Treatment of migraine

Abstract

16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one is used for the treatment of migraine via nasal administration.

Description

Technical Field

[0001] The present invention relates to the treatment of migraine. Background Art

[0002] Migraine

[0003] According to Burstein et al., “Migraine: Multiple Processes, Complex Pathophysiology”, J. Neuroscience, vol. 35(17), pp. 6619-6629 (2015), migraine is a recurrent headache disorder that affects approximately 15% of people aged 22-55 years, during the mature and most productive period of their lives. It often begins in childhood, especially around puberty, and affects women more than men (the ratio of women to men is 3:1). It tends to run in families and is therefore considered a hereditary disease. According to Merck Manual, Professional Version, online, https: / / www.merckmanuals.com / professional / neurologic-disorders / headache / migraine, evidence based on evaluations of veterans of the Iraq and Afghanistan conflicts suggests that migraine may often occur after mild traumatic brain injury.

[0004] In some cases, a migraine begins without warning signs and ends with sleep. In other cases, a migraine may be preceded by a premonitory or prodromal phase that may begin up to 3 days before the migraine begins, allowing patients to predict the onset of a migraine well in advance of its onset. Common aura symptoms involve the hypothalamus, brainstem, limbic system, and certain cortical areas, and include fatigue; hyperactivity; depression; irritability / anger; food cravings; constipation; stiff neck; increased yawning; and / or abnormal sensitivity to light, sound, and smell. A migraine may also be preceded by an aura phase (seen in about 25% of migraine sufferers), which includes a variety of focal cortically mediated neurological symptoms that occur just before and / or during the headache phase. The symptoms of a migraine aura develop gradually, with phases of excitement and inhibition, and resolve completely. When the visual cortex is affected, positive (gain of function) and negative (loss of function) symptoms may manifest as flickering lights and dark spots (scotomas); when the somatosensory cortex is affected, paresthesias and numbness of the face and hands; when the motor cortex or basal ganglia are affected, tremors and unilateral muscle weakness may occur; and when the speech areas are affected, difficulty in articulating words (aphasia).

[0005] Migraines are usually unilateral, pulsating, aggravated by daily physical activity, and can last from hours to days. As migraines progress, they may be accompanied by a variety of autonomic symptoms (nausea, vomiting, nasal / sinus congestion, runny nose, tearing, ptosis, yawning, frequent urination, and diarrhea), affective symptoms (depression and irritability), cognitive symptoms (attention deficit, difficulty finding words, transient amnesia, and decreased ability to navigate familiar environments), and sensory symptoms (photophobia, phonophobia, taste phobia, muscle tenderness, and skin allodynia).

[0006] Fluctuations in estrogen levels are potent migraine triggers. Many women experience migraines at the onset of their menstrual period, have severe attacks during their menstrual period (menstrual migraines), and their attacks worsen during menopause. For most women, migraines ease during pregnancy but sometimes worsen during the first or second trimester; they often worsen after delivery, when estrogen levels drop rapidly. Oral contraceptives and other hormone therapies occasionally trigger or worsen migraines and have been linked to strokes in women with migraine aura.

[0007] Patients with episodic migraine (EM) who have headaches no more than fourteen days per month can develop chronic migraine. Patients diagnosed with chronic migraine (CM) have an average of at least 15 headache days per month, with at least eight of those headaches having migraine features, for at least three months. This headache disorder was previously called combined or mixed headache because it has features of both migraine and tension-type headaches. These CM headaches often occur in patients who have overused medications for acute treatment of their EM headaches.

[0008] Based on current knowledge, brain regions associated with pain processing and regulation include the prefrontal cortex, cingulate cortex, insular cortex, thalamus, basal ganglia, cerebellum, and periaqueductal grey matter. Recent high-resolution magnetic resonance imaging (MRI) studies have reported increased activation and functional connectivity of the hypothalamus and amygdala in the very early stages of a migraine attack, and have proposed that the hypothalamus is the site of occurrence of migraine attacks. Denuelle et al., "Hypothalamic Activation in Spontaneous Migraine Attacks", Headache, vol. 47(1), pp. 1418-1426 (2007) reported a study using H 2 15O A positron emission tomography (PET) study of 7 migraine patients was performed during spontaneous migraine attacks, after headache relief with sumatriptan, and during an attack-free interval of 15-60 days after the measured attack; and significant activation of the midbrain, pons, and hypothalamus was observed during headache, all of which persisted after headache relief. The literature Chen et al., "Altered functional connectivity of amygdala underlying the neuromechanism of migraine pathogenesis", J. Headache Pain, vol. 18 (7), DOI 10.1186 / s10194-017-0722-5 (2017) reported an MRI study, including functional magnetic resonance imaging (fMRI) of normal controls (NC) and EM & CM patients; and found that the functional connectivity of the left amygdala was increased in EM, the functional connectivity of the right amygdala was decreased in CM relative to NC, and the functional connectivity of the bilateral amygdala in CM was increased relative to EM. They inferred that changes in amygdala functional connectivity indicate that the neurolimbic pain network contributes to the pathogenesis of EM and the chronicity of CM. The literature Lee et al., "Increased connectivity of pain matrix in chronic migraine: a resting-state functional MRI study", J. Headache Pain, vol. 20(29), DOI10.1186 / s10194-019-0986-z (2019) reported an fMRI study of EM and CM patients; and inferred that CM patients had stronger functional connectivity activity in the pain matrix than EM patients, the pain matrix was functionally related to the hypothalamus and dorsal raphe nucleus, and functional changes in the pain matrix may play a role in the chronicity of migraine. May et al., “Hypothalamic regulation of headache and migraine”, Cephalalgia, vol. 39(13), pp. 1710-1719 (2019), discusses recent work in this area and “reviews the clinical and neuroscientific evidence that places the hypothalamus at the center of scientific attention when discussing seizure generation.”

[0009] For some patients, migraine is a rare, tolerable inconvenience. For others, it is a devastating disorder that causes frequent periods of disability, lost productivity, and severely impaired quality of life.

[0010] Medication for migraine

[0011] Migraine treatment can include preventive treatments aimed at reducing the frequency and / or severity of migraine attacks (i.e., suppressing the occurrence of a migraine or one or more of its symptoms, or making a migraine or its symptoms less severe when it occurs), as well as acute therapies for aborting a migraine attack (suppressing a migraine or its symptoms when it occurs, and relieving or alleviating a migraine or its symptoms).

[0012] According to the literature Kahriman et al., "Migraine and Tension-Type Headache", Semin. Neurol., vol. 38(6), pp. 608-618 (2018), acute treatment of migraine can be divided into three categories: (1) nonspecific analgesics (e.g., acetaminophen), (2) migraine-specific analgesics (e.g., triptans and ergots), and (3) adjunctive treatments for other related symptoms (e.g., antiemetics).

[0013] The American Headache Society considers acetaminophen, ibuprofen, naproxen, and diclofenac "effective for acute treatment of migraine," ketorolac "possibly effective," and the antiemetics metoclopramide and prochlorperazine "possibly effective." Triptans and ergots are considered "proven effective," but triptans have largely replaced ergots because of their more side effects and lower convenience; however, triptans also cause vasoconstriction and are contraindicated in patients with vascular disease, such as coronary artery disease, ischemic stroke, peripheral artery disease, and Raynaud's disease. Finally, butalbital and opioids are considered "possibly effective," but their routine use is not recommended due to the risk of dependence and abuse.

[0014] According to the document “Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults”, Neurology, vol. 78 (17), pp. 1337-1345 (2012)”, the American Academy of Neurology and the American Headache Society believe that the antiepileptic drugs divalproex sodium, sodium valproate, and topiramate have “established efficacy” as migraine prevention therapies, but valproate may cause many side effects, including alopecia, gastrointestinal discomfort, liver dysfunction, thrombocytopenia, tremor, and weight gain, and is contraindicated in pregnant women due to the risk of teratogenicity, while topiramate can cause weight loss and adverse reactions to the central nervous system. The β-blockers metoprolol, propranolol, and timolol are also considered to have “established efficacy”, but can only be used in forms without intrinsic sympathomimetic activity. Beta-blockers are considered "possibly effective" and should be avoided in patients with bradycardia, hypotension, diabetes, or asthma. Other beta-blockers, atenolol and nadolol, are considered "possibly effective." The antidepressants amitriptyline and venlafaxine are also considered "possibly effective," but amitriptyline has anticholinergic effects and causes weight gain. Many other drugs in the same and different classes have been tested but were considered "possibly effective," lacked adequate data, or were even "definitely ineffective" (lamotrigine), "probably ineffective" (clomipramine), or "probably ineffective" (several compounds).

[0015] Onabotulinumtoxin A (Allergan's ) has been approved by the US FDA for the treatment of chronic migraine. A single treatment consists of 0.1 ml (5 units) of botulinum toxin A injected into 31 different sites in 7 different head and neck muscle regions superficially. The initial course of treatment consists of two treatments separated by 12 weeks, and retreatment is recommended every 12 weeks. According to the American Academy of Neurology practice guideline, "Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache", Neurology, vol. 86(19), pp. 1818-1826 (2016), botulinum toxin A "should be considered as a treatment option for patients with chronic migraine to increase the number of headache-free days" and "should be considered to reduce the impact of headache on health-related quality of life", but should not be used as a treatment for episodic migraine.

[0016] As discussed in "AHS Consensus Statement: The American Headache Society Position Statement on Integrating New Migraine Treatments Into Clinical Practice", Headache, vol. 59(1), pp. 1-18 (2019), emerging preventive options include humanized monoclonal antibodies against calcitonin gene-related peptide (CGRP), and the US FDA has approved three drugs: erenumab (targeting the CGRP receptor) and fremanezumab and galcanezumab (targeting the CGRP ligand). All three drugs are administered by subcutaneous injection every 4 weeks, and fremanezumab can also be administered by subcutaneous injection every quarter, with 4-week dosing for 3 times.

[0017] Despite the existence of existing medications, there remains a need for effective and tolerable migraine treatments.

[0018] Nasal chemosensory receptors and pherines

[0019] In most species, including humans, the dorsal nasal recesses and the nasal septum mucosal lining, including the neuroepithelial cells in the vomeronasal organ ("VNO", a bilateral chemosensory organ found in most vertebrates, including humans), possess chemosensory receptors associated with odor and pheromone detection (see generally Muller-Schwarze and Silverstein, "Chemical Signals", Plenum Press, New York (1980); Monti-Bloch et al., "Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium", J. Steroid Biochem. Mol. Biol., vol. 39(4), pp. 573-582 (1991); Monti-Bloch et al., "The Human Vomeronasal System: A Review", Ann. NY Acad. Sci., vol. 855, pp. 373-389 (1998)). The axons of the neuroepithelial cells of the nasal chemosensory receptors, including the VNO, have direct oligosynaptic inputs to the hypothalamus and limbic amygdala of the brain, while the distal processes (microvilli) have chemosensory receptors (Stensaas et al., "Ultrastructure of the human vomeronasal organ", J. Steroid Biochem. Mol. Biol., vol. 39(4), pp. 553-560 (1991)).

[0020] Human putative pheromones delivered to the nasal septum region bind to local chemosensory receptors and trigger neural signals that reach the brain, inducing physiological and behavioral changes (Grosser et al., "Behavioral and electrophysiological effects of androstadienone, a human pheromone", Psychoneuroendocrinology, vol. 25, pp. 289-299 (2000)). Synthetic analogs of human pheromones called pherines (odorless substances that bind to nasal chemosensory receptors, including those in the VNO), can induce strong physiological, pharmacological, and behavioral effects when airborne to these receptors via the nasal passages. This information is supported by multiple studies using fMRI and PET on human volunteers, showing that pherines selectively activate brain regions (hypothalamus, limbic system, cingulate gyrus, anterior thalamus, and prefrontal cortex) where their physiological, pharmacological, and behavioral effects are integrated. Studies with a variety of feline compounds have shown that administration of these compounds produces effects on physiological markers (e.g., autonomic nervous system responses and EEG) within seconds less than a minute, and on behavior and on endocrine and neurotransmitter metabolite markers within about 10-15 minutes, because these compounds act directly on nasal chemoreceptors connected to the brain via short neural circuits.

[0021] 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one

[0022] U.S. Patent No. 6,057,439, "Steroids as neurochemical stimulators of the VNO to alleviate symptoms of PMS and anxiety," describes the use of a number of steroidal ferlines for the treatment of premenstrual dysphoric disorder ("PMDD," also known as "premenstrual syndrome" or "PMS") and anxiety by administration to the vomeronasal organ of individuals suffering from these symptoms. 16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one is described in the patent and is referred to as 16α,17α-epoxy-estr-4-en-10β-ol-3-one. The patent discloses the synthesis of the compound and claims the compound and pharmaceutical compositions containing the compound for alleviating symptoms of PMDD. U.S. Patent No. 6,331,534, "Steroids as neurochemical stimulators of the VNO to alleviate pain," describes the same steroids for the relief of pain by vomeronasal administration. U.S. Patent No. 8,431,559, "Treatment of hot flashes," describes the synthesis of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one and the use of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one for the relief of hot flashes via vomeronasal administration. Summary of the invention

[0023] In a first aspect, the present invention is for treating migraine (treating a subject suffering from migraine) by nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one.

[0024] In other aspects, the present invention therefore comprises:

[0025] 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one for or adapted for treating migraine by nasal administration;

[0026] Use of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one for or in the manufacture of a medicament for treating migraine via nasal administration; and

[0027] Pharmaceutical preparations and devices containing 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one for treating migraine via nasal administration; and

[0028] Method for treating migraine by nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one.

[0029] 16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one has particular utility in the treatment of migraine (treating individuals suffering from migraine); and is expected to have the following advantages over conventional treatments:

[0030] (1) Ease of administration while retaining the ability to be used for acute purposes;

[0031] (2) Rapid onset of action, as the compound is delivered topically directly to the nasal chemosensory receptors and takes effect immediately. Current oral anti-migraine medications, like other oral medications in general, may take 30 minutes or longer to achieve a therapeutic effect; and

[0032] (3) Due to the local route of administration, its effect on peripheral (nasal) chemosensory receptors and its demonstrated lack of systemic bioavailability, as well as its effects on the central nervous system by activating short (oligosynaptic) neural circuits, there are no local nasal adverse reactions and no systemic effects or toxicity.

[0033] Preferred embodiments of the invention are characterized by the features of the description of the application as filed and by claims 1 to 15 . DETAILED DESCRIPTION

[0034] definition

[0035] Migraine and its treatment are described in the sections entitled "Migraine" and "Pharmacological Treatment of Migraine" of the Background Art.

[0036] "Comprising" or "containing" and their grammatical variations are inclusive rather than limiting words, and are intended to specify the presence of stated components, groups, steps, etc., but do not exclude the presence or addition of other components, groups, steps, etc. Thus, "comprising" does not mean "consisting of," "consisting essentially of," or "consisting only of; and, for example, a formulation "comprising" a compound must contain the compound but may also contain other active ingredients and / or excipients.

[0037] "Nasal administration" is administration to human nasal chemosensory receptors, including those of the VNO. In a clinical setting, this can be accomplished using a probe specifically designed to deliver 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one essentially exclusively to the VNO (such a probe is also designed to measure effects on vomeronasal tissue, as described in Monti-Bloch, U.S. Pat. No. 5,303,703, "Combined neuroepithelial sample delivery electrode device and methods of using same"). More commonly, however, nasal administration involves administration to the nasal passages in a manner that desirably directs 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one generally to nasal chemosensory receptors, including those of the VNO, such as by using conventional nasal spray techniques commonly used for nasal administration of steroids for the treatment of allergies and asthma.

[0038] "Therapeutically effective amount" refers to an amount of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one sufficient to achieve treatment of migraine when administered to the nasal chemosensory receptors of an individual suffering from migraine, but which is insufficient to produce a systemic effect on migraine through absorption into the circulation. "Treatment" or "therapy" of migraine disorders includes one or more of the following:

[0039] (1) Inhibit the occurrence of migraine or its symptoms;

[0040] (2) relieve migraine headaches or their symptoms when they occur, and

[0041] (3) Relieve the symptoms of migraine.

[0042] 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one and preparation method thereof

[0043] US Patent No. 6057439 describes the preparation of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one; US Patent No. 8431559 describes a method for preparing 3-hydroxyestr-1,3,5(10)-trien-17-one from the commercially available steroid estrone.

[0044] One of ordinary skill in the art, in view of this technology and US Pat. Nos. 6,057,439 and 8,431,559, will have no difficulty in preparing 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one.

[0045] Preparation and administration

[0046] 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one can be administered nasally by any suitable route. Routes of administration include, but are not limited to, topical application (e.g., nasal cream or gel), nasal spray, nasal powder spray, aerosol, etc. Pharmaceutical formulations are generally formulations designed for transmucosal administration. For example, in the literature Gennaro, ed., "Remington: The Science and Practice of Pharmacy", 20 ed., Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, (2003), suitable formulations for each of these administration methods can be found. A typical preferred formulation will be an aqueous solution for nasal spray and will contain 16α, 17α-epoxy-10β-hydroxyestr-4-ene-3-one and water, and will usually contain one or more other pharmaceutical excipients to increase the water solubility of 16α, 17α-epoxy-10β-hydroxyestr-4-ene-3-one, such as alcohols and glycols (e.g., ethanol and propylene glycol) and surfactants (e.g., polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)), and may also contain one or more other pharmaceutical excipients, such as buffers, preservatives (antioxidants, chelating agents, etc.), tonicity agents, viscosity enhancers (dextran, cyclodextrin, polyvinyl pyrrolidone, polyethylene glycol, etc.), etc., as is well known in aqueous nasal sprays. Suitable delivery devices for these formulations are metered dose nasal spray pumps that are commonly used for nasal delivery of steroids for allergies and asthma. Such pumps are manufactured by many manufacturers, for example, Aptar. The volume of liquid should be such that the formulation can be effectively delivered without exceeding the nasal retention volume, where excess would flow back into the sinuses or drip from the nose, and it has been found that a volume of 100 μL is convenient, but larger or smaller volumes (50 μL has been tested as satisfactory) may also be satisfactory. Ideally, the aqueous solution formulation and delivery device used to administer it are selected to achieve maximum retention of the spray formulation in the nasal passages, for example, by selecting it so that the average size of the spray droplets is between about 30-50 microns. For powder formulations, a particle size of about 50-100 microns is generally considered to be suitable.

[0047] Exemplary aqueous solution formulations include the two formulations discussed below in Example 4. A further exemplary formulation is as follows:

[0048] Components Dosage grade 16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one 16 μg / mL GMP Ethanol 2% v / v USP Propylene glycol 3% v / v USP Polysorbate 80 0.5%w / v USP Benzalkonium chloride 50% 0.001% v / v USP Sterile Water for Injection (WFI) to 100% USP

[0049] Given this skill and this disclosure, one of ordinary skill in the art will have no difficulty in preparing suitable formulations and delivery systems for nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one.

[0050] When administered in a nasal spray formulation of the type described above, the therapeutically effective amount of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one is about 0.8-19.2 μg per administration, preferably 1.6-9.6 μg per administration, for example, about 1.6 μg, 3.2 μg or 6.4 μg per administration. For a 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one concentration of 16 mg / L (16 ppm) in the formulation, 1.6 μg per administration would be 100 μL of formulation, which is convenient for a single administration of 100 μL per nostril, 3.2 μg per administration would be 200 μL of formulation, which is convenient for a single administration of 100 μL per nostril, and 6.4 μg per administration would be 400 μL of formulation, which is convenient for two administrations of 100 μL per nostril. It is expected that no more than a few percent of this dose will actually reach the nasal chemosensory receptors and VNO, and thus the therapeutically effective amount may be reduced by 20-fold when administered substantially only to the nasal chemosensory receptors. Given this skill and this disclosure, one of ordinary skill in the art will have no difficulty determining a therapeutically effective amount of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one for other formulations. These doses, including nasal and direct vomeronasal / nasal chemosensory receptors, will be well below any levels that would cause systemic effects, except for those effects mediated through nasal chemosensory receptors (including VNO receptors).

[0051] The initial pharmacological response to intranasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one occurs very rapidly, typically within seconds to a minute after administration. The more complete pharmacological response occurs somewhat more slowly; however, an effect on migraine (or one or more migraine symptoms) is expected within 5-15 minutes. Because the action of intranasally administered 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one is rapid and safe, it is expected that the compound can be administered on demand, for example, immediately after an individual senses the onset of a migraine attack (e.g., prodrome or aura), to preemptively inhibit a migraine attack, or when an individual senses overt symptoms of a migraine attack (e.g., headache or other symptoms described in the section entitled "Migraine" in the Background of the Invention), to relieve and alleviate the symptoms of the episode. If the compound is first administered when the prodrome occurs to continue to prevent or minimize migraine or its symptoms, it is expected that the compound can be administered more than once, such as over a period of several days, by scheduled administration throughout the day, such as 2-6 times / day, such as 3-5 times / day, such as 4 times / day. The scheduled administration can be carried out according to a unified schedule, for example, at 8 am, noon, 4 pm and 8 pm (for 4 times / day administration), or in a non-uniform schedule, whether in a migraine symptom population or in an individual receiving treatment, the administration is selected to maximize the administration at the time when the expected occurrence of migraine symptoms is most frequent or most severe. Therefore, for example, the administration time may be 9 am, 3 pm, 5 pm and 8 pm (again for 4 times / day) to maximize the administration at the time when the symptoms are expected to occur most frequently. Of course, even with scheduled administration, if symptoms still exist, the compound can be administered as needed. However, due to its rapid action, it is expected that long-term use is not required: treatment can be interrupted when the individual no longer feels migraine symptoms or the risk of migraine, and treatment can be resumed when needed next time.

[0052] In addition, due to the rapid onset of action of intranasally administered 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one, it is expected that the compound can be administered as an adjunct to conventional (e.g., oral or injectable) anti-migraine therapy. For example, it can be used as a "rescue" drug for individuals who may still experience migraine symptoms even when receiving conventional anti-migraine therapy to relieve and alleviate the symptoms of such attacks as needed.

[0053] Therefore, nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one can be used acutely or intermittently, alone or in combination with conventional antimigraine therapy, to treat migraine.

[0054] Example 1: Electrophysiological study of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one

[0055] 16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one induces inward currents in isolated human nasal chemosensory neurons and electrical depolarization of the nasal septal chemosensory mucosa: the first event in peripheral receptor chemotransduction. The amplitude of this response increases depending on the concentration of the compound, with a maximal response of 10 -7 -10 -6 M. In vitro, it has no agonist or antagonist activity at estrogen, androgen, progesterone, and glucocorticoid receptors, nor does it have any affinity for receptors of indoleamines, monoamines, ion channels, receptors, peptides, opioids, glutamate neurotransmitters, steroid hormones, or glucocorticoid receptors, indicating that the compound exerts its effect through a specific receptor distinct from the binding sites described by the others.

[0056] Example 2: Preclinical study of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one

[0057] Acute and multiple-dose (28-day) toxicity studies in rats, mice, rabbits, and dogs using single (up to 100 μg / rat, 400 μg / rat, 600 μg / dog) and repeated (up to 50 μg / rat / day, 300 μg / dog / day) nasal doses and single (up to 2.5 mg / kg for rats, mice, rabbits) and repeated (up to 2.5 mg / kg / day for rats and rabbits) intravenous doses of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one showed that the compound was well tolerated in all species tested, with no deaths or adverse clinical signs or effects on laboratory or pathological parameters observed.

[0058] Genotoxicity testing revealed no evidence of mutagenic or teratogenic potential for the compound when examined in the Ames reverse mutation assay and in vivo bone marrow micronucleus assay. Reproductive toxicity studies in pregnant rabbits showed no adverse effects on maternal or litter parameters when administered intravenously up to 2.5 mg / kg / day of the compound during organogenesis. Preclinical pharmacokinetic studies with the compound showed very low systemic exposure when the compound was administered by repeated or single ascending nasal doses up to 100 μg / rat, 400 μg / rabbit, 600 μg / dog. Plasma concentrations of the compound were generally dose proportional and declined rapidly when administered to rats, rabbits or dogs in single repeated intravenous doses up to 2.5 mg / kg.

[0059] Example 3: Preliminary human study of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one (prediction of efficacy)

[0060] Preliminary findings indicate that microgram amounts of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one administered intranasally to human volunteers of both sexes induced a concentration-dependent activation of electrograms recorded from nasal chemosensory mucosal surfaces. The half effective dose for this effect was 0.087 μg. Immediately after the electrograms were induced during intranasal administration of 1.6 μg of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one (latency 5-10 seconds), reflex activity integrated in the limbic system, hypothalamus, and cerebral cortex was modulated. The depth and amplitude of the inspiratory cycle of breathing increased significantly, the respiratory rate within the physiological range decreased, the amplitude of the skin conductance measured as electrodermal activity or cutaneous edge reflex of the palmar surface of the fourth and fifth fingers increased, the skeletal muscle tone (relaxation) measured by electromyography recorded transcutaneously from the jaw muscles decreased, and the body core temperature recorded from the external auditory canal decreased. There were no significant changes in heart rate.

[0061] The effects of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one on physiological parameters are explained as follows:

[0062] (a) Decreased respiratory rate and increased breathing depth are the result of reduced airway resistance caused by bronchiolar dilation. 16α,17α-Epoxy-10β-hydroxyestr-4-en-3-one decreases the tone of the parasympathetic nervous system, leading to increased sympathetic nerve activity and stimulating the β-junctional activity in bronchiolar smooth muscle. 2 adrenergic receptors, thereby inducing bronchodilation;

[0063] (b) Increased skin conductance amplitude is the result of increased skin secretions due to the dominance of sympathetic nervous system tone (or decreased parasympathetic nervous system tone);

[0064] (c) The decrease in body temperature is due to increased posterior (adrenergic) hypothalamic activity and decreased parasympathetic tone (anterior hypothalamic). This effect has also been shown in menopausal women to reduce the number, severity, and bothersomeness of hot flashes after nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one; and

[0065] (d) Muscle tone reduction or relaxation is induced via efferent limbic-hypothalamic neural connections to cortical areas.

[0066] Example 4: Human clinical study of 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one (prediction of efficacy and safety)

[0067] In a group of 14 women of childbearing age, nasal administration of a nasal spray containing 0.5 μg of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one / administered (50 μL of 10 μg / mL 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one in water with 2% propylene glycol and 2% ethanol administered via an Aptar nasal spray pump) caused statistically significant decreases in respiratory rate, skeletal muscle tone, galvanic skin reflexes, and core body temperature compared to vehicle alone; and did not cause a statistically significant increase in heart rate.

[0068] In another study, also in women of childbearing age, nasal delivery of a nasal spray containing 1.6 μg of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one (administered once per nostril via an Aptar nasal spray pump in 50 μL of 16 μg / mL 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one in water (containing 2% propylene glycol and 2% ethanol) induced a rapid (0.5-4 minute latency) decrease in core body temperature by 1±0.23°C, which lasted for 9±2.5 minutes. It also altered the tone of the sympathetic adrenergic system (assessed by measuring physiological sinus arrhythmia) within 5 minutes of administration, and the effect lasted for 15-20 minutes.

[0069] In a randomized, double-blind, placebo-controlled trial in women diagnosed with PMDD, intranasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one induced significant improvements in hypothalamic (fatigue, anger, appetite), limbic (mood swings, depression, anhedonia), and cortical (headache, tension) behavioral symptoms. These improvements occurred within 30 minutes after a single intranasal dose of the formulation and persisted for approximately 5 hours. Because 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one has an excellent safety profile and demonstrated no systemic exposure in pharmacokinetic bioavailability studies, dosing was repeated up to 6 times daily. No serious adverse events were reported, and side effects were minimal and similar to placebo.

[0070] Therefore, the nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one, initiated at the onset of behavioral symptoms of PMDD (similar to the prodromal symptoms of migraine), activates neural circuits in the limbic-hypothalamic region of the brain, thus improving behavioral functions (emotional fluctuations, anger, tension, stress). This prevents the increase in the tone of the parasympathetic nervous system and the release of vasoactive and nociceptive molecules from the meningeal vessels, leading to the inactivation of the trigeminovascular pathway.

[0071] These effects, particularly decreased skeletal muscle tone, decreased galvanic skin reflex frequency, and decreased fatigue, headache, tension, depression, irritability / anger, anhedonia, and appetite, would predict the efficacy and safety of intranasal 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one for the treatment of migraine.

[0072] Example 5: Human clinical study using 16α,17α-epoxy-10β-hydroxyestr-4-ene-3-one in patients with migraine (demonstration of efficacy and safety)

[0073] In an exploratory single-blind study, one control subject and two subjects with chronic migraine (diagnosed according to the International Classification of Headache Disorders, 3rd edition) with a history of regular migraine attacks that usually lasted one to three days participated in two identical study sessions separated by one week, with the migraine subjects instructed to participate on the first day of their migraine attack. Each subject was evaluated at baseline using the Hamilton Anxiety Scale (HAM-A), a clinician-administered rating scale developed to quantify the severity of anxiety symptoms, and the Hamilton Depression Rating Scale (HAM-D), a clinician-administered rating scale developed to quantify the severity of depression; and each subject was asked to rate their migraine using a 6-point visual reference scale (VRS), 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = very severe, 5 = worst pain imaginable. Each subject was then treated with a single intranasal dose of a placebo formulation during the first study period and a single intranasal dose of 6.4 μg of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one during the second study period. After 15 minutes, each subject was asked to re-rate their pain level and underwent a resting-state fMRI scan. They were then re-rated on the HAM-A and HAM-D scales. The study was designed to accrue a total of 30 subjects.

[0074] The control subject was a 35-year-old female without migraine, anxiety, or depression; the two migraine subjects were a 38-year-old female (14-year history of migraine, 19 headache days / month, 9 of which were severe, migraine with aura, anxiety, and depression) and a 41-year-old male (5-year history of migraine, 13 headache days / month, 4 of which were severe, with depression).

[0075] All three subjects tolerated nasal 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one, and no side effects or adverse reactions were reported. Although both migraine subjects presented with mild anxiety and depression at admission, nasal 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one significantly improved anxiety scores (p<0.01), and there was a trend toward improvement in depression scores in both subjects, but this did not reach statistical significance. Nasal 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one produced a significant improvement in headache intensity scores in migraine subjects assessed using the VRS, with a mean reduction of 2.5 relative to placebo (p<0.01). Migraine patients showed improvements in the functional connectivity of the brain regions studied: relative to placebo, nasal 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one decreased functional connectivity of the hypothalamus with the anterior orbital gyrus, right middle anterior orbital gyrus, and pons, increased functional connectivity of the amygdala with the anterior occipital lobe and right middle occipital lobe, decreased functional connectivity of the right thalamus with the left orbitofrontal cortex, superior parietal lobe, left insular cortex, and left primary motor cortex, and increased functional connectivity with the left somatosensory cortex; representing a trend towards values ​​of healthy controls.

[0076] These effects of nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one, particularly including relief of pain, anxiety and depression, demonstrate the effectiveness and safety of nasal administration of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one in the treatment of migraine.

Claims

1. Use of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one in the preparation of a medicament for treating migraine in an individual via nasal administration.

2. The use according to claim 1, wherein the migraine is associated with a previous traumatic brain injury in the individual being treated.

3. The use according to claim 1, wherein the medicament is a nasal spray.

4. The use according to claim 3, wherein the nasal spray is an aqueous solution of 16α,17α-epoxy-10β-hydroxyestr-4-en-3-one.