EP3672570A1 - Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headaches - Google Patents

Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headaches

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Publication number
EP3672570A1
EP3672570A1 EP17764703.9A EP17764703A EP3672570A1 EP 3672570 A1 EP3672570 A1 EP 3672570A1 EP 17764703 A EP17764703 A EP 17764703A EP 3672570 A1 EP3672570 A1 EP 3672570A1
Authority
EP
European Patent Office
Prior art keywords
zolmitriptan
patch
coating
drug
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17764703.9A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mahmoud Ameri
Donald Kellerman
Yi Ao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Emergex USA Corp
Original Assignee
Zosano Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zosano Pharma Corp filed Critical Zosano Pharma Corp
Publication of EP3672570A1 publication Critical patent/EP3672570A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles

Definitions

  • the present invention relates to the field of transdermal or intracutaneous delivery of pharmaceutical agents, and more particularly to the delivery of triptans, including zolmitriptan.
  • migraine affects 30 million men, women and children in the United States. Most migraines last between four and 24 hours, but some last as long as three days. According to published studies, 63% of migraine patients experience between one and four migraines per month. The prevalence in women (about 18%) is on par with asthma and diabetes combined. Approximately one-third of those afflicted with migraines have three or more migraines per month and over half report severe impairment or the need for bed rest. Migraines are most prevalent in the third decade of life, affecting both productivity and quality of life. In surveys of desirable attributes for therapies for migraine, fast relief consistently scores very high as one of the most important factors for a migraine therapy.
  • Acute migraine is an incapacitating headache disorder that is
  • migraine without aura is usually associated with nausea, vomiting, sensitivity to light, sound or movement, and can last for 4-72 hours if untreated.
  • Previously termed "common migraine,” migraine without aura is experienced by approximately 65% of patients.
  • Migraine with aura is experienced by about 15- 20%) of patients; individuals suffer from transient focal neurological symptoms, usually visual. The visual symptoms are known as an aura. The remainder of migraine patients experience both types of migraine.
  • Cluster headaches are excruciating headaches that recur in a cyclical pattern (a "cluster"), usually daily, for a period of 1 week or more, usually for six to twelve weeks. In chronic cluster headache, clusters last for a year or more without remission. Cluster headaches are considered to be among the worst headaches known to medical science, and are known to result in pain more severe than migraines. In approximately 47% of cases, cluster headache attacks recur at the same time of day or night, and, in particular, during sleep. Clusters can start at the same time and have a similar duration year after year. These recurrence patterns suggest a role of the hypothamlamus (the body's biological clock), although the exact cause is unknown.
  • cluster headache The pain of a cluster headache is typically on one side (unilateral) or localized and is around or above the eye.
  • patients may become agitated and restless, and they may have trouble resting in one place.
  • patients may rock, sit, pace, crawl, scream in pain, or even bang their head against a hard surface.
  • 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 which provide rapid and effective responses. See, e.g., Law et al, Triptans for acute cluster headache, Cochrane Database of Systematic Reviews (2013), Issue 7. While migraines are different from cluster headaches, it is believed that certain treatments for migraines including triptans could also be effective for cluster headaches. However, oral and nasal routes of administration are not particularly effective due to slow absorption rates and the short duration of the headache. Injected triptans have shown some efficacy, but they are limited by needle phobia, lack of portability, complex preparation, the requirement for sharps disposal, and safety issues related to needle prick, cutting, and cross contamination infection.
  • triptan class such as sumatriptan and zolmitriptan.
  • the triptans are serotonin derivatives displaying highly selective and potent agonist activity at the vascular 5-HTi B receptor and the neuronal 5-HTi D receptor.
  • the mode of action of the triptans is hypothesized to be three-fold: (1) binding of postsynaptic vascular 5-HTi B receptors, to stimulate vasoconstriction of meningeal vessels; (2) binding of presynaptic neuronal 5-HTi D receptors, to inhibit release of pro-inflammatory neuropeptides; and (3) binding of presynaptic neuronal 5-HTi D receptors, to diminish the firing rate in trigeminal neurons and the trigeminal nucleus caudalis (central action).
  • Triptans have similarly shown improved efficacy in treating cluster headaches over placebos.
  • Each of the currently available methods of administering triptans including oral, nasal spray, subcutaneous injection and iontophoretic intracutaneous patch (which is a device that delivers medicine through the skin by a low electrical current), has significant disadvantages.
  • Some migraine patients fail to respond consistently to oral triptans, and oral treatments may be ineffectual and/or unpleasant for patients who are suffering from the nausea, vomiting, or gastric stasis that can be associated with migraine.
  • Oral, nasal and iontophoretic patch triptan products are also characterized by delayed absorption and relatively slow onset of action causing insufficient relief, especially early in the episode.
  • Cluster headaches are often accompanied by stuffy or runny nose, which may impact absorption following nasal delivery. Nasal sprays may be unpleasant in taste, and use of injectables can cause discomfort.
  • Sumatriptan (EVIITREX®) has been commercially available in a number of dosage forms, such as a tablet, subcutaneous (SC) injection, nasal spray and by transdermal electrophoresis. Oral administration (as a succinate) suffers from poor bioavailability (about 15%) due to poor absorption and pre-systemic metabolism. The time to reach maximum concentration in the bloodstream (T max ) after oral tablet administration is about 2 hours. A rapid- release tablet formulation has roughly the same bioavailability, although the T max is achieved on average 10-15 minutes earlier than the conventional tablet. When injected, sumatriptan is faster- acting (usually within 10 minutes), but the duration of action is lower. Although SC is faster, the tablet formulations of sumatriptan have been much more widely prescribed than the injection because many patients do not like injecting themselves.
  • the triptans have an excellent safety profile when used appropriately and their adverse effect profile is similar to that observed with placebo in clinical trials. Like other compounds in the triptan class, zolmitriptan has been shown to be effective and well-tolerated in placebo-controlled clinical trials. It is available in a number of commercial formulations (ZOMIG®): (a) a conventional release tablet (2.5 mg and 5.0 mg); (b) a "fast melt” orally disintegrating tablet (2.5 mg and 5.0 mg); and (c) a nasal spray (5.0 mg).
  • ZOMIG® commercial formulations
  • the bioavailability of the orally disintegrating tablets is similar to that of the conventional tablets but the T max is (somewhat surprisingly) higher, at about 3 hours for the disintegrating tablets compared with 1.5 hours for the conventional tablet.
  • the disintegrating tablets may also exacerbate nausea often concomitant with a migraine attack.
  • Zolmitriptan has significant advantages over other triptans when contemplated for alternate delivery routes and methods. Only three triptans, zolmitriptan, naratriptan, and frovatriptan have a lowest oral dose less than 5 mg. However, at this lowest dose, zolmitriptan significantly outperforms naratriptan in terms of pain relief at 2 hours (62%> vs. 49%>), and pain freedom 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.
  • iontophoresis, patches and liquid injectors have the disadvantages of skin irritation and scarring, pain and inability to deliver a therapeutically effective dose.
  • Subcutaneously injected sumatriptan has been available for years but has never been widely used because it is difficult to prepare and due to issues related to needle phobia, sharps disposal, and accidental pricking, cutting, and cross contamination that are related to delivery with a needle.
  • the present disclosure relates to compositions, devices, methods of treatment, kits and methods of manufacture of pharmaceutical products useful in the treatment of migraines and other conditions, including cluster headaches. More specifically, the disclosure is directed to administration of a triptan, such as zolmitriptan, as the active pharmaceutical ingredient to a subject in need thereof. In particular, the present disclosure is directed to transdermally or intracutaneously, or otherwise through the skin, administering a therapeutically effective dose of the active ingredient that is more rapidly available in the subject's bloodstream as compared to a therapeutically effective oral dose of the active ingredient, in a format that is easy to use and portable for rapid administration.
  • a triptan such as zolmitriptan
  • the transdermal delivery of a triptan generally comprises a patch assembly having a microprojection member that includes a plurality of microprojections (or “needles” or “microneedles” or “array”) that are coated with, in fluid contact with a reservoir of, or otherwise comprise the drug.
  • the patch assembly further comprises an adhesive component, and in a preferred embodiment the microprojection member and adhesive component are mounted in a retainer ring.
  • the microprojections are applied to the skin to deliver the drug to the bloodstream or, more particularly, are adapted to penetrate or pierce the stratum corneum at a depth sufficient to provide a therapeutically effective amount to the bloodstream.
  • the insertion of the drug-coated microneedles into the skin is controlled by a hand-held applicator that imparts sufficient impact energy density in less than about 10 milliseconds.
  • the microprojection member includes a biocompatible coating formulation comprising the drug, such as zolmitriptan, in a dose sufficient to provide therapeutic effect.
  • the coating may further comprise one or more excipients or carriers to facilitate the administration of the drug across the skin.
  • the biocompatible coating formulation comprises zolmitriptan and a water-soluble carrier that is first applied to the microprojections in liquid form and then dried to form a solid biocompatible coating.
  • zolmitriptan, excipients, the coating and drying process lead to a drug coating that is non-crystalline (amorphous) with a surprisingly rapid dissolution rate.
  • the coating upon its application to the skin via the microneedles, dissolves at a rate sufficient for rapid uptake of the drug into the epidermis and bloodstream. In one embodiment, such 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.
  • this rapid uptake leads to greater than about 10% of patients being pain free in 1 hour after administration, more preferably greater than about 20% of patients, most preferably about 25% of patients or more are pain free. In another embodiment, this rapid uptake leads to greater than 40% of patients achieving pain relief in 1 hour after administration, or greater than 50 percent of patients, or about 65% of patients or more achieve pain relief 1 hour after administration.
  • the drug coating remains amorphous for 1 year, more preferably 2 years, following gamma or e-beam irradiation.
  • Such intracutaneous delivery system may be in the form of a device that is adapted for easy use directly by the patient.
  • the system may be a drug-device combination product comprising: (a) a disposable microprotrusion member with titanium microneedles that are coated with a drug product formulation and dried, the microprotrusion member being centered on an adhesive backing thus forming a patch, and (b) a reusable handheld applicator that ensures the patch is applied to the skin with a defined application energy sufficient to press the microneedles into the stratum corneum thereby resulting in drug absorption.
  • the delivery system comprises a patch comprising 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 zolmitriptan.
  • the delivery system is designed to deliver about 0.2 mg to about 10 mg zolmitriptan intracutaneously, or about 1 mg to about 4 mg, or about 1 mg, or about 1.9 mg, or about 2 mg, or about 3 mg, or about 3.8 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or more than about 1 mg, or more than about 1.9 mg, or more than about 2 mg, or more than about 3 mg, or more than about 3.8 mg, or more than about 4 mg, or more than about 5 mg, or more than about 6 mg, or more than about 7 mg, or more than about 8 mg or more than about 9 mg zolmitriptan.
  • the present disclosure relates to a method for transdermally or intracutaneously administering a triptan to a patient in need thereof, comprising the steps of: (a) providing a transdermal patch adapted to intracutaneously deliver a triptan, comprising a microprojection member having a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of the patient, wherein the microprojections comprise a biocompatible coating partially or fully disposed on the microprojections, the coating comprising a therapeutically effective amount of the triptan; and (b) applying the microprojection member of the device to the skin of the patient, whereby the plurality of microprojections penetrate or pierce the stratum corneum and deliver the triptan to the patient's bloodstream.
  • the triptan is zolmitriptan and is coated on the microprojections in a total amount of approximately 0.2 to 10 mg of which approximately 50%, or 60%, or 65%, or 75%, or 80%, or 85%, or 90%, or 95%), or 100%) of such dose reaches the bloodstream of the patient after administration, preferably wherein more than approximately 50%, or 60%>, or 65%>, or 75%, or 80%>, or 85%>, or 90%), or 95%) of such dose reaches the bloodstream of the patient after administration.
  • the present disclosure encompasses a method for treatment or alleviation of migraine or cluster headache in a human patient in need thereof, comprising the transdermal or intracutaneous administration of a therapeutically effective amount of zolmitriptan that produces a therapeutic concentration of zolmitriptan in the bloodstream faster than
  • the method for treatment or alleviation of migraine or cluster headache in a patient results in a plasma T ma x as quick as about 2 minutes and not later than about 30-40 minutes in most subjects.
  • the method results in a maximum plasma concentration (C max ) of zolmitriptan of less than 50 ng/ml.
  • the zolmitriptan-coated microneedle patch as disclosed herein achieves rapid blood plasma concentrations after application during a migraine or cluster headache attack.
  • Such patch provides pain freedom and freedom from bothersome migraine or cluster headache symptoms for at least 45 minutes post administration.
  • a patient's most bothersome migraine symptom in addition to pain is usually selected from sensitivity to light, particularly bright lights (photophobia), sensitivity to sound, particularly loud sounds
  • cluster headache common symptoms include excruciating pain, often on one side of the head and generally situated in or around one eye, but which may radiate to other areas of face, head, neck and shoulders, restlessness, excessive tear production and redness in the eye on the affected side, stuffy or runny nose, forehead or facial sweating, pale skin (pallor), facial flushing, swelling around the eye on the affected side, and/or drooping eyelid.
  • This application file contains at least one drawing executed in color.
  • Figure 1(A) and (B) are scanning electron micrographs (SEM) of
  • Figure 2(A)-(B) show views of the patch and the retainer ring structure.
  • (A) provides a top view of the patch and retainer ring.
  • (B) provides a bottom perspective view of the patch attached to a retainer ring.
  • Figure 3(A)-(B) illustrates the patch assembly, comprised of a patch in a retainer ring.
  • A provides a side view of the patch assembly.
  • B illustrates an exploded view of a patch assembly.
  • Figure 4(A)-(B) illustrates how the used plastic retainer ring is removed from the applicator and discarded. The fingers are used to pull the used retainer ring off the applicator.
  • A provides a side view of the retainer ring attached to the applicator.
  • (B) provides a side view of the retainer ring separated from the applicator.
  • FIG. 5(A)-(E) are photographs of the steps for application of the patch of the present invention.
  • A) illustrates step 1 : snap patch assembly onto applicator.
  • B) further illustrates step 1 and provides a bottom front perspective of the patch assembly with the applicator.
  • C) illustrates step 2: twist applicator cap clockwise from position 1 to position 2 to unlock for patch application.
  • D) illustrates step 3 : press applicator downward to apply patch to skin.
  • step 4 patch is applied to the patient's skin and the retainer ring remains attached to the applicator.
  • Figure 6(A)-(C) provides in vitro release profiles of ZP-Zolmitriptan
  • top left provides in vitro release profiles of ZP-Zolmitriptan M207 1.9 mg patches that have been E-beam irradiated and stored at RT for 10 months, L/N0164004.
  • B top right, provides in vitro release profiles of ZP-Zolmitriptan M207 1.9 mg patches that have been non-irradiated and stored at 40°C/75% RH for 10 months, L/N0203149-NI.
  • C bottom left, provides in vitro release profiles of ZP-Zolmitriptan M207 1.9 mg patches that have been E-beam irradiated and stored at 40°C/75% RH for 10 months, L/N0203149-IR.
  • Figure 7 is a line graph of mean zolmitriptan and sumatriptan plasma concentrations over time (zero to 24 hours) in normal human volunteers, wherein 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 the zolmitriptan (2.5 mg oral tablet); Treatment E is the Sumatriptan (6.0 mg SC using auto-injector pen); Treatment F is the Zolmitriptan system (1.9 mg x 2); and Treatment G is the Zolmitriptan system (3.8 mg). Sumatriptan was scaled 6/90 to show the sumatriptan concentration-time profile relative to other treatments.
  • Figure 8 is a line graph of mean zolmitriptan and sumatriptan plasma concentrations over time (zero to two hours), wherein 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 the Sumatriptan (6.0 mg SC using auto-injector pen); Treatment F is the Zolmitriptan system (1.9 mg x 2); and Treatment G is the Zolmitriptan system (3.8 mg).
  • sumatriptan was scaled 6/90 to show the sumatriptan concentration-time profile relative to other treatments.
  • Figure 9 is a line graph of dose linearity of M207 C max , for single patch and multiple patches, excluding 3.8 mg.
  • Figure 10 is a line graph of dose linearity of M207 AUQ, for single patch and multiple patches, excluding 3.8 mg.
  • Figure 11 is a line graph of mean plasma zolmitriptan concentrations in females over zero to two hours.
  • Figure 12 is a line graph of mean plasma zolmitriptan concentrations in males over zero to two hours.
  • Figure 13 is a line graph of mean plasma N-desmethyl zolmitriptan concentration over zero to two hours.
  • Figure 14 is a line graph of mean N-desmethyl zolmitriptan plasma concentrations over zero to twenty-four hours.
  • Figure 15 is a line graph of dose linearity of M207 C max for single patch and multiple patches.
  • Figure 16 is a line graph of dose linearity of M207 AUQ for single patch and multiple patches.
  • Figure 17 is a line graph of dose linearity of M207 AUQ nf for single patch and multiple patches.
  • Figure 18 is a line graph of dose linearity of M207 AUCi nf for single patch and multiple patches, excluding 3.8 mg patch.
  • Figure 19 is a line graph of N-desmethyl zolmitriptan dose linearity C max as a function of M207 dose for single patch and multiple patches.
  • Figure 20 is a line graph of N-desmethyl zolmitriptan dose linearity AUC t as a function of M207 dose for single patch and multiple patches.
  • Figure 21 is a line graph of N-desmethyl zolmitriptan dose linearity
  • AUCi nf as a function of M207 dose for single patch and multiple patches.
  • Figure 22 is a line graph of N-desmethyl zolmitriptan dose linearity C max as a function of M207 dose for single patch and multiple patches, excluding 3.8 mg.
  • Figure 23 is a line graph of N-desmethyl zolmitriptan dose linearity AUC t as a function of M207 dose, for single patch and multiple patches, excluding 3.8 mg.
  • Figure 24 is a line graph of N-desmethyl zolmitriptan dose linearity
  • AUCin f as a function of M207 dose, for single patch and multiple patches, excluding 3.8 mg.
  • Figure 25 is a graphical comparison of "% pain free" at 1, 2, and 4 hours after treatment.
  • Figure 26 is a graphical comparison of "% pain relief at 1, 2, and 4 hours after treatment.
  • Figure 27 is a graphical comparison of "% pain free" at 1, 2, and 4 hours after treatment.
  • Figure 28 is a graphical comparison of "% pain relief at 1, 2, and 4 hours after treatment.
  • Figure 29 is a graphical comparison of "% subjects with pain freedom" for up to 4 hours after treatment.
  • Figure 30 is a graphical representation of the mean flux results from ex vivo human skin samples.
  • Figure 31 depicts the interaction of microprojections with the skin, and, specifically, how the microprojections penetrate the stratum corneum for effective drug delivery.
  • Figure 32 demonstrates an embodiment of a microprojection with a shape and dimensions before the microprojection is bent outward from the substrate and coated with drug.
  • the delivery of zolmitriptan generally comprises a delivery system comprising a microprojection member (or system) that includes a plurality of microprojections (or array thereof) that are adapted to penetrate or pierce the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers.
  • a microprojection member or system
  • the microprojection member includes a biocompatible coating comprising zolmitriptan.
  • amorphous means a non-crystalline solid, i.e., a solid that lacks the long-range order that is characteristic of a crystal.
  • AUC area under the curve
  • biocompatible coating means and includes a coating formed from a “coating formulation” that has sufficient adhesion characteristics and no (or minimal) adverse interactions with the biologically active agent (a/k/a active pharmaceutical ingredient, or therapeutic agent, or drug).
  • bioequivalent denotes a scientific basis on which two or more pharmaceutical products, compositions or methods containing same active ingredient are compared with one another.
  • Bioequivalence means the absence of a significant difference in the rate and extent to which the active agent in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action when administered in an appropriately designed study. Bioequivalence can be determined by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Parameters often used in bioequivalence studies are T ma x, C ma x, AUC o-inf, AUC 0 . t . In the present context, substantial bioequivalence of two compositions or products is established by 90% confidence intervals (CI) of between 0.80 and 1.25 for AUC and Cma X .
  • cluster refers to a series of recurring cluster headaches. Cluster duration is usually from one week to one year, although in chronic cluster headache the duration exceeds one year. The end of a cluster is identified by at least 1 month of remission.
  • cluster headache refers to a condition characterized by excruciating headache pain that recurs, usually daily (although bouts may recur up to 8 times per day), for a period of a week or longer.
  • Cluster headaches pain is usually localized on one side of the head ("unilateral") usually the same side although in some patients the side can vary. The pain usually reaches full intensity in under 10 minutes and lasts for between 15 minutes and 3 hours (usually between 30 and 60 minutes). Because of the rapid onset of symptoms and short duration, treatment via a route by which the drug is rapidly absorbed is required.
  • coating formulation means and includes a freely flowing composition or mixture, which is employed to coat a delivery surface, including one or more microprojections and/or arrays thereof.
  • degradation means the purity of the biological agent decreases from an initial time point.
  • the term "desiccant,” as used herein, means an agent that absorbs water, usually a chemical agent.
  • deteriorate means that the biologically active agent is diminished or impaired in quality, character, or value.
  • electrotransport refers, in general, to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface such as skin, mucous membranes, nails, and the like.
  • a beneficial agent e.g., a drug or drug precursor
  • the transport of the agent is induced or enhanced by the application of an electrical potential, which results in the application of electric current, which delivers or enhances delivery of the agent, or, for "reverse” electrotransport, samples or enhances sampling of the agent.
  • the electrotransport of the agents into or out of the human body may be attained in various manners.
  • half life refers to the time required for a drug' s blood or plasma concentration to decrease by one half. This decrease in drug concentration is a reflection of its excretion or elimination after absorption is complete and distribution has reached an equilibrium or quasi-equilibrium state.
  • the half life of a drug in the blood may be determined graphically from a pharmacokinetic plot of a drug' s blood-concentration time plot, typically after intravenous administration to a sample population.
  • the half life can also be determined using mathematical calculations that are well known in the art.
  • the term “half life” also includes the "apparent half-life" of a drug.
  • the apparent half life may be a composite number that accounts for contributions from other processes besides elimination, such as absorption, reuptake, or enterohepatic recycling.
  • headache pain scale means a scale used to allow patients to quantify their level of pain.
  • a scale of 0 - 3 is used, wherein severe pain has a pain score of 3, moderate pain has a score of 2, mild pain has a score of 1, and no pain (also referred to as "pain freedom”) has a score of 0.
  • Intracutaneous is a generic term that refers to delivery of an active agent (e.g., a therapeutic agent, such as a drug, pharmaceutical, peptide, polypeptide or protein) through the skin to the local tissue or systemic circulatory system without substantial cutting or penetration of the skin, such as cutting with a surgical knife or piercing the skin with a hypodermic needle.
  • Intracutaneous agent delivery includes delivery via passive diffusion as well as delivery based upon external energy sources, such as electricity (e.g., iontophoresis) and ultrasound (e.g., phonophoresis).
  • intracutaneous flux means the rate of intracutaneous delivery of a drug.
  • microprojection member or "microneedle array,” and the like as used herein, generally connotes a microprojection grouping comprising a plurality of microprojections, preferably arranged in an array, for penetrating or piercing the stratum corneum.
  • the microprojection member can be formed by etching or punching a plurality of microprojections from a thin sheet of metal or other rigid material, and folding or bending the microprojections out of the plane of the sheet to form a configuration.
  • the microprojection member could alternatively be fabricated with other materials, including plastics or polymers, such as polyetheretherketone (PEEK).
  • the microprojection member can be formed in other known techniques, such as injecting molding or micro-molding, microelectromechanical systems (MEMS), or by forming one or more strips having microprojections along an edge of each of the strip(s), as disclosed in U.S. Pat. Nos. 6,083,196; 6,091,975; 6,050,988; 6,855,131; 8,753,318; 9,387,315; 9, 192,749; 7,963,935; 7,556,821; 9,295,714; 8,361,022; 8,633, 159; 7,419,481;
  • MEMS microelectromechanical systems
  • microprojections and "microneedles,” as used
  • the piercing elements refers to piercing elements that are adapted to penetrate, pierce or cut into and/or through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a mammal and, more particularly, a human.
  • the piercing elements have a projection length less than 1000 microns.
  • the piercing elements have a projection length of less than 500 microns, more preferably less than 400 microns.
  • the microprojections further have a width in the range of approximately 25 to 500 microns and a thickness in the range of approximately 10 to 100 microns.
  • the microprojections may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof.
  • "Most bothersome other symptom” means a symptom, usually a migraine symptom, that is most bothersome to a patient, in addition to pain.
  • a most bothersome other symptom is identified by a patient at the start of a clinical trial.
  • most bothersome other symptom is selected from nausea, photophonia, and phonophobia.
  • migraine patients are 1 hour, 2 hours, and 4 hours.
  • Preferred times for cluster headache patients are 15 minutes and 30 minutes.
  • “Nausea freedom” means the patient reports the absence of nausea at a pre-specified time period after drug administration.
  • migraine patients are 1 hour, 2 hours, and 4 hours.
  • Preferred times for cluster headache patients are 15 minutes and 30 minutes.
  • Preferred times for migraine patients are 1 hour, 2 hours, and 4 hours.
  • Preferred times for cluster headache patients are 15 minutes and 30 minutes.
  • Phonophobia refers to a fear of or aversion to sounds, especially loud sounds.
  • Phonophobia freedom means the patient reports the absence of phonophobia at a pre-specified time period after drug administration.
  • Photophobia refers to increased, often painful sensitivity to light, especially bright light.
  • Photophobia freedom means the patient reports the absence of photophobia at a pre-specified time period after drug administration.
  • Partial AUC means an area under the drug concentration-time curve
  • AUC calculated using linear trapezoidal summation for a specified interval of time, for example, AUC(O-lhr), AUC(0-2hr), AUC(0-4hr), AUC(0-6hr), AUC(0-8hr) etc.
  • a drug "release rate,” as used herein, refers to the quantity of drug released from a dosage form or pharmaceutical composition per unit time, e.g., milligrams of drug released per hour (mg/hr).
  • Drug release rates for drug dosage forms are typically measured as an in vitro rate of dissolution, i.e., a quantity of drug released from the dosage form or pharmaceutical composition per unit time measured under appropriate conditions and in a suitable fluid.
  • stable refers to an agent formulation, means the agent formulation is not subject to undue chemical or physical change, including
  • Stable refers to a coating also means mechanically stable, i.e., not subject to undue displacement or loss from the surface upon which the coating is deposited.
  • subject or “patient” are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.
  • therapeutic-effective refers to the amount of the biologically active agent needed to stimulate or initiate the desired beneficial result.
  • the amount of the biologically active agent employed in the coatings of the invention will be that amount necessary to deliver an amount of the biologically active agent needed to achieve the desired result. In practice, this will vary widely depending upon the particular biologically active agent being delivered, the site of delivery, and the dissolution and release kinetics for delivery of the biologically active agent into skin tissues.
  • transdermal means the delivery of an agent into and/or through the skin for local or systemic therapy.
  • transdermal flux means the rate of transdermal delivery.
  • T max refers to the time from the start of delivery to C ma x, the maximum plasma concentration of the biologically active agent.
  • zolmitriptan includes, without limitation, zolmitriptan salts, simple derivatives of zolmitriptan and closely related molecules.
  • the intracutaneous delivery system is a transdermal or intracutaneous drug delivery technology which comprises a disposable patch comprised of a microprojection member centered on an adhesive backing.
  • the microprojection member comprises titanium (or other rigid material, including a plastic or polymeric material like polyetheretherketone (PEEK)) microneedles that are coated with a dry drug product formulation.
  • PEEK polyetheretherketone
  • the patch is mounted in a retainer ring to form the patch assembly.
  • the patch assembly is removably mounted in a handheld applicator to form the intracutaneous delivery system.
  • the applicator ensures that the patch is applied with a defined application speed and energy to the site of intracutaneous administration.
  • the applicator may be designed for single use or be reusable.
  • the patch can comprise an array of about 3 to 6 cm 2 of titanium microneedles approximately 200-350 microns long, coated with a hydrophilic formulation of the relevant drug, and attached to an adhesive backing.
  • the maximum amount of active drug that can be coated on a patch' s microneedle array depends on the active moiety of the drug formulation, the weight of the excipients in the drug formulation, and the coatable surface area of the microneedle array. For example, patches with about 1 cm 2 , 2 cm 2 , 3 cm 2 , 4 cm 2 , 5 cm 2 , and 6 cm 2 microneedle arrays may be employed.
  • the patch is applied with a hand-held applicator that presses the microneedles into the skin to a substantially uniform depth in each application, close to the capillary bed, allowing for dissolution and absorption of the drug coating, yet short of the nerve endings in the skin.
  • the typical patch wear time is about 15 to 45 minutes or less, decreasing the potential for skin irritation.
  • Nominal applicator energies of about 0.20 to 0.60 joules are generally able to achieve a good balance between sensation on impact and array penetration. The actual kinetic energy at the moment of impact may be less than these nominal values due to incomplete extension of the applicator's spring, energy loss from breaking away the patch from its retainer ring, and other losses, which may comprise approximately total 25% of the nominal.
  • a number of variables play a role in the type of array utilized for a particular active agent.
  • different shapes e.g., shapes similar to an arrowhead as shown in Figure 31, hook, conical, or the Washington monument, Figure 1(A)-(B)
  • the stratum corneum has a thickness of about 10-40 ⁇ , and microprojections must have an adequate size, thickness, and shape to penetrate and effect drug delivery through the stratum corneum.
  • Figure 31 not drawn to scale, demonstrates how an array interacts with the skin, such that the microprojections penetrate the stratum corneum and the substrate interfaces with the surface of the skin.
  • Exemplary intracutaneous delivery systems that may be used in the present disclosure include the drug delivery technologies described in U.S. Patent Nos.
  • the disclosed systems and apparatus employ piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin, and thus enhance the agent flux.
  • the piercing elements generally extend perpendicularly from a thin, flat substrate member, such as a pad or sheet.
  • the piercing elements are typically small, some having a microprojection length of only about 25 to 400 microns and a microprojection thickness of about 5 to 50 microns.
  • the active agent to be delivered is associated with one or more of the microprojections, preferably by coating the microprojections with a triptan- or zolmitriptan-based formulation to form a solid, dry coating, or optionally, by the use of a reservoir that communicates with the stratum corneum after the microslits are formed, or by forming the microprojections from solid triptan-based formulations that dissolve after application.
  • the microprojections can be solid or can be hollow, and can further include device features adapted to receive and/or enhance the volume of the coating, such as apertures, grooves, surface irregularities or similar modifications, wherein the features provide increased surface area upon which a greater amount of coating can be deposited.
  • the microneedles may be constructed out of stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials, such as polymeric materials.
  • 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 .
  • microprojections/cm 2 At least about 10 microprojections/cm 2 , or in the range of about 200 to 2000 microprojections/cm 2 , or about 500 to 1000 microprojections/cm 2 , or about 650 to 800 microprojections/cm 2 , or approximately 725 microprojections/cm 2
  • Number of microprojections/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 about 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.
  • Mi croproj ecti on 1 en gth 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, or about 387 microns. In other embodiments, the length is less than 1000 microns, or less than 700 microns, or less than 500 microns.
  • the microneedles penetrate 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.
  • Mi croproi ecti on wi dth 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 • Microprojection thickness: about 1 micron to about 500 microns, or about 5 microns to 300 microns, or about 10 microns to 100 microns, or about 10 microns to 50 microns, or about 20 microns to 30 microns, or about 25 microns.
  • Tip angle about 10-70 degrees, or about 20-60 degrees or about 30 to 50
  • 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.
  • the amount of inactive ingredient is from one to three times less than the active agent, or from about 0.033 mg to about 3.33 mg.
  • Coating Thickness about 100 ⁇ to about 500 ⁇ , or about 200 ⁇ to about 350 ⁇ , or about 250 ⁇ to about 290 ⁇ , or about 270 ⁇ .
  • Active agent per microprojection About 0.01 to about 100 ⁇ g, or about 0.1 to 10 ⁇ g, or about .5 to 2 ⁇ g, or about 1 ⁇ g, or about 0.96 ⁇ g.
  • a particularly preferred embodiment has a patch area of about 5 cm 2 adhered to a titanium substrate with an area of about 3.1 cm 2 and a thickness of about 25 ⁇ .
  • the substrate is comprised of a microprojection array with an area of about 2.74 cm 2 containing about 1987 microprojections at a density of about 725 microprojections/cm 2 .
  • formulation contained on each microprojection may have the approximate shape of an American football with a thickness that tapers down from a maximum of about 270 ⁇ and consists of about 0.96 ⁇ g of zolmitriptan and about 0.32 of tartaric acid, or about 1.9 mg of zolmitriptan and about 0.63 mg of tartaric acid per patch.
  • Figure 32 demonstrates the shape of the microprojection, in a preferred embodiment, prior to bending (forming).
  • Array forming is a process that bends the individual microprojections at right angles to the plane of the substrate.
  • An array is placed over the forming tool, which contains cavities that are registered with the microprojections.
  • An elastomeric forming disk is placed on top of the array and forced under pressure into the cavities in the forming tool. The elastomer flows into the cavities, causing the microprojections to be bent to the desired angle.
  • the use of the elastomer has the advantage that no careful registration of the forming disk to the microprojections and the cavities is required in order to have effective array forming.
  • the microprojections may be substantially rectangular, with a width of about 120 ⁇ 13 ⁇ and a thickness of about 25.4 ⁇ 2.5 ⁇ .
  • the microprojections end with a triangular tip to facilitate penetration.
  • the tip has an angle of 40 ⁇ 5 degrees, and is about 165 ⁇ 25 microns long.
  • the microprojections Prior to bending (forming) out from the substrate, the microprojections have a length of about 387 ⁇ 13 ⁇ , and after bending, they protrude perpendicular to the substrate about 340 ⁇ .
  • Another preferred embodiment has a patch area of about 5 cm 2 adhered to a titanium substrate of about 6 cm 2 to and a thickness of about 25 ⁇ .
  • the substrate is comprised of an array with an area of about 5.5 cm 2 containing about 4000 microprojections at a density of about 725 microprojections/cm 2 .
  • microprojection is in the approximate shape of an American football with a thickness that tapers down from a maximum of about 270 and consists of about 0.96 ⁇ g of zolmitriptan and about 0.32 of tartaric acid, or about 3.8 mg of zolmitriptan and about 1.3 mg of tartaric acid per patch.
  • the microprojections have a length of about 387 ⁇ 13 ⁇ , a width of about 120 ⁇ 13 ⁇ , and a thickness of about 25.4 ⁇ 2.5 ⁇ .
  • the microprojections are rectangular, with a triangular tip to facilitate penetration. The tip has an angle of 40 ⁇ 5 degrees, and is about 165 ⁇ 25 microns long.
  • the exact combination of bulk, length, and density that produces the desired penetration will vary, and may depend on the drug, its dose, the disease or condition to be treated and the frequency of administration.
  • the drug delivery efficiency of a particular array i.e., the amount of drug delivered to the bloodstream
  • the drug delivery efficiency of a particular array will vary between 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%.
  • the intracutaneous drug delivery system of the present disclosure may further comprise an impact applicator having a body and a piston movable within the body, wherein the surface of the piston impacts the patch against the skin causing the microprojections to pierce the stratum corneum.
  • the applicator is adapted to apply the microneedle array to the stratum corneum with an impact energy density of at least 0.05 joules per cm 2 in 10 milliseconds or less, or about 0.26 joules per cm 2 in 10 milliseconds or less, or about 0.52 joules per cm 2 in 10 milliseconds or less.
  • the intracutaneous delivery system comprises a patch having an adhesive backing on one surface and a shiny metal surface on the other side comprised of the array of drug-coated microneedles.
  • the patch may be applied to the skin by pressing the shiny metal surface against the skin either manually, or preferably by an applicator.
  • the applicator applies the patch to the skin with an impact energy density of 0.26 joules per cm 2 in 10 milliseconds or less.
  • the patch may be connected to and supported by a retainer ring structure forming a patch assembly.
  • the retainer ring is adapted to fit onto the impact adaptor and removably attach the patch to the applicator.
  • the retainer ring structure may comprise an inner ring and outer ring, which are designed to receive the adhesive patch and microneedle array.
  • Figures 5(A)-(E) demonstrate one embodiment of the claimed invention, in which the user facilitates the connection of the impact applicator to the retainer ring, which is already loaded with the patch and the microneedle array. As shown, once the retainer ring and impact applicator are connected, a user can unlock the impact applicator by twisting the applicator cap.
  • Figure 5(C) shows that the user may then press the applicator downward on the skin to dispense the patch and apply it to the skin.
  • the patch will removably attach to the patient's skin, and the retainer ring remains attached to the applicator.
  • the retainer ring reversibly attaches to the impact applicator such that the impact applicator can be reused during subsequent dosing events with additional patch assemblies and potentially for other active ingredients and disease states.
  • the patch and applicator are supplied as a single, integrated unit, with packaging that ensures the stability and sterility of the formulation. The user removes the system from the packaging and applies the patch much as described above. The used applicator is then disposed of.
  • This embodiment while somewhat higher cost per dose, provides a system that is less complex, smaller, lighter, and easier to use.
  • the present disclosure can also be employed in conjunction with a wide variety of active transdermal systems (as opposed to passive, manual intracutaneous delivery devices described herein), as the disclosure is not limited in any way in this regard.
  • Electroosmosis another type of electrotransport process involved in the transdermal transport of uncharged or neutrally charged molecules (e.g., transdermal sampling of glucose), involves the movement of a solvent with the agent through a membrane under the influence of an electric field.
  • Electroporation still another type of electrotransport, involves the passage of an agent through pores formed by applying an electrical pulse, a high voltage pulse, to a membrane. In many instances, more than one of the noted processes may be occurring simultaneously to different extents. Accordingly, the term
  • electrotransport is given herein its broadest reasonable interpretation, 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) by which the agent is actually being transported with.
  • any other transport enhancing method including but not limited to chemical penetration enhancement, laser ablation, heat, ultrasound, or piezoelectric devices, can be used in conjunction with the disclosure herein.
  • the coating formulations applied to the microproj ection member described above to form solid coatings are comprised of a liquid, preferably an aqueous formulation having at least one biologically active agent, which can be dissolved within a biocompatible carrier or suspended within the carrier.
  • the biologically active agent may be a triptan, including zolmitriptan, sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan, avitriptan, and donitriptan, and pharmaceutically acceptable salts, fragments, analogs, or prodrugs thereof.
  • the biologically active agent is zolmitriptan.
  • Examples of pharmaceutically acceptable salts include, without limitation, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarballylate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpropionate, tiglate, glycerate, methacrylate, isocrotonate, ⁇ -hydroxibutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, methane sulfonate, sul
  • the concentration of biologically active ingredient and excipients must be carefully controlled to achieve the desired amount of the active ingredient with an acceptable coating thickness, avoid wicking of the coating formulation onto the base of the microneedle array, maintain the uniformity of the coating, and ensure stability.
  • the active agent is present in the coating formulation at a concentration of between about 1% w/w to about 60% w/w, preferably between about 15% and 60%, or more preferably between 35% and 45%.
  • the formulation may further comprise an acid at a concentration of between about 0.1% w/w to about 20%) w/w.
  • Such acid may be selected from tartaric acid, citric acid, succinic acid, malic acid, maleic acid, ascorbic acid, lactic acid, hydrochloric acid, either individually or in combination.
  • the active agent to acid ratio is about 1 : 1, about 2: 1, about 3 : 1, about 4: 1, or about 5 : 1.
  • the present disclosure further encompasses a coating formulation comprising about 33%> w/w zolmitriptan base and about 1 1%) w/w tartaric acid.
  • the acid is one of tartaric acid, citric acid, succinic acid, malic acid or maleic acid, and is present in an amount of about 0.33%> 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.
  • the coating formulation comprises 45%> w/w of the active agent, 15%> w/w of the acid, and 40%> w/w of water.
  • Surfactants may be included in the coating formulation.
  • Surfactants suitable for inclusion in the coating formulations include, but are not limited to, polysorbate 20 and polysorbate 80.
  • Surfactants are commonly used to improve drug delivery as penetration enhancers.
  • Applicant found that surfactants resulted in undulations in the coating formulation, which is indicative of an uneven film and is highly disadvantageous.
  • Applicant found that the need for surfactants and other penetration enhancers can be avoided through the use of the claimed invention— specifically, through the claimed zolmitriptan transdermal delivery patches.
  • microneedle coating avoided wi eking, and the coating sufficiently adhered to the microproj ections during the manufacturing process of the microneedle arrays, despite the lack of a surfactant.
  • Antioxidants may be included in the coating formulation.
  • Antioxidants suitable for inclusion in the coating formulations include, but are not limited to, methionine, ascorbic acid, and EDTA.
  • the coating formulation further comprises a liquid, preferably water, in an amount sufficient (qs ad) to bring the formulation to 100% prior to being dried onto the microneedles.
  • the pH of the liquid coating formulation may be below about pH 8. In other cases, the pH is between about pH 3 and 7.4, or between about pH 3.5 to 4.5.
  • liquid coating formulations according to the present disclosure are set forth in Table 1 below.
  • the coatings generally contain at least one acid.
  • Lactic acid 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10 0-10
  • the liquid coating formulations according to the present disclosure generally exhibit the ability to consistently coat the microneedles with adequate content and morphology, and result in a stable solid-state (dried) formulation, containing less than 5% water, preferably less than 3%.
  • the liquid formulations are applied to the microneedle arrays and the microprojection tips thereof using an engineered coater which allows accurate control of the depth of the microprojection tips dipping into the liquid film. Examples of suitable coating techniques are described in U.S. Patent No. 6,855,372, included herein by reference in its entirety. Accordingly, the viscosity of the liquid plays a role in microprojection member coating process as has been described.
  • the coating formulations comprising zolmitriptan have a viscosity less than approximately 500 centipoise (cP) and greater than 3 cP, or less than approximately 400 cP and greater than 10 cP, or less than approximately 300 cP and greater than 50 cP, or less than 250 cP and greater than approximately 100 cP.
  • the viscosity of the liquid formulation prior to coating is at least 20 cP.
  • 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.
  • the viscosity is more than about 25 cP, or a more than about 30 cP, or more than about 35 cP, or more than about 40 cP, or more than about 45 cP, or more than about 50 cP, or more than about 55 cP, or more than about 60 cP, or more than about 65 cP, or more than about 70 cP, or more than about 75 cP, or more than about 80 cP, or more than about 85 cP, or more than about 90 cP, or more than about 95 cP, or more than about 100 cP, or more than about 150 cP, or more than about 200 cP, or more than about 300 cP, or more than about 400 cP, or less than about 500 cP.
  • the viscosity of the coating formulation is more than about 80 cP and less than about 350 cP; in another preferred embodiment, the viscosity is more than about 100 cP and less than about 350 cP; and, in another preferred embodiment, the viscosity is more than about 100 cP and less than about 250 cP.
  • the coating formulation may have an average thickness of about 10 to about 400 microns, or from about 30 to about 300 microns, or from about 100 microns to about 175 microns, or from about 115 to about 150 microns, or about 135 microns, as measured from the microprojection surface.
  • the coating formulation may vary slightly as a result of the manufacturing process. As shown in Figure 31, the microprojections are generally coated uniformly because they penetrate the stratum corneum.
  • the microprojections are not coated the entire distance from the tip to the base; instead, the coating covers a portion of the length of the microprojection, measured from tip to the base, of at least about 10% to about 80%, or 20% to about 70%, or about 30% to about 60%), or about 40% to about 50% of the length of the microprojection.
  • the liquid coating formulation is applied to an array of microprojections so as to deliver a dose of the active agent in the amount of about 0.1 mg to 10 mg per array.
  • the dose is about 0.25 mg to about 10 mg, or about 1 mg or more, or about 1.9 mg or more, or about 2 mg or more, or about 3 mg or more, or about 3.8 mg or more, or about 4 mg or more, or about 5 mg or more delivered to the stratum corneum per array (via a patch or other form).
  • the amount of the zolmitriptan contained in coating formulation is 1-1000 ⁇ g or 10-100 ⁇ g.
  • 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 3 cm 2 , comprising a dose of about 1.9 mg.
  • the amount of zolmitriptan or similar active agent per microprojection could range from about 0.001 to about 1000 ⁇ g, or about 0.01 to about 100 ⁇ g, or about 0.1 to about 10 ⁇ g, or about 0.5 to about 2 ⁇ g. In one embodiment, the amount of zolmitriptan or similar active agent per microprojection is about 1 ⁇ .
  • the microprojection shape and size has a significant bearing on the drug loading capacity and on the effectiveness of drug delivery.
  • the formulations of the present disclosure do not primarily rely on penetration enhancers to facilitate absorption of the active agent into the bloodstream.
  • Penetration enhancers such as Azone® and fatty acids, often cause skin irritation and have other disadvantages.
  • the systems of the present disclosure are either completely free of a penetration enhancer, or are substantially free thereof.
  • the biologically active agent formulations are generally prepared as a solid coating by drying a coating formulation on the microprojection, as described in U.S. Application Pub. No. 2002/0128599.
  • the coating formulation is usually an aqueous formulation. During a drying process, all volatiles, including water are mostly removed;
  • the final solid coating may still contain 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.
  • the oxygen and/or water content present in the formulations are reduced by the use of a dry inert atmosphere and/or a partial vacuum.
  • the drug may be present in an amount of less than about 10 mg per unit dose or less than about 4 mg or less than about 3 mg or less than about 2 mg or less than about 1 mg. With the addition of excipients, the total mass of solid coating may be less than about 15 mg per unit dose.
  • the microprotrusion member is usually present on an adhesive backing, which is attached to a disposable polymeric retainer ring.
  • This assembly is packaged individually in a pouch or a polymeric housing.
  • this package contains a dead volume that represents a volume of at least 3 mL.
  • This large volume (as compared to that of the coating) acts as a partial sink for water.
  • the amount of water present in a 3 mL atmosphere as a result of its vapor pressure would be about 0.05 mg at saturation, which is typically the amount of residual water that is present in the solid coating after drying. Therefore, storage in a dry inert atmosphere and/or a partial vacuum will further reduce the water content of the coating resulting in improved stability.
  • the coating can be applied to the microprojections by a variety of known methods.
  • the coating may be only applied to those portions of the microprojection member or microprojections that pierce the skin (e.g., tips).
  • the coating is then dried to form a solid coating.
  • One such coating method comprises dip- coating. Dip-coating can be described as a method to coat the microprojections by partially or totally immersing the microprojections into a coating solution. By use of a partial immersion technique, it is possible to limit the coating to only the tips of the microprojections.
  • a further coating method comprises roller coating, which employs a roller coating mechanism that similarly limits the coating to the tips of the microprojections.
  • the roller coating method is disclosed in U. S. Application Pub. No. 2002/0132054. As discussed in detail therein, the disclosed roller coating method provides a smooth coating that is not easily dislodged from the microproj ections during skin piercing.
  • a further coating method that can be employed within the scope of the present invention comprises spray coating.
  • Spray coating can encompass formation of an aerosol suspension of the coating composition.
  • an aerosol suspension having a droplet size of about 10 to 200 picoliters is sprayed onto the microprojections and then dried.
  • Pattern coating can also be employed to coat the microprojections.
  • the pattern coating can be applied using a dispensing system for positioning the deposited liquid onto the microprojection surface.
  • the quantity of the deposited liquid is preferably in the range of 0.1 to 20 nanoliters/microprojection. Examples of suitable precision-metered liquid dispensers are disclosed in U.S. Patent Nos. 5,916,524; 5,743,960; 5,741,554; and 5,738,728; which are fully incorporated by reference herein.
  • Microprojection coating formulations or solutions can also be applied using inkjet technology using known solenoid valve dispensers, optional fluid motive means and positioning means which is generally controlled by use of an electric field.
  • Other liquid dispensing technology from the printing industry or similar liquid dispensing technology known in the art can be used for applying the pattern coating of this invention.
  • the thickness of the dried coating formulations comprising zolmitriptan range from about 10 to 100 microns as measured from the microprojection surface, or from about 20 to 80 microns, or from about 30 to 60 microns, or from about 40 to 50 microns.
  • the desired coating thickness is dependent upon several factors, including the required dose and, hence, coating thickness necessary to deliver the dose, the density of the microprojections per unit area of the sheet, the viscosity, the solubility and concentration of the coating composition and the coating method chosen.
  • the thickness of coating applied to microprojections can also be adapted to optimize stability of the zolmitriptan.
  • Known formulation adjuvants can also be added to the coating formulations provided they do not adversely affect the necessary solubility and viscosity characteristics of the coating formulation nor the physical integrity of the dried coating.
  • the coating is applied to the microneedles, which protrude from the base, or streets, of the microneedle array.
  • the coating is applied to the tips of the microneedles, and is not intended to cover the microneedles and the surface of the microneedle array.
  • the coating formulation is dried onto the microprojections by various means.
  • the coated microprojection member may be dried in ambient room conditions. However, various temperatures and humidity levels can be used to dry the coating formulation onto the microprojections. Additionally, the coated member can be heated, stored under vacuum or over desiccant, lyophilized, freeze dried or similar techniques used to remove the residual water from the coating.
  • Coating was conducted at ambient temperature utilizing a roller drum, rotating at 50 rpm, in a drug formulation reservoir (2 mL in volume) to produce a film of controlled thickness of around 270 ⁇ in thickness. Further information about the coating process can be found in U.S. Pat. No. 6,855,372, incorporated herein in its entirety by reference. Microprojection arrays are dipped into the drug film, and the amount of coating is controlled by the number of dips (passes) through the drug film. [00145] During the drying process, there may be issues related to forming a uniform coating the microprojection with a controlled and consistent thickness.
  • Preferred liquid coating formulations comprise zolmitriptan in an amount of 30% w/w to about 60% w/w, preferably about 40% w/w to about 50% w/w, more preferably about 45% w/w, and tartaric acid in an amount of about 5% w/w to about 25% w/w, preferably about 10% w/w to about 20% w/w, more preferably about 15% w/w, in a liquid carrier, preferably water, more preferably deionized water.
  • the route of administration of zolmitriptan is
  • a formulation designed for intramuscular or subcutaneous delivery would contain 1 mg of zolmitriptan (base) and 0.3 mg of tartaric acid in 1 mL of 0.9 % w/v saline.
  • a formulation designed for pulmonary delivery would be in the form of zolmitriptan salt dissolved or suspended in water or a zolmitriptan powder generated using milling, supercritical fluid process, spray drying or spray freeze drying for inhalation delivery and would produce respirable particles with a controlled particle size of about 0.5- 5.8 ⁇ mass median aerodynamic diameter (MMAD) to ensure that a significant fraction of zolmitriptan would be deposited in the lung.
  • MMAD mass median aerodynamic diameter
  • the processes to produce zolmitriptan powder can be used directly by metering in from a powder reservoir or premetering into a dry powder inhaler (DPI) format, or the particulates may be suspended/dispersed directly into a suspending media, such as a pharmaceutically acceptable propellant e.g., hydrofluoralkanes (selected from the group consisting of: 1,1, 1,2-tetrafluoroethane, 1, 1,1,2,3,3,3-heptafluoro-n- propane and a mixture of 1,1, 1,2-tetrafluoroethane and 1, 1,1,2,3,3,3-heptafluoro-n-propane or a mixture of thereof), in a metered dose inhaler (MDI) format.
  • MDI metered dose inhaler
  • the particles produced may be crystalline or may be amorphous depending on the process to generate the zolmitriptan powder.
  • the zolmitriptan dose ranges from 0.5 to 4 mg, administered at the onset of migraine
  • the present disclosure comprises an active agent formulation wherein the deterioration by oxygen and/or water is minimized and/or controlled by the manufacture and/or packaging of the active agent formulation in a dry inert atmosphere.
  • the formulation may be contained in a dry inert atmosphere in the presence of a desiccant, optionally in a chamber or package comprising a foil layer.
  • the desiccant can be any known to those skilled in the art. Some common desiccants include, but are not limited to molecular sieve, calcium oxide, clay desiccant, calcium sulfate, and silica gel.
  • the desiccant may be one that can be placed with the biologically active agent-containing formulation in the presence of an inert atmosphere in a package comprising a foil layer.
  • the active agent formulation is packaged in a chamber comprising a foil layer after the formulation is coated onto the microprojection array delivery device.
  • a desiccant is contained in the chamber, preferably attached to a chamber lid which comprises a foil layer, and the chamber is purged with dry nitrogen or other inert gas such as a noble gas prior to the delivery device-containing foil chamber being sealed by the foil lid. Any suitable inert gas can be used herein to create the dry inert atmosphere.
  • the compositions of and methods for formulating and delivering zolmitriptan suitable for intracutaneous delivery utilize a patch assembly.
  • This patch assembly is manufactured and/or packaged in a dry inert atmosphere, and in the presence of a desiccant.
  • the patch assembly is manufactured in a dry inert atmosphere and/or packaged in a chamber comprising a foil layer and having a dry inert atmosphere and a desiccant.
  • the patch assembly is manufactured and/or packaged in a partial vacuum.
  • the patch assembly is manufactured and/or packaged in a dry inert atmosphere, and a partial vacuum.
  • patch assembly is manufactured in a dry inert atmosphere under a partial vacuum and/or packaged in a chamber comprising a foil layer and having a dry inert atmosphere, a partial vacuum, and a desiccant.
  • the inert atmosphere should have essentially zero water content.
  • nitrogen gas of essentially zero water content dry nitrogen gas
  • Purge systems can be also used to reduce moisture or oxygen content.
  • a range for a partial vacuum is from about 0.01 to about 0.3 atmospheres.
  • the zolmitriptan further comprises a biocompatible carrier.
  • an intracutaneous delivery system adapted to deliver zolmitriptan, comprising: (a) a microprojection member including a plurality of microprojections that are adapted to pierce the stratum corneum of a patient; (b) a hydrogel formulation comprised of zolmitriptan, wherein the hydrogel formulation is in communication with the microprojection member; and (c) packaging purged with an inert gas and adapted to control environmental conditions sealed around the microprojection member, wherein the sealed package has been exposed to radiation to sterilize the microprojection member.
  • an intracutaneous delivery system adapted to deliver zolmitriptan, comprising: (a) a microprojection member including a plurality of microprojections that are adapted to pierce the stratum corneum of a patient; (b) a solid film disposed proximate the microprojection member, wherein the solid film is made by casting a liquid formulation comprising zolmitriptan, a polymeric material, a plasticizing agent, a surfactant and a volatile solvent; and (c) packaging purged with an inert gas and adapted to control environmental conditions sealed around the microprojection member, wherein the sealed package has been exposed to radiation to sterilize the microprojection member.
  • the present disclosure is also to a method for terminally sterilizing a patch assembly adapted to deliver zolmitriptan, comprising the steps of: (a) providing a
  • microprojection member having a plurality of microprojections that are adapted to pierce the stratum corneum of a patient having a biocompatible coating comprising zolmitriptan disposed on the microprojection member; and (b) exposing the microprojection member to radiation selected from the group consisting of gamma radiation and e-beam, wherein the radiation is sufficient to reach a desired sterility assurance level.
  • sterility assurance level may be 10 "6 or 10 "5 .
  • the method may further comprise sealing the microprojection member with a desiccant inside packaging purged with an inert gas and exposing the packaged microprojection member to radiation selected from the group consisting of gamma radiation and e-beam radiation, wherein the radiation is sufficient to reach a desired sterility assurance level.
  • the method further comprises the step of mounting a patch comprised of a microprojection member attached to an adhesive backing on a pre-dried retainer ring to form a patch assembly, and subsequently sealing the microprojection member inside the packaging.
  • the system further comprises a desiccant sealed inside the packaging with the patch assembly, and/or the packaging is purged with nitrogen, and/or the packaging comprises a pouch comprised of a foil layer.
  • the foil layer comprises aluminum.
  • the step of exposing the microprojection 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 be in the range of approximately 5 to 50 kGy, or approximately 10 to 30 kGy, or approximately 15 to 25 kGy, or approximately 21 kGy, or approximately 7 kGy.
  • the radiation is delivered to the microprojection member at a rate of at least approximately 3.0 kGy/hr.
  • Applicant developed a zolmitriptan formulation which, when coated on the microneedle members of the present disclosure, is stable and maintains its amorphous character for at least 6 months, or at least 9 months, or at least 12 months, or at least 18 months, or at least 24 months after being exposed to radiation as described above.
  • microneedles retains for at least 6 months approximately 100% of initial purity, or
  • the zolmitriptan coating on the microneedles retains its purity as described in this paragraph, and also substantially maintains its amorphous character for at least 6 months, or at least 9 months or at least 12 months, or at least 18 months, or at least 24 months after packaging.
  • a method for manufacturing a patch assembly for an intracutaneous delivery system adapted to deliver a zolmitriptan comprises the steps of:
  • microneedle member having a plurality of microneedles that are adapted to penetrate or pierce the stratum corneum of a patient having a biocompatible coating disposed on the microneedle member, the coating being formed from a coating formulation having zolmitriptan and disposed thereon; sealing the microneedle member with a desiccant inside packaging purged with nitrogen and adapted to control environmental 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 a desired sterility assurance level.
  • a method for delivering stable biologically active agent formulations comprises the following steps: (i) providing a microprojection member having a plurality of microprojections, (ii) providing a stabilized formulation of biologically active agent; (iii) forming a biocompatible coating formulation that includes the formulation of stabilized biologically active agent, (iv) coating the microprojection member with the biocompatible coating formulation to form a biocompatible coating; (v) stabilizing the biocompatible coating by drying; and (vi) applying the coated microprojection member to the skin of a subject.
  • biocompatible coating that is solid and substantially dry.
  • the kinetics of the coating dissolution and agent release can vary appreciably depending upon a number of factors. It will be appreciated that in addition to being storage stable, the biocompatible coating should permit desired release of the therapeutic agent.
  • a method for terminally sterilizing a transdermal device adapted to deliver a zolmitriptan comprising the steps of: providing a microprojection member having a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of a patient having a biocompatible coating disposed on the microprojection member, the coating being formed from a coating formulation having at least one triptan, preferably zolmitriptan, disposed thereon; and exposing the microprojection member to radiation selected from the group consisting of gamma radiation and e-beam, wherein the radiation is sufficient to reach a desired sterility assurance level.
  • a further aspect of this method comprises the further step of sealing the microprojection member inside packaging adapted to control environmental conditions surrounding the microprojection member.
  • the packaging comprises a foil pouch.
  • a further aspect of this method comprises the further step of sealing a desiccant inside the packaging.
  • the method comprises the step of mounting the microprojection member on a pre-dried retainer ring prior to sealing the microprojection member inside the packaging.
  • a further aspect of this method comprises the step of purging the packaging with an inert gas prior to sealing the packaging.
  • the inert gas comprises nitrogen.
  • the intracutaneous/transdermal systems of the present invention provide serum concentrations to the bloodstream faster and with less overall drug exposure as compared to oral doses of the same drug.
  • the absorption of intracutaneously administered zolmitriptan delivered via the systems of the present disclosure results in a C max of less than 50 mg/mL and the T ma x is between about 2 minutes and 30 minutes.
  • the plasma zolmitriptan AUC for the first 2 hours is greater than that seen following oral administration, but the plasma zolmitriptan AUC( 0- 24hr) is less than that seen after oral administration.
  • the absorption of the zolmitriptan results in an increase in the maximum plasma zolmitriptan, but the N-desmethyl zolmitriptan production (AUCo-24hr) is reduced and thus has a lower likelihood for metabolite accumulation.
  • the intracutaneous administration of triptans, including zolmitriptan avoids the first pass metabolism in the liver found with oral administration, resulting in higher bioavailability.
  • metabolism is significantly reduced resulting in at least about 20% less serum concentration of N-desmethyl zolmitriptan at time points (e.g., 1.5 hours, 2 hours, 5 hours, 10 hours) post-application than seen in oral products.
  • zolmitriptan plasma levels may be increased, but the N- desmethyl zolmitriptan production is reduced relative to that produced upon oral administration of a comparable dose of zolmitriptan. Therefore, there is a lower likelihood for metabolite accumulation.
  • N-desmethyl zolmitriptan is more active at the target sites than zolmitriptan, the present invention is surprisingly effective at treating migraine or cluster headache as detailed below.
  • the apparent half-life of zolmitriptan is reduced compared to oral administration, such that the duration of side effects may be reduced.
  • the plasma concentration of N-desmethyl zolmitriptan is about 0.05 to 0.9 ng/ml after about 15 minutes after application, or about 0.1 to 1.4 ng/ml after about 30 minutes, or about 0.1 to 1.6 ng/ml after about 1 hour, 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 less than about 0.2 ng/ml after 10 hours.
  • the intracutaneously delivered biocompatible coating comprises a dose of the zolmitriptan in the range of approximately 0.2 to 10 mg, preferably 1 to 5 mg, more preferably approximately 1.9 or 3.8 mg, wherein intracutaneous delivery of the zolmitriptan results in a plasma C ma x of at least 2 ng/mL zolmitriptan, at least 3.6 ng/mL zolmitriptan, at least 4 ng/mL zolmitriptan, at least 6 ng/mL zolmitriptan, at least 9 ng/mL zolmitriptan, at least 10 ng/mL zolmitriptan, at least 12 ng/mL zolmitriptan, at least 14 ng/mL zolmitriptan, at least 16 ng/mL zolmitriptan, at least 18 ng/mL zolmitriptan, at least 20 ng/mL zolmitriptan, at least 25 ng/mL zolmit
  • the T max of intracutaneously administered is administered
  • zolmitriptan via the inventive systems occurs about 2 hours or more before conventional release oral zolmitriptan tablets, or about 1.8 hours or more before such tablets, or about 1.6 hours or more before such tablets, or about 1.4 hours or more before such tablets, or about 1.2 hours or more before such tablets, or about 1.0 hours or more before such tablets, or about 0.8 hours or more before such tablets, or about 0.6 hours or more before such tablets, or about 0.4 hours or more before such tablets, or about 0.2 hours or more before such tablets.
  • the T max of intracutaneously administered zolmitriptan via the inventive systems occurs about 3 hours or more before ZOMIG®
  • the T max of intracutaneously administered zolmitriptan via the inventive systems occurs about 3 hours or more before zolmitriptan nasal spray, or about 2.5 hours or more before such spray, or about 2.0 hours or more before such spray, 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.
  • the elimination rate (t 1 ⁇ 2 ) for intracutaneously administered zolmitriptan via the inventive systems is about 0.75 hour, or 1 .0 hour, or 1 . 1 hour, or 1 .2 hour, or 1 .3 hour, or 1 .4 hour, or 1 .5 hour, or 1 .6 hour, or 1 .7 hour, or 1 .8 hour, or 1 .9 hour, or 2.0 hours.
  • Such elimination rate (t 1 ⁇ 2 ) is approximately three times the rate of zolmitriptan conventional tablets, or approximately twice the rate of zolmitriptan conventional tablets.
  • the C ma x for intracutaneously administered zolmitriptan via the inventive systems is about 1 to about 8 times higher than the C ma x of conventional oral 2.5 mg zolmitriptan tablets, or about 1 .5 to about 7 times higher, or about 2 to about 6 times higher, or about 3 to about 5 times higher, or about 4 times higher.
  • the mean peak exposure (Cmax) is about 2 to about 5 times higher for intracutaneous zolmitriptan relative to the oral tablets.
  • the mean peak exposure (C max ) for the intracutaneous 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.
  • intracutaneous zolmitriptan of the invention at doses ranging from about 0.5 mg to about 4.0 mg have a bioavailability of about 50% to about 100% of the oral bioavailability.
  • the bioavailability of intracutaneous is about 55% to about 95%, or about 60% to about 90%), or about 65% to about 85%, or about 70% to about 80%, or about 75% of the oral bioavailability.
  • the present invention encompasses formulations and devices that are bioequivalent to the M207 Intracutaneous Delivery System described herein.
  • the disclosure covers products where bioequivalence is established by (i) a 90% Confidence Interval (CI) for AUC which is between 0.80 and 1 .25; and (ii) a 90% CI for C ⁇ which is between 0.80 and 1 .25. VII. Methods of Treatment
  • the drug-device combinations of the present invention can be used to treat a variety of diseases and conditions, including migraine and cluster headache.
  • a method for treatment or alleviation of migraine or cluster headache to an individual in need thereof comprising administration of a
  • a zolmitriptan-based agent wherein the absorption of the zolmitriptan-based agent results in a plasma Cmax of less than 50 ng/mL.
  • Doses include about 0.2 mg to about 10 mg zolmitriptan. The dose may also be 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mg zolmitriptan. Doses also include a single patch administration of either 1.0 mg, 1.9 mg, or 3.8 mg, or two patches of 1.9 mg. These doses can be delivered utilizing the patch(es) described herein and can be applied to the skin of any part of the body. In a preferred embodiment, the zolmitriptan dose(s) is delivered via the patch to the upper arm to treat a single migraine or cluster headache attack.
  • the methods of treatment of migraine or cluster headache as described herein result in improvement with respect to the following therapeutic endpoints: Migraine Pain freedom at 1 hour, 2 hours, or 4 hours after dosing; Cluster headache pain freedom at 15 or 30 minutes after dosing, most bothersome other migraine symptom freedom at 1 hour or 2 hours after dosing; freedom from a patient's previously identified most bothersome other cluster headache symptom at 15 or 30 minutes after dosing, migraine pain relief at 1 hour, 2 hours or 4 hours; Cluster headache pain relief at 15 or 30 minutes after dosing, pain relief at 30 minutes; photophobia freedom at 2 hours; phonophobia freedom at 2 hours; pain relief at 15 minutes; pain relief at 3 hours; pain relief at 4 hours; nausea freedom at 2 hours; pain freedom at 30 minutes; pain freedom at 24 hours; and pain freedom at 48 hours. Further, there is an improvement in terms of treated patients requiring rescue medication. Improvement as to pain, most bothersome other symptom, photophobia, phonophobia, nausea, and other bothersome symptoms, is assessed sequentially
  • Tables 45-48 demonstrate effectiveness of the claimed invention for reducing or eliminating pain from migraine or cluster headaches, as compared to triptans and alternative forms of zolmitriptan. These results are based on one embodiment of the claimed invention, but are not so limited. [00181] Shown in Table 45, methods described herein demonstrate that the one embodiment of the claimed invention shows significant improvement in patients being pain free at 1 hour after dosing, as compared to a tablet of zolmitriptan. The results shown in Table 45 are merely one example of the significant efficacy that the claimed invention provides over the known methods for treating migraine or cluster headache with zolmitriptan.
  • zolmitriptan dose of 1 mg more than 15% of patients were pain free at 1 hour after treatment. In another embodiment (1.9 mg), more than 20% of patients were pain free at 1 hour. In a third embodiment (3.8 mg), more than 25% of patients were pain free at 1 hour.
  • the current invention is also significantly more efficacious than 2.5 mg, 5 mg, and 10 mg tablets and 2.5 mg orally dissolving tablets, all of which only achieve pain freedom after 1 hour of 10% or less.
  • the claimed invention also shows significant improvements in pain free results at 2 hours and 4 hours after treatment.
  • Table 46 provides a comparison of resulting pain relief between the claimed invention and the current methods for treating migraine or cluster headaches with zolmitriptan.
  • pain relief of over 45%, 55%, and 65% respectively was achieved at just one hour after dosing. More than 65%, 68%, and 80% respectively experienced pain relief at two hours after dosing.
  • Tables 47 and 48 demonstrate the significant improvements of the claimed inventions over other triptans used for treating migraine or cluster headaches, for eliminating or reducing migraine or cluster headache pain.
  • the claimed invention shows significant improvements in pain free results over other triptans which are currently used in the art.
  • the 3.8 mg embodiment was still superior to all of the other triptans.
  • the claimed invention shows significant improvements in pain relief results, over other triptans which are currently used in the art.
  • the plasma T max of the administered zolmitriptan based agent is between about 2 minutes and 30 minutes.
  • administration of the zolmitriptan based agent is by transdermal or intracutaneous administration.
  • the route of administration of a zolmitriptan based agent is intravenously, subcutaneously, orally, intranasally, oral inhalation, intracutaneously, transdermally, buccally, or sublingually.
  • a method for treatment or alleviation of migraine or cluster headache in an individual in need thereof comprising administering a therapeutically effective amount of a zolmitriptan based agent, wherein the plasma zolmitriptan AUC for the first 2 hours is greater than the plasma zolmitriptan AUC following oral administration of an equivalent dose of zolmitriptan, but the plasma zolmitriptan AUCo-inf following intracutaneous administration of a therapeutically effective amount of a zolmitriptan based agent is less than the plasma zolmitriptan AUCo-inf seen after the oral administration of an equivalent dose of zolmitriptan.
  • administration of the zolmitriptan based agent is transdermal or intracutaneous administration.
  • the route of administration of a zolmitnptan based agent is intravenously, subcutaneously, orally, intranasally, oral inhalation, intracutaneously, transdermally, buccally, or sublingually.
  • a method for treatment or alleviation of migraine or cluster headache in an individual in need thereof of a therapeutically effective amount of a zolmitriptan based agent, wherein, in comparison to oral administration of an equivalent dose of zolmitriptan, the zolmitriptan plasma levels are increased, but the N- desmethyl zolmitriptan production is reduced, thereby reducing the likelihood for metabolite accumulation.
  • administration of the zolmitriptan based agent is transdermal or intracutaneous administration.
  • the route of administration of a zolmitriptan based agent is intravenously, intramuscularly, intracutaneously, subcutaneously, orally, intranasally, oral inhalation, transdermally, buccally, or sublingually.
  • a method for treatment or alleviation of migraine or cluster headache in an individual in need thereof comprising the administration of a therapeutically effective amount of a zolmitriptan based agent, wherein, in comparison to oral administration of an equivalent dose of zolmitriptan, the apparent half-life of zolmitriptan is reduced, thereby indicating a likelihood of a reduced duration of side effects.
  • administration of the zolmitriptan based agent is transdermal or intracutaneous administration.
  • the route of administration of a zolmitriptan based agent is intravenously, intramuscularly, intracutaneously, subcutaneously, orally, intranasally, oral inhalation, transdermally, buccally, or sublingually.
  • the route of administration of a zolmitriptan based agent is selected from the group consisting of intravenously,
  • intramuscularly intracutaneously, subcutaneously, orally, intranasally, oral inhalation, transdermally, buccally, and sublingually.
  • the intracutaneously administered zolmitriptan based agent provides a pharmacokinetic profile similar to the pharmacokinetic profile provided by subcutaneous administration of an equivalent dose to the intracutaneously administered sumatriptan based agent.
  • the administration of the zolmitriptan is not associated with effects on blood pressure greater than those seen with oral zolmitriptan, despite faster absorption.
  • a method for treatment or alleviation of migraine or cluster headache in an individual in need thereof comprising administration of a therapeutically effective amount of a zolmitriptan based agent, wherein the time to achieve maximum plasma concentration (T ma x) was comparable to or less than the Tmax of an equivalent oral dose of zolmitriptan.
  • administration of the zolmitriptan based agent is transdermal or intracutaneous administration.
  • the route of administration of a zolmitriptan based agent is intravenously, subcutaneously, orally, intranasally, oral inhalation, intracutaneously, transdermally, buccally, or sublingually.
  • the generation of N-desmethyl zolmitriptan is reduced relative to the generation of N-desmethyl zolmitriptan resulting from an oral dose of an equivalent amount of the zolmitriptan based agent.
  • the absorption of the intracutaneously administered zolmitriptan based agent results in a C max of less than 50 ng/mL.
  • the microprojection arrays were fabricated by a photo/chemical etching and formed using a controlled manufacturing process.
  • the method is substantially similar to that described in M. Cormier et al., "Device for enhancing transdermal agent delivery or sampling,” EP0914178B1, incorporated herein by reference in its entirety.
  • Drug formulation coating on the microprojection array was conducted at ambient temperature utilizing a roller drum, rotating at 50 rpm, in a drug formulation reservoir (2 mL in volume) to produce a drug coating formulation film of controlled thickness.
  • the method is substantially similar to that described in J.C. Trautman et al., "Method and apparatus for coating skin piercing microprojections," U.S.
  • Microprojections are dipped into the film.
  • the amount of coating is controlled by the number of dips (passes) through the drug film as well as the drug coating formulation properties.
  • the time between each dip was a few seconds which was sufficient to dry the coated liquid formulation under ambient conditions.
  • the reservoir was circulated with coolant to maintain a film temperature of 1°C. Since the reservoir is open to the ambient air, the coating apparatus was positioned inside a dew-point control system.
  • Dew point control minimizes moisture condensation into or evaporation from the liquid formulation during coating.
  • the zolmitriptan-coated microneedle arrays were assembled with 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 England, PA, USA), purged with dry nitrogen and heat-sealed with a Multivac heat sealer (model C400) (Multivac, Kansas City, MO, USA).
  • Zolmitriptan is a weak base with a pKa of 9.6. Solubility measurements were conducted by adding excess zolmitriptan base to 0.5 ml of 0.1 M acid and rotating the suspension overnight at 2-8°C. The suspension was then centrifuged. The supernatant was then collected and subsequently the concentration of zolmitriptan dissolved was determined. Table 2 presents the solubility results of zolmitriptan in the various acids.
  • Zolmitriptan exhibits good solubility in the various acids. It was noted that the rheological behavior of the zolmitriptan solution was affected by the counterion in the formulation for pH control. Several weak acid buffers, including one triacid (citric acid), two diacids (maleic acid and tartaric acid) were tested. The zolmitriptan formulations that were prepared with citric, maleic and tartaric acids were at pH 5.2, 4.3 and 6.2 respectively, at the pKa of the acids. The viscosity profiles of formulations including these acids were measured as a function of time.
  • Citric and maleic acid buffered formulations exhibited rheopectic behavior, i.e., an increase in viscosity as a function of time, while formulations buffered by tartaric acid maintained relatively uniform viscosity with time. Given the overall rheological effect, tartaric acid was selected as the counterion for pH adjustment.
  • a liquid coating formulation of 33 %w/w zolmitriptan, 11 %w/w tartaric acid and 56 %w/w de-ionized water formulation was prepared at pH 4.5 and contact angle on titanium substrate was determined to be 65.8 degrees indicative of poorly wettable formulation.
  • polysorbate 20 at concentration of 0.2 % w/w was added to the zolmitriptan formulation. Contact angle decreased to 51.6 degrees.
  • Static contact angle of drug solution formulations on titanium surface was determined using a FDS contact angle meter (Model OCA15) employing an optical contact angle method called "Sessile drop".
  • a photo snapshot is taken once a drop of the solution (5 ⁇ .) is dispensed from the syringe and laid on a clean titanium foil surface. The angle between the baseline of the drop and the tangent at the drop boundary is measured on both sides. Complete measurement was obtained by averaging the two numbers. At least five readings were recorded for each sample.
  • the coating apparatus was positioned inside a dew-point control system.
  • the process is designed to match the drug film temperature to the air dew point, which prevents evaporation of the coating formulation over the duration of the manufacturing run.
  • undulations in the zolmitriptan liquid formulation were noted visually, which is symptomatic of an uneven film. 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). Undulations in film were still noted with the higher solids content formulations. Subsequently, the polysorbate 20 was removed, and it was noted that the undulations were no longer present. This is a surprising and non-obvious result, because conventional teachings in pharmaceutics supported the use of surfactants to facilitate the production of a smooth, uniform coating.
  • a 33% w/w zolmitriptan, 11% w/w tartaric acid and 56% w/w deionized water formulation caused high incidence of wicking on the particular microprojection array utilized, whereby the drug did not adhere to the
  • microprojections Although the viscosity of the formulation was 22 cP, the design of the microprojection (width of 120 ⁇ , length 340 ⁇ ) and the thick drug film (calculated film thickness 270 ⁇ ) are such that, in each dip into the drug film the microprojections would pick a volume of liquid that cannot be dried fast enough, which leads to the drug film spreading onto the base of the microprojections.
  • Viscoelastic Properties The 40 %w/w zolmitriptan liquid formulation was evaluated for viscoelastic properties. Viscoelastic characterization of a fluid can be a useful tool for predicting the fluid's gelation tendency. H. A. Barnes, J. F. Hutton, and K. Walters, An Introduction to Rheology (Elsevier, New York, 1989). Measurement of viscoelasticity (i.e., elastic and viscous components) in a viscometer is based on a complex, theoretical model. Briefly subjecting the material to an oscillatory stress or strain, whose value is small enough not to destroy the material's structure, produces the output of phase angle. The phase angle is the ratio between the viscous modulus and the elastic modulus.
  • phase angle of 0 degrees corresponds to a fully elastic material, following Hooke's law of elasticity, hence suggesting a more rigid, and ordered structure.
  • a phase angle of 90 degrees corresponds to a material with fully viscous behavior, indicating a less ordered structure which is less prone to gelation.
  • the 40 % w/w zolmitriptan liquid formulation exhibited high phase angle around 83 degrees indicating that the formulation is not susceptible to gelation.
  • Toughness was determined by fracture toughness using Tribolndenter with a cube corner indenter. Five indents were made for each patch sample.
  • X-Ray diffraction (XRD) analysis was performed to characterize the solid state phases of dried zolmitriptan coating on patch for the M207 1.9 mg system.
  • Non-irradiated and gamma- irradiated M207 patches were analyzed and compared to an uncoated patch of the same array design. For each patch sample to be analyzed, approximately 45-50
  • microprojections with zolmitriptan coating were broken off at the base of the titanium array and analyzed as bulk by XRD.
  • XRD data was collected by a coupled Theta: 2-Theta scan on a Bruker D8 Vantec diffractometer equipped with a micro-focus copper x-ray tube with Montel optics monochromator, 0.5mm collimator, a Vantec 500 2-D area detector and laser alignment system.
  • XRD pattern of zolmitriptan coated microprojections were compared to that of uncoated microprojections. All the sharp peaks present in zolmitriptan coated patch samples were matched with those in the uncoated patch sample.
  • Mechanical properties of zolmitriptan coating were evaluated as function of time and storage condition. Mechanical properties such as hardness, which is a measure of a material's resistance to localized plastic deformation, elastic modulus a measure of material's resistance to being deformed elastically when a force is applied to it (measure of material's stiffness) and fracture toughness, which describes the ability of a material containing a crack to resist fracture, were evaluated. Multiple coated microprojections from different areas of individual ZP -Zolmitriptan patches were sampled for testing.
  • Table 5 summarizes the results of nanohardness (H), reduced modulus elastic modulus (E r ), and fracture toughness (K c ) for gamma irradiated M207 1.9 mg patches stored at 25°C/60% RH for up to 12 months and at 40°C/75% RH for up to 3 months.
  • the stability results suggest a decreasing trend in hardness and fracture toughness, and an increasing trend in the elastic modulus.
  • zolmitriptan Purity of zolmitriptan was determined by the reverse phase high performance liquid chromatography (RPHPLC) method (TM-601) at wavelength of 225 nm. Chromatography for the assay was performed using a Phenomenex Kinetex EVO CI 8, (4.6 mm ID x 150mm, 5 ⁇ ) maintained at 30 °C.
  • the mobile phase involved a gradient elution, with 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), and was pumped at the flow rate of 0.6 mL/min on an HPLC system (Water Alliance 2695) equipped with a binary pump, a thermostatted autosampler, column compartment, and a PDA detector. Data were collected and analyzed using Empower Pro (Empower 2 software, Waters
  • the in vitro, Franz, human skin finite dose model is a tool for the study of percutaneous absorption of topically applied drugs.
  • the model uses ex vivo, human torso skin mounted in specially designed diffusion cells allowing the skin to be maintained at a temperature and humidity that match typical in vivo conditions.
  • a finite dose for example, 2 mg/cm 2 - 10 mg/cm 2 of a semisolid, or a transdermal delivery system
  • a finite dose for example, 2 mg/cm 2 - 10 mg/cm 2 of a semisolid, or a transdermal delivery system
  • Data defining total absorption, rate of absorption, as well as skin content can be determined in this model.
  • Dermal Receptor Medium Normal phosphate buffered saline (pH 7.4 ⁇ 0.1) with 0.008% gentamicin sulfate (PBSg) solution was utilized when the diffusion cells were first mounted.
  • PBSg gentamicin sulfate
  • Diffusion Cell and Skin Preparation Percutaneous absorption was measured using the in vitro, human skin, Franz finite dose technique. Ex vivo, dermatomed, human torso skin, without obvious signs of skin disease or damage was used in this study. The skin was provided to the testing facility as dermatomed, cryopreserved, and sealed in a water- impermeable bag with continuous storage at ⁇ -70 °C. Prior to use, it was thawed in ⁇ 37°C water and then rinsed in distilled, de-ionized water (ddH20) to remove any adherent blood or other material from the surface.
  • ddH20 de-ionized water
  • the dermal receptor compartment was filled to capacity with PBSg.
  • the epidermal chamber also known as the chimney or donor compartment
  • the cells were then placed within a rack system and attached to a water circulation system from which the receptor solution was stirred magnetically at approximately 600 RPM, and its temperature was maintained to achieve a skin surface temperature of 32 ⁇ 1 °C (data on file). Skin was left to equilibrate for a minimum of 1 hour prior to the barrier integrity test.
  • the receptor solution was removed in its entirety, refilled with stock receptor solution, and an approximate 5 mL aliquot of the collected sample was saved for subsequent analysis.
  • a 5 mL aliquot was lyophilized using vacuum centrifugation and reconstituted in 0.25 mL of ddH 2 0.
  • the patch was removed for subsequent extraction and analysis.
  • the skin surface wash was performed using two successive refluxing washes of ddH20. Each wash cycle consisted of at least 10 refluxes. The two wash volumes from each donor cell were pooled to generate a single surface wash sample for the diffusion cell.
  • M207 patch assemblies were irradiated by e-beam and gamma irradiation up to 25 kGy dose. Subsequent irradiated patch assemblies were placed on stability at storage conditions of 25 °C /60% RH and 40 °C/75% RH. Results of the e-beam and gamma irradiated
  • M207 patches are shown in Tables 11-17.
  • Table 11 Purity of non-irradiated and e-beam irradiated Zolmitriptan Patches stored at 25 °C/ 60 %RH and 40 °C/75% RH (L N 203149)
  • Table 12 ZP-Zolmitriptan content of non-irradiated and e-beam irradiated Zolmitriptan Patches stored at 25 °C/ 60 %RH and 40 °C/75% RH (L/N 203149)
  • Table 13 Purity of gamma irradiated Zolmitriptan Patches stored at 25 °C/ 60 %RH and 40 °C/75% RH (L/N 203154)
  • Table 14 ZP-Zolmitriptan content of non-irradiated and ⁇ - irradiated Zolmitriptan
  • Table 15 Total Impurity of non-irradiated and e-beam irradiated Zolmitriptan Patches stored at 25°C/60% RH and 40°C/75% RH (L N 203122)
  • Table 16 ZP-Zolmitriptan content of non-irradiated and e-beam irradiated Zolmitriptan Patches stored at 25°C/ 60% RH and 40°C/75% RH (L/N 203122)
  • Solid-state physical stability was evaluated by XRD. Phase changes in amorphous vs. crystalline for zolmitriptan coating were examined by XRD analysis. M207 1.9 mg patches at initial time point (TO), 6 month and 12 month storage were analyzed. The drug coating was amorphous for both non-irradiated and gamma irradiated patches at TO. Gamma irradiated zolmitriptan patches stored at 25°C/60% RH for 12 months and 40°C/75% RH showed similar XRD pattern to that of TO patches. Percent crystallinity was calculated with peak profile fitting and the results are summarized in Table 16, below. No crystalline phase was detected for zolmitriptan formulation solids coated on gamma-irradiated patches stored under both intended (25°C /60% RH) and accelerated storage conditions (40°C/75% RH) for 12 and 6 months respectively.
  • Table 17 Phase identification and percent crystallinity for gamma-irradiated
  • zolmitriptan coated microneedles were exposed to a dose of radiation in the range of approximately 7-30 kGy. More preferably in the range of 15- 30 kGy to a sterility assurance level of 10 "5 to 10 "6 .
  • Table 17 shows 12 month stability results of irradiated and non-irradiated zolmitriptan patches that were stored at 25 °C and 40 °C.
  • M207 is an intracutaneous delivery system comprising a disposable titanium microprojection member centered on an adhesive backing to form a patch.
  • This patch was mounted in a plastic retainer ring to form a patch assembly.
  • the patch is comprised of microneedles that are coated with the drug product formulation and dried.
  • the retainer ring facilitates mounting of the patch to the bottom of a handheld applicator.
  • This applicator ensures the patch is applied with a defined application energy to the site of administration.
  • the combination of the patch assembly and the applicator comprises the intracutaneous delivery system.
  • the applicator is held in one's hand to apply the patch.
  • the applicator cap is twisted to unlock the applicator.
  • a plunger pushes the patch out of the retainer ring and applies it to the skin.
  • the patch When one applies the patch to the skin, the patch stays on the skin and the plastic ring stays on the applicator and is later detached and thrown away.
  • the delivery system was designed to rapidly deliver a 1 mg, 1.9 mg, or 3.8 mg dose of zolmitriptan intracutaneously.
  • the unit formulas for the M207 drug products are provided in Table 18.
  • the zolmitriptan-coated titanium microneedle array is a 3 cm 2 array consisting of about 1987 or about 997 titanium microneedles for the 1.9 mg or 1 mg drug product, respectively. It is affixed to an approximately 5 cm 2 adhesive patch.
  • the patch may be mounted inside a polycarbonate plastic retainer ring with a co-molded desiccant. The desiccant may alternatively attached to the lid of foil pouch.
  • the completed patch assembly is packaged in a dry nitrogen-purged foil pouch.
  • the user prepares the patch for application by pressing the handheld applicator onto the patch assembly.
  • the applicator comprises a spring- loaded piston for applying the patch to the user's skin ( Figures 4(A), 4(B), and 5(A)-(E)).
  • the applicator is unlocked by twisting the outer grip relative to the base from the #1 position to #2 position ( Figure 5(C)).
  • the user applies the patch by pressing the applicator mounted patch assembly onto the skin site.
  • the applicator releases its piston at a 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 the prescribed impact energy density to ensure reproducible patch application.
  • the applicator is designed to ensure that the same force is applied for each delivery and across different users.
  • the drug-coated microneedles penetrate or pierce the stratum corneum of the skin, enabling drug delivery.
  • the solid zolmitriptan coating rapidly dissolves off of the microneedles in the interstitial fluid in the skin to form a solution and is available for absorption.
  • the patch is removed after about 30 minutes.
  • M207 consists of a titanium array of microneedles coated with zolmitriptan, administered
  • M207 0.48 mg patch assembly The zolmitriptan 0.48 mg patch consisted of a 3 cm 2 titanium array of microprojections that were nominally 340 ⁇ in length coated with 0.48 mg of zolmitriptan. The array was applied to the center of a 5 cm 2 tan adhesive backing to form the patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-molded with a desiccant, and this patch assembly was packaged in a foil pouch.
  • M207 1.9 mg patch assembly The zolmitriptan 1.9 mg patch consisted of a 3 cm 2 titanium array of microprojections that were nominally 340 ⁇ in length coated with 1.9 mg of zolmitriptan. The array was applied to the center of a 5 cm 2 tan adhesive backing to form the patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-molded with a desiccant, and this patch assembly was packaged in a foil pouch.
  • M207 3.8 mg patch assembly The zolmitriptan 3.8 mg patch consisted of a 5.5 cm 2 titanium array of microprojections that were nominally 340 ⁇ in length coated with 3.8 mg of zolmitriptan. The array was applied to the center of a 10 cm 2 tan adhesive backing to form the patch. The patch was attached to the interior of a white to off-white polycarbonate ring co-molded with a desiccant, and this patch assembly was packaged in a foil pouch.
  • Tolerability in Part 1 was considered acceptable, and following a review of the safety data and pharmacokinetic data from the first five dosing periods, and a discussion between the sponsor and the Principal Investigator, subjects proceeded to Parts 2 and 3 and completed those visits.
  • the collected serum was analyzed for zolmitriptan and N-desmethyl zolmitriptan using methods well known in the art, such as using a liquid chromatography-mass spectrometry (LC-MS-MS) method.
  • LC-MS-MS liquid chromatography-mass spectrometry
  • M207 patch was well-tolerated and rapid absorption was observed which were believed to potentially translate to fast pain relief for migraine or cluster headache patients.
  • Phase 1 results demonstrating the fast absorption of M207 that is characteristic of Zosano' s microneedle patch and applicator system are illustrated below:
  • intracutaneous administration than from oral administration.
  • N-desmethyl zolmitriptan The active metabolite, N-desmethyl zolmitriptan was detectable in all subjects dosed at the five higher dose regimens.
  • the N-desmethyl zolmitriptan pharmacokinetic parameters for each of the zolmitriptan regimens are shown in the following Table 23.
  • PK parameters were summarized by treatment group using descriptive statistics (arithmetic means, standard deviations, coefficients of variation, sample size, minimum, maximum, and median).
  • geometric means and 95% confidence intervals (CIs) were calculated for AUC2hrs, AU , AUCinf and C ma x-
  • CIs 95% confidence intervals
  • Dose proportionality was evaluated for the three doses of M207; dose proportionality was not based solely on a strict statistical rule.
  • the relationship between dose and PK parameters of zolmitriptan were examined using a graphical approach and by descriptive statistics. Graphs of apparent dose linearity and proportionality of PK parameters (AUC t , AUCinf and C ma x) were compiled.
  • C max maximum plasma concentration of zolmitriptan tablets was 3.77 ⁇ 1.51 ng/mL.
  • N-desmethyl zolmitriptan was formed following zolmitriptan oral administration (mean 59.8 ⁇ 16%) compared to those seen following M207 (Table 25).
  • Plasma concentrations of the N-desmethyl metabolite reached maximum at around 1 hour (range: 54.7-65.0 minutes) for M207 administered via the intracutaneous route compared to (162.6 minutes [2.71 H] for zolmitriptan tablets, Figure 13.
  • the elimination half life (ti /2 ) for the metabolite was comparable for all treatments including oral administration (range 2.7 H to 3.31 H]).
  • the concentration-time curve from 0-24 hours for N-desmethyl zolmitriptan is displayed in Figure 14.
  • Mean maximum plasma concentration (Cma x ) for the M207 0.48 mg dose was 0.22 ng/mL and 1.77 ng/mL for the 3.8 mg strength compared to 2.08 ng/mL for zolmitriptan tablets.
  • Mean AUCin f was 1.38 ng.H/mL for the 0.48 mg strength up to 8.17 ng.H/mL for the 3.8 mg strength versus 14.55 ng.H/mL for zolmitriptan tablets.
  • M207 also tended to have less intragroup variability (as indicated by the CV%s) for the AU nf parameter compared to the zolmitriptan tablets.
  • Tmax that occurred within 20 minutes of patch application. This compared favorably with 12.5 minutes for SC sumatriptan and offers a considerable improvement over conventional release oral zolmitriptan tablets (1.8 hours). Elimination rate (t 1/2 ) for M207 was shorter, approximately twice the rate of zolmitriptan tablets (1.2-1.5 hours versus 3.3 hours).
  • Cmax for zolmitriptan tablets was 3.77 ng/mL.
  • Treatment with M207 patches in Groups C (1.9 mg), F (1.9 mg x 2) and G (3.8 mg) produced 1.8, 3.9 and 6 times higher mean peak plasma concentration than zolmitriptan 2.5 mg tablets.
  • Multiple patch administration with 2 x 0.48 mg M207 produced a comparable C ma x (3.70 ng/mL) to oral zolmitriptan tablets.
  • the M207 intracutaneous delivery system offers pharmacokinetic advantages over zolmitriptan tablets that should result in a faster onset of action, comparable exposure and reduced first-pass metabolism with the lowered potential for drug interactions and adverse events. Importantly, delivery is via a method that does not involve the gastrointestinal route or the injection method. Further comparison to the zolmitriptan conventional oral tablet is set forth below in Tables 29 and 30.
  • PK samples was performed using established in-house LC/MS/MS methods.
  • the low limit of quantitation (LLOQ) and high-limit of quantitation (HLOQ) were 0.1 and 1000 ng/mL, respectively.
  • a four minute method utilizing high performance liquid chromatography- electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) was developed for quantitation of zolmitriptan and its two major metabolites in HGP plasma.
  • the instrumentation consist of Agilent® 1200 pumps, CTC PAL® Autosampler with cooling stack, AB Sciex® TurboV® ESI source, and API 4000® mass spectrometer.
  • Valco® valve was placed in-line with the mass spectrometer equipped with a guard cartridge (Zorbax 300SB-C8, 12.5x4.6mm) used for on-line solid phase extraction (SPE). This valve was setup such that in the "load” position, the sample was injected onto the cartridge and was washed with 10% mobile phase B for 30 seconds, next the valve was switched into the "inject” position, where the cleaned sample would eluted from the SPE cartridge in reversed direction onto the analytical column (Luna PFP(2), 100 A, 5 ⁇ , 50x2 mm) and into the mass spectrometer.
  • a guard cartridge Zorbax 300SB-C8, 12.5x4.6mm
  • SPE solid phase extraction
  • HPLC method used was a reversed phase gradient method (0.0 min,
  • HPLC mobile phases consist of 20 mM Ammonium Acetate as mobile phase A, and 80% acetonitrile in 20% 20 mM Ammonium Acetate as mobile phase B.
  • CAD Collision gas
  • CUR Curtain gas
  • ion source gas 2 (GS2) 60
  • Ion spray Voltage (IS) 5500
  • Temperature (TEM) 600
  • interface Heater (ihe) on.
  • eleven MRM transitions were monitored. All eleven MRM transitions were used for data processing. The peak areas under each corresponding MRM transitions were summed and compared to that of spiked standard plasma samples to calculated concentration for each sample. A
  • Blood samples were collected from one or more of the following blood vessels in the animals: marginal ear veins/artery (left/right), saphenous veins (left/right), mammary veins (left/right), and femoral artery (left/right). Indwelling catheters/sheaths were placed to access the preferred blood vessel and were secured in place for the duration of the blood collection period. All procedures were performed by trained staff per approved protocols and SOPs at the Testing Facilities. A 5-mL blank blood collection was obtained from each animal prior to the first dosing. One-mL blood samples were collected up to 5 hours after patch application dosing. Heparinized microtainer tubes were used to collect all blood samples. Blood volume drawn was replaced with equal volume of heparinized saline with catheter's dead volume accounted. In general, blood collection on a daily basis did not exceed 3-5% of the animal's total blood volume.
  • Zolmitriptan solution for IV dosing was prepared in-house with maximum zolmitriptan concentration of 3 mg/mL. Less than 3 mL of dosing volume was injected using a 28-30G needle into a marginal ear vein of the animal. Pressure was applied momentarily with gauze immediately after injection to prevent bleeding at the site of injection.
  • ZP-Zolmitriptan Delivery Determination Using Residual Drug Analysis Zolmitriptan residual was determined from the used patch and swabbing from the treated skin site. Once peeled off the skin, the used patches were trimmed of the adhesive band outside the microprojection array area and saved for zolmitriptan residual analysis. To recover residual zolmitriptan from the treated skin site, three synthetic fiber swabs were used. The first swab was pre-wetted by insertion into a vial containing 1 mL of swab buffer. The first swab was applied over the patch treatment skin site with slight pressure (using rolling motion) in several directions and up to the periphery of the treatment site.
  • the second and third swabs were dry and were used to capture all residual buffer from the skin site that was wetted by the first swab. All three swabs were placed in the original vial containing the swab buffer. The amounts of zolmitriptan left on the microprojection array and skin surface after each application were compared against the original coated amounts on the array, allowing for the determinations of total zolmitriptan Delivery and Delivery Efficiency. Equations to determine the total drug delivered and drug delivery efficiency are shown below as (1) and (2)
  • Table 32 PK parameters of zolmitriptan patch in animal studies
  • Example 6 Human Efficacy Clinical Trial
  • the ZOTRIP pivotal efficacy study was a multicenter, double-blind, randomized, placebo-controlled trial comparing three doses of M207 (l .Omg, 1.9mg, and 3.8mg) to placebo for the treatment of a single migraine attack.
  • Subjects were enrolled in the ZOTRIP trial at 36 centers across the United States. Those recruited into the trial had a history of at least one year of migraine episodes with or without aura. Upon recruitment, the subjects entered a run-in period that ensured they met the key eligibility criteria of 2-8 migraine attacks per month, which was documented using an electronic diary or an app on their cell phone.
  • Subjects also identified their most bothersome other symptom selected from nausea, photophobia, and phonophobia, and indicated the presence or absence of nausea, phonophobia or photophobia, during the episodes in the run-in period. Successfully screened subjects were then randomized into the treatment/dosing period in which they had 8 weeks to confirm and receive blinded treatment for a single migraine attack, termed "qualifying migraine,” in which their previously identified most bothersome other symptom had to be present.
  • M207 was not associated with any Serious Adverse Events (SAEs).
  • the 3.8 mg dose group met both co-primary endpoints with a p-value ⁇ 0.05.
  • the 1.9 mg dose group met the pain freedom endpoint with a p-value ⁇ 0.05.
  • the 1.9 mg dose group had a p-value of > 0.05.
  • the 1 mg dose group met the pain freedom endpoint with a p-value ⁇ 0.05.
  • the freedom from most bothersome other symptom endpoint at 2 hours had a p-value > 0.05.
  • Table 35 below, provides the fixed-sequence for testing each of the multiple endpoints that are described for migraines to assess whether the study was successful.
  • doses of 3.8 mg, 1.9 mg, and 1.0 mg the efficacy of treatment was tested for the co-primary and secondary endpoints in Table 35. As shown, all endpoints at or after testing order 4 are not significant under the MCP methodology.
  • Tables 38-46 provide results of a clinical study of treating with one embodiment of the claimed invention.
  • endpoints were evaluated sequentially, as described in Table 35, including pain freedom, pain relief, photophobia freedom, phonophobia freedom, and nausea freedom for treatment of 1 mg, 1.9 mg, and 3.8 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.
  • Tables 41-44 As shown in Tables 41-44,
  • Table 46 General Disorders/Administration Disorders TEAEs
  • Tables 47-50 and Figures 25-28 demonstrate the efficacy of one embodiment of the claimed invention against published results of treatments that are currently used in the art. Until the claimed invention, the state of the art included nasal treatments and standard and orally dissolving tablets.

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CA3223555A1 (en) 2019-02-28
JP2021500397A (ja) 2021-01-07
IL272776A (he) 2020-04-30
KR20210155817A (ko) 2021-12-23
CA3073442A1 (en) 2019-02-28
IL272776B1 (he) 2024-02-01
JP2023033378A (ja) 2023-03-10
CN111050749A (zh) 2020-04-21
AU2017428907B2 (en) 2021-12-16
JP7219384B2 (ja) 2023-02-08
AU2017428907A1 (en) 2020-03-05
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