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    composition comprising a serotonin receptor agonist and a diketopiperazine and a diketopiperazine for treating migraines. the present invention provides a method of treating migraines. the method utilizes a rapid drug release system that prevents deactivation or degradation of the active agent, including small molecules and peptides to be administered to a patient in need of treatment. specifically, the drug delivery system is intended for inhalation to deliver drugs to inhalation to deliver drugs to the pulmonary circulation in a rapid and therapeutically effective manner.
    公开号:BR112013011549B1
    申请号:R112013011549-1
    申请日:2011-11-09
    公开日:2022-01-04
    发明作者:Andrea Leone-Bay；Grayson W. Stowell；Joseph J. Guarneri；Dawn M. Carlson；Marshall Grant；Chad C. Smutney
    申请人:Mannkind Corporation；
    IPC主号:
    专利说明:

    CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
    [001] This patent application claims priority benefit therefrom to United States Provisional Patent Application No. 61/412,339, filed November 10, 2010, the contents of which are hereby incorporated in their entirety by reference in this application. patent.
    [002] This patent application is also a continuation in part of United States Patent Application No. 12/258,341, filed October 28, 2008, which claims the priority benefit thereof to the United States Provisional Patent Applications numbers 60/982,368, filed on October 24, 2007; 60/985 620, filed on November 5, 2007; 61/033 740, filed on March 4, 2008; 61/052 127, filed on May 9, 2008; 61/022 274, filed on January 18, 2008; and 61/094,823, filed September 5, 2008. The contents of each of these patent applications are hereby incorporated in their entirety by reference into this patent application.
    [003] This patent application is also a continuation in part of PCT/US11/41303, filed on 21st of 2011, which claims the priority benefit thereof to US Provisional Patent Application number 61/411,775, filed on 9th of November 2010 and Provisional US Patent Application No. 61/357,039, filed June 21, 2010. The contents of each of these patent applications are hereby incorporated in their entirety by reference into this patent application. Field of invention technique
    [004] Methods and compositions for treating migraine are described. The methods comprise administering a pharmaceutical formulation containing a small molecule, including triptans such as sumatriptan, to a patient in need of treatment via a pulmonary inhalation drug delivery system. Specifically, a drug delivery system comprising a breath-actuated dry powder inhaler for oral inhalation is described. Background of the invention
    [005] Drug delivery systems intended for the treatment of disease, which introduce ingredients into the circulation for the treatment of disease, exist in large numbers and include oral, transdermal, subcutaneous and intravenous administration. Although these systems have been in use for a long time and are capable of delivering drugs for the treatment of many diseases, there are numerous challenges associated with these drug delivery mechanisms. In particular, delivering effective amounts of proteins and peptides to treat a specific disease has been problematic. Many factors are involved in introducing the right amount of active agent, for example, preparing the appropriate formulation for drug delivery, so that the formulation contains an amount of active agent that can reach its site(s) of action. in effective amount.
    [006] The active agent must be stable in the formulation of the drug to be released and the formulation must allow the absorption of the active agent into the circulation and that it remains active so that it can reach the targeted site(s) of action (s) at therapeutically effective levels while minimizing the amount of dose to be administered. Therefore, drug delivery systems that can deliver a stable active agent are useful in pharmacological technologies. Summary of the invention
    [007] The present invention provides methods for introducing an active agent, such as a serotonin receptor modulator, including serotonin receptor agonists or serotonin receptor antagonists, into the circulatory system of a mammal. The methods comprise a drug delivery system that prevents deactivation or degradation of the active agent being administered to a patient in need of treatment. Specifically, the drug delivery system is intended for pulmonary drug delivery such as by inhalation to deliver active agents to the pulmonary circulation in a therapeutically effective manner. In one embodiment, the drug delivery system has advantages over other drug delivery methods, for example, oral, subcutaneous, and intravenous administration of drug products, which are sensitive to enzymatic deactivation, or prevent degradation of small molecules in local tissue. peripheral and vascular tissue before they reach the intended site.
    [008] In an embodiment of the present invention, a method is described for delivering an active agent to a patient in need thereof, comprising selecting an active agent subject to degradation in the patient, wherein the effectiveness of the active agent is reduced by degradation, associating the active agent with a diketopiperazine to produce a pharmaceutical composition suitable for pulmonary inhalation; and delivering the pharmaceutical composition to the patient so that the active agent reaches the intended site, without undergoing considerable degradation or deactivation, in therapeutically effective amounts at lower doses than standard administration by other routes of administration.
    [009] Additionally, the present invention provides a method of treating a disease or condition, comprising selecting a patient undergoing treatment with a labile active agent or a patient having a condition treatable by such an agent; providing a composition comprising the labile active agent associated with a diketopiperazine; and administering the composition to the patient via pulmonary inhalation; thus treating the disease or condition.
    [0010] In another embodiment, a drug delivery system prevents degradation of the active agent resulting from first-pass metabolism, in which the active agent is delivered into the arterial circulation of the lungs and delivered to the target organ at therapeutically effective levels, by degradation in venous blood circulation, peripheral tissue, gastrointestinal system or liver has been prevented. In this embodiment, active agents can be delivered in lower concentrations than needed through other routes of administration. In a specific embodiment, the active agent is a small molecule, including molecules that bind to serotonin receptors and are serotonin receptor agonists. In one embodiment, the molecules induce vasoconstriction of blood vessels in the brain, relieve edema and headache. In one embodiment, the compositions are used for the treatment of moderate to severe headaches that interfere with an individual's performance of daily tasks, and that demonstrate symptoms of nausea, vomiting, and sensitivity to light and noise.
    [0011] In another embodiment, the diketopiperazine is 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine; wherein X is selected from the group consisting of succinyl, glutaryl, maleyl and fumaryl; or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition is a dry powder formulation for inhalation. In yet another embodiment, the dry powder formulation for inhalation comprises a pharmaceutically acceptable carrier or excipient.
    [0012] In one embodiment, the dry powder inhalation formulation is delivered to the patient by pulmonary inhalation using a dry powder inhalation system. In another embodiment, the system comprises a dry powder inhaler with or without a container and a dry powder formulation.
    [0013] In an exemplary embodiment, a method is provided for treating a migraine-like headache, which method comprises administering to a patient in need of treatment a dry powder composition by oral inhalation, wherein the dry powder composition contains an active agent. for treating migraines, including a triptan such as sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan and pharmaceutically acceptable salts thereof, and a substituted diketopiperazine such as fumaryl diketopiperazine, or a diketopiperazine salt such as disodium fumaryl diketopiperazine. The dry powder composition can be administered to the patient at the time of onset of the migraine headache, as needed by the patient or as determined and instructed by the physician. In one embodiment, the dose of triptan can reduce or avoid unwanted side effects associated with therapy using injectable or tablet drug, including flushing, sweating, dizziness, tiredness, tingling, drowsiness, dizziness, dry mouth, heartburn, abdominal pain, abdominal cramps, weakness, feeling hot or cold, bitter taste caused by tablets and nasal sprays, and burning at the injection site, from the lower amount of triptan given than is needed with other modes of administration.
    [0014] In a specific embodiment, a method of treating symptoms associated with migraine comprises administering to a subject in need of said treatment a therapeutically effective amount of an inhalation dry powder pharmaceutical composition which contains a triptan, including sumatriptan, almotriptan , eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan and pharmaceutically acceptable salts thereof, and a substituted diketopiperazine in a composition comprising bis[3,6-(N-fumaryl-4-aminobutyl)]-2,5-diketopiperazine or disodium salt of bis[3,6-(N-fumaryl-4-aminobutyl)]-2,5-diketopiperazine. In certain embodiments, the pharmaceutical composition may comprise a dry powder containing a pharmaceutically acceptable carrier or other inactive agents. In some embodiments, the amount of triptans in the dry powder composition, for example sumatriptan succinate, may vary depending on individual needs, for example, the triptan may be present in amounts of 1 mg or greater. In exemplary embodiments, the amount of sumatriptan or its salt, including powdered sumatriptan succinate for pulmonary inhalation, can be administered in a range ranging from approximately 1 mg to approximately 50 mg. In another embodiment, the triptan is a salt of rizatriptan, including, but not limited to, benzoate. In other embodiments, the salts of the triptans can be, for example, almotriptan malate, frovatriptan succinate, eletriptan hydrobromide and naratriptan hydrochloride. In certain embodiments, the dry powder composition may optionally comprise an amino acid, such as an aliphatic amino acid, for example, alanine, glycine, leucine, isoleucine, norleucine, in amounts ranging from approximately 0.5% to approximately 30% by weight. In a specific embodiment, the dry powder composition comprises the amino acid L-leucine. In some embodiments, a pharmaceutical composition may comprise microparticles, wherein a microparticle may include 1) a diketopiperazine, and at least one of: a serotonin receptor agonist, such as a triptan, and an aliphatic amino acid. A triptan and/or an aliphatic amino acid can be incorporated, adhered to, complexed or coated onto a diketopiperazine microparticle. In some embodiments, a diketopiperazine microparticle may be coated with at least one of a serotonin receptor agonist, such as a triptan, and an aliphatic amino acid.
    [0015] In alternative embodiments, the method of treating a migraine-like headache may comprise a combined therapy whereby a dry powder composition comprising a triptan is administered by oral inhalation and, optionally, a second medicament or drug, for example, a selective serotonin reuptake inhibitor, such as fluoxetine and duloxetine, which may be provided by other routes of administration, such as oral tablets or injections. In one embodiment, the combination therapy can comprise a dry powder composition including triptan and one or more additional drugs that can be administered by inhalation.
    [0016] In another embodiment of the method described, the step of administering the composition to the patient comprises pulmonary administration of the dry powder composition by inhalation using a breath actuated dry powder inhaler with or without a container, wherein the container may be a cartridge, such as a unit dose cartridge for a reusable inhaler or a single use inhaler. In this and other embodiments, the dry powder inhaler system comprises a high strength dry powder inhaler exhibiting values of resistance to airflow through its channels in use from approximately 0.0065 to approximately 0.200 V(KPa)/L per minute, wherein the dry powder inhaler in use has an airflow distribution of approximately 10% to approximately 30% across the canister, which generates peak inhalation pressure differentials of approximately 2 KPa to approximately 20 KPa, and maximum flow rates between 7 L and approximately 70 L per minute. Brief description of the drawings
    [0017] Figure 1 depicts an HPLC chromatogram of a solution containing sumatriptan-Na2FDKP in dry powder obtained by spraying.
    [0018] Figures 2A and B are scanning electron micrographs of three powders produced by the present method, comprising sumatriptan-Na2FDKP. Panels A and B represent powder particles without L-leucine. Also shown are 10% leucine powder particles (Panel C and D) and 20% leucine powder particles (Panel E and F).
    [0019] Figure 3 depicts a graph of dose-normalized concentrations of sumatriptan in blood samples after administration of sumatriptan-Na2FDKP by insufflation, compared to sumatriptan given by subcutaneous injection and sumatriptan nasal spray by instillation for a period of 4 hours after administration.
    [0020] Figure 4 depicts a graph showing the mean blood sumatriptan levels of dogs after sumatriptan administered as a nasal spray, sumatriptan administered intravenously, and sumatriptan-Na2FDKP administered by insufflation, when compared to exposed control dogs to air supply.
    [0021] Figure 5 depicts a graph of the pharmacodynamic data showing the effects of intravenously administered sumatriptan compared to Imitrex® administered by nasal instillation and sumatriptan-Na2FDKP by insufflation on the diameter of blood vessels. Definition of terms
    [0022] Before presenting the invention, it may be useful to offer an understanding of certain terms that will be used below: Active agents: In this descriptive report, "active agent" includes drugs, pharmaceutical substances and bioactive agents. The active agents can be small molecules, which typically have a molecular weight of less than approximately 1,000 and not necessarily repeating units. The active agents can also be organic macromolecules, including nucleic acids, synthetic organic compounds, polypeptides, peptides, proteins, polysaccharides and other sugars and lipids. Peptides, proteins, and polypeptides are all chains of amino acids joined by peptide bonds. In general, peptides are considered to be made up of fewer than 40 amino acid residues, but may include more. Proteins are polymers that typically contain more than 40 amino acid residues. The term polypeptide, as known in the art and in this specification, may refer to a peptide, a protein, or any other amino acid chain of any length that contains multiple peptide bonds, while generally containing at least 10 amino acids. Active agents can fall under a variety of biological activity classes, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulatory agents, cytotoxic agents, antibiotics, antiviral agents, antigens, and antibodies. More specifically, active agents may broadly include insulin and its analogues, growth hormone, parathyroid hormone (PTH), ghrelin, granulocyte colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP- 1), and analogs of such peptides, alkynes, cyclosporines, clopidogrel and PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), antibodies and fragments thereof, including but not limited to humanized or chimeric antibodies; F(ab), F(ab)2 or single chain antibody alone or fused to other polypeptides; therapeutic or diagnostic monoclonal antibodies against cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell surface antigens.
    [0023] Diketopiperazine: In this specification, "diketopiperazine" or "DKP" includes diketopiperazine, derivatives, analogues and modifications thereof, in salt form and in non-salt form of any of the foregoing, falling within the scope of general Formula 1, in that the E1 and E2 ring atoms at positions 1 and 4 are O or N and at least one of the side chains R1 and R2 located at positions 3 and 6 respectively contains a carboxylic acid group (carboxylates). Compounds according to Formula 1 include, but are not limited to, diketopiperazines, diketomorpholines and diketodioxanes and substitution analogues thereof.Formula 1

    [0024] Diketopiperazines, in addition to composing aerodynamically suitable microparticles, can also facilitate the release of active agents by rapidly dissolving at physiological pH and thus releasing the active agent and accelerating its absorption into the circulation. Diketopiperazines can be formed into particles that incorporate a drug or into particles onto which a drug can adsorb. The combination of a drug and a diketopiperazine may impart better stability to the drug. These particles can be administered by various routes of administration. In dry powder forms, these particles can be released by inhalation to specific areas of the respiratory system, depending on the size of the particles. Additionally, the particles can be prepared in a size small enough for incorporation into an intravenous suspension dosage form. Oral delivery is also possible with the particles incorporated into a suspension, tablets or capsules.
    [0025] In one embodiment, the diketopiperazine is 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine (fumaryl diketopiperazine, FDKP). The FDKP may comprise microparticles in its acid form or salt forms, which may be aerosolized or administered in a suspension.
    [0026] In another embodiment, the DKP is a 3,6-di(4-aminobutyl)-2,5-diketopiperazine derivative, which can be formed by the (thermal) condensation of the amino acid lysine. Exemplary derivatives include 3,6-di(succinyl-4-aminobutyl)-, 3,6-di(maleyl-4-aminobutyl)-, 3,6-di(glutaryl-4-aminobutyl)-, 3,6-di (malonyl-4-aminobutyl)-, 3,6-di(oxalyl-4-aminobutyl)-, and 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine. US Patent Nos. 5,352,461, 5,503,852, 6,071,497 and 6,331,318, the contents of which are incorporated herein by reference into this patent application with respect to all that teach about diketopiperazines and diketopiperazine-mediated drug release, also describe examples of DKPs that can be used. The use of DKP salts is described in U.S. Patent No. 7,820,676, the contents of which are incorporated herein by reference into this patent application with respect to all that teaches about diketopiperazine salts. Pulmonary drug delivery using DKP microparticles is disclosed in U.S. Patent No. 6,428,771, the contents of which are incorporated herein in their entirety by reference in this patent application. Additional details regarding the adsorption of active agents onto crystalline DKP particles can be found in U.S. Patent Nos. 7,799,344 and 7,803,404, the contents of which are incorporated herein in their entirety by reference in this patent application.
    [0027] Drug Delivery System: In this descriptive report, “drug delivery system” refers to a system for delivering one or more active agents.
    [0028] Dry powder: In this specification, “dry powder” refers to a fine particulate composition that is not suspended or dissolved in propellant, vehicle or other liquid. The term does not mean that the complete absence of all water molecules is necessarily implied.
    [0029] Percent Breathable Fraction per Fill (FR%/Fill): In this descriptive report "FR%/Fill" refers to the amount of powder particles emitted from an inhaler, or drug delivery system, in which these particles are in the respirable range and can be smaller than 5.8 μm, normalized by the total amount of powder filled in the inhaler or drug delivery system. In some embodiments, the inhaler comprises a cartridge for containing the dry powder.
    [0030] Microparticles: In this specification, the term "microparticles" includes particles with a diameter of generally 0.5 to 100 microns and especially those with a diameter of less than 10 microns. Various modalities will imply more specific size ranges. The microparticles can be crystalline plate assemblies with irregular surfaces and hollow interiors as is typical of those composed by pH-controlled precipitation of DKP acids. In such embodiments, the active agents may be incorporated by the precipitation process or coated onto the crystalline surfaces of the microparticle. The microparticles may also be spherical shells or collapsed spherical shells comprising salts of DKP with the active agent fully dispersed. Typically, such particles can be obtained by spray drying a solution containing the DKP and the active agent. The DKP salt in such particles may be amorphous. The preceding descriptions are to be understood as exemplary. Other forms of microparticles are contemplated and encompassed by the term.
    [0031] Peripheral Tissue: In this descriptive report, “peripheral tissue” refers to any connective or interstitial tissue that is associated with an organ or vessel.
    [0032] Enhancing: In general, potentiation refers to a condition or action that increases the effectiveness or activity of some agent above the level at which the agent would otherwise reach. Likewise, it can refer directly to the effect or the increased activity.
    [0033] Pulmonary inhalation: In this specification, "pulmonary inhalation" is used to refer to the administration of pharmaceutical preparations by inhalation so that they reach the lungs and, in specific embodiments, the alveolar regions of the lung. Typically, inhalation is through the mouth, but, in alternative embodiments, may involve inhalation through the nose. Detailed description of the invention
    [0034] The present invention provides methods for treating a disease or disorder by means of a drug delivery system that is capable of effectively releasing an active agent into the pulmonary circulation so that the active agent enters the pulmonary circulation and can be released in therapeutic amounts to the site(s) of action. Methods of treating disease or disorders comprise administering to a patient a formulation that can release the active agent directly or indirectly into the pulmonary circulation, and thereby the arterial circulation, and that can prevent degradation of the active agent by enzymes or other mechanisms. in the local peripheral tissue and/or in the vasculature of the lungs. In one embodiment, the method comprises effective therapeutic delivery of active agents using a drug delivery system that allows very rapid absorption of the active agent from the lung into the circulation and that effectively increases its bioavailability. In this embodiment, lower doses of an active agent can be delivered by this method of administration. In similar embodiments, effective doses can be achieved when these were not feasible by other modes of administration.
    [0035] In embodiments of the present invention, a method for treating disease is described. The inventors have identified the need to deliver drugs directly to the systemic circulation, specifically, to the arterial circulation in a non-invasive manner so that the drug reaches the target organ(s) before returning through the venous system. This approach may paradoxically result in a higher peak target organ exposure to active agents than would result from comparable administration via intravenous, subcutaneous or other parenteral routes. A similar advantage can be obtained compared to oral administration, because even with formulations that offer protection against degradation in the digestive tract, upon absorption, the active agent also penetrates the venous circulation.
    [0036] In one embodiment, the drug delivery system can be used with any type of active agent that is rapidly metabolized and/or degraded by direct contact with local degrading enzymes or by other degradation mechanisms, e.g., oxidation, phosphorylation or any modification of molecules, including small molecules, proteins or peptides, in peripheral tissue or in the venous vascular found with other routes of administration such as oral, intravenous, transdermal and subcutaneous administration. In this embodiment, the method may comprise the step of identifying and selecting an active agent whose activity is metabolized or degraded by oral, subcutaneous or intravenous administration. Such a situation is in contrast to peptides, such as insulin, which can be released effectively by these modes of administration. In these embodiments, the method of administering a drug is advantageous, for example, for rapid initiation of treatment, as the drug can reach the target organ in a shorter time via the arterial circulation without the use of invasive therapy such as injectables.
    [0037] In certain embodiments, the method of treating a disease or disorder comprises the step of selecting a suitable vehicle for inhalation and delivering an active substance to the pulmonary alveoli. In this embodiment, the carrier can be combined with one or more active agents to form a drug/vehicle complex that can be administered as a composition that prevents rapid degradation of the active agent in peripheral tissue and venous vascular in the lung. In one embodiment, the carrier is a diketopiperazine.
    [0038] The described method of the present invention can be used to deliver many types of active agents, including small molecules and biological agents. In specific embodiments, the method utilizes a drug delivery system that effectively delivers a therapeutic amount of an active agent, including small molecules or peptide hormones, rapidly into the arterial circulation. In one embodiment, the single or more active agents include, but are not limited to, peptides, proteins, lipokines, small pharmaceutical molecules, nucleic acids, and the like, which are sensitive to degradation or deactivation; formulating the active agent into a dry powder composition comprising a diketopiperazine and releasing the active agent(s) into the systemic circulation by pulmonary inhalation using a cartridge and a dry powder inhaler. In one embodiment, the method comprises selecting a peptide that is sensitive to enzymes in the local vascular or peripheral tissue of, for example, the dermis or the lungs. The present method allows the active agent to avoid or reduce metabolism/degradation by contact with peripheral tissue, venous or liver. In another embodiment, for systemic delivery, the active agent must not have specific receptors in the lungs.
    [0039] In alternate modalities, the drug delivery system can also be used to deliver natural, recombinant, or synthetic therapeutic peptides or proteins to treat disorders or diseases, including but not limited to adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), parathyroid hormone, parathyroid hormone-related peptide (PTHrP), IGF-1, growth hormone releasing factor (GHRF), granulocyte macrophage colony stimulating factor (GM-CSF), anti-IL-8 antibodies, IL-8 antagonists including ABX-IL-8; integrin beta-4 (ITB4) precursor receptor antagonist, enkephalins, nociceptin, nocystatin, orphanin FQ2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, pancreatic polypeptide, neuropeptide Y, delta sleep-inducing peptide, prostaglandins including PG -12, LTB receptor blockers including LY29311, BIIL 284, CP105696; vasoactive intestinal peptide; triptans such as sumatriptan and lipokines such as C16:1n7 or palmitoleate or analogues thereof. In yet another embodiment, the active agent is a small molecule drug.
    [0040] In some embodiments, the dry powder formulation is a stable composition and may comprise microparticles that are suitable for inhalation and that rapidly dissolve in the lung and that rapidly release a drug, such as a serotonin receptor agonist, into the circulation. pulmonary. Suitable particle sizes for pulmonary administration may have a diameter of less than 10 µm, and preferably less than 5 µm. Exemplary particle sizes that can reach pulmonary alveoli range from approximately 0.5 μm to approximately 5.8 μm in diameter. Such sizes refer especially to the aerodynamic diameter, but often correspond to the actual physical diameter as well. Such particles can reach pulmonary capillaries and avoid intense contact with peripheral tissue in the lung. In this modality, the drug can be released into the arterial circulation quickly to avoid degradation of the active component by enzymes or other mechanisms before reaching its target or site of action in the body. In one embodiment, dry powder compositions for pulmonary inhalation, comprising a serotonin receptor modulator such as a serotonin receptor agonist and FDKP, may comprise microparticles, wherein from approximately 35% to approximately 75% of the microparticles have a smaller aerodynamic diameter. at 5.8 µm.
    [0041] The delivery methods presented in various modalities can provide a more direct path to the site of action of an active agent. Consequently, in addition to avoiding degradation, although in some situations it is still partly due to it, the biodistribution of the active agent may differ from that achieved with modes of release that involve absorption and travel through the venous circulation before they are reached. sites of action in the body. Therefore, venous blood samples collected to determine the concentration of active agent may underestimate the concentration of active agent at a site of action when modalities of the present invention are used while comparatively this is overestimated when other modes of administration are used. The more labile the active agent, the greater this effect. For active agents with multiple effects and sites of action, a different constellation of effects may be observed, as the relative concentrations at different sites of action will differ from those achieved using other modes of administration. This can further contribute to greater effective bioavailability, avoided unwanted effects, and the like.
    [0042] In one embodiment, the inhalation formulation comprises a dry powder formulation containing the serotonin receptor agonist with a diketopiperazine, including 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine; wherein X is selected from the group consisting of succinyl, glutaryl, maleyl and fumaryl, or a salt of diketopiperazine. In this embodiment, the inhalation formulation may comprise microparticles intended for inhalation containing the active ingredient having the aerodynamic characteristics as described above. In one embodiment, the amount of active ingredient can be determined by one skilled in the art, however, the microparticles of the present invention can be loaded with varying amounts of active ingredient as required by the patient. For example, for a serotonin receptor agonist, the microparticles may comprise from approximately 1% (w/w) to approximately 75% (w/w) of the active component in the formulation. In certain embodiments, formulations for inhalation may comprise from approximately 10% (w/w) to approximately 30% (w/w) of the pharmaceutical composition and may also comprise a pharmaceutically acceptable carrier or excipient, such as a surfactant, for example, polysorbate 80. In this embodiment, a serotonin receptor agonist can be administered to the patient from one to approximately four times daily or as needed by the patient at doses ranging from approximately 0.05 mg to approximately 5 mg in the formulation.
    [0043] In one embodiment, the formulation comprising the active ingredient may be administered to the patient in a dry powder inhalation formulation using a dry powder inhaler such as the inhaler described, for example, in US Patent No. 7,305,986 and US Patent Application Serial No. 10/655,153 (US 2004/0182387), the contents of which are incorporated herein by reference into this patent application. Repeated inhalation of dry powder formulations comprising the active ingredient can also be administered as needed. In some embodiments, the formulation may be administered once, twice, three or four times daily.
    [0044] In yet another further embodiment, the method for a migraine comprises administering a dry powder composition for inhalation which comprises a diketopiperazine of the formula 2,5-diketo-3,6-di(4-X). -aminobutyl) piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl and fumaryl. In this embodiment, the dry powder composition may comprise a diketopiperazine salt. In yet another embodiment, a dry powder composition is provided, wherein the diketopiperazine is 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier or excipient.
    [0045] In another exemplary embodiment, a method is described for treating migraines using a therapeutically effective pharmaceutical composition comprising a powder for pulmonary delivery, wherein the powder includes microparticles of a diketopiperazine and an active agent, such as a receptor agonist of serotonin to treat migraines. In this embodiment, the pharmaceutical composition comprises, for example, a diketopiperazine, including FDKP, or a salt of FDKP, for example, a divalent salt of FDKP, among these disodium FDKPs, and a small molecule, including a vasoconstrictor as the active agent. Examples of vasoconstrictors include serotonin receptor agonists, among these triptans such as sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan and pharmaceutically acceptable salts thereof, including sumatriptan succinate, rizatriptan benzoate, almotriptan malate. In one embodiment, the vasoconstrictor, e.g., a triptan, may be given to a patient in need of treatment in amounts ranging from at least approximately 0.1 mg, at least approximately 1 mg, at least approximately 5 mg, approximately 50 mg. or less, approximately 40 mg or less, from approximately 1 mg to approximately 50 mg, from approximately 5 mg to approximately 30 mg, from approximately 10 mg to approximately 20 mg, approximately 1 mg, approximately 10 mg, approximately 20 mg or any amount in a range bounded by or between any of these values. A pharmaceutical composition comprising a triptan can be provided regularly, including daily, twice a day, three times a day, etc., and/or can be provided as needed at the onset of migraine symptoms. In one embodiment, the triptan may be administered to the patient by inhalation. In a specific embodiment, triptan is given to a patient by oral inhalation for release into the arterial circulation in the lungs.
    [0046] In an exemplary embodiment, the drug formulation may comprise an aliphatic amino acid, for example, alanine, glycine, leucine, isoleucine, norleucine and serine. In certain embodiments, the aliphatic amino acid is present from approximately 0.5% to approximately 30% by weight of the composition. In a specific embodiment, the pharmaceutical composition comprises L-leucine. In one embodiment, the pharmaceutical composition comprises a dry powder for oral inhalation, including a disodium salt of FDKP, sumatriptan and L-leucine. Examples
    [0047] The following examples are included to demonstrate certain modalities. It should be recognized by those skilled in the art that the techniques described in the examples elucidate representative techniques that operate well in the practice of the present invention. However, those skilled in the art, in light of the present invention, will recognize that many changes can be made to specific embodiments and still obtain similar or similar results without departing from the spirit and scope of the invention.Example 1 Preparation and characterization of powder dried sumatriptan-fumaryl disodium diketopiperazine (Sumatriptan-Na2FDKP)
    [0048] Sumatriptan-Na2FDKP powder was prepared from commercially available sumatriptan succinate tablets. Sumatriptan succinate (Imitrex®, GlaxoSmithKline) was extracted from crushed tablets suspended in HPLC grade water to form a solution. The solution was then filtered through nylon syringe filters with 0.45 µm pores to remove undissolved excipients, and the filtrate was run through a column for quaternary amine ion exchange extraction to eliminate the succinate group. Sumatriptan in solution at a concentration greater than 10 mg/mL was then combined with a solution of Na2FDKP at a concentration greater than approximately 10 mg/mL in solution. Na2FDKP was prepared in advance or prepared from the free acid FDKP by dissolving it with two equivalents of sodium hydroxide. In some experiments, the concentration ratio of the starting sumatriptan solution to FDKP was greater than 1. The solution was spray dried (Büchi Mini Spray Dryer, Model B-290) at an inlet temperature of approximately 145°C at approximately 200°C and an outlet temperature of approximately 75°C to approximately 85°C. The drying gas was defined nitrogen at a flow rate of approximately 670 L/h. A dry powder was obtained.
    [0049] In order to certify the amount of sumatriptan in the powder, a sample of the powder was dissolved in a solution for HPLC and analyzed for content using a high pressure liquid chromatography (HPLC) system. The HPLC method quantifies sumatriptan in the presence of FDKP. Figure 1 depicts an HPLC chromatogram of a solution of the dissolved powder, which shows that the two compounds can be easily separated and identified. The powders were also tested by thermal analysis (TGA and DSC) and cascade impaction. Table 1 presents representative data of characteristics of Sumatriptan-Na2FDKP powder by this method, where the concentration ratio of sumatriptan succinate to FDKP in solution was approximately 1.5.
    *Sumatriptan target level = 40%
    [0050] The sumatriptan-Na2FDKP powders prepared by the present method contained up to approximately 40% sumatriptan by weight. The water content determined by loss on desiccation (LOD) was approximately 3.4%. The percent respirable fraction per fill was approximately 18%, and the amount of powder released or emitted from the inhaler (cartridge empty, EC) was approximately 68% using a breath-actuated inhaler as described in US Patent Application No. No. 12/473,125 (US 2009/0308390), the contents of which are incorporated herein in their entirety by reference to this patent application. Table 2 illustrates the characterization of dry bulk powder. Table 2

    *Sumatriptan target level = 40%Example 2Sumatriptan dry powder-Na2FDKP- Pharmacokinetic (PK) and pharmacodynamic (PD) studies in rats
    [0051] Powder Preparation and Characterization: Sumatriptan-Na2FDKP powder was prepared as described in Example 1 above, except that sumatriptan succinate was purchased from LGM Pharma (Boca Raton, FL) and L-leucine was added to study whether the aerodynamic performance of the resulting spray dried powder formed would be improved. Three feed solutions were prepared with a total solids concentration of 4.5% for a 5 g scale. Feed solutions were prepared by adding FDKP disodium salt, sumatriptan succinate and L-leucine (0 - 20% by weight) to deionized water with stirring. The solutions were adjusted with dilute aqueous ammonia to pH 6.00. The resulting clear feed solutions were vacuum filtered through a 0.2 μm pore PES filter membrane and spray dried as described in Example 9, however, the gas flow for drying was set at 25 kg/h, the atomization flow was approximately 4 kg/h and the atomization pressure was set to 40000 Pa. The sumatriptan succinate concentration (on a dry basis) in each solution was 56% to obtain a planned 40% sumatriptan charge. Powders were analyzed by HPLC, cascade impaction, Karl Fischer titration, scanning electron microscopy (SEM) and packed and bulk density. The results of these studies are shown in Table 2 and Figure 2.

    [0052] The data in Table 2 illustrate that the target and measured for sumatriptan content of bulk sumatriptan-Na2FDKP powders are comparable. Aerodynamic performance improved with the addition of leucine. The leucine-free powder showed FR%/fill of 9.8% with 58.8% EC, the addition of 10% leucine increased the FR%/fill to 61.3% with 93.3% EC, and the addition 20% leucine increased the RF/fill to 63.3% with 88.2% EC. The sumatriptan-Na2FDKP powders containing leucine had higher residual water content than the powder without leucine. The addition of leucine also reduced the bulk density of the powder by approximately 30%.
    [0053] Figure 2 is a scanning electron micrograph of the three powders that are characterized in Table 2. As shown in panels A - F, each powder showed distinct morphology. The leucine-free particles were non-uniformly shaped fused fragments (Panel A and B). The particles with 10% leucine (Panel C and D) were substantially spherical with smooth surfaces, and the particles prepared with 20% leucine (Panel E and F) show a raisin-like or wrinkled morphology typical of insulin salt powders. -FDKP.
    [0054] Stability of sumatriptan-Na2FDKP powders: The powders were also tested to determine their degree of stability. Powder samples were incubated for a period of three months in an open dish exposed to 25°C/60% relative humidity (RH) and 40°C/70% RH. The powder samples were analyzed by the HPLC method after 1, 2 and 3 months from the beginning of the experiments. The results are shown in Tables 3 and 4 below.


    [0055] The data show that there was no degradation of sumatriptan in the composition even after three months of exposure at 25°C/60% RH with or without L-leucine. At the higher temperature, 40°C/70% RH, however, a slight but insignificant decrease in sumatriptan content is observed after 1 and 2 weeks of incubation when compared to samples containing L-leucine.
    [0056] Rat inhalation studies using sumatriptan-Na2FDKP powders: In these experiments, powders were used that were prepared as described above. The PK profile of sumatriptan administered as sumatriptan powder-Na2FDKP (37.4% sumatriptan by weight) by lung insufflation was evaluated and compared to sumatriptan nasal spray administered by lung instillation or sumatriptan administered by intravenous injection or subcutaneous injection in females. of rat Sprague Dawley (n=6/group) (Table 5).
    * average dose reached
    [0057] Blood samples for analysis of sumatriptan were collected before administration and after 2, 5, 10, 15, 30, 60, 90, 120 and 240 minutes of administration. The animals were divided into two subgroups (n = 3/moment) for blood collection. Serum sumatriptan was analyzed using an established LCMS assay. The peak concentration and bioavailability of sumatriptan insufflated into sumatriptan-Na2FDKP powder were higher than sumatriptan administered by liquid instillation (nasal spray formulation) and comparable to sumatriptan administered by subcutaneous injection (Figure 3). Figure 3 shows that the time to peak concentration was 5 minutes in the insufflation group compared to 15 minutes in the pulmonary fluid instillation group. Overall, dose-normalized exposure was similar for lung insufflation of sumatriptan and lung fluid instillation, but the PK profiles are quite different. Sumatriptan was well tolerated in all treatment groups. Pharmacokinetic parameters were calculated using non-compartmental methods and the non-linear regression program WinNonlin v5.2 (Table 5) based on the mean concentration curve (n = 3/moment/formulation) after correction for the actual dose administered. . Table 6 summarizes representative pharmacokinetic data in female Sprague Dawley rats.
    *IV = Intravenous injection; SC = subcutaneous injection; LIS = pulmonary fluid instillation; INS = lung inflation
    [0058] It is evident that the bioavailability of sumatriptan administered as sumatriptan powder-Na2FDKP powder by lung insufflation was comparable to that of sumatriptan nasal spray administered by liquid instillation, but its PK profile (tmax, Cmax) resembled that of SC injection. Example 3Sumatriptan-Na2FDKP dry powder- PK and PD studies in Beagle dogs
    [0059] Pharmacodynamic Study: The pharmacodynamic and pharmacokinetic profiles of sumatriptan were evaluated in a recognized model of migraine in anesthetized dogs. The pathogenesis of migraine is primarily due to an accentuated and prolonged period of vasodilation of cranial vessels. A migraine model was induced by a single intra-arterial injection of capsaicin which produces carotid vasodilation. Animals received air as a control (n = 2), sumatriptan by intranasal instillation using a microatomizer (0.28 mg/kg; n = 3), sumatriptan-Na2FDKP dry powder by lung insufflation (sumatriptan 0.28 mg/kg; n = 3) or sumatriptan by intravenous bolus injection into a peripheral vessel (0.03 mg/kg; n = 2). Heart rate, mean systolic and diastolic blood pressures, and carotid blood flow and diameter (mean, maximum and minimum flow) were continuously monitored and recorded. Data were collected on an ongoing basis and reported at 1-minute averages at specific times after sumatriptan administration. The study summary is presented in Table 7 and the results are shown in Figure 5.
    The. Animals were anesthetized during all administration procedures.b. Administration of the appropriate test item started 5 minutes after model induction.c. Commercially available product (Imitrex®).d. Equivalent to 0.75 mg/kg powder dose based on 38% active ingredient powder sumatriptan-Na2FDKP content.
    [0060] Blood samples from dogs for analysis of sumatriptan were collected before administration and after 2, 5, 10, 15, 30, 60, 90, 120 and 240 minutes of administration. Serum sumatriptan was analyzed using an established LCMS assay.
    [0061] Based on the PK data, one animal in the sumatriptan-Na2FDKP powder treated group appeared not to have received the test item, presumably due to technical difficulties. This animal showed surprisingly marked vasoconstriction, which was suspicious. Another animal in this group showed little vasoconstriction and high levels of sumatriptan exposure. It was assumed that the tubes for the blood samples from these two animals were inadvertently switched during collection. Therefore, the data presented with these samples were evaluated with (n = 3) and without (n = 2) the animal with the wrong dose. The two data sets suggest similar results.
    [0062] Blood pressure and heart rate were not altered by the administration of sumatriptan or the control item, regardless of the route of administration. Systemic sumatriptan exposure was associated with reductions in vasodilation. All groups, including the control, showed a reduction in carotid artery diameters from the end of capsaicin administration to 3 hours after administration. Insufflation of sumatriptan-Na2FDKP powder resulted in more pronounced constriction of the carotid artery than the intranasal and intravenous routes of administration. The magnitude of vasoconstriction varied significantly between dose groups, so data were analyzed in terms of vessel diameter versus baseline diameter, or change in vessel diameter from the end of capsaicin administration or from the period basal.
    [0063] The pharmacokinetic profiles of sumatriptan administered as sumatriptan-Na2FDKP dry powder, nasal spray or intravenous injection (Figure 4) were consistent with the previous PK study in rats. Figure 4 depicts the pharmacokinetic profile of sumatriptan salt-FDKP powder (38% sumatriptan) administered by lung insufflation, sumatriptan administered by nasal instillation and intravenous injection in female dogs, where data are plotted in ± SD. The data show that the time to maximum mean peak of circulating sumatriptan concentrations (Tmax) was 5 minutes for sumatriptan-FDKP salt powder and 60 minutes for nasal instillation. Although Cmax and bioavailability were much lower for sumatriptan-Na2FDKP dry powder, animals insufflated with sumatriptan-Na2FDKP exhibited a similar but faster pharmacodynamic response than those given the nasal spray.
    [0064] Figure 5 shows the results of these experiments. The data indicate that the reduction in vessel diameter from the end of capsaicin administration to the end of the experiment was greater in the group treated with sumatriptan-Na2FDKP powder. Variability in initial vasodilation between groups complicates the analysis, but Group 2 (nasal spray) and Group 3 (sumatriptan dry powder-Na2FDKP) responded in a comparable way to capsaicin. The group treated with sumatriptan-Na2FDKP dry powder showed greater final constriction in blood vessels and, moreover, the effect had a faster onset of action.
    [0065] While the invention has been specially shown and described with reference to specific embodiments, it will be recognized that variations of the features and functions described above and others, or alternatives thereto, can be conveniently combined in many other different systems or applications. Additionally, it is recognized that various alternatives, modifications, variations or improvements thereto not foreseen or anticipated herein may subsequently be made by those skilled in the art, which are also intended to be encompassed by the following claims.
    [0066] Unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as molecular weight, reaction conditions and so on in the specification and claims shall be understood to be modified in all situations by the term " about". Thus, unless otherwise indicated, the numerical parameters presented in the specification and in the appended claims are approximations that may vary depending on the desired properties that are sought to be achieved by the present invention. At the very least, and not in an attempt to restrict the application of the doctrine of equivalence to the scope of the claims, every numerical parameter must be interpreted in light of the number of significant figures and by the application of common rounding techniques. While the numerical ranges and parameters that define the broad scope of the invention are approximations, the numerical values shown in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors that necessarily result from the standard deviation found in their respective test measurements.
    [0067] The terms "a", "an", "the" and "a" and similar referents used in the context in which the invention is described (especially in the context of the claims below) shall be interpreted to encompass the singular and the plural, unless otherwise indicated in this patent application or clearly contraindicated by the context. The enumeration of ranges of values in this patent application is merely intended to serve as an abbreviated method of referring individually to each separate value that falls within the range. Unless otherwise indicated in this patent application, each individual value is incorporated into the specification as if it were individually set forth herein. All methods described in this patent application may be performed in any suitable order, unless otherwise indicated herein in this patent application or clearly contraindicated by the context. The use of any and all examples, or exemplary language (eg, "as") provided in this patent application is merely intended to further clarify the invention and does not impose a limitation on the scope of the invention otherwise claimed. No language in the specification should be interpreted as indicating any unclaimed element essential to the practice of the invention.
    [0068] The groupings of elements or alternative modalities described here should not be interpreted as limitations. Each group member may be referenced and claimed individually or in any combination with other group members or other elements present in this patent application. It is envisaged that one or more members of a group may be included or excluded from a group for reasons of convenience and/or patentability. When any such inclusion or exclusion occurs, the specification is deemed to contain the group as modified, thus satisfying the written description of all Markush groups used in the appended claims.
    [0069] Certain embodiments of this invention are described in this patent application, including the best way known to the inventors to develop the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the preceding description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors' intention is that the invention be practiced otherwise than as specifically described in this patent application. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended thereto, as permitted by applicable law. Furthermore, any combination of the elements described above in all their possible variations is encompassed by the invention unless otherwise indicated in this patent application or clearly contraindicated to the contrary by the context.
    [0070] Additionally, numerous references have been made to patents and printed publications throughout this descriptive report. Each of the references and printed publications cited above is individually incorporated herein, in its entirety, by reference in this patent application.
    [0071] Finally, it should be understood that the modalities described in this patent application are illustrative of the principles of the present invention. Other modifications that may be employed are included within the scope of the invention. By way of example, but not limitation, therefore, alternative embodiments of the present invention may be used in accordance with the teachings in this patent application. Consequently, the present invention is not restricted to what has been precisely shown and described.
    权利要求:
    Claims (28)
    [0001]
    1. Pharmaceutical composition CHARACTERIZED in that it comprises an effective amount of: a serotonin receptor agonist comprising at least one of sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan and pharmaceutically acceptable salts thereof, an aliphatic amino acid comprising at least one of alanine, glycine, leucine, isoleucine, norleucine and serine, and a diketopiperazine or a salt thereof, wherein the diketopiperazine is 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine; wherein X is selected from the group consisting of succinyl, glutaryl, maleyl and fumaryl; or a pharmaceutically acceptable salt thereof.
    [0002]
    2. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that it is a dry powder.
    [0003]
    3. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that triptan is sumatriptan succinate.
    [0004]
    4. Pharmaceutical composition, according to claim 1, CHARACTERIZED by the fact that triptan is rizatriptan benzoate.
    [0005]
    5. Pharmaceutical composition, according to any one of claims 1 to 4, CHARACTERIZED in that it comprises 3,6-bis-[(N- fumaryl-4-aminobutyl)]-2,5-diketopiperazine or a salt thereof, and sumatriptan or rizatriptan.
    [0006]
    6. Pharmaceutical composition, according to any one of claims 1 to 5, CHARACTERIZED in that it comprises 3,6-bis-[(N- fumaryl-4-aminobutyl)]-2,5-diketopiperazine and sumatriptan in the form of dry powder.
    [0007]
    7. Pharmaceutical composition, according to claim 1, 5 or 6, CHARACTERIZED by the fact that sumatriptan is more than 1 mg in the composition.
    [0008]
    8. Pharmaceutical composition, according to claim 1, CHARACTERIZED in that the aliphatic amino acid is from about 0.5% to about 30% by weight of the composition.
    [0009]
    9. Pharmaceutical composition, according to any one of claims 1 to 8, CHARACTERIZED in that the composition further comprises L-leucine.
    [0010]
    10. Pharmaceutical composition, according to any one of claims 1 to 9, CHARACTERIZED by the fact that diketopiperazine is 3,6-bis-[(N-fumaryl-4-aminobutyl)]-2,5-diketopiperazine or a salt of the same.
    [0011]
    11. Pharmaceutical composition, according to claim 10, CHARACTERIZED by the fact that the diketopiperazine salt is 3,6-bis-[(N-fumaryl-4-aminobutyl)]-2,5-diketopiperazine disodium salt.
    [0012]
    12. Pharmaceutical composition, according to any one of claims 1 to 11, CHARACTERIZED in that it further comprises a pharmaceutically acceptable carrier or excipient.
    [0013]
    13. Pharmaceutical composition, according to any one of claims 1 to 12, CHARACTERIZED in that the pharmaceutical composition is produced as a unit dose for oral inhalation.
    [0014]
    A pharmaceutical composition according to any one of claims 1 to 13, CHARACTERIZED in that it is formulated for administration to a mammal for the treatment of symptoms associated with migraine.
    [0015]
    15. Pharmaceutical composition, according to claim 14, CHARACTERIZED by the fact that the pharmaceutical composition is formulated to be administered by inhalation.
    [0016]
    A pharmaceutical composition according to claim 15, CHARACTERIZED in that the pharmaceutical composition is formulated to be administered to said patient by pulmonary inhalation using a breath-actuated dry powder inhalation system.
    [0017]
    17. Pharmaceutical composition, according to claim 16, CHARACTERIZED in that the breath-actuated dry powder inhalation system comprises a cartridge containing said pharmaceutical composition.
    [0018]
    18. Pharmaceutical composition, according to any one of claims 14 to 17, CHARACTERIZED in that the serotonin receptor agonist is intended for the treatment of moderate to severe headache associated with migraine.
    [0019]
    19. A pharmaceutical composition for administration to a mammal for the treatment of symptoms associated with migraine CHARACTERIZED in that it comprises: a dry powder composition comprising 3,6-bis-[(N-fumaryl-4-aminobutyl)]-2, 5-diketopiperazine, L-leucine and a triptan, said triptan comprising at least one of sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan and pharmaceutically acceptable salts thereof, wherein a therapeutically effective amount of said powder composition Dry is formulated to be administered to said patient by oral inhalation.
    [0020]
    20. Pharmaceutical composition, according to any one of claims 1 to 19, CHARACTERIZED by the fact that diketopiperazine is in a salt form.
    [0021]
    21. Pharmaceutical composition, according to any one of claims 1 to 19, CHARACTERIZED by the fact that diketopiperazine is in a non-salt form.
    [0022]
    22. Use of a pharmaceutical composition, as defined in claim 19, CHARACTERIZED in that it is in the manufacture of a medicament for the treatment of symptoms associated with migraine.
    [0023]
    23. Use, according to claim 22, CHARACTERIZED by the fact that the pharmaceutical composition is formulated to be administered by inhalation.
    [0024]
    24. Use according to claim 23, CHARACTERIZED in that the pharmaceutical composition is formulated to be administered to said patient by pulmonary inhalation using a breath-actuated dry powder inhalation system.
    [0025]
    25. Use according to claim 24, CHARACTERIZED by the fact that the breath-actuated dry powder inhalation system comprises a cartridge containing said pharmaceutical composition.
    [0026]
    26. Use according to any one of claims 22 to 25, CHARACTERIZED by the fact that triptan is intended for the treatment of moderate to severe headache associated with migraine.
    [0027]
    27. Use according to any one of claims 22 to 26, CHARACTERIZED by the fact that diketopiperazine is in a salt form.
    [0028]
    28. Use according to any one of claims 22 to 26, CHARACTERIZED by the fact that diketopiperazine is in a non-salt form.
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    同族专利:
    公开号 | 公开日
    JP6458064B2|2019-01-23|
    JP6092113B2|2017-03-08|
    BR112013011549A2|2017-07-25|
    JP2013545748A|2013-12-26|
    CA2817337C|2020-04-14|
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    KR20140008314A|2014-01-21|
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    ES2732818T3|2019-11-26|
    AU2011326529B2|2015-07-30|
    EP3536368A1|2019-09-11|
    MX340112B|2016-06-27|
    EP2637657B1|2019-05-22|
    CN103200940A|2013-07-10|
    KR101931392B1|2018-12-20|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-05-21| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2021-07-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2021-08-17| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-12-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2022-01-04| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/11/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    US41177510P| true| 2010-11-09|2010-11-09|
    US61/411.775|2010-11-09|
    US41233910P| true| 2010-11-10|2010-11-10|
    US61/412.339|2010-11-10|
    PCT/US2011/060057|WO2012064892A1|2010-11-09|2011-11-09|Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines|
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