# US 10,117,848 B2 · Highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker and uses thereof

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- Number: US 10,117,848 B2
- Document ID: US10117848B2
- Status: Granted
- Kind: B2
- Application number: 15/566,122
- Filed: 2016-04-13
- Published: 2018-04-26
- Granted: 2018-11-06
- Earliest claimed: 2015-04-14
- Assignees: Milestone Pharmaceuticals Inc.
- Applicants: Milestone Pharmaceuticals Inc.
- Inventors: Martin P. Maguire
- Web page: https://patentgrep.com/patent/US10117848B2

## CPC

- A61K 31/277: having a ring, e.g. verapamil
- A61K 9/0043: {Nose}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- 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 9/06: Antiarrhythmics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/06: Antimigraine agents
- C07C 255/42: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention includes surprisingly water-soluble salts of a phenylalkylamine compound that are potent antagonists of L-type calcium channels. Aqueous solutions including salts of the instant invention are formulated for nasal administration and provide a novel therapeutic platform for the treatment of stable angina, migraine, and cardiac arrhythmia, such as paroxysmal supraventricular tachycardia.

## Claims

### Claim 1

An aqueous composition formulated for nasal administration comprising a pharmaceutically acceptable salt or free base of compound I:
or a racemate or enantiomer thereof, wherein compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL.

### Claim 2 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition comprises the S-enantiomer of compound I.

### Claim 3 (depends on 1)

The aqueous composition of claim 1, wherein the concentration is 350 mg/mL±25 mg/mL.

### Claim 4 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition comprises from 40% to 85% (w/v) water.

### Claim 5 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition has a pH of 4.5±1.5.

### Claim 6 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition comprises compound I, or the racemate or enantiomer thereof, and between 0.5 and 1.5 molar equivalents of acetic acid relative to the compound.

### Claim 7 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition comprises compound I, or the racemate or enantiomer thereof, and between 0.5 and 1.5 molar equivalents of methanesulfonic acid relative to the compound.

### Claim 8 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition further comprises a chelating agent.

### Claim 9 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition further comprises EDTA.

### Claim 10 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition further comprises a pharmaceutically acceptable excipient.

### Claim 11 (depends on 1)

The aqueous composition of claim 1, wherein the aqueous composition is a homogeneous composition at room temperature.

### Claim 12 (depends on 1)

A nasal delivery system comprising an aqueous composition of claim 1 in a unit dosage form comprising no more than four single pump spray dosages.

### Claim 13 (depends on 1)

A nasal delivery system comprising an aqueous composition of claim 1 in a unit dosage form comprising no more than two single pump spray dosages.

### Claim 14 (depends on 13)

The nasal delivery system of claim 13, wherein the unit dosage form is configured for administration of no more than 200 microliters of the composition to each nostril of a patient.

### Claim 15

A method of treating a disease selected from the group consisting of cardiac arrhythmia, stable angina, and migraine, said method comprising nasally administering to a patient in need thereof an aqueous composition comprising a pharmaceutically acceptable salt of compound I:
or a racemate or enantiomer thereof, wherein compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL.

### Claim 16 (depends on 15)

The method of claim 15, wherein said cardiac arrhythmia is PSVT, atrial fibrillation, or ventricular tachycardia.

### Claim 17 (depends on 15)

The method of claim 15, the method comprising administering between 150 microliters and 200 microliters of the aqueous composition to the patient.

### Claim 18 (depends on 1)

A method of making a solution formulated for nasal administration to a patient, the method comprising the steps of
a) adding a solution comprising a first dissolved acid to the free base of a compound of claim 1 to form a mixture;
b) adding to the mixture a solution comprising ethylenediaminetetracetic acid;
c) heating and mechanically stirring the resulting mixture until the compound has fully dispersed within the mixture;
d) adjusting the pH of the mixture to be between 3.5 and 5.5 by adding a solution comprising a second dissolved acid to the mixture; and
e) diluting the mixture such that the final concentration of the compound in solution is at least 300 mg per 1 milliliter.

### Claim 19 (depends on 18)

The method of claim 18, wherein the first dissolved acid is selected from the group consisting of acetic acid and methanesulfonic acid.

### Claim 20 (depends on 18)

The method of claim 18, wherein the second dissolved acid is selected from the group consisting of acetic acid, sulfuric acid, and methanesulfonic acid.

### Claim 21 (depends on 1)

The aqueous composition of claim 1, wherein the pharmaceutically acceptable salt is the acetate salt of the S-enantiomer of compound I.

### Claim 22

An aqueous composition formulated for nasal administration comprising the acetate salt of the S-enantiomer of compound I:
dissolved in the aqueous composition at a concentration of 350 mg/mL±25 mg/mL.

### Claim 23 (depends on 22)

The aqueous composition of claim 22, wherein the S-enantiomer of compound I is dissolved in the aqueous composition at a concentration of 350 mg/mL.

### Claim 24 (depends on 22)

The aqueous composition of claim 22, wherein the aqueous composition has a pH of 4.5±0.1.

### Claim 25 (depends on 22)

The aqueous composition of claim 22, wherein the aqueous composition further comprises between 0.5 and 1.5 molar equivalents of acetic acid relative to the compound.

### Claim 26 (depends on 22)

The aqueous composition of claim 22, wherein the aqueous composition further comprises sulfuric acid.

### Claim 27 (depends on 22)

The aqueous composition of claim 22, wherein the aqueous composition further comprises EDTA.

### Claim 28 (depends on 13)

The nasal delivery system of claim 13, wherein the aqueous composition comprises the S-enantiomer of compound I.

### Claim 29 (depends on 13)

The nasal delivery system of claim 13, wherein each of the two single pump spray doses comprises 35 mg of the S-enantiomer of compound I.

### Claim 30 (depends on 13)

The nasal delivery system of claim 13, wherein each of the two single pump spray doses comprises 100 microliters of the aqueous composition.

### Claim 31 (depends on 16)

The method of claim 16, wherein said cardiac arrhythmia is PSVT.

### Claim 32

A method of treating PSVT, said method comprising nasally administering to a patient in need thereof an aqueous composition comprising the acetate salt of the S-enantiomer of compound I:
wherein the compound is dissolved in the aqueous composition at a concentration of 350 mg/mL±25 mg/mL.

### Claim 33 (depends on 32)

The method of claim 32, wherein 70 mg of the acetate salt of the S-enantiomer of compound I is administered to the patient.

### Claim 34 (depends on 32)

The method of claim 32, wherein the S-enantiomer of compound I is dissolved in the aqueous composition at a concentration of 350 mg/mL.

### Claim 35 (depends on 18)

The method of claim 18, wherein the final concentration of the compound in solution is 350 mg/mL±25 mg/mL.

### Claim 36 (depends on 18)

The method of claim 18, wherein the first dissolved acid is acetic acid and the second dissolved acid is sulfuric acid.

### Claim 37 (depends on 18)

The method of claim 18, wherein, in step d), the pH is adjusted to be 4.5±0.1.

### Claim 38

A method of making a solution formulated for nasal administration to a patient, the method comprising the steps of
a) adding a solution comprising acidic acid to the free base of the S-enantiomer of compound I:
to form a mixture;
b) adding to the mixture a solution comprising ethylenediaminetetracetic acid;
c) heating and mechanically stirring the resulting mixture until the S-enantiomer of compound I has fully dispersed within the mixture;
d) adjusting the pH of the mixture to be 4.5±0.1 by adding a solution comprising sulfuric acid to the mixture; and
e) diluting the mixture such that the final concentration of the S-enantiomer of compound I in solution is 350 mg/mL±25 mg/mL.

### Claim 39 (depends on 38)

The method of claim 38, wherein the final concentration of the S-enantiomer of compound I in solution is 350 mg/mL.