Phenylalkylcarboxylic acid delivery agents

Abstract

The present invention provides phenylalkylcarboxylic acid compounds and compositions containing such compounds which facilitate the delivery of biologically active 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
 R 1 -R 5  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 4  alkenyl, halo, C 1 -C 4  alkoxy, hydroxyl, C 6 -C 14  aryloxy, or C 1 -C 6  alkylhalo group; and 
 (a) n is 1 or 3-12; or 
 (b) n is 1-12 and at least one of R 1 -R 5  is not hydrogen. 
 
     
     
         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-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. 
     
     
         3 . (canceled) 
     
     
         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 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The composition of  claim 1 , wherein the biologically active agent is insulin. 
     
     
         9 . (canceled) 
     
     
         10 . The composition of  claim 9 , wherein the weight ratio of delivery agent to active agent ranges from about 800:1 to about 10:1. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . 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. 
   
     
     
         15 - 19 . (canceled) 
     
     
         20 . The dosage unit form of  claim 14 , wherein the dosage unit form comprises a dosing vehicle comprising a tablet, a capsule, a powder, or a liquid. 
     
     
         21 . (canceled) 
     
     
         22 . 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 . 
     
     
         23 . (canceled) 
     
     
         24 . 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. 
     
     
         25 - 30 . (canceled) 
     
     
         31 . 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. 
     
     
         32 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is methyl, methoxy, C 1 -C 4  alkoxy, hydroxy or halogen. 
     
     
         33 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is methyl, methoxy, hydroxy or halogen. 
     
     
         34 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is methyl. 
     
     
         35 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is methoxy. 
     
     
         36 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is hydroxy. 
     
     
         37 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is C 6 -C 14  aryloxy. 
     
     
         38 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is C 1 -C 4  alkoxy. 
     
     
         39 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is C 1 -C 6  alkylhalo. 
     
     
         40 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is halogen. 
     
     
         41 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is chlorine. 
     
     
         42 . The composition of  claim 1 , wherein at least one of R 1  to R 5  is fluorine.