Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile

The present invention relates to the treatment of migraine. In particular, the present invention relates to the treatment of migraine and related symptoms, while minimizing the side effects or side effects associated with the use of migraine relieving drugs. More specifically, the invention relates to pharmaceutical compositions comprising dihydroergotamine (DHE) for use in methods in which these pharmaceutical compositions are administered to individuals for the treatment of migraine headaches without side effects.

BACKGROUND ART [0002] Migraine is the most common type of headache patients complain about. According to the American Migraine Study II, approximately 28 million Americans 12 years of age and older (approximately 13% of the population) suffer from headaches that correspond to the medical definition of migraine formulated by the International Headache Society. This means that in every fourth household in the United States, one person suffers from migraine. The percentage of individuals diagnosed whose headaches correspond to the medical definition of migraine has increased compared to the last decade. Most migraine sufferers (53%) describe their pain as causing severe disorder or forcing them to go to bed for several days. Over the past 10 years, there have been no radical changes in the way migraines are treated. (Lipton RB et al., Headache. (2001) 41: 638645, 646-657) [0003] To diagnose migraine, a three-point rule for issuing a clinical decision on migraine identification (ID Migraine) has been developed. (Stewart WF et al., Neurology 1994; 44 (6 Appendix 4): S17-23). Migraine is a type of primary headache that some people experience repeatedly over a long period of time. Migraines are different from other headaches because they are accompanied by symptoms such as nausea, vomiting and sensitivity to light. Most people experience throbbing pain only on one side of the head. Migraines are classified as 'migraines with aura' or 'migraines without aura'. Aura is a group of neurological symptoms, usually visual disturbances, which are a warning. Patients with auras usually see flashes of bright or flickering light shortly before they feel pain. However, most migraine sufferers do not see these "warning signs".

[0004] Many humoral factors have been considered to be the main factor in migraine. These include serotonin, histamine, prostaglandins, platelet factors, endorphins and vasoactive neuropeptides. The etiology of migraine has been the subject of many researchers. Current research no longer fully confirms the assumption of the headache mechanism associated with vasoconstriction and relaxation, according to which the expansion of the arteries causes pain, and narrowing brings relief. Studies also show that the causative agent of vascular headache is sterile inflammation, probably found in dura mater. An unknown factor activates perivascular nerve axons

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Trigeminal, which release vasoactive neuropeptides (substance P, calcitonin gene-derived peptide, etc.). These factors cause local inflammation, i.e. vasodilatation, plasma extravasation and mast cell degranulation, resulting in impulse transmission to the brainstem and higher centers, which in turn is registered as a headache (Moskowitz, MA (1992) Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol. Sci. 13, 307-311).

[0005] Migraine is treated prophylactically or symptomatically. In the case of an individual suffering from headaches at least two or four times a month, a prophylactic drug may be used if the pain is so strong that it hinders daily activities. The most commonly used are beta blockers, e.g. propranolol (INDERAL^®). Other commonly used drugs include: serotonin antagonists, e.g. methysergide maleate (SANSERT^®), calcium channel blockers (VERAPAMIL^®), amitriptyline (ELAVIL^®) and ergotamine preparations with wolfberry alkaloids and phenobarbital. All these drugs cause serious side effects, such as sedation under the influence of pharmacological agents, loss of energy and motivation, dry mouth, constipation, weight gain as well as cramps and gastrointestinal disorders. For symptomatic treatment, ergotamine and caffeine (CAFERGOT are commonly used)^®). Other medications used to treat migraine include, but are not limited to, isometeptene mucilage (MIDRIN^®), nonsteroidal anti-inflammatory drugs (such as MOTRIN^®, NAPROXEN^® etc.), dihydroergotamine and newer triptans such as sumatriptan (IMITREX^®) etc. In the case of _® frequent use of narcotic drugs such as FIORINAL WITH CODEINE^® (butalbital with codeine), patients are additionally exposed to recurrence of headaches and habituation.

[0006] It is common practice in the treatment of migraine headache to administer serotonin agonists to individuals. The most commonly used serotonin agonists are triptans such as sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan and almotriptan. These compounds bind specifically to 5-HT1D / 1B serotonin receptors. In various disease states, including in acute migraine, ergot alkaloids such as ergotamine tartrate (also referred to as ergotamine) and dihydroergotamine mesylate (also called dihydroergotamine or DHE) are also used, albeit to a lesser extent.

[0007] Ergotamine and DHE have very low bioavailability for rectal, oral, sublingual and nasal administration (only between 2% and 10% of the administered dose gets into the circulation). These methods of drug administration also result in relatively late observation of the therapy effectiveness: from 45 minutes after drug administration by nasal method to 2 hours when the drug is administered orally or sublingually. The intravenous drug has high bioavailability and the effectiveness of the therapy can be quickly observed, usually in less than 30 minutes. However, infusions are painful, cause local inflammation and reduce compliance, and because intravenous administration requires costly clinical supervision, it would be highly advisable to administer ergot alkaloids by pulmonary inhalation. Inhalation of ergot alkaloids into the lungs would minimize metabolism before the drugs entered the circulation, since they would be transported quickly from the alveolar epithelium to the capillary bloodstream, and metabolism is virtually absent in the lungs. It has been proven for pulmonary administration

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The availability of ergotamine tartrate is up to 92% bioavailability. By administering the drug by pulmonary inhalation, the gastrointestinal intolerance typical of migraine drugs would also be avoided, and the undesirable bitter taste of ergot alkaloids experienced by nasal and sublingual administration of the drug would be minimized. Inhalation to the lungs would also minimize the reluctance to use this type of treatment, resulting from the infusion invasiveness and the cost of clinical supervision. In addition, pulmonary inhalation (inhalation) would allow rapid relief of migraine symptoms because the drug would be delivered to the circulatory system as quickly as with an intravenous bolus, i.e. in less than 30 minutes, with no invasiveness as with injection.

[0008] The effectiveness of dihydroergotamine (DHE) in the treatment of migraine was discovered almost fifty years ago (Raskin, Neurology 36: 995 997 (1986); Silberstein et al. Headache 30: 334 339 (1990); Saadah,

Headache 32:18 20 (1992); and Winner, Headache 33: 471 475 (1993)). Despite many sources describing the delivery of ergotamine tartrate, also known as ergotamine, in the form of an aerosol for inhalation into the lungs, there are very few teaching materials about the administration of DHE by inhalation into the lungs.

Administration of DHE by the same method as for ergotamine tartrate is not easy because _® it is very difficult to stabilize DHE in each of the above-mentioned preparations. DHE (DHE 45^® - Novartis) has been administered by intramuscular injection or infusion for over 50 years (Belgrade et al., Neurology 39: 590 592 (1989); Winner, Headache 33: 471 475 (1993)), while DHE _® (MIGRANAL^® - Novartis) has been administered intranasally for 10 years. DHE is also effective for subcutaneous administration (Klapper et al., Headache 32:21 23 (1992); Winner, et al., Arch. Neurol. 53: 180 184 (1996); Becker et al. Headache 36: 144 148 (1996 )). However, its use has an undesirable side effect profile: nausea, vomiting, chest tightness, and associated cardiovascular effects such as instability of blood pressure and narrowing of the arteries.

[0009] Although DHE is effective in treating migraines, its use is often associated with side effects such as nausea, vomiting and chest pain (Winner et al., Arch. Neurol. 53: 180 184 (1996)). Other side effects seen in the post-marketing setting of subjects receiving DHE 45® (dihydroergotamine mesylate) in the form of injections, USP, include: vasoconstriction, paresthesia, hypertension, dizziness, anxiety, shortness of breath, headache, redness, diarrhea, rash, increased sweating, heart valve damage, and pleural fibrosis and retroperitoneal fibrosis observed after long-term use of dihydroergotamine. At least one side effect, nausea, occurs more frequently after intravenous administration than intramuscularly or intranasally. It was found that when administered subcutaneously at a concentration of only 1.5 mM DHE causes nausea in almost 16% of patients treated (Winner et al., Arch. Neurol. 53: 80 184 (1996)). Currently accepted treatment algorithms for DHE injection or intravenous administration (see Figure 6) require an antiemetic before or during DHE administration to prevent nausea. Patients who have been diagnosed with cardiovascular disease are not eligible for treatment with DHE.

[0010] Despite these side effects, DHE is still considered the "gold standard" in the treatment of acute migraine and cluster and chronic daily headache. DHE works for a longer time than sumatriptan, so when it is used, the frequency of pain relapses is

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EP 2 425 820 B1 smaller. (Winner P. et al. A double blind study of subcutaneous dihydroergotamine versus subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol (1996) 53: 180-184). There is therefore a need for procedures for the rapid delivery of therapeutically effective amounts of DHE without causing the side effects that are typically associated with its use.

BRIEF DESCRIPTION OF THE INVENTION [0011] A method of rapidly treating a disease or condition in humans with a compound that (a) binds to one or more of the first receptors is described, wherein binding of the compound to the first receptors alleviates the symptoms of the disease or condition and (b) binds to one or more of the second receptors, where binding to the second receptors causes a side effect, wherein the method comprises administering to the subject a certain amount of a compound at a rate sufficient to achieve such a concentration of the compound in the blood plasma that the compound acts as a first receptor agonist, providing relief from the disease or disease, wherein the level of the compound's plasma concentration remains below the level necessary for binding to the second receptor, which has a side effect.

[0012] A method of rapid migraine treatment with DHE has been described while minimizing side effects. This method takes into account the reduction in the maximum plasma concentration (Cmax) and its slight delay to avoid saturation of dopaminergic and adrenergic receptors, while obtaining binding to serotonin receptors sufficient to alleviate migraine symptoms in time allowing their rapid resolution.

[0013] A method of administering DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs and metabolites to needy patients has been described, wherein the amount of DHE is sufficient to reduce migraine symptom within 2 hours, without causing side effects.

[0014] Methods of providing the subject with sufficient DHE to achieve such a concentration of the compound in the blood plasma that the DHE can act as a serotonin receptor agonist associated with the relief of migraine symptoms have been described, which concentration is insufficient to actively bind the adrenergic or dopaminergic receptor associated with nausea and other side effects.

[0015] In some embodiments, DHE exhibits reduced (<50%) ability to actively bind dopaminergic receptors such as D2, or no (<20%). In some embodiments, DHE also has an inability to actively bind 5-HT3 receptors (<20%). In addition, in some embodiments, DHE has a reduced (<60%) ability to actively bind to or lack adrenergic receptors (<20%).

[0016] The present invention provides a dihydroergotamine compound or a salt, hydrate, polymorph or ion pair thereof, for use in a method of treatment of human migraine,

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Wherein the treatment comprises providing a total dose of dihydroergotamine or a salt, hydrate, polymorph or ionic pair thereof of 0.1 to 10 mg per migraine attack, by inhalation into the lungs via a device containing a pressurized metered dose inhaler;

and this dose is in the form of an aerosol formulation adapted for delivery by means of said device for the administration of dihydroergotamine or its salt, hydrate, polymorph or ion pair in a unit dose less than 3.0 mg at a rate such that the maximum concentration of dihydroergotamine in plasma (Cmax) was less than 15,000 pg / ml and the time to reach dihydroergotamine Cmax (Tmax) was less than 20 minutes after dosing.

[0017] In some embodiments, the DHE Cmax concentration in blood plasma is less than 15,000 pg / ml, or less than 10,000 pg / ml, or less than 7,500 pg / ml. For some embodiments, the DHE Tmax in blood plasma is preferably less than 15 minutes.

[0018] According to one aspect of the invention, the Cmax concentration of DHE administered with the use of the invention is at least 5-, 10- or 15-fold lower than the concentration of Cmax DHE administered intravenously by direct or slow bolus.

[0019] According to one aspect of the invention, the Tmax time for DHE administered with the use of the invention is at least 1 minute longer compared to the Tmax time for DHE administered directly intravenously, and AUC (area under the curve for high circulating drug concentration in the ratio pending) the drug delivered by the method of the invention is in the range of 75% of a comparable intravenous dose.

[0020] According to one aspect of the invention, the DHE formulation is for administration to a subject by means of an inhaler-activated dispenser inhaler, wherein DHE is administered at a rate such that the maximum concentration in human blood plasma (Cmax) is less than 10,000 pg / ml, and the time (Tmax) from administration to peak plasma concentration was less than 20 minutes after administration. In addition, DHE is administered to a subject without an antiemetic.

[0021] When used according to the invention, administration of DHE to achieve Cmax concentration and Tmax time as described above results in at least partial relief of the migraine symptom, including pain, nausea, phonophobia and photophobia within 30 minutes, as well as prolonged relief for 24 hours without causing drug-induced nausea, cardiovascular side effects and other side effects.

[0022] According to one embodiment, at least partial alleviation of the migraine symptom is measured by a decrease on the IHS scale from a value greater than "0" for the migraine symptom during DHE administration to <1 after 30, 60, 90 or 120 minutes after drug administration.

[0023] When used according to the invention, the administration of the drug results in maximum plasma concentrations of active primary metabolites, including 8'-hydroxy-dihydroergotamine, less than 40,000 pg / ml at Cmax. In some embodiments, the Cmax concentration of primary metabolites in the blood plasma is preferably less than 1000 pg / ml, more preferably less than

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500 pg / ml, and most preferably less than 200 pg / ml. In some embodiments, the Tmax time of primary metabolites in the blood plasma is preferably shorter than 90 minutes, and most preferably shorter than 60 minutes.

[0024] The use of the invention relates to a method comprising providing a large unit dose of DHE or its salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites that is less than 3.0 mg to the circulation. In a preferred embodiment, a unit dose of 1.0 mg is administered.

[0025] The invention also provides the use of a dihydroergotamine compound or a salt, hydrate, polymorph or ion pair thereof in the manufacture of a medicament for the treatment of migraine in man;

wherein the treatment comprises providing a total dose of dihydroergotamine or a salt, hydrate, polymorph or ionic pair thereof of 0.1 to 10 mg per one migraine attack by inhalation into the lungs by means of a device containing a pressurized metered dose inhaler;

and this dose is in the form of an aerosol formulation adapted for administration by means of said dihydroergotamine or salt, hydrate, polymorph or ion pair delivery device at a unit dose less than 3.0 mg at a rate such that the maximum dihydroergotamine plasma concentration (Cmax) was less than 15,000 pg / ml and the time to reach dihydroergotamine Cmax (Tmax) was less than 20 minutes after administration.

[0026] The method of administering the drug is inhalation into the lungs using a pressurized metered dose inhaler (PMDI). In a more preferred embodiment, a pMDI device such as an inhaler-activated metered dose inhaler (e.g., TEMPO ™ Inhaler from Map Pharmaceutical based in Mountain View, California) is used to administer DHE.

[0027] Kits containing DHE formulations and instructions for use of these formulations have been described. In a preferred embodiment, an inhaler is attached. In one embodiment of said kit, the inhaler contains DHE. In another embodiment, the kit contains at least one unit dose of DHE. In one embodiment, the inhaler is a pMDI device such as a breath activated inhaler (TEMPO ™ Inhaler).

[0028] The inhaler described contains at least one unit dose of DHE, each unit dose being administered at a rate such that the maximum concentration in human blood plasma (Cmax) is less than 10,000 pg / ml and time (Tmax) from administration to maximum plasma concentration was less than 30 minutes after administration.

[0029] The present invention and other objects, features and advantages thereof will be set out in more detail in the following Detailed Description of the Invention and in the attached descriptions of the embodiments and the attached figures.

BRIEF DESCRIPTION OF THE FIGURES [0030]

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In FIG. 1 shows the percentage of subjects who experienced relief of pain after DHE versus placebo.

In FIG. 2 shows pharmacokinetic profiles for pain relief while minimizing side effects.

In FIG. 3 shows the radioligand receptor binding profile for serotonergic receptor subtypes based on dose and mode of administration. Less than 20% is classified as inactive binding, with "(h)" being cloned subtypes of human receptors.

In FIG. 4 shows the radioligand receptor binding profile for adrenergic and dopaminergic receptor subtypes based on dose and mode of administration. Less than 20% was classified as inactive binding, with "(h)" cloned subtypes of human receptors and "NS" for non-specific binding.

In FIG. 5 shows the selective agonist effect at 5-HT1B and 5-HT2B receptors at various concentrations of DHE.

In FIG. 6 shows the currently accepted treatment algorithms for DHE injection or intravenous administration.

In FIG. 7 shows the geometric mean of 8'OH-DHE concentrations relative to the time since inhalation and intravenous administration of DHE.

DETAILED DESCRIPTION OF THE INVENTION [0031] The use of the term dihydroergotamine (DHE) in accordance with the invention includes DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs and metabolites.

[0032] The invention relates to DHE or its salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites for use in a method of treating migraine, comprising administering to a needy patient an amount of DHE sufficient to reduce migraine symptoms over a given period of time, without causing side effects.

[0033] Reduction of a migraine symptom over a given period of time may be associated with partial relief of at least one migraine symptom, including pain, nausea, phonophobia and photophobia within 30, 60, 90, 120 or 180 minutes. Reducing migraine symptoms may also include providing long-term relief for 6, 12, 18, 24 or 36 hours.

[0034] Relief of any migraine symptoms is measured by a decrease on the IHS scale from a value greater than "0" (values> 1 for pain) during DHE administration to a value of 1 30, 60, 90, 120 or 180 minutes after drug administration. However, the complete elimination of pain (or other acute symptoms) requires a reduction in the classification of this symptom from an initial value of> 0 (values> 1 for pain) to 0 at the appropriate time point.

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[0035] Relief of migraine without side effects may require the administration of therapeutically effective amounts of non-drug-inducing DHE, nausea, vomiting, chest tightness and related cardiovascular effects such as instability of blood pressure and narrowing of the arteries. , or any other side effects associated with migraine treatment with DHE.

[0036] The use of the invention involves providing humans with sufficient DHE to achieve such a concentration of DHE in the blood plasma that it acts as a serotonin receptor agonist associated with the relief of migraine symptoms, wherein the Cmax concentration is obtained in time Tmax sufficient to partially alleviate at least one migraine symptom, including pain, nausea, phonophobia and photophobia for 30, 60, 90, 120 or 180 minutes, or provide long-term relief for 6, 12, 18, 24 or 36 hours.

[0037] Furthermore, the Cmax achieved over time (Tmax) using the present invention is insufficient to actively bind DHE to the adrenergic or dopaminergic receptor and to cause nausea and other side effects.

[0038] When binding of DHE to an adrenergic or dopaminergic receptor is insufficient to cause nausea or other side effects, DHE shows reduced (less than 50%) ability to bind to dopaminergic receptors such as D2 or no (20% or less) and reduced (less than 60%) ability to bind to, or lack of, adrenergic receptors (20% or less).

[0039] According to the invention, DHE is for use in a method in which it is administered at such a rate that the Cmax concentration in human blood plasma is less than 5000 or 10,000 pg / ml, and the time from drug administration to reaching maximum plasma concentration (Tmax) is 10, 15 or 20 minutes after administration.

[0040] Administration of the drug results in maximum concentrations of active primary metabolites, including 8'-hydroxy-dihydroergotamine, in plasma of less than 5000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 100,000 or 200,000 pg / ml at Cmax. The Tmax of primary metabolites is less than 30, 45, 60, 90 or 120 minutes after administration.

[0041] According to one aspect, the Cmax concentration of DHE administered in the use according to the invention is at least 5-, 10- or 15-fold lower than the concentration of Cmax DHE administered directly intravenously.

[0042] According to one aspect, the Tmax time for DHE administered in accordance with the use of the invention is at least 1, 2, 5, 10 or 15 minutes longer compared to the Tmax time for DHE directly administered intravenously, and AUC (area under the curve for drug concentration in the circulation over time) the drug delivered using the invention is in the range of 75% of a comparable dose delivered intravenously.

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[0043] In one aspect of the use according to the invention, the method comprises administering a unit dose containing 0.5, 1.0, 2.0 or 3.0 mg DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs. and metabolites.

[0044] Described ready vials, containers, ampoules or packaging containing at least one DHE unit dose. DHE doses are packaged in a suitable way for inhalation into the lungs.

[0045] Suitable DHE aerosol formulations have been described which, when administered to a mammal under appropriate conditions, achieve the required drug delivery profile determined by the AUC, Cmax and Tmax values ​​listed above.

[0046] Typically, DHE will be delivered to clinics, doctors or patients in administration kits. Such kits include at least one administration device (e.g., an inhaler, etc.) and multiple unit doses, a reservoir or reservoir configured to provide multiple unit doses of the composition described above. In one embodiment, the administration device comprises a DHE formulation. The kit may additionally contain a carrier or diluent, a case, and instructions for using the appropriate drug delivery device. For some implementations, an inhaler is included. In one embodiment of said kit, the inhaler comprises a reservoir with DHE. In another embodiment, the kit contains at least one unit dose of DHE. The inhaler is a pMDI device such as a breath activated inhaler (TEMPO ™ Inhaler).

Dihydroergotamine (DHE) for the treatment of migraine [0047] Dihydroergotamine (DHE) is a semi-synthetic ergot alkaloid that has been used in the treatment of migraines since 1946. Due to structural similarities to physiological molecules, DHE has a broad pharmacological use (Table 1) mediated by effects on biogenic amine receptors, especially serotonin (5-HT), adrenergic (α and β) and dopaminergic (D) subtypes.

[0048] Dihydroergotamine is commonly used in the treatment of cluster migraine, pediatric migraine, migraine and chronic daily headache, formerly known as migraine _® "Transformed." Currently, DHE is administered orally and nasally (MIGRANAL^® - Novartis

US5942251, EP0865789A3 and BE 1006872A). However, in clinical conditions DHE most often_® administered by intramuscular / subcutaneous or intravenous injection (DHE 45^® - Novartis). (Raskin NH, Neurol Clin. November 1990; 8 (4): 857-65).

[0049] Dihydroergotamine forms high affinity binding to 5-HT receptors_1DA and 5HT-iDe, as well as with 5-HT serotonin receptors_1A, 5-HT_2A and 5-HT_2C, noradrenaline receptors α_2Α, α_2Β and α₁ and D dopamine receptors_2L and D₃.

[0050] The therapeutic effect of dihydroergotamine on migraine is generally attributed to the agonist effect of DHE on 5-HT1D receptors. There are currently two theories explaining the effectiveness of 5-HT1D receptor agonists in the treatment of migraine. According to one theory, the activation of 5-HT1D receptors located on intracranial blood vessels, including receptors on

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In arteriovenous anastomoses, it leads to vasoconstriction, which correlates with the relief of migraine headache. An alternative hypothesis suggests that activation of 5-HT1D receptors at the sensory nerve endings of the trigeminal system results in inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine has oxytotic properties.

[0051] Ergot alkaloids are less selective than triptans in binding to 5-HT1D, 5-HTiA, 5-HT receptors_2A and 5-HT_2C, noradrenaline receptors α_2Α, α_2Β and α and D2L and D3 dopamine receptors. It is thought that the treatment of acute migraine with DHE is mediated by 5-HT1B receptors (causing narrowing of intracranial extracranial blood vessels) and 5-HTiD receptors (causing inhibition of trigeminal nerve transmission).

[0052] DHE is known to bind specifically to the receptors listed in Table 1. Table 1 shows the affinities of DHE (measured as IC50) for specific biogenic amine receptors. In the case of DHE, strong effects on 5-HTiB and 5-HTiD receptors and a wide range of ability to bind to receptors are observed. (Silberstein, SD, McCrory, DC Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache (2003) 43: i44-i66).

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Formulations and dosage forms [0054] A number of studies have been conducted in adults to demonstrate the efficacy and safety of intravenous use of DHE. The current method of treating acute migraines by administering DHE intravenously at repeated doses has been introduced by Raskin. (Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986; 36: 995-997). The reference to "direct intravenous administration" in technical data should be understood as reference to direct intravenous administration of DHE according to the procedure outlined by Raskin (Neurology 36: 995-997 (1986)).

[0055] Recently, DHE preparations as well as DHE preparations in combination with nonsteroidal analgesics for automatic intramuscular injectors have been developed (US20030040537, US6077539, W0005781A3, EP1165044A2, CN1347313T, and AU0038825A5). DHE formulations in combination with strong painkillers for nasal administration have also been developed (US5756483, EP0689438A1, AU6428894A1 and W09422445A3). Spray or aerosol preparations for sublingual administration of DHE (US20030017994) have also been developed. Ergotamine tartrate was administered by injection, rectally using suppositories and inhaled using a metered dose inhaler (MEDIHALER-ERGOTAMINE^® 3M Health Care based in Northridge, CA), but most often it is given orally and sublingually.

[0056] Recent publications contain many descriptions of ergotamine tartrate formulations for use by inhalation (inhalation) (US6488648, US6451287, US6395300, US6395299, US6390291, US 6315122, US6179118, US6119853, US6406681), in particular with MDI inhalers ) powered with carrier gas (US5720940, US5683677, US5776434, US5776573, US6153173, US6309624, US6013245, US6200549, US6221339, US6236747, US6251368,

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US6306369, US6253762, US6149892, US6284287, US5744123, US5916540, US5955439, US5992306, US5849265, US5833950, US5817293, US6143277, US6131566, US5736124, US5696744). At the end of the eighties of the last century, 3M developed and - after obtaining authorization - introduced the market for the preparation of ergotamine tartrate for inhalation (MEDIHALER-ERGOTAMINE^®). However, it was withdrawn from sale in the next decade due to stability issues.

[0057] Powders containing ergotamine tartrate for inhalation with dry powder inhalers have also been described (US6200293, US6120613, US6183782, US6129905, US6309623, US5619984, US4524769, US5740793, US5875766, US6098619, US6012454, US5972386388) aqueous spray forms for pulmonary administration (US5813597).

[0058] The invention relates to a pharmaceutical composition in unit dosage form comprising DHE in an amount such that at least one unit dose administered to an individual is effective in the symptomatic treatment of migraine headache. The composition may contain auxiliaries. At least one antioxidant may be added to reduce the rate of oxidative degradation of the composition. Any DHE salt can be used, however, the mesylate salt is preferred. In all cases, the preparations can be prepared by methods that are standard in the art (see, e.g., Remington: The Science and Practice of Pharmacy, twenty-first edition, Lippincott Williams &amp; Wilkins (2005)). In general, patients receive a total dose of 0.1 to 10.0 mg. The preferred dose is 0.5 to 5.0 mg, more preferably 1.0 to 2.0 mg for one migraine attack. The dose of DHE given into your body (e.g. human) will vary depending on the particular composition and method of administration to achieve the biogenic amine receptor binding profile required for migraine treatment, without side effects or side effects.

[0059] The term "unit dosage form" refers to a physically discrete unit suitable for unit dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the required therapeutic effect in association with a suitable carrier pharmaceutical, diluent or excipient. These unit dosage forms may be stored in suitable packaging individually or in several unit doses. They can also be sterilized and sealed.

[0060] Articles containing the compositions described herein, in appropriate packaging, have been described. Packaging suitable for the compositions described herein are known in the art and include, for example, vials (e.g., sealed vials), containers with dispensing valves, vessels, ampoules, bottles, jars, flexible packaging (e.g., sealed plastic bags or made made of Mylar foil) etc. In addition, these products can be sterilized and / or sealed.

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[0061] The compositions may also contain additional ingredients, for example: preservatives, buffers, tonics, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity enhancing agents, absorption enhancers etc.

[0062] Suitable absorption enhancers include, but are not limited to, N-acetylcysteine, polyethylene glycols, caffeine, cyclodextrin, glycerol, alkyl saccharides, lipids, lecithin, dimethyl sulfoxide, etc.

[0063] Suitable preservatives for use in solution include, but are not limited to, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, disodium edetate, sorbic acid, benzylammonium chloride, etc. Usually (but not necessarily ) said preservatives are used in an amount of 0.001% to 1.0% by weight.

[0064] Suitable buffers include, but are not limited to, boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium diphosphate, etc. in amounts sufficient to maintain a pH in the range of about 6 to 8 , preferably from about 7 to 7.5.

[0065] Suitable antioxidants and stabilizers include, but are not limited to, sodium disulfite, sodium metabisulfite, sodium thiosulfite, thiourea, caffeine, cromoglycan salts and cyclodextrins. Suitable wetting and clarifying agents include, but are not limited to, polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity enhancers include dextran 40, dextran 70, gelatin, glycerin, hydroxyethyl cellulose, hydroxymethylpropyl cellulose, lanolin, methyl cellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone and carboxymethyl cellulose.

Methods of administration [0066] The compositions described herein can be administered to patients by pulmonary route. Nanoparticles (including protein and carbohydrate nanoparticles included in the drug formulation) of the compounds included in the invention can be administered by any acceptable route using an inhaler.

[0067] DHE is provided by the method of inhalation therapy. Many preclinical and clinical studies on inhaled compounds have demonstrated their efficacy in both the lungs and systemic. In addition, pulmonary administration of the drug has many advantages, such as: quick action, convenient application by the individual himself, the ability to reduce side effects associated with taking the drug, ease of inhalation, no need to use needles, etc.

[0068] Aerosols for inhalation by means of a pressurized metered dose inhaler usually contain excipients or solvents that increase the stability and ease of delivery of these drugs in the form of an aerosol. Furthermore, the particle size of the aerosol drugs can be controlled to provide absorbency in accordance with the methods used in the invention. Usually the particles are sized to be required by those skilled in the art. For example, when using a dry powder inhaler (DPI), drug particles are formed from the active drug ingredient in friction processes such as comminution, micronization and milling, or multiphase precipitation processes such as drying

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Spraying, solution precipitation, supercritical extraction / precipitation or freeze drying resulting in powders that can be dispersed in a carrier gas to obtain a particle size suitable for delivery to the lungs. Dry powder formulations are susceptible to aggregation and often have low flowability, which may result in less efficiency. Therefore, during milling, mixing, powder flow, filling, and even drug administration, special care should be taken to ensure that the dry aerosol powder is delivered correctly and that particles of the correct size enter the lungs.

[0069] Pressure metered dose inhalers (pMDI) is a class of aerosol dispensing devices. By means of pMDI, the compound is placed in a pressurized container, also containing a solvent and a mixture of carrier gases, usually chlorofluorocarbons (CFCs) or hydrofluoroalkanes (HFAs). At the time of dosing, the stream of the mixture is ejected through the valve and nozzle, and the carrier gas "expands", leaving the compound in the aerosol. Due to the high speed of the aerosol being ejected from the nozzle, some of the medicine may stop on the tongue, mouth and throat and not reach the lungs.

[0070] Although the method of delivering ergotamine tartrate by inhalation is widely known, DHE is rarely administered in this way because it is very difficult to stabilize it in formulations suitable for pulmonary use. For DHE to have adequate potency and effectiveness, its preparations must be in the form of a solution, powder or suspension that can be stabilized without the use of excipients or using excipients that are not toxic to the lungs. Due to the fact that DHE is extremely sensitive and decomposes under the influence of light, oxygen, heat, as well as in the presence of many chemical compounds commonly used in medicinal preparations, its stabilization is not easy. Current preparations for the delivery of DHE in nasal water sprays or by injection require the use of chelating or complexing agents, such as dextran or cyclodextrin, to stabilize DHE in solution. To prevent the DHE solution from decomposing, it is sealed into difficult-to-use dark glass vials that must be opened with a complicated opener and transferred to an injector or spray applicator just before use. Only recently have U.S. Patent Application Serial No. 10 / 572,012 and W02005 / 025506A2 described stable DHE preparations for pulmonary use.

[0071] WO2005 / 025506A2 describes suitable stable formulations of dihydroergotamine or pharmaceutically acceptable salts thereof allowing the administration of dry powders and suspensions of carrier gas by inhalation of an aerosol or nasal inhalation of a spray. In one embodiment, DHE is used as the mesylate salt. The DHE powdered form is obtained in supercritical fluid extraction processes, which allows significant benefits in the production of DHE particles for inhalation and the production of respirable particles of the required size in one step.

[0072] In a preferred embodiment, inhalational dosing is by means of an inhaled activated inhaler such as Tempo ™ Inhaler from Map Pharmaceuticals, Inc. with headquarters in

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Mountain View, California). Tempo ™ Inhaler is a pressure metered dose inhaler (pMDI) that overcomes the limitations of standard pMDI inhalers: non-uniform dosing and inefficiency of drug delivery. The rate of Inhaler is activated by inhalation, increases the individual's compliance and ensures effective uniform dosing, independent of the inhalation flow rate. These advantages are achieved by combining proprietary features, such as a breath-synchronized trigger and a flow control chamber, with a dose counter / lock in a small, easy-to-use device. These advanced aerodynamic control components are powered only by the individual's breath. This resulted in an inexpensive, reliable disposable platform that does not require the use of expensive, energy-consuming electronic devices.

Measuring the effectiveness of DHE [0073] The present invention indicates a method of administering DHE that minimizes or eliminates side effects, while achieving a dosage profile sufficient to provide effective and rapid relief of the four initial symptoms of migraine syndrome: pain, nausea, phonophobia and photophobia. An unexpected phenomenon has been observed during clinical studies carried out by the inventors. When DHE was administered in the above-mentioned manner, it was surprisingly avoided to have a very large "jump" in maximum plasma concentration. As a result, side effects such as nausea, chest pain or tightness, instability of blood pressure and vomiting could be minimized or completely eliminated, while achieving rapid relief of migraine symptoms.

[0074] The efficacy of migraine treatment can be assessed on the basis of primary and secondary endpoints. The primary end point may be pain relief approximately 2 hours after dosing. Secondary endpoints relate to 3 areas of interest: pain disappearance less than 2 hours postdose, headache not increasing, and effects on normal activities.

[0075] All four migraine symptoms - pain, nausea, phonophobia and photophobia - are classified at each time point according to a four-point scale developed by the International Headache Society Committee on Clinical Trials in Migraine. Guidelines for controlled clinical trials of drugs in migraine, first edition. Cephalalgia 1991; 11: 1-12):

= none = mild symptom, not affecting the performance of normal daily activities = moderate symptom, somewhat limiting the performance of ordinary activities = acute symptom preventing normal daily activities [0076] Headache is measured according to a 4-grade scale (0 = no pain, l = mild pain, 2 = moderate pain, 3 = severe pain). The average time needed to relieve the headache is measured (by one

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EP 2 425 820 Bi point below primary severity), to achieve mild headache and to eliminate pain. Effective migraine treatment would reduce the headache symptom to mild or eliminate it within 1.5 to 2 hours.

[0077] Relief of any of the four symptoms requires a decrease on the scale from a value of&gt; 0 at the time of reporting the onset of a migraine attack (value&gt; 1 for pain) to a value of 1 at a given time point. However, the complete elimination of pain (or other symptom) requires a reduction of this symptom classification from an initial value of&gt; 0 (value&gt; 1 for pain) to 0 at this time.

[0078] Functional disability (ability to perform normal daily activities) is measured according to a 4-point scale:

= no disorder = mild disorder = moderate disorder = acute disorder or total disability [0079] After a certain period of time, ask the subjects another question ("How effective was the study drug?") to assess "total efficacy" according to 7- gradual scale:

= very big improvement = big improvement = slight improvement = no change = slight deterioration = significant deterioration = very significant deterioration

Mechanism of action [0080] Investigating the ability of DHE to bind to receptors at the Cmax concentrations described in detail in Examples 2 and 3 explains the differences observed in the adverse reaction profile. Without being limited by theory, it has been hypothesized that a method of treating migraine with DHE that would not cause side effects could be developed by controlling Cmax in such a way as to minimize DHE's ability to bind to dopaminergic and adrenergic receptors, thereby avoiding side effects while achieving binding to serotonin receptors sufficient to effectively treat migraine symptoms.

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[0081] Clinical data (Table 2) show that inhaled dihydroergotamine reduces the incidence of nausea compared to intravenous administration (8% and 63%, respectively). It is known that 5-HT3 receptors are responsible for the occurrence of nausea. Antagonists of these receptors, e.g. ondaserton and graniserton, prevent chemotherapy-induced nausea and vomiting. However, the potential for DHE as an agonist of 5-HT3 receptors can be excluded due to inactive binding (&lt;20%) for all DHE administration methods studied (Figure 3). Further functional tests also confirmed the lack of agonist and antagonistic effects on 5-HT3 receptors.

[0082] The likely adverse reaction profile of DHE is secondary to agonist activity at 5-HT1A and 5-HT2A receptors and D2 dopaminergic receptors. (Silberstein, SD, McCrory, DC Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache (2003) 43: 144-166). Similar levels of ability to bind to the 5-HT1A receptor for all doses and modes of administration exclude this receptor as the cause of the diverse profile of adverse effects, especially in the case of dizziness. In fact, 5-HT1A receptors are thought to play a role in DHE-mediated prophylactic treatment of migraine. (Hanoun, N. et al. Dihydroergotamine and its metabolite, 8-hydroxy-dihydroergotamine, as 5HT1A receptor agonists in the rat brain. British Journal of Pharmacology 2003; 139: 424-434).

[0083] DHE has a stimulating effect on vascular α-adrenergic receptors and agonistically on 5-HT2A receptors responsible for narrowing the blood vessels. These effects underlie peripheral vasoconstriction, especially in coronary artery smooth muscle. Therefore, the use of DHE and related ergot compounds in individuals suffering from coronary artery disease and peripheral vascular disease is not recommended. However, it is worth noting that the ability to bind to 5-HT2A receptors at Cmax was lower at higher inhalation doses (14%) than at intravenous doses (83%). The effect of other serotonergic subtypes and adrenergic types on the adverse reaction profile is not clearly defined. However, the drug exhibits significantly greater binding capacity at Cmax after intravenous administration than by inhalation (Figures 3-5), which may play a role in nausea, especially in adrenergic blockade.

[0084] Both neuronal and vascular mechanisms have been identified as the basis for 5-HT receptors during migraine. The theory that migraine is the effect of vasodilatation suggests that migraine pain is associated with dilatation of extracranial arteries during an attack. In turn, according to the theory of neurogenic dermatitis as a cause of migraine, dermatitis surrounding the brain is caused by the release of neuropeptides from the primary sensory nerve endings. Substance P, a calcitonin gene peptide and NO, play a role in the cascade reaction caused by dermatitis. NO is suspected to play a key role in causing migraine because nitric oxide donors cause dose-dependent headache with several migraine features. Migraine may be caused by increased amounts and / or affinity of the enzyme in the NO-induced cascade reaction (Olesen et al., Trends Pharmacol. Sci. 1994; 15: 149-153).

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[0085] 5-HT2B receptors have been shown to stimulate NO production in cell lines (Manivet P et al., PDZ-dependent activation of nitric oxide synthases by the serotonin 2B receptor. J. Biol. Chem. 2000; 275: 9324-9331) and relaxation of the cerebral artery in pigs (Schmuck et al., Eur. J. Neurosci. 1996; 8: 959-967). Therefore, it has been suggested that 5-HT2B receptors, which are found on endothelial cells of meningeal blood vessels, cause migraine headache by releasing NO. The long half-life of DHE may explain the low headache recurrence rate at least in part by the persistent inhibition of 5-HT2B receptor-dependent secondary messengers (NO) via the main active metabolite DHE, 8'OH-DHE. (Schaerlinger B. et al., British Journal of Pharmacology (2003) 140, 277-284).

[0086] D2 receptor antagonists, i.e. metoclopramide and domperidone, are effective nausea inhibitors. DHE at an intravenous dose of Cmax has a 50% ability to bind to receptors in D2 tests (Figure 5) and therefore may cause clinically nausea and dizziness, indirectly due to agonist effects. Conversely, no binding affinity was found after inhalation dose administration. In addition to the data contained in this document, it should be added that DHE also has minimal ability to bind to muscarinic (M) receptors, thus eliminating nausea induced by the M receptor in the chemoreceptive trigger zone. (McCarthy, BG, Peroutka, SJ, Comparative neuropharmacology of dihydroergotamine and sumatriptan (GR43175). Headache 1989; 29: 420-422).

[0087] Studies on the ability to bind to receptors, described in Examples 2 and 3, may explain the unexpected results of using a novel method of rapidly treating migraine with DHE while minimizing side effects. The method involves lowering the maximum plasma concentration (Cmax) and a slight delay in reaching it to avoid saturation of dopaminergic and adrenergic receptors, while achieving binding to serotonin receptors sufficient to achieve the required therapeutic effect of migraine treatment.

EXAMPLES [0088] Apart from a more detailed discussion of this issue, it is believed that a medical practitioner can make the most of the present invention using the description above. The following examples are for illustrative purposes only and do not in any way limit the rest of the information disclosed in this document.

Example 1: Pharmacokinetic DHE profile necessary for pain relief.

[0089] Figure 1 shows a rapid relief of pain (within 10 minutes) by administering DHE by a method that allows achieving two lower maximum concentration profiles shown in Figure 2.

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[0090] Figure 2 shows DHE plasma profiles for 1 mg of intravenous DHE compared to 6 (1.22 mg of inhaled drug per fine particle dose), 4 (0.88 mg of inhaled drug per dose dose 2) and 2 inhalations (0.44 mg of inhaled drug per dose of fine particles) DHE. A large rapid increase in plasma concentration was observed after intravenous DHE administration, but not with inhaled DHE. It has been hypothesized that said difference in rapid increase in plasma concentration (at least 10-fold) is associated with a reduced adverse reaction profile, despite the smaller differences in AUC between 1 mg intravenous DHE and 0.88 mg inhaled DHE.

[0091] Figure 7 shows the plasma profile of the primary metabolite DHE, 8'-OHdihydroergotamine, after intravenous and inhalational administration of DHE. A greater rapid increase in plasma 8'-OH dihydroergotamine concentration was observed after intravenous DHE administration, but not by inhalation of DHE. It has been hypothesized that this sharp increase in plasma concentration is also associated with a reduced adverse reaction profile. Inhalation of the drug results in a maximum plasma concentration of 8'-hydroxy-dihydroergotamine (Cmax) of less than 1000 pg / ml. Preferred concentration is less than 500 pg / ml, more preferred - less than 200 pg / ml. Inhalation also results in Tmax of primary metabolites (e.g., 8'OH-dihydroergotamine) in plasma less than 90 minutes.

[0092] The inventors have found that said pharmacokinetic profiles with slightly delayed, lower maximum concentration are associated with minimized side effects. Side effects caused by these drug use profiles are shown in Table 2. For the two lower curves in Figure 2, for 0.88 mg and 0.44 mg DHE doses, therapeutic efficacy was achieved within 30 minutes, but the 0.88 mg dose only caused minor side effects, and for the 0.44 mg dose no no side effects have been observed. For the highest curve, 1.0 mg of DHE given intravenously, which is typical treatment currently used in clinics, had serious side effects, including nausea and vomiting. The theory was presented that the observed difference in Cmax, i.e. concentration in the blood plasma, which was about 10 times lower than in the case of intravenous drug use, is associated with the observed differentiated profile of adverse effects, with smaller differences in AUC - only 1.2 times lower value - between 1 mg administered intravenously and 0.88 mg administered by inhalation made the drug therapeutically effective. The drug delivery profiles shown in Figure 2 in this case were obtained by inhalation of the drug, but could also be obtained by using an infusion pump as well as by administering the drug intranasally, transdermally using iontophoresis or other methods developed in such a way as to achieve a similar slight delay achieving maximum plasma concentrations and similar suppression of maximum concentrations, while achieving similar AUC.

<td></td><td>1 mg DHE intravenously, n = 16 (%)</td><td>0.88 mg DHE by inhalation, n = 12 (%)</td>

<td>The nervous system</td><td></td><td></td>

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<td>Dizziness</td><td>7 (44) 7r</td><td> 1 (8)</td>

<td>paraesthesia</td><td>5 (31) 5years</td><td> 0</td>

<td>Digestive system</td><td></td><td></td>

<td>Nausea</td><td>10 (63) 10</td><td> 1 (8)</td>

<td>Vomiting</td><td>2 (13) 2r</td><td> 0</td>

<td>General disorders</td><td></td><td></td>

<td>Feeling hot</td><td>3 (19) 3r</td><td> 0</td>

<td colspan="3">r = value taken into account by the researcher analyzing the drug</td>

Table 2: Side effects associated with the pharmacokinetic profiles shown in figure 2

Example 2: The ability to bind to receptors at Cmax concentrations [0093] In a clinical study, comparing 1 mg of intravenous DHE with inhaled DHE, a different adverse reaction profile was found (Table 2). A significantly higher incidence of adverse reactions has been observed after intravenous administration. In order to investigate the differences in pharmacologically induced side effects between dihydroergotamine mesylate (DHE) administered (1) intravenously and (2) inhaled, the in vitro ability of dihydroergotamine mesylate to bind to biogenic (serotonin - 5HT, adrenergic and dopaminergic) amine receptors was determined based on concentrations corresponding to Cmax levels found after inhalation and intravenous administration in a clinical trial.

[0094] To investigate the unexpected result, which showed that lower rapid increases in DHE could have resulted in a different profile of the ability to bind to receptors, so that the drug was effective and did not cause side effects, a clinical study of the ability to bind to receptors was conducted at Cmax concentrations.

[0095] Maximum plasma DHE concentrations (Cmax) were determined based on plasma samples (LCMS / MS) after intravenous administration (1 mg) by infusion over 3 minutes and on plasma samples (LC-MS / MS) after administration inhalation (at 0.88 mg and 0.44 mg) by repeatedly activating the inhaler for 2-4 minutes. The inhaled doses represent the expected dose delivered to the large bloodstream. They were estimated based on the dose of fine particles given by the method of inhaler activation. Data on the observed Cmax DHE concentration are shown in Figure 2. A similar method was also used for the primary metabolite, 8'-OH-DHE.

[0096] Table 3 shows the in vitro concentrations corresponding to the Cmax concentration. These concentrations were selected for studies on the ability of DHE and 8'-OH-DHE to bind to receptors.

<td>Dose</td><td>Dihydroergotamine mesylate (pg / ml)</td><td>8'-OH-dihydroergotamine (pg / ml)</td>

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<td>1 mg iv</td><td> 53 215</td><td> 378</td>

<td>0.88 mg by inhalation</td><td> 4 287</td><td> 149</td>

<td>0.44 mg inhaled</td><td> 1 345</td><td> 58</td>

Table 3. Concentrations corresponding to maximum plasma concentrations, tested for their ability to bind to receptors.

Example 3: Ability of DHE to bind to serotonin, adrenergic and dopaminergic receptors at concentrations corresponding to maximum plasma concentrations.

[0097] Test results regarding the ability to bind to radioligand receptors clearly show that DHE has a multilateral pharmacological effect on many receptors. (Figures 3-5) For most DHE receptors, it exhibits high binding capacity at concentrations corresponding to the Cmax of the intravenous drug, whereas when inhaled, each dose has a different binding profile. In most cases, the binding capacity is reduced when the drug is administered by a method other than intravenously.

[0098] The efficacy of DHE in the treatment of migraine is due to its agonist activity at 5HT1B and 5-HT1D receptors. Figure 3 shows data on the ability to bind to various serotonergic receptor subtypes. Increased reactivity of several receptor subtypes to drug at intravenous Cmax. The annotation "(h)" means cloned subtypes of human receptors. Similar trends were observed for adrenergic and dopaminergic subtypes. It has been shown to be 100% capable of binding to 5-HT1B receptors after both 1 mg intravenous and 0.88 mg inhalation. (Figure 3) However, after inhalation of the drug, the ability to bind to 5-HT1D receptors is significantly less than when administered intravenously. The longer presence of DHE in the bloodstream after reaching Cmax is probably due to biphasic elimination. (Wyss, PA, Rosenthaler, J., Nuesch, E., Aellig, WH Pharmacokinetic investigation of oral and IV dihydroergotamine in healthy subjects. Eur. J. Clin. Pharmacol. 1991; 41: 597-602). These results suggest that the maximum ability to bind to receptors is not absolutely necessary to achieve a lasting clinical response.

[0099] As shown in Figures 3-5, the drug, administered intravenously at high Cmax concentrations that cause side effects, showed a high ability to bind to dopaminergic and adrenergic receptors at concentrations corresponding to the rapid increases in maximum plasma concentration (Cmax) resulting from drug administration intravenously. Figure 4 shows data on the ability to bind to adrenergic receptors (left panel) and dopaminergic (right panel). Increased reactivity of several receptor subtypes to drug at intravenous Cmax. The annotation "(h)" means cloned subtypes of human receptors and "NS" - non-specific binding.

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[0100 Daminations D1 and D2 are primarily responsible for causing nausea and vomiting. By using concentrations corresponding to rapid increases in maximum plasma concentration (Cmax) resulting from the use of an innovative method of drug administration consisting in lowering and delaying the maximum concentration, as shown in Figure 2, the ability to bind to dopaminergic receptors, in particular D2 and D1, was significantly reduced, as shown in figure 4, which ultimately resulted in a reduction of symptoms such as nausea and vomiting in individuals.

[0101] Similarly, the reduced ability to bind to adrenergic receptors, shown in figure 4, corresponded to the reduction of symptoms such as vasoconstriction, blood pressure instability and cardiovascular disorders in individuals. Although the ability to bind to adrenergic and dopaminergic receptors was lower at concentrations corresponding to the rapid increases in maximum plasma concentration (Cmax) resulting from the use of an innovative method of drug administration, the ability to bind to serotonin receptors, in particular 5-HT1a / d obtained through the use of these methods of drug administration were sufficient to provide effective migraine treatment. (Figure 3) [01102 It is known that 5-HT1B receptor agonists are substances useful in the treatment of migraine and related symptoms. It is also known that 5-HT2B receptors play a role in causing migraine. Figure 5 shows the selective agonist effect on 5-HT1B and 5-HT2B receptors after regulation of high concentration (5 μΜ), intravenous administration at concentration C_max (77.6 nM), 4 inhalations at Cmax (6.25 nM) and at significantly reduced concentration (0.25 nM). Although at all concentrations, the drug showed a strong agonist effect on 5-HT1B receptors, in the case of DHE inhaled orally there was no agonist effect on 5-HT2B receptors.

[0103] It was noted that with all three methods of drug use, sufficient plasma concentrations to form binding to serotonin receptors are achieved rapidly - within 20 minutes, allowing rapid treatment of migraines. (Figure 2)

Example 4: Pulmonary administration of DHE preparations using a Tempo device^TM Inhaler [01104 The DHE powder form is obtained in supercritical fluid extraction processes, which allows significant benefits to be obtained in the production of DHE particles for inhalation and the production of respirable particles of the required size in one process (see W02005 / 025506A2). One of the properties of the drug containing processed DHE is the fact that the crystals formed in the process of extraction with a supercritical fluid have extremely smooth surfaces with low surface energy, which allows them to be efficiently distributed in carrier gas systems. A controlled particle size of microcrystals was selected to ensure pulmonary deposition of a significant DHE fraction.

[0105] During the development of the medicament containing the formulation, a mixture of two inert and non-flammable HFA carrier gases was selected: HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227ea (1,1,1,2,3,3,3heptafluoropropane). The final product contained a mixture of HFA 227ea and HFA 134a w. Gases

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70:30, corresponding to the density of DHE crystals and promoting the maintenance of the physical stability of the suspension for use in the pMDI device. The resulting suspension did not settle or spread (which could lead to its irreversible accumulation), but was in the form of a suspended, loosely flocculated system, easy to spread after shaking. It is widely believed that loosely flocculated systems provide optimal stability for pMDI device containers. Due to such properties, the preparation did not contain ethanol or any surfactants and stabilizers.

[0106] The DHE formulation was administered to individuals using a TEMPO device^TM, an innovative inhaler with a dispenser, activated by inhalation. In the TEMPO device^TM it was possible to solve the problem with dose variability found in standard metered dose inhalers (pMDI) and to achieve uniform dosing of the drug into the lung circumference, from where it can be absorbed into the large bloodstream. The TEMPO device is equipped for this purpose^TM in four innovative functions: 1) trigger synchronized with inspiration, adjustable for various drugs and target populations to deliver the drug at a specific point in the respiratory cycle, 2) ejection control - a colliding stream, used to slow down the aerosol stream in the activator, or 3) a vortex chamber consisting of a porous a wall that serves as an airbag that maintains a slowed aerosol flow in the suspension, and air intakes on the rear wall, which cause the slow motion of the aerosol to vortex, keeping the aerosol suspended and allowing the particle size to be reduced when the HFA carrier gas evaporates, and 4) a dose counter that will determine how many doses remain and prevent the number of doses from one container being exceeded from the maximum intended dose. Functions 2 and 3 have been shown to significantly slow down aerosol flow and provide better pulmonary deposition of emitted dose (ED) by increasing the fine particle fraction (FPF).

[0107] Although, for the sake of clarity and ease of understanding, the above-mentioned invention has been described in detail by means of illustrations and examples, for persons having ordinary medical knowledge, in the light of the teaching materials of the present invention, it will be quite obvious that some of the present invention may incorporate certain changes and modifications, which, however, will not depart from the spirit and scope of the appended claims.

ASPECTS OF THE INVENTION

1. A method of rapidly treating a subject's migraine with DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs and metabolites while minimizing side effects, which method comprises administering to the subject a certain amount of DHE at a rate sufficient to alleviate the migraine symptom, wherein the amount and rate of DHE administration significantly reduce the side effect.

2. The method of aspect 1, wherein the amount and rate of DHE administration are sufficient to achieve such a concentration of DHE in the blood plasma that DHE acts as a serotonin receptor agonist, relieving the migraine symptom; whereas the DHE concentration in the blood plasma remains below the level necessary for active binding of the adrenergic receptor, the receptor

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A dopaminergic or serotonin receptor responsible for narrowing the arteries, which binding produces a side effect.

3. The method of aspect 1, wherein the side effect is selected from the group consisting of: nausea, vomiting, vasospasm, paresthesia, hypertension, dizziness, anxiety, shortness of breath, headache, redness, diarrhea, rash, increased sweating , cardiac valve damage, pleural and retroperitoneal fibrosis, cardiovascular adverse reaction, blood pressure instability and narrowing of the arteries.

4. The method of aspect 1, wherein the side effect is selected from the group consisting of nausea and vomiting.

5. The method of aspect 2, wherein the concentration of DHE in the blood plasma is such that DHE actively binds less than 50% of dopaminergic receptors.

6. The method of aspect 5, wherein the dopaminergic receptor is selected from the group consisting of D1 and D2 receptors.

7. The method of aspect 5, wherein the side effect is selected from the group consisting of nausea and vomiting.

8. The method of aspect 2, wherein the DHE plasma concentration is such that DHE actively binds less than 20% of dopaminergic receptors.

9. The method of aspect 8, wherein the dopaminergic receptor is selected from the group consisting of D1 and D2 receptors.

10. The method of aspect 8, wherein the side effect is selected from the group consisting of nausea and vomiting.

11. The method of aspect 2, wherein the concentration of DHE in the blood plasma is such that DHE actively binds less than 20% of 5-HT3 receptors.

12. The method of aspect 11, wherein the side effect is nausea.

13. The method of aspect 2, wherein the concentration of DHE in the blood plasma is such that DHE actively binds less than 20% of the serotonin receptor responsible for narrowing the arteries.

14. The method of aspect 13, wherein the serotonin receptor responsible for the narrowing of the arteries is the 5-HT2A receptor.

15. The method of aspect 13, wherein the serotonin receptor responsible for the narrowing of the arteries is the 5-HT2B receptor.

16. The method of aspect 13, wherein the side effect is selected from the group consisting of vasoconstriction and cardiovascular diseases.

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17. The method of aspect 2, wherein the concentration of DHE in the blood plasma is such that DHE actively binds less than 60% of adrenergic receptors.

18. The method of aspect 17, wherein the concentration of DHE in the blood plasma is such that DHE actively binds less than 20% of adrenergic receptors.

19. The method of aspect 17, wherein the side effect is selected from the group consisting of vasoconstriction, elevated blood pressure and cardiovascular diseases.

twenty. The method of aspect 2, wherein the DHE plasma concentration is such that DHE actively binds to a serotonin receptor selected from the group consisting of 5HT1A, 5-HIT1B and 5-HT1D receptors sufficient to alleviate the migraine symptom.

21. The method of aspect 1, wherein DHE is administered at a rate such that the maximum plasma concentration in humans (Cmax) is less than 15,000 pg / ml and the time (Tmax) from administration to reaching maximum plasma concentration is shorter than 30 minutes after administration.

22. The method of aspect 21, wherein the Cmax DHE concentration in the blood plasma is less than 10,000 pg / ml.

23. The method of aspect 21, wherein the Cmax DHE concentration in the blood plasma is less than 7500 pg.

24. The method of aspect 21, wherein DHE is administered at a rate such that its Tmax in plasma is less than 20 minutes after administration.

25. The method of aspect 1, wherein DHE is administered at a rate such that the maximum concentration of DHE in the blood plasma (Cmax) is at least 10 times lower than the concentration of Cmax of DHE administered directly intravenously.

26. The method of aspect 1, wherein DHE is administered at a rate such that the maximum plasma DHE concentration (Cmax) is delayed by at least 1 minute relative to the time Tmax DHE administered directly intravenously.

27. The method of aspect 24, wherein administering DHE to achieve Cmax and Tmax results in at least partially alleviating a migraine symptom selected from the group consisting of pain, nausea, phonophobia and photophobia. This symptom relief is achieved in 30 minutes or less, and side effects, i.e. drug-induced nausea and cardiovascular effects or other side effects, are reduced.

28. The method of aspect 1, wherein the relief of migraine is measured by a decrease on the IHS scale greater than "0" for migraine symptom during DHE administration to &lt;1 after 30, 60, 90 or 120 minutes after administration.

29. The method of aspect 1, wherein a unit dose less than 2.0 mg DHE or its salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites is administered.

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thirty. The method of aspect 14, wherein a unit dose less than 2.0 mg DHE or its salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites is administered, and the area of ​​the circulating drug concentration curve is large in relation to time (AUC) of the delivered drug within 75% of a comparable intravenous dose.

31. The method of aspect 1, wherein the use of the drug results in a maximum plasma concentration of the active primary DHE (Cmax) of less than 1000 pg / ml.

32. The method of aspect 31, wherein the active primary metabolite of DHE is 8'hydroxy dihydroergotamine.

33. The method of aspect 31, wherein the Cmax concentration of primary metabolites in blood plasma is less than 500 pg / ml.

34. The method of aspect 31, wherein the Cmax concentration of primary metabolites in blood plasma is less than 200 pg / ml.

35. The method of aspect 31, wherein the Tmax time of primary metabolites in blood plasma is less than 90 min,

36. A preparation containing DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs and metabolites, said preparation being suitable for administration in the method of aspect 1.

37. The preparation according to aspect 36, wherein the use of DHE in an amount sufficient to achieve such a concentration of DHE in the blood plasma that DHE acts as a serotonin receptor agonist, leading to the relief of the migraine symptom, does not cause such a concentration of DHE in the blood plasma that DHE binds the adrenergic receptor. , dopaminergic receptor or serotonin receptor responsible for narrowing the arteries to a degree that causes a side effect.

38. The method of aspect 1, wherein the DHE preparation is administered in a manner selected from the group consisting of: intravenous, intraarterial, intraperitoneal, pulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesical, intramuscular, intratracheal, subcutaneous , by iontophoresis and transdermally.

39. The method of aspect 38, wherein the DHE formulation is administered by inhalation using aerosols, dry powder inhalers, nebulizers, vaporizers or metered dose inhalers (pMDI).

40. The method of aspect 38, wherein the DHE formulation is administered using a pressurized inhaler with an inspiratory activated dispenser.

41. The method of aspect 1, wherein the DHE preparation is administered by a method selected from the group consisting of: intravenous, intraarterial, intraperitoneal, pulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesical, intramuscular, intratracheal, subcutaneous, by iontophoresis and transdermally at such a rate that after drug administration

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The maximum concentration of DHE in human plasma (Cmax) is less than 10,000 pg / ml, and the time from drug administration to achieving maximum DHE plasma concentration (Tmax) is less than 30 minutes after administration.

42. The method of aspect 41, wherein the DHE is administered by inhalation using aerosols, dry powder inhalers, nebulizers, vaporizers or metered dose inhalers (pMDI).

43. The method of aspect 42, wherein the DHE formulation is administered using a pressurized inhaler with an inhalation activated dispenser.

44. The method of aspect 43, wherein the DHE is administered without an anti-emetic.

45. The method of aspect 1, wherein the DHE preparation is administered to the subject by means of an inhaler-activated metered dose inhaler, wherein the DHE is administered at a rate such that the maximum concentration in human blood plasma (Cmax) is less than 10,000 pg / ml, and the time (Tmax) from administration to the maximum plasma concentration was less than 20 minutes. In addition, DHE is given without an anti-emetic.

46. A kit comprising a unit dose of DHE or its salts, hydrates, polymorphs, prodrugs, ionic pairs and metabolites, wherein the unit dose administered to the subject is sufficient to alleviate the migraine symptom in conditions where the dose and rate of DHE administration do not produce a side effect.

47. The kit described in aspect 46, further comprising an inhaler.

48. The kit described in aspect 46, further comprising a nebulizer.

49. The kit described in aspect 46, further comprising a pressurized inhaler with dispenser.

50. An inhaler containing at least one unit dose of DHE, each unit dose being administered at such a rate that the maximum plasma concentration in humans (Cmax) is less than 10,000 pg / ml and the time (Tmax) from administration to achieving maximum plasma concentration was less than 30 minutes.

51. The inhaler described in aspect 50, wherein the DHE formulation is provided in a sealed container.

52. A method of rapid treatment of a disease or condition in humans by means of a compound that (a) binds to at least one of the first receptors, wherein the reaction of the compound with the first receptors alleviates the symptoms of the disease or condition and (b) binds to at least one of the second receptors, whereby the reaction of the compound with the second receptors causes a side effect, wherein the method comprises administering to the subject a certain amount of the compound at a rate sufficient to achieve such a concentration of the compound in the blood plasma that the compound acts as an agonist of the first

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A receptor which relieves a disease or condition wherein the concentration of the compound in the blood plasma remains below the level necessary for binding to the second receptor which binding causes a side effect.

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EP 2 425 820 B1