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
 n is 1-12, 
 and 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. 
 
     
     
         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 . 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 biologically active agent is selected from insulin, leutenizing-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. 
     
     
         8 . The composition of  claim 7 , wherein the biologically active agent is insulin. 
     
     
         9 . The composition of  claim 1 , wherein the weight ratio of delivery agent to active agent ranges from about 1000:1 to 1:10. 
     
     
         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 . A method of preparing pharmaceutical composition, comprising mixing at least one delivery agent compound of  claim 1 , and a biologically active agent. 
     
     
         12 . The method of  claim 11 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, lipid, or any combination thereof. 
     
     
         13 . The method of  claim 12 , 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. 
     
     
         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 . The dosage unit form of  claim 14 , wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid. 
     
     
         16 . The dosage unit form of  claim 15 , 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. 
     
     
         17 . The dosage unit form of  claim 16 , wherein the biologically active agent is selected from insulin, leutenizing-hormone releasing hormone, heparin, recombinant human growth hormone, glucagon, caspofungin acetate, calcitonin, parathyroid hormone, zanamivir, erythropoietin or combinations thereof. 
     
     
         18 . The dosage unit form of  claim 17 , wherein the active agent is insulin. 
     
     
         19 . The dosage unit form of  claim 17 , wherein the active agent is glucagon. 
     
     
         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 . The dosage unit form of  claim 20 , wherein the dosing vehicle is a liquid selected from the group consisting of water, 1,2-propane diol, ethanol, and any combination thereof. 
     
     
         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 . 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 14 . 
     
     
         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 . 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 14  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. 
     
     
         26 . 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. 
     
     
         27 . The method of  claim 26 , wherein the biologically active agent is a protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid. 
     
     
         28 . The method of  claim 27 , 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. 
     
     
         29 . A method for increasing the bioavailability of a biologically active agent comprising administering to an animal a composition of  claim 1 . 
     
     
         30 . 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.   
     
     
         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.