Oral dosage formulations of protease-resistant polypeptides

• US 20080260820A1
• Filed: 04/19/2007
• Published: 10/23/2008
• Est. Priority Date: 04/19/2007
• Status: Abandoned Application

• Current Assignee: Hanall Pharmaceutical Company Limited
• Original Assignee: Hanall Pharmaceutical Company Limited
• Inventors: Drittanti, Lila, Vega, Manuel, Borrelly, Gilles, Chauchard, Caroline
• Application Number:
  US11/788,836
• Publication Number:
  US 20080260820A1
• Time in Patent Office: Days
• US Class Current: 424/463
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

Oral dosage formulations of the protease-resistant therapeutic polypeptides are provided. The dosage formulations for administration per dosage per day or per week are higher than the subcutaneous dosage. Included among the oral dosage formulations are tablets and capsules, including enteric-coated forms. Methods for treatment or prevention of diseases or conditions that are treatable or preventable by the administration of such oral dosage formulations of protease-resistant polypeptides are provided.

Claims

1. A dosage formulation, comprising an amount of a therapeutic polypeptide sufficient, upon oral administration to a subject, to reach therapeutically effective levels in the bloodstream in the subject, wherein:

the therapeutic protein is modified in its primary sequence of amino acids, whereby it is more protease resistant than in the absence of the modifications, and the protein can reach therapeutically effective levels in the bloodstream upon oral administration; and

the amount is about or is 10-100 times the subcutaneous dose for the same indication and for the same therapeutic polypeptide that is not modified to be protease resistant.

2. The dosage formulation of claim 1, wherein the therapeutic polypeptide contains one or two amino acid sequence substitutions that render it more protease resistant than in the absence of the modifications.

3. The dosage formulation of claim 1, wherein the amount is 10-50 times the subcutaneous dose for the same indication and for the same therapeutic polypeptide.

4. The dosage formulation of claim 1, wherein the amount is 15-40 times the subcutaneous dose for the same indication and for the same therapeutic polypeptide.

5. The dosage formulation of claim 1, wherein:

the dosage formulation comprises a plurality of dosage units; and

each dosage unit comprises a fractional amount of the total amount of the therapeutic polypeptide in the dosage formulation.

6. The dosage formulation of claim 5, wherein the dosage unit is a tablet or capsule.

7. The dosage formulation of claim 6, wherein the dosage unit is enterically coated.

8. The dosage formulation of claim 1, wherein:

the dosage formulation comprises one or more dosage units containing the therapeutic polypeptide; and

each dosage unit is a tablet or capsule.

9. The dosage formulation of claim 8, wherein the dosage unit is a tablet.

10. The dosage formulation of claim 9, wherein the dosage unit is enterically coated.

11. The dosage formulation of claim 1, wherein the therapeutic polypeptide is a cytokine or a blood coagulation factor.

12. The dosage formulation of claim 1, wherein the therapeutic polypeptide is selected from among interleukin-10, an interferon-β

, an interferon alpha, interferon gamma, granulocyte colony stimulating, leukemia inhibitory factor, a growth hormone, ciliary neurotrophic factor, leptin, insulin, oncostatin M, relaxin, interleukin-6, interleukin-12, erythropoietin, granulocyte-macrophage colony stimulating factor, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-13, Flt3 ligand, a monoclonal antibody or fragment thereof and stem cell factor.

13. The dosage formulation of claim 1, wherein the modifications to increase protease resistance are the only modifications in the sequence of amino acids compared to a wild-type polypeptide or polypeptide not modified to exhibit increased protease resistance.

14. The dosage formulation of claim 1, wherein the polypeptide includes further modifications that alter properties other than protease resistance in the sequence of amino acids compared to a wild-type polypeptide or polypeptide not modified to exhibit increased protease resistance.

15. The dosage formulation of claim 1, wherein the polypeptide includes modifications that add new glycosylation sites to the polypeptide, whereby the polypeptide is hyperglycosylated.

16. The dosage formulation of claim 1, wherein the protease-resistant polypeptide is selected from among protease-resistant variants of coagulation factors, cytokines, growth factors, hormones, hydrolases, immunoglobulins, inhibitor polypeptides, nuclear polypeptides and proteases.

17. The dosage formulation of claim 16, wherein the unmodified polypeptide is selected from among interleukin-10 (IL-10;

SEQ ID NO;

     809), interferon beta (IFN-β

;

SEQ ID NO;

     147), interferon alpha-2a (IFNα

-2a;

SEQ ID NO;

     2162), interferon alpha-2b (IFNα

-2b;

SEQ ID NO;

     2067), interferon gamma (IFN-γ

;

SEQ ID NO;

     661), granulocyte colony stimulating factor (G-CSF;

SEQ ID NO;

     85), leukemia inhibitory factor (LIF;

SEQ ID NO;

     1148), growth hormone (GH;

SEQ ID NO;

     1260), ciliary neurotrophic factor (CNTF;

SEQ ID NO;

     1), leptin (SEQ ID NO;

     1126), oncostatin M (SEQ ID NO;

     1181), interleukin-6 (IL-6;

SEQ ID NO;

     1080), interleukin-12 (IL-12;

SEQ ID NO;

     860);

erythropoietin (EPO;

SEQ ID NO;

     1886), granulocyte-macrophage colony stimulating factor (GM-CSF;

SEQ ID NO;

     47), interleukin-2 (IL-2;

SEQ ID NO;

     946), interleukin-3 (IL-3;

SEQ ID NO;

     995), interleukin-4 (IL-4;

SEQ ID NO;

     1018), interleukin-5 (IL-5;

SEQ ID NO;

     1044), interleukin-13 (IL-13;

SEQ ID NO;

     917), Flt3 ligand (SEQ ID NO;

     118) and stem cell factor (SCE;

SEQ ID NO;

     1215).

18. The dosage formulation of claim 17, wherein the polypeptide is selected from modified therapeutic polypeptides who sequences are set forth in any of SEQ ID NOS:

2-46, 48-84, 86-117, 119-146, 148-660, 662-808, 810-859, 861-916, 918-945, 947-994, 996-1017, 1019-1043, 1045-1079, 1081-1125, 1127-1147, 1149-1180, 1182-1214, 1216-1259, 1261-1885, 1887-1981, 1983-2066, and 2176-2182.

19. The dosage formulation of claim 1, wherein the modified polypeptide is IFN-α

2b or human growth hormone.

20. The dosage formulation of claim 19, wherein the polypeptide is IFN-α

2b containing a modification that is or corresponds to E41Q of SEQ ID NO;

2067.

21. The dosage formulation of claim 19, wherein the modified therapeutic polypeptide is a human growth hormone containing a modification that is or corresponds to Y421 of SEQ ID NO:

1260.

22. The dosage formulation of claim 20, wherein the sequence of amino acids of the IFN-α

2b is set forth in SEQ ID NO;

1995.

23. The dosage formulation of claim 21, wherein the sequence of the growth hormone is set forth in SEQ ID NO:

1318.

56. A method of treatment of a disease or condition, comprising administering a dosage formulation of claim 1.

24. A tablet or capsule, comprising 10-100 μ

g of an interferon-α

(IFN-α

), wherein the IFN-α

is protease resistant by virtue of modifications in its primary sequence of amino acids.

25. The tablet or capsule of claim 24, wherein the IFN-α

is IFN-α

2a or IFN-α

2b.

26. The tablet or capsule of claim 24, comprising a second therapeutic agent for the same indication as the interferon.

27. The tablet or capsule of claim 26, wherein the second therapeutic agent is selected from among a nucleoside analog, an L-nucleoside, a type II interferon receptor antagonist, a tumor necrosis factor (TNF) antagonist, thymosin-α

, a SAPK inhibitor, amantidine, an NS3 inhibitor, an NS5B inhibitor, and an alpha-glucosidase inhibitor.

28. The tablet or capsule of claim 27, wherein the nucleoside analog is ribavirin.

29. A tablet or capsule of claim 24, comprising 10-50 μ

g of an interferon-α

protease-resistant polypeptide.

30. The tablet or capsule of claim 24, wherein the IFN-α

further comprises additional modifications, whereby it is hyperglycosylated.

31. The tablet or capsule of claim 24 that is enterically coated.

32. The tablet or capsule of claim 25, wherein the IFN-α

2b contains a modification that is or corresponds to E41Q of SEQ ID NO;

2067.

33. The tablet or capsule of claim 25, wherein the IFN-α

2b comprises the sequence of amino acids set forth in SEQ ID NO;

1995.

42. A dosage formulation, comprising a plurality of tablets or capsules of claim 24.

57. A method of treatment of a disease or condition, comprising administering the tablet or capsule of claim 24.

34. A tablet or capsule, comprising 1-50 mg, 10-50 mg, 10-40 mg, 15-35 mg, 1-40 mg, 1-45 mg, 5-30 mg, 10-20 mg or 3-30mg of human growth hormone, wherein the human growth hormone is protease resistant.

35. The tablet or capsule of claim 34, comprising a second therapeutic agent for the same indication as the growth hormone.

36. The tablet or capsule of claim 35, wherein the second therapeutic agent is selected from among a gonadotropin releasing hormone (GNRH) analog, insulin-like growth factor 1, (rhIGF-1), a growth hormone-releasing peptide (GRP), a free fatty acid regulation agent, leutenizing hormone releasing hormone, and an anabolic steroid.

37. The tablet or capsule of claim 34, wherein the tablet or capsule contains 3 mg, 12 mg, 24 mg or 30 mg of the protease-resistant growth hormone polypeptide.

38. The tablet or capsule of claim 34 that is enterically coated.

39. The tablet or capsule of claim 34, wherein the human growth hormone further comprises additional modifications, whereby it is hyperglycoslated.

40. The tablet or capsule of claim 34, wherein the human growth hormone contains a modification that is or corresponds to Y42I of SEQ ID NO:

1260.

41. The tablet or capsule of claim 34, wherein the human growth hormone comprises the sequence of amino acids set forth in SEQ ID NO:

1318.

43. A dosage formulation, comprising a plurality of tablets or capsules of claim 34.

58. A method of treatment of a disease or condition, comprising administering the tablet or capsule of claim 34.

44. A method of treatment of a disease or condition, comprising administering an oral dosage formulation of a modified therapeutic polypeptide, wherein:

the therapeutic polypeptide is modified in its primary sequence of amino acids, whereby it is more protease resistant than in the absence of the modifications, and the polypeptide can reach therapeutically effective levels in the bloodstream upon oral administration; and

the amount of therapeutic polypeptide in the formulation is 15-40 times the subcutaneous dose for the same indication and for the same therapeutic polypeptide that is not modified to be protease resistant.

45. The method of claim 44, wherein the therapeutic polypeptide is an IFN-α

polypeptide.

46. The method of claim 44, wherein the disease or condition is selected from among a viral infection, a fibrotic disorder, condylomata acuminate and cancer.

47. The method of claim 46, wherein the viral infection is a hepatitis C infection or a hepatitis B infection.

48. The method of claim 46, wherein the cancer is selected from among hairy cell leukemia, malignant lymphoma, follicular lymphoma and AIDS-related Karposi sarcoma.

49. The method of claim 46, wherein the fibrotic disorder is selected from among idiopathic pulmonary fibrosis, liver fibrosis and renal fibrosis.

50. The method of claim 44, wherein the therapeutic polypeptide is a growth hormone polypeptide.

51. The method of claim 44, wherein the disease or condition is selected from among a growth deficiency disorder, AIDS wasting, aging, impaired immune function of HIV-infected subjects, a catabolic illness, surgical recovery, a congestive cardiomyopathy, liver transplantation, liver regeneration after hepatectomy, chronic renal failure, renal osteodystrophy, osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia, a chronic inflammatory disorder, Crohn'"'"'s disease, short bowel syndrome, juvenile chronic arthritis, cystic fibrosis, male infertility, X-Iinked hypophosphatemic rickets, Down'"'"'s syndrome, Spina bifida, Noonan Syndrome, obesity, impaired muscle strength and fibromyalgia.

52. The method of claim 51, wherein the growth deficiency disorder is selected from among Turner'"'"'s syndrome, intrauterine growth retardation, idiopathic short stature, Prader Willi syndrome, and thalassaenua.

53. The method of claim 44, wherein the dosage formulation contains a plurality of dosage units and all are administered in a single day.

54. The method of claim 44, wherein a dosage formulation is administered one, two, three, four, five, six or seven times a week.

55. The method of claim 44, wherein a dosage formulation is administered one, two or three times a day.