# US 2012/0083446 A1 · Novel albumin-free factor viii formulations

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- Number: US 2012/0083446 A1
- Document ID: US20120083446A1
- Status: Published application
- Kind: A1
- Application number: 13/250,789
- Filed: 2011-09-30
- Published: 2012-04-05
- Earliest claimed: 1999-02-22
- Assignees: University of Connecticut; Baxter International Inc.
- Inventors: Marc Besman; Erik Bjornson; Feroz Jameel; Ramesh Kashi; Michael Pikal; Serguei Tchessalov; John Carpenter
- Web page: https://patentgrep.com/patent/US20120083446A1

## CPC

- A61K 38/37: Factors VIII
- 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 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- 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
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- Y10S 530/829: Blood
- 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
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

An albumin-free Factor VIII formulation comprising, 4% to 10% of a bulking agent selected from the group consisting of mannitol, glycine and alanine; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent Alternatively, the formulation can comprise 2% to 6% hydroxyethyl starch; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent. In a further embodiment, the formulation can comprise: 300 mM to 500 mM NaCl; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; and a buffering agent.

## Claims

### Claim at position 1

1-34. (canceled)

### Claim 35

A Factor VIII composition formulated without adding albumin to said composition and comprising the following formulation excipients in addition to Factor VIII:
4% (w/v) to 10% (w/v) of a bulking agent, wherein said bulking agent is mannitol;
1% (w/v) to 4% (w/v) of a stabilizing agent selected from the group consisting of sucrose, trehalose, and raffinose;
1 mM to 5 mM calcium salt;
100 mM to 300 mM NaCl; and
a buffering agent for maintaining a pH of approximately between 6 and 8.

### Claim 36 (depends on 35)

The Factor VIII composition of claim 35, wherein said bulking agent is present in an amount of about 8% (w/v).

### Claim 37 (depends on 35)

The Factor VIII composition of claim 35, wherein said stabilizing agent is present in an amount of about 2% (w/v).

### Claim 38 (depends on 35)

The Factor VIII composition of claim 35, wherein said stabilizing agent is sucrose.

### Claim 39 (depends on 35)

The Factor VIII composition of claim 35, wherein said stabilizing agent is trehalose.

### Claim 40 (depends on 35)

The Factor VIII composition of claim 35, wherein said calcium salt is calcium chloride.

### Claim 41 (depends on 35)

The Factor VIII composition of claim 35, wherein said NaCl is present in an amount of from 150 mM to 250 mM.

### Claim 42 (depends on 35)

The Factor VIII composition of claim 35, wherein said NaCl is present in an amount of about 225 mM.

### Claim 43 (depends on 35)

The Factor VIII composition of claim 35, wherein said calcium salt is present in an amount of from 1 mM to 5 mM.

### Claim 44 (depends on 35)

The Factor VIII composition of claim 35, wherein said composition is in lyophilized form.

### Claim 45 (depends on 35)

The Factor VIII composition of claim 35, wherein said buffering agent comprises between about 10 mM and about 50 mM histidine,

### Claim 46 (depends on 45)

The Factor VIII composition of claim 45, wherein the histidine is present in an amount of about 25 mM.

### Claim 47 (depends on 35)

The Factor VIII composition of claim 35,wherein said buffering agent comprises a member selected from the group consisting of tris-(hydroxymethyl)-aminomethane, 1,3-bis-[tris-(hydroxy-methyl)methylamino]-propane, piperazine-N,N′-bis-(2-ethanesulfonic acid), 3-(N-morpholino)propanesulfonic acid, N-2-hydroxyethyl-piperazine-N′-2-ethanesulfonic acid, 2-(N-morpholino)ethane-sulfonic acid and N-2-acetamido-2-aminoethanesulfonic acid.

### Claim 48 (depends on 45)

The Factor VIII composition of claim 45, wherein said buffering agent further comprises a member selected from the group consisting of tris-(hydroxymethyl)aminomethane, 1,3-bis-[tris-(hydroxy-methyl)methylamino]-propane, piperazine-N,N′-bis-(2-ethanesulfonic acid), 3-(N-morpholino) propanesulfonic acid, N-2-hydroxyethyl-piperazine-N′-2-ethanesulfonic acid, 2-(N-morpholino)ethane-sulfonic acid and N-2-acetamido-2-aminoethanesulfonic acid.

### Claim 49 (depends on 48)

The Factor VIII composition of claim 48, wherein said buffering agent further comprises tris-(hydroxymethyl)-aminomethane.

### Claim 50 (depends on 49)

The Factor VIII composition of claim 49, wherein the tris-(hydroxymethyl)-aminomethane is present in an amount of about 20 mM.

### Claim 51 (depends on 35)

The Factor VIII composition of claim 35, further comprising a surfactant.

### Claim 52 (depends on 51)

The Factor VIII composition of claim 51, wherein the surfactant is present in an amount of about 0.03% (w/v).

### Claim 53 (depends on 51)

The Factor VIII composition of claim 51, wherein said surfactant is selected from the group consisting of polyoxyethylene (20) sorbitan fatty acid ester, polyoxyethylene (80) sorbitan fatty acid ester, polyoxyalkylene ether, and polyoxyethylene 35 lauryl ether.

### Claim 54 (depends on 53)

The Factor VIII composition of claim 53, where said surfactant is polyoxyethylene (80) sorbitan fatty acid ester and is present in an amount of between 0.02% (w/v) and 0.1% (w/v).

### Claim 55 (depends on 35)

The Factor VIII composition of claim 35, further comprising an antioxidant.

### Claim 56 (depends on 55)

The Factor VIII composition of claim 55, wherein said antioxidant is glutathione.

### Claim 57 (depends on 56)

The Factor VIII composition of claim 56, wherein said glutathione is present in an amount of between 0.05 mg/ml and 1.0 mg/ml.

### Claim 58 (depends on 35)

The Factor VIII composition of claim 35 in combination with a diluent.

### Claim 59 (depends on 35)

The Factor VIII composition of claim 35 in combination with 2 ml of diluent.

### Claim 60 (depends on 35)

The Factor VIII composition of claim 35 in combination with 5 ml of diluent.

### Claim 61

A Factor VIII composition formulated without adding albumin to said composition and comprising the following formulation excipients in addition to Factor VIII:
2% (w/v) to 6% (w/v) hydroxyethyl starch;
1% (w/v) to 4% (w/v) of a stabilizing agent selected, from the group consisting of sucrose, trehalose, and raffinose;
1 mM to 5 mM calcium salt;
100 mM to 300 mM NaCl; and
a buffering agent for maintaining a pH of approximately between 6 and 8.

### Claim 62 (depends on 61)

The Factor VIII composition of claim 61, wherein said hydroxyethyl starch is present in an amount of about 4%.

### Claim 63 (depends on 61)

The Factor VIII composition of claim 61, wherein said NaCl is present in an amount of about 200 mM.

### Claim 64 (depends on 61)

The Factor VIII composition of claim 61, wherein said stabilizing agent is present in an amount of about 2% (w/v).

### Claim 65 (depends on 61)

The Factor VIII composition of claim 61, wherein said buffering agent comprises between about 10 mM and about 50 mM histidine.

### Claim 66

An improved method of lyophilizing an aqueous pharmaceutical formulation comprising
a crystallizable bulking agent, a stabilizing agent, a calcium salt, and NaCl, wherein said method comprises the steps of:
(a) freezing the aqueous pharmaceutical formulation at a temperature of less than about 35° C.;
(b) annealing the pharmaceutical formulation at between about −30° C., and −19° C.;
(c) lowering the temperature of the pharmaceutical formulation to between −45° C. and −55° C.;
(d) annealing the pharmaceutical formulation at between about −30° C. and −39° C.; and
(e) freeze-drying the pharmaceutical formulation.

### Claim 67 (depends on 66)

The method of claim 66, wherein the temperature in step (c) is less than −50° C.

### Claim 68 (depends on 66)

The method of claim 66, wherein said pharmaceutical formulation further comprises Factor VIII.

### Claim 69 (depends on 66)

The method of claim 66, wherein said pharmaceutical formulation further comprises a buffering agent.

### Claim 70 (depends on 69)

The method of claim 69, wherein said buffering agent comprises histidine.

### Claim 71 (depends on 69)

The method of claim 69, wherein said buffering agent comprises tris-(hydroxymethyl)-aminomethane.

### Claim 72 (depends on 66)

The method of claim 66, wherein said bulking agent is mannitol.

### Claim 73 (depends on 66)

The method of claim 66, wherein said stabilizing agent is trehalose.

### Claim 74 (depends on 66)

The method of claim 66, wherein said calcium salt is calcium chloride.