Taste-masked compositions of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate and orally disintegrating tablets containing the same

Abstract

The present disclosure provides a novel, palatable pharmaceutical composition in the form of taste-masked 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and an orally disintegrating tablet comprising the same. The taste-masked orally disintegrating tablet of the present invention significantly reduces the strong bitter taste of lasmiditan and allows administration of this product form to migraine patients, particularly pediatric patients and patients who suffer from nausea due to migraine attacks.

Description

[Technical Field]

[0001] Embodiments of the present invention relate to the field of pharmaceutical composition chemistry, and include the use of 5-HT 1F Provided are coated compositions, processes, and formulations for orally disintegrating formulations of the receptor agonist 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, as well as product forms made by these processes, and their use for the rapid oral administration of lasmiditan for the treatment of migraine. [Background technology]

[0002] In October 2019, the U.S. Food and Drug Administration approved REYVOW® (lasmiditan) 50 and 100 mg tablets for the acute, on-demand treatment of migraine with or without aura in adults. Lasmiditan is a selective and highly potent 5-HT inhibitor. 1F It is a receptor agonist (see, for example, Rubio-Beltran et al., Pharmacol Ther 2018;186:88-97, and Lasmiditan for the Treatment of Migraine, Capi, M. et al., Expert Opinion Investigational Drugs, (2017), Vol. 26, No. 2, 227-234). Lasmiditan (COL 144, LY 573144, CAS Registry Number 439239-90-4) can be chemically described as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide. US Patent No. 7,423,050 and US Patent Publication No. 2008 / 0300407 describe the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, having the following structural formula:

[0003] [ka]

[0004] Currently available solid dosage forms of lasmiditan hemisuccinate, which are tablets, are acceptable for therapeutic purposes. However, the strong bitter taste of this solid dosage form and lasmiditan pose significant compliance issues for patients who are unable or unwilling to take the current solid dosage form of this compound. Solid dosage forms are generally difficult to swallow for young children and migraine sufferers who experience nausea. Although many methods exist to suppress certain undesirable drug tastes, due to the unique properties of various drugs, no universal formulation can solve this problem. Currently, the development of a taste-masked orally disintegrating tablet (ODT) for lasmiditan has not been reported.

[0005] The taste-masked and coated orally disintegrating tablet formulations of lasmiditan disclosed in this patent application address this need. There is a need to develop a palatable, orally disintegrating dosage form of lasmiditan to reduce or eliminate its strong bitter taste and other undesirable palatability characteristics and to avoid difficult-to-swallow solid dosage forms such as tablets.

[0006] The currently marketed dosage form of lasmiditan is an immediate-release tablet that provides a rapid onset of action (time to symptom relief) of approximately two hours. Migraine treatment is complicated in that migraine triggers are often unknown and the timing of migraine attacks is difficult to predict. Therefore, convenient administration of the therapy is important for treatment. Most solid oral dosage forms are intended to be swallowed whole and require the co-administration of a liquid to facilitate swallowing, reducing the convenience of administration. Nausea is a common symptom of migraine, making oral administration of medication difficult. If a dosage form requires swallowing a liquid or has poor palatability, migraine sufferers may be reluctant to undergo treatment and / or the medication may further exacerbate nausea. Furthermore, migraine is one of the most common symptoms seen in emergency rooms, and patients often have difficulty administering tablets due to nausea and / or vomiting. In general, many adults, especially children, have difficulty swallowing tablets whole, even when co-administered with a liquid. In cases where swallowing difficulties exist, a dosage form other than an immediate-release tablet that is easier to swallow but still has good palatability is desirable. The aforementioned problems of orally delivering migraine treatments to adults, especially pediatric patients, can be solved by the use of orally disintegrating or orally dispersible tablets, provided that the required formulation and performance factors for the tablet can be met. If an orally disintegrating tablet dosage form can be taken without the need for co-administration with a liquid, it would be a clinically advantageous solution for migraine sufferers. These ODTs are intended to rapidly disintegrate or disperse with a small amount of saliva in the mouth into small particles that are easily swallowed without the need for additional liquid to facilitate swallowing.

[0007] However, the development of ODTs presents many substantial technical challenges, the primary one being taste or palatability. Compounds such as active pharmaceutical ingredients have a variety of taste profiles, some of which are highly undesirable. The unpleasant taste of many drugs often necessitates the use of flavor-masking strategies, such as the addition of flavors, sweeteners, complexing agents, or other approaches to mask the unpleasant taste of drugs. In some instances, other negative sensory attributes associated with drugs, such as trigeminal irritation, tongue tingling, and throat burning, further complicate the development of palatable ODTs. The challenge of formulating ODT drug products becomes even more complex when the drug in question is highly soluble and doses exceeding several tens of milligrams are required. Minimizing the negative sensory attributes of high-dose, highly soluble drugs with poor palatability presents a challenge to the extent that those skilled in the art cannot predict whether a clinically relevant ODT product form can be successfully formulated for a compound with very low palatability.

[0008] The use of sweeteners and flavoring agents to enhance the taste of drugs is one of the most widely used approaches for taste masking, especially in pediatric formulations such as chewable tablets and liquid formulations. However, this approach has not been very successful for very bitter and highly water-soluble drugs. (See, for example, Taste Masking Approaches, Vishani et al., International Journal of Pharmacy and Integrated Life Sciences, April 2013, Vol. I(5), pp. 48-61.) Lasmiditan has been found to be a very bitter and highly water-soluble drug. In addition, it has a lingering bitter taste. Therefore, it is expected that it would be very difficult to produce an acceptable, palatable ODT dosage form of lasmiditan. However, the present disclosure surprisingly provides a pharmaceutical taste-masking composition of lasmiditan in an orally disintegrating tablet. The ODT product form provides a compatible dosage form that is particularly useful in the pediatric population and migraine patients who experience nausea and vomiting when attempting to swallow a solid tablet with a liquid. Safe and effective treatment of migraine with lasmiditan for patients unable to administer conventional oral tablets is made possible by the availability of an orally disintegrating tablet that does not require swallowing. The present disclosure addresses this unmet need for lasmiditan, a recently approved migraine treatment. Summary of the Invention

[0009] The present disclosure relates to a taste-masked pharmaceutical composition for lasmiditan. Specifically, the present disclosure relates to a taste-masked pharmaceutical composition comprising a therapeutically effective amount of taste-masked lasmiditan particles containing lasmiditan or a pharmaceutically acceptable salt thereof, wherein the particles are coated with one or more taste-masking layers that mask the taste of lasmiditan, and the taste-masking layers comprise at least one water-insoluble polymer. Preferably, the water-insoluble polymer is a non-enteric coating. Preferably, the non-enteric coating is Kollicoat® Smartseal 30 D. In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof and a non-enteric coating. In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate and a non-enteric coating. In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate and a non-enteric coating, wherein the non-enteric coating is Kollicoat® Smartseal 30 D, comprising methyl methacrylate-di(ethyl)aminoethyl methacrylate copolymer. In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the non-enteric coating is Kollicoat® Smartseal 30 D. In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, the coated lasmiditan further comprising talc, and the non-enteric coating is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns.

[0010] In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the composition further comprises a coating degree of about 20 to 40% when coated with Kollicoat® Smartseal 30 D.

[0011] In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the composition further comprises a coating degree of about 37% when coated with Kollicoat® Smartseal 30 D.

[0012] In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the coated lasmiditan further comprises talc, and a non-enteric coating which is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns; (i) about 55.5% w / w of lasmiditane hemisuccinate; (ii) about 6.0% w / w of hypromellose (HPMC); (iii) about 0.15% w / w sodium lauryl sulfate; (iv) about 2.8% w / w triethyl citrate; (v) about 18.6% w / w of Kollicoat® Smartseal 30 D, and (vi) further comprising about 16.9% w / w talc.

[0013] In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, which comprises granular particles having a size range of about 50 to about 275 microns, the coated lasmiditan further comprising talc, and a non-enteric coating which is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns, and which comprises a disintegrant and a lubricant.

[0014] In one embodiment, the present disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the coated lasmiditan further comprises talc, and a non-enteric coating that is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns, and the composition further comprises talc, Pharmaburst® 500, and sodium stearyl fumarate.

[0015] In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the coated lasmiditan further comprises talc, and a non-enteric coating that is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns, and the composition further comprises talc, Pharmaburst® 500, and sodium stearyl fumarate, and further comprises a sweetener and a flavoring agent.

[0016] In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the coated lasmiditan further comprises talc, and a non-enteric coating that is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns, and the composition further comprises talc, Pharmaburst® 500, and sodium stearyl fumarate, and further comprises aspartame and cherry berry flavoring.

[0017] In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, and the coated lasmiditan further comprises talc, and a non-enteric coating that is Kollicoat® Smartseal 30 D, wherein the final coated particles have a size range of about 75 to about 300 microns, and the composition further comprises talc, Pharmaburst® 500, and sodium stearyl fumarate, and the composition further comprises aspartame and cherry berry flavoring; (i) about 40.2% w / w of Kollicoat® Smartseal 30 D coated lasmiditane hemisuccinate (37% coating degree); (ii) about 0.80% w / w talc; (iii) about 54.0% w / w of Pharmaburst® 500; (iv) about 2.0% w / w sodium stearyl fumarate; (v) about 1.0% w / w cherry berry flavoring, and (vi) providing a pharmaceutical composition further comprising about 2.0% w / w aspartame;

[0018] In one embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan hemisuccinate, wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns, the coated lasmiditan further comprises talc and a non-enteric coating, the non-enteric coating is Kollicoat® Smartseal 30 D, the final coated particles have a size range of about 75 to about 300 microns, the composition further comprises talc, Pharmaburst® 500, and sodium stearyl fumarate, the composition further comprises aspartame and cherry berry flavoring, and the composition about 37% to 46% w / w of Kollicoat® Smartseal 30 D coated lasmiditane hemisuccinate, about 47% to 58% w / w Pharmaburst® 500, about 3.9% to 4.9% w / w of an aspartame / cherry berry flavor blend (about 68% aspartame to about 32% cherry berry flavor w / w), and The pharmaceutical composition further comprises about 1.3% to 1.7% w / w of sodium stearyl fumarate.

[0019] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 25 mg to about 200 mg.

[0020] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 25 mg to about 100 mg.

[0021] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 25 mg.

[0022] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 50 mg.

[0023] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 75 mg.

[0024] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 100 mg.

[0025] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 150 mg.

[0026] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises lasmiditan in a dosage amount of about 200 mg.

[0027] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises an orally disintegrating tablet.

[0028] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises an orally disintegrating tablet, and the tablet further comprises a 25 mg unit dosage form.

[0029] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises an orally disintegrating tablet, and the tablet further comprises a 50 mg unit dosage form.

[0030] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the above embodiments, wherein the composition further comprises an orally disintegrating tablet, and the tablet further comprises a 100 mg unit dosage form.

[0031] In one embodiment, the present disclosure provides a method of treating migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of a composition according to any of the above embodiments of a lasmiditan composition.

[0032] In one embodiment, the present disclosure provides a composition according to any of the above embodiments of a lasmiditan composition for use in therapy.

[0033] In one embodiment, the present disclosure provides a composition according to any of the above embodiments of a lasmiditan composition for use in treating migraine.

[0034] The present disclosure also relates to an immediate-release (IR) orally disintegrating tablet (ODT) comprising a therapeutically effective amount of lasmiditan particles, each particle comprising 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof coated with one or more taste-masking layers, the taste-masking layers comprising a water-insoluble polymer. The present disclosure provides a palatable pharmaceutical composition in the form of taste-masked 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and an orally disintegrating tablet comprising the same.

[0035] The present disclosure further provides a disintegrant and a plurality of units comprising: i) a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; ii) a non-enteric coating covering the particles, the non-enteric polymer being present in an amount of 20% to 40% of the coating degree, The present invention provides a compressed orally disintegrating tablet, in which a disintegrant and a plurality of units are compressed into an orally disintegrating tablet having a friability of 1% or less when a compression force of 6 kN to 50 kN is applied during tablet production.

[0036] The present disclosure further provides a process for making the orally disintegrating tablet of any of the above embodiments, comprising: a) forming a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; b) applying a coating comprising a non-enteric polymer to the particles of step (a), thereby obtaining a plurality of units; c) mixing the plurality of units of step (b) with at least one tablet excipient comprising a disintegrant, thereby obtaining a blend; d) mixing the blend of step (c) with flavors and sweeteners to form a taste-masked blend; e) mixing the taste-masked blend with a dry lubricant; f) compressing the blend of step (e), thereby obtaining a compressed orally disintegrating tablet.

[0037] The present disclosure also provides methods for making the taste-masked ODT compositions and methods for using the compositions to treat patients prone to migraine attacks. The taste-masked orally disintegrating tablets of the present disclosure significantly reduce the strong bitter taste of lasmiditan, allowing for administration of this product form to migraine sufferers, particularly pediatric patients, and patients who suffer from nausea due to migraine attacks.

[0038] The present disclosure relates to a solid pharmaceutical composition comprising taste-masked lasmiditan or a pharmaceutically acceptable salt thereof incorporated into an orally disintegrating tablet (ODT), preferably wherein the tablet disintegrates within about 30 seconds. The present disclosure further provides an ODT comprising taste-masked lasmiditan together with one or more pharmaceutically acceptable excipients, having desired mechanical strength and a desired in vitro release profile. [Brief explanation of the drawings]

[0039] [Figure 1] 1 is a process flow chart for lasmiditan ODT formulation. [Figure 2] FIG. 1 is a process flow diagram of an intermediate for the lasmiditan ODT formulation. [Figure 3] 1 is a taste profiling of lasmiditan ODT embodiments using the flavor profiling method. [Figure 4] Illustrative example of lasmiditan hemisuccinate orally disintegrating tablet. DETAILED DESCRIPTION OF THE INVENTION

[0040] The following description includes information useful for understanding the present disclosure.

[0041] Definition: As used above, and throughout the description of this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: As used herein, the terms "drug," "active," "active ingredient," or "active pharmaceutical ingredient" include any pharmaceutically acceptable, therapeutically effective compound or a pharmaceutically acceptable salt thereof. A preferred compound of the present disclosure is 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide. A preferred compound of the present disclosure is 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A preferred compound of the present disclosure is solid form A of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A preferred compound of the present disclosure is solid form D of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate.

[0042] Methods for preparing lasmiditan and salts, as well as certain polymorphic forms, formulations, and dosage forms thereof, are known to those skilled in the art and are described, for example, in WO 2003 / 084949, WO 2011 / 123654, WO 2018 / 106657, and WO 2021 / 007155. As used herein, useful forms of lasmiditan (also referred to as LY573144) include 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide monohydrochloride and pharmaceutically acceptable salts thereof, including, but not limited to, 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A synthetic route for the preparation of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide has been previously disclosed (see, for example, WO 2021 / 007155).

[0043] "Pharmaceutically acceptable salt(s)" refers to relatively non-toxic inorganic and organic salt(s) of the compounds of the present invention. Those skilled in the art will understand that the compounds of the present invention can form salts. The compounds of the present invention contain basic heterocycles and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and the general methodology for their preparation are well known in the art. For example, see P. Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2008); S.M. Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0044] As used herein, the term "non-enteric coating" refers in its broadest sense to a non-enteric polymer used as a barrier coat. As used herein, the term "non-enteric coating" refers to a coating containing a "non-enteric polymer," which refers to a pH-sensitive polymer that is insoluble at pH values ​​higher than those found in the stomach (i.e., pH values ​​higher than 5.0) but soluble at acidic pH values. Thus, suitable non-enteric polymers are insoluble in the oral cavity and soluble in the stomach. In some embodiments, the non-enteric polymer is a copolymer of hydrophobic and / or basic monomers. Non-limiting examples of such non-enteric polymers are described in U.S. Patent Application Publication No. 2006 / 0134054. In certain embodiments, the monomer is an acrylic or methacrylic acid ester, including, but not limited to, methyl (meth)acrylate, benzyl (meth)acrylate, dodecyl (meth)acrylate, octyl (meth)acrylate, cyclohexyl (meth)acrylate, phenyl (meth)acrylate, tert-butyl (meth)acrylate, butyl (meth)acrylate, ethylhexyl (meth)acrylate, propyl (meth)acrylate, or a combination thereof. Each possibility represents a separate embodiment. In other embodiments, the monomer is a substituted acrylic or methacrylic acid ester, including, but not limited to, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, piperidine ethyl (meth)acrylate, tert-butylaminoethyl (meth)acrylate, EUDRAGIT® E100, Eudragit® EPO, or a combination thereof. Each possibility represents a separate embodiment. Preferred non-enteric coatings of this embodiment include Kollicoat® Smartseal 30 D or Kollicoat® Smartseal 100 P (BASF PRD numbers (product numbers) are listed as 30492630 for Kollicoat® Smartseal 30 D and 30585559 for Kollicoat® Smartseal 100 P).The Kollicoat® Smartseal 100 P coating can be applied using the 100 P (powder) grade with an organic solvent system (e.g., alcohol or acetone). A particularly preferred non-enteric coating of this embodiment is Kollicoat® Smartseal 30 D (30% dispersion). As used herein, the term "unit" refers to the application of a coating comprising a non-enteric polymer to granular particles of lasmiditan or a pharmaceutically acceptable salt thereof, thereby obtaining a plurality of units of the coated API.

[0045] As used herein, the term "patient" refers to a human. As used herein, the terms "treatment," "treating," or "mitigating" are intended to refer to any process, which may include slowing, interrupting, preventing, controlling, or halting an existing disorder and / or reducing its symptoms, but does not necessarily indicate the complete elimination of all symptoms. As used herein, the term "effective amount" of a lasmiditan compound refers to an amount, i.e., a dosage, that is effective in treating a patient's migraine headache. A preferred "effective amount" is determined as an amount that can treat or eliminate the signs and symptoms of a migraine attack in a patient compared to an untreated patient. Preferred amounts of lasmiditan include the range of 25-200 mg, as well as unit dosage forms of 25 mg, 50 mg, 100 mg, and 200 mg.

[0046] "Dose" refers to a predetermined amount of lasmiditan calculated to produce a desired therapeutic effect in a patient. As used herein, "mg" refers to milligrams. As used herein, a dose stated in mg refers to the active pharmaceutical ingredient lasmiditan as the free base equivalent by mass; for example, a "100 mg" dose refers to 100 mg of the active pharmaceutical ingredient lasmiditan as the free base equivalent. As used herein, a given dose may be interpreted as describing the approximate indicated amount of dose, in that doses up to 10 percent higher or lower than the indicated dose are also contemplated to provide a useful dosing regimen in a manner similar to the indicated dose. The lasmiditan pharmaceutical composition of the present disclosure can be provided in bulk or in unit dosage form. It is particularly advantageous to formulate a lasmiditan pharmaceutical composition in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for a subject to be treated. Each unit contains a predetermined amount of the active compound lasmiditan calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The unit dosage form may be, for example, an orally disintegrating tablet containing a preferred dose of lasmiditan, such as 25 mg, 50 mg, 100 mg, and 200 mg.

[0047] In embodiments, the present disclosure provides pharmaceutical compositions comprising lasmiditan in ODT form in an amount described herein, wherein the amount is 25 mg to 200 mg per dose. In embodiments, the present disclosure provides pharmaceutical compositions comprising lasmiditan in ODT form in an amount described herein, wherein the amount is 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg per dose. The foregoing doses are based on an average weight adult, and / or lower doses may be tolerated for individuals of lower weight, such as the elderly or children.

[0048] In some embodiments of the present disclosure, the patient is a human diagnosed with a condition or disorder requiring prevention with the pharmaceutical compositions described herein. In some embodiments, the patient is a human characterized by being at risk for a condition or disease indicating the need for administration with the pharmaceutical compositions described herein. When the disorders that can be treated by the methods of the present invention are known by established and accepted classifications, such as migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache, the classifications can be found in various sources. For example, currently, the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools for identifying many of the disorders described herein. Additionally, the International Classification of Diseases, 10th edition (ICD-10) provides classifications for many of the disorders described herein. Those skilled in the art will recognize that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve with advances in medical science. Migraine sufferers may also be diagnosed with migraine with or without aura (1.1 and 1.2), as defined by the International Headache Society's (IHS) International Classification of Headache Disorders, Third Edition (Beta), (ICHD-3) Beta (The International Classification of Headache Disorders, Third Edition (Beta), Cephalalgia 2013;33:629-808). In some embodiments, the human patient has been diagnosed with episodic migraine prior to receiving lasmiditan for migraine prevention. In some embodiments, the human patient has been diagnosed with chronic migraine prior to receiving lasmiditan. In some embodiments, the human patient experiences migraine aura.In some embodiments, the human patient does not experience migraine aura.

[0049] As used herein, "migraine" includes, but is not limited to, a migraine attack. As used herein, "migraine attack" refers to the following description: Symptoms may overlap during the various phases of a migraine attack, and not all patients experience the same clinical signs. During the prodromal phase, the majority of patients experience prodromal symptoms, which may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, food cravings, recurrent yawning, stiff shoulders, and phonophobia. These symptoms may persist into the aura, headache, and even post-symptom phases. Some patients experience a prodromal phase, during which approximately one-third of patients experience transient neurological deficits. ICHD-3 defines an aura as one or more transient, fully reversible neurological deficits lasting 5 minutes or more, each lasting 5 to 60 minutes, at least one of which must be unilaterally localized. Visual aura, which may be positive (scintillating scotoma), negative (scotoma), or both, is found in over 90% of cases, but sensory, motor, language, brainstem, and retinal aura symptoms, the most common deficits, may also occur. A transient wave of cortical neuronal depolarization is thought to be the pathophysiological brain mechanism underlying the clinical phenomenon of migraine aura. During the headache phase, headache attacks, which may last 4 to 72 hours, are accompanied by nausea, photophobia, phonophobia, or both. The headache is characterized as moderate or severe, unilateral, pulsatile, and worsened by physical activity. Two of these characteristics are sufficient to meet the diagnostic criteria. During the post-symptom phase, characteristic symptoms mirror those observed during the prodromal phase. Typical post-symptom symptoms include fatigue, impaired concentration, and stiff neck. It remains unclear whether these symptoms begin in the prodromal phase and persist through the headache and post-symptom phases, whether they also begin during the headache phase, or whether they appear after the headache phase has ended.

[0050] As used herein, "migraine" refers to a headache of ≥ 30 minutes duration, with or without aura, that has both of the following required features (A and B): A) at least two of the following headache features: 1) unilateral location, 2) pulsatile quality, 3) moderate or severe pain intensity, and 4) causing aggravation by or avoidance of usual physical activity, and B) at least one of the following during the headache: a) nausea and / or vomiting, and / or b) photophobia and phonophobia. As used herein, "moderate migraine" refers to a headache with or without aura that is greater than 30 minutes in duration but lacks one of the features of migraine in the International Headache Society's ICHD-3 definition.

[0051] The abbreviations listed below, as used herein, are defined as follows: "CAS No." means Chemical Abstracts Registry Number; "hr" or "h" means hour; "NMT" means: "RT" means room / ambient temperature; "sec" means second(s) as a unit of time; "w / w" means weight to weight ratio.

[0052] The compositions, processes, product forms, and uses of the present disclosure are further described with respect to certain preferred embodiments, including the preparation of orally disintegrating tablets containing non-enteric-coated lasmiditan and coated lasmiditan. Orally disintegrating tablets of the commercially available, palatable masking lasmiditan hemisuccinate salt were developed for inclusion in a bioequivalence study (LAIA). In this disclosure, lasmiditan refers to 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide itself. The specific salt used in this disclosure is the hemisuccinate salt, although other salts, such as the hydrochloride salt or other suitable salts, are also within the scope of the presently disclosed embodiments.

[0053] Challenges in preparing orally disintegrating tablets of lasmiditan: Orally disintegrating tablets (ODTs) are solid oral dosage forms that rapidly dissolve in saliva in the oral cavity, allowing the medication to be easily swallowed without water. This is beneficial for patients with swallowing disorders (e.g., children), conditions where symptoms may prevent the consumption of liquids (e.g., nausea), and conditions where convenience of administration is desirable (e.g., migraine). However, ODTs present challenges in formulation development beyond the typical important quality attributes of immediate-release tablets (e.g., purity, potency). ODTs are also required to be palatable to patients to ensure compliance. Rapid oral disintegration and a pleasant taste are paramount. The present disclosure addresses these challenges and provides a novel solution for an ODT product form for REYVOW® (lasmiditan) for pediatric and / or adult populations.

[0054] Lasmiditan is highly soluble (dissolves easily in the mouth), but has a very bitter taste and other negative sensory attributes that preclude conventional ODT development. Lasmiditan's solubility is 35-9.8 mg / mL at pH 5-6.8, approximately the oral pH range. Effective doses range from 25-200 mg, depending on patient weight and other factors. Taste studies using trained taste panelists and crushed 50 mg (e.g., 2 x 50 mg) lasmiditan immediate-release tablets have shown that lasmiditan has very poor palatability. Extremely bitter taste, mouth numbness, and other negative sensory attributes are present and persist for 30 minutes.

[0055] [Table 1]

[0056] Approaches to limiting the negative sensory attributes of particularly bad-tasting drugs can include applying a barrier coating to the drug substance to prevent dissolution in the oral cavity. One approach is to use an insoluble film containing a soluble pore-forming agent, such as cellulose acetate with polyethylene glycol or ethylcellulose with hypromellose. The challenge with this approach is to balance the amount of soluble pore-forming agent with the insoluble polymer to ensure adequate taste masking of the drug while still allowing rapid release in the gastrointestinal tract to ensure sufficiently rapid absorption and onset of action. This is particularly critical for migraine sufferers. Non-enteric polymers have also been used as barrier coatings. These polymers are designed to be insoluble at salivary pH but rapidly dissolve at gastric pH. Non-enteric polymers have also been demonstrated as pore-forming agents in otherwise insoluble films.

[0057] US Patent No. 5,489,436 describes the use of non-enteric polymer Eudragit® 100E as a pore former in insoluble cellulose ester film.This approach has the limitation that it requires efforts to determine the optimal amount of pH-sensitive pore former contained in the film to achieve good taste masking performance without impairing in vivo release due to insoluble film coating.In the case of drugs for alleviating migraine symptoms, any delay in drug release can lead to delayed absorption and delayed pharmacodynamic effect.An ideal taste masking film has almost no release in the mouth, but has immediate and complete drug release in the GI tract, equivalent to that of conventional immediate release tablets.

[0058] Orally disintegrating tablets must also meet other constraints, such as rapid disintegration. FDA guidance states that tablets should meet the traditional USP <711> The FDA also states that ODT tablets must disintegrate within 30 seconds using a disintegration test. The FDA also generally recommends that ODT tablets not exceed 500 mg in weight. However, if a tablet intended for use as an ODT weighs more than 500 mg, its ability to function effectively as an ODT should be justified based on product performance. Finally, the ODT must be sufficiently hard and robust so that the integrity and elegance of the tablet are not compromised during manufacturing, packaging, or patient handling. Achieving these requirements for doses above a few tens of mg is difficult because many of the desired attributes, such as tablet hardness and rapid disintegration, are not met. Soft tablets disintegrate quickly but are difficult to handle, and vice versa; hard tablets are easy to handle but disintegrate slowly.

[0059] Compositions and orally disintegrating tablet formulations and product forms of the present disclosure The present disclosure describes embodiments of an orally disintegrating tablet (ODT) form of lasmiditan, herein referred to as "lasmiditan ODT," useful for the acute treatment of migraine headaches in patients with and without aura. The following preparation of lasmiditan ODT tablets further illustrates the invention and represents an exemplary preparation. The reagents and starting materials are readily available or can be readily synthesized by one of ordinary skill in the art. It should be understood that the preparations and examples are given by way of illustration and that various modifications can be made by one of ordinary skill in the art.

[0060] Preparation of taste-masked drug substances The active ingredient, lasmiditane hemisuccinate, is preferably prepared in a size range of approximately 50 to 275 μm or less to be suitable for small particle coating. It is recognized that coating particles smaller than approximately 50 μm (referred to herein as fines) is generally not practical or feasible. Large surface area particulates may require a high level of coating for taste masking and / or require a granulation process to bind the particulates. Furthermore, it is recognized that the presence of particulates may result in an insufficient final coating, potentially compromising the taste masking effect, and therefore the retention of particulates should be minimized during coating. It is also recognized that particles larger than approximately 300 μm in size are undesirable in ODTs because they may result in a gritty mouthfeel in the final product.

[0061] Small particles, as defined herein, are particles within the general range of a d10 of about 50 μm and a d90 of not more than about 275 μm, and coating can be accomplished by several methods, including coacervation and fluidized bed coating. A common method is to use a Wurster-type fluidized bed coater, as this process generally provides an efficient coating process and is well understood. In one embodiment of the present disclosure, Wurster-type fluidized bed coating is used to coat the lasmiditan drug substance.

[0062] Determining particle size is well known to those skilled in the art, and well-known methods can be used. Materials and equipment used can include a Malvern Mastersizer 3000 particle size analyzer equipped with an Aero S Module, a dispersion system: a microtray standard venturi disperser, and current windows software equipped with Malvern Mastersizer 3000 software (version 3.0 or equivalent) or equivalent. Measurements are performed according to standard procedures (see, for example, "Operation, Calibration, and Maintenance of the Malvern Mastersizer 3000 Laser Diffraction Particle Size Dispersion Analyzer," PPD SOP 10-1237 latest edition, and "Optical Diffraction Measurement of Particle Size," USP latest edition), and the average d10, d50, and d90 values ​​of the three test preparations are calculated.

[0063] According to a preferred embodiment of the present disclosure, the drug substance is first granulated / subcoated with HPMC E5 before application of the non-enteric copolymer topcoat. A surfactant can also be included in the coating solution to ensure good wetting of the coating solution onto the particles. Sodium lauryl sulfate is a preferred surfactant. The subcoating / granulation process serves both to bind the microparticles into granules and to provide greater particle core integrity to avoid particle attrition during coating, both of which serve to improve the yield and quality of the taste masking coating.

[0064] In one aspect, the present invention relates to the discovery and incorporation into an ODT of a non-enteric coated lasmiditan composition that achieves a balance between in vitro taste masking, in vitro dissolution (supporting rapid bioavailability), fast disintegration time, and adequate tablet hardness.

[0065] The present disclosure provides an ODT comprising a lasmiditane hemisuccinate drug substance coated with an effective amount of a polymer coating for taste masking, preferably a non-enteric coating. A non-enteric coating is defined herein as a polymer or copolymer coating that is not soluble at pH levels higher than those typical in the mouth (typically about pH 6-7), but is soluble in gastric fluids having a lower pH, e.g., pH 1.0 to about 3.5-5.0. Preferably, the composition of the present disclosure includes a coating of Kollicoat® Smartseal 30 D (commercially available from BASF), a non-enteric methyl methacrylate di(ethyl)aminoethyl methacrylate copolymer. Prior to application of the copolymer coating, the pure drug substance is preferably granulated using an inert polymer (e.g., HPC or HPMC, preferably HPMC E5). Talc may be added to any coating to facilitate processing. The particle size of the starting API is preferably in the size range of about 50 to 275 microns to facilitate particle coating while maintaining a size that does not cause the coated particles to feel gritty in the mouth in the final dosage form. The resulting coated particles may also be dusted with an anti-caking agent, such as colloidal silicon dioxide or talc, preferably talc, to minimize caking on storage.

[0066] The coating process is made easier by incorporating talc into the coating suspension to minimize particle stickiness during coating. High stickiness during processing leads to increased interparticle adhesion and agglomeration. Particle agglomeration reduces coating efficiency and results in erratic drug release profiles between batches. In addition, if stickiness occurs extensively during processing, the granules will spheronize into solid masses (or agglomerates) greater than 300 μm, which can have a gritty feel in the mouth. The final coated particles are desirably in the size range of approximately 75 to 300 μm to facilitate processing into ODTs while avoiding a gritty feel in the mouth in the final product. The following unit formulations can be used to manufacture ODT lasmiditan tablets as follows for 25 mg, 50 mg, and 100 mg doses:

[0067] [Table 2] A The amount of drug substance (drug intermediate, coated API) is based on an assay of the active ingredient. B The amount of Pharmaburst® 500 is adjusted accordingly to maintain theoretical tablet weight.

[0068] The taste-masking coated lasmiditan is preferably directly compressed with suitable excipients to prepare ODTs. The excipients may be any of those commonly used in the manufacture of ODTs, such as polyols (mannitol, sorbitol), fillers (starch, microcrystalline cellulose), lubricants (sodium stearyl fumarate, magnesium stearate, talc), flow aids (colloidal silicon dioxide), and disintegrants (crospovidone, croscarmellose sodium). Preferably, co-processed excipients designed for ODTs, such as Pharmaburst® 500 (commercially available from SPI Pharma), can be used to simplify processing and optimize tablet properties. Flavors (mint, cherry berry, peppermint) and sweeteners (aspartame, sucralose, neotame) may also be added, as is common in ODT preparations. A preferred flavor is FONA NC Cherry Berry Flavor ART#825.0062U. The preferred sweetener is aspartame. Alternative flavors are NC cherry flavor ART-825.0597U, bubble gum flavor ART-815.0084U, NC strawberry flavor ART-915.0435U, Fonatech mango flavor NAT WONF-870.0235U, and juicy orange flavor NAT WONF-884.0107U. Tablets are compressed to a solids content high enough to ensure low tablet friability (less than 1%) in downstream processing while also maintaining an in vitro disintegration time of 30 seconds or less. [Example]

[0069] The following examples are provided to illustrate, but not limit, the claimed invention. The results of the following methods and procedures demonstrate that the exemplified compositions, formulations, and tablets of the present disclosure provide useful formulation intermediates and dosage forms of lasmiditan for orally disintegrating tablets, and therefore may be used to treat migraine and / or headache disorders.

[0070] Example 1 - General procedure for coating lasmiditan The following procedure describes a method for coating 1.2 kg of lasmiditane hemisuccinate with particle sizes such as d10 = 55.0 μm, d50 = 117.9 μm, and d90 = 220.9 μm. The lasmiditane hemisuccinate is loaded into a fluidized bed coater as described in Table 3. Many vendors supply fluidized bed coaters capable of Wurster coating, and equipment settings may vary between vendors, particularly with regard to nozzle type and fluidization parameters. While the example cited here is for one particular style of fluidized bed coater, it is understood that other fluidized bed coaters may be used to achieve similar results.

[0071] [Table 3]

[0072] Prepare a subcoat / granulation solution of HPMC E5 and SLS in purified water as shown in Table 4.

[0073] [Table 4]

[0074] Apply the subcoat granulation solution to the desired degree of coating, also referred to as degree of coating, as defined and used herein, where a 10% degree of coating is desired for the granulation, with 900 g of API and 100 g of HPMC / SLS system for 1 kg of final granulated material.

[0075] It is recognized that similar processing results may be achieved using a variety of conditions and equipment, and those shown herein are examples.

[0076] [Table 5]

[0077] [Table 6]

[0078] The subcoated granules may optionally be sieved to remove remaining fines and over-granulated material. The following general procedure may be used to coat 0.3 kg of lasmiditan HPMC subcoating / granules with a topcoat of non-enteric Kollicoat® Smartseal 30 D.

[0079] [Table 7]

[0080] Prepare a topcoat taste masking dispersion of Kollicoat® Smartseal 30 D in purified water as shown in Table 7.

[0081] [Table 8]

[0082] It is recognized that other plasticizers may be used to ensure good film formation during coating. It is also recognized that antioxidants other than BHT may be used and / or may be omitted entirely if appropriate for product stability.

[0083] The topcoat dispersion is applied to the desired percent coating, preferably 37% theoretical coating. As used herein, coating level, coating degree, or coating may be described as a percentage of the coated material relative to the weight of the coating material on a weight-to-weight basis. Thus, a 37% theoretical coating degree is represented by 1 kg of final coating API with 630 g of granule API and 370 g of taste-masking matrix, e.g., Kollicoat® Smartseal 30 D topcoat taste-masking dispersion in purified water as shown in Table 7. Useful conditions are shown in Table 8. It is recognized that similar processing results can be achieved with a variety of conditions and equipment, using the conditions and equipment presented herein as illustrative examples. Embodiments of the present disclosure include a non-enteric coating, preferably Kollicoat® Smartseal 30 D, with a coating degree of, for example, 20-40% coating degree, preferably 30-40% coating degree, and more preferably about 31-38% coating degree, using the conditions described herein. Preferred embodiments of the present invention are 32% coating degree and / or 37% coating degree. 37% coating degree is particularly preferred. As used herein, coating or coated refers to the degree of coating and related methods and specifications.

[0084] [Table 9]

[0085] [Table 10]

[0086] The final coated material may optionally be further dried in a fluidized bed coater at a temperature of 30-45°C to remove residual water and improve coating quality. The final coated material may optionally be sieved to remove any remaining fines and / or granular material. Additional talc may be blended with the coated API to prevent caking during storage. Taste masking performance and subsequent drug release in the GI tract can be modeled by measuring API release from representative dosage forms using a USP II paddle dissolution apparatus with a pH shift method. Representative tablet dosage forms were first prepared, as shown in Tables 10 and 11.

[0087] [Table 11]

[0088] Blends were prepared and blended in a 125 mL container using a Turbula mixer at 44 rpm for 9 minutes. 100 mg of lasmiditan ODT was compressed at approximately 90 MPa compression stress using a Natoli single station manual tablet press and 12 mm circular concave tooling.

[0089] [Table 12]

[0090] Blends were prepared and blended in a 125 mL container using a Turbula mixer at 44 rpm for 9 minutes. 100 mg of lasmiditan ODT was compressed at a compression stress of approximately 35 MPa using a Natoli single station manual tablet press and 12 mm circular concave tooling.

[0091] To evaluate taste-masking and release properties, the ODT was placed in 900 mL of 10 mM Na-phosphate / 15 mM NaCl dissolution medium. This medium was chosen to represent the pH (approximately 6.5) and salinity of human saliva. The release of lasmiditan from the dosage form was monitored every 10 seconds by measuring UV absorbance at 259 nm while stirring at 100 rpm at 37°C. After 300 seconds, 1.5 mL of 5 N HCl was added to the dissolution vessel to lower the pH to approximately pH 2.6, mimicking the transition to the gastric compartment.

[0092] The dissolution results shown in Table 12 demonstrate the inhibition of lasmiditan dissolution in simulated saliva when coated with Kollicoat® Smartseal to a target coating degree of 37%. Similarly, the results show that the drug is rapidly released from the dosage form when the pH shifts to about 2.6, which is a desired release profile to ensure good taste masking and rapid release in the GI tract to ensure drug absorption.

[0093] [Table 13]

[0094] Example 2: Manufacturing process for the production of coated lasmiditan Preparation of coated lasmiditan The present disclosure provides formulations including orally disintegrating tablets with dosage strengths of 25 to 200 mg, including 25 mg, 50 mg, 100 mg, and 200 mg. A manufacturing process for producing coated lasmiditan is provided herein for lasmiditan hemisuccinate, which is film-coated for taste-masking purposes prior to incorporation into orally disintegrating tablets. Lasmiditan hemisuccinate undergoes two coating steps in a Wurster-style bottom-spray fluidized-bed coater at an 18" scale. A process flow chart and exemplary process controls, parameters, and process ranges are described. The lasmiditan formulation intermediate manufacturing process consists of three main processes: HPMC granulation, Smartseal coating, and talc blending. The process used to manufacture the lasmiditan ODT formulation intermediate is shown in Figure 2.

[0095] HPMC granulation: The primary purpose of the HPMC granulation process is to agglomerate fine particles of the active pharmaceutical ingredient to control the particle size distribution that will go into the subsequent taste-masking coating. The HPMC granulation process consists of the following steps, outlined below:

[0096] Preparation of HPMC solution: Prepare an HPMC solution (8% w / w solids) with an appropriate excess (if necessary) to allow for settling and loss of the liquid addition system. Fill a container with purified water. Dissolve the HPMC in the purified water using a mixer that provides a moderate vortex. Once the HPMC is visibly dissolved, reduce the mixer speed to provide a small vortex and continue mixing to degas the solution. Increase the stirring speed to provide a medium vortex and add the sodium lauryl sulfate to the HPMC solution. Once all solids are visibly dissolved, reduce the mixing speed to provide a low vortex while degassing the suspension. Turn off the mixer. QS the solution to its final weight with purified water. Mix the solution at a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer.

[0097] HPMC granulation: Prepare an 18" Wurster-type coater by installing the specific coater chamber, base plate and plate sieves, nozzle, partition, plenum distribution plate, and filter. Prepare the classifier by installing the specific sieve. Calculate the amount of HPMC solution to deliver (target will result in a theoretical 10% coating degree for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery lines and tare the scale. Lower the coater cart and charge the lasmiditane hemisuccinate. Close the cart and adjust the process parameters to the coating parameters specified in the batch record. Adjust the inlet temperature to achieve the specific target bed temperature. Once the target amount of solution has been delivered, adjust the coater parameters to the specified values ​​for drying and dry the granules as specified. Transfer the granules to a drum and collect the knockdown fines from the coater separately. Sift the granules using a 249 micron sieve to remove agglomerates and a 75 micron sieve to remove fines.

[0098] Kollicoat® Smartseal 30 D Coating: The primary purpose of the Kollicoat® Smartseal 30 D coating process is to apply a polymer coating to HPMC granules for the purpose of taste-masking the material. The Kollicoat® Smartseal 30 D coating process consists of the following steps, as outlined below:

[0099] Preparation of Kollicoat® Smartseal 30 D Coating Suspension: Prepare Kollicoat® Smartseal 30 D suspension (19.71% w / w solids) with an appropriate excess (if necessary) to allow for settling and loss of the liquid addition system. Fill the container with purified water. Set the stirring speed to 50 RPM. While stirring at this speed, slowly add the triethyl citrate to the water. Slowly add the Kollicoat® Smartseal 30 D to the water / TEC mixture and pass it through a 60-mesh sieve. Continue mixing at a moderate vortex without introducing bubbles for a minimum of 90 minutes from the end of the complete addition of the Kollicoat® Smartseal 30 D. Increase the stirring speed to provide a moderate vortex and add the talc to the suspension. After the talc addition is complete, continue mixing using a moderate vortex for a minimum of 30 minutes. Turn off the mixer and bring the suspension to its final weight with purified water. Mix the final suspension on low vortex for a minimum of 5 minutes. Continue mixing the suspension on low vortex throughout the coating operation.

[0100] Kollicoat® Smartseal 30 D Coating: Prepare an 18" Wurster-type coater by installing the specified coater chamber, base plate and plate sieve, nozzle, partition, plenum distribution plate, and filter. (For example, settings may be as follows: chamber is 18" 375°C, plate is W18-10, plate sieve is 325 mesh, nozzle is a CPI nozzle with a no. 2 tip, partition is 8.5" x 20" mounted 1.5" above the plate, plenum distribution plate is 1 x spoke plate / 1 x perforated plate with 1 / 16" hole size, and filter is 16 x 48" 16 oz PTFE. Prepare the classifier by installing the specified sieve. Calculate the amount of D suspension. Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Lower the coater cart and load the classified HPMC granules. Close the cart and adjust the process parameters to the coating parameters specified in the batch record. Adjust the inlet temperature to achieve the specific target bed temperature. Once the target amount of suspension has been delivered, adjust the coater parameters to the specified values ​​for the curing step and cure the coated API as specified. Transfer the coated API to a drum and separately collect the knocked-down fines from the coater. Sift the coated API using a 300 micron sieve to remove agglomerates and a 75 micron sieve to remove fines.

[0101] Talc Blending: The primary purpose of the talc blending step is to dust the coated API with a small amount of talc. This is done to mitigate the extended disintegration times of tablets stressed at high temperatures. These extended disintegration times are due to agglomerates retained on the disintegration basket sieve. The coated API is dusted with approximately 2% w / w talc in the diffusion blender. The actual weight of the coated API is used to calculate the required amount of talc. Talc blending can be done in one step or in portions. To minimize talc loss on the interior surfaces of the blender, talc should be sandwiched between each section of API addition. Approximately half of the coated API is placed in the blender. The talc is added to the blender, followed by the remaining coated API. The mixture is blended using the speed and time parameters specified in the batch record. The final DPI material is discharged into the designated bulk packaging container.

[0102] Unit formulation of lasmiditan ODT formulation intermediate: To illustrate embodiments of the present disclosure, the theoretical composition of a lasmiditan ODT formulation intermediate is shown in Table 13. The composition information provided in this table is a theoretical value based on 100% process efficiency. The composition of the manufactured formulation intermediate may vary by as much as ±10% during development due to scale accuracy and coating efficiency. The lasmiditan hemisuccinate drug substance is manufactured as a single polymorphic form (anhydrous, designated Form A) for the coating process described herein.

[0103] [Table 14] A The composition information provided in the table above is theoretical based on 100% process efficiency. The composition of manufactured formulation intermediates can vary by as much as ±10% during development due to scale accuracy and coating efficiency. BPurified water is used in both the HPMC granulation and Kollicoat® Smartseal 30 D coating operations. Most of this water is removed during drying / curing. C represents the solids portion of the Kollicoat® Smartseal 30 D suspension. Kollicoat® Smartseal 30 D is an aqueous suspension containing 30% by weight solids. D represents the talc present in the Kollicoat® Smartseal 30 D coating suspension. E represents the talc used in the final blending step of the coating composition manufacturing process.

[0104] Lasmiditan ODT formulation intermediate batch formulation: The theoretical batch recipe for the lasmiditan ODT formulation intermediate is shown in Table 14.

[0105] [Table 15] A The amount of API loaded into the HPMC granulation can be adjusted based on the assay value of the API. The theoretical free base content of the API is given by the ratio of molecular weights (377.36 / 436.41=0.86469). B Represents the amount of solution / suspension delivered during coating. Excess solution / suspension may be prepared to account for priming of delivery lines, line losses, and to provide an adequate heel in the delivery tank. C Purified water is used in both the HPMC granulation and Kollicoat® Smartseal 30 D coating operations. Most of this water is removed during drying / curing. DThe amount of Kollicoat® Smartseal 30 D coating suspension is adjusted based on the yield of the HPMC granules after classification, calculated to provide a theoretical Kollicoat® Smartseal 30 D coating degree of 37%. E Kollicoat® Smartseal 30 D is an aqueous suspension containing 30% w / w solids. F The amount of talc used in the final blending step is adjusted based on the yield of Kollicoat® Smartseal 30 D coated API after classification, and the amount of talc used in the final blending step is 20.763 g per kg of Kollicoat® Smartseal 30 D coated API.

[0106] Preparation of orally disintegrating tablets with taste-masked lasmiditan: Example 3: A representative unit and batch formula for preparing 100 mg lasmiditan ODT for a theoretical batch size of 650 tablets is shown in Table 15.

[0107] [Table 16]

[0108] The coated API may be sieved through a #50 mesh to break up loose agglomerates and ensure the coated API is in discrete particle form before further processing. The coated API and talc were weighed into a 500 mL container and blended on a Turbula at 44 rpm for 18 minutes.

[0109] Pharmaburst® 500 is weighed into a separate 1000 mL container, and the cherry berry flavor, aspartame sweetener, and sodium stearyl fumarate are added on top of the Pharmaburst® in the container. The API and talc preblend is then added on top. The 1 L container is then rolled on a Turbula mixer at 44 rpm for approximately 10 minutes.

[0110] The final blend was compressed on a FlexiTab single station press using a 12 mm circular dimple tooling. The following compression profile was produced:

[0111] [Table 17]

[0112] The result was a low compressive stress of 65 MPa, which is equivalent to USP <1216> This demonstrates that tablets of sufficient strength are produced to meet the target 1.0% friability target in USP <1216> It is recognized that the test may not be appropriate for ODTs; however, it is a recognized and accepted characterization test. Acceptable performance in this test would be recognized as more than sufficient for orally disintegrating tablets with respect to friability. A target disintegration time of 30 seconds or less is met across the compression profile.

[0113] The surprising discovery is that the use of talc not only does not adversely affect the disintegration performance of ODTs, but also helps improve the disintegration of ODTs when subjected to stress stability. Talc is a hydrated magnesium silicate whose crystals form thin, layered structures, making it suitable as a lubricant and anti-adherent in pharmaceutical applications. Its main characteristic is that it is naturally hydrophobic and lipophilic, which is generally thought to adversely affect disintegration performance when used in dosage forms at high levels.

[0114] The following coated API-talc blends were prepared by weighing the ingredients into 20 mL glass scintillation vials and blending in a Turbula mixer at 44 rpm for 40 minutes.

[0115] [Table 18]

[0116] Pharmaburst® 500 was weighed into a 2 oz. glass jar, followed by sodium stearyl fumarate, then the coated API or coated API-talc preblend was added on top. The blend was rolled on a Turbula mixer at 44 rpm for 9 minutes.

[0117] [Table 19]

[0118] [Table 20]

[0119] Tablets were compressed at 9 kN using a Natoli single station press with a 12 mm circular dimple tool. Tablets were stressed in an open pan at 70°C for the specified time. Tablets were removed from the oven and kept at room temperature until analysis. Disintegration was measured using USP <711> The procedure was repeated at least three times.

[0120] [Table 21]

[0121] Surprisingly, despite the hydrophobic nature of talc, disintegration performance is not impaired for unstressed tablets. When used at levels of 1% or greater, improved disintegration stability is obtained for tablets subjected to extreme temperature stress.

[0122] Taste studies of lasmiditan ODT compositions described herein or known to those skilled in the art indicate that the cherry / berry & aspartame flavor system has high overall flavor quality, the bitter & green / stemmy attributes of the flavored formulation are significantly lower than the unflavored coated granules, and chewing the unit does not alter the flavor quality profile when patients chew contrary to label instructions.

[0123] The challenge for the compositions and tablets of the present disclosure is to ensure that lasmiditan hemisuccinate dissolves rapidly in the stomach while preventing it from going into solution in the mouth, achieving the required efficacy with an onset of action generally comparable to the approved tablet version. A clinically successful orally disintegrating tablet for lasmiditan is intended to be palatable, bioequivalent to the approved REYVOW® tablet product form, and consistently manufacturable.

[0124] The first hurdle to enabling an ODT product form was preparing core drug substance particles for coating, with particles between 75 μm and 250 μm in size, large enough to coat, yet small enough so that orally disintegrating tablets containing the coated particles would not feel gritty in the mouth upon administration. Drug substance batches were found to meet the particle size criteria that would allow the composition to use lasmiditane hemisuccinate as a core for further coating, rather than relying on more elaborate formulation approaches. Development experiments were conducted to determine whether lasmiditane hemisuccinate particles could be coated by a fluidized-bed process and to obtain good coverage of the coating on the core, with minimal or acceptable loss to the coating process. The procedure described in this example was determined to meet these criteria.

[0125] The compositions and orally disintegrating tablets of the present disclosure result from the discovery of a successful barrier coat that facilitates oral disintegration while effectively masking the highly unpleasant taste characteristics of lasmiditan. Using the functional coating Kollicoat® Smartseal, lasmiditan API-containing core particles were masked, usefully inhibiting dissolution in the mouth. To achieve clinically acceptable taste and palatability for the target dose strengths of 50 and 100 mg, the desired product generally yields less than 1% of the administered dose of free (solubilized) drug in the oral cavity. To achieve bioequivalence, the desired product generally provides rapid dissolution in the gastrointestinal tract, thus providing good absorption of lasmiditan. While numerous taste-masking technologies and approaches exist, they cannot be predicted prior to clinical trials, and clinical trials, if any, must adequately meet multiple criteria for a clinically beneficial and useful product. To achieve the desired performance characteristics, optimal coating excipients are insoluble at pH above 5.5 but highly soluble at pH below 5.5. Kollicoat® Smartseal 30 D can be used in combination with lasmiditan for this purpose and has been found to provide excellent taste masking for this API in orally disintegrating tablets. To provide a composition that can serve as an orally disintegrating tablet, conditions and procedures had to be further tested to determine whether lasmiditan hemisuccinate particles coated with Kollicoat® Smartseal could also be effectively tableted. The Kollicoat® Smartseal coated API had acceptable processing range, masking capabilities, and produced effective and usable tablets that met the required specifications.

[0126] Example 4 - Manufacturing process of lasmiditan orally disintegrating tablets The present disclosure provides formulation embodiments comprising orally disintegrating tablets having lasmiditan dosage strengths of 25 to 200 mg, including 25 mg, 50 mg, 100 mg, and 200 mg for oral administration. Provided herein is a manufacturing process for producing lasmiditan orally disintegrating tablets, as exemplified for lasmiditan hemisuccinate, in which the product is film-coated for taste-masking purposes prior to incorporation into the lasmiditan orally disintegrating tablet. A process flow chart and exemplary process controls, parameters, and process ranges are described.

[0127] Table 20 below provides unit formulations for examples of Kollicoat® Smartseal 30 D coated lasmiditan hemisuccinate formulation intermediates, as well as 50 mg and 100 mg orally disintegrating tablets. One skilled in the art may vary the amounts to prepare, for example, 25 mg and / or 200 mg or other desired unit dosage tablets. The lasmiditan ODT manufacturing process is shown in Figure 1.

[0128] [Table 22] A Unit formulations provided as illustrative examples. B The composition and theoretical unit formulation information provided for the drug product intermediate portion is theoretical based on 100% process efficiency. The composition of the manufactured pharmaceutical intermediate may vary by as much as ±10% during development due to scale accuracy and coating efficiency. C Pharmaceutical intermediates are prepared as described herein and / or according to methods known to those skilled in the art. D Purified water is used during the formulation intermediate process and is removed during the process. E Kollicoat® Smartseal 30 D (commercially available from BASF) is an aqueous suspension containing a nominal 30 w / w% solids content, the amounts shown in the tables being the solid portion of the suspension. F Unless otherwise stated, a reasonable variation of ±10% is allowed for each orally disintegrating tablet excipient. G The amount of coated hemisuccinate API is adjusted based on "as is" or standard release potency. The amount of Pharmaburst® 500 can be adjusted accordingly to maintain the target tablet weight.

[0129] Acceptable ranges for ingredient feeding per feeder as a percentage of total tablet weight are listed in Table 11. For drug substances, the ranges are based on maintaining unit dose mean assay values ​​below 110% and above 90%. For excipients, the ranges are based on scientific judgment of reasonable variability of ±10% around the target. Calculation of values ​​is within the knowledge of one of ordinary skill in the art.

[0130] [Table 23] A The amount of coated lasmiditan hemisuccinate API is adjusted based on the "as is" or standard release potency. The amount of Pharmaburst® 500 may be adjusted accordingly to maintain the target tablet weight. The targets (% of tablets) per feeder for the coated API and Pharmaburst® 500 are adjusted accordingly, allowing for reasonable variation of ±10% around the potency-adjusted target. B See Table 22 for dispense weight ranges of pre-blend materials.

[0131] Acceptable pre-blend component distribution amounts are listed in Table 22 as a percentage of the total blend weight and are based on scientific judgment with reasonable variance of ±10% for both components simultaneously. Calculation of values ​​is within the knowledge of one skilled in the art.

[0132] [Table 24]

[0133] A process flow chart for manufacturing a lasmiditan ODT formulation is provided in Figure 2. The following procedure further describes how the ODT product can be prepared. Those skilled in the art will recognize that certain variations can be used as needed for alternative processes.

[0134] Powder Sifting and Blending (Sweetener / Flavor Preblend): Aspartame and cherry berry flavor are safely sieved through a US standard #6 mesh sieve. The material is layered by sequentially adding the following ingredients to the tumble bin: approximately half of the aspartame, all of the cherry berry flavor, and the remaining aspartame. The tumble bin is placed on the tumble bin base and blended. Prior to or while the material is being loaded into the loss-in-weight (LIW) feeder, the coated lasmiditane hemisuccinate API, Pharmaburst® 500, and sodium stearyl fumarate are safely sieved through a US standard #6 mesh sieve. The LIW feeder material allocation and setup configuration is listed in the table, with preferred configuration items in bold.

[0135] [Table 25] A A continuous production series is set up for mixing by methods known to those skilled in the art. Table 24 below shows the equipment and setup parameters.

[0136] [Table 26] A Recommended specifications based on typical equipment capabilities / specifications from the manufacturer and scientific judgment. B The material is sieved before being loaded into the feeder.

[0137] [Table 27] ARecommended specifications based on typical equipment capabilities / specifications from the manufacturer.

[0138] [Table 28] A Recommended range based on typical equipment capabilities and development experience.

[0139] Mixing: A mixer is used in which the mixer shaft has paddles in an alternating 22.5° configuration (odd paddles facing the outlet, even paddles facing the inlet), except for paddles #1 and #12, which both face the outlet at 45° (see Table 24). The mixer is equipped with an adjustable weir assembly integrated into the outlet piece, which is used to adjust the material holdup in the mixer. The weir is maintained in a fully open position during the product collection (runtime) phase of the process, but may be adjusted for initial process setup to ensure uniformity while adjusting tablet weight and thickness parameters. If the weir needs to be closed, the impeller speed is reduced to below 100 rpm so that the centripetal force is less than the inertial force of the powder in the mixer (Froude number less than 1).

[0140] Tableting: The final blend is compressed into round dimpled flat bevel edge (FFBE) tablets of the dimensions given in the table using the listed tooling HOB number. Tablets are made using a rotary compression machine (e.g., Korsch XL200). The tablet press production rate, which determines the target turret speed, is a DCS recipe parameter. All other tablet press process parameters for each tablet strength are defined by the tablet press recipe. Exemplary orally disintegrating tablets (50 mg and 100 mg) are shown in Figure 4.

[0141] [Table 29]

[0142] The turret speed may be adjusted to control the mass flow rate from the press to match the mass flow rate from the mixer to the press surge hopper. This adjustment may be manual or automated via a surge hopper level sensor to maintain a proper column of powder throughout the stable product collection phase.

[0143] Compression parameters are configured during setup to achieve the target tablet physical attributes (listed in Table 26 and the tables therein). Tablet press dose is adjusted to achieve the target tablet weight. Tablet press feed frame (feeder) paddle speed is adjusted to minimize the main compression force RSD ("Srel"), which is a measure of tablet weight variation. Tip-to-tip (edge) distance of the pre-compression and main compression tooling is adjusted to achieve the desired tablet compact strength and / or thickness. Tablet press recipe parameters are considered initial conditions to start the process, and parameters can be adjusted as needed to obtain the desired tablet characteristics (values ​​such as dose, edge thickness, compression force, etc.).

[0144] Tablet weight, thickness, breaking force, disintegration, and friability are assessed at the start. Tablet weight and thickness, and the corresponding calculated solids content, are routinely assessed throughout the compression run. All tablets are passed through a tablet de-duster and metal grid. Tablets can be sorted as needed.

[0145] Physical attributes of the tablet The tablets are evaluated by methods known to those skilled in the art and / or as described herein.

[0146] Average tablet weight: The average tablet weight is determined by weighing each tablet individually on a balance and calculating the average value.

[0147] Average breaking strength (hardness): Tablet breaking force is measured under load across the diameter of a round tablet using a hardness tester. The maximum compressive load (breaking force) achieved at tablet failure is recorded for each tablet and the average is calculated. For more detailed information, see USP Guidance <1217> Please refer to.

[0148] Average tablet thickness: The maximum distance between the tablet faces is measured with a micrometer and recorded for each tablet, and the average is calculated.

[0149] Average solids content: The average solids content is calculated using Equations 1 and 2.

[0150]

number

[0151] Equation 1 can be further explained for a given set of tablet forming tools by Equation 2:

[0152]

number

[0153] Alternatively, the average solids content can be the average of the solids content calculated individually for a given set of tablets using the weight and thickness values ​​for each tablet.

[0154] Wear and tear: The total weight of the de-dusted tablets is measured before and after 100 revolutions at 25 rpm in the drum of the friability tester. To ensure accuracy of the tablet weight, the tablets should be exposed to atmospheric room conditions before testing to allow equilibration with ambient conditions. The resulting calculated weight percentage difference is the tablet friability. For more detailed information, see USP Guidance <1216> Please refer to.

[0155] Disintegrant: Place the tablets on a separate sieve while rotating them up and down in a 37±2°C water bath until the tablet fragments fall through the sieve. USP Guidance <701> Please refer to.

[0156] The physical attributes of the tablets are evaluated at the beginning of the batch and periodically during the batch to control tablet weight and monitor thickness, solids, and / or tablet strength.

[0157] [Table 30] A Physical attributes of tablets used as in-process controls are marked with an asterisk ( * )

[0158] [Table 31] A Physical attributes of tablets used as in-process controls are marked with an asterisk ( * )

[0159] Storage conditions: USP controlled room temperature Taste masking can be evaluated by a taste profiling procedure using the flavor profile method. Sensory panelists evaluate samples using the flavor profile method of descriptive sensory analysis (Keane, P. The Flavor Profile Method. In C. Hootman (Ed.), Manual on Descriptive Analysis Testing for Sensory Evaluation ASTM Manual Series: MNL 13. Baltimore, MD (1992)). For illustrative purposes, the taste profiling procedure tablet evaluation protocol is as follows: 1. Panelists rinse their mouths with spring water and unsalted crackers. 2. One lasmiditan tablet is distributed to each panelist. 3. Starting simultaneously, panelists place the tablet in their mouths and gently swirl it around until it is placed on their tongue (ODT) or chewed (chewable tablet) to the point at which they would normally swallow it. Any material remaining in their mouths is then expelled, and the disintegration time or chewing time is recorded. 4. Panelists then independently rate and record the initial and aftertaste attributes at regular intervals of up to 30 minutes as the flavor persists. 5. Panelists recite their individual results, and a preliminary flavor profile is generated for the sample. 6. Using the preliminary flavor profile from step 5 as a guide, steps 1-4 are repeated for the second sample, and panelists make any necessary modifications. 7. Panelists recite their individual results, and a final flavor profile is generated for the sample.

[0160] It has been discovered that combining an API coated with Kollicoat® Smartseal 30 D with appropriately selected flavors and sweeteners provides a palatable ODT (less than about 1.5 on the bitterness intensity scale). Exemplary flavor profile results obtained for lasmiditan ODT embodiments are summarized below. The flavored formulations were significantly less bitter than the unflavored granules, as shown in Figure 3, Taste Profiling of Lasmiditan ODT Embodiments Using the Flavor Profile Method (Figure 3, dashed line: unflavored, solid line: flavored). Comparing the two coating degrees, a 32% coating degree was only slightly more bitter than the 37% coated lasmiditan. The resulting rolling and chewing resulted in comparable bitterness profiles.

[0161] The sweetened / flavored lasmiditan ODT formulation of the present disclosure has a moderately high overall flavor quality. The target balance and sufficiency for an oral formulation is approximately 1.5 or less, and the 37% coated flavor system achieved this goal when rolled. Chewed tablets were only slightly lower. The bitterness of the lasmiditan-flavored ODT formulation was significantly lower than that of the unflavored coated lasmiditan granules. Based on flavor quality, this sweetened / flavored lasmiditan blend is suitable for an ODT product form. The patient's chewing choice will not significantly alter or worsen the tablet's flavor profile (i.e., the granule coating remains largely intact).

[0162] In addition to the taste-masking provided by the coating system, a "flavor system" (sweeteners and identified aromatics) was added to the powder blend with the highest coating degree (37%) to further improve the palatability of the lasmiditan ODT. This effort resulted in preferred excipients. High-intensity (artificial) sweeteners—aspartame and cherry berry flavor—were found to offset the residual bitterness, surprisingly providing a palatable lasmiditan ODT product form. Other negative sensory attributes, such as tongue tingling, throat burning, and mouth numbness, were virtually eliminated. Furthermore, in vitro data and modeling indicate that the lasmiditan ODT formulation of the present disclosure is expected to be bioequivalent to approved immediate-release tablets, as tested in the clinical trial LAIA (Bioequivalence of Lasmiditan Orally Disintegrating Tablets Compared to Current Immediate-Release Tablet Formulations to Support the Treatment of Migraine).

[0163] Example 5 - Comparative Example Surprisingly, the performance of an alternative but similar non-enteric coating, Eudragit® E100, was found to be inferior to that of Kollicoat® Smartseal in terms of both taste-masking and disintegration performance when processed into ODTs. EUDRAGIT® E 100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, manufactured by Evonik Healthcare. It is supplied as a polymeric solid (E100), a solution in alcohol (E12.5), and a ready-to-use dry mix powder. Eudragit® E is commercially available as a non-enteric polymer for taste-masking applications and is expected to perform similarly to Kollicoat® Smartseal (also a non-enteric polymer in a similar chemical class).

[0164] The following procedure can be applied to coat 0.3 kg of lasmiditane hemisuccinate with d10=55.0 μm, d50=117.9 μm, and d90=220.9 μm or similar particle sizes with Eudragit® EPO. Load the drug substance into a fluidized bed coater as described in Table 28. There are many vendors that supply fluidized bed coaters capable of Wurster coating, and equipment setups may vary between vendors, particularly with regard to nozzle type and fluidization parameters. While the cited example is for one particular style of fluidized bed coater, those skilled in the art will understand that other fluidized bed coaters can be used to achieve similar results.

[0165] [Table 32]

[0166] Prepare a subcoat / granulation solution of HPMC E5 and SLS solution in purified water as shown in Table 29.

[0167] [Table 33]

[0168] Apply subcoat granulation solution to a desired weight gain of 5-15% weight gain, preferably 10% weight gain, using the target conditions shown in Table 30. It will be recognized by those skilled in the art that similar processing results can be achieved with a variety of conditions and equipment, and those presented herein are examples.

[0169] [Table 34]

[0170] [Table 35]

[0171] The subcoated granules may optionally be sieved to remove remaining fines and over-granulated material. 0.253 kg of Lasmiditan HPMC subcoating / granules is coated with a topcoat of non-enteric coated Eudragit® E PO. A topcoat taste-masking dispersion of Eudragit E PO in purified water is prepared as shown in Table 32.

[0172] [Table 36]

[0173] The topcoat dispersion is applied to a desired weight gain of 44% theoretical (based on the input weight of granular material) using the conditions set forth in Table 33. It will be recognized by those skilled in the art that similar processing results can be achieved with a variety of conditions and equipment, and those presented herein are examples.

[0174] [Table 37]

[0175] [Table 38]

[0176] The final coated material can optionally be sieved to remove any remaining fines and / or granular material.

[0177] Preparation of ODT using Eudragit® E PO coated drug substance: A representative unit and batch formula for preparing 100 mg lasmiditan ODT for a theoretical batch size of 300 tablets is shown in Table 35.

[0178] [Table 39]

[0179] The coated API can be sieved through a #50 mesh to break up loose agglomerates and ensure that the coated API is in discrete particle form. Pharmaburst® 500 is weighed into a 500 mL container, and then sodium stearyl fumarate is weighed into the coated API. The container is then rotated at 44 rpm on a Turbula mixer for approximately 7 minutes. The final blend was compressed on a FlexiTab single-station press using 12 mm round convex tooling. The following compression profile was generated:

[0180] [Table 40]

[0181] As the results show, a compression stress of 60 MPa produces tablets of sufficient strength to meet the target 1.0% friability. However, the disintegration time of 44 seconds at this compression stress exceeds the acceptable limit of 30 seconds. To reduce the disintegration time to a more acceptable 18 seconds, a compression stress of 33 MPa is required, but this produces soft tablets, as reflected in the high friability value of 2.21%, which poses a risk to manufacturing and downstream handling. Therefore, the compression operating window for producing tablets of adequate strength with low disintegration times is narrow and impractical.

[0182] The same dissolution procedure described earlier herein is used to evaluate the taste masking and release properties of API coated with Eudragit® E PO. Table 37 shows the pH-shift dissolution profiles of ODTs prepared using uncoated API, Kollicoat® Smartseal-coated API, and Eudragit® E PO-coated API. Dissolution of an API from a tablet generally follows a sequence in which the tablet must first disintegrate before API dissolution. In this case, the tablet made with Eudragit® E PO disintegrates slower than the other two tablets. Therefore, the early dissolution time point for the Eudragit® E PO tablet indicates an artificially low drug release because the tablet did not completely disintegrate until approximately 4 minutes, compared to the preferred 20 seconds for the other tablets. Looking beyond approximately 120 seconds, when at least 50% of the Eudragit® E PO tablet has disintegrated, it is clear that the release rate from the Eudragit® E PO-coated API particles is significantly faster than that of the Kollicoat® Smartseal-coated API particles. The data show that Eudragit® E PO is less effective at inhibiting the release of lasmiditan hemisuccinate after complete tablet disintegration. This is even more evident at the 300 second time point, just prior to the pH shift, where the % release is 17.51% for the Kollicoat® Smartseal coated API versus 53.26% for the Eudragit® E PO coated lasmiditan hemisuccinate.

[0183] [Table 41] The inventions described in the original claims of this application are set forth below. [1] A pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof and a non-enteric coating. [2] The composition described in [1], wherein the lasmiditan or a pharmaceutically acceptable salt thereof is lasmiditan hemisuccinate. [3] The composition according to [1] or [2], wherein the lasmiditan comprises granular particles having a size range of about 50 to about 275 microns. [4] The composition according to any one of [1] to [3], wherein the non-enteric coating is Kollicoat® Smartseal 30 D containing methyl methacrylate di(ethyl)aminoethyl methacrylate copolymer. [5] The composition according to [4], wherein the composition further comprises a coating degree of about 20 to 40% based on the weight of the granular lasmiditan particles when coated with Kollicoat® Smartseal 30 D. [6] The composition described in [5], wherein the composition further comprises a coating degree of about 37% based on the weight of the granular lasmiditan particles when coated with Kollicoat® Smartseal 30 D. [7] The composition according to any one of [1] to [6], wherein the lasmiditan coated with Kollicoat (registered trademark) Smartseal 30 D further contains talc. [8] The composition according to any one of [1] to [7], wherein the lasmiditan coated with Kollicoat® Smartseal 30 D further comprises talc, and the final coated particles have a size range of about 75 to about 300 microns. [9] [8] The composition described in [8], further comprising talc, Pharmaburst® 500, and sodium stearyl fumarate.

[10] The composition described in [9], further comprising a sweetener and a flavoring agent.

[11]

[10] The composition described in

[10] , wherein the sweetener is aspartame and the flavoring agent is cherry berry.

[12] The composition comprises: about 37% to 46% w / w of Kollicoat® Smartseal 30 D coated lasmiditane hemisuccinate, about 47% to 58% w / w Pharmaburst® 500, about 3.9% to 4.9% w / w aspartame / cherry berry flavor blend (about 68% aspartame to about 32% cherry berry flavor); and The composition according to

[11] , comprising about 1.3% to 1.7% w / w sodium stearyl fumarate.

[13] The composition comprises: (i) lasmiditane hemisuccinate coated with about 40.2% w / w Kollicoat® Smartseal 30 D (about 37% coating degree); (ii) about 0.80% w / w talc; (iii) about 54.0% w / w of Pharmaburst® 500; (iv) about 2.0% w / w sodium stearyl fumarate; (v) about 1.0% w / w cherry berry flavoring, and (vi) The composition described in

[11] , comprising about 2.0% w / w aspartame.

[14] The composition according to any one of [1] to

[13] , further comprising lasmiditan in a dose of about 25 mg to about 200 mg.

[15] The composition according to

[14] , further comprising lasmiditan in a dose of about 25 mg to about 100 mg.

[16]

[15] The composition described in

[15] , wherein the composition further comprises lasmiditan in a dose of about 25 mg.

[17]

[15] The composition described in

[15] , wherein the composition further comprises lasmiditan in a dose of about 50 mg.

[18]

[15] The composition described in

[15] , wherein the composition further comprises lasmiditan in a dose of about 75 mg.

[19]

[15] The composition described in

[15] , wherein the composition further comprises lasmiditan in a dosage of about 100 mg.

[20]

[14] The composition described in

[14] , wherein the composition further comprises lasmiditan in a dose of about 150 mg. [twenty one] The composition according to any one of [1] to

[20] , further comprising an orally disintegrating tablet. [twenty two] A method for treating migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of the composition described in any one of [1] to

[20] . [twenty three] The composition according to any one of [1] to

[20] , for use in treatment. [twenty four] The composition according to any one of [1] to

[20] for use in treating migraine. [twenty five] 1. A compressed, orally disintegrating tablet comprising a disintegrant and a plurality of units, said plurality of units comprising: i) a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; ii) a non-enteric coating on the particles, the non-enteric polymer being present in an amount of 20% to 40% coating degree; A compressed orally disintegrating tablet, wherein the disintegrant and the plurality of units are compressed into an orally disintegrating tablet having a friability of 1% or less when a compression force of 6 kN to 50 kN is applied during tablet production.

[26]

[21] A process for producing the orally disintegrating tablet according to

[21] , a) forming a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; b) applying a coating comprising a non-enteric polymer to the particles of step (a), thereby obtaining a plurality of units; c) mixing the plurality of units of step (b) with at least one tablet excipient including a disintegrant, thereby obtaining a blend; d) mixing the blend of step (c) with flavors and sweeteners to form a taste-masked blend; e) mixing the taste-masked blend with a dry lubricant; f) compressing the blend of step (e), thereby obtaining the compressed orally disintegrating tablet.

Claims

1. A pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof and a non-enteric coating, and further comprising talc, Pharmaburst® 500, and sodium stearyl fumarate.

2. 2. The composition of claim 1, wherein the lasmiditan or a pharmaceutically acceptable salt thereof is lasmiditan hemisuccinate.

3. 3. The composition of claim 1 or 2, wherein the lasmiditan comprises granular particles having a size range of 50 to 275 microns.

4. 10. The composition of claim 1, wherein the non-enteric coating is Kollicoat® Smartseal 30 D comprising methyl methacrylate di(ethyl)aminoethyl methacrylate copolymer.

5. 5. The composition of claim 4, wherein the composition further comprises, when coated with Kollicoat® Smartseal 30 D, a coating degree of 20 to 40% based on the weight of the granular lasmiditan particles.

6. 6. The composition of claim 5, wherein the composition further comprises a coating degree of 37% by weight of the granular lasmiditan particles when coated with Kollicoat® Smartseal 30 D.

7. 5. The composition of claim 4, wherein the lasmiditan coated with Kollicoat® Smartseal 30 D further comprises talc.

8. 8. The composition of claim 7, wherein the lasmiditan coated with Kollicoat® Smartseal 30 D further comprises talc, and the final coated particles have a size range of 75 to 300 microns.

9. 10. The composition of claim 8, further comprising a sweetener and a flavoring agent.

10. 10. The composition of claim 9, wherein the sweetener is aspartame and the flavoring agent is cherry berry.

11. The composition comprises: 37% to 46% w / w of Kollicoat® Smartseal 30 D coated lasmiditane hemisuccinate, 47% to 58% w / w of Pharmaburst® 500, 3.9% to 4.9% w / w of an aspartame / cherry berry flavor blend (68% aspartame to 32% cherry berry flavor); and 11. The composition of claim 10, comprising 1.3% to 1.7% w / w of sodium stearyl fumarate.

12. The composition comprises: (i) 40.2% w / w of Kollicoat® Smartseal 30 D-coated lasmiditane hemisuccinate (37% coating degree), (ii) 0.80% w / w of talc; (iii) 54.0% w / w of Pharmaburst® 500; (iv) 2.0% w / w of sodium stearyl fumarate; (v) 1.0% w / w cherry berry flavor, and 11. The composition of claim 10, comprising (vi) 2.0% w / w aspartame.

13. The composition of claim 1, wherein the composition comprises a dosage of lasmiditan between 25 mg and 200 mg.

14. The composition of claim 13, wherein the composition comprises a dosage of lasmiditan between 25 mg and 100 mg.

15. 15. The composition of claim 14, wherein the composition comprises a 25 mg dose of lasmiditan.

16. 15. The composition of claim 14, wherein the composition comprises a 50 mg dose of lasmiditan.

17. 15. The composition of claim 14, wherein the composition comprises a 75 mg dose of lasmiditan.

18. 15. The composition of claim 14, wherein the composition comprises a 100 mg dose of lasmiditan.

19. 14. The composition of claim 13, wherein the composition comprises a dose of 150 mg of lasmiditan.

20. The composition of claim 1 , wherein the composition is formulated into an orally disintegrating tablet.

21. A pharmaceutical composition for treating migraine, comprising an effective amount of the composition of claim 1.

22. A pharmaceutical comprising the composition of claim 1 for use in treatment.

23. The pharmaceutical composition according to claim 22, which is used to treat migraine.

24. 1. A compressed, orally disintegrating tablet comprising a disintegrant and a plurality of units, said plurality of units comprising: i) a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; ii) a non-enteric coating on said particles comprising a non-enteric polymer in an amount of 20% to 40% coating degree, wherein said non-enteric coating is Kollicoat® Smartseal 30 D; A compressed orally disintegrating tablet, wherein the disintegrant and the plurality of units are compressed into an orally disintegrating tablet having a friability of 1% or less when a compression force of 6 kN to 50 kN is applied during tablet production.

25. 21. A process for producing the orally disintegrating tablet of claim 20, comprising: a) forming a plurality of particles comprising a therapeutically effective amount of lasmiditan or a pharmaceutically acceptable salt thereof; b) applying a coating comprising a non-enteric polymer to the particles of step (a), thereby obtaining a plurality of units; c) mixing the plurality of units of step (b) with at least one tablet excipient comprising a disintegrant, thereby obtaining a blend; d) mixing the blend of step (c) with flavors and sweeteners to form a taste-masked blend; e) mixing the taste-masked blend with a dry lubricant; f) compressing the blend of step (e), thereby obtaining the compressed orally disintegrating tablet.

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