Formulation suitable for stabilizing proteins, which is free of mammalian excipients

• US 9,173,944 B2
• Filed: 10/11/2011
• Issued: 11/03/2015
• Est. Priority Date: 10/12/2010
• Status: Active Grant

• Current Assignee: Merz Pharma GmbH & Company Kgaa
• Original Assignee: Merz Pharma GmbH & Company Kgaa
• Inventors: Taylor, Harold Victor, Mander, Gerd J., Burger, Markus
• Primary Examiner(s): Swartz, Rodney P
• Application Number:
  US13/878,629
• Publication Number:
  US 20130224248A1
• Time in Patent Office: 1,484 Days
• Field of Search: 424/400
• US Class Current: 1/1
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/08 Clostridium, e.g. Clostridium tetani
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A formulation free of protein which stabilizes pharmaceutical active proteins, peptides, or mixtures thereof in large scale production processes comprising a mixture of a hydrophilic polymer and a non-ionic detergent, and a mixture of a polyalcohol and a sugar. In some embodiments the polyalcohol is absent.

Claims

1. A formulation free of proteins comprising,

(a) a hydrophilic polymer;

(b) a sugar;

(c) a non-ionic detergent; and

(d) a polyalcohol,

wherein the weight ratio of polyalcohol to sugar is from 2;

1 to 5;

1 (wt-%), wherein the weight ratio between the hydrophilic polymer and the non-ionic detergent is from 18;

1 to 22;

1 (wt-%), and wherein the non-ionic detergent is present in said formulation in an amount between 0.2 and 0.01 mg/g.

3. The formulation of claim 1, wherein the hydrophilic polymer is selected from the group consisting of hyaluronic acid, polyvinylpyrollidone (PVP), copolymers of N-vinylpyrollidone, a cellulose derivative, Polyethyleneglycol (PEG), PEG/PPG block copolymers, homo- and copolymers of acrylic and methacrylic acid, polyurethanes, polyvinyl alcohol, polyvinylethers, maleic anhydride based copolymers, polyesters, vinylamines, polyethyleneimines, polyethyleneoxides, poly(carboxylic acids), polyamides, polyanhydrides, polyphosphazenes, and mixtures thereof.

4. The formulation of claim 1, wherein the polyalcohol is selected from the group consisting of mannitol, inositol, lactilol, isomalt, xylitol, erythritol, sorbitol, and mixtures thereof.

5. The formulation of claim 1, wherein the sugar is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and mixtures thereof.

6. The formulation of claim 1, which is in the form of a composition further comprising a pharmaceutically active peptide, a protein or a mixture thereof.

7. The composition of claim 6, which is lyophilized.

8. The composition of claim 6, wherein said pharmaceutically active protein is selected from the group consisting of toxins, chondroitin, elastin, actin, myosin, aprotinin, growth hormone, growth hormone releasing factor, parathyroid hormone, thyroid stimulating hormone, lipoproteins (LDL, IDL, VLDL, VHDL, HDL), apolipoproteins (ApoA-1, ApoA-II, ApoA-IV, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE), α

-1 Antitrypsin, insulin, proinsulin, follicle stimulating hormone, calcitonin, oxytocin, vasopressin, leuprolide acetate, somatostatin, luteinizing hormone, glucagons, clotting factors, anti-clotting factors, plasminogen activator, human macrophage inflammatory protein, vascular endothelin growth factor (VEGF), rheumatoid factors, Done derived neurotrophic factor (BDNF), nerve growth factor-β

(NGF-β

), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF-β

1, TGF-β

2, TGF-β

3, TGE-β

4, TGE-β

5), erythropoietin, interleukins (IL-1 to IL-10), bone morphogenic protein (BMP) parathyroid hormone, DNAse, cationic ferritin, interferon α

, interferon β

, interferon γ

, and mixtures thereof.

9. The composition of claim 6, wherein the pharmaceutically active protein is selected from the group consisting of Botulinum toxin, diphtheria toxin, tetanus toxin and mixtures thereof.

10. The composition of claim 9, which comprises botulinum toxin, hyaluronic acid, mannitol, sucrose, polysorbate 80 and, optionally, water for injection.

11. The composition of claim 6, which is comprised in a medicament, a cosmetic product, a cosmeceutical product or a diagnostic product.

12. An injectable solution comprising the composition of claim 11.

13. A kit comprising,

(a) one or more containers comprising the composition of claim 6;

and

(b) instructions for use of the composition.

14. A method for stabilizing pharmaceutically active proteins, peptides, or mixtures thereof, comprising admixing such pharmaceutically active protein, peptide, or a mixture thereof, with the formulation of claim 1.

15. The kit of claim 13, further comprising a container of a pharmaceutically acceptable sterile solvent selected from the group consisting of water for injection, isotonic salt solution, Ringer'"'"'s solution, pH-buffered solution, an aqueous solution of 5% glucose, and mixtures thereof.

2. A formulation free of proteins comprising,

(a) a hydrophilic polymer;

(b) a sugar; and

(c) a non-ionic detergent,

wherein the weight ratio between the hydrophilic polymer and the non-ionic detergent is from 2;

1 to 30;

1 (wt-%), and wherein the non-ionic detergent is present in the formulation in an amount between 0.2 and 0.01 mg/g, and wherein no polyalcohol is present.