Pharmaceutical formulations for a liquid dosage form and a controlled release dosage form

Abstract

A method for treating an autoimmune neurological disease and/or a neurodegenerative disease is provided. The method includes administering an effective amount of at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer or diastereomer to a subject in need thereof:wherein is a single or double bond, X is NCH3 or CH2, Y is null, O or N, Z is O or N, R1 is H, OH, and R2 is null, H, C1-C8 alkyl, —(C═O)-alkyl, —(C═O)-aryl, —(C═O)-alkyl-aryl, —(C═O)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of —OH, —NO2, —NH2, —NR3R4, carbonyl, alkoxyl, alkyl or —OCF3, wherein R3 and R4 independently are H, alkyl, O2CH3, —(C═O)—CH3 or (C═O)—NH2.

What is claimed is: 
     
         1 . A pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III), comprising:
 0.1-30% by weight of at least one compound having Formula (I), Formula (II) or Formula (III), or its enantiomer, diastereomer or pharmaceutically acceptable salt;   
       
         
           
           
               
               
           
         
         wherein 
            is a single or double bond, 
         X is NCH 3  or CH 2 , 
         Y is null, O or N, 
         Z is O or N, 
         R 1  is H, OH, and 
         R 2  is null, H, C 1 -C 8  alkyl, —(C═O)-alkyl, —(C═O)-aryl, —(C═O)-alkyl-aryl, —(C═O)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of —OH, —NO 2 , —NH 2 , NR 3 R 4 , carbonyl, alkoxyl, alkyl or —OCF 3 , wherein R 3  and R 4  independently are H, alkyl, —SO 2 CH 3 , —(C═O)—CH 3  or —(C═O)—NH 2 ; and 
         0.1-15% by weight of a copolymer of poly(ethylene oxide) and poly(propylene oxide); 
         0.1-60% by weight of cyclodextrin or a derivative thereof; and 
         1-99% by weight of solvent, 
         wherein the at least one compound having Formula (I) comprises at least one compound having any one of Formula (IV) to Formula (XVI): 
       
       
         
           
           
               
               
           
         
       
       as trans-sobrerol; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the at least one compound having Formula (II) comprises at least one compound having Formula (XVII): 
       
       
         
           
           
               
               
           
         
       
       and
 wherein the at least one compound having Formula (III) comprises at least one compound having Formula (XVIII): 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 1 , wherein the copolymer of poly(ethylene oxide) and poly(propylene oxide) comprises poly(ethylene oxide)x-poly(propylene oxide)y-poly(ethylene oxide)x (PEO-PPO-PEO),
 in which, x is an integer of 30-120 and y is an integer of 10-50.   
     
     
         3 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 1 , wherein the derivative of cyclodextrin comprises 2-hydroxypropyl-beta cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, β-CD sulfobutyl ether sodium salt or randomly methylated β-cyclodextrin. 
     
     
         4 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 1 , wherein the pharmaceutical formulation comprises:
 0.1-30% by weight of the at least one compound having Formula (I), Formula (II) or Formula (III), or its enantiomer, diastereomer or pharmaceutically acceptable salt;   0.1-15% by weight of the copolymer of poly(ethylene oxide) and polypropylene oxide), wherein the copolymer of poly(ethylene oxide) and poly(propylene oxide) is poly(ethylene oxide)x-poly(propylene oxide)y-poly(ethylene oxide)x (PEO-PPO-PEO), in which, x is an integer of 76 and y is an integer of 30; and   0.1-60% by weight of the cyclodextrin or derivative thereof, wherein the cyclodextrin or derivative thereof is 2-hydroxypropyl-beta cyclodextrin.   
     
     
         5 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as Formula (I) is at least one compound having Formula (IV) as trans-sobrerol: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 5 , wherein the sobrerol comprises (+) trans-sobrerol, (−) trans-sobrerol or a combination thereof 
     
     
         7 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 5 , wherein the sobrerol is (+) trans-sobrerol. 
     
     
         8 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 5 , wherein the sobrerol is (−) trans-sobrerol. 
     
     
         9 . The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 5 , wherein the sobrerol is a mixture of (+) trans-sobrerol and (−) trans-sobrerol. 
     
     
         10 . A pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III), comprising:
 a composition of a particle carrier;   a composition of a drug layer coated on the carrier, which comprises:
 at least one compound having Formula (I), Formula, (II) or Formula (III), or its enantiomer, diastereomer or pharmaceutically acceptable salt; 
   
       
         
           
           
               
               
           
         
         
           wherein 
              is a single or double bond, 
           X is NCH 3  or CH 2 , 
           Y is null, O or N, 
           Z is O or N, 
           R 1  is H, OH, and 
           R 2  is null, H, C 1 -C 8  alkyl, —(C═O)-alkyl, —(C═O)-aryl, —(C═O)-alkyl-aryl, —(C═O)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of —OH, —NO 2 , —NH 2 , —NR 3 R 4 , carbonyl, alkoxyl, alkyl or —OCF 3 , wherein R 3  and R 4  independently are H, alkyl, —SO 2 CH 3 , —(C═O)—CH 3  or —(C═O)—NH 2 ; and 
           at least one binder; and 
         
         a composition of a controlled release layer coated on the drug layer, 
         wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-98% by weight, the composition of a drug layer occupies 1-64% by weight, and the composition of a controlled release layer occupies 0.5-50% by weight, 
         wherein the at least one compound having Formula (I), Formula (II) or Formula (III), or its enantiomer, diastereomer or pharmaceutically acceptable salt occupies 1-99% by weight of the composition of a drug layer, 
         wherein the at least one compound having Formula (I) comprises at least one compound having any one of Formula (IV) to Formula (XVI): 
       
       
         
           
           
               
               
           
         
       
       as trans-sobrerol; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the at least one compound having Formula (II) comprises at least one compound having Formula (XVII): 
       
       
         
           
           
               
               
           
         
         wherein the at least one compound having Formula (III) comprises at least one compound having Formula (XVIII): 
       
       
         
           
           
               
               
           
         
       
     
     
         11 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , wherein the composition of a particle carrier comprises microcrystalline cellulose, lactose, corn starch, mannitol, sodium carboxymethyl cellulose, common salt, or germanium dioxide. 
     
     
         12 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , wherein the at least one binder comprises hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl, polyvinyl alcohol or a combination thereof. 
     
     
         13 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , wherein the composition of a drug layer further comprises an anti-adherent and/or a plasticizer. 
     
     
         14 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , wherein the composition of a controlled release layer comprises at least one water-insoluble polymer or wax-like ingredient. 
     
     
         15 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 14 , wherein the at least one water-insoluble polymer or wax-like ingredient comprises ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl acrylate-methyl methacrylate-trimethyl ammonium chloride ethyl methacrylate copolymer, methyl methacrylate-ethyl acrylate copolymer, polyvinylpyrrlidone, polyvinyl alcohol, hydrogenated castor oil, hydrogenated coconut oil, stearic acid, stearyl alcohol or a combination thereof. 
     
     
         16 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 14 , wherein the composition of a controlled release layer further comprises an anti-adherent and/or a plasticizer. 
     
     
         17 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , wherein the at least one compound having Formula (I) is at least one compound haying Formula (IV) as trans-sobrerol: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 , wherein the sobrerol comprises (+) trans-sobrerol, (−) trans-sobrerol or a combination thereof. 
     
     
         19 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 , wherein the sobrerol is (+) trans-sobrerol. 
     
     
         20 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 , wherein the sobrerol is (−) trans-sobrerol. 
     
     
         21 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 , wherein the sobrerol is a mixture of (+) trans-sobrerol and (−) trans-sobrerol. 
     
     
         22 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 ,
 wherein   the composition of a particle carrier comprises microcrystalline cellulose,   the composition of a drug layer comprises (−) trans-sobrerol, at least one binder comprising hydroxypropyl methyl cellulose, and an anti-adherent comprising talcum powder,   the composition of a controlled release layer comprises at least one water-insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and an anti-adherent comprising talcum powder, and   wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 40-90% by weight, the composition of a drug layer occupies 15-50% by weight, and the composition of a controlled release layer occupies 1-15% by weight, and   wherein the (−) trans-sobrerol occupies 40-90% by weight of the composition of a drug layer.   
     
     
         23 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 ,
 wherein   the composition of a particle carrier comprises microcrystalline cellulose,   the composition of a drug layer comprises (−) trans-sobrerol and at least one binder comprising polyvinyl pyrrolidone,   the composition of a controlled release layer comprises at least one water-insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and   wherein the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-95% by weight, the composition of a drug layer occupies 5-60% by weight, and the composition of a controlled release layer occupies 0.5-20% by weight, and   wherein the (−) trans-sobrerol occupies 40-90% by weight of the composition of a drug layer.   
     
     
         24 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 17 ,
 wherein   the composition of a particle carrier comprises microcrystalline cellulose,   the composition of a drug layer comprises a mixture of (+) trans-sobrerol and (−) trans-sobrerol and at least one binder comprising polyvinyl pyrrolidone,   the composition of a controlled release layer comprises at least one water-insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and   wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-95% by weight, the composition of a drug layer occupies 5-60% by weight, and the composition of a controlled release layer occupies 0.5-20% by weight, and   wherein the mixture of (+) trans-sobrerol and (−) trans-sobrerol occupies 40-90% by weight of the composition of a drug layer.   
     
     
         25 . The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in  claim 10 , further comprising a composition of a coating layer coated on the controlled release layer,
 wherein the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-98% by weight, the composition of a drug layer occupies 1-64% by weight, the composition of a controlled release layer occupies 1-50% by weight, and the composition of a coating layer occupies 1-35% by weight.