WO2022079591A1

WO2022079591A1 - Pharmaceutical composition of lasmiditan and process of preparation thereof

Info

Publication number: WO2022079591A1
Application number: PCT/IB2021/059337
Authority: WO
Inventors: Sagar SHETH; Mehul UMARAVKAR; Viral Vaidya
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2020-10-14
Filing date: 2021-10-12
Publication date: 2022-04-21

Abstract

The present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.

Description

PHARMACEUTICAL COMPOSITION OF LASMIDITAN AND PROCESS

OF PREPARATION THEREOF

TECHNICAL FIELD:

The present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.

BACKGROUND:

Lasmiditan (COL-144, LY573144) is a serotonin (5-HT) IF receptor agonist. It was developed by CoLucid (now part of Eli Lilly) for the treatment of migraine. Lasmiditan is available as hemisuccinate salt and is also known by its chemical name: 2,4,6- trifluoro- N- [6-(l- methylpiperidine -4- carbonyl) pyridine-2-yl] benzamide hemisuccinate salt and is reported to have the following chemical structure:

Lasmiditan is approved in the USA as 50 mg and 100 mg film coated tablets under the brand name Reyvow®. It is administered orally, as needed, with or without food for the acute treatment of migraine with or without aura in adults.

Lasmiditan hemisuccinate is a white, crystalline powder that is sparingly soluble in water, slightly soluble in ethanol, and soluble in methanol. A 1 mg/mL aqueous solution of lasmiditan hemisuccinate is estimated to have a pH of 6.8 at ambient conditions. United States Patent No. US8748459 discloses lasmiditan and its hemisuccinate salt. It further discloses method of treatment of migraine in a mammal comprising administering to a mammal effective amount of lasmiditan or salt thereof.

United States Patent Application Publication US20100256187 (US’ 187 publication) discloses oral delivery compositions comprising 50 to 200mg of lasmiditan or salt therefore for the treatment of migraine.

US’ 187 publication also discloses lasmiditan compositions in the form of dry powder inhaler, tablet, capsule, suspension, intravenous formulation, sublingual or buccal tablet. The sublingual and buccal tablets are also disclosed with HC1 and succinate salts of lasmiditan. It further discloses specific tablets containing certain excipients and also discloses wet granulation as manufacturing process for one such tablet.

United States Patent No. US8697876 discloses solid crystalline Form A, Form B and Form C of lasmiditan hemisuccinate.

United States Patent Application No. US2020087279 (US’279) discloses new pseudo-polymorphic crystalline Form D, Form E and Form F of lasmiditan hemisuccinate. It also discloses that starting with either Form A or the amorphous form of lasmiditan hemisuccinate, addition of water alone or water/solvent mixtures results in the conversion from Form A or the amorphous form to one of the pseudo-polymorphic Forms D, E, or F. Form A is the dominant form in the absence of water (up to 10% by volume of water; a water activity of approximately 0.6) or at low water activities, e.g. in pure ethanol, at any temperature. At higher water activities, temperature and water content are determinative.

Further US’279 disclose that conversion of Form A to Form D occurs as water is introduced, for example, through high humidity conditions or in solvent-water mixtures with a high water activity. Form D is the most stable form at intermediate water activities and higher temperatures. Polymorphic Form A of lasmiditan hemisuccinate is unstable in the presence of water and can convert to other pseudo-polymorphic Forms such as D, E or F. It also discloses that lasmiditan in the form of the dihydrate form D can be produced by subjecting the form A of lasmiditan to a wet granulation process using purified water as the granulating medium.

There is a need to develop a solid oral pharmaceutical composition containing lasmiditan or its pharmaceutically acceptable salt thereof in stable crystalline form, wherein the solid oral pharmaceutical composition is prepared by dry manufacturing process. Alternatively, the manufacturing process is a non-aqueous wet granulation process.

Accordingly, the present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or its pharmaceutically acceptable salt there of as an active ingredient and at least one excipients, wherein the solid oral pharmaceutical composition is prepared by dry manufacturing process. The present subject matter also relates to a non-aqueous wet granulation process.

SUMMARY OF THE SUBJECT MATTER:

The present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.

Further, the present subject matter relates to solid oral pharmaceutical composition comprising lasmiditan hemisuccinate as an active ingredient and at least one excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process. The dry manufacturing process according to the subject matter refers to processes such as direct compression process, dry granulation process, roller compaction etc.

Another objective of the present subject matter is to provide a pharmaceutical composition comprising,

(a) Lasmiditan or a pharmaceutically acceptable salt thereof,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant.

(a) Lasmiditan hemisuccinate,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant.

Another objective of the present subject matter is to provide pharmaceutical composition comprising,

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant. Another objective of the present subject matter is to provide a pharmaceutical composition comprising,

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical disintegrant,

(d) one or more pharmaceutical surfactant,

(e) one or more pharmaceutical lubricant.

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical disintegrant,

(d) one or more pharmaceutical surfactant,

(e) one or more pharmaceutical lubricant,

(f) one or more pharmaceutical glidant.

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical disintegrant,

(d) one or more pharmaceutical surfactant,

(e) one or more pharmaceutical lubricant. wherein a pharmaceutical composition is prepared by dry manufacturing process.

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent, (c) one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant wherein a pharmaceutical composition is prepared by dry manufacturing process.

(a) Lasmiditan hemisuccinate Form A,

(b) one or more pharmaceutical diluent,

(c) optionally one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant wherein a pharmaceutical composition is prepared by a non-aqueous wet granulation process.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:

Accordingly, the present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof as an active ingredient, at least one pharmaceutically acceptable excipient, where in the solid oral pharmaceutical composition is prepared by a dry manufacturing process.

The dry manufacturing process according to the subject matter refers to a process generally known in the art. Non-limiting examples of such processes are direct compression process, dry granulation process, roller compaction etc. The non-aqueous wet granulation process according to the subject matter refers to a process generally known in the art such as rapid mixer granulation, fluidized bed granulation, spray granulation etc.

In an embodiment, solvent used in non-aqueous wet granulation process is selected from isopropyl alcohol, ethanol, methanol, acetone, dichloromethane, acetonitrile or mixture thereof.

In an embodiment, the processes described on this subject matter does not involve substantial use of water.

For the purpose of the present subject matter, pharmaceutical composition may comprise lasmiditan in the ‘free base form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.

In one embodiment, lasmiditan present in pharmaceutical composition is in the form of hemisuccinate salt form.

In one embodiment, lasmiditan hemisuccinate is in crystalline form.

In one embodiment, lasmiditan hemisuccinate crystalline form is polymorphic Form A (wherein polymorphic Form A of the lasmiditan hemisuccinate may be defined in any of the ways described in United States Patent No. US8697876).

In one embodiment, crystalline lasmiditan hemisuccinate salt exhibits an x-ray diffraction pattern using Cu-Ka radiation includes peaks at about 15.3, 16.4, 19.3, 22.1, 23.6 and 25.9 degrees 29.

Further, the present subject matter provides a pharmaceutical composition comprising,

(a) Lasmiditan hemisuccinate, (b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical binder,

(d) one or more pharmaceutical disintegrant,

(e) one or more pharmaceutical surfactant,

(f) one or more pharmaceutical lubricant.

(a) Lasmiditan hemisuccinate,

(b) one or more pharmaceutical diluent,

(c) one or more pharmaceutical disintegrant,

(d) one or more pharmaceutical surfactant,

(e) one or more pharmaceutical lubricant.

The term “diluent” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluents according to the present subject matter can be selected from the group of, but not limited to microcrystalline cellulose (MCC), pregelatinized starch, sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, maltose, polydextrose, sucrose, trehalose, xylitol, calcium carbonate, dicalcium phosphate, calcium sulfate, cellulose acetate, ethylcellulose, inulin, magnesium carbonate, magnesium oxide, maltodextrin, sodium bicarbonate, sodium carbonate and sodium chloride.

In one of the aspect, the diluent is microcrystalline cellulose.

The term “binder” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable binder according to the present subject matter can be selected from the group of, but not limited to povidone, pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)), and polyethylene glycol. In one of the aspect, the binder is povidone.

The terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected from but not limited to croscarmellose sodium (CCS), sodium starch glycolate (SSG), pregelatinized starch, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose and starch.

In one aspect, one or more disintegrants are selected from the group of croscarmellose sodium, pregelatinized starch or a mixture thereof.

The terms “surfactant” and “surfactants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical surfactant according to the present subject matter can be selected from but not limited to sodium lauryl sulfate (SLS), poloxamers, polysorbate, sodium dodecyl benzene sulfonate, alkali metal or ammonium salts of lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate, polyoxyethylene sorbitan monostearate, isostearate and laurate, sodium lauryl sulfoacetate, N-lauroyl sarcosine, the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl or N-palmitoyl sarcosine, polyethylene oxide condensates of alkyl phenols, cocoamidopropyl betaine, lauramidopropyl betaine, palmityl betaine and the like.

In one aspect, the surfactant is sodium lauryl sulphate.

The terms “lubricant” and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present subject matter can be selected from but not limited to magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g. a mixture of glyceryl dibehenate, tribehenin and glyceryl behenate), magnesium stearate, myristic acid, palmitic acid, stearic acid, talc, tribehenin, sodium stearyl fumarate (SSF) and sucrose stearate.

In one aspect, the one or more pharmaceutical lubricants comprise magnesium stearate, stearic acid or a mixture thereof.

In further aspect, the lubricant is magnesium stearate.

Glidants are frequently used in tablet formulations to improve flow. In this specification the terms “glidant” and “glidants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable glidants according to the present subject matter can be selected from but not limited to magnesium oxide, colloidal silicon dioxide, pyrogenic silica and hydrated sodium silicoaluminate.

In one aspect glidant is colloidal silicon dioxide.

As used herein, the word “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In one aspect there is provided a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.

In one embodiment there is provided a pharmaceutical tablet comprising a pharmaceutical composition in the form of tablet core, wherein the tablet core is coated with a layer of coating. In one embodiment the coating is a film coating. When the tablet has a film coating, the film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation or to modify or control the release of lasmiditan hemisuccinate from the formulation.

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration to a human.

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration for the treatment of migraine.

In one embodiment, the pharmaceutical tablet comprises 100 mg lasmiditan free base, equivalent to 115.65 mg of lasmiditan hemisuccinate respectively.

In one embodiment, the pharmaceutical tablet comprises 50 mg lasmiditan free base, equivalent to 57.824 mg of lasmiditan hemisuccinate respectively.

In a further aspect, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.

In one embodiment, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of migraine.

In one aspect, there is provided a pharmaceutical composition, as defined herein, for use as a medicament.

In one embodiment, a pharmaceutical composition is a pharmaceutical tablet. In one embodiment, there is provided a method of acute treatment of migraine with or without aura in adults in need thereof, which method comprises the oral administration of the pharmaceutical tablet(s), as needed, to the patient.

According to present subject matter, lasmiditan hemisuccinate tablet is prepared by dry manufacturing process or a non-aqueous wet manufacturing process.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical composition and dosage form provided herein, but is not in any way limiting.

Example 1

Table 1 - Pharmaceutical composition of Lasmiditan hemisuccinate

Example 2

Table 2 - Pharmaceutical composition of Lasmiditan hemisuccinate.

Procedure

1. Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), povidone, croscarmellose sodium (Ac-di-sol) and sodium lauryl sulfate were sifted and mixed properly to get uniform blend.

2. Magnesium stearate was sifted and a blend obtained in step 1 was lubricated using magnesium stearate in step 2.

3. The lubricated blend of step 2 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature 38-44°C.

Above example 2 can be prepared using a dry manufacturing process, e.g. direct compression process, dry granulation process, roller compaction etc.

Dissolution tests The dissolution described herein was performed according to the general procedure of the United States Pharmacopoeia using Apparatus II (Paddle), at 75 rpm with 500 ml of 0.01N HC1 media at a temperature of 37° C. The samples were withdrawn at 5, 10, 15, 20 and 30 minutes.

The dissolution profile of tablets having the Example 2 formulation was tested in 0.01N HC1 dissolution media. The results are presented in Table 3.

Table 3- Dissolution data of Lasmiditan hemisuccinate 100 mg Tablet

(Example 2) composition

Examples 3 to 10

Table 4 - Pharmaceutical composition of Lasmiditan hemisuccinate

Procedure

1. The intragranular material was sifted and mixed properly to get uniform blend.

3. The lubricated blend of step 2 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.

The dissolution profile of tablet formulations in Examples 3 to 10 were tested in 0. IN HC1 dissolution media. The results are presented in Table 5.

Table 5- Dissolution data of Lasmiditan hemisuccinate tablet composition

(Example 3 to 10)

Table 6- Stability data of Lasmiditan tablet composition of Ex.5

Example 11

Table 7 - Pharmaceutical composition of Lasmiditan hemisuccinate

Procedure

1. Sodium lauryl sulfate and microcrystalline cellulose (Avicel PH 112) were passed through Quadro comil with 0.610mm screen.

2. Step 1 excipients were mixed with lasmiditan and pass through Quadro comil with 0.610mm screen.

3. L-HPC LH-11 was mixed with Step 2 excipients and pass through Quadro comil with 0.610mm screen.

4. Magnesium stearate was mixed with mixture of step 3 excipients.

5. Lubricated blend of step 4 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.

Table 8- Dissolution data of Lasmiditan hemisuccinate Tablet (Example 11) composition

Example 12

Table 9 - Pharmaceutical composition of Lasmiditan hemisuccinate

Procedure:

1. Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), L- HPC LH-11 and sodium lauryl sulphate were passed through suitable sieve and mixed properly to get uniform blend.

2. The material obtained in step 1 was subjected to roller compaction and granules were prepared.

3. Extragranular L-HPC LH 11 was sieve and mixed with step 2 granules.

4. Step 3 material was lubricated using magnesium stearate and compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C. Table 10- Dissolution data of Lasmiditan hemisuccinate Tablet (Example 12) composition

Example 13

Table 11 - Pharmaceutical composition of Lasmiditan hemisuccinate

Procedure:

1. Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), PVPK-30, croscarmellose sodium and sodium lauryl sulphate were passed through suitable sieve and mixed properly to get uniform blend.

2. Magnesium stearate was sieved and mixed with step 1 material. 3. Slugs were prepared using lubricated blend of Step 2.

4. The material obtained in step 3 was milled and granules were obtained.

5. Extragranular microcrystalline cellulose (Avicel PH 112) and croscarmellose sodium were sieved and mixed with step 4 granules.

6. Step 5 material was lubricated using magnesium stearate and compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.

Example 14

Table 12 - Pharmaceutical composition of Lasmiditan hemisuccinate

Procedure

1. Lasmiditan hemisuccinate, sodium lauryl sulfate, microcrystalline cellulose (Avicel PH 112) and L HPC LH 11/ croscarmellose sodium were passed through suitable sieve and mixed properly to get uniform blend.

2. Step 1 material was granulated with solvent (IPA/Ethanol).

3. Wet mass was dried at suitable temperature until LOD <2% achieved.

4. Dried granules were sifted through #24 sieve and oversized granules were passed through 1mm sieve. Milled granules were sifted through #24 sieve.

5. Sifted and milled granules were mixed in blender for 5 min. 6. Magnesium stearate was mixed with step 5 granules in blender for 5 min.

7. Lubricated blend of step 6 was compressed into tablet at target weight i.e. 230 mg.

8. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.

Table 13- Dissolution data of Lasmiditan hemisuccinate Tablet (Example 14) composition

Claims

CLAIMS:

1. A pharmaceutical composition comprising a therapeutically effective amount of Lasmiditan or a pharmaceutically acceptable salt thereof, at least one pharmaceutical diluent and one or more pharmaceutical acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is prepared by a dry manufacturing process.

3. The pharmaceutical composition as claimed in claim 2, wherein the dry manufacturing process comprises direct compression process or dry granulation process.

4. The pharmaceutical composition as claimed in claim 1, wherein the manufacturing process comprises non-aqueous granulation process.

5. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutical acceptable excipients are selected from disintegrant, binder, surfactant, lubricant and glidant.

6. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 35 to 65 % w/w of the at least one pharmaceutical diluent based on the total weight of the composition.

7. The pharmaceutical composition as claimed in claim 6, wherein the pharmaceutical composition comprises 0 to 7 % w/w of the disintegrant, 0 to 7 % w/w of the binder, 0 to 5 % w/w of the surfactant, 0 to 3 % w/w of the lubricant and 0 to 1% w/w of glidant based on the total weight of composition.