Phenylalkylcarboxylic acid delivery agents

1. A composition comprising:

(A) at least one biologically active agent; and

(B) at least one delivery agent compound represented by formula I

or a pharmaceutically acceptable salt thereof, wherein

n is 1-12,

and R 1 -R 5 are independently hydrogen, C 1 -C 6 , alkyl, C 2 -C 4 alkenyl, halogen, C 1 -C 4 alkoxy, hydroxyl, C 6 -C 14 aryloxy, or C 1 -C 6 alkylhalo group,

with the proviso that at least one of R 1 -R 5 is methyl, C 1 -C 4 alkoxy, hydroxyl or halogen.

2. The composition of claim 1 , wherein the delivery agent is selected from 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3-methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-n-propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n-butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n-propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4-isobutoxyphenyl)propanoic acid, or pharmaceutically acceptable salts thereof.

3. The composition of claim 1 , wherein the delivery agent is conjugated to a polymer by a linkage group selected from the group consisting of —NHC(O)NH—, —C(O)NH—, —NHC(O)—; —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH 2 NH—NHCH 2 —, —CH 2 NHC(O)O—, —OC(O)NHCH 2 —, —CH 2 NHCOCH 2 O—, —OCH 2 C(O)NHCH 2 —, —NHC(O)CH 2 O—, —OCH 2 C(O)NH—, —NH—, —O—, and carbon-carbon bond.

4. The composition of claim 1 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, lipid, or combination thereof.

5. The composition of claim 1 , wherein the biologically active agent is selected from the group consisting of: argatroban, BIBN-4096BS, growth hormones, human growth hormones recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone releasing hormones, growth hormone releasing factor, glucagon, 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, eel 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, thrombopoeitin, filgrastim, postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), fragments of PTH, glucagon-like peptide 1 (GLP-1), antimicrobials, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; gallium or gallium salts; glucagons; zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, caspofungin acetate, CPHPC, siRNA and any combination thereof.

6. The composition of claim 1 , further comprising at least one enzyme inhibitor.

7. The composition of claim 1 , wherein the weight ratio of delivery agent to active agent ranges from about 800:1 to about 10:1.

8. A method of preparing pharmaceutical composition, comprising mixing at least one delivery agent compound of claim 1 , and a biologically active agent.

9. A dosage unit form comprising:

(A) a delivery agent according to claim 1 ; and

(B) a biologically active agent; and

(C) (a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) an enzyme inhibitor

(h) a dosing vehicle, or

(i) any combination thereof.

10. The dosage unit form of claim 9 , wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

11. The dosage unit form of claim 10 , wherein the biologically active agent is selected from the group consisting of: argatroban, BIBN-4096BS, growth hormones, human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone releasing hormones, growth hormone releasing factor, interferons, glucagon, α-interferon, β-interferon, γ-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor, insulin-like growth factor-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin; erythropoietin, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoeitin, filgrastim, postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine, parathyroid hormone, fragments of PTH, glucagon-like peptide 1 (GLP-1), antimicrobials, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol-modified derivatives of these compounds; gallium or gallium salts; glucagons, zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, capsofungin acetate, CPHPC, SiRNA and any combination thereof.

12. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering orally to the animal the composition of claim 1 .

13. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering orally to the animal the dosage unit form of claim 9 .

14. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering to the animal the composition of claim 1 intranasally, sublingually, intraduodenally, subcutaneously, buccally, intracolonicly, rectally, vaginally, mucosally, pulmonary, transdermally, intradermally, parenterally, intravenously, intramuscularly, via the ocular system, or by traversing the blood-brain barrier.

15. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering to the animal the dosage unit of claim 9 intranasally, sublingually, intraduodenally, subcutaneously, buccally, intracolonicly, rectally, vaginally, mucosally, pulmonary, transdermally, intradermally, parenterally, intravenously, intramuscularly, via the ocular system, or by traversing the blood-brain barrier.

16. A method for administering a biologically active agent comprising administering a delivery agent compound of claim 1 , followed by administration of a biologically active agent.

17. The method of claim 16 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

18. A method for increasing the bioavailability of a biologically active agent comprising administering to an animal a composition of claim 1 .

19. A method for preparing a composition comprising mixing:

(A) at least one active agent;

(B) at least one delivery agent compound of claim 1 ;

(C) optionally, an enzyme inhibitor; and

(D) optionally, a dosing vehicle.

20. A compound selected from the group consisting of 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3-methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl) propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n-propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n-butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n-propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4-isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid, or pharmaceutically acceptable salts thereof.