# US 10,117,836 B2 · Tablet formulation for CGRP active compounds

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,117,836 B2
- Document ID: US10117836B2
- Status: Granted
- Kind: B2
- Application number: 15/115,026
- Filed: 2015-01-30
- Published: 2016-12-01
- Granted: 2018-11-06
- Earliest claimed: 2014-02-05
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Mary Ann Johnson; Leonardo Resende Allain; W. Mark Eickhoff; Craig B. Ikeda; Chad D. Brown; Francis J. Flanagan, Jr.; Rebecca Nofsinger; Melanie Marota; Lisa Lupton; Paresh B. Patel; Hanmi Xi; Wei Xu
- Web page: https://patentgrep.com/patent/US10117836B2

## CPC

- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 9/146: {with organic macromolecular compounds}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to compositions comprising an extrudate or solid solution of a compound, or a salt thereof, of Formula I (API): Formula I, wherein “Ra” is independently H or —F, in a water-soluble polymer matrix which further comprises a disintegration system allowing a tablet made therefrom to rapidly disintegrate in the environment in which the API is to be released.

## Claims

### Claim 1

A tablet comprising:
(a) an extrudate comprising:
(i) a water-soluble polymer matrix;
(ii) a dispersing agent; and
(iii) a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein “Ra” is independently —H or —F, and wherein the dispersing agent and compound of Formula I is dispersed within said polymer matrix; and
(b) a disintegration system,
wherein said tablet has a hardness of from about 12 kP to about 18 kP, and wherein said tablet achieves complete disintegration in less than about 5 minutes in a tablet disintegration test complying with USP 31-NF26 Chapt. 701 using aqueous HCl at pH 1.8 at 37° C.

### Claim 2 (depends on 1)

The tablet of claim 1 wherein the polymer matrix in said extrudate is a water soluble polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer.

### Claim 3 (depends on 1)

The tablet of claim 1 wherein said disintegration system comprises powdered sodium chloride and croscarmellose sodium.

### Claim 4 (depends on 1)

The tablet of claim 1 wherein the compound of Formula I is a compound of Formula Ia, or a salt thereof:
wherein, each of “Rb” is —H or each of “Rb” is —F.

### Claim 5 (depends on 4)

The tablet of claim 4 which further comprises: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate.

### Claim 6 (depends on 1)

The tablet of claim 1 wherein said extrudate comprises about 50 wt % of said tablet and said extrudate is comprised of from about 5 wt % to about 23 wt % of a compound of Formula I.

### Claim 7

A tablet comprising:
(a) an extrudate comprising:
(i) a polymer matrix which is a water soluble polyvinylpyrrolidone/vinyl acetate copolymer;
(ii) a dispersing agent; and
(iii) a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein “IV” is independently —H or —F, and wherein the dispersing agent and compound of Formula I is dispersed within said polymer matrix; and
(b) a disintegration system comprising powdered sodium chloride and croscarmellose sodium.

### Claim 8 (depends on 7)

The tablet of claim 7 wherein the disintegration system comprises a 1:1 weight ratio of powdered sodium chloride and croscarmellose sodium.

### Claim 9 (depends on 8)

The tablet of claim 8 wherein the dispersing agent in said extrudate is d-alpha-tocopheryl polyethyleneglycol succinate (TPGS).

### Claim 10 (depends on 7)

The tablet of claim 7 wherein the tablet has a hardness of from about 12 kP to about 18 kP, and wherein when said tablet is subjected to a dissolution test complying with USP 30 NF25 Chapt. 711, in a paddle-stirring apparatus equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid at pH 1.8 at 37° C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes.

### Claim 11 (depends on 7)

The tablet of claim 7 wherein the tablet has a tensile strength of 1.75 MPa, and wherein when said tablet is subjected to a dissolution test complying with USP 30 NF25 Chapt. 711, in a paddle-stirring apparatus equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid at pH 1.8 at 37° C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes.

### Claim 12 (depends on 7)

The tablet of claim 7 wherein the compound is (S)—N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide.

### Claim 13 (depends on 7)

The tablet of claim 7 wherein the compound is (S)—N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide.

### Claim 14 (depends on 7)

The tablet of claim 7 wherein said powdered sodium chloride has: (i) a d50 value of less than about 210 microns; (ii) a d10 value of less than about 50 microns; and (iii) a d90 value of less than about 470 microns.

### Claim 15 (depends on 7)

The tablet of claim 7 wherein the water-soluble polymer matrix of said extrudate is a copolymer having about a 6:4 polyvinylpyrrolidone/vinyl acetate monomer unit ratio.

### Claim 16

A formulation suitable for pressing into a tablet, said formulation comprising:
a) an extrudate composition comprising a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA copolymer) matrix and dispersed therein:
(i) a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein all of Rb are either —H or all of Rb are —F; and
and
(ii) tocopherol polyethylene glycol succinate (TPGS),
wherein said compound of Formula Ia comprises from about 5 wt % to about 23 wt % of said extrudate and TPGS comprises at least about 5 wt % of said extrudate; and
b) a disintegration system comprising: (i) croscarmellose sodium; and (ii) powdered sodium chloride, wherein said disintegration system comprises about 20 wt % of said formulation.

### Claim 17 (depends on 16)

The formulation of claim 16 further comprising: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate, and wherein said powdered sodium chloride is characterized by: (i) a d50 value of less than about 210 microns; (ii) a d10 value of less than about 50 microns; and (iii) a d90 value of less than about 470 microns.

### Claim 18 (depends on 17)

The formulation of claim 17 wherein the weight ratio of compound of Formula Ia: powdered sodium chloride:croscarmellose sodium is 9:10:10.

### Claim 19 (depends on 18)

The formulation of claim 18 wherein said compound of Formula Ia is (S)—N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide or (S)—N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide.

### Claim 20 (depends on 17)

The formulation of claim 17 wherein said extrudate is present in an amount of about 50 wt % of the formulation.

### Claim 21 (depends on 16)

A tablet made by pressing a formulation of claim 16 in a tableting press to provide a tablet with a tensile strength of about 1.75 MPa.