# US 2019/0167797 A1 · Stabilized factor ix formulations containing trehalose

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- Number: US 2019/0167797 A1
- Document ID: US20190167797A1
- Status: Published application
- Kind: A1
- Application number: 16/028,736
- Filed: 2018-07-06
- Published: 2019-06-06
- Earliest claimed: 2007-12-21
- Applicants: Aptevo Biotherapeutics, Inc.
- Inventors: Samia Mankarious; Michael J. Griffith
- Web page: https://patentgrep.com/patent/US20190167797A1

## CPC

- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- 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 47/02: Inorganic compounds
- 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
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- C12Y 304/21022: Coagulation factor IXa (3.4.21.22)
- 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
- C12Y: ENZYMES

## Abstract

Methods of preparing lyophilized preparations of Factor IX which preserve more than 90% of the calcium binding property of Factor IX are disclosed. Factor IX formulated with trehalose shows a superior stability profile after 12 weeks storage at 25° C./60% relative humidity (RH) and 40° C./75% RH relative to Factor IX formulated without trehalose. The data suggest that the inclusion of trehalose in the formulation could allow for temperature excursions or even long-term room temperature storage of a Factor IX lyophilized product. The formulations tested contained 10 mM histidine pH 6.8, 3% mannitol, 66 mM sodium chloride, 0.0075% Polysorbate 80, with and without 1% trehalose. Upon storage at 40° C./75% RH or 25° C./60% RH over 12 weeks the trehalose-containing formulation was comparable to product stored at 2-8° C. while the formulation without trehalose was found to undergo significant aggregation and loss of activity. The two formulations demonstrated comparable stability over 26 weeks of real time storage at −20° C. and 2-8° C.

## Claims

### Claim 1

A lyophilized composition comprising Factor IX and trehalose, wherein the trehalose is present in an amount from 0.5 to 3% by volume.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The composition of claim 1 wherein trehalose is present in an amount from 1 to 2% by volume.

### Claim 4 (depends on 1)

The composition of claim 1, further comprising histidine.

### Claim 5 (depends on 1)

The composition of claim 1, further comprising mannitol.

### Claim 6 (depends on 1)

The composition of claim 1, further comprising sodium chloride.

### Claim 7 (depends on 1)

The composition of claim 1, further comprising polysorbate 80.

### Claim 8 (depends on 1)

The composition of claim 1, wherein, before lyophilization, the composition further comprising histidine at a concentration of 5 to 20 mM, mannitol at a concentration of 2 to 5% by volume, sodium chloride at a concentration of 50 to 80 mM, and polysorbate 80 at a concentration of 0.001 to 0.005% by volume.

### Claim 9

A method for preparing a composition of Factor IX, comprising: mixing a solution comprising Factor IX with trehalose to obtain a cryoprotective solution; and freeze drying the cryoprotective solution to obtain a composition of Factor IX, wherein the trehalose is present in an amount from 0.5 to 3% by volume.

### Claim 10

(canceled)

### Claim 11 (depends on 9)

The method of claim 9, wherein trehalose is present in an amount from 1 to 2% by volume.

### Claim 12 (depends on 9)

The method of claim 9, wherein the solution further comprises histidine.

### Claim 13 (depends on 9)

The method of claim 9, wherein the solution further comprises mannitol.

### Claim 14 (depends on 9)

The method of claim 9, wherein the solution further comprises sodium chloride.

### Claim 15 (depends on 9)

The method of claim 9, wherein the solution further comprises polysorbate 80.

### Claim 16 (depends on 9)

The method of claim 9, wherein the solution further comprises histidine at a concentration of 5 to 20 mM, mannitol at a concentration of 2 to 5%, sodium chloride at a concentration of 50 to 80 mM, and polysorbate 80 at a concentration of 0.001 to 0.005% by volume.

### Claim 17 (depends on 9)

The method of claim 9, wherein the freeze drying comprises one annealing step.

### Claim at position 18

-19. (canceled)