A flavor-masked composition of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide hemisuccinate, and orally disintegrating tablets containing the same.

Abstract

We provide orally disintegrating tablets of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide (rastamidine) hemisuccinate with masked taste. [Solution] This disclosure provides a pharmaceutical composition comprising a taste-masked 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and a non-enteric coating. The taste-masked orally disintegrating tablet of the present invention significantly reduces the strong bitterness of rasmiditane, enabling the administration of this product form to migraine patients, particularly pediatric patients and patients suffering 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 5-HT 1F Receptor agonists A certain 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl Co-pyridine-2-yl]-benzamide hemisuccinate for orally disintegrating formulations Compositions, processes, and formulations produced by these processes Product forms, as well as those for rapid oral administration of rasmiditan for the treatment of migraines Provides usage. [Background technology]

[0002] In October 2019, the U.S. Food and Drug Administration announced that aura- or absence-associated hepatitis in adults is a serious condition. REYVOW® (Rasmiditane) 50 and for the acute on-demand treatment of pain The use of 100mg tablets has been approved. Rasmiditan is a selective and very potent 5-HT1 F It is a receptor agonist (e.g., Rubio-Beltran et al., Ph armacol Ther 2018;186:88-97, and Lasmiditan for the Treatment of Migraine, Capi, M.et al.,Expert Opinion Investigational Drug See s, (2017), Vol.26, No.2, 227-234. Gitanes (COL 144, LY 573144, CAS Registry Number 439239-90-4) ) is 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-ylcal It can be chemically described as bonyl-pyridine-2-yl]-benzamide. U.S. Patent No. 7,423,050 and U.S. Patent Publication No. 2008 / 0300407 are, The following structural formula is found: 2,4,6-trifluoro-N-[6-(1-methyl-piperidine- The hemisuccinate of 4-carbonyl)-pyridine-2-yl]-benzamide is described.

[0003] [ka]

[0004] The currently available solid dosage form of rasmiditan hemisuccinate, which is a tablet, is acceptable for therapeutic purposes. However, this solid dosage form and the strong bitterness of rasmidan are the current state of this compound. Patients who cannot or do not want to take solid dosage forms face significant medication adherence problems. This is imposed. The solid dosage form is generally difficult to swallow for young children and migraine sufferers who are experiencing nausea. It is difficult to do so. Many methods exist to suppress the specific undesirable taste of drugs. However, due to the unique properties of various drugs, a universal formula that can solve this problem is not available. No such drug exists. Currently, there are no flavor-masked orally disintegrating tablets (ODTs) for rasmiditan. No development has been reported.

[0005] Flavor-masking and coated oral cavity disclosed in this patent application Disintegrating tablets address this need, as do their strong bitter taste and other undesirable palatability characteristics. To reduce or eliminate symptoms and avoid swallowing difficulties with solid dosage forms such as tablets, a palatable texture is used. There is a need to develop a rasmiditane in an orally disintegrating dosage form.

[0006] The currently available dosage form of rasmiditan has a rapid onset of action of approximately 2 hours (until symptom relief). An immediate release tablet that provides (the time of). The treatment of migraine is complicated in that the trigger of migraine is often unknown and it is difficult to predict the timing of migraine. Therefore, the convenience of administration of the therapy is important for treatment. Most solid oral dosage forms are intended to be swallowed whole and require co - administration of liquid to facilitate swallowing, which reduces the convenience of administration. Nausea is a common symptom of migraine and makes oral administration of drugs difficult. When the dosage form requires swallowing of liquid or has low palatability, migraine patients may be unwilling to receive treatment and / or the drug may further worsen nausea. Furthermore, migraine is one of the most common symptoms in the emergency department, and patients often have difficulty taking tablets due to nausea and / or vomiting. Generally, many adults, especially children, have difficulty swallowing the whole tablet even with co - administration of liquid. When there is difficulty swallowing, 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 treatment to adults, especially pediatric patients, can be solved by using orally disintegrating tablets or orally dispersible tablets if they can meet the formulation and performance factors required for tablets. If the dosage form of orally disintegrating tablets can be taken without the need for co - administration of liquid, it is a clinically advantageous solution for migraine patients. These ODTs rapidly disintegrate or disperse into small particles that can be easily swallowed with a small amount of saliva in the mouth without the need for additional liquid to facilitate swallowing.

[0007] However, the development of ODTs presents many substantial technical challenges, the main of which This refers to taste or palatability. Compounds such as active pharmaceutical ingredients have various taste profiles. This is highly undesirable. The unpleasant taste of many drugs is due to flavor masking strategies, for example, fragrance Addition of flavorings, sweeteners, complexing agents, or other approaches to mask the unpleasant taste of drugs. The use of medication is often required. In some cases, other negative sensations associated with the medication. These include attributes such as trigeminal nerve stimulation, tongue tingling, and throat burning, which affect the palatability. This further complicates the development of ODT. The drug in question is highly soluble, and can be found in quantities of several tens of milligrams. When doses exceeding a certain level are required, the challenge of formulating ODT drug products becomes even more complex. Minimizing the negative sensory attributes of high-dose, highly soluble drugs with poor palatability is Clinically appropriate ODT product forms have been successfully formulated for compounds with very low palatability. The problem is described to such an extent that a person skilled in the art cannot predict whether or not it will be achieved.

[0008] The technique of using sweeteners and flavorings to enhance the taste of drugs is particularly applicable to chewable tablets and In the case of pediatric formulations such as liquid formulations, the most widely used app for taste masking is It is one of the roaches. However, this approach involves a very bitter and highly water-soluble drug. They haven't been very successful with products. (For example, the taste masking approach, Visha) ni et al, International Journal of Pharma cy and Integrated Life Sciences,April 20 See 13, Vol I(5), pp. 48-61. Rasmijitan is very bitter. Furthermore, it has been found to be a highly water-soluble drug. In addition, rasmidan has a long bitter taste. Therefore, to produce rasmiditane in an acceptable, palatable ODT dosage form. This is expected to be extremely difficult. However, this disclosure surprisingly shows that oral cavity collapse This invention provides a medicinal taste-masking composition for rasmidan in broken tablets. The ODT product form is solid. A group of children who experience nausea and vomiting when attempting to swallow tablets with liquid, and migraines. To provide a suitable dosage form that is particularly useful for patients. For patients with migraines, the safe and effective treatment of migraines with rasmiditan is to swallow the tablet. This is made possible by the availability of orally disintegrating tablets that do not require [something]. This disclosure is a recently approved [something]. This addresses the unmet need for rasmiditane, a migraine treatment. [Overview of the project]

[0009] This disclosure relates to a pharmaceutical composition for masking the taste of rasmiditan. Specifically, this disclosure relates to: A therapeutically effective amount of flavor-masked rasmidan or a pharmaceutically acceptable salt thereof A taste-masked pharmaceutical composition containing mijitan particles, wherein the particles mask the taste of mijitan. Coated with one or more flavor-masking layers that mask the taste, and the flavor-masking layer is small The present invention relates to a composition comprising at least one water-insoluble polymer. Preferably, a water-insoluble polymer - is a non-enteric coating. Preferably, the non-enteric coating is Kolli This is coat(registered trademark) Smartseal 30 D. In one embodiment, this opening The indication is a medical product comprising rasmiditan or a pharmaceutically acceptable salt thereof and a non-enteric coating. A pharmaceutical composition is provided. In one embodiment, the disclosure provides rasmiditane hemisuccinate and The present invention provides a pharmaceutical composition comprising a non-enteric coating. In one embodiment, the present invention relates to a pharmaceutical composition comprising a non-enteric coating. A pharmaceutical composition comprising sumiditan hemysuccinate and a non-enteric coating, wherein the non-enteric coating The coating is methyl methacrylate di(ethyl)aminoethyl methacrylate. Kollicoat® Smartseal 30 D, which contains rimer, is a medical product. A pharmaceutical composition is provided. In one embodiment, the disclosure provides a composition in which rasmiditan is about 50 to about 275 Rasmiditane hemisuccinate containing granular particles having a micron size range, and Koll icoat(registered trademark) Smartseal 30 D is a non-enteric coating. The present disclosure provides a pharmaceutical composition containing about 50 to about Lasmijitan contains granular particles with a size range of 275 microns and is coated. It contains talc, as well as rasmiditane hemisuccinate and Kollicoat(registered trademark) S The final coated granules contain a non-enteric coating called martseal 30 D. The present invention provides a pharmaceutical composition in which the particles have a size range of approximately 75 to 300 microns.

[0010] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising rasmiditane hemisuccinate. Furthermore, Rasmijitan contains granular particles having a size range of approximately 50 to 275 microns. The composition is coated with Kollicoat® Smartseal 30 D. The present invention provides a pharmaceutical composition that further includes a coating degree of approximately 20-40% during application.

[0011] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising rasmiditane hemisuccinate. Furthermore, Rasmijitan contains granular particles having a size range of approximately 50 to 275 microns. The composition is coated with Kollicoat® Smartseal 30 D. The present invention provides a pharmaceutical composition that further includes a coating degree of approximately 37% during application.

[0012] In one embodiment, the disclosure shows that the rasmijitan is in a size range of about 50 to about 275 microns. The granular particles having a casing, the coated rasmiditan further contains talc, Miditan hemisuccinate and Kollicoat® Smartseal 30 A pharmaceutical composition comprising a non-enteric coating D, the final coated The particles have a size range of approximately 75 to 300 microns. (i) Approximately 55.5% w / w rasmiditane hemisuccinate, (ii) Approximately 6.0% w / w hypromellose (HPMC), (iii) Approximately 0.15% w / w sodium lauryl sulfate, (iv) Approximately 2.8% w / w triethyl citrate, (v) Approximately 18.6% w / w of Kollicoat® Smartseal 3 0 D, and (vi) Provide a pharmaceutical composition further comprising approximately 16.9% w / w talc.

[0013] In one embodiment, the disclosure relates to granules having a size range of about 50 to about 275 microns. Rasmijitan, which contains particles and is coated, further contains talc. The citrate and Kollicoat® Smartseal 30 D are non-enteric coated A pharmaceutical composition comprising a coating, wherein the final coated particles are approximately 75- The present invention provides a pharmaceutical composition having a size range of approximately 300 microns and containing a disintegrant and a lubricant. .

[0014] In one embodiment, the disclosure shows that the rasmijitan is in a size range of about 50 to about 275 microns. The granular particles having a casing, the coated rasmiditan further contains talc, Miditan hemisuccinate and Kollicoat® Smartseal 30 A pharmaceutical composition comprising a non-enteric coating D, the final coated The particles have a size range of approximately 75 to 300 microns, and the composition is talc, Pharma A pharmaceutical compound further comprising burst(registered trademark) 500 and sodium stearyl fumarate. To provide finished products.

[0015] In one embodiment, the disclosure shows that the rasmijitan is in a size range of about 50 to about 275 microns. The granular particles having a casing, the coated rasmiditan further contains talc, Miditan hemisuccinate and Kollicoat® Smartseal 30 A pharmaceutical composition comprising a non-enteric coating D, the final coated The particles have a size range of approximately 75 to 300 microns, and the composition is talc, Pharma burst(registered trademark) 500, and further containing sodium stearyl fumarate, sweetener The present invention provides a pharmaceutical composition further comprising a flavoring agent.

[0016] In one embodiment, the disclosure shows that the rasmijitan is in a size range of about 50 to about 275 microns. The granular particles having a casing, the coated rasmiditan further contains talc, Miditan hemisuccinate and Kollicoat® Smartseal 30 A pharmaceutical composition comprising a non-enteric coating D, the final coated The particles have a size range of approximately 75 to 300 microns, and the composition is talc, Pharmab It further contains urst(registered trademark)500 and sodium stearyl fumarate, and aspar The present invention provides a pharmaceutical composition further comprising tame and cherry berry flavoring agents.

[0017] In one embodiment, the disclosure shows that the rasmijitan is in a size range of about 50 to about 275 microns. The granular particles having a casing, the coated rasmiditan further contains talc, Miditan hemisuccinate and Kollicoat® Smartseal 30 A pharmaceutical composition comprising a non-enteric coating D, the final coated The particles have a size range of approximately 75 to 300 microns, and the composition is talc, Pharma The composition further comprises burst(registered trademark) 500 and sodium stearyl fumarate. However, it further contains aspartame and cherry berry flavoring agents. (i) Approximately 40.2% w / w of Kollicoat® Smartseal 3 0D coated rasmiditane hemisuccinate (37% coating degree), (ii) Approximately 0.80% w / w talc, (iii) Approximately 54.0% w / w of Pharmaburst® 500, (iv) Approximately 2.0% w / w stearyl sodium fumarate, (v) Approximately 1.0% w / w cherry berry flavoring, and (vi) Provide a pharmaceutical composition further comprising approximately 2.0% w / w aspartame.

[0018] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising rasmiditane hemisuccinate. Furthermore, Rasmijitan contains granular particles with a size range of approximately 50 to 275 microns, The coated rasmiditan further contains talc and a non-enteric coating, and is non-enteric. The coating is Kollicoat® Smartseal 30 D. The final coating particles have a size range of approximately 75 to 300 microns, and the composition is tar Pharmaburst® 500 and stearyl fumarate Furthermore, the composition further contains aspartame and cherry berry flavoring agent, and the composition is Kollicoat® Smartseal 30 with approximately 37%~46% w / w D-coated rasmiditane hemisuccinate, Approximately 47%~58% w / w of Pharmaburst(registered trademark) 500, Approximately 3.9%~4.9% w / w aspartame / cherry berry flavor blend (as Partham (approximately 68%), cherry berry flavoring (approximately 32% w / w), and A pharmaceutical composition further containing approximately 1.3% to 1.7% w / w of sodium stearyl fumarate. To provide.

[0019] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises rasmiditan in doses ranging from approximately 25 mg to approximately 200 mg.

[0020] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises rasmiditan in doses ranging from approximately 25 mg to approximately 100 mg.

[0021] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 25 mg of rasmiditan.

[0022] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 50 mg of rasmiditan.

[0023] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 75 mg of rasmiditan.

[0024] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 100 mg of rasmiditan.

[0025] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 150 mg of rasmiditan.

[0026] In one embodiment, the present disclosure provides a pharmaceutical composition according to any of the embodiments described above. The composition further comprises approximately 200 mg of rasmiditan.

[0027] In one embodiment, the present disclosure relates to the above embodiment in which the composition further comprises an orally disintegrating tablet. The present invention provides a pharmaceutical composition based on one of the following:

[0028] In one embodiment, the present disclosure relates to a pharmaceutical composition according to any of the above embodiments, A pharmaceutical composition comprising an orally disintegrating tablet, the tablet further comprising a 25 mg unit dosage form. provide.

[0029] In one embodiment, the present disclosure relates to a pharmaceutical composition according to any of the above embodiments, A pharmaceutical composition comprising an orally disintegrating tablet, the tablet further comprising a 50 mg unit dosage form. provide.

[0030] In one embodiment, the present disclosure relates to a pharmaceutical composition according to any of the above embodiments, A pharmaceutical composition comprising an orally disintegrating tablet, the tablet further comprising a 100 mg unit dosage form. To provide.

[0031] In one embodiment, the present disclosure is a method for treating migraines in a patient, such For patients requiring treatment, an effective amount of the rasmijitan composition according to any of the above embodiments. The present invention provides a method comprising administering a composition.

[0032] In one embodiment, the present disclosure relates to the above-mentioned practical aspects of a rasmiditane composition for therapeutic use. The present invention provides a composition in one of the following application forms.

[0033] In one embodiment, the present disclosure relates to a rasmiditane composition for use in the treatment of migraines. A composition according to any of the above embodiments is provided.

[0034] This disclosure also states that each particle is coated with one or more flavor masking layers, 2,4,6 -Trifluoro-N-[6-(1-methyl-piperidine-4-ylcarbonyl)-pyridyl It contains n-2-yl-benzamide or a pharmaceutically acceptable salt thereof, and the taste masking layer Immediate-release (IR) intraoral solution containing a therapeutically effective amount of rasmiditane particles with a water-insoluble polymer. This disclosure relates to disintegrating tablets (ODTs). This disclosure relates to taste masking 2,4,6-trifluoro-N-[ 6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamidehemico The present invention provides a palatable pharmaceutical composition in the form of a citrate and orally disintegrating tablets containing the same.

[0035] This disclosure further includes a disintegrant and multiple units, including the following: i) Multiple particles containing a therapeutically effective amount of rasmidan or a pharmaceutically acceptable salt thereof ii) A non-enteric polymer coating the particles, containing a coating amount of 20% to 40%. A compressed orally disintegrating tablet comprising an enteric coating, When the disintegrant and multiple units are subjected to a compressive force of 6kN to 50kN during the manufacture of the tablet... The present invention provides compressed orally disintegrating tablets that are compressed into orally disintegrating tablets having a wear rate of 1% or less. do.

[0036] This disclosure further relates to a process for manufacturing orally disintegrating tablets of any of the embodiments described above, a) Generate multiple particles containing a therapeutically effective amount of rasmidan or a pharmaceutically acceptable salt thereof. The process of doing so, b) Apply a coating containing a non-enteric polymer to the particles of step (a), thereby The process of obtaining multiple units, c) Mix the multiple units of step (b) with at least one tablet excipient containing a disintegrant, This process involves obtaining a blend, d) Mix the blend from step (c) with flavorings and sweeteners to create a flavor-masked blend. The process of making the do, e) The step of mixing the flavor-masked blend with a drying lubricant, f) The step of compressing the blend from step (e) to obtain a compressed orally disintegrating tablet. It provides a process that includes the following.

[0037] This disclosure also relates to a method for preparing a taste-masked ODT composition and to inducing a migraine attack. This disclosure provides a method for using this composition to treat patients prone to irritation. The orally disintegrating tablets significantly reduce the strong bitter taste of rasmiditan, making it suitable for migraine patients, especially children. This allows for the administration of this product form to individuals and patients suffering from nausea due to migraine attacks.

[0038] This disclosure preferably incorporates an orally disintegrating tablet (ODT) in which the tablet disintegrates within approximately 30 seconds. Solid medicine containing flavor-masked rasmiditan or its pharmaceutically acceptable salts This disclosure relates to a pharmaceutical composition. This disclosure further relates to a timulant with one or more pharmaceutically acceptable excipients. Kinged Rasmizitan contains desired mechanical strength and desired in vitro emission profile We provide ODT with an iL. [Brief explanation of the drawing]

[0039] [Figure 1] This is a process flowchart for the rasmiditane ODT formulation. [Figure 2] This is a process flow diagram of the rasmiditane ODT formulation intermediate. [Figure 3] This is a taste profiling of a Rasmizitan ODT embodiment using the flavor profile method. [Figure 4] This is an example of a rasmiditan hemisuccinate orally disintegrating tablet. [Modes for carrying out the invention]

[0040] The following explanation contains information useful for understanding this disclosure.

[0041] Definition: As used above and throughout this disclosure, the following terms mean unless otherwise indicated. It shall be understood that it has the following meanings. The terms "drug," "activity," "active ingredient," or "active pharmaceutical ingredient" as used herein are used in this specification. The term refers to any pharmaceutically acceptable and therapeutically effective compound or its pharmaceutically acceptable salt. Includes. Preferred compounds in this disclosure include 2,4,6-trifluoro-N-[6-(1-methyl It is [2-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide. The preferred compound shown is 2,4,6-trifluoro-N-[6-(1-methyl-piperidi It is n-4-carbonyl)-pyridine-2-yl]-benzamide hemisuccinate. The preferred compound of the disclosure is 2,4,6-trifluoro-N-[6-(1-methyl [Tyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide hemicohm It is an acid salt. Preferred compounds in this disclosure are 2,4,6-trifluoro-N- in solid form D [6-(1-methyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzalkonium It is midhemisuccinate.

[0042] Methods for preparing rasmidan and salts, as well as specific polymorphs, formulations, and dosage forms thereof, are available. This is known to the company, for example, International Publication No. 2003 / 084949, and International Publication No. 2011 / 12 As described in Issues 3654, 2018 / 106657, and 2021 / 007155. When used herein, Rasmijitan (also known as LY573144) The useful form is 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4- Ilcarbonyl)-pyridine-2-yl]-benzamide monohydrochloride, and 2,4,6- rifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2- [Il]-benzamide hemisuccinate, including but not limited to those pharmaceutically acceptable Contains the salt 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4) For the preparation of the hemisuccinate of [-carbonyl)-pyridine-2-yl]-benzamide The synthesis route has been previously disclosed (see, for example, International Publication No. 2021 / 007155). I want to be illuminated.

[0043] "Medically acceptable salts (plural)" are relatively nontoxic inorganic and This refers to organic salts (multiple salts are possible). The fact that the compounds of the present invention can form salts means that Those skilled in the art will understand that the compounds of the present invention contain a basic heterocycle, and therefore It then reacts with one of many inorganic and organic acids to form a pharmaceutically acceptable acid addition salt. To form such pharmaceutically acceptable acid addition salts and general methods for preparing them. Such methodologies are well known in the relevant technical field. For example, P. Stahl et al. ,HANDBOOK OF PHARMACEUTICAL SALTS:PROPER TIES,SELECTION AND USE,(VCHA / Wiley-VCH,2 008);SMBerge, et al., “Pharmaceutical Sa lts”, Journal of Pharmaceutical Sciences, Please refer to Vol. 66, No. 1, January 1977.

[0044] As used herein, the term "non-enteric coating" is used in its broadest sense. In this specification, it refers to a non-enteric polymer used as a barrier coat. In this case, the term "non-enteric coating" refers to a pH-sensitive polymer. This refers to a coating containing polymers, which have a pH value higher than that found in the stomach. It is insoluble at pH values ​​(i.e., pH values ​​higher than 5.0), but soluble at acidic pH values. Therefore, a suitable non-enteric polymer is insoluble in the oral cavity and soluble in the stomach. In some embodiments, the non-enteric polymer is a hydrophobic monomer and / or base. It is a copolymer of non-enteric monomers. Non-exclusive examples of such non-enteric polymers include those from the United States. It is described in application No. 2006 / 0134054. In a particular embodiment, mono MAR is not limited to methyl (meth)acrylate or benzyl (meth)acrylate. , dodecyl (meth)acrylate, octyl (meth)acrylate, cyclohexyl (meth)acrylate )Acrylate, Phenyl(meth)acrylate, Tert-butyl(meth)acrylate ethylhexyl methacrylate, propyl( meth)acrylate, or acrylic acid esters or methacrylic containing combinations thereof It is an acid ester. Each possibility represents a distinct embodiment. In other embodiments, monomer - is a substituted acrylic acid or methacrylic acid ester, and dimethylaminoethyl (meth) Acrylate, diethylaminoethyl (meth)acrylate, piperidine ethyl (meth) Acrylate, tert-butylaminoethyl (meth)acrylate, EUDRAGIT (Registered Trademark) E100, Eudragit (Registered Trademark) EPO, or a combination thereof This includes, but is not limited to, these possibilities. Each possibility represents a distinct embodiment. As for non-enteric coatings, Kollicoat® Smartsea is a good example. l 30 D or Kollicoat (registered trademark) Smartseal 100 P are listed. (BASF PRD number (product number) is Kollicoat® Sm Regarding artseal 30 D, the license number is 30492630, and Kollicoat (registered trademark) (Smartseal 100 P is listed as 30585559) Kollicoat (registered trademark) Smartseal 100 P coating is available Using an organic solvent system (e.g., alcohol or acetone), 100 P (powder) grade It can be applied using this method. A particularly preferred non-enteric coating in this embodiment is K This is ollicoat® Smartseal 30 D (30% dispersion). As used herein, the term “unit” refers to a coating containing a non-enteric polymer. Applied to granular particles of rasmidan or its pharmaceutically acceptable salt, thereby multiple single This refers to obtaining a coded API.

[0045] As used herein, the term "patient" refers to a human being. In some cases, the terms "treatment," "treating," or "mitigating" are used. It is intended to refer to all processes, and here, existing failures causing delays, interruptions, and blockages. Control, cessation, and / or reduction of symptoms may be possible, but not necessarily complete cessation of all symptoms. This does not necessarily indicate complete exclusion. When used herein, the "possibility" of the compound of rasmiditane is used. The term "effective dose" refers to the amount of medication that is effective in treating a patient's migraine. The preferred “effective dose” is the amount that reduces the signs and symptoms of a patient’s migraine attack compared to an untreated patient. The amount is determined to be effective in treating or resolving the condition. A preferred amount of rasmidan is 25-2 The range is 00 mg, and the unit dosage forms are 25 mg, 50 mg, 100 mg, and 200 mg. It can be listed.

[0046] "Dosage" is a predetermined amount calculated to produce the desired therapeutic effect in the patient. Refers to milligrams. As used herein, "mg" refers to milligrams. When used in [unspecified use], the dose indicated in mg is the active pharmaceutical ingredient as the free base equivalent by mass. This refers to fractional rasmiditane; for example, a dose of "100 mg" means 100 mg of free base equivalent. This refers to mg of the active pharmaceutical ingredient rasmiditan. When used herein, a given dose is A dose up to 10 percent higher or lower than the indicated dose may be equivalent to the indicated dose. The amount shown is similarly intended to provide a useful dosing plan in terms of the method. This may be interpreted as stating the dosage. The pharmaceutical compositions of rasmiditane of this disclosure are available in bulk or It can be provided in unit dosage form. For ease of administration and uniformity of dosage, it is provided in unit dosage form. Formulation of pharmaceutical compositions of rasmiditane is particularly advantageous. The term "unit dosage form" refers to a physically distinct unit dose suitable for the target being treated. This refers to a unit. Each unit is calculated to produce the desired therapeutic effect in conjunction with the necessary drug carriers. It contains a predetermined amount of the active compound rasmiditane. The unit dosage form is, for example, 25 mg, 5 Oral disintegration containing rasmiditan in preferred doses such as 0 mg, 100 mg, and 200 mg. It could be a broken lock.

[0047] In embodiments, this disclosure provides rasmidan in ODT form in the amounts described herein. A pharmaceutical composition containing is provided, the amount being 25 mg to 200 mg per dose. In this disclosure, a pharmaceutical compound comprising rasmiditane in the amount described herein in the form of ODT The product is available in quantities of 25mg, 50mg, 75mg, 100mg, and 150mg per dose. g, or 200 mg. The aforementioned doses are based on the average weight of an adult, and / Alternatively, lower doses are acceptable for individuals with lighter body weight, such as the elderly or children.

[0048] In some embodiments of this disclosure, a patient is prescribed by the pharmaceutical composition described herein. A person diagnosed with a condition or disorder requiring protection. In some embodiments... In addition, the patient has a condition or disease that indicates the need for administration of the pharmaceutical composition described herein. This is a human being characterized by having a risk factor. This can be treated by the method of the present invention. Disorders include migraines, accidental headaches, chronic headaches, chronic cluster headaches, and / or accidental cluster headaches. If known by an established and accepted classification, the classification is known by various factors. It can be found in the source of information. For example, currently, Diagnostic and Static stical Manual of Mental Disorders (DSM-IV TM)(1994, American Psychiatric Association The fourth edition of (n, Washington, DC) identifies many of the defects described herein. It provides diagnostic tools for this purpose. Also, International Classif The ICD-10, 10th edition, is described herein. This provides a classification for many of the disorders. Those skilled in the art will know the classifications described in DSM-IV and ICD-10. Alternative nomenclature, disease classification, and classification for the disorders described herein, including those listed herein. It is important to recognize that there are different classification systems, and that terminology and classification systems evolve along with advances in medical science. This will result in migraine patients also being able to use the International Headache Society (IHS) International l Classification of Headache Disorders 3rd Edition, (ICHD-3) Beta Version (The International Classification) Ication of Headache Disorders, 3rd Edition (Beta), It is defined by Cephalalgia 2013;33:629-808. Therefore, it may be diagnosed as migraine with or without aura (1.1 and 1.2). Several practices Morphologically, human patients, before receiving rasmiditan for the prevention of migraines, , diagnosed as accidental migraine. In some embodiments, human patients are given Rasmidr Before receiving treatment, the patient has been diagnosed with chronic migraine. In some embodiments, human patients The person experiences an aura associated with a migraine. In some embodiments, the human patient experiences a migraine. I do not experience any warning signs.

[0049] As used herein, “migraine” includes, but is not limited to, a migraine attack. Not applicable. As used herein, “migraine attack” refers to the following description: The symptoms are, There can be overlaps in various phases of headache attacks, and not all patients experience the same clinical signs. No. In the prodromal phase, the vast majority of patients experience a pre-headache phase that can precede it by up to 72 hours. It presents with prodromal symptoms, including changes in mood and activity, irritability, fatigue, food cravings, and recurrent episodes. These include yawning, stiff shoulders, and phonophobia. These symptoms are accompanied by a prodromal phase, a headache phase, and more In some cases, symptoms may persist even after entering the post-symptomatic phase. Some patients, about one-third of patients, experience seizures. Some experience transient neurological deficits, while others experience a prodromal phase. ICHD-3 describes the prodromal phase as 5 One or more transient complete absences that last for more than a minute, with each absence lasting 5 to 60 minutes. Defined as a reversible neurological deficit, of which at least one instance does not have unilateral localization. It must be a visual system capable of exhibiting positive (scintillating scotoma), negative (scotoma), or both phenomena. Auras are found in over 90% of cases, but the most common are impairments in sensation, movement, language, and brainstem. And retinal prodromal symptoms may also occur. Transient waves of depolarization of cortical neurons. This is thought to be the underlying pathophysiological brain mechanism behind the clinical phenomena of migraine aura. During the headache phase, headache attacks that can last 4 to 72 hours may include nausea, photophobia, and phonophobia. The symptoms, or both, are present. The headache is characterized as moderate to severe, unilateral, and pulsating. It worsens with physical activity. Two of these characteristics are sufficient to meet the diagnostic criteria. In the subsequent symptom phase, characteristic symptoms reflect the symptoms observed in the prodromal phase. Typical post-symptom symptoms include fatigue, difficulty concentrating, and stiff shoulders. Do the symptoms begin in the prodromal phase and persist through the headache phase to the post-symptom phase, or do they occur during the headache phase? It remains unclear whether the headache begins while the patient is present or appears after the headache phase has ended.

[0050] As used herein, "migraine" refers to a condition having both of the following required characteristics (A and B): This refers to headaches with or without aura, lasting for ≥30 minutes: A) Among the following headache characteristics At least two: 1) unilateral location, 2) pulsating quality, 3) moderate or severe pain intensity. and 4) causing aggravation or avoidance of daily physical activity, and B) during headache At least one of the following: a) nausea and / or vomiting, and / or b) photophobia and Sound phobia. As used herein, “mid-range migraine” refers to persistent, with or without aura. Although the duration is over 30 minutes, among the characteristics of migraine according to the International Headache Society's ICHD-3 definition... It refers to a headache that lacks one of the following:

[0051] The abbreviations listed below are defined as follows when used herein: "C The "AS number" refers to the Chemical Abstracts registration number. "hr" or "h" means time. "NMT" means the following. "RT" means room This refers to ambient temperature. "sec" means second (singular or plural) as a unit of time. Yes. "w / w" means the ratio of weight to weight.

[0052] The compositions, processes, product forms, and uses of the present disclosure are for non-enteric coated laths. Specific preferences include the preparation of orally disintegrating tablets containing mijitan and coated rasmijitan. Further details regarding specific embodiments are provided. For the introduction of bioequivalence testing (LAIA) Therefore, we offer commercially available, easy-to-drink, orally disintegrating tablets of masking grass miditan hemisuccinate. We developed rasmiditane in this disclosure is 2,4,6-trifluoro-N-[6-( This refers to [1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide itself. The specific salt used in the disclosure is hemisuccinate, but hydrochloride or other suitable salts may also be used. Other salts are also within the scope of the embodiments of this disclosure.

[0053] Challenges in preparing orally disintegrating tablets of rasmiditan: Orally disintegrating tablets (ODTs) dissolve rapidly in saliva in the mouth, allowing for easy swallowing of the medication without water. This is a solid oral dosage form that allows for swallowing. This is suitable for patients with swallowing difficulties (e.g., children). Diseases in which symptoms may interfere with the consumption of liquids (nausea), and diseases in which convenience of administration is desirable (migraine). ) is beneficial in this regard. However, ODT is a typical important quality of immediate-release tablets. This document presents challenges in formulation development beyond properties (e.g., purity, potency). The ODT (Official Drug Therapy) requires adherence to the following guidelines. To ensure this, it must also suit the patient's palate. Rapid disintegration in the mouth and a pleasant taste are required. Most importantly, this disclosure addresses the challenges and provides a solution for REYVO for pediatric and / or adult populations. Providing a novel solution for the ODT product form for W(registered trademark) (Rasmijitan). ru.

[0054] Rasmijitan is very soluble (dissolves easily in the mouth), but it tastes very bitter. It has other negative sensory attributes that hinder conventional ODT development. In the case of Rasmijitan, dissolve The solution concentration is approximately 35-9.8 mg / mL at a pH of 5-6.8, which is roughly the pH range of the oral cavity. The effective dose is 25-200 mg depending on the patient's weight or other factors. (Trained taste) Panelists and crushed 50 mg (e.g., 2 x 50 mg) tablets of Rasmiditan Immediate Release Taste studies using tablets have shown that rasmiditan has very poor palatability. An extreme bitterness, numbness in the mouth, and other negative sensory attributes are present and last for 30 minutes.

[0055] [Table 1]

[0056] Approaches to limit the negative sensory attributes of drugs with particularly bad taste include oral dissolution. This may include applying a barrier coating to the drug substance to prevent it. Roaches are cellulose acetate with polyethylene glycol, or cellulose acetate with hypromellose. This involves using an insoluble film containing a soluble pore-forming agent such as cellulose. The challenge with this approach is balancing the amount of soluble pore-forming agent with the amount of insoluble polymer. While ensuring that the drug's taste is properly masked, it still remains fast in the gastrointestinal tract. The goal is to ensure rapid release, sufficient absorption, and prompt onset of action. This is especially important for headache sufferers. Non-enteric polymers are also used as barrier coats. These polymers are insoluble at the pH of saliva, but dissolve rapidly at the pH of the stomach. It is designed to be non-enteric polymers also have an odor that would otherwise be insoluble in the film. It has been proven to be a pore-forming agent.

[0057] U.S. Patent No. 5,489,436 concerns pore formation in insoluble cellulose ester films. This document describes examples of the use of the non-enteric polymer Eudragit® 100E as an agent. This approach addresses the issue of in vivo release due to insoluble film coating. To achieve good flavor masking performance without compromising quality, the pH level contained within the film is important. It has the limitation that efforts are needed to determine the optimal amount of pore-receptive agent. In the case of medications used for relief, any delay in drug release results in delayed absorption and delayed pharmacodynamic effects. This can result in an ideal taste masking film that is hardly released in the mouth, It provides immediate and complete drug release within the GI tubule, equivalent to conventional immediate-release tablets.

[0058] Orally disintegrating tablets must also meet other requirements, such as rapid disintegration. FDA Guide The tablets are conventional USP <711> It must disintegrate within 30 seconds using a disintegration test. The FDA also states that, generally, ODT tablets should not exceed 500 mg in weight. It is recommended that the weight of the tablet intended for use as an ODT is 50 If the amount exceeds 0 mg, its ability to function effectively as an ODT is determined based on product performance. It should be corrected. Finally, ODT should be used during manufacturing, packaging, or handling by patients. The tablets must be sufficiently hard and sturdy so as not to impair their integrity and quality. Achieving these requirements for doses exceeding several tens of mg requires tablet hardness and rapid disintegration. It is difficult because many of the desired attributes, such as disintegration, are not met. Soft tablets disintegrate quickly, however. , difficult to handle, and vice versa; hard tablets are easy to handle, but crumble It's slow to break.

[0059] Compositions, orally disintegrating tablet formulations, and product forms disclosed herein. This disclosure is useful for the acute treatment of migraine in patients with and without aura. In this specification, the orally disintegrating tablet of rasmiditan referred to as "rasmiditan ODT" ( The following describes embodiments of the ODT form. The preparation of the following ODT tablets of rasmidan is in accordance with the present invention. Further explanation will be given, and a typical preparation will be shown. Reagents and starting materials are readily available, or It can be easily synthesized by those skilled in the art. Preparations and examples are described by illustration and are not representative of those skilled in the art. It should be understood that various changes may be made by different people.

[0060] Preparation of active pharmaceutical ingredients that mask taste The active ingredient, rasmiditan hemisuccinate, is preferably suitable for small particle coating. As such, they are prepared in a size range of approximately 50 to 275 μm or less. Particles smaller than approximately 50 μm (this Coating with fine powder (referred to as "fine powder" in the specification) is generally impractical and not feasible. It is recognized that large surface area particles provide a high level of coating for masking flavor. When a granulation process is required to bind fine particles and / or when a granulation process is required to bind fine particles. Furthermore, the presence of fine particles results in an insufficient final coating and a taste masking effect. Because it could damage the coating, the remaining particles should be minimized during the coating process. It has been recognized that particles larger than approximately 300 μm in size are present in the final product. It is also recognized that this can result in a rough texture, which is undesirable in ODT. It is.

[0061] As defined herein, small particles are d10 with a diameter of approximately 50 μm and d9 with a diameter not exceeding approximately 275 μm. The particles are within the general range of 0, and the coating is for coacervation and fluidized bed coating. It can be done in several ways, such as wringing. A common method is Wurster (Wur This involves using a ster-type fluidized bed coater, which is generally efficient for this process. This is because it provides a reliable coating process and is a well-understood process. In one embodiment of the disclosure, a Wurster-type fluidized bed coating is used to create a raspberry bush. Coat the phlegm active ingredient.

[0062] The determination of particle size is known to those skilled in the art, and well-known methods can be used. The device is a Malvern Mastersiz equipped with an Aero S Module. ER 3000 particle size analyzer, dispersion system: micro tray standard venturi disperser, and Malvern Mastersizer 3000 software (version 3.0 or This may include current Windows software or equivalents (which have equivalent features). Standard procedure (e.g., Malvern Mastersizer 3000 laser diffraction particle size) Dispersion analyzer operation, calibration, and maintenance, PPD SOP IO 237 latest version, and particle size The measurement was performed by photodiffraction (see the latest USP edition), and the d10 of the three test preparations was Calculate the average of d50 and d90.

[0063] According to preferred embodiments of this disclosure, the raw material is a non-enteric copolymer topcoat Before application, the particles are first granulated / subcoated with HPMC E5. To ensure proper wetting of the coating solution, include a surfactant in the coating solution. It is also possible. Sodium lauryl sulfate is a preferred surfactant. Subcoat / granules The granulation process involves binding fine particles together to form granules, as well as reducing particle abrasion during coating. It helps both to avoid larger particle core integrity and to provide a better taste mass. It helps improve the yield and quality of King coatings.

[0064] In one embodiment, the present invention relates to the discovery of a non-enteric coated rasmiditan composition, and Regarding incorporation into ODT, in vitro flavor masking, in vitro dissolution (rapid biological It achieves a balance between usability, rapid disintegration time, and appropriate tablet hardness.

[0065] This disclosure relates to an effective amount of polymer coating for taste masking, preferably non-enteric coated. We propose an ODT consisting of a coated rasmiditane hemisuccinate active pharmaceutical ingredient. Provided. Non-enteric coatings, as specified herein, have a pH (typical in the mouth) It is not soluble at pH levels higher than approximately pH 6-7, but it is soluble at lower pH levels, for example, pH 1 Polymers or copolymers soluble in gastric fluids having a viscosity of approximately 0.0 to 3.5 to 5.0 Defined as a coating. Preferably, the composition of the present disclosure is a non-enteric methyl methacrylate. Kollicoat (registered as a di(ethyl)aminoethyl methacrylate copolymer) (Registered trademark) Smartseal 30 D (commercially available from BASF) coating It includes. Before application of copolymer coating, the pure active pharmaceutical ingredient is preferably inert polymer Granulated using a polymer (e.g., HPC or HPMC, preferably HPMC E5) To facilitate processing, talc may be added to any coating. Starting AP The particle size of I is preferably in the size range of about 50 to 275 microns, and the particle coping While making coating easier, the coated particles may feel rough in the mouth in the final dosage form. Maintain a size that does not feel rough. The resulting coated particles also solidify during storage. To minimize this, colloidal silicon dioxide or talc, preferably a solid such as talc, is used. You can sprinkle an anti-corrosion agent on it.

[0066] The coating process involves incorporating talc into the coating suspension, and then coating This becomes easier by minimizing the stickiness of the particles inside. High stickiness during processing This leads to increased adhesion and aggregation between particles. Particle aggregation reduces the efficiency of the coating. This results in an irregular drug release profile between batches. In addition, the stickiness is widespread during processing. When occurring in the mouth, the granules are solid masses larger than 300 μm that give a gritty feeling in the mouth. They form spheroids (or aggregates). The final coated particles facilitate processing into ODT. At the same time, in order to avoid a gritty feeling in the mouth in the final product, approximately 75 A size range of ~300 μm is desirable. The following unit formulations are 25 mg, 50 ml. The following are used when manufacturing ODT Rasmiditane tablets for g and 100 mg doses. It is possible.

[0067] [Table 2] A The amount of active pharmaceutical ingredient (pharmaceutical intermediate, coated API) is determined based on the assay of the active ingredient. Ku. B The amount of Pharmaburst(registered trademark) 500 is designed to maintain the theoretical tablet weight. It will be adjusted as needed.

[0068] Flavor-masking coated Rasmizitan is preferably used to prepare ODT. It is directly compressed with a suitable excipient. The excipient is a polyol (mannitol, sorbitol). (L), fillers (starch, microcrystalline cellulose), lubricant (stearyl sodium fumarate) (Magnesium stearate, talc), fluidizing agent (colloidal silicon dioxide), disintegration In the manufacture of ODTs such as crospovidone and croscarmellose sodium, It may be any of the ones used for the purpose. Preferably, Pharmaburst ( Designed for ODT, such as (Registered Trademark) 500 (Commercially available from SPI Pharma) Using co-processed excipients can simplify processing and optimize tablet properties. Ingredients (mint, cherry berry, peppermint) and sweeteners (aspartame, sucralose) (S, neotame) may also be added, as is common in ODT preparations. The preferred flavoring is FONA NC Cherry Berry Flavor AR. T#825.0062U. The preferred sweetener is aspartame. Alternative flavorings. This includes NC Cherry Flavoring ART-825.0597U and Bubblegum Flavoring ART-81 5.0084U, NC Strawberry Flavoring ART-915.0435U, Fontate ch Mango Flavoring NAT WONF-870.0235U, Juicy Orange Flavoring N The drug is AT WONF-884.0107U. The tablet has an in vitro disintegration time of less than 30 seconds. While maintaining this, it is also sufficiently high to ensure low tablet abrasion (less than 1%) in downstream processing. It is compressed into solid components. [Examples]

[0069] The following examples are provided to illustrate the claimed invention, and are not intended to limit it. This is not the case. The results of the following methods and procedures are not related to the compositions, formulations, and tablets illustrated in this disclosure. However, it provided useful formulation intermediates and formulation forms of rasmiditan for orally disintegrating tablets. Therefore, it is demonstrated that it can be used to treat migraines and / or headache disorders.

[0070] Example 1 - General procedure for coating Rasmizitan The following procedure applies to d10=55.0μm, d50=117.9μm, and d90=220 Method for coating 1.2 kg of rasmiditane hemisuccinate with a particle size of 0.9 μm or similar. The following is described. As shown in Table 3, rasmiditane hemisuccinate is used in a fluid bed coater. Fill it. Many vendors supply fluidized bed coaters capable of Wurster coating. —There exists, and the device settings, especially regarding nozzle type and fluidization parameters, are vendor It can vary between them. The example cited here is for one particular type of fluidized bed coater. However, it is understood that other fluidized bed coaters can be used to achieve similar results. It can be done.

[0071] [Table 3]

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

[0073] [Table 4]

[0074] Apply the subcoat granulation solution until the desired degree of coating is reached. The amount of coating is... Also known as coating degree, as defined and used herein, 10% for granulation. The degree of coating is desirable, and 900g of API is used for 1kg of final granular material. 100g is HPMC / SLS type.

[0075] Similar processing results may be achieved using various conditions and apparatus as shown herein. It is recognized that what is being described is an example.

[0076] [Table 5]

[0077] [Table 6]

[0078] Subcoat granules optionally remove any remaining fine powder and excess granulated material. Therefore, it can be filtered. Non-enteric coated Kollicoat(registered trademark) Smartse Using al 30 D topcoat, 0.3 kg of Lasmiditane HPMC subcoat The following general procedure can be used to coat the coating / granules.

[0079] [Table 7]

[0080] As shown in Table 7, Kollicoat® Smartseal in purified water Prepare a 30 D topcoat flavor masking dispersion.

[0081] [Table 8]

[0082] To ensure good film formation during coating, a different plasticizer may be used. It is recognized that other antioxidants may be used, and / or product stability. It is also recognized that they may be completely excluded if appropriate for the purpose of doing so.

[0083] The topcoat dispersion is applied to the desired percentage of coating, preferably 37% theoretically. Apply to the desired coating level. When used in this specification, the coating level or coating The degree of coating or coating is the amount of coating relative to the weight of the coating material. It can be expressed as a percentage of the material's weight relative to its weight basis. Therefore, 37% theoretical code The flavoring is achieved using 630g of granular API and 370g of flavor masking matrix, for example. Kollicoat® Smartseal in purified water as shown in Table 7. 1kg of final coating API with 30D topcoat flavor masking dispersion. This is represented by [the formula]. Useful conditions are shown in Table 8. Similar processing results are shown in the present invention as an exemplary example. It is recognized that this can be achieved under various conditions and with various devices using the conditions and devices presented in the detailed document. Embodiments of this disclosure relate to a non-enteric coating, preferably Kollicoat. (Registered Trademark) Smartseal 30 D is included, and the degree of coating is as described herein. Using the conditions, for example, a coating degree of 20-40%, preferably 30-40% The degree of coating is, more preferably, about 31-38%. The application method is a coating degree of 32% and / or 37%. A degree of coating is particularly preferred. The coating or coating used herein "Coated" refers to the degree of coating and related methods and specifications.

[0084] [Table 9]

[0085] [Table 10]

[0086] The final coated material is optionally treated to remove residual water and improve the quality of the coating. To improve this, the fluidized bed coater may be further dried at a temperature of 30-45°C. The final coated material can be optionally used to remove any remaining fine powder and / or granular material. It can be sifted for this purpose. Additional talc coated API and brush This prevents solidification during storage. It also improves taste masking performance and subsequent GI tube Drug release in this area is performed using a USP II paddle dissolution apparatus in conjunction with the pH shift method. This can be modeled by measuring the API released from typical dosage forms. As shown in 10 and 11, representative tablet dosage forms were prepared first.

[0087]

Table 11

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

[0089]

Table 12

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

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

[0092] The dissolution results shown in Table 12 were obtained with Kollicoat® Smartseal ​​​​​​Rasmiditan in simulated saliva when coated to a target coating degree of 37% This demonstrates the suppression of dissolution. Similarly, the results show that when the pH shifts to approximately 2.6, the dosage form This indicates that the drug is released rapidly. This is due to good taste masking and GI tube This is the desired release profile to ensure rapid release and reliable drug absorption. .

[0093] [Table 13]

[0094] Example 2: Manufacturing process for producing coated Rasmizitan Preparation of coated Rasmizitan This disclosure includes 25 mg, 50 mg, 100 mg, and 200 mg of 25-200 mg The present invention provides a formulation comprising orally disintegrating tablets having dose strength. The manufacturing process for producing Rasmijitan involves incorporating the flavor mask before it is incorporated into the orally disintegrating tablet. We offer film-coated rasmiditane hemisuccinate for the purpose of coating. Rasmiditane hemisuccinate is used in Wurster-style bottom spray fluid beds. The coater undergoes two coating steps on an 18" scale. Process flowchart The process, as well as exemplary process controls, parameters, and process ranges, are described. The manufacturing process for intermediates in pharmacy formulations consists of three main processes. These operations are performed by HPM. It is a C granule, Smartseal coated, and talc blend. The process used to manufacture the ODT formulation intermediate is shown in Figure 2.

[0095] HPMC granulation: The main purpose of the HPMC granulation process is to aggregate the fine particles of the active pharmaceutical ingredient and then control the particle size distribution entering the taste masking coating. The HPMC granulation process consists of the following steps outlined below. The HPMC granulation process consists of the following steps outlined below. The HPMC granulation process consists of the following steps outlined below.

[0096] Preparation of HPMC solution: Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with a low vortex for a minimum of 5 minutes and a maximum of 10 minutes to homogenize the solution. Turn off the mixer. Prepare an HPMC solution (8% w / w solids) in an appropriate excess amount (if necessary) to allow for setting and losses in the liquid addition system. Fill the container with purified water. Using a mixer that provides a medium vortex, dissolve the HPMC in the purified water. Once the HPMC has visually 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 sodium lauryl sulfate to the HPMC solution. Once all solids have visually dissolved, reduce the mixing speed to provide a low vortex during suspension degassing. Turn off the mixer. Adjust the solution to its final weight with purified water. Mix the solution with 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 specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Prepare an 18” Wurster type coater by installing specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Prepare an 18” Wurster type coater by installing specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Prepare an 18” Wurster type coater by installing specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Prepare an 18” Wurster type coater by installing specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Prepare an 18” Wurster type coater by installing specific coater chambers, base plates and plate sieves, nozzles, partitions, plenum distribution plates, and filters. Prepare a classifier by installing specific sieves. Calculate the amount of HPMC solution to be delivered (the target is to provide a theoretical coating degree of 10% for the HPMC granulation process). Preheat the empty coater using the process parameters specified in the batch record. Fill the solution delivery line and tare the scale. Lower the temperature and add rasmiditan hemisuccinate. Close the cart and process parameters. Adjust the settings to the coating parameters specified in the batch record. Adjust the inlet temperature, Achieve a specific target floor temperature. Once the target amount of solution has been delivered, dry the coater parameters. Adjust to the specified value and dry the granules as specified. Transfer the granules to a drum and cook separately. Collect knockdown fine powder from the tether. Use a 249 micron sieve to remove aggregates. Using this method, the granules are sieved using a 75-micron sieve to remove fine particles. .

[0098] Kollicoat (Registered Trademark) Smartseal 30 D Coating: Kollicoat® Smartseal 30 D Coating Process The main purpose is to mask the taste of the ingredients by coating the HPMC granules with polymer. The application is to apply. Kollicoat (registered trademark) Smartseal 30 D The coating process consists of the following steps, which are outlined below.

[0099] Kollicoat (registered trademark) Smartseal 30 D coating suspension Preparation: Kollicoat® Smartseal 30 D suspension (19.7 Add 1% w / w solids in an appropriate excess amount to allow for the setting and loss of the liquid addition system. Prepare (if necessary). Fill the container with purified water. Set the stirring speed to 50 RPM. While stirring at this speed, slowly add triethyl citrate to the water. Kollic Slowly add oat(registered trademark) Smartseal 30 D to the water / TEC mixture. Then, pass it through a 60-mesh sieve. Kollicoat(registered trademark)Smartse Mix with a moderate vortex without introducing bubbles for at least 90 minutes after the completion of adding al 30 D. Continue mixing. Increase the stirring speed to create a moderate vortex and add the talc to the suspension. After adding talc, continue mixing for at least 30 minutes using a moderate vortex. Turn off the mixer. Then, add purified water to the suspension to the appropriate final weight. Stir the final suspension for at least 5 minutes. Mix in a flow. Continue mixing the suspension with a low vortex flow throughout the coating operation.

[0100] Kollicoat (registered trademark) Smartseal 30 D coating: Specified Coater chamber, base plate and plate sieve, nozzle, partition, By installing a plenum distribution plate and filter, an 18" Wurster type can be used. Prepare the data (for example, the settings may be as follows: Chamber 18” 375°C The plate is W18-10, the plate sieve is 325 mesh, and the nozzle The nozzle is a CPI nozzle with a No. 2 tip, and the partition is 1.5 inches from the plate. It is mounted on top as 8.5" x 20", and the plenum distribution plate is 1 x spoke plate It is a 1x perforated plate with a 1 / 16" pore size, and the filter is 16x48" 16O (It is PTFE). Prepare the classifier by installing a specific sieve. Calculate the amount of Kollicoat(registered trademark) Smartseal 30 D suspension. Preheat the empty coater using the process parameters specified in the batch record. Solution transfer Fill the output line and tare the scale. Lower the coater's cart and classify the HPM. Add C granules. Close the cart and record the process parameters in the batch record as specified. Adjust the setting parameters. Adjust the inlet temperature to achieve a specific target floor temperature. Once the standard amount of suspension is delivered, the coater parameters are adjusted to the specified values ​​for the curing process. The coated API is cured as specified. The coated API is placed on a drum. Transfer and collect the knockdown particles separately from the coater. The coated API, The material is sieved using a 300-micron sieve to remove aggregates, and then sieved using a 75-micron sieve. Use a tool to remove fine particles.

[0101] Talc Blending: The main purpose of the talc blending process is to add a small amount of talc to the coated API. The method involves sprinkling talc on the tablets. This extends the disintegration time of tablets that have been stressed by high temperatures. This is done to mitigate the length of the collapse. These long collapse times are held on the collapse basket sieve. This is due to aggregates formed. Approximately 2% of the coated API in the diffusion blender. Sprinkle with w / w talc. Use the actual weight of the coated API, talc Calculate the required amount of talc. The talc blend can be done in one step or in stages. Good. To minimize the loss of talc on the inner surface of the blender, AP in each section Talc should be added between the additions of I. Add about half of the coated API to the blender. Add the talc to the blender, then fill with the remaining coated API. Blend the mixture using the rate and time parameters specified in the batch recording. Discharge the final DPI material into the designated bulk packaging container.

[0102] Unit prescription of rasmiditane ODT preparation intermediate: To illustrate embodiments of this disclosure, the theoretical composition of the rasmiditane ODT formulation intermediate is shown in Table 1. As shown in 3. The composition information provided in this table is a theoretical value based on 100% process efficiency. The composition of the manufactured pharmaceutical intermediate can vary by up to ±10% during development due to scale accuracy and coating efficiency. The raw drug of lasmiditan hemisuccinate is manufactured as a single polymorphic form (anhydrous, referred to as Form A) for the coating process described herein.

[0103]

Table 14

[0104] Batch formulation of lasmiditan ODT pharmaceutical intermediate: The theoretical batch formulation of the lasmiditan ODT pharmaceutical intermediate is shown in Table 14.​​​​​​​​​​

[0105] [Table 15] A The amount of API packed into the HPMC granules is adjusted based on the assay value of the API. It is possible. The theoretical free base content of API is the ratio of molecular weights (377.36 / 436.4). It is given by (1 = 0.86469). B This represents the amount of solution / suspension delivered during coating. Excess solution / suspension will not be delivered. Considering line priming and line loss, and providing appropriate heel within the delivery tank. It can be prepared for this purpose. C Purified water, HPMC granulation and Kollicoat® Smartseal Used in both 30D coating operations. Most of this water is removed during drying / curing. It will be done. D Kollicoat® Smartseal 30 D Coating Suspension The amount is adjusted based on the yield of HPMC granules after classification. The amount is 37% theoretically. Kollicoat (registered trademark) Smartseal 30 D coating degree It is calculated in such a way. E Kollicoat® Smartseal 30 D is 30% w / w It is an aqueous suspension containing solid components. F The amount of talc used in the final blending process is Kollicoat® Sm Adjusted based on the yield after classification of artseal 30 D coated APIs. The amount of talc used in the final blending process is Kollicoat® Sm The amount of artseal 30 D coated API is 20.763 g per 1 kg.

[0106] Preparation of orally disintegrating tablets using flavor-masked rasmidan: Example 3: For a theoretical batch size of 650 tablets, a typical 100mg rasmiditan OD is... Table 15 shows the units and batch formulations for preparing T.

[0107] [Table 16]

[0108] The coated API is sieved through a #50 mesh to remove loose aggregates. The body is destroyed, and the coated API is confirmed to be in discrete particle form before further processing. Indeed, this can be done. Weigh the coated API and talc into a 500 mL container and Turb Blended on ULA at 44 rpm for 18 minutes.

[0109] Weigh Pharmaburst® 500 into another 1000 mL container, and Cherry - Berry flavoring, aspartame sweetener, and sodium stearyl fumarate in the container Add to the top of Pharmaburst®. Then add the API and talc. Add the blend to the top. Then, mix the 1L container on the Turbula mixer at 44rp. Rotate at m for approximately 10 minutes.

[0110] The final blend is processed on a FlexiTab single-station press using a 12mm circular die. The file was compressed using a simple tool. The following compression profile was created.

[0111] [Table 17]

[0112] The result was that with a low compressive stress of 65 MPa, USP <1216> Target 1.0% This demonstrates that tablets with sufficient strength to meet the abrasion resistance target are produced. Furthermore, USP < 12 16> It is recognized that the test may not be suitable for ODT. However, This is a recognized and accepted characterization test. Acceptable performance in this test This will be considered more than sufficient for orally disintegrating tablets in terms of abrasion resistance. 30 seconds The following target decay times are met across the compression profile.

[0113] The surprising discovery is that the use of talc does not negatively affect the disintegration properties of ODT, This also helps to improve the breakdown of ODT when placed under stress stability. Luk is magnesium hydrated silicate, and its crystals are formed in thin, layered structures, and are used in pharmaceutical applications. It is suitable as a lubricant and anti-stick agent. Its main characteristic is that it is naturally hydrophobic and Being lipophilic is generally a characteristic that, when used at high levels in a dosage form, affects disintegration performance. It is thought to have a negative impact.

[0114] The following coated API-talc blends are used in a 20 mL glass scintillator. Weigh the mixture into a ration vial and blend in a Turbula mixer at 44 rpm for 40 minutes. It was prepared in a way that could be difficult.

[0115] [Table 18]

[0116] Weigh Pharmaburst® 500 into a 2-ounce glass jar, then... Then sodium stearyl fumarate, followed by coated API or coated I added the API-Talc pre-blend to the top. I mixed this blend in a Turbula mixer. It was rotated at 44 rpm for 9 minutes.

[0117] [Table 19]

[0118] [Table 20]

[0119] The tablets were pressed using a Natoli single-station press to create 12mm circular dimples. The tablets were compressed to 9kN using a tool. The tablets were then stressed for a specific period of time in an open dish at 70°C. The tablets were removed from the oven and kept at room temperature until analysis. The decay was USP<71 The procedure was repeated at least three times according to step 1.

[0120] [Table 21]

[0121] Surprisingly, despite the hydrophobic nature of talc, its disintegration properties are under stress. The tablets that have not been used are not damaged. When used at levels above 1%, extreme temperatures may cause damage. Improved disintegration stability can be obtained for tablets exposed to Tres.

[0122] Taste studies of the Rasmijitan ODT compositions described herein or known to those skilled in the art are conducted by Cherry - A flavored formulation with a high overall flavor quality, featuring a berry and aspartame flavor profile. The bitter and green stemmy attributes are more pronounced than in unflavored coated granules. The chewing rate is quite low, and if the patient chews contrary to the label instructions, the chewing rate per unit of product may affect the flavor quality profile. This indicates that the file will not be changed.

[0123] The problem with the compositions and tablets disclosed herein is that rasmiditan hemysuccinate becomes a solution in the mouth. It prevents this while dissolving rapidly in the stomach, providing effects roughly comparable to the approved tablet version. The goal is to ensure that the required effectiveness is achieved as soon as the use occurs. The orally disintegrating tablets for rasmidan, which have been successfully developed, have a pleasant taste and are approved by REYVOW (registered (Registered trademark) The aim is for the product to be biologically equivalent to the tablet product form and to be consistently manufacturable. .

[0124] The first hurdle to making ODT product form possible is that the particles are 75 μm to 250 μm. It is the size, and therefore large enough to coat, on the other hand, coated The particles in the orally disintegrating tablets are small enough so that the mouth does not feel gritty when administered. The objective was to prepare core API particles for coating. The API batch had a composition that was more Rather than relying on sophisticated formulation approaches, we use Lasmi as a core for further coating. It was found that the particle size criteria were met, making it possible to use ditanhemisuccinate. Can rasmiditane hemisuccinate particles be coated by a fluidized bed process? Determine the good coverage of the coating on the core and the minimum requirements for the coating process. Development experiments were conducted to obtain a loss of or an acceptable loss. The procedure described in this embodiment is as follows: It was decided that these criteria would be met.

[0125] The compositions and orally disintegrating tablets of this disclosure facilitate oral disintegration and simultaneously provide rasmiditan. This stems from the discovery of a successful barrier coat that effectively masks the extremely unpleasant taste characteristics. It uses Kollicoat® Smartseal, a functional coating. This is used to mask the core particles containing Rasmiditan API, thereby effectively suppressing their dissolution in the mouth. It was achieved. Clinically acceptable taste and palatability for target dose strengths of 50 and 100 mg. To achieve this, the desired product is generally released (solubilized) in the oral cavity at a rate of less than 1% of the administered dose. ) produces a drug. To achieve bioequivalence, the desired product is generally produced in the gastrointestinal tract. It provides rapid dissolution and, therefore, good absorption of rasmicin. Numerous techniques and approaches exist for skinning, but predicting before clinical trials... It is not possible to do so, and if there are clinical trials, to properly define the numerous criteria for a clinically advantageous and useful product. To satisfy the desired performance characteristics, the optimal coating excipient is greater than 5.5. It is insoluble at pH 5.5, but highly soluble even at pH levels below 5.5. (Kollicoa) t(registered trademark) Smartseal 30 D is used in combination with Rasmijitan for this purpose. They can be used together, and in orally disintegrating tablets, this API provides excellent taste masking. It was discovered that it can provide a composition that can be used as an orally disintegrating tablet. Lambs coated with Kollicoat (registered trademark) Smartseal Tanhemisuccinate particles are also used to determine whether they can be effectively tableted, and The procedure had to be tested further. Kollicoat(registered trademark) Smart The seal-coated API has an acceptable machining range and masking ability, and requires We manufactured an effective and useful tablet that meets the required specifications.

[0126] Example 4 - Manufacturing process for orally disintegrating rasmiditan tablets This disclosure includes 25 mg, 50 mg, 100 mg, and 200 mg for oral administration. This document presents embodiments of a formulation including orally disintegrating tablets having a dose strength of 5 to 200 mg of rasmiditane. Provided herein, as exemplified with respect to rasmiditan hemisuccinate, rasmiditan hemisuccinate is provided. A manufacturing process for producing orally disintegrating tablets of thamditan, wherein the process for producing orally disintegrating tablets of thamditan Before assembly, the product is film-coated for flavor masking purposes, Rasmijitan Oral A manufacturing method for producing internally disintegrating tablets is provided. A process flowchart and illustrative methods are provided. Process control, parameters, and process range are described.

[0127] Table 20 below shows Kollicoat® Smartseal 30 D Code A rasumiditane hemisuccinate intermediate preparation, and a 50 mg orally disintegrating tablet. And unit formulations for an example of 100 mg are provided. Those skilled in the art will know, for example, 25 mg and / Alternatively, the amount may be changed to prepare 200 mg or other desired unit dosage form tablets. The manufacturing process for Mijitan ODT is shown in Figure 1.

[0128] [Table 22] A A unit prescription is provided as an exemplary example. B The composition and theoretical unit formulation information provided for the drug product intermediate portion is 100% process efficacy. It is theoretical based on the ratio. The composition of the manufactured formulation intermediate is scale accuracy and coating accuracy. Due to manufacturing efficiency, the result can fluctuate by ±10% during development. CThe formulation intermediate is prepared as described herein and / or according to methods known to those skilled in the art. It is manufactured by [unclear / unclear]. D Purified water is used during the intermediate manufacturing process and is removed during the process. E Kollicoat (registered trademark) Smartseal 30 D (commercially available from BASF) (as shown) is an aqueous suspension containing nominal 30 w / w% solid components, as shown in the table. The amount present is the solid portion of the suspension. F Unless otherwise stated, a reasonable variation of ±10% is acceptable for each oral disintegrating tablet excipient. It can be done. G The amount of coated hemisuccinate API is either "as is" or standard release potency. The amount of Pharmaburst® 500 is adjusted based on the target tablet weight. It can be adjusted as needed to maintain this.

[0129] Table 11 lists the acceptable range of ingredient supply per feeder as a percentage of the total tablet volume. For drug substances, the range is 110% or less and 90% or more of the unit dose mean assay value. It is based on maintaining [the specified range]. With respect to excipients, the range is a reasonable variation of ±10% around the target. Based on scientific judgment. The calculation of the value is within the scope of the knowledge of a person skilled in the art.

[0130] [Table 23] A The amount of coated rasmiditane hemisuccinate API is either "as is" or "standard". The amount of Pharmaburst® 500 is adjusted based on the quasi-release potency. The coated AP can be adjusted as needed to maintain the target tablet weight. Target per feeder for I and Pharmaburst(registered trademark) 500 (tablets) The %) of the agent is adjusted, and a reasonable variation of ±10% around the potency-adjusted target is permitted. B Please refer to Table 22 for the distribution weight range of the pre-blended materials.

[0131] Table 22 lists the acceptable distribution amounts of pre-blended components as a percentage of the total blend weight. This is based on a scientific judgment of a reasonable variation of ±10% for both components simultaneously. The calculation of the value is within the scope of the knowledge of a person skilled in the art.

[0132] [Table 24]

[0133] A process flowchart for the manufacture of the rasmiditane ODT formulation is provided in Figure 2. The procedure further explains how the ODT product can be prepared. Those skilled in the art will understand that It is important to recognize that specific modifications can be used as needed for alternative processes. Ro.

[0134] Powder sieving and blending (sweetener / flavoring pre-blend): aspartame and Safely sift the cherry berry flavoring through a US standard #6 mesh sieve. The ingredients are as follows: about half aspartame, all of the cherry berry flavoring, and the rest Spartame is stratified by sequentially adding it to tumble bottles. Place on the blending bin base and blend. Before loading ingredients into the reduce-weight (LIW) feeder. or during loading, coated rasmiditane hemisuccinate API, Ph Armaburst® 500 and stearyl fumarate sodium are US standard Safe sieving is performed through a semi-#6 mesh sieve. LIW feeder material allocation and The configuration options are listed in the table, with preferred configuration items highlighted in bold.

[0135] [Table 25] A A series of continuous production processes are set up for mixing by methods known to those skilled in the art. See the table below. 24 indicates the equipment and setting parameters.

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

[0137] [Table 27] A Recommended 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: The mixer shaft is excluding paddles #1 and #12, both of which face the outlet at a 45° angle. The paddles are arranged in an alternating 22.5° configuration (odd-numbered paddles face the exit, and even-numbered paddles face the entrance). Use a mixer with a control (see Table 24). The mixer adjusts the amount of material remaining in the mixer. It features an adjustable weir assembly integrated within the outlet piece, used for weirs. It remains in the fully open position during the process product collection (runtime) phase, but the tablet Initial process settings to ensure uniformity while adjusting weight and thickness parameters. It may be adjusted for this purpose. If it is necessary to close the weir, the impeller speed should be set to 100 rpm. The following is how to reduce the centripetal force so that it becomes smaller than the inertial force of the powder in the mixer (flue (The number of d's is less than 1).

[0140] Tableting: The final blend is processed using the listed tool HOB numbers, according to the dimensions given in the table. Compress into circular dimpled planar bevel edge (FFBE) tablets. Rotary compressor (for example, Tablets are prepared using a Korsch XL200. These tablets determine the target turret velocity. The production rate of the tablet press is a DCS recipe parameter. All other parameters for each tablet strength are also included. The tablet pressing process parameters are defined by the tablet pressing recipe. (Example: Oral Cavity) The internally disintegrating tablets (50 mg and 100 mg) are shown in Figure 4.

[0141] [Table 29]

[0142] The turret speed is set to match the mass flow rate from the mixer to the press surge hopper. It may be adjusted to control the mass flow rate from it. This adjustment may be manual. Alternatively, through automation using a surge hopper level sensor, a stable product collection stage can be achieved. A suitable column for the powder may be maintained.

[0143] The compression parameters are set to achieve the target tablet physical attributes (listed in Table 26 and the table below). It is configured during setup. Adjust the tablet press dosage to achieve the target tablet weight. The paddle speed of the feeder frame is an indicator of the main compressive force (RSD), which is the variation in tablet weight. ("Srel") is adjusted to minimize it. From the tip of the pre-compression and main compression tools The distance to the edge is adjusted to achieve the desired tablet molded strength and / or thickness. The tablet press recipe parameters are considered initial conditions for starting the process. Lameters are used as needed to obtain the desired tablet characteristics (values ​​such as dosage, edge thickness, and compressive force). It can be adjusted.

[0144] The weight, thickness, destructive force, disintegration, and abrasion of the tablet are evaluated at the start. Furthermore, the corresponding calculated solid content is evaluated according to the specifications through the execution of compression. The tablets are passed through a tablet dust remover and a metal grid. The tablets can be sorted as needed. .

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

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

[0147] Average destructive power (hardness): Tablet breaking strength is measured using a hardness tester under a load applied across the diameter of a round tablet. The maximum compressive load (breaking force) achieved when a tablet breaks was recorded for each individual tablet, and the average was calculated. Calculate. For more detailed information, see USP guidance. <1217> Please refer to the following.

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

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

[0150]

number

[0151] Equation 1 is further explained by Equation 2 for a given set of tablet forming tools. It is possible.

[0152]

number

[0153] Alternatively, the average solid content is determined using the weight and thickness values ​​for each tablet. This could be the average of the solid content calculated individually for each set.

[0154] Abrasion level: The total weight of the dust-removed tablets is rotated 100 times at 25 rpm in the drum of the abrasion tester. Measure before and after. To ensure the accuracy of the tablet weight, the tablet is allowed to balance with the ambient conditions. To achieve this, the sample should be exposed to ambient indoor conditions before the test. The calculated weight obtained... The percentage difference represents the degree of tablet abrasion. For more detailed information, see USP Guidance <121> See 6>.

[0155] Disintegrant: The tablets are sifted up and down in a 37±2℃ water bath until the tablet pieces fall through the sieve. Place the agents on separate sieves. (USP guidance) <701> Please refer to the following.

[0156] The physical attributes of the tablets are evaluated at the start of each batch and periodically throughout the batch to control the tablet weight. Monitor the thickness, solids content, and / or tablet strength.

[0157] [Table 30] A The physical attributes of the tablets used as in-process controls are indicated by an asterisk ( * ) It is being used.

[0158] [Table 31] A The physical attributes of the tablets used as in-process controls are indicated by an asterisk ( * ) marked It is being done.

[0159] Storage conditions: USP controlled room temperature Taste masking is evaluated using a taste profiling procedure that employs the flavor profile method. This is possible. The sensory panelists tried using the flavor profiling method of descriptive sensory analysis. Evaluating the Flavor (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. The panelists will rinse their mouths with spring water and salt-free crackers. 2.1 Distribute one Rasmiditan tablet to each panelist. 3. Start simultaneously, the panelists take the tablets Place the tablet in your mouth, then on your tongue (in the case of ODT), or after chewing (in the case of chewable tablets). (In this case) Gently rotate the panelist to the point where they would normally swallow. Then, inside the mouth The remaining material was spit out, and the disintegration time or chewing time was recorded. 4. Next, the panelists As the flavors persist, the initial and aftertaste characteristics are independently evaluated at regular intervals of up to 30 minutes. Evaluate and record. 5. Panelists will list their individual results and pre-flavor profile. A flavor profile is generated for the sample. 6. Use the pre-flavor profile from step 5 as a guide. Then, repeat steps 1-4 for the second sample, and the panelists make any necessary modifications. 7. The panelists will list their individual results and the final flavor profile of the sample. It is generated accordingly.

[0160] Coated with Kollicoat® Smartseal 30 D By combining API with appropriately selected flavors and sweeteners, the mouthfeel is improved. It was discovered that an ODT (bitterness intensity scale of less than approximately 1.5) was provided. The following is a summary of exemplary flavor profiles obtained for the Tan ODT embodiment. The flavored formulation underwent rasmiditan ODT using the flavor profile method, as shown in Figure 3. As shown in the morphological flavor profiling (Figure 3, dashed lines indicate unflavored, solid lines indicate unflavored) The flavored granules had significantly less bitterness than the unflavored granules. When comparing the degree of coating, a 32% coating was found to be more effective than a 37% coating. It was only slightly more bitter than the Rasmijitan. The resulting rolling and chewing were equivalent. This resulted in a bitter profile.

[0161] The sweetened / flavored rasmiditane ODT formulations disclosed herein have appropriate overall flavor quality. The percentage is high. The target balance and satisfaction for oral formulations is approximately 1.5 or less, with 37% being high. The coated flavoring achieved this goal when rolled. The chewed tablets were It was slightly lower. The bitterness of the flavored ODT preparation of Rasmiditan was due to the unflavored version. It is considerably lower than coated Rasmizitan granules. Based on flavor quality, this sweetened... Flavored / flavored Rasmidan formulations are suitable for ODT product forms. The choice to chew will not significantly alter or worsen the flavor profile of the tablet. (However, the granular coating remains almost completely intact.)

[0162] In addition to the flavor masking provided by coating agents, "flavoring agents" (sweeteners and the same Aromatic compounds are added to the powder blend with the highest coating degree (37%), and Rasmiditan O The palatability of DT was further improved. This effort resulted in a desirable excipient. High (artificial) The sweeteners aspartame and cherry berry flavoring are found to counteract the residual bitterness. It is released, and surprisingly, offers a pleasant-tasting Rasmizitan ODT product form. Negative sensory attributes, such as tongue stinging, throat burning, and mouth numbness, were virtually eliminated. Furthermore, in vitro data and modeling were obtained when the rasmiditane ODT formulation of this disclosure was approved. This demonstrated that it is expected to be bioequivalent to the immediate-release tablet, and this is consistent with clinical trials of LAI. In A, it is being tested (compared to current immediate-release tablet formulations to support the treatment of migraines). (Bioequivalence of orally disintegrating tablets of rasmiditan compared).

[0163] Example 5 - Comparative Example Surprisingly, Eudragit is an alternative but similar non-enteric coating. The performance of (registered trademark) E100 is its flavor masking performance and disintegration properties when processed into ODT. In terms of both performance aspects, it is inferior to the performance of Kollicoat® Smartseal. It was found that EUDRAGIT(registered trademark)E 100 is Evonik Dimethylaminoethyl methacrylate, manufactured by Healthcare Cationic copolymers based on butyl methacrylate and methyl methacrylate Yes, there are polymer solids (E100), solutions in alcohol (E12.5), and It is supplied as a ready-to-use dry mixed powder. Eudragit® is It is commercially available as a non-enteric polymer for taste masking applications, Kollicoa t(registered trademark) Smartseal (this is also a non-enteric polymer of a similar chemical class) It is expected to function similarly to ).

[0164] Apply the following procedure to obtain d10 = 55.0 μm and d50 = 117.9 μm for 0.3 kg. , and rasmiditane hemisuccinate with a particle size of d90 = 220.9 μm or similar to Eudr It can be coated with agit(registered trademark)EPO, as shown in Table 28. The fluidized bed coater is filled with the drug substance. Fluidized bed coater capable of Wurster coating There are many vendors that supply the equipment, and the setup of the device depends especially on the nozzle type and flow Dynamic parameters can vary between vendors. The cited example is a fluidized bed coater. This pertains to one specific type, but those skilled in the art will know that other fluidized bed coaters can achieve similar results. They will understand that it can be used to achieve results.

[0165] [Table 32]

[0166] As shown in Table 29, subcoating / granulation of HPMC E5 and SLS solutions in purified water Prepare the solution.

[0167] [Table 33]

[0168] Using the target conditions shown in Table 30, an increase of 5-15% by weight, preferably 10% by weight, is achieved. Apply the subcoat granulation solution until the desired weight increase is achieved. Similar treatment results can be obtained under various conditions and This can be achieved with the apparatus, and those presented herein will be recognized by those skilled in the art as examples. ru.

[0169] [Table 34]

[0170] [Table 35]

[0171] Subcoat granules optionally remove any remaining fine powder and excess granulated material. It may be filtered for this purpose. 0.253 kg of Rasmijitan HPMC subcoating The granules are coated with a non-enteric Eudragit® E PO topcoat. To do this, as shown in Table 32, Eudragit E PO top coat flavor in purified water. Prepare a masking dispersion.

[0172] [Table 36]

[0173] Using the conditions described in Table 33, the topcoat dispersion was prepared (relative to the weight of the added granular material). Apply until the desired weight increase reaches 44% by weight of the theoretical value. Similar processing results can be obtained under various conditions. Those that can be achieved by the art will be recognized by those skilled in the art, and those presented herein are examples. be.

[0174] [Table 37]

[0175] [Table 38]

[0176] The final coated material can be optionally free of any remaining fine and / or granular material. It can be used to filter them out.

[0177] ODT preparation using Eudragit® E PO coated active pharmaceutical ingredient Made by: Regarding the theoretical batch size of 300 tablets, a typical 100mg rasmiditan OD Table 35 shows the units and batch formulations for preparing T.

[0178] [Table 39]

[0179] The coated API was sieved through a #50 mesh to break up loose aggregates. By breaking and coating the API, it is possible to ensure that it is in discrete particle form. Weigh Pharmaburst® 500 into a 500 mL container, then add fumarate. Weigh the sodium stearyl into the coated API. Then, turn the container to Turb Rotate on the ULA mixer at 44 rpm for approximately 7 minutes. For the final blend, transfer to the FlexiTab. Compression was performed on a single-station press using a 12mm circular convex tool. The following compressions were performed. I created a profile.

[0180] [Table 40]

[0181] As the results show, a compressive stress of 60 MPa is sufficient to meet the target abrasion rate of 1.0%. A tablet of considerable strength is produced. However, the disintegration time of 44 seconds under this compressive stress is It exceeds the acceptable limit of 30 seconds. To reduce the decay time to a more acceptable 18 seconds, 33 A compressive stress of MPa is required, but this poses risks to manufacturing and downstream handling. The soft tablets are manufactured in such a way that they reflect the high wear rate of 2.21% presented. Therefore, the compression operation window for producing tablets of appropriate strength with a low disintegration time is narrow and impractical. It is useful.

[0182] Eudragit® E PO coated API for flavor masking and To evaluate the release characteristics, the same dissolution procedure described above in this specification is used. do. Table 37 shows uncoated APIs, Kollicoat® Sma rtseal coated APIs, and Eudragit® E PO Code This shows the pH shift dissolution profile of ODT prepared using coated API. In general, the dissolution of API from tablets requires that the tablet first disintegrate before the API dissolves. Follow the correct order. In this case, it is created using Eudragit(registered trademark)E PO. The tablet that was selected disintegrates more slowly compared to the other two tablets. Therefore, Eudragit ( (Registered Trademark) The early dissolution time of E PO tablets is compared to the preferred 20 seconds for other tablets. Because it did not completely disintegrate until approximately 4 minutes, it exhibits artificially low drug release. Eudragit (Registered Trademark) EPO tablets: Looking at the time from approximately 120 seconds after at least 50% of the tablet has disintegrated. The emission rate from Eudragit®E PO-coated API particles is Kolli The emission rate is significantly faster than that of coat(registered trademark) Smartseal coated API particles. This is clear. The data shows that Eudragit(registered trademark) E PO completely disintegrates tablets. This indicates that it is not very effective in suppressing the release of rasmiditane hemisuccinate after decomposition. This is even more evident at 300 seconds immediately before the pH shift, and the release percentage is Kol Regarding APIs coated with licoat(registered trademark) Smartseal: 17. In contrast to 51%, Eudragit® E PO coated The figure for sumiditan hemisuccinate is 53.26%.

[0183] [Table 41]

Claims

1. A pharmaceutical compound comprising rasmiditan or a pharmaceutically acceptable salt thereof and a non-enteric coating. Finished product.

2. The aforementioned rasmiditane or a pharmaceutically acceptable salt thereof is rasmiditane hemisuccinate. The composition according to claim 1.

3. The aforementioned Rasmijitan contains granular particles having a size range of approximately 50 to approximately 275 microns. or the composition according to claim 1 or 2.

4. The aforementioned non-enteric coating is methyl methacrylate di(ethyl)aminoethyl methacrylate Kollicoat® Smartseal 30 containing a relate copolymer The composition according to any one of claims 1 to 3, which is D.

5. The aforementioned composition is coated with Kollicoat® Smartseal 30 D. When coated, the coating is approximately 20-40% of the weight of the granular Rasmiditan particles. The composition according to claim 4, further comprising a certain degree of glycation.

6. The aforementioned composition is coated with Kollicoat® Smartseal 30 D. When coated, the coating degree is approximately 37% relative to the weight of the granular Rasmiditan particles. The composition further includes the composition according to claim 5.

7. Coated with Kollicoat® Smartseal 30 D The composition according to any one of claims 1 to 6, wherein the rasmiditan further comprises talc.

8. Coated with Kollicoat® Smartseal 30 D The aforementioned rasmijitan further contains talc, and the final coated particles are approximately 75 to 3 A composition according to any one of claims 1 to 7, having a size range of 00 microns.

9. Talc, Pharmaburst® 500, and stearyl sodium fumarate The composition according to claim 8, further comprising um.

10. The composition according to claim 9, further comprising a sweetener and a flavoring agent.

11. Claim 10, wherein the sweetener is aspartame and the flavoring agent is cherry berry. The composition described above.

12. The composition is Approximately 37% to 46% w / w of Kollicoat® Smartseal 30 D-coated rasmiditane hemisuccinate, Approximately 47% to 58% w / w of Pharmaburst® 500, approximately 3.9% 4.9% w / w aspartame / cherry berry flavor blend (approximately 6% aspartame) 8% to approximately 32% w / w cherry berry flavoring; and The present invention, which contains approximately 1.3% to 1.7% w / w of stearyl sodium fumarate, as described in claim 11. The composition of the listed items.

13. The composition is (i) Approximately 40.2% w / w of Kollicoat® Smartseal 3 Rasmiditane hemisuccinate coated with 0D (approximately 37% coating degree), (ii) Approximately 0.80% w / w talc, (iii) Approximately 54.0% w / w of Pharmaburst® 500, (iv) Approximately 2.0% w / w stearyl sodium fumarate, (v) Approximately 1.0% w / w cherry berry flavoring, and (vi) The composition according to claim 11, comprising about 2.0% w / w aspartame.

14. Claim that the composition further comprises rasmiditan in an amount of about 25 mg to about 200 mg. A composition according to any one of items 1 to 13.

15. Claim that the composition further comprises rasmiditan in an amount of about 25 mg to about 100 mg. The composition described in 14.

16. The combination according to claim 15, wherein the composition further comprises about 25 mg of rasmiditan. Finished product.

17. The combination according to claim 15, wherein the composition further comprises about 50 mg of rasmiditan. Finished product.

18. The combination according to claim 15, wherein the composition further comprises about 75 mg of rasmiditan. Finished product.

19. The composition further comprises about 100 mg of rasmiditan, as described in claim 15. composition.

20. The composition further comprises about 150 mg of rasmiditan, as described in claim 14. composition.

21. The composition according to claims 1 to 20, further comprising an orally disintegrating tablet.

22. A method for treating migraines in patients, and for patients who require such treatment, A method comprising administering the composition according to any one of claims 1 to 20 for an efficacy.

23. A composition according to any one of claims 1 to 20 for use in treatment.

24. A composition according to any one of claims 1 to 20 for use in the treatment of migraines.

25. A compressed orally disintegrating tablet comprising a disintegrant and a plurality of units, wherein the plurality of units are i) Multiple particles containing a therapeutically effective amount of rasmiditane or a pharmaceutically acceptable salt thereof, ii) A non-enteric polymer containing a coating degree of 20% to 40% on the particles Includes a non-enteric coating, The disintegrant and the plurality of units are subjected to a compressive force of 6 kN to 50 kN during the manufacture of the tablets. When compressed, it is compressed into an orally disintegrating tablet having a wear degree of 1% or less. Tablet.

26. A process for manufacturing an orally disintegrating tablet according to claim 21, a) Generate a plurality of particles containing a therapeutically effective amount of rasmiditane or a pharmaceutically acceptable salt thereof. The process of doing so, b) Apply a coating containing a non-enteric polymer to the particles of step (a), thereby The process of obtaining multiple units, c) Mix the plurality of units of step (b) with at least one tablet excipient containing a disintegrant. And the process of obtaining the blend through that process, d) Mix the blend from step (c) with flavorings and sweeteners to create a flavor-masked blend The process of creating the lend, e) A step of mixing the flavor-masked blend with a drying lubricant, f) Compress the blend from step (e) and thereby compress the orally disintegrating tablet A process that includes the steps involved in obtaining something.

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