Spray-dried composition containing a CGRP receptor antagonist

Abstract

The present invention provides a pharmaceutically acceptable composition in the form of a solid amorphous single-particle powder, comprising a mixture of (a) a pharmacologically effective dosage of a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier material comprising maltodextrin having more than 15 dextrose equivalents (DE). The composition is suitable for transmucosal drug delivery, for example, nasal delivery, so that the composition can be loaded into a single-use nasal applicator. The composition may further comprise a disaccharide, such as lactose or trehalose, which may be prepared by spray drying and spray-dried together with the active ingredient and maltodextrin. The composition may further comprise one or more alkylsaccharides. Preferred alkylsaccharides include sucrose esters such as sucrose monolaurate. Preferred CGRP receptor antagonists include gepants such as ubrogepant, atogepant, rimegepant, and zabegepant. Therefore, the composition is particularly useful in the treatment of migraine-related conditions.

Description

[Technical Field]

[0001] This invention relates to novel pharmaceutical compositions. The invention also relates to methods for producing such compositions and formulating them into dosage forms. [Background technology]

[0002] Any listing or discussion of documents that have clearly been previously published in this specification should not necessarily be taken as an endorsement that the documents are part of the latest technology or common general knowledge.

[0003] Calcitonin gene-related peptide (CGRP) receptor antagonists block CGRP receptors, and their excessive activation has been reported in neurogenic vasodilation, neurogenic inflammation, migraines, cluster headaches and other headaches, heat injuries, cardiovascular shock, menopausal flushing, and asthma.

[0004] Monoclonal antibodies that bind to CGRP receptors or peptides are approved for the acute and / or prophylactic treatment of migraines (including fremanezumab, galcanezumab, eptinezumab, and erenumab). In addition, a class of small molecule CGRP receptor antagonists (collectively known as "gepant") are known to be useful as anti-migraine agents.

[0005] Commercially available gepants include Hubrogepant (Ubrelvy®), Atogepant (Qulipta®), Rimegepant (Nurtec®), and Zabegepant (Zavzpret®). Others under development include Orsegepant and Terukagepant. Other small molecule CGRP receptor antagonists include those with the codenames BI44370, MK-3207, and SB-268262. Gepants are typically marketed as oral tablets, while Zabegepant is marketed as a nasal spray.

[0006] In the treatment of acute injuries, a rapid onset of pharmacological effects is often required. In contrast to oral drug delivery, the principle of administration that immediately makes the drug available in the systemic circulation is more likely to result in such a rapid onset of action.

[0007] Transmucosal administration offers the possibility of directly delivering drug molecules into the systemic circulation via mucous membranes (e.g., rectum, sublingual, buccal, lung, and nasal cavity), potentially leading to benefits such as increased patient compliance, improved drug bioavailability, and therefore lower doses, faster onset of action, and reduced side effects.

[0008] However, the transmucosal administration of drugs presents its own very clear problems. Unlike the gastrointestinal tract, which is a large organ containing a relatively large amount of bodily fluids, spaces such as the oral cavity and nasal cavity are relatively small and contain much smaller amounts of bodily fluids such as saliva and / or mucus. This inevitably imposes considerable limitations on the amount of active ingredient that can be administered in a single dose.

[0009] Furthermore, while the gastrointestinal tract is a dynamic system, it is, for the most part, a somewhat "closed" system. Conversely, the rapid clearance mechanisms that occur in both the oral and nasal cavities often mean that there is also limited time available for absorption across the mucosal surface for already limited amounts of drugs.

[0010] To solve this problem, numerous formulation principles have been proposed, including bioadhesive formulation principles such as cheek patches for oral mucosal drug delivery (see, for example, Shojaei, J. Pharm. Pharmaceutical Sci., 15, 19 (1998) and Gandhi, Advanced Drug Delivery Reviews, 43, 67 (1994)) and in situ gel-forming compositions for intranasal drug delivery (see, for example, Bertan et al, Eur. J. Pharm. Sci., 27, 62 (2006)).

[0011] Solid transmucosal drug delivery systems may have a significant advantage in that they allow for higher drug loading in formulations. However, while solid drug delivery compositions are far more common when administered to the mucous membranes of the rectum, cheek, sublingual, and lungs, the majority of intranasal drug delivery systems remain in the form of liquid sprays, typically aqueous solutions, where drug solubility is another factor that limits the amount of drug that can be absorbed.

[0012] The reason why liquid sprays for intranasal delivery are almost everywhere is that it is not easy to formulate solid drug formulations in the form of nasal powders. Unlike powders that are frequently used for inhalation of active ingredients into the lungs, there are very few commercially available intranasal powder formulations.

[0013] When formulated as a dry powder, pulmonary drug delivery compositions typically take the form of an "aggregated" mixture containing finely ground API particles on larger carrier particles. These aggregates are intended to dissociate / decompose upon inhalation or activation of the device, leaving only the fine particles of the active ingredient to deposit in the lungs.

[0014] However, it is understood that such drug delivery systems do not work effectively in the case of intranasal drug delivery. This is because the presence of such microparticles poses a significant risk of exposure to the lungs, which are not the intended site of administration. If the particle size of the drug is increased to circumvent this problem, it is likely to become difficult to ensure proper interaction in heterogeneous "interacting" mixtures, which would then depend on a substantial difference in the sizes of the two components to ensure interaction, leading to potential manufacturing problems such as separation during filling. Attempting to counteract this by increasing the particle size of the corresponding carrier does not necessarily solve the problem, as it inevitably increases the mass of inactive excipients in the already finitely limited total mass of the dosage form, potentially leading to a reduction in the dose of the active ingredient.

[0015] The difficulty in formulating dry powders for intranasal delivery is addressed in U.S. Patent Application No. 2005 / 001411A1. This document states that powders for nasal administration need to be fine enough to be efficiently carried by gas flow and efficiently deposited in the nose, while also being coarse enough to facilitate the introduction of the powder into the appropriate powder device, which is always necessary for intranasal administration. U.S.2005 / 001411A1 apparently solves this problem by creating loosely formed secondary particles (aggregates) of primary particles containing the active ingredient. These aggregates are said to be several hundred microns in size, allowing for more efficient loading into appropriate intranasal administration (applicator, dispenser, or inhaler) devices. When such a device is activated and the composition is administered, the aggregates apparently rapidly decompose into primary particles of the active ingredient. These primary particles are only a few microns in size and are said to promote dissolution, and subsequently, the intranasal absorption of the active ingredient.

[0016] As mentioned above, transmucosal (e.g., intranasal) delivery of drugs intended for systemic absorption inevitably bypasses first-pass metabolism, which is a component of oral administration. Drug metabolism occurs through chemical reactions with enzymes that can alter the chemical structure, physical structure, and / or biological activity of the active ingredient.

[0017] Since most drugs are organic molecules containing functional groups that can undergo such chemical reactions, they are often susceptible to some form of chemical degradation when they come into contact with substances outside the body that can interact with those functional groups.

[0018] As summarized by Kou and Zhou in Chapter 16 of the textbook Amorphous Solid Dispersions, Shah et al (Eds.), Springer (2014), when drugs are formulated in an amorphous state, as opposed to a crystalline physical state, they are typically delivered in a higher energy state, making them more likely to be chemically and physically unstable, which presents a challenge for pharmaceutical manufacturers.

[0019] Therefore, chemical stability is often improved by providing the drug in a crystalline state via salt formation. The primary purpose of salt formation is usually to increase the hydrophilicity of the active ingredient and address the problem of poor aqueous solubility and dissolution rate. In salt preparation, other physicochemical and biological concerns, such as chemical stability, can often be addressed simultaneously. For example, basic drugs (e.g., drugs containing at least one amine group) are often provided in the form of acid addition salts, which are typically more chemically stable than the corresponding "free" amine base.

[0020] However, while crystalline salts can be stored more easily without chemical degradation and potentially provide the active ingredient in a more efficient form in terms of the rate and / or degree of dissolution after administration, they generally dissolve more slowly and are less efficiently absorbed across mucous membranes than when the corresponding active ingredient is provided in amorphous and / or non-ionized forms, respectively.

[0021] Therefore, while active pharmaceutical ingredients formulated as amorphous solid dispersions generally have the advantage of high bioavailability, they typically present challenges in the form of reduced physical and chemical stability. On the other hand, drugs formulated in crystalline and / or salt forms are generally more stable but tend to have lower bioavailability.

[0022] The latter problem can be particularly disadvantageous in cases of transmucosal drug delivery, such as intranasal or sublingual delivery, where, as discussed above, the residence time of the drug in the relevant cavity necessary for absorption into the systemic circulation is limited. This, coupled with poor transmucosal permeability at physiological pH, can result in unacceptably low and / or slow transmucosal absorption for adequate therapeutic effect.

[0023] To address the balancing act between solubility and permeability in a transmucosal drug delivery system, many sophisticated formulation principles have been devised over the years. Such formulation principles include the addition of pH modifiers that convert the ionized salt form of the active ingredient to a more permeable non-ionized state.

[0024] However, considering all of the aforementioned potential benefits it offers, the need for improved solid (e.g., powder-based) transmucosal, particularly intranasal, drug delivery systems still remains.

[0025] Particularly in the field of transmucosal drug delivery, there remains a significant unmet clinical need for the following powder drug delivery compositions: (i) Stable both physically and chemically, (ii) · At a sufficient dose and / or · In a form that penetrates sufficiently to provide the necessary therapeutic effect (such as rate of onset and / or access to the drug target) at a (relatively speaking) as low a dose as possible and with a short residence time available in a transmucosal situation such as intranasally.

[0026] In the more specific field of intranasal drug delivery, there remains a significant unmet clinical need for such drug delivery compositions that contain appropriately sized particles that enable both of the following efficiently: · Filling of the drug delivery device, and · Deposition within the associated (e.g., nasal) cavity. <00001,00><00001,01>Intranasal dry powder formulations are known, inter alia, from International Patent Applications Nos. 2010 / 142696 and 2019 / 038756, U.S. Patent No. 10,653,690B2, and U.S. Patent Application No. 2018 / 0092839A. See also U.S. Patents Nos. 7,947,742B2, 8,415,397B2, and 8,747,813B2. <00001,02><00001,03><00001,04>Russo et al (J.Pharm.Sci., 95, 2253 (2006)) disclose the spray-drying of opioid analgesic compounds, namely morphine, with numerous excipients. Spray-dried formulations are also disclosed in Vengerovich et al., Bulletin of Experimental Biology and Medicine, 163, 737 (2017), and attempts have been made to microencapsulate the active ingredient in various substances containing 2-hydroxypropyl-β-cyclodextrin, with a view to developing sustained-release formulations based on polymer carriers for emergency medical use.

[0029] In any case, there is a significant unmet clinical need for alternative or better (e.g., more versatile) drug delivery compositions containing one or more of the gepants.

[0030] Specifically, as disclosed below, one or more gepants can be formulated in the form of amorphous dry powder compositions by, for example, a process of spray-drying one or more of these active ingredients together with a carrier material. Such compositions are highly chemically stable during storage and before administration, and in addition, may provide improved bioavailability and / or absorption rate of gepant after administration. [Overview of the project]

[0031] According to a first aspect of the present invention, a pharmaceutically acceptable composition in the form of a solid amorphous single-particle powder, (a) a pharmacologically effective dose of a low-molecular-weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof, (b) A pharmaceutically acceptable composition is provided, comprising a mixture of a pharmaceutically acceptable carrier material, the carrier material comprising maltodextrin having more than 15 dextrose equivalents (DE), Pharmacologically acceptable compositions are collectively referred to as "the compositions of the present invention" below.

[0032] The term “CGRP receptor antagonist” includes any compound that can block the CGRP receptor and / or inhibit the activity of that receptor to a measurable degree. The term “low molecular weight CGRP receptor antagonist” includes any such compound having a molecular weight less than about 1,000 (e.g., about 900), such as about 300 to about 750. This term also includes hubrogepant, atogepant, rimegepant, zabegepant, orsegepant and terkagepant, as well as BI44370 (4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepine-3-yl)piperidine-1-carboxylic acid (R)-alpha-((4-morpholino-piperidino)carbonyl)-3,5-dimethyl-4-hydroxyphenyl ester), MK-3207 (2-[(8R)-8-(3,5-difluorophenyl)-10-oxo Compounds collectively known as “gepant” are also understood to include (-6,9-diazaspiro[4.5]decane-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroinden-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) and SB-268262 (N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)benzamide), as well as salts of any of these compounds. Preferred CGRP receptor antagonists include ubrogepant, atogepant, more preferably rimegepant, and in particular zabegepant, as well as salts of any of the aforementioned.

[0033] The compositions of the present invention are in the form of amorphous single-particle powders. "Single particle" means that the plurality of particles forming the powder composition of the present invention comprise a homogeneous or heterogeneous mixture in which a low molecular weight CGRP receptor antagonist or a salt thereof is encapsulated in an amorphous state within the carrier material defined above, optionally in the presence of other components. Thus, the particles of the powder composition of the present invention are provided as amorphous composites of a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof (hereinafter referred to as the "active ingredient"), the aforementioned carrier material, and optionally other components.

[0034] Due to their amorphous properties, the compositions of the present invention may be entirely amorphous and / or mainly amorphous (e.g., more than 50% amorphous, such as more than 75% amorphous including more than 80% amorphous, more than 90% amorphous including more than 99% amorphous, or more than 95% amorphous). Alternatively, the compositions of the present invention may be less than 50% crystalline, such as less than 25%, more preferably less than 20%, for example, less than 10% crystalline, such as less than 5% or less than 1%. The degree of crystallineness (%) may be determined by those skilled in the art using powder X-ray diffraction (PXRD). Other techniques such as solid-state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) trace calorimetry, and calculation of true density may also be used.

[0035] As will be described later, despite being in an amorphous physical state, the compositions of the present invention exhibit surprisingly unexpected physical and chemical stability and can therefore be provided in pharmaceutical form that exhibits excellent shelf life when stored under normal storage conditions.

[0036] The compositions of the present invention are produced by a suitable technique, at least initially in the form of several small particles (i.e., as powder). Generally, suitable techniques are classified into “solvent-based” methods, including spray drying, fluidized bed techniques, coprecipitation, supercritical fluid techniques, spray granulation, cryogenic techniques (including freeze-drying), electrospinning, and rotary jet techniques, or “fusion-based” methods, including melt granulation, melt extrusion, high-shear mixing (e.g., KinetiSol®), milling, and molten material techniques on a carrier (e.g., Meltdose®). Preferred methods include freeze-drying, and more preferably, the compositions of the present invention are produced by a spray-drying process.

[0037] Such powder may be suitable for direct delivery to a patient via any pharmaceutically acceptable route of administration, or may be provided as an intermediate composition that can be later formulated into a pharmaceutically acceptable dosage form for administration to one or more patients.

[0038] In this regard, pharmaceutical formulations and / or pharmaceutically acceptable dosage forms are provided, which are administered to a patient and contain one or more compositions of the present invention.

[0039] Therefore, suitable pharmaceutical dosage forms may include liquid formulations such as solutions, which can be prepared by dissolving the composition of the present invention in a pharmaceutically acceptable solvent (such as water) (for example, immediately before administration) for delivery to such patient by injection or infusion.

[0040] Alternative pharmaceutical dosage forms may include liquid or semi-solid formulations such as liquid suspensions and / or gel compositions that contain the composition of the present invention (e.g., its particles) suspended or dissolved in a suitable liquid or semi-solid carrier, which can be loaded into a suitable dosage form, or delivered by, for example, injection or infusion, or formed to form an implant or depot formulation after injection (e.g., subcutaneous or intramuscular).

[0041] Alternatively, the compositions of the present invention may be provided as part of an essentially solid pharmaceutical dosage form. It will be well understood by those skilled in the art that the term “solid” includes any form of substance that retains its shape and density when not confined and / or whose molecules are generally compressed as tightly as the repulsive forces between them allow. Thus, an essentially solid dosage form is a formulation in which at least about 80% is in such a form, such as at least about 90%, or at least about 95% (or at least about 99%).

[0042] In this regard, the compositions of the present invention may be provided in any particle form (e.g., simple powder, granules, pellets and / or beads) comprising a plurality of particles, which may be essentially composed of and / or comprise one or more such compositions individually and / or collectively.

[0043] Therefore, the compositions of the present invention may be provided after being prepared (for example by spray drying) in the form of a simple powder mixture, powder microspheres, coated powder microspheres, lyophilized liposome dispersions, or combinations thereof.

[0044] If a pharmaceutically acceptable dosage form of the present invention "essentially consists of" particles of one or more compositions of the present invention, this is understood to mean that the dosage form comprises only one or more compositions of the present invention, along with other features and / or components that do not substantially affect the basic and novel properties of the dosage form. Alternatively, in situations where a dosage form of the present invention "essentially consists of" one or more compositions of the present invention, this may be understood to mean that the dosage form comprises at least about 90% of one or more compositions of the present invention, such as at least about 95% including at least about 97% by weight (e.g., about 99%).

[0045] Alternatively, the pharmaceutical dosage form may comprise one or more compositions of the present invention in a single unit dosage form such as a pessary, suppository or other form of insert, pill, capsule, cake, patch (e.g., cheek patch), film (e.g., intraoral film), or tablet (e.g., sublingual tablet).

[0046] Capsules can be prepared by directly loading the composition of the present invention as a spray-dried powder into pharmaceutically acceptable capsules made from suitable materials designed for sublingual or preferably oral delivery, or by mixing the composition with excipients before loading into capsules for such delivery, which may involve the granulation step described below.

[0047] In this regard, the compositions of the present invention can be granulated into pellets or pills, but they can also be formulated in the form of a dry, free-flowing powder (i.e., provided for administration).

[0048] "Dry" means essentially free of water and other liquid solvents, and this includes less than 10%, more preferably less than 3%, such as less than 2%, including less than 1%, of the formulation being a liquid such as water, including less than 5% or less than 4%, including less than 6%.

[0049] The fluidity of the powder composition of the present invention can be measured by standard techniques known to those skilled in the art, including measurements performed with a powder flow analyzer (for example, both sold by Stable Micro Systems or Meritics in the UK), which includes bulk density measurement, powder flow rate dependence tests, cake formation tests, and agglomeration tests. A preferred measurement of fluidity is the standard angle of repose, which can be performed using a rotating cylinder, a stationary funnel, or an inclined box.

[0050] In the context of the present invention, the term “freely flowable” is intended to include powders that enable the composition of the present invention to be efficiently filled into a drug delivery device during manufacturing and / or provide sufficient shot weight when discharged from the device (see below).

[0051] This term may also include the powder exhibiting an angle of repose of approximately 50° or less, such as approximately 35° or less, including approximately 45° or less, including approximately 40° or less; a bulk density of approximately 0.4 g / mL or more, such as approximately 0.5 g / mL or more, including approximately 0.6 g / mL or more; and / or a tap density of approximately 0.5 g / mL or more, such as approximately 0.7 g / mL or more, particularly approximately 0.8 g / mL or more.

[0052] Suitable techniques for producing dosage forms containing dry powder or granules include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletizing, and spray granulation), extrusion / spheroidizing, or more preferably freeze-drying or spray-drying (see below).

[0053] Dry granulation techniques are also well known to those skilled in the art and include any technique in which primary powder particles are agglomerated under high pressure, including slugging and roller compression, as described below, for example.

[0054] Wet granulation techniques are well known to those skilled in the art and include any technique involving the agglomeration of a mixture of dry primary powder particles using a granulation fluid containing a volatile inert solvent such as water, ethanol, or isopropanol, alone or in combination, and optionally in the presence of a binder or conjugate. This technique may involve passing the wet agglomeration through a sieve to produce wet granules, which are then dried, preferably with a drying loss of less than about 3% by weight.

[0055] It is known to those skilled in the art that melt granulation includes any technique by which granules are obtained via the addition of a molten binder or a solid binder that melts during the process (these binder materials may include pharmaceutically acceptable carrier materials of the composition of the present invention). After granulation, the binder solidifies at room temperature. Thermoplastic pelletizing is known to be similar to melt granulation, but the plastic properties of the binder are utilized. In both processes, the resulting aggregates (granules) contain a matrix structure.

[0056] It is well known to those skilled in the art that extrusion / spheroidization includes any process involving dry mixing of components, wet agglomeration with a binder, extrusion, spheroidization of the extruded material into a uniformly sized ellipsoid, and drying.

[0057] It is known to those skilled in the art that spray granulation includes any technique involving the simultaneous drying of a liquid (solution, suspension, or melt) and accumulation of granules in a fluidized bed. Therefore, in addition to generally including any spray coating granulation technique, the term includes the process of providing external supply particles (sources) upon which granules accumulate, as well as the process of forming intrinsic supply particles (sources) in the fluidized bed by abrasion and / or crushing. The sprayed liquid covers the source, aiding further aggregation of particles. It is then dried to form granules in the form of a matrix.

[0058] The term "freeze-drying" includes lyophilization or cryodesication, and any low-temperature desolvation (e.g., dehydration) process in which the product is frozen, the pressure is reduced, and the freezing solvent (e.g., water) is removed by sublimation.

[0059] Alternatively, the compositions of the present invention may be provided in the form of tablets for oral, buccal, and / or sublingual use. Such tablets may be formed by direct compression / compaction of the compositions of the present invention after being mixed with one or more suitable excipients, optionally, such as diluents, disintegrants, flow enhancers, and / or lubricants, and may be achieved using techniques such as those described in Pharmaceutical Dosage Forms: Tablets. Volume 1, 3rd Edition, Augsburger et al (eds.), CRC Press (2008) and the documents cited therein. Suitable compression equipment includes standard tablet presses such as the Kilian SP300 or Korsch EK0, XP1, XL100, and XL200.

[0060] Suitable disintegrants that can be used in tablets (as defined, for example, in Rowe et al, Handbook of Pharmaceutical Excipients, 6th ed. (2009)) include cellulose derivatives such as hydroxypropylcellulose (HPC), low-substituted HPC, methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, and modified cellulose gum; starch derivatives such as cross-linked starch, modified starch, hydroxypropyl starch, and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, magnesium aluminum silicate, polariline potassium, and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used.

[0061] Preferred disintegrants include so-called "super-disintegrants" (as defined, e.g., Mohanachandran et al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as cross-linked polyvinylpyrrolidone, sodium starch glycolate, and croscarmellose sodium. Combinations of two or more super-disintegrants may be used.

[0062] When disintegrants and / or superdisintegrants are used in tablets, they may be used in amounts of 0.5 to 15% by weight (e.g., total) based on the total weight of the composition. A preferred range is 1 to 8% by weight (e.g., about 5% by weight, such as about 4% by weight), such as about 2 to about 7% by weight.

[0063] If present, the binder is preferably used in an amount of 0.5 to 20% by weight based on the total weight of the tablet formulation. A preferred range is 1.0 to 15% by weight, for example, about 2.0 to about 12% by weight (for example, about 10% by weight). Suitable binders include cellulose gum and microcrystalline cellulose.

[0064] As described herein, the compositions of the present invention are preferably prepared by a spray-drying process.

[0065] Furthermore, dosage forms containing the compositions of the present invention, whether in powder form or not, can otherwise be prepared using standard equipment and by standard techniques known to those skilled in the art. In this regard, the compositions of the present invention can be combined with conventional pharmaceutical excipients and / or excipients used in the art for related preparations to produce dosage forms containing the compositions of the present invention, and incorporated into various types of pharmaceutical preparations using standard techniques (see, for example, Lachman et al, 'The Theory and Practice of Industrial Pharmacy', CBS, 4th edition (2015), 'Remington: The Science and Practice of Pharmacy', Troy (ed.), Elsevier, 23rd edition (2020), and / or 'Aulton's Pharmaceutics: The Design and Manufacture of Medicines', Taylor and Aulton (eds.), Elsevier, 5th edition, 2017).

[0066] Regardless of the manufacturing method, the composition of the present invention is preferably suitable for transmucosal delivery of the active ingredient to the systemic circulation and / or is formulated for that purpose.

[0067] Those skilled in the art will understand that the term “transmucosal” means that the composition is provided to the relevant mucosal surface in such a form that, regardless of how it is administered to the patient, the active ingredient(s) can be absorbed across the mucosal surface after dissolution. Thus, the relevant mucosal surfaces include the mucosa of the oral cavity, nose, eyes, vagina, cervix, lungs and / or anorectum, more particularly the oral mucosa (including the mucosa of the cheeks and sublingual area) and especially the nasal mucosa.

[0068] Therefore, dosage forms containing the composition of the present invention can be administered directly to the mucosal surface of a patient (including the lungs, rectum, vagina, cheek, sublingual or intranasal cavity) for transmucosal delivery of the active ingredient.

[0069] When administered sublingually, the compositions of the present invention may be in the form of, for example, sublingual tablets, which may contain disintegrants or disintegrating agents (defined as any material capable of accelerating the disintegration / dispersion of such compositions of the present invention to a measurable degree), which can be achieved, for example, by a material capable of swelling and / or expanding when in contact with an aqueous medium, as described below.

[0070] Alternatively, the compositions of the present invention may be administered sublingually in the form of powder as described herein, or they may be dispensed orally and under the tongue from a suitable container such as a capsule or pouch.

[0071] If the compositions of the present invention are suitable for sublingual administration, or in particular intranasal administration, and / or formulated for that purpose, they are preferably administered in the form of powder compositions in which the dosage of the active ingredient is about 150 mg or less, such as about 100 mg. Such sublingual and / or nasal powder compositions may include the compositions of the present invention mixed with other excipients, or may essentially consist of the compositions of the present invention as defined above.

[0072] Compositions of the present invention suitable for intranasal administration and / or formulated for that purpose are preferably provided by a drug delivery means suitable for nasal delivery. Such a drug delivery means may contain one, for example, a spray-dried powder composition of the present invention, or two or more such compositions, in the reservoir of a suitable applicator. In the latter case, the drug delivery means contains two or more doses of the composition of the invention, each dose containing a pharmacologically effective dose(s) of the active ingredient.

[0073] Two or more compositions of the present invention can be administered intranasally by repeated activation of a device that is equipped with a means for administering the drug, or communicates with such means. Accordingly, the compositions of the present invention may be provided in a suitable device (e.g., a nasal applicator or dispenser (inhaler), e.g., as described below) and / or in a container or reservoir that is part of, attached to, and / or suitable for being attached to, such an applicator. Such a container or reservoir may contain one or more compositions of the present invention, each containing a pharmacologically effective dosage of the active ingredient.

[0074] Thus, a suitable dispensing means and / or nasal applicator may be activated once to deliver a single composition of the present invention containing an appropriate dose of the active ingredient (i.e., a single-use dispensing unit), or activated two or more times to deliver two or more compositions of the present invention, each containing an appropriate dose of the active ingredient, with each such activation (i.e., a multi-use dispensing unit), and / or the applicator may be refilled with a source (e.g., a container or reservoir) of one or more such compositions of the present invention to provide single and / or multi-use doses and / or dispensing regimens.

[0075] Therefore, the composition of the present invention can be administered in the form of multiple particles, which may individually and / or collectively constitute and / or contain the composition of the present invention.

[0076] Therefore, the compositions of the present invention can be prepared (first) in the form of a solid, dry, free-flowing powder, as described herein.

[0077] As described above, the compositions of the present invention are provided in the form of amorphous single-particle powders. They do not consist of a physical association of two or more distinct and isolated sets of particles of different components, but rather in the form of mixtures such as regular or interacting mixtures in which smaller particles of the active ingredient are associated with larger, but separated, chemically distinct particles of a carrier material. That said, the compositions of the present invention can then be provided as small particles that can adhere to separated larger carrier particles in an interacting mixture, and such a provision is useful in the case of dosage forms intended for inhalation, e.g., the lungs (see, for example, J. Drug Delivery, Art. ID 5635010, 1-19 (2018)).

[0078] As described above, the process for producing the compositions of the present invention enables the formation of pharmaceuticals that exhibit excellent shelf life in terms of both physical and chemical stability when stored under normal storage conditions as defined herein.

[0079] The compositions of the present invention are preferably prepared by a spray-drying process. Those skilled in the art will understand that the “spray-drying” process includes any method of producing a dry powder from a liquid, including a solution or suspension (including a slurry), which involves rapidly drying the liquid flow using a high-temperature gas to convert it into solid particles containing a vaporized solvent, as well as solutes that were previously dissolved in the solution and / or particles that were previously suspended in the evaporated liquid.

[0080] A suitable spray drying apparatus includes some form of atomizing means, such as a spray nozzle, which disperses the liquid into a spray having a relatively uniform droplet size. Such means may include any means capable of producing a dry, free-flowing powder, and may include a high-pressure swirl nozzle, a rotating disk and / or atomizer wheel, a high-pressure single-fluid nozzle, a two-fluid nozzle and / or an ultrasonic nozzle.

[0081] The spray dryer may be a single-effect or multi-effect spray dryer and may include an integrated and / or external vibrating fluidized bed, a particle separator, and / or a collection means which may be a drum or cyclone.

[0082] A further aspect of the present invention provides a process for producing the composition of the present invention, the process being: i) A step of mixing a small molecule CGRP receptor antagonist or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier material in a suitable volatile solvent, ii) a step of spray-drying the mixture from step i).

[0083] Preferred volatile solvents include water and / or lower alkyl alcohols (e.g., methanol, isopropanol, or more particularly, ethanol), hydrocarbons (e.g., C 5-10 Organic solvents include alkanes, haloalkanes (e.g., dichloromethane), dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone, or mixtures thereof.

[0084] Preferably, the active ingredient, the pharmaceutically acceptable carrier material(s) defined herein, and any other optional component described herein (e.g., the alkyl saccharides described below) are mixed together with a solvent to obtain a solution that can be spray-dried.

[0085] The pharmaceutically acceptable carrier material used in the composition of the present invention must be solid under normal storage conditions, suitable (and / or approved) for pharmaceutical use and / or transmucosal (e.g., sublingual or especially intranasal) delivery, capable of maintaining its physical and / or chemical integrity, and / or not affecting the physical and / or chemical integrity of the active ingredient and / or any other components (such as alkyl saccharides) present or potentially present in the composition.

[0086] It is well known that significant difficulties can arise when attempting to obtain solid compositions, such as powders, that are chemically and physically stable. If the physical form of the composition changes under normal storage conditions (for example, from a freely flowing powder to agglomerated clumps that are difficult to dispense), the reproducibility of the active ingredient dose may be lost. This is especially true when dispensing the composition from or through the nasal applicators described herein, where such aggregation may make it completely impossible to dispense the active ingredient, which can be fatal in an emergency.

[0087] Accordingly, the compositions of the present invention may have individual powder shot weights relative to about 80% of the target weight, such as about 85% (e.g., about 90%) to a maximum of about 120% (e.g., about 115%), and / or a minimum shot weight measured by the average powder shot weight relative to about 85% of the target weight, such as about 90% (e.g., about 95%) to a maximum of about 115% (e.g., about 110%).

[0088] Similarly, in the case of multi-dose units containing two or more doses of the composition, such stability is important to ensure the reproducibility of the active ingredient dose over time. Any of these issues could have adverse effects on the subject's health and / or put the subject's well-being at significant risk.

[0089] In the case of certain compositions of the present invention, exposure to moisture in the atmosphere may result in powder compositions with low solid stability. For example, exposure to certain (e.g., relatively high) relative humidity may affect the physical form of the composition, for example, by deliquescence and / or by lowering the glass transition temperature of the composition and / or individual components of the composition such as the carrier material, or in other ways.

[0090] Accordingly, the compositions of the present invention, as well as pharmaceutical formulations and means of administration (such as nasal applicators) containing them, are preferably packaged in a container that substantially prevents the ingress of moisture from the atmosphere under the storage conditions defined herein. Such containers may include packaging materials such as blister packs for tablets and capsules and heat-sealed aluminum pouches and / or thermoformed plastics. Such containers may also include a desiccant, for example, silica gel with a pore size of 3 Å or 4 Å and / or a suitable molecular sieve.

[0091] The phrase "maintain physical and chemical integrity" essentially means chemical stability and solid stability.

[0092] "Chemical stability" means that any composition of the present invention, when formulated into a pharmaceutical formulation or dosage form and / or loaded into a pharmaceutical delivery device such as a nasal applicator or reservoir (with or without appropriate pharmaceutical packaging as described herein), or otherwise can be stored in an isolated solid form with slight chemical degradation or decomposition of the composition itself or any of the active ingredients contained herein under normal storage conditions.

[0093] The term "chemical stability" also includes "stereochemical" and / or "constitutive" stability, which refers to resistance to stereochemical transformations, such as racemization, at one or more chiral centers within the molecule of the active ingredient.

[0094] "Physical stability" or "solid stability" means that any composition of the present invention, when formulated into a pharmaceutical formulation or dosage form and / or loaded into a pharmaceutical delivery means such as a nasal applicator or reservoir (with or without a suitable pharmaceutical package as described herein), or otherwise, can be stored in an isolated solid form with some degree of solid change (e.g., crystallization, recrystallization, loss of crystallinity, solid phase transition (e.g., between glassy and rubbery states, or to aggregated forms)), hydration, dehydration, solvation, or desolvation of the composition itself or any of the active ingredients contained therein.

[0095] Examples of “normal storage conditions” for the compositions of the present invention include, whether in the form of a pharmaceutical formulation or dosage form and / or loaded into a pharmaceutical dispensing means loaded into an applicator, device, drug reservoir (such as a canister or container that can substantially prevent the ingress of moisture from the atmosphere as described herein), or otherwise, for a long period of time (i.e., about 12 months or more, such as about 6 months), a temperature of about -50°C to about +80°C (preferably about -25°C to about +75°C, such as about 50°C), and / or a pressure of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to UV / visible light of at least about 460 lux, and / or relative humidity of about 5 to about 95% (preferably about 10 to about 40%).

[0096] Under such conditions, it may be found that the compositions of the present invention (and / or the active ingredients contained herein), whether contained in an applicator or its reservoir (with or without suitable pharmaceutical packaging as described herein), or otherwise, may be chemically degraded / decomposed and / or converted to solids, as needed, by less than about 15%, more preferably less than about 10%, and particularly less than about 5%. Those skilled in the art will understand that the above upper and lower limits of temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes are not experienced during normal storage (e.g., 50°C and 0.1 bar pressure).

[0097] Such chemical stability, and especially physical stability, is important in solid compositions such as powders to ensure that the appropriate dose is delivered to the patient.

[0098] Notwithstanding the above definition of “normal storage conditions,” the compositions of the present invention (and / or the active ingredients contained herein) may be chemically and / or stereochemically degraded to less than 5%, such as less than 4%, after storage (including less than 2.5%, such as less than 3%, such as less than 2%, including less than 1%, and less than 1.5%, such as less than 1% and less than 0.5%), respectively: whether contained in an applicator or its reservoir (neither of which may be accompanied by a suitable pharmaceutical package and may or may not provide a barrier to moisture as described above), or otherwise: (a) At 40°C and 75% relative humidity, for at least about 3 months, including at least about 6 months or at least about 12 months. (b) at a temperature of less than approximately 30°C, such as approximately 30°C or approximately 25°C, and / or at a relative humidity of approximately 65%, such as approximately 60%, for at least approximately 18 months, such as at least approximately 24 months, including at least approximately 36 months, and / or (c) UV light exceeding approximately 1 million lux for at least approximately 18 hours.

[0099] Therefore, the compositions of the present invention can be stored in a dosage form such as an applicator or its reservoir (with or without appropriate pharmaceutical packaging / moisture barrier) at any temperature from a low temperature of approximately -20°C to a maximum of approximately 25°C (for example, up to approximately 30°C), preferably with fluctuations of up to approximately 40°C or even further up to approximately 50°C.

[0100] The compositions of the present invention include, at least in part, a carrier material comprising maltodextrin having a DE of 15 or more, for example, up to 47 such as 38, 39, preferably 23, 24, 25, or 26, or more preferably 16, 17, 18, 20, 21, or 22, particularly 19 DE. Maltodextrin having a DE of 20 or more will be understood by those skilled in the art to be referred to as "glucose syrup".

[0101] Maltodextrins are classified by their DE (Depth Equivalent), with higher DE values ​​indicating shorter average glucose chain lengths. Therefore, maltodextrins with a DE greater than 15 have a lower average molecular weight than those with a DE of 15 or less. All maltodextrins are mixtures of polysaccharides with different chain lengths, and maltodextrins with a DE greater than 15 have fewer sugar units with larger molecular weights.

[0102] Maltodextrin suitable for use in the compositions of the present invention, however, needs to have a sufficiently high molecular weight so that, when used in any given amount, it can form a solid carrier material suitable for the active ingredient, including providing an appropriate degree of physical stability.

[0103] More preferred pharmaceutically acceptable carrier materials that can be used in the compositions of the present invention include combinations of the relevant maltodextrin and disaccharide components. Preferred disaccharides include maltitol, sucralose, sucrose, isomalt, maltose, preferably trehalose, and especially lactose (including β-D-lactose and α-D-lactose, especially α-D-lactose monohydrate).

[0104] We have found that maltodextrins with lower DEs, such as maltodextrins with a DE of 12 or less, contain longer polysaccharide chains (e.g., those with approximately 24 or more glucose units) and tend to form helical structures that can form aggregates when present in aqueous solution with the active ingredient and / or other components such as surfactants like sucrose esters, resulting in a turbid solution before spray drying. These aggregates can cause stability and / or processability problems during manufacturing, necessitate the use of in-line filters, and / or adversely affect the dissolution and / or absorption of the active ingredient.

[0105] We have found that the aforementioned aggregate / turbidity problem can be mitigated to some extent by reducing the relative amount of maltodextrin contained in the composition of the present invention, which can be achieved by increasing the amount of other components such as other carrier materials (e.g., disaccharides), active ingredients, or certain additives such as sucrose esters, and the higher the molecular weight of maltodextrin, the more disaccharides or sucrose esters need to be added to mitigate turbidity.

[0106] If more sucrose esters are added to reduce the number of aggregates and / or this turbidity, more may need to be added than is required to provide the appropriate (e.g., physical, chemical, and / or biological) effects, including the absorption-enhancing effect, as described herein. Conversely, increasing the amount of disaccharide relative to maltodextrin in the carrier material may have a negative effect on Tg and therefore a negative effect on the solid stability of the compositions described herein.

[0107] We found that such problems can be reduced, and perhaps even completely avoided, by using completely different maltodextrins, i.e., those with higher DEs, such as those with DE15 or more, e.g., DE18, DE20, or more preferably DE19.

[0108] A mixture from any of the aforementioned lists of disaccharides and / or maltodextrins having more than 15 DEs may be used.

[0109] The total amount of carrier material that can be used in the composition of the present invention is typically in the range of about 5% to about 99.9% by weight, including up to about 99% by weight (e.g., up to about 95% or about 90%), such as about 10% by weight (e.g., about 25% by weight including about 35% by weight) to about 85% by weight, including about 50% by weight to about 75% by weight, based on the total weight of the composition.

[0110] Whether or not provided as a combination of materials, or otherwise, the carrier material is preferably capable of producing a composition of the present invention having the following glass transition temperature (Tg): (a) It can be produced as a hard and / or brittle, “glassy,” amorphous, powdery physical form that can be easily formulated into pharmaceutical preparations or dosage forms and / or can be easily loaded into a suitable drug dispensing means such as a nasal applicator described herein, or a drug reservoir and / or container attached to such applicator, and (b) As described above, such pharmaceutical formulation, dosage form, or means of administration such as an applicator or reservoir is packaged and subsequently exposed to a high external temperature (e.g., up to about 50°C to about 80°C) such that the composition remains in its glassy state rather than converting to a more viscous or rubbery state and / or a crystalline state.

[0111] Such extreme external temperatures can be experienced inside a vehicle, for example, in warm and / or sunny climates, and such vehicles are frequently parked in direct sunlight for extended periods, resulting in enormous heat. If the Tg of a composition (e.g., powder) is low, the composition may convert to such a viscous / rubbery state after exposure to such high temperatures, which results in inefficient administration of the composition of the present invention, for example, inefficient release of the composition (and dose(s) of the active ingredient) from the dispensing means such as an applicator or reservoir contained therein when the dispensing means or applicator is activated. Furthermore, if the Tg is too low, it may affect the disintegration and / or dissolution of the composition of the present invention in the form of tablets for sublingual or oral use.

[0112] In this regard, the lowest measurable Tg of the composition of the present invention is preferably at least about 35°C, including at least about 40°C, including at least about 50°C, including at least about 60°C, when measured at relative humidity up to about 35%, including at least about 25%, including at least about 30%, including at least about 25% (e.g., up to about 20%, including less than about 15%, e.g., less than about 10%). The “lowest measurable Tg” includes the fact that the composition of the present invention may contain particles that are heterogeneous in their properties. In particular, the particles may contain distinct regions of the carrier material or composite mixtures thereof, and therefore may have individual and distinct Tg values. It will be apparent to those skilled in the art that the value of the lowest measurable Tg has a strong influence on the physical stability of the composition.

[0113] We have found that the composition of the present invention can provide an appropriate level of physical and chemical stability for the composition and its active ingredients.

[0114] Therefore, particularly preferred combinations of carrier materials include trehalose, or more particularly lactose, and maltodextrin having a DE greater than 15, such as maltodextrin 19DE. The inventors have found that such combinations of carrier materials can be spray-dried in appropriate ratios together with the active ingredients and, if present, alkyl saccharides, to produce compositions of the present invention having both the desired physical and chemical stability under normal storage conditions as defined herein.

[0115] We have found that when used as the main components of a carrier material, the relative amounts of the disaccharide and maltodextrin components can be adjusted to ensure the desired level of physical and / or chemical stability of the active ingredient, while simultaneously preventing a decrease in the Tg of the composition of the present invention in a manner that would affect its physical stability.

[0116] Depending on the active ingredient used, it has been found that a disaccharide:maltodextrin ratio of about 50:1 to about 1:50 by weight may work, based on the total weight of the composition. Preferred ratios are in the range of disaccharide:maltodextrin ratios of about 10:1 to about 1:40 by weight (including up to about 1:30 or up to about 1:20), based on the total weight of the composition, including about 7:1 to about 1:5, including about 5:1 such as about 4:1, about 3:1, or about 2:1, including about 1:10, including about 1:8 such as about 1:3 or 1:2, and more preferably about 8:1 (e.g., 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1) to about 1:8 (e.g., about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1) by weight. More specific disaccharide:maltodextrin ratios that may be mentioned include approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, approximately 2.5:1, approximately 2.25:1, approximately 2:1, approximately 1.75:1, approximately 1.5:1, approximately 1.25:1, approximately 1:1, approximately 1:1.25, approximately 1:1.5, approximately 1:1.75, approximately 1:2, approximately 1:2.25, approximately 1:2.5, more preferably approximately 2:1, approximately 1.5:1, or approximately 1.75:1.

[0117] Regardless of their proportions in the final mixture, the compositions of the present invention may be prepared by spray-drying the relevant components to form a composite carrier material, either before spray-drying the carrier material together with other essential components to form the powder composition of the present invention. More preferably, the compositions of the present invention may be prepared in situ by spray-drying all of the essential components of the composition of the present invention together.

[0118] A combination of a low-molecular-weight CGRP receptor antagonist or a salt thereof may be used in the composition of the present invention.

[0119] Salts of small molecule CGRP receptor antagonists include any such salts known in the art and described in medical literature such as Martindale—The Complete Drug Reference, 40th Edition, Pharmaceutical Press, London (2020) and the documents referenced therein (all disclosures relating to those documents are incorporated herein by reference).

[0120] Otherwise, pharmaceutically acceptable salts include acid addition salts and base addition salts, which can be formed by conventional means, for example, by reacting the relevant active ingredient in the form of a free acid or free base with one equivalent or more of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying, or filtration). Salts can also be prepared using techniques known to those skilled in the art, for example, by exchanging a counterion of the compound of the present invention in the form of a salt with another counterion using a suitable ion-exchange resin.

[0121] Certain acid addition salts that may be mentioned include carboxylates such as succinates, tartrates, formates, acetates, benzoates, oxalates, fumarates, maleates, and xinafoates; sulfonates such as methanesulfonates, ethanesulfonates, and toluenesulfonates; halides such as hydrochlorides and hydrobroms; and sulfates and phosphates such as sulfates, hemisulfates, or phosphates.

[0122] Certain salts of rimegepant that may be mentioned include sulfates and hemisulfates. Certain salts of zabegepant that may be mentioned include hydrochlorides.

[0123] When the compositions of the present invention are prepared by the aforementioned solvent-based processes, including those by spray drying, this may result in the presence of the active ingredients in a form that is no longer in the form of crystalline salts, as they are freely dispersed and encapsulated within an amorphous carrier material. However, despite not being in the form of crystalline salts that are typically present in the case of solid mixtures and / or powder compositions, the compositions of the present invention may retain little to no chemical stability of their active ingredients under the storage conditions referred herein.

[0124] The amount of the active ingredient that can be used in a single dose of the composition of the present invention must be sufficient to exert its pharmacological effect. For compositions of the present invention administered transmucosally (e.g., sublingually, buccally, and especially intranasally), the amount should not exceed about 150 mg in a single dose. Actual doses of the relevant active ingredients are known in the art and are described in medical literature such as Martindale—The Complete Drug Reference, 40th Edition, Pharmaceutical Press, London (2020) and the documents referenced therein, and all relevant disclosures in those documents are incorporated herein by reference. However, compositions of the present invention may be found to exhibit better bioavailability and / or rapid absorption compared to prior art compositions containing the same active ingredients, resulting in a faster onset of action and / or higher plasma concentrations.

[0125] In this regard, the pharmacologically appropriate amount of the active ingredient in the composition of the present invention may be less than the amount mentioned in the literature (see above). Nevertheless, such an amount may be determined by those skilled in the art and may vary depending on the type and severity of the condition being treated, as well as what is best suited to the individual patient. This is also likely to vary depending on the properties of the formulation, the type and severity of the condition being treated, and the age, weight, sex, renal function, hepatic function, and response of the particular patient being treated.

[0126] Depending on the potency of the active ingredient and the final dosage form used, the total amount of the active ingredient that can be used in the composition of the present invention may range from about 0.0002% by weight, for example, about 0.01% by weight including about 0.1% by weight (e.g., about 1%, about 2%, or about 5%), to about 10% by weight (e.g., about 20%), up to a maximum of about 95% by weight, for example, about 50% by weight, for example, about 40% by weight. This is independent of the number of distinct doses of the composition initially present in the drug delivery means according to the present invention (these doses must be the same).

[0127] For transmucosal administration, including administration to the lungs, cheeks, sublingually, or preferably intranasally, appropriate doses of the active ingredient (calculated as free acid / base) per kg of body weight range from approximately 10 μg / kg to approximately 2.5 mg / kg, including approximately 1 mg / kg, approximately 800 μg / kg, approximately 500 μg / kg, or approximately 250 μg / kg, such as approximately 30 μg / kg, approximately 20 μg / kg, or approximately 60 μg / kg, such as approximately 20 μg / kg, such as approximately 20 μg / kg, such as approximately 30 μg / kg, approximately 50 μg / kg, or approximately 60 μg / kg, such as approximately 2.5 mg / kg, such as approximately 1 mg / kg, approximately 800 μg / kg, approximately 500 μg / kg, or approximately 250 μg / kg.

[0128] Alternatively, the appropriate dose of the active ingredient per unit dose (calculated as free acid / base) ranges from approximately 1 mg (e.g., approximately 5 mg, such as approximately 8 mg) to approximately 150 mg (e.g., approximately 100 mg), depending on the active ingredient used, ranging from approximately 10 mg to approximately 75 mg (e.g., approximately 10 mg to approximately 60 mg, such as approximately 20 mg).

[0129] When administered via mucosal administration, including administration into the lungs, cheeks, sublingually, or preferably intranasally, a specific dose is: Hubrogepant is available in doses ranging from approximately 10 mg (e.g., approximately 25 mg) to a maximum of approximately 125 mg, including a maximum of approximately 100 mg, and / or a maximum of approximately 150 mg (e.g., approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg or approximately 50 mg to a maximum of approximately 150 mg, approximately 125 mg, approximately 100 mg, approximately 90 mg, approximately 80 mg, approximately 70 mg or approximately 60 mg) per day and / or per unit dose. Atogepant is administered in doses ranging from approximately 1 mg (e.g., approximately 5 mg) to a maximum of approximately 100 mg (e.g., approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg or approximately 10 mg to a maximum of approximately 100 mg, approximately 75 mg, approximately 60 mg, approximately 50 mg, approximately 40 mg, approximately 30 or approximately 20 mg) per day and / or per unit dose. Rimegepant is administered daily, every other day, and / or per unit dose in the range of approximately 5 mg (e.g., approximately 10 mg) to approximately 100 mg (e.g., approximately 5 mg, approximately 10 mg, approximately 25 mg, approximately 40 mg or approximately 50 mg to a maximum of approximately 100 mg, approximately 90 mg, approximately 80 mg, approximately 70 mg or approximately 60 mg). Zabegepant is administered in doses ranging from approximately 1 mg (e.g., approximately 5 mg) to approximately 30 mg (e.g., approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg or approximately 9 mg to a maximum of approximately 30 mg, approximately 20 mg, approximately 15 mg or approximately 10 mg) per day and / or per unit dose. In each case, these are calculated as free (acid / base) compounds.

[0130] The dose of the active ingredient may be delivered into the nasal cavity by a composition of the present invention comprising the specifics described below. A dose greater than the relevant amount so so specified below may, alternatively, be delivered by pre-loading a larger amount of the relevant composition, including a nasal applicator as defined herein, into a nasal device to provide a higher predetermined dose of the active ingredient (i.e., increasing the “filling weight” below).

[0131] For other forms of administration (e.g., injection or oral administration), the appropriate dose of the active ingredient per unit dose (calculated as free acid / base) ranges from approximately 1 mg (e.g., approximately 5 mg, such as approximately 8 mg) to approximately 300 mg (e.g., approximately 200 mg), such as approximately 10 mg to approximately 250 mg (e.g., approximately 30 mg to approximately 200 mg).

[0132] When administered via routes other than transmucosal administration, a specific dose: • Hubrogepant is available in doses ranging from approximately 25 mg (e.g., approximately 50 mg) to a maximum of approximately 100 mg or a maximum of approximately 200 mg (e.g., approximately 25 mg or approximately 50 mg to a maximum of approximately 200 mg, approximately 150 mg or approximately 100 mg) per day and / or per unit dose. Atogepant is available in doses ranging from approximately 5 mg (e.g., approximately 10 mg) to approximately 100 mg per day and / or per unit dose, up to approximately 125 mg (e.g., approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg or approximately 50 mg to approximately 125 mg, approximately 100 mg, approximately 75 mg, approximately 70 mg or approximately 60 mg); Limegepant is administered daily, every other day, and / or per unit dose in the range of approximately 20 mg or 50 mg (e.g., approximately 60 mg) to a maximum of approximately 150 mg (e.g., approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg or approximately 60 mg to a maximum of approximately 150 mg, approximately 125 mg, approximately 100 mg, approximately 90 mg or approximately 75 mg). Zabegepant is administered in doses ranging from approximately 5 mg (e.g., approximately 10 mg) to a maximum of approximately 200 mg (e.g., approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 or approximately 50 mg to a maximum of approximately 200 mg, approximately 175 mg, approximately 150 mg, or approximately 125 mg) per day and / or per unit dose. In each case, these are calculated as free (acid / base) compounds.

[0133] As described above, the compositions of the present invention may also contain one or more alkylsaccharides, or may be administered together with them. In this regard, the compositions of the present invention may be found to exhibit remarkably good bioavailability and absorption rates compared to corresponding compositions, for example, those that do not contain alkylsaccharides and / or contain different excipients known to act as surfactants.

[0134] The alkylsaccharides that can be used include alkyl glycosides, which are C7-18 Alkylglycosides can be defined as any sugar linked by linkage to an alkyl group, such as an alkylglycoside. Therefore, alkylglycosides may include alkylmaltosides (such as dodecylmaltoside), alkylglucosides, alkylsucrosides, alkylthiomaltosides, alkylthioglucosides, alkylthiosucroses, and alkylmaltotriosides. However, alkylsaccharides are preferably sugar esters.

[0135] The sugar esters that can be used in the compositions of the present invention include trisaccharide esters such as raffinose ester, monosaccharide esters such as glucose ester, galactose ester and fructose ester, and / or preferably disaccharide esters such as maltose ester, lactose ester, trehalose ester, and especially one or more sucrose esters.

[0136] The sucrose esters that can be used in the compositions of the present invention have a hydrophilic-lipophilic balance value of 6 to 20. The term "hydrophilic-lipophilic balance" (HLB) is a technical term that will be well understood by those skilled in the art (see, for example, 'The HLB System: A Time-Saving Guide to Emulsifier Selection' published by ICI Americas Inc. in 1976 (revised in 1980), Chapter 7 (pages 20-21) of the document provides a method for determining the HLB value). The longer the fatty acid chain of the sucrose ester and the higher the degree of esterification, the lower the HLB value. A preferred HLB value is 10 to 20, more preferably 12 to 20.

[0137] Therefore, sucrose esters contain C 8-22 Saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters, preferably C 10-18 Fatty acid esters, most preferably C 12Fatty acid esters are included. Particularly suitable fatty acids from which such sucrose esters can be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid, and lauric acid. Lauric acid is a particularly preferred such fatty acid. Commercially available sucrose esters include those sold under the trademarks of Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan).

[0138] Sucrose esters may be diesters or monoesters of fatty acids, preferably monoesters such as sucrose monolaurate. Those skilled in the art will understand that the term “monolaurate” refers to the monoester of lauric acid, and that the terms “lauric acid ester” and “laurate” are synonymous and therefore interchangeable. Commercial sucrose monolaurate products are sometimes referred to as “sucrose laurate.” Commercial sucrose monolaurate (or sucrose laurate) products such as Surfhope® D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan) may contain small amounts of diesters and / or higher sucrose esters, as well as small amounts of other sucrose esters and free sucrose, and are suitable for use in the present invention. Those skilled in the art will understand that any reference herein to a particular sucrose ester includes commercial products containing that sucrose ester as a main component.

[0139] A preferred sucrose ester is one containing only one sucrose ester, meaning that a single sucrose ester (e.g., a commercially available sucrose ester product) contains a single sucrose ester as its main component (commercial products may contain impurities, for example, a monoester product may contain small amounts of diesters and / or higher esters, and the product may be considered to "contain only one sucrose ester" in the context of this invention). As used herein, the term "main component" will be understood to refer to the major component (e.g., more than about 50%, such as about 70% by weight or volume) in a mixture of sucrose esters, such as a common commercially available surfactant product, which is sold in a certain range of ester compositions.

[0140] A particularly preferred sucrose ester is sucrose monolaurate.

[0141] Whether or not it is included in the composition of the present invention or in the final dosage form containing one or more compositions of the present invention, the amount of alkyl saccharide that can be used may range from about 0.5% to about 5% by weight, preferably about 0.75% to about 4.5% by weight (e.g., about 2.5%, such as about 2%, and about 4%, such as about 3%, such as about 1%, such as about 1.5%), based on the total weight of the composition.

[0142] Furthermore, optional additional excipients, including one or more (further) surfactants, may be used in or administered together with the composition of the present invention.Surfactants that may be mentioned include polyoxyl 8 stearate (Myrj® S8), polyoxyl 32 stearate (Gelucire® 48 / 16), polyoxyl 40 stearate (Myrj® S40), polyoxyl 100 stearate (Myrj® S100), and polyoxyl 15 hydroxystearate (Kolliphor® HS 15) Polyoxyethylene alkyl ethers (e.g., Brij®), including polyoxyethylene esters (e.g., Myrj®), polyoxylcetostearyl ethers (e.g., Brij® CS12, CS20 and CS25), polyoxyl lauryl ethers (e.g., Brij® L9 and L23), and polyoxyl stearyl ethers (e.g., Brij® S10 and S20), as well as polyoxyglycerides (e.g., Gelucire®), including lauroyl polyoxyglyceride (Gelucire® 44 / 14) and stearoyl polyoxyglyceride (Gelucire® 50 / 13), sorbitan esters (e.g., Span®), including sorbitan monopalmitate (Span® 40) and sorbitan monostearate (Span® 60), polysorbate Polysorbates (Tweens®) include polysorbate 80 (polyoxyethylene (80) sorbitan monopalmitate), such as polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), as well as sodium lauryl sulfato; and monoacylglycerols (monoglycerides) such as 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerol monopalmitate, glyceryl hydroxystearate, and preferably monoacylglycerols (monoglycerides) such as glycerol monostearate, glycerol monooleate (e.g., Cithrol®) and glycerol monocaprylate (e.g., Capmul®).Other surfactants include lauryl lactate, dipalmitoyl phosphatidylcholine (DPPC), and poloxamer.

[0143] Other optional additional components (excipients) that may be included in or administered together with the compositions of the present invention include isotonic and / or osmotic agents (e.g., sodium chloride), sterols such as cholesterol and phytosterols (e.g., campesterol, sitosterol, and stigmasterol) (or steroid alcohols); antioxidants (e.g., sodium metabisulfite, or in addition, α-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbic acid palmitate) Glue, butylated hydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E succinate polyethylene glycol, or thymol); chelating (complexing) agents (e.g., salt forms of any of these agents, including EDTA, citric acid, tartaric acid, malic acid, maltol, and galactose); preservatives (e.g., benzalkonium chloride, or in addition, benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol); (L, or xylitol); viscosity modifiers or gelling agents (cellulose derivatives including hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc., starch and modified starch, colloidal silicon dioxide, aluminum metasilicate, polycarbophil (e.g., Noveon®), carbomer (e.g., Carbopol®), and polyvinylpyrrolidone, etc.); mucosal adhesive polymers such as carboxymethylcellulose, modified cellulose gum, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as cross-linked starch, modified starch, and sodium starch glycolate; acrylic polymers such as cross-linked polyvinylpyrrolidone, carbomer and its derivatives (e.g., polycarbophil, Carbopol®); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride);and croscarmellose (e.g., croscarmellose sodium); pH buffers (e.g., citric acid, maleic acid, malic acid, or their corresponding salts such as glycine or sodium citrate); colorants; osmotic enhancers (e.g., isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin); other lipids (neutral and polar); benzoic acid optionally substituted with one or more groups selected from methyl, hydroxyl, amino, and / or nitro, aromatic carboxylic acids such as toluic acid or salicylic acid; optionally, flavorings (e.g., lemon, peppermint powder, or preferably menthol), sweeteners (e.g., neohesperidin, acesulfame K, or sucralose), and dyes. Other excipients may include trisaccharides (e.g., raffinose) and mannitol, as well as pH adjusters (e.g., hydrochloric acid and sodium hydroxide).

[0144] The total amount of such "additional" excipients (including surfactants other than alkylsaccharides that may be present in the composition of the present invention) that may be included in the composition itself (regardless of the dosage form included) may be up to about 15% by weight (e.g., about 10% by weight), such as up to about 5% by weight, based on the total weight of the composition.

[0145] The total amount of such “additional” excipients that may be contained in the final dosage form comprising one or more compositions of the present invention may be up to about 99.99%, for example, up to about 99%, including up to about 90%, if one or more additional excipients are fillers or carriers such as tablets, films, etc.

[0146] Those skilled in the art will understand that if the composition of the present invention contains any additional optional components, the properties of those components, and / or the amount of those components included, should not have any adverse effect on the Tg of the composition for the reasons stated above. In this regard, such optional components may be incorporated into a spray-drying process (i.e., mixed together with the active ingredients and carrier material(s) in a suitable volatile solvent and then spray-dried), or may be included separately in a plurality of spray-dried particles.

[0147] In particular, considering the enhanced chemical stability of the compositions of the present invention, compositions of the present invention that may be mentioned may essentially not contain such “additional” excipients, in particular benzalkonium chloride, more particularly sulfites and other antioxidants and / or preservatives, and / or chelating agents such as EDTA, and may contain such additional excipients in amounts less than about 10% by weight, e.g., less than about 6% by weight (including less than about 5% by weight or less than about 4% by weight), more preferably less than about 3% by weight, e.g., less than about 2% by weight, e.g., less than about 1% by weight, less than about 0.1% by weight (including less than about 0.01% by weight), e.g., less than about 0.001% by weight, or even less than about 0.0001% by weight.

[0148] In this regard, the compositions of the present invention may essentially consist of a pharmacologically effective dosage of a low molecular weight CGRP receptor antagonist or a salt thereof, a pharmaceutically acceptable carrier material as defined herein (i.e., maltodextrin as defined herein, and optionally a co-carrier material such as a disaccharide), and (optionally) an alkylsaccharide material as defined herein. Where the compositions of the present invention "essentially consist of" the above components, this will be understood to mean that the composition contains only those components, along with other features and / or components that do not substantially affect the basic and novel features of the composition. Alternatively, where the compositions / dosage forms of the present invention "essentially consist of" those components of the present invention, this may be understood to mean that the composition contains at least about 90% by weight of those components in total, such as at least about 95% by weight, including at least about 97% by weight (e.g., about 99% by weight or even more about 99.9% by weight).

[0149] A further aspect of the present invention provides compositions of the present invention for use in medicine (human and veterinary medicine), and thus provides compositions of the present invention for use in the treatment of patients requiring medical treatment of a condition in which the relevant active ingredients are known to treat.

[0150] The compositions of the present invention are useful in treating various disorders, depending on the active ingredients (or multiple active ingredients) contained in such compositions.

[0151] The compositions of the present invention may be useful in treating conditions such as diabetes, Raynaud's syndrome, peripheral arterial insufficiency, subarachnoid / intracranial hemorrhage, chronic obstructive pulmonary disease, and cancers such as glioma or metastatic breast cancer.

[0152] The compositions of the present invention may be further used to treat any condition characterized by neurogenic vasodilation and / or inflammation. Accordingly, the compositions of the present invention are potentially useful in treating conditions such as thermal injury, cardiovascular shock, menopausal flushing, osteoporosis, temporomandibular joint disorders, as well as inflammatory diseases such as asthma, psoriasis, COVID-19 and sinusitis, and pain-related conditions such as trigeminal neuralgia, headaches and migraines.

[0153] In this regard, the compositions of the present invention are particularly useful for the treatment of acute migraines, paroxysmal migraines and / or chronic migraines (in either case with or without aura), and migraine-related conditions understood to include all forms of migraines, such as cluster headaches and other headaches.

[0154] Treatment for such conditions includes therapeutic, symptomatic, and palliative care, as well as prophylaxis / prevention or diagnosis. Particularly useful low-molecular-weight CGRP receptor antagonists in the treatment / symptomatic therapy of the aforementioned conditions include ubrogepant and zabegepant, while atgepant is particularly useful in prevention. Others (such as rimegepant) may be indicated for both treatment / symptomatic therapy and prevention.

[0155] According to three further aspects of the present invention, the following is provided: • The composition of the present invention comprising a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof for use in the treatment of migraine-related conditions (e.g., by transmucosal administration such as intranasal administration of the composition), • Use of compositions of the present invention comprising a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof for the manufacture of drugs (e.g., transmucosal, such as intranasal) for the treatment of migraine-related conditions, and A method for treating a migraine-related condition, comprising administering (e.g., via the mucous membrane, such as intranasally) a composition of the present invention, comprising a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof, to a patient who suffers from or is prone to such a condition.

[0156] A method for treating migraine-related conditions in human patients, (a) Identify human patients who have or are at risk of having a migraine-related condition, (b) A method is further provided comprising administering a dose of a low molecular weight CGRP receptor antagonist or a pharmaceutically acceptable salt thereof in the form of the composition of the present invention, in a dosage suitable for treating the migraine-related condition, into a body cavity of the patient including a mucosal surface, presenting the composition on the mucosal surface to promote absorption of the low molecular weight CGRP receptor antagonist or a salt thereof over the mucosal surface, thereby treating or preventing the migraine-related condition.

[0157] The compositions of the present invention can be administered by any suitable drug delivery method known to those skilled in the art. The compositions of the present invention can be administered transmucosally, particularly intranasally, by a suitable nasal applicator or dispenser, which can deliver a suitable dose of the active ingredient into the nasal cavity in the form of one or more compositions of the present invention.

[0158] Accordingly, a suitable nasal administration means and / or applicator can contain and store one or more doses of the composition of the present invention itself, or can be attached to a reservoir / container that contains and stores one or more doses of the composition of the present invention, ensuring that there is no significant loss of the physical and chemical integrity of the composition, including due to water ingress. In this way, the composition is ready for use as soon as the applicator device is activated by the end user (whether this is for single-dose or multi-dose use), and the applicator then delivers the composition (e.g., powder) having an appropriate dose of the active ingredient as defined herein to the target nasal mucosa.

[0159] Suitable applicator means are described in the prior art. When used with the compositions of the present invention, such compositions may be loaded into a reservoir attached to or forming part of such applicator means and contained therein until the applicator means or dispenser is activated. Hereinafter, the terms “applicator,” “dispenser,” “device,” “applicator means,” “dispensing means,” “applicator device,” “dispensing device,” and “inhaler” may be used interchangeably and may mean the same thing.

[0160] Due to the unexpected stability of the composition of the present invention, it is not necessary to inspect the contents of the reservoir (i.e., the powder composition) before administration or use.

[0161] In light of this, the reservoir containing the composition of the present invention may be opaque, which will be understood by those skilled in the art to include being "not transparent or translucent, not allowing light to pass through, and / or not allowing light to pass through."

[0162] Accordingly, an applicator comprising the composition of the present invention does not include (or requires) an inspection window from which the contents of the applicator's reservoir can be observed, and in this respect, its properties may be completely opaque, i.e., at least about 98%, particularly about 99.9%, opaque, and / or transparent, translucent, and / or light-transmitting, with about 2% or less, particularly about 0.1%, such as about 1% or less, allowing inspection of the contents of the reservoir.

[0163] Accordingly, such applicator means may also include a mechanism for discharging the powder composition described herein from a reservoir via an outlet (or dispensing) means, the dispensing means including any nozzle of appropriate shape that is sized to be placed in a human body cavity such as a nostril.

[0164] Therefore, the mechanism for discharging the powder may include means for activating the device, which may include activation by respiration (e.g., activation by nasal inhalation) or activation means for generating force when the device is activated by the user.

[0165] Therefore, the applicator needs to be able to deliver a reproducible and sufficient amount of powder formulation in a single administration step that provides a therapeutic dose of the active ingredient (and in a manner that does not require the device to "prime").

[0166] Furthermore, due to the unexpected stability of the compositions of the present invention, and the fact that there is no need to inspect the contents of the reservoir (i.e., the powder composition) before administration and / or use, as soon as a patient is identified as exhibiting or at risk of exhibiting symptoms of a migraine-related condition, the relevant active ingredient can be administered to the mucosal surface using an applicator to treat or prevent the condition. Therefore, the administration step identified above can be performed without delay, immediately after such identified step, and this delay is, (i) Examine the composition of the present invention, and (ii) This may mean sufficient time to determine whether the relevant composition can be safely administered to the patient in order to effectively treat the migraine-related condition.

[0167] Nasal applicators / inhalation devices that can be used to administer the compositions of the present invention in powder form may include multiple-dose applications such as metered-dose inhalation devices (MDIs), dry powder inhalation devices (DPIs; including low, medium, and high-resistance DPIs), and soft mist inhalation devices (SMIs), which can be adapted based on known techniques in the field of delivery of active ingredients to the lungs.

[0168] In MDI, the composition of the present invention must be able to form a stable suspension when suspended in a solvent such as a spray agent typically used therein, and this spray agent must have a vapor pressure sufficient to form an aerosol when the delivery device is in operation (e.g., hydrocarbons, fluorocarbons, hydrogen-containing fluorocarbons, or mixtures thereof).

[0169] However, if the nasal applicator is a single-dose applicator in which the composition is dispensed after activation and then discarded after use, suitable applicator means or devices for delivering a single dose of the active ingredient include respiratory-assisted and blow-assisted designs (such as Optinose®), as well as those described in U.S. Patent Nos. 6,398,074, 6,938,798, or 9,724,713, and International Patent Applications Nos. 2017 / 118827A1, 2018 / 224762A1, and 2023 / 282821A1, in particular U.S. Patent Applications Nos. 2019 / 0358417A1 and 2023 / 0144040A1, all relevant disclosures of which are incorporated herein by reference. Figures 1 and 2 of this application are based on Figures 1 and 2 of U.S. Patent No. 6,398,074, respectively, and Figures 3-7 are based on Figures 19-23 of U.S. Patent No. 9,724,713, respectively. Both are illustrations of applicators that may be used for intranasal administration of the compositions of the present invention.

[0170] In Figure 1, the device comprises an upper body / dispenser head 1 incorporating an outlet channel 40 (i.e., part of the aforementioned “outlet means”) and a gripping means 60 that allows the user to activate the device. Inside the upper body / dispenser head 1 is mounted an element whose assembly is designated by reference no. 2, which incorporates a reservoir 10 and an air chamber 22 for the air blast 20. This element 2 can be manufactured integrally with the body 1. A lower body 3 is also provided so as to slide relative to the upper body 1 and relative to element 2, and the user activates the device by applying a pushing force to this lower body.

[0171] Reservoir 10 contains a single dose of the composition of the present invention. Reservoir 10 has an air inlet 11 and a product outlet 15. A product holding device 12, which has an air-permeable grid, is positioned in the air inlet 11 to hold the product in reservoir 10 until the composition is dispensed. The product outlet 15 is blocked by a closing ball 16, preferably in a seal manner, which is removed from its blocked position by the airflow when the applicator is activated and the product is dispensed.

[0172] When the user activates the device, pressure is applied to the plunger 25 so that the piston 21 compresses the air 20 contained in the chamber 22. Because the grid 12 is permeable to air, the compression of the air in the chamber 22 creates an air blast, which is transmitted to the reservoir 10 and consequently applied to the closing ball 16 that blocks the product outlet 15.

[0173] The dimensions of the closing ball 16 and its fixation at the reservoir product outlet 15 are such that the ball 16 is removed from its closing position when a minimum predetermined pressure is generated through the reservoir 10 by a blast of air 20.

[0174] The precompression generated by the closed ball 16 ensures that when the ball is removed from its closed position, the energy stored in the user's hand propels the piston 21, which is integrated with the plunger 25, within the chamber 22, thereby creating a powerful blast of air 20, i.e., an airflow suitable for finely atomizing a dosage of the composition of the present invention.

[0175] Once this minimum pressure is reached, the ball moves rapidly toward the device's outlet channel 40, and the flow of air 20 generated by the blast discharges substantially all of the dosage of the composition of the present invention contained within the reservoir 10.

[0176] Preferably, the outlet channel 40 has a diameter larger than the diameter of the closing ball 16 in order to allow the dose of the product to be discharged through the outlet channel 40 by flowing around the ball 16. As shown in Figure 2, which represents the same device after activation, the channel 40 includes means 41 for stopping or fixing the ball 16 in order to prevent the ball from being discharged from the device when the product is being discharged.

[0177] Further embodiments that may be used to administer the compositions of the present invention intranasally are provided in columns 7, rows 50 to 8, row 61 and Figures 19 to 23 of U.S. Patent No. 9,724,713, which are reproduced in Figures 3 to 7 of this application.

[0178] In this embodiment, the reservoir 10 is fixed within the upper body / dispenser head 1, which includes a dispenser outlet channel 40 (i.e., part of the aforementioned "outlet means") having a gripping means or finger rest 60 that allows the user to activate the device. The radial shoulders 37 of the upper body / dispenser head 1 (see Figure 5) favorably define the assembly position of the reservoir 10 within the upper body / dispenser head 1.

[0179] The mechanical opening system includes a set of rods 61 and 62, and when the device is activated, a second rod portion 62 is pushed against the first rod portion 61. At the end of their activation stroke, i.e., in the dispensing position, the set of rods 61 and 62 cooperate with a spherical closing element 16, a ball in particular as in the first embodiment discussed above, to mechanically eject it from the closed position.

[0180] In this embodiment, the piston 21 is separated from the first rod portion 61 and slides relative to both the air chamber 22 and the cylindrical surface 614 fixed to the first rod portion 61. Figure 7 is a perspective view of the air expeller of the devices of Figures 3-6 in the stationary position.

[0181] Therefore, the air chamber 22 may be cylindrical and, in the stationary position, communicates with the surrounding air through a fluting or groove 615, the fluting formed on the cylindrical surface 614 and particularly in cooperation with the piston 21 in the stationary position. Thus, the piston 21 includes an inner lip 215 that slides airtightly along the cylindrical wall 614 during firing and in cooperation with the fluting 615 in the stationary position. The piston 21 also includes an axial extension 216 that cooperates with the upper edge 251 of a pusher element 25 (called a "plunger" in the first embodiment) that moves the piston 21 within the air chamber 22 during firing.

[0182] The holding member 42 is extended downward by an axial extension 43 that contacts the upper axial end 610 of the first rod portion 61 during activation.

[0183] In addition, in this embodiment, there is no external body, and only a cover 27 assembled on the lower axial edge of the air chamber 22 exists.

[0184] A spring 80 is provided between the radial flange 225 of the air chamber 22 and the portion forming the first rod portion 61 and the cylindrical surface 614, so that the air expeller automatically returns to the stationary position after activation.

[0185] The operating principle is as follows: In the stationary position shown in Figure 3, the reservoir 10 is sealed by the retaining member 42 and the closing element / ball 16. The air expeller is opened to the atmosphere by the cooperative action between the inner lip 215 of the piston 21 and the fluting 615 of the cylindrical surface 614.

[0186] To activate the device, the user presses the pusher element 25. During this initial stroke, the inner lip 215 of the piston moves away from the fluting 615 and cooperates with the cylindrical surface 614 in an airtight manner, thereby closing the air chamber 22. Simultaneously, the upper edge 251 of the pusher element 25 contacts the axial extension 216 of the piston 21, and the upper axial end 610 of the first rod portion 61 contacts the axial extension 43 of the retaining member 42.

[0187] However, as can be seen in Figure 4, the upper axial end 621 of the second rod portion 62 still does not contact the rounded surface 55 of the closing element / ball 16.

[0188] Therefore, continuous activation simultaneously moves the piston 21 within the air chamber, thereby compressing the air contained therein and moving the retaining member 42 away from the position that closes the reservoir 10. When the second rod portion 62 contacts the rounded surface 55 of the closing element / ball 16, the closing element / ball is mechanically ejected from its closed position so that the composition can be discharged under the influence of the air compressed by the air expeller.

[0189] The dispensing position is shown in Figure 5. As can be seen in Figure 5, the retaining member 42 may detach from the first rod portion 61 while the composition is being dispensed under the influence of compressed air provided by the air expeller. In this position, the closure element / ball is discharged from the reservoir 10 so that the fluid or powder can be dispensed under the influence of compressed air. Thus, the closure element / ball 16 becomes lodged in the spline 3 of the upper body / dispenser head 1, which in particular prevents any risk of the closure element / ball 16 being discharged from the upper body dispenser head 1.

[0190] As shown in Figure 6, when the user releases the device, the spring 80, which was compressed during activation, returns the first rod portion 61 to its resting position. This creates an suction force that draws the closing element 16 and retaining member 42 toward or near their closed positions. Thus, this blocks a new suction path, leaving the empty reservoir assembled on the air expeller so that it does not become contaminated while the air expeller automatically returns to its resting position. However, the piston 21 remains in its dispensing position as a result of friction with the air chamber 22 and the suction force generated in the reservoir 30, so that the cylindrical surface 614 slides on the inner lip 215 until the inner lip once again cooperates with the fluting 615. At this point, the air chamber 22 is once again in communication with the ambient air, and no suction force is generated by returning to the resting position. Thus, the piston 21 is also pulled toward its resting position. This allows the reservoir to be closed after use.

[0191] Optionally, the unit formed by the upper body / dispenser head 1 and the empty reservoir 10 can be removed from the air expeller and replaced with a new unit containing a full reservoir.

[0192] Suitable applicator devices that can be used include those available from Aptar Pharma, France (UDS Monopowder). See, for example, International Patent Applications 2017 / 118827A1, 2018 / 224762A1, 2023 / 282821, 2022 / 208014 and 2021 / 005311, and U.S. Patent Applications 2019 / 0358417A1 and 2023 / 0144040A1 (all relevant disclosures of the documents are incorporated herein by reference). Other examples of applicator devices that can be used in combination with the compositions of the present invention (particularly in powder form) are described in U.S. Patent Application No. 2011 / 0045088, U.S. Patent No. 7,722,566 (see, for example, Figures 1 and 7) and No. 5,702,362, as well as in International Patent Applications No. 2014 / 004400, No. 2017 / 118827A1 and No. 2023 / 282821, as well as in U.S. Patent Applications No. 2019 / 0358417A1 and No. 2023 / 0144040A1, the relevant disclosures of these documents being incorporated herein by reference.

[0193] A further aspect of the present invention provides a process for manufacturing an applicator device containing a composition of the present invention, the process comprising loading the composition into or attached to the applicator device.

[0194] A further aspect of the present invention provides a needleless applicator suitable for administering the solid amorphous single-particle powder composition of the present invention into a body cavity of a human patient, wherein the cavity includes a mucosal surface, and the applicator is (i) A reservoir (optionally opaque) located in or attached to the applicator containing the composition of the present invention, (ii) an optional activation means for generating power when the user activates the device, (iii) a dispensing means through which the powder composition can be dispensed after the activation.

[0195] The term "needle-free" means a device for administering a medicinal active ingredient that does not include an injection means, for example, a means for puncturing the surface of the skin or mucous membrane, in order to inject the active ingredient into the body, for example, subcutaneously or intramuscularly (as done by an autoinjector).

[0196] According to another aspect of the present invention, an applicator and / or dispenser device is provided which contains one or more compositions of the present invention in powder form, the applicator or device which can be activated one or more times to deliver one or more compositions of the present invention, each of which contains an appropriate dose of the active ingredient, the applicator / dispenser device which comprises: An outlet from which at least one composition is dispensed. A means of generating external force (e.g., airflow) when the user activates the device. A reservoir containing one or more compositions of the present invention, which is in direct or indirect communication with, or can be arranged to communicate with, a dispenser outlet, and which contains at least one (optionally replaceable and optionally opaque) reservoir, A replaceable, optional, and reversible sealing means in the device and / or reservoir for holding one or more compositions in the reservoir until the compositions are dispensed. A single composition of the present invention cooperates with a sealing means to mechanically discharge when the device is activated, and a mechanical opening system, Optionally, a mechanism for resealing the device and / or reservoir to retain additional compositions in the reservoir until further compositions are dispensed.

[0197] In a further aspect of the present invention, an applicator and / or dispenser device is provided which comprises a single-dose composition of the present invention and is suitable for dispensing the composition, the applicator / dispenser device is Dispenser outlet, An air expeller for generating airflow while the device is activated, the air expeller includes a piston that slides within an air chamber between a stationary position and a dispensing position, The piston slides in an airtight manner within the air chamber, an air expeller, A reservoir containing a dose of the composition of the present invention, including an air inlet connected to the air expeller, It comprises a composition outlet connected to the dispenser outlet, The air inlet includes replaceable sealing means (e.g., a retaining member) for holding the composition in the reservoir until the composition is dispensed. The composition outlet is closed by a closing element fitted to the composition outlet of the reservoir. The device further includes a mechanical opening system that cooperates with the closing element to mechanically eject the closing element from the closed position while the device is activated, When the piston of the air expeller is in its stationary position, it cooperates with the air chamber in a non-airtight manner.

[0198] In the latter aspect of the present invention, the following is preferable. (i) The air chamber through which the piston slides in an airtight manner is substantially cylindrical, (ii) The closing element is pressure-fitted to the composition outlet of the reservoir, (iii) The air chamber is in communication with the atmosphere when stationary, and / or (iv) The piston includes an inner lip suitable for cooperating with a cylindrical surface, the cylindrical surface including fluting that cooperates with the inner lip of the piston in a non-airtight manner when it is in a resting position.

[0199] Such a device may be filled for single use with an appropriate amount of a single composition of the present invention in the aforementioned reservoir, the amount (also known as the "filling weight") may be up to about 200 mg of the composition of the present invention, for example, up to about 150 mg (including up to about 100 mg or up to about 75 mg), for example, up to about 50 mg, up to about 40 mg, up to about 30 mg, up to about 25 mg, up to about 20 mg, up to about 15 mg, up to about 10 mg, or up to about 5 mg.

[0200] Such nasal applicators or dispensing devices can provide a suitable and reproducible powder spray pattern and / or geometric plume shape that enables efficient delivery of the powder into the nasal cavity (e.g., nostrils).

[0201] In the compositions of the present invention, the average particle size may be expressed as the average diameter based on weight, number, or volume. As used herein, the term “weight-based average diameter” will be understood by those skilled in the art to include the average particle size being characterized and defined from a particle size distribution by weight, i.e., a distribution in which the existing fractions (relative amounts) in each size class are defined, for example, as weight fractions obtained by sieving (e.g., wet sieving). The term “volume-based average diameter” is similar in meaning to weight-based average diameter, but will be understood by those skilled in the art to include the average particle size being characterized and defined from a particle size distribution by volume, i.e., a distribution in which the existing fractions (relative amounts) in each size class are defined, for example, as volume fractions measured by laser diffraction. As used herein, the term “number-based average diameter” will be understood by those skilled in the art to include the average particle size being characterized and defined from a particle size distribution by number, i.e., a distribution in which the existing fractions (relative amounts) in each size class are defined, for example, as fractions measured by microscopic examination. Particle size can be measured using other instruments well known in this field, such as those sold by Malvern Instruments, Ltd (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).

[0202] While particle size may not be important (or rather important) when the compositions of the present invention are formulated for administration, for example, orally, topically, to the mouth, eyes or other mucous membranes, or by injection or infusion, the powder compositions of the present invention typically have a volume-based mean diameter (VMD) in the range of about 0.2 μm to a maximum of about 1,000 μm (for example, about 400 μm or about 500 μm), such as about 0.5 μm (e.g., about 1 μm), and a suitable particle size range may be selected based on the dosage form in which such compositions are intended to be included.

[0203] However, those skilled in the art will understand that, in order to enable effective intranasal administration, the powder typically has a volume-based mean diameter (VMD) in the range of about 5 μm to a maximum of about 300 μm (e.g., a maximum of about 200 μm). Depending on the applicator device used, the VMD may range from about 10 μm to about 100 μm, such as about 20 μm to about 60 μm.

[0204] A preferred particle size distribution for intranasal drug delivery may also include a particle size distribution where D10 is greater than about 3 μm and less than about 75 μm (e.g., up to about 50 μm), e.g., greater than about 5 μm, e.g., greater than about 6 μm, greater than about 7 μm, greater than about 8 μm, greater than about 9 μm, and greater than about 10 μm, and D90 may include a particle size distribution where D90 is greater than about 80 μm and less than about 1,000 μm (e.g., about 500 μm), e.g., less than about 200, less than about 150, or less than about 125, e.g., less than about 100 μm. Those skilled in the art will understand that the parameter "D10" (or "Dv(10)") means the size (or diameter) of the particle size distribution where 10% of the total volume of material in the sample is below that size. Similarly, "D90" (or "Dv(90)") means the size where 90% of the material is below that size.

[0205] Powders having particle size distribution and VMD within the above range include bulk VMD and / or discharge VMD, i.e., the particle size distribution when initially loaded into the device and / or discharged therefrom, respectively.

[0206] Particle size can be measured using standard instruments such as dry (or wet) particle sizing techniques, including dry dispersion techniques available from manufacturers such as Sympatec and Malvern.

[0207] Preferred particle shapes include spherical or substantially spherical, meaning that the particles have an aspect ratio of less than about 10, more preferably less than about 4, and particularly less than about 2, and / or at least about 90% of the particles may have a variation in radius (measured from the center of mass to the particle surface) of less than or equal to about 50% of the mean, such as less than or equal to about 30% of the mean, for example less than or equal to about 20% of the mean.

[0208] Nevertheless, particles may be of any shape, including irregular shapes (e.g., "raisin" shapes), needle-shaped (in which case particle size can best be expressed as the average length of such needles), disc-shaped, or cubic particles. For non-spherical particles, size can be expressed, for example, as the size of a corresponding spherical particle of the same weight, volume, or surface area.

[0209] The spray angle of the powder composition of the present invention released (dispensed) from the nasal applicator and / or dispenser device should preferably be less than about 90°.

[0210] Where the term “about” is used herein in the context of quantity, for example, absolute quantities such as dose, weight, volume, size, diameter, aspect ratio, angle, or relative quantities (e.g., percentages) of individual components or components of a composition (including concentration and ratio), time frame, and parameters such as temperature, pressure, and relative humidity, it will be understood that such variables are approximate and therefore may vary by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%) from the actual values ​​specified herein. This is true even when such figures are initially presented as percentages (e.g., “about 10%” could mean ±10% of the number 10, which is anywhere between 9% and 11%).

[0211] The compositions of the present invention have the advantage that they can be stored alone and / or in an applicator or reservoir for a wide range of temperatures and / or relative humidity (either of which may be packaged in a suitable pharmaceutical package, which may or may not provide a barrier to moisture as described above). Thus, the compositions of the present invention can be exposed to low temperatures (e.g., below freezing) without affecting the amount of active ingredient administered to the subject. Furthermore, applicators containing the powder compositions of the present invention may have the advantage that the compositions are physically and chemically stable at all (higher) temperatures than formulations contained in related prior art devices.

[0212] The compositions of the present invention may further have the advantage of providing higher bioavailability of the active ingredient compared to prior art compositions. The compositions of the present invention may provide this higher bioavailability along with faster absorption, which is likely to result in a faster onset of action than such prior art and / or commercially available compositions, and therefore meet important medical requirements.

[0213] The applicators, compositions, pharmaceutical formulations, uses, and methods described herein, whether for use in the treatment of a known condition involving the relevant active ingredient, whether for use in the treatment of the aforementioned condition by transmucosal administration such as intranasal administration or by other methods, may also have advantages over similar formulations or methods (treatments) known in the prior art, such as being more convenient for patients and physicians, being more effective, having lower toxicity, having a broad range of activity, being potent, producing fewer side effects, having lower patient variability, or having other useful pharmacological properties superior to similar formulations or methods (treatments).

[0214] The present invention will be described by the following embodiments with reference to the drawings, but will not be limited thereto. Figures 1–7 illustrate actuator-devices that may be used to dispense powder compositions, and Figure 8 shows a plasma concentration-time curve from a pharmacokinetic study conducted in dogs, comparing an intranasal (IN) administered composition of the present invention, containing zavegepant ("A"), with an IN administered commercially available zavegepant liquid spray (ZAVZPRET®, "B"). [Brief explanation of the drawing]

[0215] [Figure 1] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 2] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 3] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 4] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 5] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 6] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 7] This diagram shows an actuator device that can be used to dispense powdered compositions. [Figure 8] The plasma concentration-time curves from pharmacokinetic studies conducted in dogs are shown. [Examples]

[0216] Example 1 Spray-dried rimegepant preparation Limegepant hemisulfate sesquihydrate (0.137 g; Moehs, Spain) was dissolved in a 1:1 isopropanol / water mixture (19.93 g) by heating and stirring. The resulting solution was then added to aqueous solutions of α-D-lactose monohydrate (0.659 g; DFE Pharma, Germany), maltodextrin (Glucidex IT 19 DE; 2.155 g; Roquette, France), and sucrose monolaurate D-1216 (0.092 g; Mitsubishi-Kagaku Foods Corporation, Japan). The resulting mixture was dispensed into glass flasks and dissolved in MQ-water (37.02 g) by stirring under heat (total solvent volume 56.95 g).

[0217] The resulting mixture was supplied to a spray dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. The spray dryer's supply rate was set to 4.0 g / min, the inlet temperature to 160°C, the gas flow rate to 300 L / min, and the cyclone gas to 1.5 bar.

[0218] The resulting spray-dried powder was collected in a fine, dry, and free-flowing powder form, with a nominal dose of 2.0 mg of rimegepant free base per 50 mg of powder.

[0219] Dry powder laser diffraction was used to analyze the particle size distribution (PSD) of the powder. As shown in Table 1 below, the samples were dispersed in an Aero S dry dispersion unit (using 0.5 bar compressed air) before sizing with a Mastersizer 3000 laser diffraction sensor (both from Malvern Panalytical, UK). [Table 1]

[0220] The PSD of the formulation was within a distribution suitable for intranasal administration.

[0221] The assay and purity of the spray-dried rimegepant formulation were determined by HPLC / UV analysis. The assay was 100.1%, and the percentage of total related substances (RS%) (i.e., impurities and degradation products) was 0.9%.

[0222] Example 2 Spray-dried Zabegepant preparation I Zabegepant sulfate (1.0 g; Chemtronica, Sweden) was spray-dried essentially as described in Example 1 above. A solution was prepared by dissolving the zabegepant in acidified water (16 mL of 0.1 M aqueous HCl solution added to 29 mL of water), and the pH was then adjusted to a range of 4.5 to 5.5 by adding an appropriate amount of aqueous NaOH solution to the solution. This solution was then added to aqueous solutions of α-D-lactose monohydrate (1.931 g; DFE Pharma, Germany), maltodextrin (Glucidex IT 19 DE; 1.910 g; Roquette, France), and sucrose monolaurate D-1216 (0.075 g; Mitsubishi-Kagaku Foods Corporation, Japan). Spray drying yielded a fine, dry, free-flowing powder with a nominal dose of 10 mg of zabegepant free base in 50 mg of powder.

[0223] Table 2 below shows the analysis of the PSD powder described in Example 1 by dry powder laser diffraction, and it was determined that it was sufficiently within a distribution suitable for intranasal administration. [Table 2]

[0224] The assay and purity measured by HPLC / UV analysis were 103.4%, and the RS% was 1.46%.

[0225] Example 3 Chemical stability of spray-dried Zabegepant formulation Approximately 100 mg of the spray-dried powder from Example 2 above was dispensed into plastic DUMA containers placed in heat-sealed aluminum pouches together with a 4 Å molecular sieve desiccant. Two containers were placed in a climate cabinet at 40°C and 75% relative humidity (40 / 75), and two containers were placed in a climate cabinet at 25°C and 60% relative humidity (25 / 60).

[0226] The chemical stability of the active pharmaceutical ingredient after 6 months, along with the assay results and the total amount of impurities and degradation products expressed as RS% (Rating Standard), is summarized in Table 3 below for various climates. NA means "not analyzed." [Table 3]

[0227] The observed change in RS% indicates that the chemical stability of zabegepant is remarkably good when formulated in the manner described herein.

[0228] Example 4 Spray-dried Zabegepant preparation II Zabegepant (1.509 g; Chemtronica, Sweden) was spray-dried essentially as described in Example 1 above, using a cyclone gas set to a supply rate of 3.5 g / min and 1.8 bar. A solution was prepared by dissolving the zabegepant in acidified water (34 mL of 0.1 M aqueous HCl solution with 34 mL of water added), and then α-D-lactose monohydrate (2.761 g; DFE Pharma, Germany), maltodextrin (Glucidex IT 19 DE; 2.889 g; Roquette, France), and sucrose monolaurate D-1216 (0.227 g; Mitsubishi-Kagaku Foods Corporation, Japan) were added to obtain a fine, dry, free-flowing spray-dried powder with a nominal dose of 10 mg of zabegepant free base in 50 mg of powder.

[0229] Table 4 below shows the analysis of the PSD powder described in Example 1 above by dry powder laser diffraction, and it was determined that it was sufficiently within a distribution suitable for intranasal administration. [Table 4]

[0230] The assay and purity measured by HPLC / UV analysis were 104.5%, and the RS% was 1.51.

[0231] The final powder (50 mg per device) was loaded into specific intranasal devices from Aptar Pharma, France (UDS Monopowder), and then packaged in heat-sealed aluminum pouches along with a 4 Å molecular sieve desiccant.

[0232] Example 5 Pharmacokinetic studies in dogs after nasal administration of spray-dried zavegepant and liquid zavegepant. The purpose of this study was to obtain and evaluate basic pharmacokinetic profiles after intranasal administration of the spray-dried zavegepant composition of the present invention and after intranasal administration of ZAVZPRET®, a commercially available zavegepant liquid nasal spray.

[0233] This study was conducted on six Beagle dogs, three males and three females, aged approximately 29–57 months. The dogs were administered in a crossover regimen to compensate for potential sequential effects. Medication was always administered in the morning, and the dogs were fasted overnight (at least 8 hours). Water was freely available, and food was given 4 hours after administration.

[0234] Each dog was administered intranasally with the composition described in Example 4 at a dose of 10 mg / animal (IN 10 mg), and ZAVZPRET was administered intranasally with a dose of 10 mg / animal (IN 10 mg). The composition of Example 4 was administered using a specific intranasal device from Aptar Pharma, France (UDS Monopowder), and ZAVZPRET was administered using an Aptar UDS liquid spray device.

[0235] The washout period between each dose was 7 days.

[0236] The in vivo portion of the study was conducted in accordance with the European Convention on the Protection of Vertebrates Used for Experimental and Other Scientific Purposes (ETS No. 123).

[0237] Blood samples were collected from all dogs at the specified time point by venipuncture of the saphenous vein using a closed blood collection system under conventional sterile conditions. A 2 mL volume was collected in a plastic Vacuette® tube containing K2EDTA. Blood samples were kept on ice before centrifugation at 2,000 rpm for 10 minutes at +4°C.

[0238] Plasma was extracted, transferred to pre-labeled vials, and stored at -70°C or below before transport for bioanalysis. Scheduled sampling points were as follows: 0 (pre-dose), 4, 8, 16, 24, 35, 60, 180, and 360 minutes post-administration.

[0239] Frozen plasma samples were transported to Recipharm OT, Uppsala, Sweden for bioanalysis. Plasma concentrations of zavegepant were determined using HPLC-MS-MS analysis, which allows for the measurement of zavegepant concentrations in canine plasma within the range of 0.5–10,000 ng / mL, with rimegepant as an internal standard. The analytes were extracted from the sample plasma using 0.1% formic acid in acetonitrile. After centrifugation, the supernatant was used for analysis.

[0240] All samples were analyzed by first separating the analytes using a Waters Acquity UPLC BEH C8 column (2.1 mm*50 mm, 1.7 μm) and a pre-column, and then detecting them using positive electrospray ionization and multiple reaction monitoring (MRM). Quantification was performed in the range of 0.500–10,000 ng / mL.

[0241] Pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin (v8.0) and are shown in Table 5 and Figure 8 below. "Subj." is the subject (dog) number, "A" is the spray-dried zavegepant powder of the present invention, "B" is the ZAVZPRET liquid zavegepant spray, and AUC inf is the area under the plasma concentration-time curve extrapolated to infinite time, C max is the maximum measurable concentration after administration, T max is the time to reach the maximum measurable concentration, T half is the time to reduce the concentration to half of the original value. Medication errors were reported in relation to three dosages and resulted in relatively low plasma exposure. These results were excluded from the statistical analysis and are marked (-) in Table 5 below.

Table 5

[0242] On average, the nasal administration of the spray-dried zavegepant formulation of Example 4 had a total exposure (AUC inf ) 2.5 times higher and a peak exposure (C max ) 3.6 times higher compared to ZAVZPRET.

Claims

1. A pharmaceutically acceptable composition in the form of a solid amorphous single-particle powder, (a) A pharmacologically effective dose of a low-molecular-weight calcitonin gene-related peptide receptor antagonist or a pharmaceutically acceptable salt thereof, (b) A pharmaceutically acceptable composition comprising a mixture of a pharmaceutically acceptable carrier material, the carrier material comprising a maltodextrin having more than 15 dextrose equivalents (DE), the carrier material, and the pharmaceutically acceptable composition.

2. The composition according to claim 1, wherein the carrier material further comprises a disaccharide selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose, and lactose.

3. The composition according to claim 2, wherein the disaccharide comprises lactose and / or trehalose.

4. The composition according to claim 2 or 3, wherein the carrier material comprises a combination of lactose and maltodextrin 19DE.

5. The composition according to any one of claims 2 to 4, wherein the weight ratio of disaccharide to maltodextrin based on the total weight of the composition is in the range of about 10:1 to about 1:

8.

6. The composition according to any one of the prior claims, wherein the lowest measurable glass transition temperature of the composition is at least about 35°C when measured at a maximum relative humidity of about 35%.

7. The composition according to any one of the prior claims, wherein the composition further comprises a sucrose ester.

8. The composition according to claim 7, wherein the sucrose ester comprises sucrose monolaurate.

9. A composition according to any one of the prior claims, which is suitable and / or adapted for transnasal delivery.

10. The composition according to claim 9, comprising D10 having a particle size distribution of more than approximately 3 μm, more than approximately 5 μm, or more than approximately 10 μm.

11. The composition according to claim 9 or 10, wherein the powder has a particle size distribution including a volume-based average diameter in the range of about 10 μm to about 100 μm.

12. The composition according to any one of claims 9 to 11, comprising D90 having a particle size distribution of less than about 500 μm, less than about 200 μm, or less than about 100 μm.

13. The composition according to any one of the prior claims, wherein the pharmacologically effective dose of the low molecular weight calcitonin gene-related peptide receptor antagonist or a salt thereof is about 5 mg to about 150 mg.

14. The composition according to any one of the prior claims, wherein the low molecular weight calcitonin gene-related peptide receptor antagonist is selected from ubrogepant, atgepant, rimegepant, and zabegepant.

15. The composition according to claim 14, wherein the low molecular weight calcitonin gene-related peptide receptor antagonist is rimegepant.

16. The composition according to claim 14, wherein the low molecular weight calcitonin gene-related peptide receptor antagonist is zabegepant.

17. A process for producing the composition described in any one of the prior claims, i) The step of mixing the low molecular weight calcitonin gene-related peptide receptor antagonist or a pharmaceutically acceptable salt thereof with the pharmaceutically acceptable carrier material together in a suitable volatile solvent, ii) A process comprising the step of spray-drying the mixture from step i).

18. A composition that can be obtained by the process described in claim 17.

19. A nasal applicator device suitable and / or adapted for delivering a composition according to any one of claims 1 to 16 or 18 to the nose, comprising, or attached to, and / or mounted therein, a reservoir containing the composition.

20. The nasal applicator according to claim 19, wherein the device is configured to deposit a pharmacologically effective dose of the low molecular weight calcitonin gene-related peptide receptor antagonist or a pharmaceutically acceptable salt thereof onto the nasal mucosa upon activation.

21. A process for manufacturing an applicator device according to claim 19 or 20, comprising the process according to claim 17, and subsequently loading the composition thus formed into a reservoir located in, attached to, or mounted within the applicator device.

22. A container that substantially prevents the ingress of moisture from the atmosphere by comprising thermoformed plastic and / or molecular sieves having a pore size of 3 Å or 4 Å, and which can house or accept the nasal applicator device according to claim 19 or 20.

23. The container according to claim 22, comprising a heat-sealed aluminum pouch and thermoformed plastic, and / or a material selected from the group of desiccants selected from silica gel and molecular sieves having a pore size of 3 Å or 4 Å.

24. A composition according to any one of claims 1 to 16 or 18, for use in the treatment of migraine-related conditions.

25. Use of the composition according to any one of claims 1 to 16 or 18 for the manufacture of a drug for the treatment of a migraine-related condition.

26. A method for treating a migraine-related condition, comprising administering a composition according to any one of claims 1 to 16 or 18 to a patient who is suffering from or is prone to the condition.

27. The composition for use according to claim 24, the use according to claim 25, or the method according to claim 26, wherein the migraine-related condition includes acute migraine, paroxysmal migraine, or chronic migraine, each of which may or may not be accompanied by aura.

28. The composition, use, or method for use according to claim 27, wherein the composition is administered nasally by the applicator according to claim 19 or 20.

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