Disease-site-specific liposomal formulation

Abstract

The present invention provides a clinically applicable, safe and convenient, pharmaceutical composition for disease site-specific treatment. The pharmaceutical composition for disease site-specific treatment comprises a stealth liposome having a prostaglandin I2 receptor agonist encapsulated therein.

1 . A pharmaceutical composition for disease site-specific treatment, comprising a stealth liposome having a prostaglandin I2 receptor agonist encapsulated therein. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the prostaglandin I2 receptor agonist includes at least
 a compound represented by formula (I):   
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         wherein e represents an integer of 3 to 5, 
         f represents an integer of 1 to 3, 
         p represents an integer of 1 to 4, 
         q represents 1 or 2, and 
         r represents an integer of 1 to 3; 
         R 1  represents a hydrogen atom or a C 1-4  alkyl group; 
         R 2  represents (i) a hydrogen atom, (ii) a C 1-8  alkyl group, (iii) a phenyl group or a C 4-7  cycloalkyl group, (iv) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (v) a C 1-4  alkyl group substituted with a benzene ring or a C 4-7  cycloalkyl group, or (vi) a C 1-4  alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; and 
         R 3  represents (i) a C 1-8  alkyl group, (ii) a phenyl group or a C 4-7  cycloalkyl group, (iii) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (iv) a C 1-4  alkyl group substituted with a benzene ring or a C 4-7  cycloalkyl group, or (v) a C 1-4  alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; 
         provided that when 
       
       
         
           
           
               
               
           
         
         is a group represented by (iii) or (iv), —(C—(CH 2 ) p — and ═CH—(CH 2 ) s — are bound to position a or b on the ring, and cyclic structures in R 2  and R 3  are optionally substituted with one to three C 1-4  alkyl groups, C 1-4  alkoxy groups, halogen atoms, nitro groups, or trihalomethyl groups; or 
         a salt thereof. 
       
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the prostaglandin I2 receptor agonist includes at least the following compound (A):
 (A) ({5-[2-({[(1E)-phenyl(pyridin-3-yl)methylene]amino}oxy)ethyl]-7,8-dihydronaphthalen-1-yl}oxy)acetic acid (ONO-1301) represented by formula (II):   
       
         
           
           
               
               
           
         
         or a salt of compound (A). 
       
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the prostaglandin I2 receptor agonist includes at least one of the following compounds (B) to (E):
 (B) sodium (±)-(1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butanoate (beraprost), or a derivative thereof that is a carbacyclic PGI2 derivative,   (C) [4-[(5,6-diphenylpyrazinyl)(1-methylethyl)amino]butoxy]-acetic acid (MRE-269),   (D) (2E)-7-{(1R,2R,3R)-3-hydroxy-2-[(1E,3S,5S)-3-hydroxy-5-methylnon-1-en-1-yl]-5-oxycyclopentyl}hept-2-enoic acid (limaprost), ornoprostil, enprostil, or misoprostol; or a derivative of any of these compounds that is a PEF derivative, and   (E) 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide (NS-304; selexipag);   or   a salt of any of compounds (B) to (E).   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the prostaglandin I2 receptor agonist includes at least one member selected from the group consisting of ONO-1301, beraprost, limaprost, and NS-304. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the stealth liposome is obtainable by using at least a prostaglandin I2 receptor agonist and a phospholipid by the Bangham method, hydration dispersion method, reverse phase evaporation method, ethanol injection method, ethanol dilution method, homogenization method, mechanochemical method, direct dispersion method, extruder method, French press method, remote loading method, dehydration-rehydration method, freeze-thaw method, ultrasonic method, or lipid-compound film method; or an improved method of any of these methods. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the stealth liposome has an average particle size of 50 to 200 nm, and comprises 5 to 50 parts by weight of the phospholipid and 0.05 to 5 parts by weight of PEG-modified phosphoethanolamine, per part by weight of the prostaglandin I2 receptor agonist. 
     
     
         8 . The pharmaceutical composition according to  claim 1 ,
 wherein the stealth liposome comprises 0.05 to 5 parts by weight of MPEG2000-DSPE per part by weight of the prostaglandin I2 receptor agonist;   the prostaglandin I2 receptor agonist includes at least one member selected from the group consisting of ONO-1301, beraprost, limaprost, and NS-304; and   the stealth liposome releases the prostaglandin I2 receptor agonist over a period of 3 hours to 4 weeks.   
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein
 the stealth liposome comprises   a prostaglandin I2 receptor agonist,   a phospholipid,   a PEG-modified phosphoethanolamine, and   a water-miscible organic solvent, and   does not comprise a sterol;   the liposome is obtainable by a production method comprising the following steps (1) to (8):   (1) mixing the prostaglandin I2 receptor agonist, the phospholipid, and the PEG-modified phosphoethanolamine in the solvent in amounts such that at least 5 mg of the phospholipid and at least 0.05 mg of the PEG-modified phosphoethanolamine are present per mg of the prostaglandin I2 receptor agonist,   (2) heating the mixture obtained in step (1) to prepare a melt,   (3) instantly freezing the melt obtained in step (2),   (4) freeze-drying the frozen product obtained in step (3) to remove the solvent,   (5) heating the freeze-dried product obtained in step (4) to disperse the heated product in an aqueous phosphate buffer solution,   (6) sizing the dispersion obtained in step (5) with an extruder,   (7) ultrafiltrating the dispersion obtained in step (6) to remove unencapsulated material, and   (8) adding a sugar to the dispersion obtained in step (7) and freeze-drying the dispersion; and   the liposome contains at least 0.001 mg of the prostaglandin I2 receptor agonist per 1.0 mg of the phospholipid, and has an average particle size of 50 to 200 nm.   
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the composition is for intravenous administration, intracoronary administration, inhalation, intramuscular administration, subcutaneous administration, oral administration, transmucosal administration, transdermal administration, or an internal organ, and is in the form of an injectable formulation, an oral preparation, an inhalant, a nebulizer, an ointment, a patch, or a spray. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein a single intravenous dose of the composition is 0.001 to 100 mg in terms of the prostaglandin I2 receptor agonist. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein a disease to be treated with the composition is cardiovascular disease, respiratory disease, urinary disease, gastrointestinal disease, bone disease, neurodegenerative disease, vascular disease, dental disease, eye disease, skin disease, other inflammatory disease, ischemic organ disorder, diabetic complication, tissue fibrotic disease, tissue degenerative disease, or hair loss; and
 the composition comprises a liposome.   
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein a disease to be treated with the composition is a cardiovascular disease such as ischemic and dilated cardiomyopathy, atherosclerosis obliterans, vasculitis syndrome, valvular disease, aortic stenosis, chronic heart failure, or diastolic failure; a respiratory lung disease such as pulmonary hypertension, pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease; a gastrointestinal or urinary disease such as chronic kidney disease, chronic hepatitis, or chronic pancreatitis; or a neurodegenerative disease such as chronic phase of cerebral infarction, Alzheimer's disease, diabetic neuropathy, Parkinson's disease, or amyotrophic lateral sclerosis; and
 the composition comprises a liposome.   
     
     
         14 . The pharmaceutical composition according to  claim 2 , wherein the stealth liposome is obtainable by using at least a prostaglandin I2 receptor agonist and a phospholipid by the Bangham method, hydration dispersion method, reverse phase evaporation method, ethanol injection method, ethanol dilution method, homogenization method, mechanochemical method, direct dispersion method, extruder method, French press method, remote loading method, dehydration-rehydration method, freeze-thaw method, ultrasonic method, or lipid-compound film method; or an improved method of any of these methods. 
     
     
         15 . The pharmaceutical composition according to  claim 3 , wherein the stealth liposome is obtainable by using at least a prostaglandin I2 receptor agonist and a phospholipid by the Bangham method, hydration dispersion method, reverse phase evaporation method, ethanol injection method, ethanol dilution method, homogenization method, mechanochemical method, direct dispersion method, extruder method, French press method, remote loading method, dehydration-rehydration method, freeze-thaw method, ultrasonic method, or lipid-compound film method; or an improved method of any of these methods. 
     
     
         16 . The pharmaceutical composition according to  claim 4 , wherein the stealth liposome is obtainable by using at least a prostaglandin I2 receptor agonist and a phospholipid by the Bangham method, hydration dispersion method, reverse phase evaporation method, ethanol injection method, ethanol dilution method, homogenization method, mechanochemical method, direct dispersion method, extruder method, French press method, remote loading method, dehydration-rehydration method, freeze-thaw method, ultrasonic method, or lipid-compound film method; or an improved method of any of these methods. 
     
     
         17 . The pharmaceutical composition according to  claim 5 , wherein the stealth liposome is obtainable by using at least a prostaglandin I2 receptor agonist and a phospholipid by the Bangham method, hydration dispersion method, reverse phase evaporation method, ethanol injection method, ethanol dilution method, homogenization method, mechanochemical method, direct dispersion method, extruder method, French press method, remote loading method, dehydration-rehydration method, freeze-thaw method, ultrasonic method, or lipid-compound film method; or an improved method of any of these methods. 
     
     
         18 . The pharmaceutical composition according to  claim 2 , wherein the stealth liposome has an average particle size of 50 to 200 nm, and comprises 5 to 50 parts by weight of the phospholipid and 0.05 to 5 parts by weight of PEG-modified phosphoethanolamine, per part by weight of the prostaglandin I2 receptor agonist. 
     
     
         19 . The pharmaceutical composition according to  claim 3 , wherein the stealth liposome has an average particle size of 50 to 200 nm, and comprises 5 to 50 parts by weight of the phospholipid and 0.05 to 5 parts by weight of PEG-modified phosphoethanolamine, per part by weight of the prostaglandin I2 receptor agonist. 
     
     
         20 . The pharmaceutical composition according to  claim 4 , wherein the stealth liposome has an average particle size of 50 to 200 nm, and comprises 5 to 50 parts by weight of the phospholipid and 0.05 to 5 parts by weight of PEG-modified phosphoethanolamine, per part by weight of the prostaglandin I2 receptor agonist.