# US 11,028,382 B2 · Lyophilized formulations for factor Xa antidote

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

- Number: US 11,028,382 B2
- Document ID: US11028382B2
- Status: Granted
- Kind: B2
- Application number: 16/895,448
- Filed: 2020-06-08
- Published: 2020-09-24
- Granted: 2021-06-08
- Earliest claimed: 2014-08-20
- Assignees: Alexion Pharmaceuticals, Inc.
- Applicants: Portola Pharmaceuticals, Inc.
- Inventors: Juan Wang; Gregory A. Sacha; Phuong M. Nguyen
- Web page: https://patentgrep.com/patent/US11028382B2

## CPC

- C12N 9/6432: {Coagulation factor Xa (3.4.21.6)}
- 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 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 38/4846: {Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)}
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- 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
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C12Y 304/21006: Coagulation factor Xa (3.4.21.6)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12Y: ENZYMES

## Abstract

The present disclosure relates to solutions and methods of preparing lyophilized formulations of factor Xa (fXa) antidotes. A suitable aqueous formulation suitable for lyophilization can include a fXa antidote, a solubilizing agent, a stabilizer, and a crystalline component, wherein the formulation does not collapse during lyophilization.

## Claims

### Claim 1

A method for preparing a lyophilized formulation, comprising lyophilizing an aqueous solution comprising about 45 mM arginine, from 1% to 3% sucrose (w/v), from 2% to 8% mannitol (w/v), from about 0.01% to about 0.02% (w/v) polysorbate 80 and at least 5 mg/mL of a two-chain polypeptide comprising a first chain comprising the amino acid sequence of SEQ ID NO. 4, a second chain comprising the amino acid sequence of SEQ ID NO. 5, and a disulfide bond between a first Cysteine residue at position 98 (Cys98) of SEQ ID NO. 4 and a second Cysteine residue at position 108 (Cys108) of SEQ ID NO. 5, wherein the aqueous solution has a pH from 7.7 to 7.9.

### Claim 2 (depends on 1)

The method of claim 1, wherein the aqueous solution comprises about 45 mM arginine, from 1.5% to 2.5% sucrose (w/v), from 4.5% to 5.5% mannitol (w/v), from about 0.01% to about 0.02% (w/v) polysorbate 80 and at least 10 mg/mL of the polypeptide.

### Claim 3 (depends on 2)

The method of claim 2, wherein the aqueous solution comprises at least 18 mg/mL of the polypeptide.

### Claim 4 (depends on 1)

The method of claim 1, wherein the polypeptide comprises at least an intra-chain disulfide bond for each of the first and second chains.

### Claim 5 (depends on 1)

The method of claim 1, wherein the aqueous solution comprises about 45 mM arginine, about 2% sucrose (w/v), about 5% mannitol (w/v), about 0.01% polysorbate 80 and about 10 mg/mL of the two-chain polypeptide, wherein the aqueous solution has a pH of about 7.8.

### Claim 6 (depends on 1)

The method of claim 1, wherein the aqueous solution comprises about 45 mM arginine, about 2% sucrose (w/v), about 5% mannitol (w/v), about 0.02% polysorbate 80 and about 20 mg/mL of the two-chain polypeptide, wherein the aqueous solution has a pH of about 7.8.

### Claim 7 (depends on 1)

The method of claim 1, wherein the lyophilized formulation comprises L-arginine HCl:sucrose:mannitol in a weight ratio of the range of (0.5-1.4):(1-3):(2-8).

### Claim 8 (depends on 1)

The method of claim 1, wherein the lyophilized formulation comprises L-arginine HCl:sucrose:mannitol in a weight ratio of the range of (0.9-1):(1.5-2.5):(4.5-5.5).

### Claim 9 (depends on 1)

The method of claim 1, wherein the lyophilized formulation comprises L-arginine HCl:sucrose:mannitol in a weight ratio of about 0.95:2:5.