Polymers for delivery of factor viii and/or factor ix

Patent metadata

Field	Value
Publication number	US-2016136291-A1
Application number	US-201514944173-A
Country	US
Kind code	A1
Filing date	Nov 17, 2015
Priority date	Nov 18, 2014
Publication date	May 19, 2016
Grant date	—

Abstract

In some aspects, a composition comprising a pH-sensitive crosslinked copolymer of methacrylic acid and poly(ethylene glycol) monomethyl ether methacrylate and a therapeutic protein is provided. In some embodiments, the therapeutic protein is a high molecular weight protein such as factor VIII or factor IX. In some embodiments, the composition is orally administered to a patient to treat a disease or disorder such as, e.g., hemophilia.

First claim

1 . A composition comprising:
(A) a therapeutic protein; wherein the therapeutic protein is factor IX or factor VIII; and
(B1) a copolymer comprising methacrylic acid and poly(ethylene glycol) monomethyl ether monomethacrylate crosslinked with tetra(ethylene glycol) dimethacrylate (TEGDMA) or poly(ethylene glycol) dimethacrylate (PEGDMA) wherein the poly(ethylene glycol) component has an average molecular weight of about 100-1,000; or
(B2) a copolymer comprising methacrylic acid and poly(ethylene glycol) monomethyl ether monomethacrylate crosslinked with a poly(ethylene glycol) dimethacrylate (PEGDMA) wherein the poly(ethylene glycol) component has an average molecular weight of about 100-1,000.

2 . The composition of claim 1 , wherein the therapeutic protein is factor IX; and the copolymer comprises methacrylic acid and poly(ethylene glycol) monomethyl ether monomethacrylate crosslinked with tetra(ethylene glycol) dimethacrylate (TEGDMA) or poly(ethylene glycol) dimethacrylate (PEGDMA).

3 . The composition of claim 1 , wherein the therapeutic protein is factor VIII; and the copolymer comprises methacrylic acid and poly(ethylene glycol) monomethyl ether monomethacrylate crosslinked with tetra(ethylene glycol) dimethacrylate (TEGDMA) or poly(ethylene glycol) dimethacrylate (PEGDMA).

4 . The composition of claim 1 , wherein the composition is comprised in a pharmaceutical preparation formulated for oral administration.

5 . The composition of claim 1 , wherein the copolymer comprises poly(ethylene glycol) monomethyl ether monomethacrylate, wherein the poly(ethylene glycol) component has an average molecular weight of about 200 to about 2,000.

6 . The composition of claim 5 , wherein the average molecular weight is from about 400 to about 1,600.

7 . The composition of claim 6 , wherein the average molecular weight is from about 800 to about 1,200.

8 . (canceled)

9 . The composition of claim 1 , wherein the ratio of the molar percentage of methacrylic acid (MAA) to poly(ethylene glycol) monomethyl ether monomethacrylate is from about 1:1 to about 60:1.

10 . The composition of claim 9 , wherein the ratio of the molar percentage of methacrylic acid to poly(ethylene glycol) monomethyl ether monomethacrylate is from about 20:1 to about 40:1.

11 . The composition of claim 1 , wherein the copolymer comprises from about 0.1% to about 5% of crosslinking.

12 . (canceled)

13 . The composition of claim 11 , wherein the copolymer comprises from about 0.5% to about 1.5% of crosslinking.

14 . The composition of claim 1 , wherein the copolymer is crosslinked with tetra(ethylene glycol) dimethacrylate.

15 . The composition of claim 1 , wherein the copolymer is crosslinked with poly(ethylene glycol) dimethacrylate, wherein the poly(ethylene glycol) component has an average molecular weight of about 100 to about 1,000.

16 . The composition of claim 15 , wherein the average molecular weight is from about 200 to about 600.

17 . (canceled)

18 . The composition of claim 1 , wherein the copolymer comprises from about 90 mol % to about 99 mol % methacrylic acid.

19 . (canceled)

20 . The composition of claim 18 , wherein the copolymer comprises from about 96.5 mol % to about 97.5 mol % methacrylic acid.

21 . The composition of claim 1 , wherein the copolymer comprises from about 1 mol % to about 10 mol % poly(ethylene glycol) monomethyl ether monomethacrylate.

22 . (canceled)

23 . The composition of claim 21 , wherein the copolymer comprises from about 2.5 mol % to about 3.5 mol % poly(ethylene glycol) monomethyl ether monomethacrylate.

24 . The composition of claim 1 , wherein the therapeutic protein is factor IX.

25 . The composition of claim 1 , wherein the therapeutic protein is factor VIII.

26 . The composition of claim 1 , wherein the composition comprises greater than about 20 μg of therapeutic protein per mg of copolymer.

27 . The composition of claim 26 , wherein the composition comprises greater than about 30 μg of therapeutic protein per mg of copolymer.

28 . The composition of claim 1 , wherein the copolymer has a particle size less than 100 μm.

29 - 30 . (canceled)

31 . The composition of claim 30 , wherein the particle size is less than 50 μm.

32 . The composition of claim 1 , wherein the copolymer begins swelling at a pH greater than about 5.

33 . (canceled)

34 . The composition of claim 1 , wherein the composition releases greater than about 0.1 μg of therapeutic protein per mg of copolymer at pH 7.4.

35 . The composition of claim 34 , wherein the composition releases greater than about 0.25 μg of therapeutic protein per mg of copolymer at pH 7.4.

36 . The composition of claim 1 , wherein the therapeutic protein is factor VIII or IX and further comprises a targeting compound selected from an antibody, lectin, protein, or small molecule.

37 . The composition of claim 36 , wherein the targeting compound promotes bioadhesion.

38 . The composition of claim 36 , wherein the targeting compound is a lectin.

39 . The composition of claim 38 , wherein the lectin is wheat germ agglutinin.

40 - 41 . (canceled)

42 . A method of treating hemophilia in a patient comprising orally administering a pharmacologically effective amount of the composition of claim 1 to a patient in need of such treatment.

43 - 45 . (canceled)

46 . A method of preparing the composition of claim 1 , comprising:
(i) polymerizing methacrylic acid and poly(ethylene glycol) monomethyl ether monomethacrylate in the presence of a crosslinking agent to produce the copolymer; and (ii) loading the copolymer with a therapeutic protein comprising incubating the copolymer with the therapeutic protein and wherein the therapeutic protein is factor VIII or factor IX.

47 - 67 . (canceled)

Assignees

• Univ Texas

Inventors

• Peppas Nicholas A
• Horava Sarena D

Classifications

• A61K38/4846

  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) · CPC title

• C12Y304/21022

  Coagulation factor IXa (3.4.21.22) · CPC title

• A61K47/6903

  the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K47/58 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title