Pharmaceutical compositions for antibodies, and their preparation and use

Abstract

A stable pharmaceutical formulation comprising an antibody containing a canine CH2, CH3, IgG Fc region variant or a polypeptide having the canine FcRn binding region thereof, a buffer with a pH of 4.5 to 7.0, an isotonic agent and / or stabilizer, a chelating agent, and a surfactant, wherein the formulation maintains stability in solution for up to 24 months and is suitable for oral, rectal, transmucosal, intestinal, or parenteral administration.

Claims

1. It is a stable pharmaceutical formulation, (a) an antibody containing a CDR, CH2, CH3, IgG Fc region variant of a canine or feline variable antibody domain, or a polypeptide having the canine or feline FcRn binding region thereof, in a dose of 5 to 100 mg / ml, (b) A buffer solution with a pH of 4.5 to 7.0 at a concentration of 4.0 to 50 mM, (c) Isotonic agent and / or stabilizer 0.01 to 35% (w / v), (d) containing 0.01 to 10% (w / v) of a surfactant, Here, the formulation is either a single-dose formulation or a multi-dose formulation. Herein, the formulation is a stable pharmaceutical formulation that maintains stability in solution for up to 24 months.

2. The pharmaceutical preparation according to claim 1, further comprising 0.01 to 5.0 mM of a chelating agent.

3. The pharmaceutical formulation according to claim 1, wherein the multi-dose formulation further comprises an antimicrobial preservative selected from the group consisting of benzyl alcohol, phenol, m-cresol, benzalkonium chloride, benzaltonium chloride, phenoxyethanol, and methylparaben or mixtures thereof, in a concentration of about 0.1 to 1.5% (w.v).

4. The pharmaceutical formulation according to claim 1, wherein the buffering agent is selected from the group consisting of sodium acetate, histidine, histidine hydrochloride (HCl), succinate, phosphate, tris, diethanolamine, citrate, acetate, other organic acids, and mixtures thereof.

5. The pharmaceutical formulation according to claim 1, wherein the buffer is present at a concentration of 5 to 30 mM and maintains a physiologically appropriate pH in the range of pH 5 to pH 6.

5.

6. The isotonic agent and / or the stabilizing agent is CaCl ２ , NaCl, MgCl ２ A pharmaceutical formulation according to claim 1, selected from the group consisting of lactose, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and mixtures thereof.

7. The pharmaceutical formulation according to claim 6, wherein the isotonic agent and / or the stabilizer is preferably sucrose, trehalose, or sorbitol.

8. The pharmaceutical formulation according to claim 1, wherein the isotonic agent and / or the stabilizer is present in a concentration of 0.02% to 10% (w.v).

9. The chelating agents include aminopolycarboxylic acid, hydroxyaminocarboxylic acid, N-substituted glycine, 2-(2-amino-2-oxoethyl)aminoethanesulfonic acid (BES), deferoxamine (DEF), citric acid, niacinamide, deoxycholate, diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), N-2-acetamido-2-iminodiacetic acid (ADA), bis(aminoethyl) glycol ether, N,N,N',N'-tetraacetic acid (EGTA), trans-diaminocyclohexanetetraacetic acid (DCTA), glutamic acid, and aspartic acid, N-hydroxyethyliminodiacetic acid (HIMDA), N,N-bis-hydroxy A pharmaceutical formulation according to claim 1, selected from the group consisting of ethylglycine (bicine) and N-(trishydroxymethylmethyl)10-glycine (tricine), glycylglycine, sodium deoxycholate, ethylenediamine, propylenediamine, diethylenetriamine, triethylenetetraamine (triene), ethylenediaminetetraacetic acid (EDTA), disodium EDTA, calcium EDTA, oxalic acid, malic acid, citric acid, citric acid monohydrate, and trisodium citrate dihydrate, 8-hydroxyquinolate, amino acids, histidine, cysteine, methionine, peptides, polypeptides, and proteins, and mixtures thereof.

10. The pharmaceutical formulation according to claim 9, wherein the chelating agent is preferably EDTA, disodium EDTA, or calcium EDTA.

11. The pharmaceutical formulation according to claim 9, wherein the chelating agent is present at a concentration of 0.01 to 5 mM.

12. The aforementioned surfactants include polysorbates, poloxamers, tritons, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glycoside, lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, stearyl sulfobetaine, lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, stearyl sarcosine, linoleyl betaine, myristyl betaine, cetyl betaine, lauroamidopropyl betaine, cocamidopropyl betaine, and linoleamide. A pharmaceutical formulation according to claim 1, selected from the group consisting of propyl betaine, myristamidopropyl betaine, palmidopropyl betaine, isostearamidopropyl betaine, myristamidopropyl dimethylamine, palmidopropyl dimethylamine, isostearamidopropyl dimethylamine, sodium cocoyl methyl taurate, disodium oleyl methyl taurate, dihydroxypropyl PEG-5 linoleammonium chloride, polyethylene glycol, polypropylene glycol, and mixtures thereof.

13. The pharmaceutical formulation according to claim 12, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, and mixtures thereof.

14. The pharmaceutical formulation according to claim 1, wherein the surfactant is present in a concentration of 0.002 to 0.5% (w / v).

15. The pharmaceutical formulation according to claim 1, further comprising antioxidants selected from the group consisting of GLA (gamma-linolenic acid)-lipoic acid, DHA (docosahexaenoic acid)-lipoic acid, GLA-tocopherol, di-GLA-3,3'-thiodipropionic acid, DGLA (dihomo-gamma-linolenic acid), AA (arachidonic acid), SA (salicylic acid), EPA (eicosapentaenoic acid), or DHA (docosahexaenoic acid), wherein these antioxidants include phenolic antioxidants, polyenes, unsaturated sterols, ascorbic acid, organic sulfur compounds, terpenes, and amino acid antioxidants.

16. The pharmaceutical formulation according to claim 15, wherein the amino acid-based antioxidant is selected from the group consisting of methionine, cysteine, carnosine, and their analogues.

17. The pharmaceutical formulation according to claim 15, wherein the antioxidant is present at a concentration of 0.01 mM to about 50 mM.

18. The pharmaceutical formulation according to claim 1, further comprising a preservative present at a concentration of 0.001% w / v to 10% w / v, wherein the preservative is selected from the group consisting of phenols, m-cresol, benzyl alcohol, benzalkonium chloride, benzaltonium chloride, phenoxyethanol, and methylparaben.

19. The pharmaceutical formulation according to claim 1, wherein the formulation is suitable for oral, rectal, transmucosal, intestinal, or parenteral administration.

20. The pharmaceutical formulation according to claim 19, wherein the parenteral administration is selected from intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intraosseous, intradermal, or subcutaneous administration.

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