# US 11,110,055 B2 · Pharmaceutical formulations of tropomyosin related kinase (TRK) inhibitors

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- Number: US 11,110,055 B2
- Document ID: US11110055B2
- Status: Granted
- Kind: B2
- Application number: 16/239,904
- Filed: 2019-01-04
- Published: 2020-02-13
- Granted: 2021-09-07
- Earliest claimed: 2014-12-18
- Assignees: Genzyme Corporation
- Applicants: Genzyme Corporation
- Inventors: Harvey Lieberman; Donglai Yang; C. Michael Philbrook; Michael Santos; Chris Ho
- Web page: https://patentgrep.com/patent/US11110055B2

## CPC

- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- A61K 31/00: Medicinal preparations containing organic active ingredients
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Pharmaceutical formulations with a tropomyosin-related kinase inhibitor (“Trk inhibitor”) are disclosed. The pharmaceutical formulations comprise 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in microcrystalline suspension formulations in its monohydrate form, which shows improved characteristics over the anhydrate form, and in extended release formulations. The extended release pharmaceutical formulations comprise 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microspheres.

## Claims

### Claim 1

A method of manufacturing a crystalline form of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine comprising:
a. Mixing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H -pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine with a solvent to form a suspension;
b. Stirring the suspension;
c. Collecting the solids in the suspension by filtration; and
d. Drying the solids.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the solvent comprises a mixture of acetone and water.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the suspension is stirred overnight.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the solids are air dried.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the solvent comprises a mixture of acetone and water, the suspension is stirred overnight, and the solids are air dried.

### Claim 6

A method of manufacturing a monohydrate form of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine comprising:
a. Mixing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H -pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine with a solvent to form a suspension;
b. Stirring the suspension;
c. Collecting the solids in the suspension by filtration; and
d. Drying the solids.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the solvent is a mixture of acetone and water.

### Claim 8 (depends on 6)

The method according to claim 6, wherein the suspension is stirred overnight.

### Claim 9 (depends on 6)

The method according to claim 6, wherein the solids are air dried.

### Claim 10 (depends on 6)

The method according to claim 6, wherein the solvent is a mixture of acetone and water, the suspension is stirred overnight, and the solids are air dried.

### Claim 11

A method of manufacturing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microcapsules by solvent extraction, comprising:
a. Dissolving the 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in an organic solvent to form a drug solution;
b. Adding a polymer to the drug solution to form a polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine solution;
c. Mixing the polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine solution into an aqueous solution to form an emulsion;
d. Adding deionized water to the emulsion;
e. Forming microspheres from the emulsion by solvent extraction; and
f. Sieving the resulting microspheres using a surfactant solution.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the organic solvent comprises (i) dichloromethane and methanol, (ii) dichloromethane, (iii) benzyl alcohol and methanol, (iv) dichloromethane and benzyl alcohol, (v) chloroform, (vi) chloroform and methanol, or (vii) chloroform and benzyl alcohol.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the organic solvent comprises dichloromethane and methanol.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the organic solvent comprises dichloromethane, benzyl alcohol and methanol.

### Claim 15 (depends on 12)

The method according to claim 12, wherein the organic solvent comprises dichloromethane and benzyl alcohol.

### Claim 16 (depends on 11)

The method according to claim 11, wherein the polymer comprises poly(D,L-lactide).

### Claim 17 (depends on 11)

The method according to claim 11, wherein the polymer comprises poly(D,L-lactide-co-glycolide).

### Claim 18 (depends on 11)

The method according to claim 11, wherein the polymer comprises poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

### Claim 19 (depends on 11)

The method according to claim 11, wherein the aqueous solution comprises polyvinyl alcohol in water.

### Claim 20 (depends on 11)

The method according to claim 11, wherein the surfactant solution comprises poloxamer 407 in water, polysorbate 80 in water, or polysorbate 20 in water.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the surfactant solution comprises poloxamer 407 in water.

### Claim 22

A method of manufacturing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microcapsules by solvent extraction, comprising:
a. Dispersing the 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in an organic solvent to form a drug suspension;
b. Adding a polymer to the drug suspension to form a polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine dispersion;
c. Mixing the polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine dispersion with an aqueous solution to form an emulsion;
d. Adding deionized water to the emulsion;
e. Forming microspheres from the emulsion by solvent extraction; and
f. Sieving the resulting microspheres using a surfactant solution.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the organic solvent comprises (i) ethyl acetate, (ii) dichloromethane, (iii) chloroform, (iv) ethyl acetate and dichloromethane, (v) ethyl acetate and chloroform, (vi) dichloromethane and chloroform or (vii) ethyl acetate, dichloromethane and chloroform.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the organic solvent comprises ethyl acetate.

### Claim 25 (depends on 23)

The method according to claim 23, wherein the organic solvent comprises dichloromethane.

### Claim 26 (depends on 23)

The method according to claim 23, wherein the organic solvent comprises dichloromethane and ethyl acetate.

### Claim 27 (depends on 22)

The method according to claim 22, wherein the polymer comprises poly(D,L-lactide).

### Claim 28 (depends on 22)

The method according to claim 22, wherein the polymer comprises poly(D,L-lactide-co-glycolide).

### Claim 29 (depends on 22)

The method according to claim 22, wherein the polymer comprises poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

### Claim 30 (depends on 22)

The method according to claim 22, wherein the aqueous solution comprises polyvinyl alcohol in water.

### Claim 31 (depends on 22)

The method according to claim 22, wherein the surfactant solution comprises poloxamer 407 in water, polysorbate 80 in water, or polysorbate 20 in water.

### Claim 32 (depends on 31)

The method according to claim 31, wherein the surfactant solution comprises poloxamer 407 in water.