Arylsulfanyl compounds and compositions for delivering active agents

1. A compound selected from:

and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) a delivery agent compound of Formula I, or a pharmaceutically acceptable salt thereof

wherein

A is a branched or unbranched C 1 -C 13 alkylene, C 3 -C 13 arylene group, or a C 3 -C 13 alkyl(arylene) group, and

R 1 -R 5 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, halogen or hydroxy, in which at least one of R 1 -R 5 is methoxy.

3. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) a delivery agent compound selected from

and pharmaceutically acceptable salts thereof.

4. The pharmaceutical composition of claim 2 or claim 3 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

5. The pharmaceutical composition of claim 4 , wherein the biologically active agent is selected from: 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, thrombopoietin, filgrastim, prostaglandins, 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, RNAi and any combination thereof.

6. The pharmaceutical composition of claim 5 , wherein the biologically active agent is selected from insulin, leutinizing-hormone releasing hormone, heparin, recombinant human growth hormone, glucagon, caspofungin acetate, calcitonin, PTH, zanamivir, erythropoietin, analogs, fragments, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; and any combination thereof.

7. The pharmaceutical composition of claim 5 , wherein the biologically active agent comprises insulin.

8. A dosage unit form comprising:

(A) a pharmaceutical composition of claim 2 or claim 3 ;

(B) a biologically active agent; and

(C) (a) an excipient,

(b) a diluents,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

9. The dosage unit form of claim 8 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

10. The dosage unit form of claim 9 , wherein the biologically active agent is selected from: 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, un fractionated 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, thrombopoietin, filgrastim, prostaglandins, 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, RNAi and any combination thereof.

11. The dosage unit form of claim 10 , wherein the biologically active agent is insulin, Leutenizing-hormone releasing hormone, heparin, Recombinant Human Growth Hormone, glucagon, caspofungin acetate, calcitonin, PTH, zanamivir, erythropoietin or a combination thereof.

12. The dosage unit form of claim 9 , wherein the active agent is insulin.

13. The dosage unit form of claim 9 , wherein the active agent is glucagon.

14. The dosage unit form of claim 8 , wherein the dosage unit form is a tablet, a capsule, a powder, or a liquid.

15. The dosage unit form of claim 8 , wherein the dosing vehicle is a liquid selected from water, 1,2-propane diol, ethanol, and any combination thereof.

16. 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 of any one of claims 2 - 3 .

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

(A) a biologically active agent;

(B) at least one compound of claim 1 ; and

(C) optionally, a dosing vehicle

wherein the ratio of compound (B) to biologically active agent (A) ranges from about 400:1 to about 25:1.

18. A pharmaceutical composition comprising:

(A) a biologically active agent; and

(B) a compound of Formula I, or a pharmaceutically acceptable salt thereof

wherein

A is a branched or unbranched C 1 -C 13 alkylene, C 3 -C 13 arylene group, or a C 3 -C 13 alkyl(arylene) group,

R 1 -R 5 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, halogen or hydroxy, in which at least one of R 1 -R 5 is methoxy,

wherein the ratio of compound of Formula (I) to biologically active agent ranges from about 400:1 to about 25:1.

19. The pharmaceutical composition of claim 2 , wherein the ratio of delivery agent to biologically active agent is about 2:1, about 2.5:1, about 8:1, about 50:1, about 66.7:1, about 100:1, about 200:1, or about 500:1.

20. The method of claim 16 , wherein the ratio of delivery agent to biologically active agent is about 2:1, about 2.5:1, about 8:1, about 50:1, about 66.7:1, about 100:1, about 200:1, or about 500:1.

21. The pharmaceutical composition of claim 2 , wherein the ratio of delivery agent compound to biologically active agent ranges from about 400:1 to about 25:1.

22. The pharmaceutical composition of claim 3 , wherein the ratio of delivery agent compound to biologically active agent ranges from about 400:1 to about 25:1.

23. The pharmaceutical composition of claim 3 , wherein the ratio of delivery agent to biologically active agent is about 2:1, about 2.5:1, about 8:1, about 50:1, about 66.7:1, about 100:1, about 200:1, or about 500:1.