HK40083616A - Oral fast-dispersing dosage form of rimegepant - Google Patents
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Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. provisional application No. 62/982,456, filed 2/27/2020, and the contents of which are incorporated herein by reference in their entirety for all benefit accrued therefrom in accordance with 35u.s.c. § 119.
Technical Field
The present invention relates to pharmaceutical compositions of 5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl (rimegepant), a calcitonin gene-related peptide (CGRP) receptor antagonist, of (5S, 6S, 9R) -4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) -1-piperidinecarboxylic acid.
Background
Migraine is a chronic and debilitating condition characterized by recurrent attacks lasting from four to 72 hours with a variety of symptoms, usually unilateral throbbing headaches of moderate to severe pain intensity, with nausea or vomiting and/or sensitivity to sound (phonophobia) and light (photophobia). Migraine headache often precedes a transient neurological warning symptom, called aura, which typically involves visual disturbances such as flashing lights, but may also involve numbness or tingling in various parts of the body. Migraine is widespread and disabling. Migraine research foundation will list migraine as the third most prevalent disease in the world, and 2015 global disease burden research will list migraine as the seventh most specific cause of disability worldwide. According to data from the migraine research foundation, approximately 3600 million people in the united states have migraine attacks. While most patients experience one or two migraine attacks per month, over 400 million people suffer from chronic migraine, which is defined as experiencing headache for at least 15 days per month, with migraine for at least eight days and lasting for more than three months. Others suffer from sporadic migraine, which is characterized by migraine headaches that occur for less than 15 days per month. People with sporadic migraine can develop chronic migraine over time. Migraine attacks can last for four hours or up to three days. Over 90% of patients with migraine attacks fail to work or function properly during the migraine attack, with many people experiencing complications such as depression, anxiety, and insomnia. In addition, patients with migraine headache are often accompanied by nausea and aversion to food or liquids during an attack.
CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide belonging to a family of peptides comprising calcitonin, adrenomedullin and amylin. In humans, two forms of CGRP (α -CGRP and 13-CGRP) exist, and these two forms of CGRP have similar activities. They differ by three amino acids and show different distributions. At least two CGRP receptor subtypes may also account for different activities. CGRP receptors are located in pain signaling pathways, intracranial arteries, and mast cells, and their activation is thought to play a causal role in migraine pathophysiology. For example, research and clinical studies have shown that: serum levels of CGRP are elevated during migraine attacks, intravenous infusion of CGRP produces persistent pain in migraine and non-migraine patients, and treatment with anti-migraine drugs normalizes CGRP activity.
CGRP may be associated with migraine headache has been the basis for the development and clinical testing of a number of compounds including, for example, oxsegepan (olcegel < (r) > inc (Boehringer Ingelheim, ridgefield, CT)), tegam (telcagant) (Merck Sharp corporation of kenifelder, NJ (Merck Sharp & Dohme corp, kenilworth, NJ)), ubbrevipan (uble corporation of albergan, dullin, ireland), remaipam (Biohaven Pharmaceutical biology corporation of New blackland, connecticut Company, ltd., new Haven, CT)), galingalizumab (galbanezumab) (lei Lilly and Company, indianapolis, IN), remainbizumab (fremenezumab) (Teva Pharmaceutical Company of setupitake WA (Teva Pharmaceutical Industries, pentah Tikva, israel)), epratuzumab (epinezumab) (Alder biopharmaceutical, inc., botallel, WA), and renuzumab (erenuab) (Amgen inc., thousagabon, CA)). Another compound recently investigated for the treatment of migraine is lamidottan (lasmiditan) (the li-lai company of indianapolis, indiana).
Currently, clinicians use a variety of agents for acute treatment of migraine. A study published by the american headache association in 2015 concluded that drugs considered effective for acute treatment of migraine fall into the following categories: triptans, ergotamine derivatives, non-steroidal anti-inflammatory drugs ("NSAIDs"), opioids, and combinations. The current standard of care for acute treatment of migraine is serotonin 5-HT 1B/1D The prescription of receptor agonist triptans. Over the last two decades triptans have been developed and approved for acute treatment of migraine. The initial introduction of triptans represents a drug shift towards more selective targeting of the suspected pathophysiology of migraine. Although triptans account for nearly 80% of the anti-migraine therapies prescribed by healthcare providers at the clinic visit, problems such as incomplete effects or headache recurrence remain important clinical limitations. In fact, only about 30% of clinical trial patients had no pain two hours after taking triptan drugs. In addition, triptans are contraindicated in patients with cardiovascular disease, cerebrovascular disease, or significant risk factors because of 5-HT 1B The mediated effect may lead to systemic and cerebrovascular vasoconstriction. Furthermore, according to a study disclosed in journal of headache, 1 month 2017, the united states estimates that 260 million migraine sufferers are accompanied by cardiovascular events, conditions or procedures that limit the potential of triptans as treatment options.
Thus, there remains a significant unmet medical need for migraine treatments that can provide enhanced patient benefit compared to existing therapies. In addition, antagonists of CGRP receptors may be useful drugs for conditions involving other CGRP disorders. Such conditions may include, in addition to migraine, cluster headaches (Doods (2001) recent opinion on study drugs (curr. Opin. Invest. Drugs) 2, 1261-1268, edvinsson et al (1994) headache (Cephalalgia) 14, 320-327; chronic tension-type headache (Ashina et al (2000) Neurology 14, 1335-1340); pain (Yu et al (1998) J. Eur. Pharmacol.) 347, 275-282); chronic Pain (Hulsebosch et al (2000) Pain (Pain) 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer (1988) Neuroscience 24, 739-768, delay-Goyet et al (1992) Scandi Nature Neuroscience 4, 357-358, salmon et al (2001) Nature Neuroscience); eye pain (May et al (2002) headache 22, 195-196); toothache (Awawdeh et al (2002) in Int. Endocrin. J35, 30-36); non-insulin dependent Diabetes mellitus (Molina et al (1990) Diabetes mellitus (Diabetes) 39, 260-265); vascular disorders; inflammation (Zhang et al (2001) pain 89, 265); arthritis, bronchial hyperreactivity, asthma (Foster et al (1992), ann.NY Acad.Sci.) -657, 397-404 Schini et al (1994), journal of physiology in USA (am.J. Physiol.) -267, H2483-H2490; zheng et al (1993) journal of virology (J Viral.) -67, 5786-5791); shock, sepsis (Beer et al (2002) critical care medicine (crit. Care med.) 30, 1794-1798); opioid withdrawal syndrome (Salmonon et al (2001) Nature neuroscience 4, 357-358); morphine tolerance (Menard et al (1996) (J Neurosci., J.) 16, 2342-2351); hot flashes in men and women (Chen et al (1993) Lancet (Lancet) 342, 49, sttz et al (2001) journal of Urology (J Urology) 166, 1720-1723); allergic Dermatitis (Wallengren (2000) Contact Dermatitis (Contact Dermatitis) 43, 137-143); psoriasis; encephalitis, brain trauma, ischemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenebeck et al (1999) neurobiology of the disease (Neuroobiol. Dis.) 6, 15-34); skin diseases (edited by Geppetti and Holzer, neurogenic Inflammation, 1996, CRC Press, bocaRaton, FL, pokaladutana); neurogenic skin redness, skin roses and erythema; tinnitus (189, 225; obesity (Walker et al (2010) Endocrinology (151, 4257-4269)), inflammatory bowel disease, irritable bowel syndrome (Hoffman et al (2002) Scandinavian gastroenterology (Scand. J gastroenterol.) -37, 414-422), and cystitis (Herzog et al (2002) J Membrane biol.) -189, 225; obesity (Walker et al (2010) Endocrinology (151, 4257-4269)).
Disclosure of Invention
The present invention relates to the treatment of CGRP related conditions, e.g., migraine, by orally administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of remegazepam, or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutical composition may be a fast-dispersing pharmaceutical composition.
In one embodiment, administration of the pharmaceutical composition can achieve elimination of migraine pain within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition achieves elimination of migraine pain in at least 21.2% of patients within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may achieve the most annoying disappearance of symptoms within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may achieve the most annoying disappearance of symptoms in at least 35.1% of the patients within 2 hours of the time of administration.
In an embodiment, the most annoying symptom may be photophobia, nausea, phonophobia, or a combination thereof.
In one embodiment, administration of the pharmaceutical composition can achieve pain relief within 90 minutes of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve pain relief within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve pain relief in at least 59.3% of patients within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve sustained pain relief within 2 to 48 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve sustained pain relief in at least 42.2% of patients within 2 to 48 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve a sustained disappearance of pain within 2 to 48 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition can achieve a sustained pain relief in at least 13.5% of patients within 2 to 24 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may achieve a reduction in the use of the remedial drug within 24 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may result in up to 14.2% of patients using the remedial drug within 24 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may achieve normal function within 2 hours of the time of administration.
In one embodiment, administration of the pharmaceutical composition may report normal function to at least 38.1% of patients within 2 hours of the time of administration.
In one embodiment, the daily dose of remergipam may be about 75mg.
In one embodiment, the pharmaceutical composition may be administered to the patient up to 15 times within a 30 day period.
In one embodiment, the pharmaceutically acceptable salt or rimazepam may be rimazepam hemisulfate. The daily dose of reamegypam hemisulfate may be about 85.65mg.
In one embodiment, the pharmaceutical composition may further comprise benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, vanillin, or a combination thereof.
In one embodiment, 1.3% or less of patients receiving the pharmaceutical composition may experience nausea.
In one embodiment, 0.15% or less of patients receiving the pharmaceutical composition may experience hypersensitivity reactions.
In one embodiment, the hypersensitivity reaction may comprise dyspnea, rash, or a combination thereof.
Drawings
These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
figure 1 is a graph of the percentage of pain relief achieved versus time in hours (in hours) from dosing, which shows the percentage of patients in study 1 who achieved pain relief within 2 hours; and
figure 2 is a graph of the percentage of disappearance of the most annoying syndromes (MBS) achieved versus time in hours from dosing, demonstrating the additional migraine efficacy endpoints in study 1.
Detailed Description
The following detailed description is provided to assist those skilled in the art in practicing the invention. Modifications and variations of the embodiments described herein may be made by those of ordinary skill in the art without departing from the spirit or scope of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description presented herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
As used in this application, each of the following terms shall have the meaning set forth below, unless the context clearly dictates otherwise. Other definitions are set forth throughout the application. To the extent that a term is not specifically defined herein, the term is given the art-recognized meaning that one of ordinary skill in the art would apply the term in its context to describing its use in the invention.
The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.
The term "about" refers to a value or composition that is within an acceptable error range for the particular value or composition, as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or greater than 1 standard deviation, according to practice in the art. Alternatively, "about" may mean a range of up to 1%, 5%, 10%, or 20% (i.e., ± 10% or ± 20%), depending on the context of the application. For example, about 3mg may comprise any number between 2.7mg and 3.3mg (for 10%) or between 2.4mg and 3.6mg (for 20%). Furthermore, particularly for biological systems or processes, these terms may refer to values of at most an order of magnitude or at most 5-fold. When a particular value or composition is provided in the application and claims, unless otherwise stated the meaning of "about" should be assumed to be within an acceptable error range for that particular value or composition.
The term "administering" refers to physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration may also be, for example, performed once, multiple times, and/or over one or more extended periods of time, and may be a therapeutically effective dose or a sub-therapeutic dose.
The term "AUC" (area under the curve) refers to the total amount of drug absorbed or exposed to a subject. Generally, AUC can be mathematically obtained from a plot of drug concentration over time in a subject until the concentration is negligible. The term "AUC" may also refer to a partial AUC for a particular time interval.
The term "C max "refers to the maximum concentration of a drug in the subject's blood, serum, a particular compartment, or test area between administration of a first dose and administration of a second dose. If specified, the term C max It may also refer to dose normalized ratios.
The terms "in combination with" and "in combination with" mean that one treatment modality is administered in addition to another treatment modality. Thus, "in combination with" or "in conjunction with" refers to the administration of one treatment modality before, during, or after the administration of the other treatment modality to the subject.
The term "pharmaceutically acceptable salt" refers to a salt form of one or more of the compounds described herein that is typically present to increase the solubility of the compound in the gastric juices or gastrointestinal fluids of the gastrointestinal tract of a patient to facilitate dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, if applicable. Suitable salts include, for example, those derived from the alkali metals (e.g., potassium and sodium), alkaline earth metals (e.g., calcium, magnesium, and ammonium salts) of many other acids and bases well known in the pharmaceutical arts.
The terms "subject" and "patient" refer to any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.
The terms "effective amount", "therapeutically effective dose" and "therapeutically effective dose" of an agent (sometimes also referred to herein as a "drug") refer to any amount of an agent that, when used alone or in combination with another agent, protects a subject from the onset of a disease or promotes disease regression, as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of injury or disability arising from the affliction of the disease. A therapeutically effective amount of an agent can be assessed using a variety of methods known to those skilled in the art, such as in a human subject during clinical trials, in an animal model system that predicts human efficacy, or by assaying the activity of the agent in an in vitro assay.
The term "T max By "is meant that the maximum concentration (C) is reached in the subject's blood, serum, a particular compartment or test area following administration of the drug max ) Time of day or time period.
The term "treatment" refers to any treatment of a condition or disease in a subject, and may include: (i) Preventing a disease or condition in a subject who may be predisposed to the disease or condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; ameliorating the disease or condition, i.e., causing regression of the condition; or (iii) ameliorating or alleviating the condition caused by the disease, i.e., the symptoms of the disease. Treatment may be used in combination with other standard therapies or alone. Treatment or "therapy" of a subject also includes any type of intervention or process performed on the subject or administration of an agent to the subject with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, severity, or recurrence of symptoms, complications, or conditions or biochemical markers associated with the disease.
With respect to headache, "treatment" is a method for obtaining beneficial or desired results for a subject. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of headache, including lessening the severity, lessening the intensity of pain and other associated symptoms, reducing the frequency of relapse, improving the quality of life of patients suffering from headache, reducing the dosage of other medications required to treat headache, and reducing the number of headache days per month. For migraine, other related symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and/or movement. For cluster headaches, other related symptoms include, but are not limited to, swelling under or around the eyes, excessive tearing, redness, running or stuffy nose, and flushing.
For the purposes of this disclosure, reference is made to the publication industry guide of the U.S. Food and Drug Administration (FDA) "migraine: development of Drugs for Acute therapy (Migraine: developing Drugs for Acute Treatment) ",2 months 2018, said publication being available fromhttps://www.fda.gov/downloads/drugs/guidances/ ucm419465.pdfAnd (4) obtaining. Terms used in the examples, such as most annoying symptoms (MBS) and pain elimination, are described in the FDA guidelines.
The starting materials useful in preparing the pharmaceutical compositions of the present invention are readily commercially available or can be prepared by one skilled in the art.
The present invention encompasses oral fast-dispersing dosage forms of remaimeji pam. The invention further encompasses methods of modulating CGRP and treating patients with medical conditions associated with abnormal levels of CGRP or CGRP receptor signaling by oral administration of the compositions. Rimantapam is chemically described as (5s, 6s, 9r) -4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) -1-piperidinecarboxylic acid 5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl ester, and it has the structural formula:
remaizepam is described in, for example, WO 2011/046997, published on 21 days 4 months 2011.
As used herein, the phrase "fast-dispersing dosage form" refers to a composition that disintegrates or disperses within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds, and particularly 2 to 8 seconds, after being placed in contact with a fluid. The fluid is preferably a fluid as found in the oral cavity when administered orally, i.e. saliva.
In a preferred embodiment, the composition of the invention is a solid fast-dispersing dosage form comprising a solid network of the active ingredient, rimantapam and a water-soluble or water-dispersible carrier comprising fish gelatin. Thus, the carrier is inert to the active ingredient. The network is obtained by subliming the solvent from a solid composition comprising a solution of the active ingredient and the carrier in the solvent. The dosage forms of the invention may be prepared according to the method disclosed in Gregory et al, british patent No. 1,548,022, using fish gelatin as a carrier. Thus, an initial composition (or mixture) comprising a solution of the active ingredient and the fish gelatin carrier in a solvent is prepared and then sublimed. Sublimation is preferably carried out by freeze-drying the composition. The composition may be contained in a mold during freeze-drying to produce a solid form of any desired shape. In a preliminary step prior to depositing the composition in the mold, the mold may be cooled using liquid nitrogen or solid carbon dioxide. After freezing the mold and composition, it is then subjected to reduced pressure and controlled heating to assist in solvent sublimation (if desired). The reduced pressure applied during the process may be less than about 4mm Hg, preferably less than about 0.3mm Hg. If desired, the freeze-dried composition may then be removed from the mold or stored therein until later use.
When this process is used and the active ingredient and fish gelatin are used as carriers, the resulting solid fast-dispersing dosage form has the advantages associated with the use of fish gelatin as described herein. Generally, fish gelatin is classified as from cold and warm water fish sources, and as gelled or non-gelled species. Fish gelatin of the non-gelling variety contains lower proline and hydroxyproline amino acid content than gelling fish gelatin and bovine gelatin, which is associated with cross-linking properties and gelling capacity. The non-gelled fish gelatin may be maintained at solution concentrations up to about 40% and at temperatures as low as 20 ℃. In one aspect of the invention, the fish gelatin used according to the invention is preferably obtained from a cold water fish source and is a non-gelling type of fish gelatin. More preferably, in one aspect of the invention, a non-hydrolysed form of non-gelled fish gelatin is used. In an alternative embodiment, spray dried non-hydrolyzed non-gelling fish gelatin may be used. Fish gelatin suitable for use in the present invention is commercially available.
In addition to the active ingredient and the fish gelatin carrier, the composition according to the invention may also contain other matrix forming agents and minor components. Matrix-forming agents suitable for use in the present invention comprise materials derived from animal or vegetable proteins, such as other gelatins, dextrins, and soy, wheat, and psyllium seed proteins; gums, such as gum arabic, guar gum, agar, and xanthan gum; a polysaccharide; an alginate; a carboxymethyl cellulose; carrageenan; (ii) a dextran; pectin; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes, such as gelatin-gum arabic complex.
Other materials that may also be incorporated into the fast dissolving compositions of the present invention include sugars such as mannitol, dextran, lactose, galactose and trehalose; cyclic sugars, such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; and amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification (freezing). In addition to or in the absence of surfactants, matrix forming agents may be present. In addition to forming a matrix, a matrix former may help maintain dispersion of any active ingredient in solution in a suspension. This is particularly useful in cases where the active agent is not sufficiently soluble in water and therefore must be suspended rather than dissolved. Minor ingredients such as preservatives, antioxidants, surfactants, viscosity increasing agents, coloring agents, flavoring agents, pH adjusting agents, sweetening agents or taste masking agents may also be incorporated into the fast dissolving compositions. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis and effrads (Ellis & Everard). Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors and combinations of these. Suitable pH adjusters include edible acids and bases such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweeteners include, for example, sucralose, aspartame, acesulfame K, and thaumatin. Suitable taste-masking agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents, or microencapsulated actives.
A typical route of administration for the fast-dispersing dosage form of the invention is oral. Pharmaceutical compositions according to certain embodiments of the invention are formulated to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. The compositions administered to a subject or patient may be in the form of one or more dosage units. The actual methods of making such dosage forms are known, or will be apparent, to those skilled in the art; see, for example, remington: pharmaceutical sciences and practices (Remington: the Science and Practice of Pharmacy), 20 th edition (Philadelphia College of pharmaceutical and Science, 2000).
Solid compositions are generally formulated in dosage units providing from about 1mg to about 1000mg of the active ingredient per dose. Some examples of solid dosage units are 0.1mg, 1mg, 10mg, 37.5mg, 75mg, 100mg, 150mg, 300mg, 500mg, 600mg and 1000mg. Typical dosage ranges according to the invention comprise about 10-600mg, 25-300mg, 25-150mg, 50-100mg, 60-90mg and 70-80mg. Liquid compositions are generally in the unit dosage range of 1-100 mg/mL. Some examples of liquid dosage units are 0.1mg/mL, 1mg/mL, 10mg/mL, 25mg/mL, 50mg/mL, and 100mg/mL.
The pharmaceutical composition of the present invention may be prepared in any suitable dosage form, including, for example, tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
Pharmaceutical compositions of the invention containing rimazepam will typically also comprise other pharmaceutically acceptable carriers (also referred to as excipients), for example binders, lubricants, diluents, coating agents, disintegrants, barrier components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, flavoring agents, preservatives and mixtures thereof. The choice of excipient depends on the desired characteristics of the composition and the nature of the other pharmacologically active compounds in the formulation. Suitable Excipients are known to those skilled in the art (see, "Handbook of Pharmaceutical Excipients", edited by Rowe et al, fifth edition, 2005, mcGraw Hill publishing company).
Examples of pharmaceutically acceptable carriers that may be used to prepare the pharmaceutical compositions of the present invention may include, but are not limited to: fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof. If desired, disintegrating agents may also be combined, exemplary disintegrating agents being but not limited to cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. In one aspect of the invention, the flavoring agent is selected from the group consisting of mint, peppermint, berry, cherry, menthol, and sodium chloride flavors and combinations thereof. In one aspect of the invention, the sweetener is selected from the group consisting of sugar, sucralose, aspartame, acesulfame potassium, neotame, and combinations thereof.
In general, the pharmaceutical compositions of the present invention may be manufactured in conventional manners known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes, and the like.
In one aspect of the invention, the pharmaceutical composition is prepared as an oral solid molded fast-dispersing dosage form as described in U.S. patent No. 9,192,580 issued 11/24 of 2015.
In some embodiments, a method may comprise administering to a subject one or more additional agents simultaneously or sequentially with remergipam. In some embodiments, the additional agent may be an anti-headache drug, such as exemplary anti-headache drugs known in the art (e.g., 5-HT 1 Agonists, triptans, ergot alkaloids, opioids, adrenergic antagonists, NSAIDs, or antibodies). In some embodiments, the therapeutic effect may be greater than using remergipam or one or more additional agents alone. Thus, a synergistic effect between rimantapam and one or more additional agents may be achieved. In some embodiments, one or more additional agents may be taken prophylactically by the subject.
In addition to migraine, other CGRP related disorders that may be treated by the pharmaceutical compositions and methods of the present invention include, for example, cluster headache; chronic tension type headache; chronic pain; neurogenic inflammation and inflammatory pain; eye pain; toothache; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity; asthma; shock; sepsis; opioid withdrawal syndrome; morphine tolerance; male and female hot flashes; allergic dermatitis; psoriasis; encephalitis, brain trauma, ischemia, stroke, epilepsy, and neurodegenerative diseases; skin diseases; neurogenic skin redness, skin roses and erythema; tinnitus; obesity; inflammatory bowel disease; irritable bowel syndrome; and cystitis.
In one aspect, the invention also provides kits for use in the methods of the invention. The kit may comprise one or more containers comprising a pharmaceutical composition described herein and instructions for use according to any of the methods described herein. In general, these instructions include a description of administering a pharmaceutical composition to treat, ameliorate or prevent a headache (e.g., migraine) or other CRGP disorder according to any of the methods described herein. For example, the kit can include instructions for selecting an individual suitable for treatment based on identifying whether the individual has or is at risk of developing headache. The instructions are typically provided in the form of a package insert or label, in line with the requirements of the regulatory body of the jurisdiction in which the pharmaceutical composition is to be provided to the patient.
According to the present invention, administration of a pharmaceutical composition comprising remaizepam to a subject may facilitate reduction of severity (which may include reducing the need for and/or amount of other drugs and/or therapies typically used for this condition (e.g., exposure to the drug and/or therapy), including, for example, ergotamine, dihydroergotamine, or triptan-like drugs for migraine headache), duration, and/or frequency (including, for example, delaying or increasing the time to next episode in an individual).
In addition, administration of a pharmaceutical composition comprising remejipam to a subject may facilitate alleviation or amelioration of one or more symptoms of headache, or a reduction in the duration of symptoms, as compared to administration without treatment.
In addition, administration of a pharmaceutical composition comprising remaiazepam to a subject can promote a reduction in the frequency of headache episodes in an individual over a particular period of time (e.g., monthly) as compared to pre-treatment levels. For example, the frequency of episodes in an individual may be reduced by any of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% as compared to the level prior to treatment.
In addition, administration of a pharmaceutical composition comprising remegazepam to a subject may contribute to the delay of headache development, i.e., delay, hinder, slow, stabilize, and/or delay the progression of the disease. Such delays may be of varying lengths of time, depending on the history of the disease and/or the individual being treated.
In addition, administration of a pharmaceutical composition comprising remergipam to a subject may delay the development or progression of headache, i.e., delay the initial clinical presentation and/or subsequent progression of the disorder. The development of headache can be detectable and can be assessed using standard clinical techniques as are well known in the art. However, development also refers to progression that may not be detectable.
In addition, administration of a pharmaceutical composition comprising remergipam may increase the number of patients who achieve disappearance of migraine pain within 2 hours of the time of administration. For example, the number of patients who achieve migraine pain disappearance within 2 hours of the administration time can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients who achieve migraine pain disappearance within 2 hours of the administration time may be about 21.2%.
Administration of the pharmaceutical composition may achieve elimination of migraine pain within 2 hours of the time of administration. For example, administration of the pharmaceutical composition can achieve disappearance of migraine pain within 1.9 hours, within 1.8 hours, within 1.7 hours, within 1.6 hours, within 1.5 hours, within 1.4 hours, within 1.3 hours, within 1.2 hours, within 1.1 hours, within 1.0 hour, within 0.9 hours, within 0.8 hours, within 0.7 hours, within 0.6 hours, within 0.5 hours, within 0.4 hours, within 0.3 hours, within 0.2 hours, or within 0.1 hours of the time of administration.
In addition, administration of a pharmaceutical composition comprising remergipam may increase the number of patients achieving the most annoying disappearance of symptoms within 2 hours of the time of administration. For example, the number of patients achieving the disappearance of the most annoying symptoms within 2 hours of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients who achieve migraine pain disappearance within 2 hours of the administration time may be about 35.1%. The most disturbing symptoms include photophobia, nausea, phonophobia, or a combination thereof.
The administration of the pharmaceutical composition may achieve the most annoying disappearance of symptoms within 2 hours of the administration time. For example, administration of the pharmaceutical composition may achieve the most annoying disappearance of symptoms within 1.9, within 1.8, within 1.7, within 1.6, within 1.5, within 1.4, within 1.3, within 1.2, within 1.1, within 1.0, within 0.9, within 0.8, within 0.7, within 0.6, within 0.5, within 0.4, within 0.3, within 0.2, or within 0.1 hour of the time of administration.
In addition, administration of a pharmaceutical composition comprising rimantapam may increase the number of patients achieving pain relief within 90 minutes of the time of administration. For example, the number of patients achieving pain relief within 90 minutes of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients achieving pain relief within 90 minutes of the time of administration may be about 49.6%.
Administration of the pharmaceutical composition may achieve pain relief within 90 minutes of the time of administration. For example, administration of the pharmaceutical composition can achieve pain relief within 85 minutes, within 80 minutes, within 75 minutes, within 70 minutes, within 65 minutes, within 60 minutes, within 55 minutes, within 50 minutes, within 45 minutes, within 40 minutes, within 35 minutes, within 30 minutes, within 25 minutes, within 20 minutes, within 15 minutes, within 10 minutes, or within 5 minutes of the time of administration.
In addition, administration of a pharmaceutical composition comprising rimantapam may increase the number of patients achieving pain relief within 2 hours of the time of administration. For example, the number of patients achieving pain relief within 2 hours of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients achieving pain relief within 2 hours of the administration time may be about 59.3%.
Administration of the pharmaceutical composition may achieve pain relief within 2 hours of the time of administration. For example, administration of the pharmaceutical composition can achieve migraine pain relief within 1.9 hours, within 1.8 hours, within 1.7 hours, within 1.6 hours, within 1.5 hours, within 1.4 hours, within 1.3 hours, within 1.2 hours, within 1.1 hours, within 1.0 hour, within 0.9 hours, within 0.8 hours, within 0.7 hours, within 0.6 hours, within 0.5 hours, within 0.4 hours, within 0.3 hours, within 0.2 hours, or within 0.1 hours of the time of administration.
In addition, administration of a pharmaceutical composition comprising rimantapam can increase the number of patients achieving sustained pain relief within 2 to 48 hours of the time of administration. For example, the number of patients achieving sustained pain relief within 2 to 48 hours of the administration time can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients achieving sustained pain relief within 2 to 48 hours of the administration time may be about 42.2%.
In addition, administration of a pharmaceutical composition comprising rimantapam can increase the number of patients achieving sustained pain relief within 2 to 24 hours of the time of administration. For example, the number of patients achieving sustained pain relief within 2 to 24 hours of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients achieving sustained pain relief within 2 to 24 hours of the administration time may be about 15.7%.
In addition, administration of a pharmaceutical composition comprising remergipam may increase the number of patients achieving sustained pain relief within 2 to 48 hours of the time of administration. For example, the number of patients achieving sustained pain relief within 2 to 48 hours of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients achieving sustained pain relief within 2 to 48 hours of the administration time may be about 13.5%.
In addition, administration of a pharmaceutical composition comprising rimantapam may enable a reduction in the number of patients using the remedial drug to be achieved within 24 hours of the time of administration. For example, the number of patients using a remedial drug within 24 hours of the time of administration may be about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less. For example, the number of patients taking remedial drugs within 24 hours of the time of administration may be about 14.2%.
In addition, administration of a pharmaceutical composition comprising rimantapam may increase the number of patients reporting normal function within 2 hours of the time of administration. For example, the number of patients reporting normal function within 2 to 24 hours of the time of administration can be about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%. For example, the number of patients reporting normal function within 2 hours of the time of administration may be about 38.1%.
Administration of the pharmaceutical composition may achieve reporting normal function within 2 hours of the time of administration. For example, administration of the pharmaceutical composition can achieve reporting normal function within 1.9 hours, within 1.8 hours, within 1.7 hours, within 1.6 hours, within 1.5 hours, within 1.4 hours, within 1.3 hours, within 1.2 hours, within 1.1 hours, within 1.0 hour, within 0.9 hours, within 0.8 hours, within 0.7 hours, within 0.6 hours, within 0.5 hours, within 0.4 hours, within 0.3 hours, within 0.2 hours, or within 0.1 hours of the time of administration.
A patient may have 15 migraines or less within a 30 day period. For example, a patient may have 15 migraines, 14 migraines, 13 migraines, 12 migraines, 11 migraines, 10 migraines, 9 migraines, 8 migraines, 7 migraines, 6 migraines, 5 migraines, 4 migraines, 3 migraines, 2 migraines, or 1 migraine within a 30 day period of time.
The pharmaceutical composition may be administered to the patient up to 15 times within a 30 day period. For example, the pharmaceutical composition may be administered to a patient once, twice, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, or 15 times over a period of 30 days.
In one embodiment, the oral fast dispersing dosage form may contain a rimmed diazepam hemisulfate salt chemically described as (5s, 6s, 9r) -4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) -1-piperidinecarboxylic acid 5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl ester hemisulfate sesquihydrate and having the formula:
the empirical formula of the hemisulfate salt of rimazepam is C 28 H 28 F 2 N 6 O 3 0.5 H 2 SO 4 1.5 H 2 O, molecular weight 610.63. The molecular weight of the reamijpam free base is 534.56. The daily dose of reamegypam hemisulfate may be about 85.65mg.
Generally, rimaizepam may be included in the compositions of the present invention in all pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts are those in which the counterion does not contribute significantly to the physiological activity or toxicity of the compound and acts as a pharmacological equivalent by itself. These salts can be prepared according to conventional organic techniques using commercially available reagents. Some anionic salt forms include, but are not limited to, acetate stearate, benzenesulfonate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, methanesulfonate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinafoate. Some cationic salt forms include, but are not limited to, ammonium, aluminum, benzathine (benzathine), bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
The present invention is intended to encompass all isotopes of atoms occurring in compounds having formula I. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example, and not by way of limitation, isotopes of hydrogen include deuterium and tritium. Isotopic inclusion of carbon 13 C and 14 C. isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the unlabeled reagent otherwise used. Such compounds may have a variety of potential uses, for example, as standards and reagents for determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably alter biological, pharmacological, or pharmacokinetic properties.
The therapeutically active component may comprise two or more compounds, each of which may be an orally bioavailable active pharmaceutical ingredient ("API"), e.g., an anti-migraine drug.
The invention is further illustrated by the following non-limiting examples.
Examples of the invention
The present invention is exemplified by rimazepam hemisulfate, which is a slightly water-soluble white to off-white crystalline solid. The oral fast-dispersing dosage form containing rimazepam hemisulphate is hereinafter referred to as "NURTEC ODT".
The NURTEC ODT may be an orally disintegrating tablet for sublingual or buccal use and may contain 85.65mg remexicam pam hemisulfate, equivalent to 75mg remexicam pam free base. The NURTEC ODT may further comprise the following inactive ingredients: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin.
Indications and uses
The NURTEC ODT is suitable for acute treatment of adults with or without aura migraine. NURTEC ODT is not suitable for prophylactic treatment of migraine.
Dosage and administration
Drug administration information
The recommended dose of NURTEC ODT is 75mg orally. The maximum dose over a 24 hour period was 75mg. The safety of treating migraine more than 15 times over a 30 day period has not been established.
Application information
Patients taking NURTEC ODT should be instructed as follows:
open the blister pack with dry hands.
The aluminum foil cover of one blister was peeled off and the Orally Disintegrating Tablets (ODT) were gently removed. The ODT was not pushed through the aluminum foil.
When the blister is opened, the ODT is removed and placed on the tongue; alternatively, the ODT may be placed under the tongue.
ODT will break down in saliva and therefore swallow without additional liquid.
ODT was taken immediately after opening the blister pack. The ODT is not stored outside the blister package for future use.
Concomitant administration of a strong or moderate inhibitor of CYP3A4
Concomitant administration of NURTEC ODT and a strong inhibitor of CYP3A4 should be avoided. Another dose of NURTEC ODT over 48 hours should also be avoided when concomitantly administered with a moderate inhibitor of CYP3A4 [ see drug interactions and clinical pharmacology ].
Concomitant administration with strong or moderate inducers of CYP3A
Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A should be avoided, which may lead to a loss of NURTEC ODT efficacy [ see drug interactions and clinical pharmacology ].
Concomitant administration with an inhibitor of P-gp or BCRP
Concomitant administration of NURTEC ODT with inhibitors of P-glycoprotein (P-gp) or Breast Cancer Resistance Protein (BCRP) should be avoided [ see drug interactions and clinical pharmacology ].
Dosage form and specification
The NURTEC ODT may be in the form of an orally disintegrating tablet, which may be white to off-white, may be circular, and may have concave symbols.Each tablet may contain 75mg of remejipam.
Contraindication
NURTEC ODT is contraindicated in patients with a history of hypersensitivity to remegypam, NURTEC ODT, or any component thereof. However, delayed severe hypersensitivity reactions have occurred [ see warnings and precautions ].
Warnings and notices
Hypersensitivity reaction
In clinical studies, the NURTEC ODT has developed hypersensitivity reactions, including dyspnea and skin rash. Hypersensitivity reactions may occur several days after administration and delayed severe hypersensitivity reactions have occurred. If hypersensitivity occurs, the use of NURTEC ODT should be discontinued and appropriate therapy initiated [ see contraindications ].
Adverse reaction
Clinically significant adverse reactions may include hypersensitivity reactions, which are discussed in warnings and precautions.
Experience of clinical trials
Since clinical trials are conducted under widely different conditions, the rate of adverse effects observed in a clinical trial of one drug cannot be directly compared to the rate of occurrence in a clinical trial of another drug, and may not reflect the rate of occurrence observed in clinical practice.
The safety of NURTEC ODT has been evaluated in a randomized, double-blind, placebo-controlled trial (study 1) on 682 migraine patients who received a single 75mg dose of NURTEC ODT [ see clinical study ]. Approximately 85% are women, 74% are whites, 21% are blacks, and 17% are hispanic or hispanic. The mean age at study entry was 40 years (age range 18-75 years).
Long-term safety was evaluated in an open label extension study using different oral dosage forms of rimazepam. This study evaluated 1,798 patients who were intermittently administered for up to one year, including 1,131 patients exposed to 75mg remaigkin for at least 6 months, and 863 patients exposed for at least one year, all of which patients treated on average at least two migraine attacks per month.
The most common adverse effect in study 1 was nausea (2% in patients receiving NURTEC ODT compared to 0.4% in patients receiving placebo).
Among patients receiving NURTEC ODT treatment, less than 1% of patients develop hypersensitivity reactions, including dyspnea and severe skin rash [ see contraindications and warnings and precautions ].
Drug interaction
CYP3A4 inhibitor
Concomitant administration of NURTEC ODT with a strong inhibitor of CYP3A4 resulted in a significant increase in remaiazepam exposure. Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 was avoided [ see clinical pharmacology ].
Concomitant administration of NURTEC ODT with a moderate inhibitor of CYP3A4 may result in increased exposure to rimazepam. When concomitantly administered with a moderate inhibitor of CYP3A4, another dose of NURTEC ODT over 48 hours was avoided [ see clinical pharmacology ].
CYP3A inducer
Concomitant administration of NURTEC ODT with a strong or moderate inducer of CYP3A may result in a significant reduction in remametpam exposure, which may lead to a loss of NURTEC ODT efficacy. Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A is avoided [ see clinical pharmacology ].
Transporter proteins
Rimaizepam is a substrate for P-gp and BCRP efflux transporters. Concomitant administration of NURTEC ODT with inhibitors of P-gp or BCRP may result in a significant increase in remaigilpam exposure [ see clinical pharmacology ]. The use of NURTEC ODT with inhibitors of P-gp or BCRP is avoided.
Used in a specific population
In gestation period
Risk summary
Insufficient data indicates a developmental risk associated with the use of NURTEC ODT by pregnant women. In animal studies, oral administration of rimazepam during organogenesis adversely affects the development of rats (reduces fetal weight and increases the incidence of fetal variation), with exposure greater than that used clinically and associated with maternal toxicity. Evaluation of developmental effects following oral administration of rimaizepam throughout pregnancy and lactation was inadequate (see data).
In the general population of the united states, the estimated background risk of major birth defects and miscarriages in pregnancy is clinically recognized to be 2% to 4% and 15% to 20%, respectively. The estimated incidence of major birth defects (2.2% to 2.9%) and miscarriages (17%) at parturition in women with migraine headache was similar to that reported for women without migraine.
Clinical considerations
Disease-related maternal and/or embryonic/fetal risk
Published data indicates that women with migraine headache may have an increased risk of developing preeclampsia and gestational hypertension during pregnancy.
Data of
Animal data
Oral administration of remaigkam (0 mg/kg/day, 10 mg/kg/day, 60 mg/kg/day or 300 mg/kg/day) to pregnant rats during the organogenic phase reduced fetal weight and increased the incidence of fetal variation at the highest dose tested (300 mg/kg/day), which correlated with maternal toxicity. The plasma exposure (AUC) to adverse effects on embryo development at a non-effective dose (60 mg/kg/day) was approximately 45-fold that of the human Maximum Recommended Human Dose (MRHD) of 75 mg/day.
Oral administration of remaizepam (0 mg/kg/day, 10 mg/kg/day, 25 mg/kg/day or 50 mg/kg/day) to pregnant rabbits during the organogenesis phase had no adverse effect on embryo development. The highest dose tested (50 mg/kg/day) correlated with plasma exposure (AUC), approximately 10-fold that of human MRHD.
Prenatal and postpartum development studies in rats, in which oral administration of remometrazepam (0 mg/kg/day, 10 mg/kg/day, 25 mg/kg/day or 60 mg/kg/day) throughout pregnancy and lactation, was insufficient to assess adverse effects of remometrazepam during these developmental periods.
Lactation period
There is no data on the presence of remergam or its metabolites in human milk, the effect of remergam on breast-fed infants, or the effect of remergam on milk production. There is no animal data on the excretion of rimazepam in milk. The developmental and health benefits of breast feeding should be considered along with the clinical needs of the mother for NURTEC ODT and any potential adverse effects of NURTEC ODT or potential mother conditions on breast-fed infants.
For paediatrics
The safety and effectiveness of NURTEC ODT in pediatric patients has not been established.
For the elderly
No clinically significant pharmacokinetic differences were observed between the elderly and the young subjects in the pharmacokinetic study. Clinical studies of NURTEC ODT do not contain a sufficient number of patients 65 years of age and older to determine whether their responses differ from those of younger patients.
Liver injury
Patients with mild (Child-Pugh grade A) or moderate (Child-Pugh grade B) liver injury do not need to adjust the dose of NURTEC ODT. Subjects with severe (Child-Pugh grade C) liver injury had significantly higher plasma concentrations of Remetrazepam. The use of NURTEC ODT in patients with severe liver damage should be avoided [ see clinical pharmacology ].
Injury of kidney
Patients with mild, moderate, or severe kidney injury do not need to adjust the dose of NURTEC ODT. NURTEC ODT has not been studied in patients with end-stage renal disease and dialysis patients. The use of NURTEC ODT in patients with end stage renal disease (CLcr < 15 ml/min) [ see clinical pharmacology ] should be avoided.
Overdose
Clinical experience with overdosing of NURTEC ODT is limited. Treatment of overdosing of the NURTEC ODT should consist of general supportive measures including monitoring vital signs and observing the clinical status of the patient. There are no specific antidotes available to treat overdoses of rimazepam.
Due to high serum protein binding, remaizepam is unlikely to be significantly removed by dialysis [ see clinical pharmacology ].
Clinical pharmacology
Mechanism of action
Rimazepam is a calcitonin gene-related peptide receptor antagonist.
Pharmacodynamics
The relationship between pharmacodynamic activity and the mechanism by which remaiazepam exerts its clinical effect is not clear. When remaimage diazepam was concomitantly administered with sumatriptan (12 mg subcutaneously given at 6mg intervals of one hour), no clinically relevant difference in resting blood pressure was observed compared to sumatriptan alone in healthy volunteers.
Cardiac electrophysiology
Remaizepam did not prolong the QT interval to any clinically relevant extent at a single dose of 4-fold the recommended dose.
Pharmacokinetics
Absorption of
After oral administration of NURTEC ODT, remaizepam was absorbed at maximum concentration over 1.5 hours. The absolute oral bioavailability of reamaizepam was about 64%.
Influence of food
T after administration of NURTEC ODT with a high fat meal under fed conditions max Delayed for 1 hour, and let C max Decrease was 42% to 53%, and AUC decreased 32% to 38%. In clinical safety and efficacy studies, NURTEC ODT was administered without food consideration. The effect of reducing rimaigil exposure due to administration with food on rimaigil efficacy is not clear.
Distribution of
The steady state distribution volume of remometrazpam was 120L. The plasma protein binding of rimaizepam was approximately 96%.
Cancellation of
Metabolism
Rimantapam is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C 9.
Remaizepam is eliminated predominantly in an unaltered form (about 77% of the dose), with no major metabolites detected in plasma (i.e., > 10%).
Excretion device
In healthy subjects, the elimination half-life of remaiazepam was about 11 hours. Oral administration of [ 2 ] to a healthy male subject 14 C]After-reamegypam, 78% of the total radioactivity was recovered in the feces and 24% in the urine. Unaltered remaigilpam is the major single component in excreted feces (42%) and urine (51%).
Specific group
Injury of kidney
In a specialized clinical study comparing the pharmacokinetics of remaimage pam in subjects with mild (estimated creatinine clearance [ CLcr ]60-89 ml/min), moderate (CLcr 30-59 ml/min) and severe (CLcr 15-29 ml/min) kidney injury with normal subjects (healthy matched controls), exposure to remaimage pam was approximately 40% higher in subjects with moderate kidney injury after a single 75mg dose. However, there was no clinically meaningful difference in remaiazepam exposure for subjects with severe renal injury compared to subjects with normal renal function (CLcr > =90 ml/min). NURTEC ODT has not been studied in patients with end stage renal disease (CLcr < 15 ml/min) [ see use in a specific population ].
Liver injury
In a dedicated clinical study comparing the pharmacokinetics of rimaigilpam in subjects with mild, moderate and severe liver injury with normal subjects (healthy matched controls), exposure of rimaigilpam (C) in subjects with severe injury (Child-Pugh grade C) after a single 75mg dose (C) max And AUC) is approximately 2-fold higher. Remegzepam exposure in subjects with mild (Child-PughA grade) and moderate liver injury (Child-Pugh B grade) was not clinically meaningful compared to subjects with normal liver functionDifferences [ see use in specific population]。
Other specified groups
No clinically significant differences in the pharmacokinetics of remejipam were observed based on age, sex, race/ethnicity, body weight or CYP2C9 genotype [ see clinical pharmacology ].
Study of drug interactions
In vitro study
An enzyme
Rimazepam is a substrate for CYP3A4 and CYP2C9 [ see in vivo studies ]. Rimantapam is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6 or UGT1A1 at clinically relevant concentrations. However, remimezepam is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimazepam is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.
Transport proteins
Rimazepam is a substrate for P-gp and BCRP. Concomitant administration of inhibitors of P-gp or BCRP may increase exposure to rimazepam [ see drug interactions ]. No specific drug interaction studies were performed to evaluate their effect on the pharmacokinetics of remergipam.
Rimazepam is not a substrate for OATP1B1 or OATP1B 3. Given its low renal clearance, remejipam was not assessed as a substrate for OAT1, OAT3, OCT2, MATE1 or MATE 2-K.
Rimantadine is not an inhibitor of P-gp, BCRP, OAT1 or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT 3. Rimaizepam is an inhibitor of OATP1B3, OCT2 and MATE 1. The NURTEC ODT is not expected to interact with these transporters at clinically relevant concentrations as a clinical drug.
In vivo studies
CYP3A4 inhibitors
In a dedicated drug interaction study, concomitant administration of 75mg remaiazepam (single dose) with itraconazole (itraconazole), a strong CYP3A4 inhibitor at steady state, resulted in increased exposure to remaiazepam (A4-fold increase in AUC, and C £ C |) max Increase by about1.5 fold) [ see drug interaction]. No special drug interaction studies were performed to evaluate the effect of concomitant administration of a weak CYP3A4 inhibitor on the pharmacokinetics of remaiazepam. Concomitant administration of remaiazepam and a CYP3A4 moderate inhibitor may increase exposure (AUC) of remaiazepam by less than 2-fold [ see drug interactions]. Concomitant administration of remaiazepam and a weak CYP3A4 inhibitor is not expected to have a clinically significant effect on remaiazepam exposure.
CYP3A inducer
In a dedicated drug interaction study, concomitant administration of 75mg remaiazepam (single dose) with the CYP3A4 strong inducer rifampin (rifampin) at steady state resulted in reduced exposure of remaiazepam (80% reduction in AUC, and C) in a dedicated drug interaction study max 64% reduction) which may lead to loss of efficacy [ see drug interactions]. No specific drug interaction studies were performed to assess the effect of concomitant administration of moderate or weak inducers of CYP3A4 on the pharmacokinetics of remaiazepam. Because rimantapam is a moderately sensitive substrate for CYP3A4, drugs that are moderately inducers of CYP3A4 can also significantly reduce rimantapam exposure, thereby losing efficacy [ see drug interactions]. It is expected that the concomitant administration of a weak inducer of CYP3A4 and remaimezepam will not produce a clinically significant interaction.
CYP2C9 inhibitor
In a dedicated drug interaction study, concomitant administration of 75mg rimaizepam (single dose) with fluconazole (fluconazole), a combined CYP3A4 and CYP2C9 moderate inhibitor, resulted in increased exposure to rimaizepam (1.8-fold increase in AUC), wherein C is increased max There is no relevant effect. Rimantapam is metabolized primarily by CYP3A4 and to a lesser extent by CYP2C 9. The increase in exposure to reamaizepam may be attributed to the combined inhibition of CYP2C9 and CYP3A4 and fluconazole administration, indicating that the contribution of CYP2C9 is small. Thus, CYP2C9 inhibition alone is not expected to significantly affect remaigilpam exposure.
Other drugs
No significant pharmacokinetic interaction was observed when remaimexapam was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (midazolam), a sensitive CY3A4 substrate, or sumatriptan [ see clinical pharmacology ].
Pharmacogenomics
Individuals with genetic variants such as CYP2C9 x 2 and CYP2C9 x 3 alleles have reduced CYP2C9 activity. Reamegypam C in CYP2C9 intermediary metabolisers (i.e.,. About.1/. About.2,. About.2/. About.2,. About.1/. About.3, n = 43) compared to normal metabolisers (i.e.,. About.1/. About.1, n =72) max And AUC 0-inf Similarly. Sufficient PK data could not be obtained from CYP2C9 poor metabolizers (i.e.. X2/. X3). Since the CYP2C9 contribution to the metabolism of rimantapam is considered to be minor, CYP2C9 polymorphisms are not expected to significantly affect exposure.
Non clinical toxicology
Canceration, mutagenesis, fertility impairment
Canceration of cancer
Remaigkin (0 mg/k/day, 10 mg/k/day, 100 mg/k/day, or 300 mg/k/day) was orally administered to tg.rash2 mice for 26 weeks, and remaigkin (0 mg/k/day, 5 mg/k/day, 20 mg/k/day, or 45 mg/kg/day) was orally administered to rats for 91-100 weeks, with no evidence of drug-induced tumors in both species. In rats, the plasma exposure (AUC) at the highest dose tested (45 mg/kg/day) was approximately 30-fold higher than the Maximum Recommended Human Dose (MRHD) of 75 mg/day in humans.
Mutagenesis
Remaizepam was negative in both in vitro (bacterial reverse mutation, chromosomal aberration in chinese hamster ovary cells) and in vivo (rat micronuclei) assays.
Impairment of fertility
Remedzepam (0 mg/kg/day, 30 mg/kg/day, 60 mg/kg/day, or 150 mg/kg/day) was administered orally to male and female rats pre-and during mating and continued in female rats until day 7 of Gestation (GD) for uterine atrophy at all doses and for reduced fertility at the highest dose tested. In the second fertility study, which tested lower doses (0 mg/kg/day, 5 mg/kg/day, 15 mg/kg/day or 25 mg/kg/day), no adverse effects on fertility, uterine histopathology or early embryo development were observed. The non-effective dose (25 mg/kg/day) for rat fertility and early embryonic development impairment correlated with plasma drug exposure (AUC), approximately 15-fold that of human MRHD.
Clinical research
The efficacy of NURTEC ODT for acute treatment of migraine with and without aura in adults was demonstrated in the following randomized, double-blind, placebo-controlled trial: study 1 (NCT 03461757). This study randomized patients to either 75mg NURTEC ODT (N = 732) or placebo (N = 734). The patient is instructed to treat migraine headache of moderate to severe headache pain intensity. Remedial drugs (i.e., NSAIDs, acetaminophen, and/or antiemetics) are allowed to be administered 2 hours after the initial treatment. No other forms of remedial drugs, such as triptans, are allowed within 48 hours of the initial treatment. Approximately 14% of patients are taking migraine-preventative medications at baseline. None of the patients in study 1 were concomitantly taking prophylactic drugs acting on the CGRP pathway.
The primary efficacy analysis was performed in patients treated for moderate to severe pain migraine. Compared to placebo, NURTEC ODT 75mg showed an effect on pain elimination and the disappearance of the most disturbing symptoms (MBS) two hours after administration. Pain disappearance is defined as moderate or severe headache with a reduction to no headache, and MBS disappearance is defined as absence of self-identified MBS (i.e. photophobia, phonophobia or nausea). Among the patients selecting MBS, the most commonly selected symptoms are photophobia (54%), followed by nausea (28%) and phonophobia (15%).
In study 1, the percentage of patients who achieved headache pain relief and MBS disappearance two hours after a single dose was statistically significantly higher in patients receiving NURTEC ODT compared to patients receiving placebo (table 1).
Table 1: migraine efficacy endpoint of study 1
* N = number of responders/N = number of patients in this treatment group
Figure 1 presents the percentage of patients achieving migraine pain relief within 2 hours after treatment in study 1.
In study 1, the statistically significant effect of the NURTEC ODT compared to placebo was demonstrated with additional efficacy endpoints of 2 hour pain relief, 2-48 hour sustained pain disappearance, use of remedial drugs within 24 hours, and percentage of patients reporting normal function two hours after dosing (table 2). Pain relief is defined as a reduction in migraine pain from moderate or severe severity to mild or absent. The measurement of the percentage of patients reporting normal function two hours after dosing is from a single questionnaire asking the patients to select one response on a 4-point scale: normal function, mild injury, severe injury or need to rest in bed.
TABLE 2 additional migraine efficacy endpoints in study 1
* N = number of responders/N = number of patients in this treatment group
* This assay only included the use of NSAIDs, acetaminophen or antiemetic agents within 24 hours after administration; triptans or other acute migraine medications are not allowed.
The incidence of photophobia and phonophobia was reduced after administration of NURTEC ODT 75mg compared to placebo.
How to supply/store and handle
How to supply
The NURTEC ODT 75mg may be in the form of an orally disintegrating tablet, which may be white to off-white, may be round, may have concave symbolsAnd may be supplied in the form of a blister-packaged carton containing 8 orally disintegrating tablets. Each ODT can contain 75mg of RuimeiIs a diazepam.
NDC：72618-3000-2
Storage and handling
The NURTEC ODT is stored at a controlled room temperature of 20 ℃ to 25 ℃ (68 ° F to 77 ° F); wherein an offset between 15 ℃ to 30 ℃ (59 ° F to 86 ° F) is allowed [ see USP controlled room temperature ].
Patient counseling information
The patient should be advised to read an FDA approved patient label (patient information).
Treatment of orally disintegrating tablet packaging
The patient should be instructed not to remove the blister from the outer aluminum bag [ see dose and administration ] before being ready to use the orally disintegrating tablets in said outer aluminum bag.
Hypersensitivity reaction
Patients should be informed about the signs and symptoms of hypersensitivity reactions, and these reactions may occur days after NURTEC ODT administration. Patients should be advised to contact their healthcare provider immediately if signs or symptoms of hypersensitivity develop [ see warnings and precautions ].
Points of prescription information
Indications and use. The NURTEC ODT is a calcitonin gene related peptide receptor antagonist useful in the acute treatment of adults with or without migraine aura. NURTEC ODT is not suitable for prophylactic treatment of migraine.
Dosage and administration. The recommended dose is 75mg orally, as required. The maximum dose over a 24 hour period was 75mg. The safety of treating more than 15 migraines over a 30 day period has not been established.
Dosage form and strength. NURTEC ODT orally disintegrating tablets: 75mg.
Contraindicated. Patients with a history of hypersensitivity to rimantapam, NURTEC ODT, or to any component thereof.
Warnings and notes. Hypersensitivity reaction: if severe hypersensitivity occurs, the NURTEC ODT is stopped and appropriate therapy is initiated. Severe hypersensitivity reactions already involve dyspnea and rash, and may occur days after administration.
Adverse reaction. Among patients treated with NURTEC ODT, an adverse reaction reported by > 1% of patients is nausea.
Drug interactions.
Strong inhibitors of CYP3 A4: concomitant administration is avoided.
CYP3A4 moderate inhibitor: when administered with a moderate inhibitor of CYP3A4, another dose within 48 hours is avoided.
CYP3A strong and moderate inducer: concomitant administration is avoided.
Inhibitors of P-gp or BCRP: concomitant administration is avoided.
Use in a specific population. Exposure was significantly higher in subjects with severe liver injury. Use in patients with severe liver injury (Child-Pugh grade C) was avoided.
Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled in the art at the time of the invention described and claimed herein. However, citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed herein in the specification and examples may be used. Further, a particular item in a list of items or a subset group of items in a larger group of items can be combined with other particular items, subset groups of items, or larger groups of items, regardless of whether or not there is a particular disclosure herein identifying such a combination.
Claims (26)
1. A method of treating migraine in a patient in need thereof, comprising orally administering to the patient a fast-dispersing pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of remeggpam (rimegepant) or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein administration of the pharmaceutical composition achieves elimination of migraine pain within 2 hours of the time of administration.
3. The method of claim 1, wherein administration of the pharmaceutical composition achieves elimination of migraine pain in about 21.2% of patients within 2 hours of the time of administration.
4. The method according to claim 1, wherein administering the pharmaceutical composition achieves a disappearance of the most annoying symptoms within 2 hours of the time of administration.
5. The method according to claim 1, wherein administration of the pharmaceutical composition achieves a disappearance of the most disturbing symptoms in about 35.1% of the patients within 2 hours of the time of administration.
6. The method of claim 5, wherein the most distressing symptom comprises photophobia, nausea, phonophobia, or a combination thereof.
7. The method of claim 1, wherein administering the pharmaceutical composition achieves pain relief within 90 minutes of the time of administration.
8. The method of claim 1, wherein administration of the pharmaceutical composition achieves pain relief in about 49.6% of patients within 90 minutes of the time of administration.
9. The method of claim 1, wherein administration of the pharmaceutical composition achieves pain relief within 2 hours of the time of administration.
10. The method of claim 1, wherein administration of the pharmaceutical composition achieves pain relief in about 59.3% of patients within 2 hours of the time of administration.
11. The method of claim 1, wherein administration of the pharmaceutical composition achieves sustained pain relief within 2 to 48 hours of the time of administration.
12. The method of claim 1, wherein administration of the pharmaceutical composition achieves sustained pain relief in about 42.2% of patients within 2 to 48 hours of the time of administration.
13. The method of claim 1, wherein administration of the pharmaceutical composition achieves a sustained disappearance of pain within 2 to 48 hours of the time of administration.
14. The method of claim 1, wherein administration of the pharmaceutical composition achieves a sustained pain disappearance in about 13.5% of patients within 2 to 48 hours of the time of administration.
15. The method of claim 1, wherein administering the pharmaceutical composition achieves a reduction in the use of a remedial drug within 24 hours of the time of administration.
16. The method of claim 1, wherein administration of the pharmaceutical composition results in about 14.2% of patients using a remedial drug within 24 hours of the time of administration.
17. The method of claim 1, wherein administering the pharmaceutical composition achieves normal function within 2 hours of the time of administration.
18. The method of claim 1, wherein administration of the pharmaceutical composition results in about 38.1% of patients reporting normal function within 2 hours of the time of administration.
19. The method of claim 1, wherein the daily dose of remaiazepam is about 75mg.
20. The method of claim 1, wherein the pharmaceutical composition is administered to the patient up to 15 times within a 30 day period.
21. The method of claim 1, wherein the pharmaceutically acceptable salt or remegazepam is remegazepam hemisulfate.
22. The method of claim 1, wherein the daily dose of rimazepam hemisulfate is about 85.65mg.
23. The method of claim 1, wherein the pharmaceutical composition further comprises benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, vanillin, or a combination thereof.
24. The method of claim 1, wherein about 1.3% or less of patients receiving the pharmaceutical composition experience nausea.
25. The method of claim 1, wherein about 0.15% or less of patients receiving the pharmaceutical composition experience hypersensitivity reactions.
26. The method of claim 25, wherein the hypersensitivity reaction comprises dyspnea, rash, or a combination thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/982,456 | 2020-02-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK40083616A true HK40083616A (en) | 2023-06-30 |
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