# US 10,478,498 B2 · Excipient compounds for biopolymer formulations

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- Number: US 10,478,498 B2
- Document ID: US10478498B2
- Status: Granted
- Kind: B2
- Application number: 15/331,197
- Filed: 2016-10-21
- Published: 2017-08-17
- Granted: 2019-11-19
- Earliest claimed: 2014-06-20
- Assignees: Reform Biologics, LLC
- Applicants: ReForm Biologics, LLC
- Inventors: David S. Soane; Philip Wuthrich; Rosa Casado Portilla; Robert P. Mahoney; Mark Moody; Daniel G. Greene
- Web page: https://patentgrep.com/patent/US10478498B2

## CPC

- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 38/1816: {Erythropoietin [EPO]}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/32: against translation products of oncogenes
- C12N 9/2462: {Lysozyme (3.2.1.17)}
- C12N 9/96: Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
- C12Y 302/01017: Lysozyme (3.2.1.17)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The invention encompasses formulations and methods for the production thereof that permit the delivery of concentrated protein solutions. The inventive methods can yield a lower viscosity liquid protein formulation or a higher concentration of therapeutic or nontherapeutic proteins in the liquid formulation, as compared to traditional protein solutions. The inventive methods can also yield a higher stability of a liquid protein formulation.

## Claims

### Claim 1

An injectable, liquid pharmaceutical formulation comprising at least about 100 mg/ml therapeutic protein and a viscosity-reducing amount of caffeine, wherein the viscosity-reducing amount of caffeine is about 15 mg/ml or less, and wherein the formulation further comprises niacinamide, and
wherein the viscosity of the formulation is at least about 30% less than the viscosity of a control formulation, wherein the control formulation does not contain caffeine but is otherwise identical on a dry weight basis to the liquid pharmaceutical formulation.

### Claim 2 (depends on 1)

The formulation of claim 1, wherein the therapeutic protein is an antibody.

### Claim 3 (depends on 1)

The formulation of claim 1, wherein the therapeutic protein is selected from the group consisting of bevacizumab, trastuzumab, adalimumab, infliximab, etanercept, darbepoetin alfa, epoetin alfa, cetuximab, pegfilgrastim, filgrastim, and rituximab.

### Claim 4 (depends on 1)

The formulation of claim 1, wherein the viscosity of the formulation is at least about 50% less than the viscosity of the control formulation.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the viscosity is less than about 20 cP.

### Claim 6 (depends on 5)

The formulation of claim 5, wherein the viscosity is less than about 10 cP.

### Claim 7 (depends on 1)

The formulation of claim 1, wherein the formulation contains at least about 200 mg/mL of the therapeutic protein.

### Claim 8 (depends on 1)

The formulation of claim 1, wherein the viscosity-reducing amount of caffeine is about 15 mg/ml.

### Claim 9 (depends on 8)

The formulation of claim 8, wherein the amount of niacinamide is about 15 mg/ml.

### Claim 10 (depends on 7)

The formulation of claim 7, wherein the therapeutic protein is an antibody.