount of zolmitriptan to produce a therapeutic concentration of zolmitriptan in the bloodstream more rapidly. In one aspect, a method for the treatment or relief of a migraine or cluster headache in a patient results in plasma T _max as quickly as about 2 minutes in most subjects and within about 30-40 minutes. In another aspect, the method results in a maximum plasma concentration (C _max ) of zolmitriptan of less than 50 ng / ml.

In one embodiment, a zolmitriptan-coated microneedle patch as disclosed herein achieves rapid plasma concentrations after application in migraine or cluster headache triggering. This patch provides no pain and no annoying migraine or cluster headache symptoms for at least 45 minutes after administration. Migraine headaches also include vomiting, sensitivity to smell, signs, vision changes, numbness, tingling, weakness, dizziness, vertigo, feeling light headed or dizziness, eyelids Puffy eyelids, impaired concentration, fatigue, diarrhea, constipation, mood swings, food cravings, hives and / or fever, but the most annoying migraine symptoms in patients, in addition to pain, are generally light, especially bright Sensitivity to light (photophobia), sensitivity to sounds, especially loud sounds (phobia), and nausea. Conventional symptoms of cluster headaches often include extreme pain located on one side of the head and usually located inside or around one eye, but the face, head, neck and shoulders, anxiety, excessive tearing, and the affected eye Redness, choking or runny nose, sweat on the forehead or face, pale skin (pallor), flushing of the face, swelling and / or sagging around the affected eye.

Additional embodiments of the devices, compositions, methods, and the like will become apparent from the following detailed description, drawings, examples, and claims. As can be understood from the detailed description above and below, each and every feature described herein, and each and every combination of two or more of these features, unless the features contained in such combinations contradict each other, the scope of the invention Is included within. Also, any feature or combination of features can be explicitly excluded from any embodiment or aspect. Additional aspects and embodiments are set forth in the following detailed description and claims, particularly when considered in conjunction with the accompanying examples and drawings.

Reference of color drawing
This application file contains at least one drawing in color. Copies of this patent application publication with color drawings will be provided by the office upon request and payment of the necessary costs.
Brief description of the drawing
The above-described features of the embodiments will be more readily understood by referring to the following detailed description with reference to the accompanying drawings as follows.
1 (a) and (b) are scanning electron micrographs (SEM) of the MF1663 array design coated with 1.9 mg zolmitriptan.
Figure 2 (a) and (b) shows the appearance of the patch and retainer ring (retainer ring) structure. (a) provides the top surface of the patch and retainer ring. (b) provides a bottom perspective view of the patch attached to the retainer ring.
3 (a) and (b) illustrate a patch assembly composed of patches in a retainer ring. (a) provides a side view of the patch assembly. (b) illustrates an exploded view of the patch assembly.
4 (a) and (b) illustrate how the used plastic retainer ring is removed from the applicator and discarded. A finger is used to pull the retainer ring used out of the applicator. (a) provides a side view of a retainer ring attached to the applicator. (b) provides a side view of the retainer ring separated from the applicator.
5 (a) to (e) are photographs of the step of applying the patch of the present invention. (a) illustrates Step 1: Snap the patch assembly into the applicator. (b) further illustrates step 1 and provides a perspective view of the bottom front of the patch assembly with the applicator. (c) illustrates Step 2: Unlock the applicator cap by twisting it clockwise from position 1 to position 2 for patch application. (d) illustrates Step 3: Applying the patch to the skin by pressing the applicator down. (e) illustrates Step 4: A patch is applied to the patient's skin, and the retainer ring remains attached to the applicator.
Figures 6 (a)-(c) provide an in vitro release profile of the 1.9 mg patch of ZP-zolmitriptan M207. The top left (a) provides an in vitro release profile of the 1.9 mg patch of ZP-zolmitriptan M207, L / N0164004, E-beam irradiated and stored at room temperature (RT) for 10 months. The top right (b) provides an in vitro release profile of L / N0203149-NI, a 1.9 mg patch of ZP-zolmitriptan M207, which was non-irradiated and stored for 10 months at 40 ° C / 75% relative humidity (RH). . The bottom left (c) provides an in vitro release profile of L / N0203149-IR, a 1.9 mg patch of ZP-zolmitriptan M207, which was E-beam irradiated and stored at 40 ° C./75% relative humidity for 10 months.
7 is a line graph of mean zolmitriptan and sumatriptan plasma concentrations over time (0 to 24 hours) 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 subcutaneous (SC) with auto-syringe pen); Treatment F is the zolmitriptan system (1.9 mg x 2); Treatment G is the zolmitriptan system (3.8 mg). Sumatriptan was scaled to 6/90 to show the sumatriptan concentration-time profile compared to other treatments.
8 is a line graph of mean zolmitriptan and sumatriptan plasma concentrations over time (0 to 2 hours), 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 intradermal (SC) with auto-syringe pen); Treatment F is the zolmitriptan system (1.9 mg x 2); Treatment G is the zolmitriptan system (3.8 mg). In the graph above, sumatriptan is scaled to 6/90, showing sumatriptan concentration-time profiles for different treatments.
9 is a line graph of dose linearity of M207 C _max for single and multiple patches excluding 3.8 mg.
10 is a line graph of dose linearity of M207 AUC _t for single and multiple patches excluding 3.8 mg.
FIG. 11 is a line graph of mean plasma zolmitriptan concentration in women over 0 to 2 hours.
12 is a line graph of mean plasma zolmitriptan concentration in men over 0 to 2 hours.
13 is a line graph of mean plasma N-desmethyl zolmitriptan concentration over 0-2 hours.
14 is a line graph of mean N-desmethyl zolmitriptan plasma concentrations over 0 to 24 hours.
15 is a line graph of dose linearity of M207 C _max for single and multiple patches.
16 is a line graph of dose linearity of M207 AUC _t for single and multiple patches.
17 is a line graph of dose linearity of M207 AUC _inf for single and multiple patches.
18 is a line graph of dose linearity of M207 AUC _inf for single and multiple patches excluding 3.8 mg patch.
19 is a line graph of N-desmethyl zolmitriptan dosage linearity C _max as a function of M207 dosage for single and multiple patches.
20 is a line graph of N-desmethyl zolmitriptan dose linearity AUC _t as a function of M207 dose for single and multiple patches.
FIG. 21 is a line graph of N-desmethyl zolmitriptan dose linearity AUC _inf as a function of M207 dose for single and multiple patches.
22 is a line graph of N-desmethyl zolmitriptan dosage linearity C _max as a function of M207 dosage for single and multiple patches excluding 3.8 mg.
23 is a line graph of N-desmethyl zolmitriptan dose linearity AUC _t as a function of M207 dose for single and multiple patches excluding 3.8 mg.
24 is a line graph of N-desmethyl zolmitriptan dose linearity AUC _inf as a function of M207 dose for single and multiple patches excluding 3.8 mg.
25 is a graphical comparison of “% Pain” at 1, 2 and 4 hours after treatment.
26 is a graphical comparison of “% Pain Relief” 1, 2 and 4 hours after treatment.
Figure 27 is a graphical comparison of "% Pain" at 1, 2 and 4 hours after treatment.
28 is a graphical comparison of “% Pain Relief” 1, 2 and 4 hours after treatment.
29 is a graphical comparison of “% Painless Subjects” for up to 4 hours after treatment.
30 is a graphical representation of average flux results from ex vivo human skin samples.
Fig. 31 shows the interaction of the microprotuberance with the skin, and in particular how the microprotrusion penetrates the stratum corneum for an effective drug.
FIG. 32 demonstrates one embodiment of a microprotrusion having a certain shape and dimensions before the microprotrusion is bent outward from the substrate and coated with the drug.

Various aspects and embodiments will now be fully described herein. However, these aspects and embodiments can be implemented in many different forms and should not be construed as limiting; Rather, these embodiments are provided to make the present disclosure thorough and complete and to fully convey the scope of the subject matter to those skilled in the art. All publications, patents and patent applications cited herein, whether above or below, are incorporated herein by reference in their entirety.

I. Introduction

Applicants have surprisingly found that, in particular, the dosage of zolmitriptan, which is typical for oral delivery, has good tolerability in delivery routes other than oral delivery, eg intradermal or transdermal delivery of zolmitriptan as described herein. According to the present disclosure, the delivery of zolmitriptan is generally a microprotrusion member (or system) comprising a plurality of microprotrusions (or arrays thereof) adapted to penetrate or pierce from the stratum corneum to the basal epidermal layer, or the epidermal and dermal layers. ). Applicants have customized transdermal delivery of zolmitriptan through significant trial and error and development efforts. In one embodiment, the microprotrusion member comprises a biocompatible coating comprising zolmitriptan. The system provides superior pharmacokinetics and pharmacodynamics over existing treatments and can be extended to other trytans useful for the treatment of migraine, cluster headaches and other diseases or conditions.

II. Justice

Unless otherwise defined, all terms and phrases used herein include the meanings obtained in the art by the term or phrase unless the term or phrase is clearly pointed out or clarified in the context in which it 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, specific methods and materials are now described.

Unless otherwise stated, the use of individual numerical values is approximated as if the term “about” or “approximately” preceded the value. Similarly, unless expressly indicated otherwise, numerical values within the various ranges specified in this application are described as approximations as if “about” or “approximately” terms preceded both the minimum and maximum values within the stated range. In this way, deviations above and below the stated range can be used to achieve results that are substantially the same as values within the range. As used herein, the terms “about” and “approximately” when referring to numerical values refer to ordinary and conventional meanings in the art to those skilled in the art to which the disclosed subject matter is most closely related or to the scope or component under discussion. Will have The amount extending from the strict numerical boundary depends on many factors. For example, some of the factors that may be considered include the importance of the component and / or the effect that a given amount of deviation has on the performance of the claimed subject matter, as well as other considerations known to those skilled in the art. As used herein, the use of different amounts of significant digits for different numerical values does not imply that the use of the terms “about” or “approximately” limits the way in which specific numerical values or ranges are extended. Thus, in general matter, "about" or "approximately" extends the numerical value. Also, the disclosure of ranges is intended as a continuous range that includes all values between the minimum and maximum values and range extensions conferred by the use of the terms “about” or “approximately”. Consequently, reference to a range of values herein is intended to function only as an abbreviated method of individually referring to each distinct value falling within the range, and each distinct value is incorporated herein as individually recited herein. .

The term "amorphous" refers to a non-crystalline solid, ie a solid that lacks a long-range order characteristic of crystals.

The term “area under the curve” or “AUC” refers to the area under the curve (known as a static in mathematics) in a graph of plasma drug concentration versus time. Typically, the area is calculated as starting at the time the drug is administered and ending when the concentration in plasma is negligible. Indeed, the drug concentration is measured at a specific discontinuous time point, and trapezoidal rules are used to estimate the AUC.

As used herein, the term “biocompatible coating” is a coating formed from a “coating formulation” that has sufficient adhesion characteristics and does not have (or minimally) adverse interactions with a biologically active agent (so-called active pharmaceutical ingredient or therapeutic agent or drug). Means and includes.

As used herein, the term "biological equivalent" refers to the scientific basis for comparison of two or more pharmaceutical products, compositions or methods containing the same active ingredient. “Biological equivalent” means that there is no significant difference in the rate and extent to which the active agent in a pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of action when administered in a properly designed study. Biological equivalents can be determined by in vivo studies comparing pharmacokinetic parameters for the two compositions. The parameters often used in biological equivalent studies are T _max , C _max , AUC _0-inf , AUC _0-t . In this context, the substantial biological equivalent of two compositions or products is established by a 90% confidence interval (CI) of 0.80 to 1.25 for AUC and C _max .

As used herein, the term "cluster" refers to a series of repeated cluster headaches. In chronic cluster headaches, even if the duration exceeds 1 year, the cluster duration is generally 1 week to 1 year. The end of the cluster is confirmed by a driveway of at least 1 month.

As used herein, the term “clustering headache” generally refers to a disease characterized by a painful headache that recurs for more than one week every day (although the disease can recur up to eight times a day). Cluster headache pain is usually localized on one side of the head ("one side"), usually on the same side, but in some patients the side may vary. The pain typically reaches maximum intensity in 10 minutes and lasts for 15 minutes to 3 hours (typically 30 minutes to 60 minutes). Because the symptoms start quickly and the duration is short, treatment via a route through which the drug is rapidly absorbed is required.

As used herein, the term “coating formulation” means and includes a free flowing composition or mixture used to coat a delivery surface, including one or more microprotrusions and / or an array thereof.

The term "degradation" as used herein means that the purity of the biological agent decreases from the initial time point.

As used herein, the term "drying agent" means a water absorbing agent, generally a chemical agent.

As used herein, the term "deterioration" means that the quality, characteristics or value of the biologically active agent is reduced or impaired.

The term "electrotransport" generally refers to the passage of beneficial agents, such as drugs or drug precursors, through the body surface such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or enhanced by the application of a potential, and the application of the potential results in the application of a current to deliver the agent or to enhance the delivery, or to sample the agent in the case of "reverse" electron transport. Or improve sampling. Electronic transport of the agent into or out of the human body can be accomplished in a variety of ways.

The term "half-life" as used herein refers to the time required to reduce the blood or plasma concentration of a drug in half. This decrease in drug concentration reflects its discharge or elimination after absorption is complete and the distribution reaches an equilibrium or semi-equilibrium state. The half-life of the drug in the blood can typically be determined graphically from the pharmacokinetic graph of the blood-concentration time graph of the drug after intravenous administration to the sample population. The half-life can also be determined using mathematical calculations well known in the art. In addition, as used herein, the term "half-life" also includes "apparent-half-life" of a drug. The apparent half-life may be a composite number described by contributions from processes other than removal, such as absorption, reuptake or intestinal recycling.

The term "headache pain grade" as used herein refers to the grade used to allow a patient to quantify his pain level. Preferably, a scale of 0 to 3 is used, with severe pain having a pain score of 3, moderate pain having a score of 2, minor pain having a score of 1 and no pain ("pain" None (also referred to as "pain freedom") has a score of zero.

The term “intradermal” as used herein refers to an active agent (e.g., therapeutic agent) through the skin to the local tissue or systemic circulatory system without substantial incision or penetration of the skin, such as incision with a surgical knife or piercing the skin with a hypodermic needle. , For example, a generic term referring to the delivery of a drug, drug, peptide, polypeptide or protein). Intradermal formulation delivery includes delivery based on external energy sources such as electricity (eg, iontophoresis) and ultrasound (eg, sonophoresis), as well as delivery via passive diffusion.

As used herein, the term “intradermal flux” refers to the rate of intradermal delivery of a drug.

As used herein, terms such as “microprotrusion member” or “microneedle array” generally encompass a group of microprotrusions that includes a plurality of microprotrusions, preferably arranged in an array to penetrate or penetrate the stratum corneum. The microprotrusion member may be formed by etching or punching a plurality of microprotrusions from a thin metal sheet or other stiff material, and forming a certain configuration by folding or bending the microprotrusions out of the sheet plane. The microprotrusion member can alternatively be made of other materials including plastics or polymers such as polyetheretherketone (PEEK). The microprotrusion member is formed by other known techniques such as injection molding or micro molding, microelectromechanical systems (MEMS), or US Patent No. 6,083,196; No. 6,091,975; 6,050,988; No. 6,855,131; 8,753,318; 8,753,318; No. 9,387,315; No. 9,192,749; No. 7,963,935; No. 7,556,821; No. 9,295,714; 8,361,022; 8,633,159; No. 7,419,481; 7,131,960; No. 7,798,987; 7,097,631; No. 9,421,351; 6,953,589; No. 6,322,808; No. 6,083,196; 6,855,372; 6,855,372; No. 7,435,299; 7,087,035; No. 7,184,826; No. 7,537,795; 8,663,155; 8,663,155; And US Publication No. 20080039775; US Publication No. 20150038897; US Publication No. 20160074644; And as described in U.S. Publication No. 20020016562, forming one or more strips with microprotrusions along each edge of the strip (s). As will be appreciated by those skilled in the art, the dosage of therapeutic agent delivered when a microprotrusion array is used can also be altered or manipulated by changing the microprotrusion array size, density, and the like.

As used interchangeably herein, the terms “microprotuberance” and “microneedle” refer to the basal epidermal layer, or epidermis and dermis, into and / or through the stratum corneum of the skin of living animals, particularly mammals, more particularly humans. Refers to a piercing component adapted to penetrate, pierce or cut into a layer. In one embodiment of the invention, the perforation component has a protrusion length of less than 1000 microns. In a further embodiment, the perforating component has a protrusion length of less than 500 microns, more preferably less than 400 microns. The microprotrusion further has a width in the range of approximately 25 to 500 microns and a thickness in the range of approximately 10 to 100 microns. The microprotrusion may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof.

The term "minimize" or "reduce" as used herein means reduction.

“Most annoying other symptoms” means symptoms other than pain, migraine symptoms that are generally the most annoying to the patient. Preferably, other most annoying symptoms are identified by the patient at the start of the clinical trial. The other most annoying symptoms are usually selected from nausea, photophobia, and soundphobia.

“No most annoying other symptoms” means that after drug administration, the patient reports the absence of other most annoying symptoms at one or more pre-specified times. Preferred times for migraine sufferers are 1 hour, 2 hours and 4 hours. Preferred times for cluster headache patients are 15 and 30 minutes.

“No nausea” means that the patient reports the absence of nausea at a pre-specified time after drug administration.

"Optional" or "optionally" may or may not occur a component, component, or situation described subsequently, so that the detailed description of the invention occurs when and when the component, component, or situation occurs This includes cases that have not been done.

“No pain” means that the patient reports absence of headache pain (headache pain score = 0) at one or more pre-specified times after drug administration. Preferred times for migraine sufferers are 1 hour, 2 hours and 4 hours. Preferred times for cluster headache patients are 15 and 30 minutes.

“Pain relief” means that the patient has at least one pre-specified time after drug administration, mild or no pain in the reduction of headache pain, moderate or severe pain (headache pain score = 3 or 2) (headache pain score = 1 or 0) This means reporting a decrease. Preferred times for migraine sufferers are 1 hour, 2 hours and 4 hours. Preferred times for cluster headache patients are 15 and 30 minutes.

"Sorphophobia" refers to the fear or disgust of sound, especially loud sounds.

“No phobia” means that the patient reports the absence of phobia at a pre-specified time after drug administration.

“Photophobia” refers to increased, often painful sensitivity to light, especially bright light.

“No photophobia” means that the patient reports the absence of photophobia at a pre-specified time after drug administration.

“Partial AUC” is the area under the drug concentration-time curve calculated using linear trapezoidal summation for a specified time interval (AUC), eg, AUC (O-1 hour), AUC (0-2 hours), AUC (0-4 hours), AUC (0-6 hours), AUC (0-8 hours), and the like.

The drug “release rate” as used herein refers to the dosage form per unit time or the amount of drug released from the pharmaceutical composition, for example milligrams of drug released per hour (mg / hr). The drug release rate for a drug dosage form is typically measured as the in vitro dissolution rate, ie the amount of drug released from the dosage form or pharmaceutical composition per unit time measured under suitable conditions and in a suitable fluid.

As used herein, the term "stable" refers to a formulation formulation, meaning that the formulation formulation does not undergo excessive chemical or physical changes, including degradation, decay or inactivation. “Stable” as used herein means that the coating is also mechanically stable, ie, the coating is not excessively displaced or lost from the deposited surface.

The term "subject" or "patient" is used interchangeably herein and refers to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.

As used herein, the term “therapeutically-effective” or “therapeutically-effective amount” refers to the amount of biologically active agent required to stimulate or initiate the desired beneficial outcome. The amount of biologically active agent used in the coating of the present invention will be that required to deliver the amount of biologically active agent needed to achieve the desired result. In practice, this will vary greatly depending on the specific biologically active agent delivered, the site of delivery, and the dissolution and release kinetics for delivering the biologically active agent to skin tissue.

The term "dermal" as used herein refers to the delivery of an agent into and / or through the skin for topical or systemic therapy.

As used herein, the term "dermal flux" refers to the rate of transdermal delivery.

The term “T _max ” refers to the time from the start of delivery of the biologically active agent to the maximum plasma concentration, C _max .

It will be understood that the term “package” or “packaging” also includes referring to “storage” or “storage”.

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

III. Intradermal delivery system

In one embodiment, the intradermal delivery system is a transdermal or intradermal drug delivery technique comprising a disposable patch consisting of a microprotrusion member centered on the adhesive backing. The microprotrusion member comprises titanium coated with a dry drug formulation (or other rigid material including plastic or polymeric materials such as polyetheretherketone (PEEK)). The patch is mounted on a retainer ring to form a patch assembly. The patch assembly is removably mounted to a handheld applicator to form an intradermal delivery system. The applicator ensures that the patch is applied to the site of intradermal administration at a defined application rate and energy. The applicator can be designed for single use or reused.

More specifically, the patch can include an array of about 3 to 6 cm 2 of titanium microneedle approximately 200 to 350 microns long, coated with a hydrophilic blend of related drugs and attached to the adhesive backing. The maximum amount of active drug that can be coated on the microneedle array of a patch depends on the active moiety of the drug formulation, the weight of excipients in the drug formulation, and the coatable surface area of the microneedle array. For example, patches having about 1 cm 2, 2 cm 2, 3 cm 2, 4 cm 2, 5 cm 2 and 6 cm 2 microneedle arrays can be used. The patch is a hand that, in each application, presses the microneedle close to the capillary layer to a substantially uniform depth to the skin, allowing dissolution and absorption of the drug coating, but not reaching the nerve endings in the skin. Apply using a hand applicator. Typical patch wear times are about 15 to 45 minutes or less, reducing the possibility of skin irritation. A nominal applicator energy of about 0.20 to 0.60 joules can generally achieve a good balance between shock sensation and array penetration. The actual kinetic energy at the time of impact may be less than the nominal value due to incomplete extension of the applicator spring, energy loss from patch detachment from the retainer ring, and other losses that can constitute approximately 25% of the nominal.

A. Array Design

Many variables play a role in the type of array used in a particular active agent. For example, different shapes (eg, arrowheads, hooks, cones or similar shapes to the Washington Monument, as shown in FIG. 31, FIGS. 1 (a)-(b)) have higher drug loading capacity. At the same time, it is possible to increase the length of the microprotrusion to provide a greater driving force for penetration. The stratum corneum has a thickness of about 10 to 40 μm, and the micro-protrusions must have an appropriate size, thickness and shape to penetrate and achieve drug delivery through the stratum corneum. 31, not shown in scale, shows how the array interacts with the skin such that the microprotrusions penetrate the stratum corneum and the substrate interfaces with the skin surface. While achieving a thicker coating on the microprotrusions that will penetrate the stratum corneum, it is advantageous to prevent the coating from being applied to the substrate or base ("branch") of the array that will not penetrate the stratum corneum. The larger surface area allows for a thicker coating without extending to the base or branch of the array. The coating is applied only to the microprotrusion. In addition, the higher penetration force required for the more bulky projections with coating can be compensated for by the longer length of the projections and the lower density per cm 2.

Exemplary intradermal delivery systems that can be used in the present disclosure include US Pat. No. 6,083,196; No. 6,091,975; 6,050,988; No. 6,855,131; 8,753,318; 8,753,318; No. 9,387,315; No. 9,192,749; No. 7,963,935; No. 7,556,821; No. 9,295,714; 8,361,022; 8,633,159; No. 7,419,481; 7,131,960; No. 7,798,987; 7,097,631; No. 9,421,351; 6,953,589; No. 6,322,808; No. 6,083,196; 6,855,372; 6,855,372; No. 7,435,299; 7,087,035; No. 7,184,826; No. 7,537,795; 8,663,155, and US Publication No. 20080039775; US Publication No. 20150038897; US Publication No. 20160074644; And drug delivery techniques described in US Publication No. 20020016562. The disclosed systems and devices use perforated components of various shapes and sizes to penetrate the outermost layer of the skin (ie, the stratum corneum) and thereby enhance the formulation flux. The perforated component generally extends vertically from a thin, flat substrate member such as a pad or sheet. The perforation component is typically small, some only having a microprotrusion length of about 25 to 400 microns and a microprotrusion thickness of about 5 to 50 microns. These small perforation / incision elements create correspondingly small microslits / fine incisions in the stratum corneum for enhanced transdermal / intradermal formulation delivery. The active agent to be delivered preferably is coated with a triptan- or zolmitriptan-based blend of the microprotuberance to form a solid, dry coating, or, optionally, a reservoir in communication with the stratum corneum after the micro-incision is formed. By using or by forming a microprotrusion from a solid tryptan-based formulation that dissolves after application, it is associated with one or more microprotrusions. The microprotrusions can be solid or hollow and adapted to accommodate and / or increase the coating volume, such as apertures, grooves, surface irregularities, or similar deformations. It may further include device features, which provide an increased surface area on which larger amounts of coating can be deposited. The microneedle can be made of a similar biocompatible material such as stainless steel, titanium, nickel titanium alloy, or polymeric material.

Accordingly, the present disclosure includes patches and microneedle arrays having the following features:

Patch size : about 1 to 20 cm 2, or about 2 to 15 cm 2, or about 4 to 11 cm 2, or about 5 cm 2, or about 10 cm 2.

Substrate size : about 0.5 to 10 cm 2, or about 2 to 8 cm 2, or about 3 to 6 cm 2, or about 3 cm 2, or about 3.13 cm 2, or about 6 cm 2.

Array size : about 0.5 to 10 cm 2, or about 2 to 8 cm 2, or about 2.5 to 6 cm 2, or about 2.7 cm 2, or about 5.5 cm 2, or about 2.74 cm 2, or about 5.48 cm 2.

Density ( microprotrusions / cm 2) : at least about 10 microprotrusions / cm 2, or a range of about 200 to 2000 microprotrusions / cm 2, or about 500 to 1000 microprotrusions / cm 2, or about 650 to 800 microprotrusions / Cm2, or approximately 725 microprotrusions / cm2.

· Microprotrusion Number / array : about 100 to 4000, or about 1000 to 3000, or about or about 1500 to 2500, or about 1900 to 2100, or about 2000, or 1987, or about 200 to 8000, or About 3000 to 5000, or about or about 3500 to 4500, or about 4900 to 4100, or about 4000, or about 3974.

Microprotrusion length : about 25 to 600 microns, or about 100 to 500 microns, or about 300 to 450 microns, or about 320 to 410 microns, or about 340 microns, or about 390 microns, about 387 microns. In other embodiments, the length is less than 1000 microns, or less than 700 microns, or less than 500 microns. Thus, the microneedle penetrates the skin to about 25 to 1000 microns.

Tip length : about 100 to 250 microns, or about 130 to about 200 microns, or about 150 to 180 microns, or about 160 to 170 microns, or about 165 microns.

Microprotrusion width : about 10 to 500 microns, or about 50 to 300 microns, or about 75 to 200 microns, or about 90 to 160 microns, or about 250 to 400 microns, or about 300 microns, or about 100 microns, or About 110 microns, or about 120 microns, or about 130 microns, or about 140 microns, or about 150 microns.

Microprotrusion thickness : about 1 micron to about 500 microns, or about 5 microns to 300 microns, or about 10 microns to about 100 microns, or about 10 microns to 50 microns, or about 20 microns to 30 microns, or about 25 microns.

Tip angle : about 10 to 70 degrees or about 20 to 60 degrees or about 30 to 50 degrees, or about 35 to 45 degrees, or about 40 degrees.

Total active agent per array : about 0.1 mg to 10 mg, or about 0.5 mg to 5 mg, or about 1 mg to 4 mg, or about 1 mg, or about 1.9 mg or about 3.8 mg.

Amount of inactive ingredient per array : about 0.1 to 10 mg, or about 0.2 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 ingredient is 1-3 times less than the 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 microprotrusion : about 0.01 to about 100 μg, or about 0.1 to 10 μg, or about .5 to 2 μg, or about 1 μg, or about 0.96 μg.

A particularly preferred embodiment has a patch area of about 5 cm 2 attached to a titanium substrate having an area of about 3.1 cm 2 and a thickness of about 25 μm. The substrate is composed of an array of microprotuberances having an area of about 2.74 cm2 including about 1987 microprotuberances with a density of about 725 microprotrusions / cm2. The dry blend contained on each microprotrusion can have an approximate American football shape with a tapering thickness at up to about 270 μm, about 0.96 μg zolmitriptan per patch and about 0.32 tartaric acid, Or about 1.9 mg of zolmitriptan and about 0.63 mg of tartaric acid.

32 shows the shape of the microprotrusion prior to bending (molding) in a preferred embodiment. Array molding is a process of bending individual microprotrusions at an angle perpendicular to the plane of the substrate. The array is located on the forming tool and includes cavities that are registered with the microprotrusions. An elastomeric forming disk is placed over the top surface of the array and is forced into the cavity in the forming tool. The elastomer flows into the cavity, so that the microprotrusion is bent at a desired angle. The use of the elastomer has the advantage that there is no need to carefully register a forming disk with respect to the microprotrusions and the cavity in order to ensure effective array forming. As shown in FIG. 32, the microprotrusion has a width of about 120 ± 13 μm and a thickness of about 25.4 ± 2.5 μm, and may be substantially rectangular. The microprotrusion has a triangular tip end to facilitate penetration. The tip has an angle of 40 ± 5 degrees and a length of about 165 ± 25 microns. Before bending (molding) from the substrate, the microprotrusions have a length of about 387 ± 13 μm, and after the bending, they project about 340 μm perpendicular to the substrate.

Another preferred embodiment has a patch area of about 5 cm 2 and a thickness of about 25 μm attached to a titanium substrate of about 6 cm 2. The substrate consists of an array having an area of about 5.5 cm 2 containing about 4000 microprotrusions at a density of about 725 microprotrusions / cm 2. The dry blend included on each microprotrusion had an approximate shape of an American football ball with a tapered thickness of up to about 270 and about 0.96 μg zolmitriptan and about 0.32 tartaric acid per patch, or about 3.8 mg Zolmitriptan and about 1.3 mg of tartaric acid. The microprotrusion has a length of about 387 ± 13 μm, a width of about 120 ± 13 μm and a thickness of about 25.4 ± 2.5 μm. The microprotrusion is rectangular and has a triangular tip to facilitate penetration. The tip has an angle of 40 ± 5 degrees and a length of about 165 ± 25 microns.

The exact combination of bulk, length, and density that produces the desired penetration will vary, and may depend on the drug, its dosage, the disease or condition to be treated, and the frequency of administration. Thus, a particular array of drug delivery efficiencies (i.e., the amount of drug delivered to the bloodstream) is 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. Shock Applicator  (impact applicator)

As illustrated in Figures 4 (a)-(b), 5 (a)-(e), the intradermal drug delivery system of the present disclosure has an impact with a body and a piston movable within the body. It may further include an applicator, and the surface of the piston impacts the patch toward the skin, causing the microprotrusion to penetrate the stratum corneum. The applicator applies the microneedle array to the stratum corneum with an impact energy density of at least 0.05 joules per cm 2 at 10 milliseconds or less, about 0.26 joules per cm 2 at 10 milliseconds or less, or about 0.52 joules per cm 2 at 10 milliseconds or less. It is adapted to.

2 (a) and 2 (b), the intradermal delivery system includes a patch having an adhesive backing on one surface and a glossy metal surface on the other side consisting of an array of drug-coated microneedles. do. The patch can be applied to the skin by hand or preferably by pressing the shiny metallic surface towards the skin by an applicator. Preferably, the applicator applies a patch to the skin with an impact energy density of 0.26 Joules per cm 2 at 10 milliseconds or less. 2A, 2B, 3A and 3B, the patch can be connected and supported by a retainer ring structure forming a patch assembly. The retainer ring fits onto the impact adapter and is adapted to removably attach the patch to the applicator. The retainer ring structure can include an inner ring and an outer ring, which are designed to accommodate an adhesive patch and microneedle array. 5 (a)-(e) show an embodiment of the claimed invention, the user facilitates the connection of the impact applicator to the retainer ring, wherein the patch and the microneedle array are already in the retainer ring. It is loaded. As shown, when the retainer ring and the impact applicator are connected, the user can unlock the impact applicator by twisting the applicator cap. 5 (c) shows that the user can then press the applicator down on the skin, dispensing the patch and applying it to the skin. The patch will be removably attached to the patient's skin, and the retainer ring remains attached to the applicator. 4 (a) and 4 (b), the retainer ring is reversibly attached to the impact applicator, impacting during subsequent dosing cases with additional patch assemblies and potentially for other active ingredients and disease states The applicator can be reused.

In another embodiment, the patch and applicator are supplied as a single, integrated unit with packaging that ensures stability and sterility of the formulation. The user takes the system out of the packaging and applies the patch as described above. The used applicator is then discarded. This embodiment provides a slightly higher cost per dose, but less complex, smaller, lighter, and easier to use system.

The present disclosure can also be used with a wide range of active transdermal systems (as opposed to the passive intradermal devices described herein), as the present disclosure is not limited in any way in this regard. .

Some active transdermal systems use electron transport. Exemplary electron transport drug delivery systems include US Patent Nos. 5,147,296; 5,080,646; 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, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process involved in transdermal transport of uncharged or neutrally charged molecules (e.g., transdermal sampling of glucose), involves the movement of the agent and solvent through the membrane under the influence of an electric field. do. Another type of electroporation, electroporation, involves the passage of the agent through the pores formed by applying electrical pulses, high voltage pulses to the membrane. In many cases, more than one of the processes mentioned can occur simultaneously to different degrees. Thus, the term “electrotransport” is intended to include the electrically induced or enhanced transport of at least one charged or uncharged agent or mixtures thereof, regardless of the specific mechanism (s) in which the agent is actually transported. It is provided herein in a broad rational interpretation.

In addition, any other transport enhancement method including, but not limited to, chemical penetration enhancement, laser ablation, thermal, ultrasonic, or piezoelectric devices can be used with the disclosure herein.

IV. Active formulation and biocompatible coating

The coating formulation applied to the microprotrusion member described above to form a solid coating consists of a liquid, preferably an aqueous formulation having at least one biologically active agent, wherein the at least one biologically active agent is in a biocompatible carrier. It can be dissolved or suspended in the carrier. The biologically active agents include zolmitriptan, sumatriptan, lizatriptan, naratriptan, eletriptan, almotriptan, provatriptan, atriptriptan and adonittriptan, and pharmaceutically active agents thereof. It can be an acceptable salt, fragment, analog or prodrug. Preferably, the biologically active agent is zolmitriptan.

Examples of pharmaceutically 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, tricavalylate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpro Cypionate, tiglate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydraacrylate, ascorbate, aspartate, glutamate, 2-hydroxy Isobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, Benzene sulfonate, methane sulfonate, sulfate and sulfonate.

The concentration of biologically active ingredient and excipients achieves the desired amount of active ingredient with an acceptable coating thickness, while maintaining the uniformity of the coating, while avoiding wicking of the coating formulation on the base of the microneedle array, It must be carefully controlled to ensure safety. In one embodiment, the active agent is present 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% do. The formulation may further include an acid at a concentration of about 0.1% w / w to about 20% w / w. These acids can be selected individually or in combination from tartaric acid, citric acid, succinic acid, malic acid, maleic acid, ascorbic acid, lactic acid, hydrochloric acid. In another embodiment, in the coating formulation, the ratio of active agent to acid is about 1: 1, about 2: 1, about 3: 1, about 4: 1 or about 5: 1. The present disclosure further includes a coating formulation comprising about 33% w / w zolmitriptan base and about 11% w / w tartaric acid. In some embodiments, the acid is one of tartaric acid, citric acid, succinic acid, malic acid or maleic acid, and is about 0.33% to 10% w / w, or about 8.33% to about 16.67% w / w, or about 13.33% w / w , Or about 15% w / w, or about 6.67% w / w. In some embodiments, the coating formulation comprises 45% w / w active agent, 15% w / w acid and 40% w / w water.

Surfactants can be included in the coating formulation. Surfactants suitable for inclusion in the coating formulation include, but are not limited to, polysorbate 20 and polysorbate 80. Surfactants are commonly used as penetration enhancers to improve drug delivery. However, Applicants have found that the surfactant causes undulation in the coating formulation, which represents an uneven film and is very disadvantageous. Applicants have found that the use of the claimed invention, particularly through the claimed zolmitriptan transdermal delivery patch, can avoid the need for surfactants and other penetration enhancers. In addition, Applicants have surprisingly found that the microneedle coating prevents wicking, and despite the absence of surfactant, the coating sufficiently adheres to the microprotrusion during the manufacturing process of the microneedle array.

Antioxidants can be included in the coating formulation. Antioxidants suitable for inclusion in the coating formulation include, but are not limited to, methionine, ascorbic acid, and EDTA.

The coating formulation further comprises a sufficient amount (qs ad) of liquid, preferably water, to make the formulation 100% before drying on the microneedle. The liquid coating formulation may have a pH of less than about pH 8. In other cases, the pH is about pH 3 to 7.4, or about pH 3.5 to 4.5.

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

Table 1. Coating formulations

The present disclosure contemplates that sumatriptan or other tryptane can replace zolmitriptan in an amount or ratio similar to that described above.

Liquid coating formulations according to the present disclosure generally exhibit the ability to consistently coat the microneedle in an appropriate amount and form, and are stable solid-state (dried) containing less than 5% water, preferably less than 3%. Resulting in formulation. The liquid formulation is applied to the microneedle array and its microprotrusion tip using an engineered coater that precisely controls the depth of the microprotrusion tip being dip into the liquid film. Examples of suitable coating techniques are described in US Pat. No. 6,855,372, which is incorporated herein by reference in its entirety. Thus, the viscosity of the liquid plays a role in the microprotrusion member coating process as described. Ameri, M .; Fan, SC; Maa, YF (2010); "Parathyroid hormone PTH (1-34) formulation that enables uniform coating on a novel transdermal microprojection delivery system;" Pharmaceutical Research, 27, 303-313; See also Ameri M, Wang X, Maa YF (2010); See also "Effect of irradiation on parathyroid hormone PTH (1-34) coated on a novel transdermal microprojection delivery system to produce a sterile product-adhesive compatibility," Journal of Pharmaceutical Sciences, 99, 2123-34.

Coating formulations comprising zolmitriptan may be 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 250 cP and about 100 cP Has an excess viscosity. In some embodiments, the viscosity of the liquid formulation prior to coating is at least 20 cP. In other embodiments, the viscosity is about 25 cP, or about 30 cP, or about 35 cP, or about 40 cP, or about 45 cP, or about 50 cP, or about 55 cP, or about 60 cP, or about 65 cP, or about 70 cP, or about 75 cP, or about 80 cP, or about 85 cP, or about 90 cP, or about 95 cP, or about 100 cP, or about 150 cP, or about 200 cP, or about 300 cP or about 400 cP, or about 500 cP. In other embodiments, the viscosity is greater than about 25 cP, or greater than about 30 cP, or greater than about 35 cP, or greater than about 40 cP, or greater than about 45 cP, or greater than about 50 cP, or greater than about 55 cP, or Greater than about 60 cP, or greater than about 65 cP, or greater than about 70 cP, or greater than about 75 cP, or greater than about 80 cP, or greater than about 85 cP, or greater than about 90 cP, or greater than about 95 cP, or greater than about 100 greater than 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.

When the coating formulation is applied to the microprotrusion, the coating formulation is about 10 to about 400 microns, or about 30 to about 300 microns, or about 100 microns to about 175 microns, or about 115 as measured from the microprotrusion surface To about 150 microns, or about 135 microns. The coating formulation preferably has a uniform thickness that covers the microprotrusions, but the formulation may vary slightly as a result of the manufacturing process. As shown in FIG. 31, the microprotrusions are generally uniformly coated because they penetrate the stratum corneum. In some embodiments, the microprotrusion is not coated with the entire distance from the tip to the base; Instead, the coating is at least about 10% to about 80%, or 20% to about 70%, or about 30% to about 30% of the length of the microprotrusion, which is part of the length of the microprotrusion measured from the tip to the base 60%, or about 40% to about 50%.

The liquid coating formulation is applied to an array of microprotrusions to deliver a dosage of the active agent in an amount of about 0.1 mg to 10 mg per array. For zolmitriptan, the dosage 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, delivered to the stratum corneum per array (via patches or other forms), 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 to 1000 μg or 10 to 100 μg. In one embodiment, the array size is about 5.5 cm 2 comprising a dose of about 3.8 mg zolmitriptan, or the array size is about 3 cm 2 comprising a dose of about 3.8 mg, or the array size is about 1.9 about 3 cm 2, including the dosage of mg. The amount of zolmitriptan or similar active agent per microprotuberance can range from about 0.001 to about 1000 μg, or from about 0.01 to about 100 μg, or from about 0.1 to about 10 μg, or from about 0.5 to about 2 μg. In one embodiment, the amount of zolmitriptan or similar active agent per microprotuberance is about 1 μg. The shape and size of the microprotrusion have a significant effect on the drug loading capacity and the effect of drug delivery.

Importantly, the combinations of the present disclosure are not so dependent on penetration enhancers to facilitate the absorption of the active agent into the bloodstream. Penetration enhancers such as Azone® and fatty acids often cause skin irritation and have other disadvantages. Thus, the system of the present disclosure is completely or substantially free of penetration enhancers. In other embodiments, less than 15% w / w penetration enhancer is present, 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 It is present in the dried formulation.

The biologically active agent formulation is generally prepared as a solid coating by drying the coating formulation on the microprotuberance as described in US Application Publication No. 2002/0128599. The coating formulation is generally an aqueous formulation. During the drying process, most of all volatiles, including water, are removed; However, the final solid coating is still about 1% w / w water, or about 2% w / w water, or about 3% w / w water, or about 4% w / w water, or about 5% w / w water It may contain. The oxygen and / or moisture content present in the formulation is reduced by using a dry inert atmosphere and / or partial vacuum. In solid coatings on microprotrusion arrays, 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 can be less than about 15 mg per unit dose.

The microprotrusion member is typically on an adhesive backing attached to a disposable polymer retainer ring. This assembly is individually packaged in a pouch or polymer housing. In addition to the assembly, this package contains a dead volume corresponding to a volume of at least 3 mL. This large volume (compared to the coating volume) acts as a partial sink for water. For example, at 20 ° C., the amount of water present in a 3 mL atmosphere as a result of vapor pressure is about 0.05 mg upon saturation, which is typically the amount of residual moisture present in the solid coating after drying. Therefore, storage in a dry inert atmosphere and / or partial vacuum will further reduce the moisture content of the coating, improving stability.

According to the present disclosure, the coating can be applied to the microprotrusion by various known methods. For example, the coating may be applied only to the microprotrusion member or the microprotrusion portion that penetrates the skin (eg, a tip). Thereafter, the coating is dried to form a solid coating. One such coating method involves dip-coating. Dip-coating may be described as a method of coating the microprotrusion by partially or completely immersing the microprotrusion in a coating solution. By using a partial immersion technique, it is possible to limit the coating to only the tip of the microprotrusion.

Additional coating methods include roller coating, which similarly utilizes a roller coating mechanism that limits the coating to the tip of the microprotrusion. The roller coating method is disclosed in US Patent Publication No. 2002/0132054. As discussed in detail herein, the disclosed roller coating method provides a smooth coating that is not easily removed from the microprotrusions while piercing the skin.

Additional coating methods that can be used within the scope of the present invention include spray coating. Spray coating can include the formation of an aerosol suspension of the coating composition. In one embodiment, an aerosol suspension having a droplet size of about 10 to 200 picolitres is sprayed onto the microprotrusion and then dried.

Pattern coating may also be used to coat the microprotrusions. The pattern coating can be applied using a dispensing system to place the deposited liquid on the microprotrusion surface. The amount of the deposited liquid is preferably in the range of 0.1 to 20 nanoliters / microprojection. Examples of suitable precision-metered liquid dispensers are described in US Pat. No. 5,916,524; 5,743,960; No. 5,741,554; And 5,738,728, which are fully incorporated herein by reference.

The microprotrusion coating formulation or solution can also be applied using inkjet technology using known solenoid valve dispensers, optional fluid power means, and positioning means generally controlled using an electric field. Other liquid dispensing techniques in the printing industry or similar liquid dispensing techniques known in the art can be used to apply the pattern coating of the present invention.

In one embodiment of the present disclosure, the thickness of the dried coating formulation comprising zolmitriptan is about 10 to 100 microns, or about 20 to 80 microns, or about 30 to 60 microns, or about as measured from the microprotrusion surface It ranges from 40 to 50 microns. The desired coating thickness depends on several factors, including the required dosage and thus the coating thickness required to deliver the dosage, the density of microprotrusions per unit area of the sheet, the viscosity, solubility and concentration of the coating composition, and the coating method chosen. The thickness of the coating applied to the microprotrusions can also be adapted to optimize the stability of zolmitriptan. Known formulation adjuvants can also be added to the coating formulation as long as it does not adversely affect the required solubility and viscosity characteristics of the coating formulation, or the physical integrity of the dried coating.

The coating is applied to the microneedle, which protrudes from the base or branch 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 is advantageous in light of FDA guidance on the risk of residual drugs on transdermal delivery systems, which reduces the amount of drug per transdermal patch and suggests 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). Applicant's strategy was to maximize drug release to the skin per unit area without using an excess of drug for coating.

After the coating is applied, the coating formulation is dried on the microprotrusion by various means. The coated microprotrusion member can be dried under ambient space conditions. However, various temperature and humidity levels can be used to dry the coating formulation on the microprotrusion. Additionally, the coated member can be heated, stored under vacuum or on a desiccant, lyophilized, or freeze dried, or similar techniques are used to remove residual moisture from the coating. Can be.

Coating was performed at ambient temperature using a roller drum rotating at 50 rpm in a drug formulation reservoir (2 mL volume), resulting in a film with a controlled thickness of about 270 μm thickness. Additional information about the coating process can be found in US Pat. No. 6,855,372, which is incorporated herein by reference in its entirety. The microprotrusion array is dipping into the drug film, and the amount of coating is controlled by the number of dippings (passes) passing through the drug film.

During the drying process, there may be problems with forming a uniform coating on the microprotrusions with a controlled consistent thickness. One conventional problem in transdermal patch coatings, called "dripping" or "teardrop" formation, is that the coating is dried and the coating is shaped like a "drop of water" at the end of the microprotrusion. It occurs when it accumulates. This teardrop shape can blunt the sharp end of the microneedle and affect the effectiveness and uniformity of penetration. The uneven layer of the formulation on the microprotuberance results in non-uniform and sometimes inappropriate drug delivery. In addition, problems in the drying process cause quality control problems of the formulation coating. Preferred liquid coating formulations contain 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 Amount, 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 Liquid carrier, preferably water, more preferably in deionized water. Using these liquid coating formulations, Applicants surprisingly 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 about 50 mNm ^-1 to about 72 It has been found that maintaining a surface tension of mNm- ¹ , preferably about 55 mNm- ¹ to about 65 mNm- ¹ , more preferably about 62.5 mNm- ¹ , is required to avoid dropping. Teardrop formation could be prevented by allowing each dipping into the liquid coating formulation of the microprotrusions to pick up a sufficient volume of the liquid coating formulation to achieve the desired drug dosage by a minimum number of dippings. When the viscosity and surface tension of the coating solution are sufficiently high, the coated liquid does not quickly drop or form a teardrop shape after dipping and before drying.

The products and methods described herein in connection with the delivery of zolmitriptan in a method of rapidly achieving a therapeutic concentration of zolmitriptan for the treatment of migraine or cluster headache include sumatriptan, lizatriptan, naratriptan, eletrip It can be applied to other triptans, including charcoal, almotriptan, probartriptan, avitriptan, and dontriptan.

In one aspect, the route of administration of zolmitriptan is intramuscular, intracutaneously, subcutaneously, intranasally, oral inhalation, transdermal, buccal, lung or sublingual. For example, a formulation designed for intramuscular or subcutaneous delivery will contain 1 mg of zolmitriptan (base) and 0.3 mg of tartaric acid in 1 mL of 0.9% w / v saline. In addition, formulations designed for pulmonary delivery may include zolmitriptan salts dissolved or suspended in water or zolmitriptan powder produced using milling, supercritical fluid processing, spray drying or spray freeze drying for inhalation delivery. It will be in the form and will produce respirable particles with a controlled particle size of about 0.5 to 5.8 μm mass aerodynamic median diameter (MMAD) to ensure that a significant portion of zolmitriptan is deposited in the lungs. The process for producing zolmitriptan powder can be used directly by metering from a powder reservoir or by pre-weighing in the form of a dry powder inhaler (DPI), or the particulate is a pharmaceutically acceptable propellant in the form of a metered dose inhaler (MDI). Suspension media such as hydrofluoroalkanes (1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, and 1, Suspension / dispersion directly in a mixture selected from the group consisting of 1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof) Can be. The resulting particles may be crystalline or amorphous depending on the process generating zolmitriptan powder. In one aspect, the dosage of zolmitriptan is in the range of 0.5-4 mg administered at the onset of migraine or cluster headache.

V. Packaging, Sterilization

The improved physical stability of dry coated formulations not only provides the advantage of increased shelf or shelf life of the therapeutic agent itself, but once stabilized according to the compositions and methods for formulation and delivery of the present invention, the therapeutic agent It improves efficacy as it becomes useful in a larger range of possible formulations and with a wider variety of therapeutic delivery means.

The present disclosure includes active agent formulations in which the active agent formulation is prepared and / or packaged in a dry inert atmosphere such that degradation by oxygen and / or water is minimized and / or controlled. The formulation may be contained in a dry inert atmosphere in the presence of a desiccant, optionally in a chamber or package comprising a layer of foil.

The desiccant may be any known to those skilled in the art. Some conventional desiccants include, but are not limited to, molecular sieves, calcium oxide, clay desiccants, calcium sulfate and silica gel. The desiccant can be one that can be co-located with the biologically active agent-containing formulation in the presence of an inert atmosphere in a package comprising a foil layer.

In another aspect, the active agent formulation is packaged in a chamber comprising a layer of foil after the formulation is coated on the microprotrusion array delivery device. In this embodiment, the desiccant is contained within the chamber, preferably attached to a chamber lid comprising a layer of foil, and the chamber is dried nitrogen or other inert before the transfer device-containing foil chamber is sealed with the foil lid. It is purged with a gas, for example, a noble gas. Any suitable inert gas can be used herein to form a dry inert atmosphere.

In one embodiment, compositions and methods for the formulation and delivery of zolmitriptan suitable for intradermal delivery utilize patch assemblies. This 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 made in a dry inert atmosphere and / or is packaged in a chamber comprising a layer of foil and having a dry inert atmosphere and a desiccant. In one embodiment, the patch assembly is manufactured and / or packaged in partial vacuum. In one embodiment, the patch assembly is manufactured and / or packaged in a dry inert atmosphere and partial vacuum. In one embodiment, the patch assembly is made in a dry inert atmosphere under partial vacuum and / or is packaged in a chamber comprising a foil layer and having a dry inert atmosphere, partial vacuum and desiccant.

Generally, in the mentioned embodiments of the present invention, the inert atmosphere should have a moisture content of essentially zero. For example, a nitrogen gas (dry nitrogen gas) with an essentially zero moisture content can be produced by electrical controlled boiling of liquid nitrogen. Purging systems can also be used to reduce moisture or oxygen content. The partial vacuum ranges from about 0.01 to about 0.3 atmosphere.

In aspects of this embodiment, the zolmitriptan further comprises a biocompatible carrier. In another embodiment, an intradermal delivery system adapted to deliver zolmitriptan, comprising: (a) a microprotrusion member comprising a plurality of microprotrusions adapted to penetrate a patient's stratum corneum; (b) a hydrogel formulation composed of zolmitriptan, wherein the hydrogel formulation is a hydrogel formulation in communication with the microprotrusion member; And (c) a packaging material purged by an inert gas and adapted to control environmental conditions sealed around the microprotrusion member, wherein the sealed package is exposed to radiation to sterilize the microprotrusion member. There is an intradermal delivery system.

In another embodiment, an intradermal delivery system adapted to deliver zolmitriptan, comprising: (a) a microprotrusion member comprising a plurality of microprotrusions adapted to penetrate a patient's stratum corneum; (b) a solid film disposed proximate to the microprotrusion member, the solid film being prepared by casting a liquid formulation comprising zolmitriptan, a polymeric material, a plasticizer, a surfactant, and a volatile solvent; And (c) a packaging material purged with an inert gas and adapted to control environmental conditions sealed around the microprotrusion member, wherein the sealed package is exposed to radiation to sterilize the microprotrusion member. There is an intradermal delivery system.

The present disclosure also relates to a method of terminally sterilizing a patch assembly adapted to deliver zolmitriptan, comprising: (a) a stratum corneum layer of a patient having a biocompatible coating comprising zolmitriptan disposed on a microprotrusion member Providing a microprotrusion member having a plurality of microprotrusions adapted to pierce; And (b) exposing the microprotrusion member to radiation selected from the group consisting of gamma radiation and e-beams, wherein the radiation is sufficient to reach a desired level of sterility assurance. These sterile assurance level of ^10-6 or 10 ^- can be ^five. The method comprises the steps of sealing the microprotrusion member with a desiccant inside the packaging material purged with an inert gas and exposing the packaged microprotrusion member to radiation selected from the group consisting of gamma radiation and e-beam radiation, wherein the radiation is intended The method may further include a step that is sufficient to reach a sterile assurance level.

In an aspect of this embodiment, the method comprises mounting a patch consisting of a microprotrusion member attached to an adhesive backing on a pre-dried retainer ring to form a patch assembly, and subsequently the microprotrusion within the packaging. And sealing the member. In aspects of this embodiment, the system further comprises a desiccant sealed inside the packaging material, together with the patch assembly, and / or the packaging material is purged with nitrogen and / or the packaging material comprises a pouch composed of a foil layer. Preferably, the foil layer comprises aluminum.

The step of exposing the microprotrusion member to radiation may occur at approximately -78.5 to 25 ° C, or the member may be exposed to radiation at ambient temperature. The radiation may range from approximately 5-50 kGy, or approximately 10-30 kGy, or approximately 15-25 kGy, or approximately 21 kGy, or approximately 7 kGy. In one aspect of this embodiment, the radiation is delivered to the microprotrusion member at a rate of at least approximately 3.0 kGy / hr.

As described herein, Applicants when coated on a microneedle member of the present disclosure at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least after exposure to radiation as described above A zolmitriptan formulation was developed that was stable for 24 months and retained its amorphous character.

In one embodiment, the dried zolmitriptan formulation on the microneedle is at least about 100% of initial purity, or about 99% of initial purity, or about 98% of initial purity, or about 97% of initial purity for at least 6 months. , Or approximately 96% of initial purity, or approximately 95% of initial purity, or approximately 90% of initial purity. In another aspect, this purity is maintained for at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months after packaging. In a further embodiment, the zolmitriptan coating on the microneedle maintains its purity as described in this paragraph, and also after packaging at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or It retains substantially its amorphous properties for at least 24 months.

In one embodiment, a method of making a patch assembly for an intradermal delivery system adapted to deliver zolmitriptan comprises the following steps: penetrating the stratum corneum of a patient, with a biocompatible coating disposed on a microneedle member. Or providing a microneedle member having a plurality of microneedles adapted to pierce, wherein the coating is formed from and disposed over a coating formulation with zolmitriptan; Sealing the microneedle member with a desiccant inside a packaging material purged with nitrogen and adapted to control the ambient conditions surrounding the microneedle; And exposing the microneedle member to radiation selected from the group consisting of gamma radiation, e-beam and x-ray, wherein the radiation is sufficient to reach the desired sterility assurance level.

According to another embodiment of the invention, a method of delivering a stable biologically active agent formulation comprises the following steps: (i) providing a microprotrusion member having a plurality of microprotrusions, (ii) of the biologically active agent. Providing a stabilized formulation; (iii) forming a biocompatible coating formulation comprising a formulation of a stabilized biologically active agent, (iv) coating the microprotrusion member with the biocompatible coating formulation to form a biocompatible coating; (v) stabilizing the biocompatible coating by drying; And (vi) applying the coated microprotrusion member to the subject's skin.

Additionally, the optimum stability and shelf life of the formulation is achieved by a solid, substantially dry biocompatible coating. However, the kinetics of dissolution of the coating and release of the formulation can vary significantly depending on a number of factors. It will be understood that, in addition to being storage stable, the biocompatible coating should allow for the desired release of the therapeutic agent.

A method of terminally sterilizing a transdermal device adapted to deliver zolmitriptan, the microprotrusion having a plurality of microprotrusions adapted to penetrate or penetrate the stratum corneum of a patient, with a biocompatible coating disposed on the microprotrusion member Providing a member, wherein the coating is formed from and disposed on a coating formulation having at least one tryptan, preferably zolmitriptan; And exposing the microprotrusion member to radiation selected from the group consisting of gamma radiation and e-beams, wherein the radiation is sufficient to reach a desired sterility assurance level. A further aspect of the method includes the additional step of sealing the microprotrusion member inside a packaging material adapted to control the ambient conditions surrounding the microprotrusion member. In one aspect, the packaging material includes a foil pouch. An additional aspect of the method includes the additional step of sealing the desiccant inside the packaging. The method also includes mounting the microprotrusion member on a pre-dried retainer ring prior to sealing the microprotrusion member in the packaging. A further aspect of the method includes purging the packaging material with an inert gas prior to sealing the packaging material. In one embodiment, the inert gas comprises nitrogen.

VI. In vivo  Pharmacokinetics (PK)

The intradermal / dermal system of the present invention provides serum concentrations to the bloodstream more rapidly at less total drug exposure compared to oral dosages of the same drug. For example, absorption of intradermal administered zolmitriptan delivered through the system of the present disclosure results in a C _max of less than 50 mg / mL and a T _max of about 2 to 30 minutes. In another embodiment, the plasma zolmitriptan AUC for the first 2 hours is greater than that seen after oral administration, but the plasma zolmitriptan AUC _{(0-24 hr)} is greater than that seen after oral administration. Less

In a further aspect, the absorption of the jolmi triptans causes an increase of Tan maximum plasma jolmi trips but, N- desmethyl jolmi triptans generated _- and is reduced (AUC _{0 24hr),} the low transfer potential metabolites accumulated by him Have Intradermal administration of tryptan, including zolmitriptan, prevents the first pass metabolism in the liver found in oral administration, resulting in higher bioavailability. In particular, the metabolism is significantly reduced, so that the serum concentration of N-desmethyl zolmitriptan at least about the post-application time point (e.g., 1.5 hours, 2 hours, 5 hours, 10 hours) than that seen in oral products. Reduce by 20% or more. In addition, zolmitriptan plasma levels may be increased, but N-desmethyl zolmitriptan production is reduced compared to that produced upon oral administration of comparable dosages of zolmitriptan. Therefore, the probability of accumulation of metabolites is lower. However, since N-desmethyl zolmitriptan is more active at the target site than zolmitriptan, the present invention is surprisingly effective in the treatment of migraine or cluster headache as detailed below. In addition, the apparent half-life of zolmitriptan is reduced compared to oral administration, and the duration of side effects may be reduced.

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

In addition, the biocompatible coating delivered intradermally comprises a dosage of zolmitriptan in the range of about 0.2 to 10 mg, preferably 1 to 5 mg, more preferably about 1.9 or 3.8 mg, and intradermal delivery of the zolmitriptan At least 2 ng / mL of zolmitriptan, at least 3.6 ng / mL of zolmitriptan, at least 4 ng / mL of zolmitriptan, at least 6 ng / mL of zolmitriptan, at least after 1 application or 2 applications 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 Resulting in plasma C _max of 60 ng / mL zolmitriptan or at least 65 ng / mL zolmitriptan.

In addition, intradermal delivery of the zolmitriptan 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, 45 minutes or less, 50 minutes or less, resulting in plasma T _max of 55 minutes or less, 2 minutes to 30 minutes, 60 minutes or less after one application .

In one embodiment, the T _max of zolmitriptan administered intradermally via the system of the invention is at least about 2 hours prior to conventional release oral zolmitriptan tablets, or at least about 1.8 hours prior to such tablets, or prior to such tablets. About 1.6 hours or more, or about 1.4 hours or more before such tablets, or 1.2 hours or more before these tablets, or about 1.0 hour or more before these tablets, or about 0.8 hours or more before these tablets, or about prior to these tablets 0.6 hours or more, or about 0.4 hours or more before such a tablet, or about 0.2 hours or more before such a tablet.

In another embodiment, the T _max of zolmitriptan administered intradermally via the system of the invention is at least about 3 hours prior to ZOMIG® (zolmitriptan) oral disintegrative tablets, or at least about 2.5 hours before such tablets, or It occurs at least about 2.0 hours before such a tablet, or at least about 1.5 hours before such a tablet, or at least about 1.0 hours before such a tablet, or at about 0.5 hours before such a tablet.

In a further embodiment, the T _max of zolmitriptan administered intradermally through the system of the invention is at least about 3 hours prior to zolmitriptan nasal spray, or at least about 2.5 hours before such spray, or about 2.0 hours before such spray Abnormality, or about 1.5 hours or more before such spray, or about 1.0 hour or more before such spray, or about 0.5 hour or more before such spray.

In another embodiment, the removal rate (t _1/2 ) for zolmitriptan administered intradermally via the system of the invention is about 0.75 hours, or 1.0 hours, or 1.1 hours, or 1.2 hours, or 1.3 hours, or 1.4 hours. , Or 1.5 hours, or 1.6 hours, or 1.7 hours, or 1.8 hours, or 1.9 hours, or 2.0 hours. The removal rate (t _1/2) is approximately twice the removal rate of the order of three times, or zolmitriptan conventional purification of the removal rate of zolmitriptan conventional tablets.

In a further embodiment, C _max for jolmi triptans that intradermal administration through the invention system is from about 1 to about 8 times as high or more C _max of tan trip conventional oral 2.5 mg jolmi tablet, or from about 1.5 to about 7 Fold higher, or about 2 to about 6 fold higher, or about 3 to about 5 fold higher, or about 4 fold higher.

In addition, the average peak exposure (C _max ) is about 2 to about 5 times higher for intradermal zolmitriptan compared to oral tablets. In a further aspect, the average peak exposure (C _max ) for the intradermal zolmitriptan of the present invention is about 1.0 to about 40.0 mg / mL, or about 5.0 to about 35.0 mg / mL, or about 10.0 to about 30.0 mg / mL , Or about 15.0 to about 25.0 mg / mL, or about 20.0 to about 30.0 mg / mL, or about 25 mg / mL.

Additionally, the intradermal zolmitriptan of the present invention has a bioavailability of about 50% to about 100% of oral bioavailability at dosages ranging from about 0.5 mg to about 4.0 mg compared to 2.5 mg of conventional oral zolmitriptan. In other embodiments, the bioavailability in the skin is about 55% to about 95%, or about 60% to about 90%, or about 65% to about 85%, or about 70% to about 80% of the oral bioavailability, or It is about 75%.

Finally, the present invention includes formulations and devices that are biologically equivalent to the M207 Intracutaneous Delivery System described herein. Accordingly, the present disclosure provides a 90% confidence interval (CI) for AUC with bioequivalence (i) 0.80 to 1.25; And (ii) a product established by 90% CI for C _{max from} 0.80 to 1.25.

VII. Treatment method

The drug-device combinations of the present invention can be used to treat a variety of diseases and conditions, including migraine and cluster headaches. In one embodiment of the invention, a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based agent And, wherein the absorption of the zolmitriptan-based agent results in a plasma C _max of less than 50 ng / mL. Dosages include from about 0.2 mg to about 10 mg of zolmitriptan. The dosage can also be 0.48 mg, 0.96 mg, 1.9 mg and 3.8 mg of zolmitriptan. Dosages also include single patch administration of 1.0 mg, 1.9 mg or 3.8 mg, or two patches of 1.9 mg. These dosages can be delivered using the patch (s) described herein and applied to the skin of any part of the body. In a preferred embodiment, the zolmitriptan dosage (s) is delivered to the upper arm via a patch to treat a single migraine or cluster headache attack.

In some embodiments, the method of treatment of migraine or cluster headache as described herein results in an improvement with respect to the following therapeutic endpoint: no migraine pain 1 hour, 2 hours or 4 hours after dosing ; No cluster headache pain 15 or 30 minutes after dosing, no annoying other migraine symptoms 1 or 2 hours after dosing; No most annoying other cluster headache symptoms previously identified by the patient at 15 or 30 minutes after dosing, migraines pain relief at 1, 2 or 4 hours; Relieve cluster headache pain at 15 or 30 minutes after dosing, relieve pain at 30 minutes; No photophobia in 2 hours; No phobia at 2 hours; Pain relief at 15 minutes; Pain relief at 3 hours; Pain relief at 4 hours; No coming in 2 hours; No pain at 30 minutes; No pain at 24 hours; And no pain at 48 hours. There is also an improvement in terms of treated patients in need of rescue medication. Improvements in pain, other most annoying symptoms, photophobia, phobia, nausea and other annoying symptoms are assessed sequentially by a fixed-sequential test method.

Tables 45-48 demonstrate the effectiveness of the claimed invention to reduce or eliminate the pain of migraine or cluster headache compared to alternative forms of tryptan and zolmitriptan. These results are based on, but not limited to, one embodiment of the claimed invention.

As shown in Table 45, the method described herein demonstrates that one embodiment of the claimed invention exhibits a significant improvement in painlessness of the patient 1 hour after dosing compared to zolmitriptan tablets. The results shown in Table 45 are just one example of the significant efficacy provided by the claimed invention, surpassing known methods for treating migraines or cluster headaches with zolmitriptan. In one embodiment of the claimed invention, at a dose of zolmitriptan at 1 mg, more than 15% of patients did not have pain at 1 hour post treatment. In another embodiment (1.9 mg), more than 20% of patients did not have pain at 1 hour. In the third embodiment (3.8 mg), more than 25% of patients did not have pain at 1 hour. This shows improved efficacy of zolmitriptan over nasal treatment, whereby only about 10% of patients have been shown to have no pain at 1 hour. The present invention is also significantly more potent than 2.5 mg, 5 mg and 10 mg tablets and 2.5 mg oral soluble tablets, all of which achieve no pain at 10% or less after 1 hour. The claimed invention also shows a significant improvement in painless results at 2 and 4 hours after treatment. In one embodiment, 2 hours after treatment, more than 30% of the patients did not have pain. In another embodiment, at 2 hours, more than 40% of patients did not have pain. In a third embodiment, 4 hours after treatment, more than 50% of the patients did not have pain. This is a significant improvement over nasal treatment with zolmitriptan, where less than 25% and 40% of the patients, respectively, after 2 and 4 hours from treatment did not have pain. These results were also comparable to other zolmitriptan dosage forms and delivery routes and did not have pain at 40% in 2 hours, better than all other zolmitriptan dosage forms and delivery routes. These results are also shown graphically in FIG. 25.

Table 46 provides a comparison of pain relief results between the present invention and current methods claimed to treat migraine or cluster headaches with zolmitriptan. In the 1 mg, 1.9 mg and 3.8 mg embodiments, pain relief of more than 45%, 55% and 65%, respectively, was achieved only 1 hour after dosing, respectively. More than 65%, 68% and 80% respectively experienced pain relief 2 hours after dosing. In an embodiment of 3.8 mg, more than 80% of patients experienced pain relief 4 hours after dosing. All three embodiments demonstrated significant improvement in pain relief at 1 hour compared to other zolmitriptan dosage forms and delivery routes, and the 3.8 mg embodiment was also superior to other zolmitriptan dosage forms at 2 and 4 hours. . These results are shown graphically in FIG. 26.

Tables 47 and 48 show a significant improvement of the claimed invention over other trytans used in the treatment of migraine or cluster headaches to eliminate or reduce migraine or cluster headache pain. As shown in Table 47, the claimed invention shows a significant improvement in painless results, over other trytans currently used in the art. At 17.7%, 20.5% and 26.8% painless at 1 hour for each of the 1 mg, 1.9 mg and 3.8 mg embodiments, all three intensities achieved a higher level of painlessness than any other tryptan . At 41.5% and 54.9% no pain at 2 and 4 hours, the 3.8 mg embodiment was much better than all other trytans. These results are shown graphically in FIG. 27. As shown in Table 48, the claimed invention shows a significant improvement in pain relief results, over other trytans currently used in the art. At 46.8%, 55.4% and 68.3% pain relief at 1 hour for each of the 1 mg, 1.9 mg and 3.8 mg embodiments above, all three intensities achieved a higher level of pain relief than any other tryptan . At 80.5% and 82.9% pain relief at 2 and 4 hours, the 3.8 mg embodiment was much better than all other trytans. These results are shown graphically in FIG. 28. In another aspect, the plasma T _max of the zolmitriptan-based formulation administered is about 2 minutes to 30 minutes. In one embodiment, administration of the zolmitriptan-based agent is by transdermal or intradermal administration. Alternatively, the route of administration of the zolmitriptan-based agent is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal or sublingual.

In another embodiment, as a method of treating or alleviating migraine or cluster headache in an individual in need thereof, administering a therapeutically effective amount of a zolmitriptan-based agent, the first 2 hours While plasma zolmitriptan AUC is greater than plasma zolmitriptan AUC after oral administration of an equivalent dosage of zolmitriptan, plasma zolmitriptan AUC _{0 -inf} after intradermal administration of a therapeutically effective amount of zolmitriptan-based agent is an equivalent dosage There is a method comprising the step of less than the plasma zolmitriptan AUC _{0 -inf} seen after oral administration of zolmitriptan. In one aspect of this embodiment, the administration of the zolmitriptan-based agent is transdermal or intradermal administration. In one aspect of this embodiment, the route of administration of the zolmitriptan-based agent is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal or sublingual.

In another embodiment, as a method of treating or alleviating migraine or cluster headache in an individual in need of a therapeutically effective amount of a zolmitriptan-based agent, zolmitriptan plasma as compared to oral administration of an equivalent dosage of zolmitriptan There are ways to increase the level, but decrease the production of N-desmethyl zolmitriptan, thereby reducing the likelihood of metabolite accumulation. In one aspect of this embodiment, the administration of the zolmitriptan-based agent is transdermal or intradermal administration. In one aspect of this embodiment, the route of administration of the zolmitriptan-based agent is intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal or sublingual.

In another embodiment, a method of treating or alleviating migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based agent, and an equivalent dosage There is a method in which the apparent half-life of zolmitriptan is reduced compared to the oral administration of zolmitriptan, thereby indicating the possibility of reducing the duration of side effects. In one aspect of this embodiment, the administration of the zolmitriptan-based agent is transdermal or intradermal administration. In one aspect of this embodiment, the route of administration of the zolmitriptan-based agent is intravenous, intramuscular, intradermal, subcutaneous, oral, intranasal, oral inhalation, transdermal, buccal or sublingual.

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

In one aspect of this embodiment, the zolmitriptan-based formulation administered intradermally provides a pharmacokinetic profile similar to the pharmacokinetic profile provided by subcutaneous administration of a dosage equivalent to the sumatriptan-based formulation administered intradermally.

In one aspect of how zolmitriptan is administered, administration of zolmitriptan is not associated with a greater effect on blood pressure than is seen with oral zolmitriptan despite faster absorption.

In one embodiment, a method of treating or alleviating a migraine or cluster headache in an individual in need thereof, comprising administering a therapeutically effective amount of a zolmitriptan-based agent, the maximum plasma concentration There is a method in which the time to achieve (T _max ) is equal to or less than T _max of the equivalent oral dosage of zolmitriptan. In one aspect of this embodiment, the administration of the zolmitriptan-based agent is transdermal or intradermal administration. In one aspect of this embodiment, the route of administration of the zolmitriptan-based agent is intravenous, subcutaneous, oral, intranasal, oral inhalation, intradermal, transdermal, buccal or sublingual. In one aspect of these embodiments, the incidence of N-desmethyl zolmitriptan is reduced compared to the occurrence of N-desmethyl zolmitriptan arising from oral administration of an equivalent amount of zolmitriptan based formulation. In another aspect of these embodiments, absorption of zolmitriptan-based agents administered intradermally results in a C _max of less than 50 ng / mL.

VIII. Example

The following examples are included to demonstrate some embodiments of the invention. However, it should be understood by those skilled in the art that, in light of the present disclosure, variations can be made in the specific embodiments disclosed and similar or similar results can be obtained without departing from the spirit and scope of the invention. Therefore, all matters described should be interpreted as illustrative rather than restrictive.

In the examples below, unless stated otherwise, the microprotrusion array is prepared by photo / chemical etching and is formed using a controlled manufacturing process. This method is incorporated herein by reference in its entirety [M. Cormier et al., "Device for enhancing transdermal agent delivery or sampling", EP 0914178B. The drug formulation coating on the microprotrusion array was performed at ambient temperature using a roller drum rotating at 50 rpm in a drug formulation reservoir (2 mL volume), resulting in a controlled thickness drug coating formulation film. This method is incorporated herein by reference in its entirety by J.C. Trautman et al., “Method and apparatus for coating skin piercing microprojections”, US Pat. No. 6,855,372; J.C. Trautman et al., “Method and apparatus for coating skin piercing microprojections”, substantially similar to that described in US Pat. No. 7,435,299. The microprotrusion is dipping into the film. The amount of coating is controlled by the properties of the drug coating formulation as well as the number of dippings (passing) through the drug film. The time between each dipping was several seconds, which was sufficient to dry the coated liquid formulation under ambient conditions. The reservoir was circulated with a coolant to maintain a film temperature of 1 ° C. Since the reservoir was open to ambient air, the coating device was placed inside the dew point control system. Dew point control minimizes moisture condensation or evaporation from the liquid formulation during coating. The zolmitriptan-coated microneedle array is combined with the adhesive backing to form a patch, and mounted on a retainer ring to form a patch assembly. The patch assembly was packaged in an aluminum pouch (Mangar, New Britain, Pa.), Purged with dry nitrogen, and heat-sealed with a Multivac heat sealer (Model C400) (Multivac, Kansas City, Missouri, USA).

Example  One- Zolmitriptan  coating Formulation , Characterization, physical properties

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

Table 2: Solubility of zolmitriptan in various acids at 2-8 ° C

Zolmitriptan shows good solubility in various acids. It was noted that the rheological behavior of the zolmitriptan solution was affected by counterion in the formulation for pH control. Several weak acid buffers were tested, including one triacid (citric acid) and two diacids (maleic acid and tartaric acid). The zolmitriptan formulations prepared using citric acid, maleic acid and tartaric acid were pH 5.2, 4.3 and 6.2, respectively, at the pKa of the acid. The viscosity profile of formulations comprising these acids was measured as a function of time. Citric acid and maleic acid buffered formulations exhibited rheological behavior, ie an increase in viscosity as a function of time, while formulations buffered with tartaric acid maintained relatively uniform viscosity over time. Given the overall rheological results, tartaric acid was chosen as the counterion for pH adjustment.

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

The static contact angle of the drug solution formulation on the titanium surface was determined using an FDS contact angle meter (Model OCA15) using an optical contact angle method called “Sessile drop”. For static contact angle measurements, once a drop of the solution (5 μL) is dispensed from the syringe and placed on a clean titanium foil surface, a photo snapshot is taken. The angle between the reference line of the droplet and the tangent at the droplet boundary is measured on both sides. The two numbers were averaged to obtain a complete measurement. At least 5 readings were recorded for each sample.

A coating test with 33% w / w zolmitriptan, 11% w / w tartaric acid, 0.2% w / w polysorbate 20, and sufficient amount of deionized water was performed. The drug formulation coating on the microprotrusion array was performed at ambient temperature using a roller drum rotating at 50 rpm in the drug formulation reservoir (2 mL volume) to produce a controlled thickness drug formulation film. The microprotrusion was dipped into the drug film. The amount of coating was controlled by the number of dipping (passing) through the drug coating formulation film. The time between each dipping was only a few seconds, which was sufficient to dry the coated liquid formulation under ambient conditions. Since the reservoir was open to ambient air, the coating device was placed inside the dew point control system. This process is designed to match the drug film temperature to the air dew point, preventing evaporation of the coating formulation during the manufacturing run. However, the undulation of the zolmitriptan liquid formulation was visually noted, which is a symptom of an uneven film. The concentration of zolmitriptan in the liquid formulation was increased up to 51% w / w (tartaric acid in the formulation was 17% w / w and 0.2% w / w polysorbate 20). At higher solids content formulations, the corrugation of the film was still noted. Subsequently, it was noted that the polysorbate 20 was removed and the waveform was no longer present. This is a surprising and non-obvious result because conventional pharmaceutical teaching supported the use of surfactants to facilitate the production of smooth and uniform coatings.

In another coating embodiment, the 33% w / w zolmitriptan, 11% w / w tartaric acid and 56% w / w deionized water combination causes a high incidence of wicking on the particular microprotrusion array used, thereby, The drug was not attached to the microprotrusion. Although the viscosity of the formulation was 22 cP, the design of the microprotrusions (120 μm wide, 340 μm long) and the thick drug film (calculated film thickness 270 μm), at each dipping into the drug film, were The microprojections take a volume of liquid that cannot be dried quickly enough to cause the drug film to spread to the base of the microprojections. A higher solids content blend of 40% w / w zolmitriptan, 13.3% w / w tartaric acid and 46.7% w / w deionized water (M207) with a viscosity of 85 cP uniformly coated the microprotuberances, no wicking This was noticed. This formulation was used for further evaluation. Representative batch formulations are provided in Tables 3 and 4 for the two strengths of the microneedle array patch (internal product name M207) based on a nominal batch size of 45 g (solmitriptan base).

[Table 3]

[Table 4]

Viscoelastic  characteristic

The 40% w / w zolmitriptan liquid formulation was evaluated for viscoelastic properties. The viscoelastic characterization of fluids can be a useful tool for predicting the tendency of fluids to gel. [H. A. Barnes, J. F. Hutton, and K. Walters, An Introduction to Rheology (Elsevier, New York, 1989)]. The measurement of viscoelasticity (i.e. elastic and viscous components) in a viscometer is based on a complex theoretical model. The result of the phase angle is produced by briefly applying the material to vibrational stresses or strains with values small enough not to destroy the structure of the material. The phase angle is the ratio between the viscous modulus and elastic modulus. The phase angle of 0 degree corresponds to a completely elastic material according to the Hooke's law of elasticity, suggesting a more rigid regular structure. A phase angle of 90 degrees corresponds to a material with full viscous behavior, indicating that it is a less regular structure with less gelation. The 40% w / w zolmitriptan liquid formulation exhibits a high phase angle of about 83 degrees, indicating that the formulation is not likely to gel.

Nanoindentation  by ZP - Zolmitriptan  Characterization of the mechanical properties of the patch

The mechanical properties of zolmitriptan coatings such as hardness and toughness were evaluated by nanoindentation for the M207 1.9 mg patch. After separating the microprotrusions from the base of the titanium array, a nanoindentation test was performed on individual microprotrusions coated with zolmitriptan. For hardness measurement, the coated microprotrusions were sampled from the center and two edge locations of the array, and ten indentation measurements were made for each of the three locations. Hardness and reduced modulus of elasticity were determined using a nanomechanical test system, a Berkovich indenter by Tribolndenter. Toughness was determined by fracture toughness using a Tribolndenter with a hexagonal indenter. Five indentations were made for each patch sample.

[Table 5]

Dynamic steam Sorption

The water sorption and desorption isotherms of the M207 1.9 mg patch were determined at 25 ° C. by DVS Intrinsic (Surface Measurement Systems, Ltd.). Each patch was exposed in incremental steps, incremented from 0% to 65% over a period of controlled relative humidity (RH) and subsequently decremented from 65% to 0%. The weight change was measured continuously with a microbalance having a resolution of 0.1 μg. In each RH step, the sample was allowed to reach equilibrium on a dm / dt basis of 0.0004 before moving on to the next RH step. Uncoated patches were analyzed under the same conditions to determine background moisture absorption by the patch components in addition to the coated drug formulation.

Crystallinity

X-ray diffraction (XRD) analysis was performed to characterize the solid phase 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 to be analyzed, approximately 45-50 microprotuberances coated with zolmitriptan were separated from the base of the titanium array and analyzed in bulk by XRD. Theta combined on a Bruker D8 Vantec diffractometer equipped with a micro-focus copper x-ray tube with a Montel optical monochromator, 0.5mm collimator, Vantec 500 2-D area detector and laser alignment system. XRD data was collected by: 2-Theta scan. The XRD pattern of the zolmitriptan-coated microprotrusion was compared with the pattern of the uncoated microprotrusion. All sharp peaks present in the zolmitriptan coated patch sample matched the sharp peaks of the uncoated patch sample. These sharp peaks were identified as titanium (Ti) metals based on reference XRD data from the ICDD / ICSD database, indicating that a crystalline phase was obtained as a result from the Ti microprotrusion substrate. The zolmitriptan coated patch showed a broad broad peak at about 18 ° 2-Theta center, which peak was not present in the uncoated patch sample, and non-irradiated and gamma-irradiated patches. In all, it indicates that the drug coating is an amorphous material. Percent crystallinity was calculated using peak profile fitting, the results are summarized in Table 6, and monitored for stability as described below.

[Table 6]

The mechanical properties of the zolmitriptan coating were evaluated as a function of time and storage conditions. Contains mechanical properties such as hardness, which is a measure of material resistance to localized plastic deformation, modulus of elasticity (a measure of material strength), which is a measure of material resistance to elastic deformation when a force is applied to the material, and cracks that resist fracture. Fracture toughness describing the ability of a material was evaluated. Multiple coated microprotrusions from different areas of individual ZP-zolmitriptan patches were sampled for testing. Table 5 shows nanohardness (H), reduced modulus elastic modulus for gamma-irradiated M207 1.9 mg patches stored at 25 ° C / 60% relative humidity for up to 12 months and 40 ° C / 75% relative humidity for up to 3 months. The results of (E _r ) and fracture toughness (K _c ) are summarized. The stability results suggest a decreasing trend of hardness and fracture toughness and an increasing trend of elastic modulus.

Zolmitriptan  Purity and content determination

The purity of zolmitriptan was determined by reverse phase high performance liquid chromatography (RPHPLC) method (TM-601) at a wavelength of 225 nm. Chromatography for the assay was performed using Phenomenex Kinetex EVO C18, maintained at 30 ° C. (4.6 mm ID × 150 mm, 5 μm). The mobile phase has 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). It was accompanied by a gradient elution and pumped at a flow rate of 0.6 mL / min on an HPLC system (Water Alliance 2695) equipped with a binary pump, temperature controlled autosampler, column compartment and PDA detector. Data were collected and analyzed using Empower Pro (Empower 2 software, Waters Corporation).

In vitro  In Vitro Dissolution

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

M207 patches stored at room temperature and 40 ° C./75% relative humidity for 10 months were evaluated. The results illustrated in Figures 6 (a)-(c) and Table 7 show the instant release of zolmitriptan with a steep slope reaching less than 1 minute at the concentration plateau of complete dissolution for all patches tested. .

[Table 7]

Example  2- Ex vivo  Human skin

In vitro, the Franz Human Skin Finite Dose Model is a tool for studying the absorption of topically applied drugs through the skin. The model uses in vitro and human torso skin mounted in a specially designed diffusion cell to ensure that the skin is maintained at a temperature and humidity consistent with typical in vivo conditions. A finite dosage of the formulation (eg, transdermal delivery system or semi-solid 2 mg / cm 2 to 10 mg / cm 2) is applied to the outer surface of the skin, and drug absorption is a receptor that bathes the inner surface of the skin It is measured by monitoring the rate of appearance in solution. In this model, data defining the total absorption, absorption rate and skin content can be determined.

dosage. The zolmitriptan patch was applied to the ex vivo skin using an applicator. After dosing, the patch and the skin were immediately mounted on the Franz diffusion cell.

Dermal receptor media. Normal phosphate buffered saline (pH 7.4 ± 0.1) containing 0.008% gentamicin sulfate (PBSg) solution was used when the diffusion cell was first mounted.

Diffusion cell and skin preparation. Absorption through the skin was measured using in vitro, human skin, Franz finite dosing techniques. In vitro dermatomed human torso skin with no obvious signs of skin disease or damage was used in this study. The skin was dermalized, cryopreserved, and provided to the test fixture sealed in a water-impermeable bag kept continuously at about -70 ° C. Thaw in water at about 37 ° C. prior to use, then rinse with distilled deionized water (ddH20) to remove any attached blood or other material from the surface.

Skin from each donor was cut into a number of smaller sections, large enough to fit onto a nominal 7 cm 2 static Franz diffusion cell. The actual thickness of each skin section was measured in triplicate using a Digital Pocket Thickness Gauge (result in Table 2). Subsequently, each skin section was mounted on a diffusion cell.

The skin receptor compartment was filled with PBSg to capacity. The epidermal chamber (also called a chimney or donor compartment) was left unoccluded and exposed to the surrounding laboratory environment. Subsequently, the cells are placed in a rack system, attached to a water circulation system, from which the receptor solution is magnetically stirred at about 600 RPM to achieve a skin surface temperature of 32 ± 1 ° C. The temperature was maintained (data on file). Skin was allowed to equilibrate for at least 1 hour prior to the barrier integrity test.

One additional skin section per donor was prepared and all study activities were performed, but placebo patches were administered to serve as a negative sample control.

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

Donor demographics. The demographics of the skin donors are summarized in Table 8.

[Table 8]

Dosage administration and sample collection. Prior to administration of the patch to the skin section, the entire volume of the receptor solution was taken out and pre-dose (0 hour) samples were collected and approximately 5 mL aliquots of the collected samples were stored for subsequent analysis. The receptor solution was replaced with a designated stock receptor solution of 0.1 x PBSg. The chimney was then temporarily removed from the Franz diffusion cell, allowing full access to the epidermal surface of the skin.

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

At the scheduled sampling time points (3, 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 min), the receptor solution is completely removed and the stock receptor solution Refilled and approximately 5 mL aliquots of collected samples were stored for subsequent analysis. For sample analysis, 5 mL aliquots were lyophilized using vacuum centrifugation and reconstituted with 0.25 mL of ddH ₂ 0.

After collecting the last receptor sample, the patch was removed for subsequent extraction and analysis. Skin surface washing was performed using two consecutive reflux washes of ddH20. Each wash cycle consisted of at least 10 refluxes. The two wash volumes from each donor cell were collected to create a single surface wash sample for the diffusion cell.

After the surface wash, the skin was dried for 10 minutes or less. Subsequently, the skin was tape stripped using a maximum of ten (10) sequential tapes (e.g., 3 M Transpore® tape) to remove and collect the stratum corneum. Tape strips were extracted overnight in ddH20. The skin was then removed from the cell and separated into epidermis and dermis by manual extraction for subsequent extraction and analysis. Skin sections were extracted overnight in ddH20.

Sample analysis. Quantification of zolmitriptan in the collected samples was achieved using validated HPLC methods.

Samples were analyzed on 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 H ₂ 0 and (solvent B) methanol, for analysis of zolmitriptan. It was carried out through a Phenomenex Luna C18 (2) column at a flow rate of 0.5 mL / min (100 x 4.6 mm, 3 μ). The column was maintained at 40 ° C.

Average flux results. Absorption across the skin of zolmitriptan (mean ± SE), passing through the human torso skin ex vivo over 300 minutes from a single application. The average flux (μg / cm 2 / hr) is summarized in Table 9 and the coordinates FIG. 30. This is a summary of the entire donor, showing the result of absorption through the skin of zolmitriptan, passing through the human torso skin ex vivo over a period of 300 minutes from a single application (mean, N = 3 donors).

[Table 9]

Total absorption and mass balance (mass balance) results. The results of absorption through the skin of zolmitriptan, into and through the human torso skin ex vivo over 300 minutes from a single application, are summarized in Table 10. Percent (%) of applied dose and mean ± SE as μg total mass.

Table 10

Conclusion and discussion. The total absorbed zolmitriptan across the skin and into the receptor solution was found to be 83.41 ± 1.33% for the 1.9 mg patch. The peak flux occurred with a peak flux of 849.4 ± 42.1 μg / cm 2 / hr approximately 4 minutes after application. Less than 1% of the zolmitriptan was recovered from three skin layers at the end of the dose duration. The mass balance was found to be approximately 90% of the applied dose.

Example  3-M207 patch stability

The M207 patch assembly was examined by e-beam and gamma irradiation at doses up to 25 kGy. Subsequent irradiated patch assemblies were placed stably at storage conditions of 25 ° C./60% relative humidity and 40 ° C./75% relative humidity. The results of the e-beam and gamma-irradiated M207 patches are shown in Tables 11-17.

[Table 11]

Table 12

[Table 13]

Table 14

Table 15

Table 16

The solid-state physical stability was evaluated by XRD. Amorphous vs. zolmitriptan coating vs. Crystalline phase changes were examined by XRD analysis. The M207 1.9 mg patch was analyzed at initial time point (TO), 6 months and 12 months storage. The drug coating was amorphous for both non-irradiated and gamma-irradiated patches in TO. The gamma-irradiated zolmitriptan patch stored at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 12 months exhibited an XRD pattern similar to that of the TO patch. The percent crystallinity was calculated using peak profile matching, and the results are summarized in Table 16 below. Zolmitriptan formulations coated on gamma-irradiated patches stored at both intended (25 ° C./60% relative humidity) and accelerated storage conditions (40 ° C./75% relative humidity) for 12 and 6 months, respectively. In the case of solids, no crystalline phase was detected.

Table 17

As described herein, zolmitriptan coated microneedles were exposed to radiation doses ranging from approximately 7 to 30 kGy. More preferably, it is 15 to 30 kGy to a sterile assurance level of 10 ^-5 to 10 ^-6 . Table 17 shows the 12-month stability results of irradiated and non-irradiated zolmitriptan patches stored at 25 ° C and 40 ° C.

Example  4-drug device  Combination products

A novel drug-device combination product (M207) was prepared according to the present disclosure. M207 is an intradermal delivery system comprising a disposable titanium microprotrusion member centered on the adhesive back to form a patch. The patch was mounted on a plastic retainer ring to form a patch assembly. The patch consists of microneedles coated and dried with a drug formulation. The retainer ring facilitates patch mounting to the bottom of the handheld applicator. This applicator ensures that the patch is applied to the site of administration with a defined applied energy. The combination of the patch assembly and the applicator includes an intradermal delivery system. Hold the applicator in hand to apply the patch. Twist the cap of the applicator to unlock the applicator. When the applicator is pressed against the skin, the patch is pushed out of the retainer ring by a plunger to apply the patch to the skin.

When the patch is applied to the skin, the patch remains on the skin and the plastic ring remains on the applicator, which is then detached and discarded. The delivery system was designed to rapidly deliver zolmitriptan at a dose of 1 mg, 1.9 mg or 3.8 mg intradermally. The unit formulation for the M207 drug is provided in Table 18.

Table 18

The zolmitriptan-coated titanium microneedle array is a 3 cm 2 array of about 1987 or about 997 titanium microneedles for 1.9 mg or 1 mg drug, respectively. It is affixed to an approximately 5 cm 2 adhesive patch. The patch can be mounted inside a polycarbonate plastic retainer ring with a co-extruded desiccant. The desiccant can alternatively be attached to the lid of a foil pouch. The finished patch assembly is packaged in a dry nitrogen-purged foil pouch. The user prepares the patch to apply by pressing the handheld applicator onto the patch assembly. The applicator includes spring-loaded pistons to apply the patch to the user's skin (FIGS. 4 (a), 4 (b) and 5 (a)-(e)). The applicator unlocks by twisting the outer grip to the base from the # 1 position to the # 2 position (FIG. 5 (c)). The user applies the patch by pressing the applicator-mounted patch assembly onto the skin area. The applicator releases its piston with sufficient impact energy, for example about 0.26 Joules. The piston breaks the patch from the retainer ring, and applies the patch to the skin with a predetermined impact energy density to ensure reproducible patch application. The applicator is designed to ensure that the same force is applied for each transmission across different users.

The drug-coated microneedle penetrates or penetrates the stratum corneum of the skin, thereby enabling drug delivery. Upon administration, the solid zolmitriptan coating is released from the microneedle and quickly dissolves in the interstitial fluid of the skin to form a solution and becomes available for absorption. The patch is removed after about 30 minutes.

The M207 system components are listed in Table 19.

Table 19

Table 19 (continued)

Example  5-human PK clinical trial

Human evaluation of the M207 product was conducted. In this phase 1 study, commercially available oral zolmitriptan tablets 2.5 mg and subcutaneous sumatriptan 6.0 mg were included as comparators. As described in the examples above, M207 consisted of a titanium array of microneedle coated with zolmitriptan and was administered subcutaneously through a patch applied by a professional applicator. The purpose of this trial was to provide information on the pharmacokinetics and tolerability of the M207 system. Tolerability evaluation of intradermal zolmitriptan at various doses to zolmitriptan at a standard oral dose (2.5 mg) was completed with an assessment of response at the site of application.

Specifically, this study compared single doses of 5 therapies of M207 in 20 healthy volunteers, as well as 7 crossover designs of 2.5 mg oral zolmitriptan tablets and 6.0 mg subcutaneous sumatriptan. Analysis of plasma samples for concentrations of zolmitriptan, N-desmethyl zolmitriptan and sumatriptan was performed on Quest Pharmaceutical Services in Groningen, The Netherlands, by analysis known in the art. In this study, administration of the M207 system resulted in rapid time to maximum concentration (T _max ), exposure comparable to orally administered zolmitriptan, but reduced exposure to the major metabolite N-desmethyl zolmitriptan. Showed. The doses evaluated in this study using the M207 system were 0.48 mg, 0.96 mg, 1.9 mg and 3.8 mg.

The first 4 doses of zolmitriptan used a 5 cm 2 patch and a 0.26 Joule applicator in the intradermal microneedle system described herein. The final treatment administered was 3.8 mg on a 10 cm 2 patch using an applicator with an applied energy of 0.52 Joules in the intradermal microneedle system described herein. The products tested were:

M207 0.48 mg patch assembly: zolmitriptan The 0.48 mg patch consisted of a 3 cm 2 titanium array of microprotrusions with a nominal length of 340 μm coated with 0.48 mg of zolmitriptan. The array was applied to the center of a 5 cm 2 tan adhesive backing to form a patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-extruded with a desiccant, and this patch assembly was packaged in a foil pouch.

M207 1.9 mg patch assembly: zolmitriptan The 1.9 mg patch consisted of a 3 cm 2 titanium array of microprotrusions with a nominal length of 340 μm coated with 1.9 mg of zolmitriptan. The array was applied to the center of the 5 cm 2 carbon adhesive back to form a patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-extruded with a desiccant, and this patch assembly was packaged in a foil pouch.

M207 3.8 mg patch assembly: zolmitriptan The 3.8 mg patch consisted of a 5.5 cm 2 titanium array of microprotrusions with a nominal length of 340 μm coated with 3.8 mg of zolmitriptan. The array was applied to the center of the 10 cm 2 carbon adhesive back to form a patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-extruded with a desiccant, and this patch assembly was packaged in a foil pouch.

Research design

This was a sequential study of two additional treatments (Parts 2 and 3) following a single centered, open-label, randomized 5 crossover study (Part 1). Each subject obtained informed consent and established eligibility, each receiving 7 study treatments once, followed by extensive blood sampling for in-clinic monitoring and pharmacokinetic analysis. Dosing days in Part 1 occurred at 48-120 hour intervals until dosing for treatments A to E (see Table 20) was completed in random order according to the treatment sequence table. Plasma samples from the initial dosing day were sent to the analytical laboratory for analysis and tolerability to each dose level was summarized. Tolerability was judged to be acceptable and the subject returned for Part 2. During Part 2, the subject received zolmitriptan (applied with the same 0.26 J applicator used in Part 1) administered intradermally with a 1.9 mg x 2 patch and completed the same procedure as Part 1. During Part 3, subjects received a single 3.8 mg patch (applied with a 0.52 J applicator) and also completed the same procedure as the previous dosing day. After the 7-day dosing day was completed, subjects were evaluated once in the final and excluded from the study.

The treatments used in the trial were as listed in Table 20 below:

Table 20

Twenty subjects, 10 males and 10 females, were enrolled in the study. The average age of the subjects was 29 ± 3.5 years old and the average BMI was 24.4 ± 3.5 years. Except for one subject who missed one treatment visit, all subjects completed all seven treatment visits in the study and received all seven study treatments. In 2 subjects (# 1010 in Treatment A and # 2010 in Treatment D), little blood samples were collected after dosing at Visit 1 due to difficulty in intravenous access, but for all of the remaining subjects, almost all of the scheduled pharmacokinetic blood samples All (14 per visit) were collected for analysis.

Tolerability in Part 1 was considered acceptable, and after reviewing safety data and pharmacokinetic data from the first 5 dosing periods and after discussions between sponsors and responsible researchers, subjects proceeded to Parts 2 and 3 and completed this visit. . Collected serum was analyzed for zolmitriptan and N-desmethyl zolmitriptan using methods well known in the art, such as using the liquid chromatography-mass spectrometry (LC-MS-MS) method.

Pharmacokinetics

The M207 patch was well tolerated and rapid absorption was observed, and it is believed that it could be converted to rapid pain relief for migraine or cluster headache patients. The phase 1 results demonstrating the rapid absorption of M207, characteristic of the Zosano microneedle patch and applicator system, are illustrated below:

Table 21

Average plasma concentration vs. in each of the six (6) zolmitriptan regimens administered. Time data is shown in FIGS. 7 and 8. FIG. 7 shows the results for the entire 24-hour sampling period, and FIG. 8 shows only the results for the first 2 hours after study drug administration. Both levels were subcutaneous sumatriptan concentration vs. Time data (scaled for display purposes to illustrate the passage of time). The results after SC sumatriptan were similar to several published studies of this dosage and route of administration.

Based on the results presented in Figures 7 and 8, plasma levels of zolmitriptan after intradermal application of zolmitriptan were dose-dependent, and absorption after patch application was much faster than that seen after administration of 2.5 mg tablets. . Plasma levels seen after a single large 3.8 mg patch were higher than those seen after the 2 x 1.9 mg patch. Graphs of dose linearity for zolmitriptan C _max , AUC _t and AUC _inf are shown in FIGS. 9, 10 and 18 (excluding large 3.8 mg patch). Graphs of dose linearity for N-desmethyl zolmitriptan C _max , AUC _t and AUC _inf are shown in FIGS. 22-24 (excluding large 3.8 mg patch). Good dose linearity was observed over the evaluated dose range. The calculated main mean (median for T _max ) pharmacokinetic parameters for zolmitriptan therapy and subcutaneous sumatriptan are shown in Table 22 below.

Table 22

The most relevant to the potential usefulness of this product for the treatment of migraine or cluster headache is the T _max for zolmitriptan therapy administered intradermally, showing much faster absorption of zolmitriptan at intradermal administration than with oral administration.

The pharmacokinetic parameters after zolmitriptan administered intradermally were, on average, very similar when compared to the results seen in female subjects, as shown in FIGS. 11 and 12.

The active metabolite, N-desmethyl zolmitriptan, could be detected in all subjects dosed with 5 higher dose regimens. The pharmacokinetic parameters of N-desmethyl zolmitriptan for each zolmitriptan therapy are shown in Table 23 below.

Table 23

The level of N-desmethyl zolmitriptan was significantly lower after M207 zolmitriptan intradermal administration than seen after oral administration (treatment D).

Descriptive statistics (arithmetic mean, standard deviation, coefficient of variation, sample size, minimum, maximum and median) were used to summarize PK parameters by treatment group. In addition, the geometric mean and 95% confidence intervals (CIs) for AUC _2hrs , AUC _t , AUC _inf and C _max were calculated. Zolmitriptan treatment In each case, the ratio of AUC _inf N-desmethyl zolmitriptan / AUC _inf zolmitriptan was calculated for each subject; The group average was determined.

The dose proportionality was evaluated for the 3 doses of M207; The dose proportionality was not based solely on strict statistical rules. The relationship between the dosage of zolmitriptan and the PK parameter was examined by descriptive statistics using a graphical approach. Graphs of apparent dose linearity and proportionality of PK parameters (AUC _t , AUC _inf and C _max ) were compiled.

Rapid absorption of zolmitriptan was seen after intradermal patch application; The mean maximum plasma concentration (T _max ) occurred between 16.1 and 18.4 minutes. This was similar to the sumatriptan SC injection (12.5 ± 4.4 minutes) and was significantly faster than zolmitriptan tablets (107.4 ± 76.4 minutes [1.8 ± 1.27 hours]).

The average for the System M207 (± SD) elimination half-life (t _1/2) was 1.53 ± 0.31 hours at the maximum dosage range of 0.48 mg to 3.8 mg from 1.15 ± 0.27 hours, respectively. Removal of zolmitriptan after zolmitriptan purification (3.27 ± 0.8 hours) was almost twice as slow as M207.

The mean (± SD) maximum plasma concentration (C _max ) of zolmitriptan tablets was 3.77 ± 1.51 ng / mL. Administration of the 2 x 0.48 mg patch provided a maximum concentration nearly equal to 3.70 ± 1.05 ng / mL; The C _max for Group C (1.9 mg) administered as a single patch was almost 2 fold (6.76 ± 2.75 ng / mL). Groups F and G produced 3.9 times (14.61 ± 4.46 ng / mL) and 6 times (22.56 ± 14.0 ng / mL) maximum plasma concentrations, respectively, than the maximum plasma concentrations of zolmitriptan tablets.

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

Plasma concentrations were slightly higher in men than women in the case of higher doses, group F (2 x 1.9 mg) and group G (3.8 mg). At lower doses (Group A [0.48 mg] to C [1.9 mg]), there did not appear to be a gender difference.

The relative bioavailability of the M207 system was compared to zolmitriptan tablets using the following formula:

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

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

Table 24

Compared to what was shown after M207, approximately twice the amount of the active metabolite N-desmethyl zolmitriptan was formed after oral administration of zolmitriptan (mean 59.8 ± 16%) (Table 25).

Table 25

The relative bioavailability of the active metabolite N-desmethyl zolmitriptan produced for the M207 patch was compared to zolmitriptan tablets using the following formula:

Compared to the zolmitriptan tab, the M207 patch was less converted to N-desmethyl zolmitriptan metabolite (F _rel AUC range: 0.32-0.46), and based on the relative bioavailability of C _max and zolmitriptan tablets. Compared to the M207 patch, the exposure rate was less than approximately 50%.

The plasma concentration of the N-desmethyl metabolite reached a maximum in about 1 hour (range: 54.7-65.0 minutes) for M207 administered via the 162.6 minute [2.71 H] intradermal route compared to zolmitriptan tablets. , Figure 13. removal of the metabolite half-life (t _1/2) was comparable for all treatment, including oral administration (2.7 H to 3.31 H range]). N- desmethyl to 0 in the case of zolmitriptan The 24-hour concentration-time curve is shown in FIG. 14.

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

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

Table 26

M207 also tended to have less intragroup variability for the AUC _inf parameter (indicated by CV%) when compared to zolmitriptan tablets.

Dosage linearity for M207 system administration

C _max (y = 4.81), AUC _t (y = 7.61) and AUC _t (y = 7.61) 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) system administrations. AUC _inf (y = 8.31). See Figures 15-17. The concentrations of both zolmitriptan and N-desmethyl zolmitriptan metabolites at the lower limit of the dose range (0.48 mg x 2) were very comparable. However, at the highest dose (1.9 mg x 2), the plasma concentration achieved by multiple patch administration was slightly less than in the single patch (and 0.52J dose force) for both zolmitriptan and N-desmethyl zolmitriptan. . For N-desmethyl zolmitriptan, see FIGS. 19-21.

Administration of the M207 patch results in a rapid peak plasma concentration (T _max ) that occurs within 20 minutes of patch application. This compares favorably to 12.5 minutes for SC sumatriptan and provides a significant improvement over conventional release oral zolmitriptan tablets (1.8 hours). The removal rate (t _1/2 ) for M207 was approximately 2 times shorter than the removal rate of zolmitriptan tablets (1.2 to 1.5 hours vs. 3.3 hours).

The C _max for zolmitriptan tablets was 3.77 ng / mL. Treatment with the M207 patch in groups C (1.9 mg), F (1.9 mg x 2) and G (3.8 mg) produced mean peak plasma concentrations 1.8, 3.9 and 6 times higher than zolmitriptan 2.5 mg tablets. Multiple patch administration with 2 x 0.48 mg M207 resulted in C _max (3.70 ng / mL) comparable to oral zolmitriptan tablets.

Treatment with the M207 patch in groups F and G produced similar exposure (AUC _inf ) to oral zolmitriptan tablets (30.12, 33.81 and 27.19 ng.H / mL, respectively). However, the average total exposure (AUC _inf ) for the M207 patch was less (0.700 to 0.86) and the average total exposure (C _max ) was 2.35 to 3.73 times higher than the oral zolmitriptan tablet.

The time from M207 to the peak plasma concentration of N-desmethyl metabolite was significantly faster at about 1 hour compared to about 2.7 hours of oral zolmitriptan. However, the degree of metabolite produced from M207 was about 50% less than that of oral zolmitriptan tablets. The main PK results are summarized in Table 27 below.

Table 27

Perhaps most related to the potential usefulness of this product for the treatment of migraine or cluster headache is probably T _max in M207 therapy, showing that zolmitriptan is absorbed much faster in intradermal administration than in oral administration.

A comparison of exposures is provided in Table 28 below.

Table 28

Good dose linearity was observed for high and low doses for C _max and AUC _inf . M207 was excellent in chemical resistance. The adverse event (AE) had a short (<24 hours) duration and was mostly mild (87%), the majority of which were consistent with previously reported phenomena in zolmitriptan (88%). There were no severe or severe AEs. Temporary changes occurred in both systolic and diastolic blood pressure, and for both systolic and diastolic blood pressure, the pressure value returned to pre-treatment levels 1-2 hours after drug administration. There was no significant ECG change. The application of the patch was well tolerated, with mostly mild to moderate reactions resolved after 24 hours. The topical tolerability of the 3.8 mg patch applied with greater force (0.52 J) was not as beneficial as other therapies.

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

Table 29

Table 30

Example  5- In vivo  Pig study

The M207 patch was tested in pigs.

By LC / MS / MS method Zolmitriptan  decision

Using conventional in-house LC / MS / MS methods, zolmitriptan analysis from used patches, skin swabs and plasma PK samples was performed. The lower limit of quantitation (LLOQ) and the upper limit of quantitation (HLOQ) were 0.1 and 1000 ng / mL, respectively. A 4-minute method using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS / MS) was developed for quantification of zolmitriptan and two major metabolites in HGP plasma. The instrument consists of an Agilent® 1200 pump, CTC PAL® autosampler with cooling stack, AB Sciex® TurboV® ESI source, and API 4000® mass spectrometer.

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

A 10-port 2 position Valco® valve was placed in line with a mass spectrometer equipped with a guard cartridge (Zorbax 300SB-C8, 12.5 x 4.6 mm) used for on-line solid phase extraction (SPE). This valve is in the "loading" position where the sample is injected onto the cartridge and washed with 10% mobile phase B for 30 seconds, then the valve is switched to the "injecting" position, whereby the washed sample is removed from the SPE cartridge from the analysis column ( Luna PFP (2), 100 A, 5 μm, 50 × 2 mm) was installed to elute backwards into the mass spectrometer.

The HPLC method used was a reverse 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 It was). The HPLC mobile phase consists of 20 mM ammonium acetate as mobile phase A and 80% acetonitrile in 20% 20 mM ammonium acetate as mobile phase B. The source settings for all analyzes 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. During the mass spectrometer acquisition, 11 MRM transitions were monitored. All 11 MRM transitions were used for data processing. The peak area under each corresponding MRM transition was summed and that of the spiked standard plasma sample was compared to the concentration calculated for each sample. A second order (1 / x) match was used for all calculations.

anesthesia

Animals were induced into Telazol muscle and maintained with isoflurane on the ventilator.

Blood sample collection for pharmacokinetic research

Blood samples were collected from one or more of the following blood vessels of the animal: peri-ear vein / artery (left / right), saphenous vein (left / right), mammary vein (left / right) and femoral artery (left / right) ). The indwelling catheter / sheaths were placed to access preferred vessels and held in place during the blood collection period. All procedures were conducted by staff trained in accordance with approved protocols and test facility SOPs. 5-mL blank blood was collected from each animal prior to the first dose. 1 mL blood samples were collected up to 5 hours after patch application dosing. To collect all blood samples, heparinized microtainer tubes were used. Considering the dead volume of the catheter, the volume of blood drawn was replaced with an equal volume of heparinized saline. In general, blood collection on a daily basis did not exceed 3 to 5% of the animal's total blood volume.

Zolmitriptan  Intravenous administration

A zolmitriptan solution was prepared in-house for intravenous (IV) dosing, with a maximum zolmitriptan concentration of 3 mg / mL. A dose of less than 3 mL was injected into the vein around the ear of the animal using a 28-30 G needle. To prevent bleeding at the injection site, pressure was briefly applied with gauze immediately after the injection.

Determination of patch delivery performance

Using residual drug analysis ZP - Zolmitriptan  Delivery decision

The zolmitriptan residue was determined from the patch used and the swab from the treated skin area. After the used patch was peeled off the skin, the adhesive band outside the microprotrusion array region was trimmed and stored for analysis of zolmitriptan residue. To recover residual zolmitriptan from the treated skin site, three synthetic fiber swabs were used. The first swab was pre-soaked in a vial containing 1 mL of swab buffer. The first swab was applied on the patched skin area by applying a slight pressure (using rolling motion) to the periphery of the treatment site in several directions. The second and third swabs were dried and used to capture all residual buffer from the skin site moistened with the first swab. All three cotton swabs were placed in original vials containing cotton swab buffer. The amount of zolmitriptan left on the microprotrusion array and skin surface after each application can be compared to the original coated amount on the array to determine the total zolmitriptan delivery and delivery efficiency. The equations for determining the total drug delivered and drug delivery efficiency are shown in (1) and (2) respectively.

Total residual amount = Patch residual amount + Skin residual amount

Total drug delivered = nominal coated amount-total residual amount (1)

Research design

Three pre-puberty Yorkshire pigs were used in the study. Naive animals were purchased from an approved supplier according to the test facility's approved protocols and SOPs and quarantined for up to 7 days. Each animal group was dosed up to 5 treatments (crossover) and had a recovery / wash period of up to 5 days between treatments. At the first dose, animals had a body weight ranging from 18 to 25 kg, and at the last dose, the animals had a body weight ranging from 25 to 41 kg. In general, treatment per group included 1 to 2 controls and 1 to 3 ZP-zolmitriptan doses. The control group included IV zolmitriptan. ZP-zolmitriptan patch positions were rotated on the left and right ventral thighs of the hind legs in each group of animals where more than one patch application treatment was performed.

result

Table 31

The average delivery was greater than 1.7 mg for both coated in vivo studies. Delivery efficiency was greater than 85% and was consistent in both studies. Subsequently, pharmacokinetic studies were performed with the MF1663 array design coated with 1.9 mg. Table 32 summarizes the patch and intravenous results.

Table 32

In vivo evaluation showed rapid systemic absorption of zolmitriptan by patch administration. Plasma levels had a median T _max of 15 minutes and remained over 5 hours. The zolmitriptan patch had an absolute bioavailability of 77%. The ZP-zolmitriptan patch showed that the required amount of drug could be coated, high delivery efficiency was consistently achieved, and the coated zolmitriptan was well absorbed in a fast time up to C _max .

Example  6-human efficacy clinical trial

The ZOTRIP central efficacy study was a multi-deliberated, double-blind, randomized placebo-controlled trial comparing three doses of M207 (1.O mg, 1.9 mg and 3.8 mg) versus placebo for the treatment of single migraine attacks. . Subjects enrolled in the ZOTRIP trial at 36 centers across the United States. Subjects recruited to the trial had a history of at least 1 year of symptoms with or without symptoms of migraine. Upon recruiting, the subjects, who reliably met the main eligibility criteria for migraine attacks 2 to 8 times per month, entered the run-in period, which was recorded using an electronic diary or their mobile phone app. Subjects also identified the most annoying other symptoms selected from nausea, photophobia, and soundphobia, and showed the presence or absence of nausea, soundphobia, or photophobia during the episode in the preparation period. Subsequently, successfully screened subjects are randomized within the treatment / dose period, so they have 8 weeks to identify and receive blind treatment for a single migraine attack called “eligible migraine”, at which time the most annoying of their previously identified Other symptoms should have been present.

During eligible migraine, subjects begin before dosing and then at various intervals over 48 hours after dosing, the severity of pain according to the 4-point headache pain rating and the presence or absence of migraine-related symptoms (photophobia, phobia, or nausea). Scored. The co-primary endpoint for this study was defined in the October 2014 FDA Draft Guidance- "Migraine: Developing Drugs for Acute Treatment" for pain and no other annoying symptoms. Subjects recorded their migraine symptoms in the patient diary at various intervals up to 48 hours before and after treatment. Safety was assessed by reported adverse events and other standard safety measures.

Five hundred eighty nine (589) subjects were enrolled in the study, of which 365 were randomized. Of those randomized, 333 subjects were treated and included in the safety analysis, and 321 were eligible for a modified treatment objective (mITT) population. Fifty-five percent (51%) of randomized subjects were found to have severe migraine headaches prior to treatment. In addition, at the time of treatment, 70% reported coming, having 37% symptoms and 51% having migraine (morning migraine). In multiple doses and multiple endpoints in the trial, sequential testing procedures were used starting with the highest dose and co-primary endpoints. Since no statistical significance was achieved for the other most annoying symptoms in the 1.9 mg group, the p-value for the secondary endpoint should be considered a nominal p-value.

All three doses of M207 (1 mg, 1.9 mg and 3.8 mg) achieved statistically significant painlessness at 2 hours. The 3.8 mg dose achieved both co-primary endpoints of no pain and no annoying other symptoms at 2 hours. The 3.8 mg dose also achieved significance at the secondary endpoint of painlessness at 45 minutes and 1 hour, and showed persistence of effect on painlessness at 24 and 48 hours. Additionally, M207 was not associated with any serious adverse event (SAE).

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

In addition, secondary endpoints measuring no pain at additional time points for the 3.8 mg dose of M207 showed that the M207 was superior to placebo with a nominal p-value less than 0.05, as shown in Table 34:

Table 34

Overall, only 13 (3.9%) reported pain at the site of application; Pain at the site of application was reported to be mild in all but 3 subjects. The most frequently reported side effect was redness at the site of application (18.3% of subjects). All cases of redness were resolved. In addition, 5 (1.5%) patients reported dizziness in the M207-treated group and 0% in placebo.

Additional data from the results of the clinical trials are listed in the following table.

Table 35

In Table 35 above, the 3.8 mg dose group had a p-value of less than 0.05 and met all of the co-primary endpoints. The 1.9 mg dose group had a p-value of less than 0.05 and met the painless metric. In the case of no other annoying symptoms in the 2-hour endpoint, the 1.9 mg dose group had a p-value of 0.05 or higher. The 1 mg dose group had a p-value less than 0.05 and met the painless metric. For the 1 mg dose group, the most annoying other symptom-free endpoint at 2 hours had a p-value of 0.05 or greater.

Table 36

Table 36 was consistent with the co-primary endpoint analysis (mITTLOCF). Table 35 below provides a fixed-order test for each of the multiple metrics described for migraine to assess whether the study was successful. For doses of 3.8 mg, 1.9 mg and 1.0 mg, treatment efficacy was tested for co-primary and secondary endpoints in Table 35. As shown, all metrics in or after Test Sequence 4 were not significant in the MCP methodology.

Table 37

Tables 38-46 provide the results of clinical studies treated with one embodiment of the claimed invention. In this embodiment, 1 mg at time points of 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 , In the case of treatment of 1.9 mg and 3.8 mg, evaluation indexes including no pain, pain relief, no photophobia, no sound phobia, and no nausea were sequentially evaluated as described in Table 35. As shown in Tables 41-44, the researchers also visually evaluated the skin after removal of the patch for side effects such as bruising, edema and erythema.

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Tables 47-50 and FIGS. 25-28 demonstrate the efficacy of one embodiment of the claimed invention compared to the published results of treatments currently used in the art. Until the claimed invention, current art in the art included nasal treatment and standard and oral soluble tablets.

Table 47

Table 48

Table 49

Table 50

The embodiments of the invention described above are intended to be exemplary only; Many variations and modifications will become apparent to those skilled in the art. All such changes and modifications are intended to be within the scope of the present invention as defined in any appended claims.

Claims (10)

As an intracutaneous delivery system,
It comprises a plurality of microprojections adapted to penetrate or pierce the stratum corneum of a human patient, the microprotrusions being the length of each microprotrusion measured from tip to base Having a solid formulation coating covering about 10% to 80% of the composition, the coating comprising zolmitriptan or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 5 mg per system, An intradermal delivery system in which at least 95% of trytans are released from the system within about 5 minutes as measured by the USP Paddle Over Disk method (Device 5).
The system of claim 1, wherein at least 95% of the zolmitriptan is released within about 1 minute.
The system of claim 1, wherein about 100% of the zolmitriptan is released within about 1 minute.
The therapeutically effective plasma concentration of T _max occurs within about 45 minutes of the application when the system is applied to a selected area of the patient's skin, wherein C _max is about 5 to about 25 ng / ml. And AUC _0-2hr is from about 5 to about 20 ng / ml * hr.
The system of claim 1, wherein upon application of the system to a selected area of the patient's skin, a T _max of therapeutically effective plasma concentration occurs within about 30 minutes of the application.
The system of claim 1, wherein prior to drying, the blend coating has a viscosity of about 150 cP to about 350 cP and a surface tension of about 50 mNm ⁻¹ to about 72 mNm ⁻¹ .
7. The system of claim 6, wherein the coating covers about 20% to about 70% of each microprotrusion length.
The system of claim 7, wherein the coating covers about 30% to about 60% of the length of each microprotrusion.
The system of claim 1, wherein the blend coating prior to drying has a viscosity of about 200 cP to about 300 cP and a surface tension of about 55 mNm ⁻¹ to about 65 mNm ⁻¹ .
The system of claim 1, wherein the blend coating on each microprotrusion has an approximate American football shape with a tapering thickness from up to about 270 μm.

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