Cyanophenoxy carboxylic acid compounds and compositions for delivering active agents

1. A compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 and R 5 are independently H, —CN, —OH, or halogen;

R 2 , and R 4 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 4 or R 5 being —CN; and

R 3 is H, —OH, —OCH 3 or halogen; and

R 6 is C 2 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene).

2. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) at least one compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 3 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 3 , R 4 or R 5 being —CN; and

R 6 is C 1 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene),

with the proviso that when R 1 is —CN, R 4 is H or —CN, and R 2 , R 3 , and R 5 are H, then R 6 is not (CH 2 ) 1 ,

wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

3. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) at least one compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 3 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 3 , R 4 or R 5 being —CN; and

R 6 is C 1 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene),

with the proviso that when R 1 is —CN, R 4 H or —CN, and R 2 , R 3 , and R 5 are H, then R 6 is not (CH 2 ) 1 ,

wherein the biologically active agent is selected from the group consisting of: growth hormones, human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone-releasing hormones, interferons, α-interferon, β-interferon, γ-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin human calcitonin; erythropoietin (EPO), atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), fragments of PTH, antimicrobials, antibiotics, antibacterials, anti-fungal agents, daptomycin, vitamins; mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; and any combination thereof.

4. The composition of claim 3 , wherein the biologically active agent comprises hGH, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, antimicrobials, antibiotics, antibacterial agents, anti-fungal agents, daptomycin, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds, or combinations thereof.

5. The composition of claim 3 , wherein the biologically active agent comprises cromolyn sodium.

6. The composition of claim 3 , wherein the biologically active agent comprises heparin.

7. The composition of claim 3 , wherein the biologically active agent comprises insulin.

8. The composition of claim 3 , wherein the biologically active agent comprises human growth hormone.

9. A dosage unit form comprising:

(A) the composition of 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.

10. The dosage unit form of claim 9 , wherein the biologically active agent is selected from the group consisting of:

growth hormones, human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone-releasing hormones, interferons, α-interferon, β-interferon, γ-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin human calcitonin; erythropoietin (EPO), atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), fragments of PTH, antimicrobials, antibiotics, antibacterials, anti-fungal agents, daptomycin, vitamins; mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; and any combination thereof.

11. The dosage unit form of claim 10 , wherein the biologically active agent comprises hGH, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, antimicrobials, antibiotics, antibacterial agents, anti-fungal agents, daptomycin, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds, or combinations thereof.

12. The dosage unit form of claim 9 , wherein the dosage unit form is in the form of a tablet, a capsule, a particle, a powder, a sachet, or a liquid.

13. The dosage unit form of claim 9 , wherein the dosing vehicle is a liquid selected from the group consisting of water, 25% aqueous propylene glycol, phosphate buffer, 1,2-propane diol, ethanol, and any combination thereof.

14. A method for administering a biologically active agent to an animal in need of the agent, the method comprising administering orally to the animal a pharmaceutical composition comprising:

(A) the biologically active agent; and

(B) at least one compound selected from the group consisting of compounds:

and salts thereof,

wherein

R 1 , R 2 , R 3 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 3 , R 4 or R 5 being —CN; and

R 6 is C 1 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene),

with the proviso that when R 1 is —CN, R 4 is H or —CN, and R 2 , R 3 , and R 5 are H, then R 6 is not (CH 2 ) 1 .

15. A method for preparing a pharmaceutical composition comprising mixing:

(A) at least one biologically active agent, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid;

(B) at least one compound selected from compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 3 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 3 , R 4 or R 5 being —CN; and

R 6 is C 1 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene),

with the proviso that when R 1 is —CN, R 4 is H or —CN, and R 2 , R 3 , and R 5 are H, then R 6 is not (CH 2 ) 1 ; and

(C) optionally, a dosing vehicle.

16. A compound selected from the group consisting of

and salts thereof.

17. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) a delivery agent selected from the group consisting of

salts thereof, and mixtures thereof.

18. The composition of claim 17 , wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

19. A method for preparing a pharmaceutical composition comprising mixing:

(A) at least one biologically active agent, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid;

(B) a compound selected from

and salts thereof; and

(C) optionally, a dosing vehicle.

20. A compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 4 or R 5 being —CN; and

R 3 is H, —OH, —OCH 3 , or halogen; and

R 6 is C 2 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene).

21. The compound of claim 20 , wherein R 6 is C 2 –C 9 alkylene.

22. The compound of claim 21 , wherein R 6 is C 4 –C 7 alkylene.

23. The compound of claim 21 , wherein R 6 is C 7 alkylene.

24. A compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 4 and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 or R 5 being —CN; and

R 3 is H, —OH, —OCH 3 , or halogen; and

R 6 is C 2 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene).

25. The compound of claim 24 , wherein R 1 is —CN.

26. The compound of claim 25 , wherein R 6 is C 2 –C 9 alkylene.

27. The compound of claim 25 , wherein R 6 is C 4 –C 7 alkylene.

28. The compound of claim 24 , wherein R 6 is C 2 –C 9 alkylene.

29. The compound of claim 24 , wherein R 6 is C 4 –C 7 alkylene.

30. The compound of claim 1 , wherein R 6 is C 2 –C 9 alkylene.

31. The compound of claim 1 , wherein R 6 is C 4 –C 7 alkylene.

32. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) at least one compound selected from the group consisting of compounds having the formula:

and salts thereof,

wherein

R 1 , R 2 , R 4 , and R 5 are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 4 , or R 5 being —CN; and

R 3 is H, —OH, —OCH 3 , or halogen; and

R 6 is C 1 –C 12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene),

with the proviso that when R 1 is —CN, R 4 is H or —CN, and R 2 , R 3 , and R 5 are H, then R 6 is not (CH 2 ) 1 .

33. A dosage unit form comprising:

(A) the composition of claim 32 ; 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.

34. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is a solid pharmaceutical composition.

35. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is a solid pharmaceutical composition.

36. The pharmaceutical composition of claim 32 , wherein the pharmaceutical composition is a solid pharmaceutical composition.

37. The compound of claim 16 , wherein the compound is selected from the group consisting of:

and salts thereof.

38. The pharmaceutical composition of claim 2 , wherein the compound is selected from

and salts thereof.