Compounds and compositions for delivering active agents

• US 6,344,213 B1
• Filed: 03/18/1997
• Issued: 02/05/2002
• Est. Priority Date: 03/29/1996
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Sarrubi, Donald J., Leone-Bay, Andrea, Milstein, Sam J., Leipold, Harry
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/820,694
• Time in Patent Office: 1,785 Days
• Field of Search: 424/451, 424/464, 424/465, 424/489, 424/452, 424/455, 424/456
• US Class Current: 424/451
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• 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 9/0043 Nose
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 233/34 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
• CPC Class Codes: C07C 233/47 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/48 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/51 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/52 : with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 233/54 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• CPC Class Codes: C07C 233/55 : having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/63 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/69 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/81 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/83 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/84 : of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/87 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/24 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/34 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/38 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/52 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/56 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/60 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/64 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/66 : with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
• CPC Class Codes: C07C 235/74 : of a saturated carbon skeleton
• CPC Class Codes: C07C 235/82 : with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 237/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07C 237/20 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/36 : having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 243/38 : with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 259/06 : having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 271/28 : to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 271/54 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 311/12 : substituted in position 3 and unsubstituted in position 7
• CPC Class Codes: C07D 311/24 : with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 311/30 : not hydrogenated in the hetero ring, e.g. flavones

Abstract

Modified amino acid compounds useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Claims

1. A pharmacological composition comprising:

(A) at least one biologically-active agent selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytosin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine, an antimicrobial, an antifungal agent, and combinations thereof; and

(B) at least one carrier compound having the formula;

2. The composition according to claim 1, wherein said biologically-active agent comprises calcitonin.

3. The composition according to claim 1, wherein R⁷ is selected from the group consisting of C₄ to C₂₀ alkyl and C₄ to C₂₀ alkenyl.

4. The composition according to claim 1, wherein R⁷ is selected from the group consisting of C₅ to C₂₀ alkyl and C₅ to C₂₀ alkenyl.

5. The composition according to claim 1 wherein the carrier has the formula:

or salts thereof.

6. A dosage unit form comprising:

(A) a pharmacological composition according to claim 3; and

(B)

(a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

7. A dosage unit form according to claim 6, comprising a tablet, a capsule, or a liquid.

8. A dosage unit form according to claim 7, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol or any combination thereof.

9. A method for administering a biologically-active agent to a mammal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 3.

10. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 3.

11. The composition according to claim 3, wherein said biologically-active agent comprises human growth hormone.

12. The composition according to claim 3, wherein said biologically-active agent comprises heparin.

13. The composition according to claim 3, wherein said biologically-active agent comprises low molecular weight heparin.

14. The composition according to claim 3, wherein said biologically-active agent comprises parathyroid hormone.

15. The composition according to claim 3, wherein said biologically-active agent comprises insulin.

35. The composition according to claim 3, wherein said biologically-active agent comprises human growth hormone, an interferon, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, cromolyn sodium, desferrioxamine or a combination thereof.

46. A dosage unit form comprising:

(A) a pharmacological composition according to claim 1; and

(B)

(a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

47. A dosage unit form comprising:

(A) a pharmacological composition according to claim 4; and

(B)

(a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

48. A dosage unit form comprising:

(A) a pharmacological composition according to claim 5; and

(B)

(a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

49. A method for preparing a pharmacological composition, said method comprising mixing:

(A) at least one biologically-active agent;

(B) at least one carrier compound according to claim 3, and

(C) optionally a dosing vehicle.

50. A method for preparing a pharmacological composition, said method comprising mixing:

(A) at least one biologically-active agent;

(B) at least one carrier compound according to claim 4; and

(C) optionally a dosing vehicle.

51. A method for preparing a pharmacological composition, said method comprising mixing:

(A) at least one biologically-active agent;

(B) at least one carrier compound according to claim 5; and

(C) optionally a dosing vehicle.

52. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 1.

53. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 4.

54. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 5.

16. A pharmacological composition comprising:

(A) at least one biologically active agent;

(B) at least one carrier compound having the formula;

17. The composition according to claim 16, wherein R⁷ is selected from the group consisting of C₄ to C₂₀ alkyl and C₄ to C₂₀ alkenyl.

18. The composition according to claim 17, wherein R⁷ is selected from the group consisting of C₅ to C₂₀ alkyl and C₅ to C₂₀ alkenyl.

19. The composition according to claim 17, wherein the biologically active agent comprises human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytosin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine, an antimicrobial, an antifungal agent, or a combination thereof.

20. The composition according to claim 19, wherein said biologically-active agent comprises human growth hormone, an interferon, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, cromolyn sodium, desferrioxamine and combinations thereof.

21. The composition according to claim 20, wherein said biologically-active agent comprises calcitonin.

22. The composition according to claim 20, wherein said biologically-active agent comprises human growth hormone.

23. The composition according to claim 20, wherein said biologically-active agent comprises heparin.

24. The composition according to claim 20, wherein said biologically-active agent comprises low molecular weight heparin.

25. The composition according to claim 20, wherein said biologically-active agent comprises insulin.

26. A dosage unit form comprising:

(A) a pharmacological composition according to claim 17; and

(B)

(i) an excipient,

(ii) a diluent,

(iii) a disintegrant,

(iv) a lubricant,

(v) a plasticizer,

(vi) a colorant,

(vii) a dosing vehicle, or

(viii) any combination thereof.

27. A dosage unit form according to claim 26, comprising a tablet, a capsule, or a liquid.

28. A dosage unit form according to claim 26, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol or any combination thereof.

29. A method for administering a biologically-active agent to a mammal in need of said agent, said method comprising administering orally to said mammal a composition as defined in claim 17.

30. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said animal a composition as defined in claim 17.

31. The composition according to claim 16, wherein said carrier has the formula:

or a salt thereof, and said biologically active agent is heparin.

32. The composition according to claim 16, wherein said carrier has the formula:

or a salt thereof, and said biologically active agent is low molecular weight heparin.

33. The composition according to claim 16, wherein said carrier has the formula:

or a salt thereof, and said biologically active agent is heparin.

34. The composition according to claim 16, wherein said carrier has the formula:

or a salt thereof, and said biologically active agent is low molecular weight heparin.

36. A pharmacological composition comprising:

(A) parathyroid hormone; and

(B) at least one carrier compound having the formula;

37. The composition according to claim 36, wherein R⁷ is selected from the group consisting of C₄ to C₂₀ alkyl and C₄ to C₂₀ alkenyl.

38. The composition according to claim 36, wherein R⁷ is selected from the group consisting of C₅ to C₂₀ alkyl and C₅ to C₂₀ alkenyl.

39. The composition according to claim 36, wherein the carrier has the formula:

or salts thereof.

40. A dosage unit form comprising:

(A) a pharmacological composition according to claim 37; and

(B)

(i) an excipient,

(ii) a diluent,

(iii) a disintegrant,

(iv) a lubricant,

(v) a plasticizer,

(vi) a colorant,

(vii) a dosing vehicle, or

(viii) any combination thereof.

41. A dosage unit form according to claim 40, comprising a tablet, a capsule, or a liquid.

42. A dosage unit form according to claim 40, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol or any combination thereof.

43. A method for administering parathyroid hormone to a animal in need thereof, said method comprising administering orally to said animal a composition as defined in claim 37.

44. A pharmacological composition comprising:

(A) at least one biologically active agent selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytosin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine, an antimicrobial, an antifungal agent, and combinations thereof; and

(B) at least one carrier compound having the formula;

45. A pharmacological composition comprising:

(A) parathyroid hormone; and

(B) at least one carrier compound having the formula;