High penetration compositions and uses thereof

Abstract

The present invention relates to compositions and uses of novel high penetration compositions or high penetration prodrugs (HPP), in particular HPPs for non-steroidal anti-inflammatory agents (NSAIAs), which are capable of crossing biological barriers with high penetration efficiency. The HPPs herein are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, due to the ability of penetrating biological barriers, the HPPs herein are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs herein can be administered to a subject through various administration routes. For example, the HPPs can be locally delivered to an action site of a condition with a high concentration due to their ability of penetrating biological barriers and thus obviate the need for a systematic administration. For another example, the HPPs herein can be systematically administer to a biological subject and enter the general circulation with a faster rate.

1 . A high penetration composition comprising
 a) a functional unit;   b) a transportational unit;   wherein the functional unit is covalently linked to the transportational unit via a linker;   the functional unit comprises a moiety of an agent;   the transportational unit comprises a protonatable amine group; and   the linker is or comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.   
     
     
         2 . The high penetration composition according to  claim 1 , wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond. 
     
     
         3 . The high penetration composition according to  claim 1 , wherein upon cleavage of the cleavable bond, the moiety of the agent is converted to the agent or a metabolite of the agent. 
     
     
         4 . The high penetration composition according to  claim 1 , wherein the functional unit comprises a lipophilic derivative of a moiety of an agent. 
     
     
         5 . The high penetration composition according to  claim 4 , wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine of the moiety of the agent. 
     
     
         6 . The high penetration composition according to  claim 1  wherein the agent is selected from the group consisting of a non-steroidal antiinflammatory agent (NSAIA), an active NSAIA metabolite, an agent that can be metabolized into the NSAIA or the active NSAIA metabolite. 
     
     
         7 . The high penetration composition according to  claim 1 , wherein the protonatable amine group is selected from the group consisting of a pharmaceutically acceptable substituted or unsubstituted primary amine group, a pharmaceutically acceptable substituted or unsubstituted secondary amine group, and a pharmaceutically acceptable substituted or unsubstituted tertiary amine group. 
     
     
         8 . The high penetration composition according to  claim 7 , wherein the protonatable amine group is selected from Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 11 -R 16  is independently selected from the group consisting of nothing, H, CH 2 COOR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NR 11 , or any other pharmaceutically acceptable groups. 
       
     
     
         9 . A high penetration composition having the following chemical structure: 
       
         
           
           
               
               
           
         
         including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
         T is selected from Group N as defined in  claim 8 ; 
         L 1  is selected from the group consisting of nothing, O, S, —N(L 3 )-, —N(L 3 )-CH 2 —O, —N(L 3 )CH 2 —N(L 3 )-, —O—CH 2 —O—, —O—CH(L 3 )O, —S—CH(L 3 )-O—; 
         L 2  is selected from the group consisting of L 1 , —O-L 3 -, —N-L 3 -, —S-L 3 - and —N(L 3 )-L 3 -; 
         L 4  is selected from the group consisting of C═O, C═S, 
       
       
         
           
           
               
               
           
         
         each L 3  is independently selected from the group consisting of nothing, H, CH 2 COOR 1 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, N L 3 , or any other pharmaceutically acceptable groups; 
         F is a moiety of a NSAIA having a structure selected from Group F-1 and Group F-2, wherein Group F-1 includes the following structures: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and Group F-2 includes the following structures; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 each R, R 1 , R 2 , R 5 -R 7  is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR 6 , CH═CH, C≡C, CHR 6 , CR 5 R 6 , aryl, heteroaryl, and cyclic groups; 
 each R 3 -R 10  is independently selected from the group consisting of nothing, H, R 6 , R 6 C(═O)—, R 6 NH(C═O), R 6 O(C═O), R 6 C(═NH)—, R 6 C(═S)—, CNR 6  and R 6 OCO(CH 2 ) n C(═O), wherein n is selected from the group of natural numbers; 
 each Y and Y 1  to Y 13  is independently selected from the group consisting of H, halogen, CN, R 10 , CH 3 C≡C, CR 6 ≡C, P(O)OR 6 , CF 3 , CF 3 O, CH 3 , CF 3 CF 2 , CF 3 CF 2 O, CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, (CH 3 ) 2 CHCH 2 , CH 3 CH 2 CH(CH 3 ), (CH 3 ) 3 C, C 4 H 9 , C 5 H 11 , CH 3 CO, CH 3 CH 2 CO, R 5 CO, CH 3 COO, R 5 COO, R 5 COOCH 2 , R 6 NHCOOCH 2 , CH 3 COS, CH 3 O, R 5 O, HO, R 10 O, CF 3 CH 2 SCH 2 , CHCl 2 , CH 2 COOR 6 , CH 3 S, R f S, HS, R 10 S, CH 3 OCH 2 CH 2 , R 5 OCH 2 , R 10 OCH 2 CH 2 , R 5 O(C═O), C 2 H 5 OCONH, CH 2 NHR, CH 3 OCONH, CH 3 SO 2 , CH 3 SO, RSO 2 , R 5 SO, NH 2 SO 2 , C 6 H 5 CH 2 , NH 2 , NHR 10 , cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH 2 ═CH, CH 2 ═CHCH 2 , CH 3 CH═CH, NHR 5 SO 2 , N(R 5 ) 2 SO 2 , R 5 OCH 2 CH 2 CH 2 , and NO 2 ; 
 each X and X 1  to X 5  is independently selected from the group consisting of nothing, CH 3 SO, S, O, NR 6 , C═O, R 6 , P(O)OR 6 ; 
 X 6  is selected from the group consisting of R 6 , CONH, CSNH, COO, OCO, COS, COCH 2 , and CH 2 CO; 
 m is selected from the group of integers; and 
 W is selected from the group consisting of H, OH and halogen; and 
 the composition is not any of the following structures: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The high penetration composition of  claim 9  wherein the NSAIA is selected from the group consisting of a salicylate, an arylalkanoic acid, an aryl propionic acid, a heteroaryl propionic acid, an aryl acetic acid, a heteroaryl acetic acid, an N-arylanthranilic acid, a Pyrazolidine derivative, and an oxicam. 
     
     
         11 . The high penetration composition of  claim 10  wherein the NSAIA is the salicylate and the high penetration composition has a structure selected form the group consisting of Structure 1 and Structure 2: 
       
         
           
           
               
               
           
         
         including stereoisomers and pharmaceutically acceptable salts thereof, wherein: 
         Z is selected from the group consisting of O and S; 
         X is selected from the group consisting of nothing, O, P(O)OR 1 , NH, NR 1  and S; 
         R is selected from the group consisting of a branched or straight chain —(CH 2 ) n —, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH 2 ) n —, any CH 2  may be independently replaced with O, S, NR 5 , CH═CH, C≡C, CHR 5 , CR 5 R 6 , aryl or heteroaryl residues, and any other pharmaceutically acceptable groups; 
         R 1  and R 2  are independently selected from the group consisting of H, C1-C12 alkyl, C1-C12 cycloalkyl, C1-C12 alkyloxyl, C1-C12 cycloalkyloxyl, C1-C12 alkenyl, C1-C12 cycloalkenyl, C1-C12 perfluoroalkyl, C1-C12 cycloperfluoroalkyl, C1-C12 alkyl halide, C1-C12 cycloalkyl halide, C1-C12 alkynyl, C1-C12 cycloalkynyl groups, aryl or heteroaryl moieties, and any CH 2  may be independently replaced with O, S, CH═CH, C≡C, CHR 5 , CR 5 R 6 , aryl or heteroaryl groups and any other pharmaceutically acceptable groups; 
         R 5 , R 6  and R 7  are independently selected from the group consisting of H, OH, Cl, F, Br, I, C1-C12 alkyl, C1-C12 cycloalkyl, C1-C12 alkyloxyl, C1-C12 cycloalkyloxyl, C1-C12 alkenyl, C1-C12 cycloalkenyl, C1-C12 perfluoroalkyl, C1-C12 cycloperfluoroalkyl, C1-C12 alkyl halide, C1-C12 cycloalkyl halide, C1-C12 alkynyl, C1-C12 cycloalkynyl, aryl and heteroaryl groups; 
         is selected from the group consisting of alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties; 
         HA represents none, HCl, HBr, HF, HI, HOAc, citric acid, or any acids which are pharmaceutically acceptable; 
         X 1  is selected from the group consisting of O, and the following structures: 
         Y 1  and Y 2  are independently selected from the group consisting of H, HO, CH 3 COO, R 8 COO, HS, NO 2 , ON, CH 3 COS, NH 2 , CH 3 CONH, R 8 CONH, CH 3 , CH 3 CH 2 , C 3 H 7 , C 4 H 9 , CH 3 O, CH 3 CH 2 O, C 3 H 7 O, C, F, Br, I, CH 3 S, CHF 2 O, CF 3 O, CF 3 CF 2 O, C 3 F 7 O, CF 3 , CF 3 CF 2 , C 3 F 7 , C 4 F 9 ,CH 3 SO 2 , R 8 SO 2 , CH 3 SO, R 3 SO, CH 3 CO, CH 3 CH 2 CO; 
         all R, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , and —(CH 2 ) n — groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds. 
       
     
     
         12 . The high penetration composition of  claim 11  having the following Structure 1a: 
       
         
           
           
               
               
           
         
       
       including stereoisomers and pharmaceutically acceptable salts thereof, wherein:
 R 1  is selected from the group consisting of CH 3 , C 2 Hr, C 3 Hr, and alkyl groups; 
 R 2 , R 3 , R 4  are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkyloxyl, C1-C6 alkenyl, and aryl groups; 
 X is selected from the group consisting of O, S and N; 
 A is selected from the group consisting of Cl—, Br—, F—, I—, AcO—, acetylsalicylate, citrate, salicylate, and any pharmaceutically acceptable acid anion; and 
 n is selected from the group of integers. 
 
     
     
         13 . The high penetration composition of  claim 12  wherein the salicylate is aspirin. 
     
     
         14 . The high penetration composition of  claim 10  wherein the salicylate is diflunisal 
     
     
         15 . The high penetration composition of  claim 10  wherein the salicylate is salicyl salicylate. 
     
     
         16 . The high penetration composition of  claim 10  wherein the arylalkanoic acid is diclofenac. 
     
     
         17 . The high penetration composition of  claim 10  wherein the arylpropionic acid is ibuprofen. 
     
     
         18 . The high penetration composition of  claim 10  wherein the arylpropionic acid is ketoprofen. 
     
     
         19 . The high penetration composition of  claim 10  wherein the arylpropionic acid is fenoprofen. 
     
     
         20 . The high penetration composition of  claim 10 , wherein the composition is selected from the group consisting of Sdimethylaminoethyl acetylthiosalicylate, S-diethylaminoethyl propionylthiosalicylate, N-diethylaminopropyl acetylsalicylamide, dipropylaminoethyl acetylsalicylate, diethylaminoethyl 5-(2,4-difluorophenyl) salicylate, diethylaminoethyl salicylsalicylate dimethylaminoethyl salicylate, S-dimethylaminoethyl 5-(2,4-difluorophenyl) thiosalicylate, N-dimethylaminoethyl 5-(2,4-difluorophenyl) salicylamide, S-diethylaminoethyl thiosalicylate, ethyl 3-N, N-diethylaminopropionyl 5-(2,4-difluorophenyl) salicylate, ethyl 3-N, N-dimethylaminopropionyl 5-(2,4-difluorophenyl) salicylsalicylate, ethyl 3-N, N-dimethylaminopropionyl salicylate, diethylaminoethyl 2-(ρ-isobutylphenyl) propionate, dimethylaminoethyl 2-(ρ-isobutylphenyl) propionate, dipropylaminoethyl 2-(ρ-isobutylphenyl) propionate, dipropylaminoethyl 2-(ρ-isobutylphenyl) propionate, 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionate, S-dimethylaminoethyl 2-(ρ-isobutylphenyl) thiopropionate, S-diethylaminoethyl 2-(ρ-isobutylphenyl) thiopropionate, N-dimethylaminoethyl 2-(ρ-isobutylphenyl) propionamide, N-dimethylaminopropyl 2-(ρ-isobutylphenyl) propionamide, diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl) phenylmethylene]-1H-indene-3-acetate, diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate S-dimethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate, N-dimethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetamide N-dimethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetamide, diethylaminoethyl 3-chloro-4-(2-propenyloxy) benzeneacetate diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate, dimethylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetate S-dimethylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetate, N-dimethylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetamide, dipropylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetate, dipropylaminoethyl dipropylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetate, 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzene acetate, diethylaminoethyl 2-(3-benzoyphenyl) propionate dimethylaminoethyl 2-(3-phenoxyphenyl) propionate, S-dimethylaminoethyl 2-(3-phenoxyphenyl) thiopropionate, N-dimethylaminoethyl 2-(3-benzoyphenyl) propionate, diethylaminoethyl 2-(3-benzoyphenyl) propionate, diethylaminoethyl 2-(6-methoxy-2-naphthyl) propionate, diethylaminoethyl α-methyl-4-(2-thienylcarbonyl) benzeneacetate, S-dimethylaminoethyl 2-(2-fluoro-4-biphenylyl) propionate, N-dimethylaminoethyl diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylamide, N-diethylaminoethyl 4, 5-Diphenyl-2-oxazole propionamide, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate, N-diethylaminoethyl 2-[(2,3-dimethylphenyl) amino]benzoamide, N-diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino] benzoamide, S-dimethylaminoethyl 2-[[(3-trifluoromethyl)phenyl]amino]benzoate, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate, including stereoisomers and pharmaceutically acceptable salts thereof. 
     
     
         21 . A pharmaceutical composition comprising a high penetration composition according any of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . The pharmaceutical composition according to  21 , wherein the pharmaceutically acceptable carrier is polar. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution. 
     
     
         24 . A method for penetrating a biological barrier, comprising administrating to the biological barrier a pharmaceutical composition according to  claim 1 . 
     
     
         25 . A method for screening a composition for a desired character, comprising the following steps:
 1) covalently linking a functional unit to a transportational unit through a linker to form a test composition;   2) administrating a test composition to a biological subject or a biological barrier; and   3) determining whether the test composition has a desired character.   
     
     
         26 . The method according to  claim 25 , wherein the desired character is selected from the group consisting of:
 1) the ability of the test composition to penetrate the biological barriers;   2) the ability of the test composition to convert to a parent drug or to an active agent;   3) the penetration rate of the test composition;   4) the efficiency of the test composition; and   5) the efficacy of the test composition.   
     
     
         27 . A method for diagnosing a condition in a biological subject, comprising the following steps:
 1) administrating a composition according to  claim 1  to the biological subject;   2) detecting the presence, location or amount of the composition in the biological subject; and   3) detecting a condition in the biological subject.   
     
     
         28 . The method according to  claim 27 , wherein the composition is labeled. 
     
     
         29 . A method for treating a condition of a biological subject, comprising administrating to the biological subject a high penetration composition of a NSAIA according to  claim 9 . 
     
     
         30 . The method according to  claim 29 , wherein the condition is selected from the group consisting of metabolism disorder, abnormal blood pressure, tumor, cardiovascular diseases, neurodegenerative disease, skin condition, autoimmune disease, eye disease, pain, injuries, inflammation, fever, conditions related to platelet aggregation, dysmenorrheal, allergy, asthma, preeclamptic toxemia in high-risk women, IUD-associated uterine bleeding, radiation-induced conditions, and bone disease. 
     
     
         31 . The method according to  claim 30 , wherein the metabolism disorder is selected from the group consisting of abnormal blood glucose level, abnormal blood lipid level, diabetes mellitus (type I or/and type II) and diabetes-induced complications, including diabetic retinopathy, necrobiotic ulcers, and diabetic proteinuria. 
     
     
         32 . The method according to  claim 30 , wherein the abnormal blood pressure is hypertension or hypotension. 
     
     
         33 . The method according to  claim 30 , wherein the cardiovascular disease is selected from the group consisting of heart attack, unstable angina, peripheral occlusive arterial disease and stroke. 
     
     
         34 . The method according to  claim 30 , wherein the neurodegerative disease is Alzheimer's diseases or Parkinson's disease. 
     
     
         35 . The method according to  claim 30 , wherein the autoimmune disease is selected from the group consisting of discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, cleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease. 
     
     
         36 . The method according to  claim 30 , wherein the inflammation is selected from the group consisting of prostate gland inflammation (prostatitis), prostatocystitis, prostate enlarge fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type-1 membranoproliferative glomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosing spondylitis, hemophilic arthropathy, inflammatory bowel disease, inflamed hemorrhoids, post irradiation (factitial) proctitis, chronic ulcerative colitis, cryptitis, periodontitis, arthritis, and an inflammatory condition in an organ selected from the group consisting of the liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, the anorectum and pruritus ani. 
     
     
         37 . The method according to  claim 30 , wherein the skin condition is selected from the group of psoriasis and psoriatic disorders, acne, cystic acne, pus-filled or reddish bumps, comedones, papules, pustules, nodules, epidermoid cysts, keratosis pilaris, abnormal vascular skin lesions, birthmarks, moles (nevi), skin tags, scleroderma, vitiligo and related diseases, or aging spots (liver spots). 
     
     
         38 . The method according to  claim 30 , wherein the tumor is benign tumor, breast cancer, colon-rectum cancer, oral cancer, lung or other respiratory system cancers, skin cancers, uterus cancer, pancreatic cancer, prostate cancer, genital cancer, urinary organs cancers, leukemia or other blood and lymph tissues cancer. 
     
     
         39 . The method according to  claim 30 , wherein the condition related to platelet aggregation is selected from the group consisting of thromboembolis after surgery, carotid endarterectomy, the recurrence of stenosis after coronary angioplasty, thromboembolic complications in chronic arterial fibrillation, aortocornonary-artery-bypass graft occlusion, heart attack, stroke, multi-infract dementia, dementia, hemodialysis shunt thrombosis and arterial embolic complications in patients' prosthetic heart valves. 
     
     
         40 . The method according to  claim 30 , wherein the eye disease is selected from the group consisting of glaucoma, ocular hypertension, loss of vision after ophthalmic surgery, vision of a warm-blooded animal impaired by cystoid macular edema and cataract. 
     
     
         41 . The method according to  claim 30 , wherein the bone disease is selected from the group consisting of osteoporosis, Paget's disease and bone metastases. 
     
     
         42 . The method according to  claim 30 , wherein the pharmaceutical composition is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration. 
     
     
         43 . The method according to  claim 29  wherein the NSAIA is selected from the group consisting of aspirin, diflunisal, diclofenac, salicyl salicylate, ibuprofen, fenoprofen, ketoprofen, a heteroaryl propionic acid, an aryl acetic acid, a heteroaryl acetic acid, an N-arylanthranilic acid, a Pyrazolidine derivative, and an oxicam. 
     
     
         44 . The method according to  claim 29  wherein the condition is selected from the groups consisting of a condition treatable by aspirin, a condition treatable by salicylate, a condition treatable by ibuprofen, a condition treatable by ketoprofen, a condition treatable by fenoprofen, a condition treatable by a aryl acetic acid or a heteroaryl acetic acid, a condition treatable by aryl- and heteroarylpropionic acid, a condition treatable by a N-aryl anthranilic acid, and a condition treatable by oxicam. 
     
     
         45 . The method according to  claim 44  wherein the condition treatable by aspirin is selected from the group consisting of gouty arthritis, pain and inflammation of arthritic and other inflammatory conditions, heart attack; stroke, tumor, Kawasaki syndrome, thromboembolism after surgery, unstable angina, gastroenteritis, aortocoronary-artery-bypass graft occlusion, thromboembolic complications in chronic arterial fibrillation, platelet aggregatioartrial in carotid endarterectomy, cataracts, recurrence of stenosis after coronary angioplasty, multi-infract dementia, diabetes mellitus and diabetes-induced complications, cardiovascular disease, hemodialysis shunt thrombosis, renal disease, peripheral occlussive arterial disease, arterial embolic complications in patients' prosthetic heart valves, and pregnancy-induced hypertension and preeclamptic toxemia.