Liposomal benzoquinazoline thymidylate synthase inhibitor formulations

Abstract

Liposomal encapsulated benzoquinazoline thymidylate synthase inhibitor formulations are provided. The liposomes have improved pharmacokinetics and enhanced efficacy as anti-tumor agents compared to the free drug. The formulations include liposomes comprising at least one phosphatidylcholine, a cholesterol, and a benzoquinazoline thymidylate synthase inhibitor.

We claim:  
     
         1 . A liposome comprising at least one phosphatidylcholine, a cholesterol, and a benzoquinazoline thymidylate synthase inhibitor.  
     
     
         2 . The liposome of  claim 1  wherein said phosphatidylcholine is selected from the group consisting of distearoylphosphatidylcholine, hydrogenated soy phosphatidylcholine, soy phosphatidylcholine, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, and dimyristoylphosphatidylcholine.  
     
     
         3 . The liposome of  claim 2  wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine.  
     
     
         4 . The liposome of  claim 2  wherein said phosphatidylcholine is soy phosphatidylcholine.  
     
     
         5 . The liposome of  claim 2  wherein said phosphatidylcholine is dioleoylphosphatidylcholine.  
     
     
         6 . The liposome of  claim 2  wherein said phosphatidylcholine is dielaidoylphosphatidylcholine.  
     
     
         7 . The liposome of  claim 2  wherein said liposome further comprises phosphatidylglycerol.  
     
     
         8 . The liposome of  claim 3  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         9 . The liposome of  claim 4  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         10 . The liposome of  claim 5  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         11 . The liposome of  claim 6  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         12 . The liposome of  claim 7  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         13 . The liposome of  claim 12  wherein said hydrogenated soy phosphatidylcholine, cholesterol and phosphatidylglycerol are in a molar ratio of about 2:1:0.1.  
     
     
         14 . The liposome of  claim 8  wherein the hydrogenated soy phosphatidylcholine to cholesterol molar ratio is from about 5:1 to 2:1.5.  
     
     
         15 . The liposome of  claim 14  wherein said molar ratio is about 2:1.  
     
     
         16 . The liposome of  claim 14  wherein said molar ratio is about 4:1.  
     
     
         17 . The liposome of  claim 15  wherein said liposome is unilamellar and less than 100 nm.  
     
     
         18 . The liposome of  claim 17  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 5:1 to 75:1.  
     
     
         19 . The liposome of  claim 9  wherein said molar ratio is about 2:1.  
     
     
         20 . The liposome of  claim 10  wherein said molar ratio is about 2:1.  
     
     
         21 . The liposome of  claim 11  wherein said molar ratio is about 2:1.  
     
     
         22 . The liposome of  claim 17  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 8:1 to 20:1.  
     
     
         23 . A liposome comprising a benzoquinazoline thymidylate synthase inhibitor (BTSI) encapsulated in a liposome, wherein said liposome is comprised of hydrogenated soy phosphatidylcholine (HSPC) and cholesterol and wherein HSPC:cholesterol are in a molar ratio of about 2:1, and wherein the HSPC:BTSI molar ratio is from 8:1 to 20:1, and wherein said liposome is unilamellar having a size of less than 100 nm.  
     
     
         24 . The liposome of  claim 23  wherein said BTSI is GW1843.  
     
     
         25 . The composition of  claim 1  produced by the process comprising: 
 a) forming a lipid film or powder comprised of phosphatidylcholine and cholesterol;  
 b) hydrating said lipid film or powder with an aqueous solution containing a benzoquinazoline thymidylate synthase inhibitor (BTSI);  
 c) applying energy whereby liposomes that are unilamellar and less than 100 nm are obtained;  
 d) cross-filtering against an aqueous solution to remove unencapsulated BTSL whereby liposomes containing a BTSI are obtained.  
 
     
     
         26 . The composition of  claim 25  wherein said phosphatidylcholine is selected from the group consisting of distearoylphosphatidylcholine, hydrogenated soy phosphatidylcholine, soy phosphatidylcholine, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, dipalmitoylpbosphatidylcholine, dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, and dimyristoylphosphatidylcholine.  
     
     
         27 . The composition of  claim 26  wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine.  
     
     
         28 . The composition of  claim 26  wherein said phosphatidylcholne is soy phosphatidylcholine.  
     
     
         29 . The composition of  claim 26  wherein said phosphatidylcholine is dioleoylphosphatidylcholine.  
     
     
         30 . The composition of  claim 26  wherein said phosphatidylcholine is dielaidoylphosphatidylcholine.  
     
     
         31 . The composition of  claim 26  wherein said liposome further comprises phosphatidylglycerol.  
     
     
         32 . The composition of  claim 25  wherein said energy is applied by a homogenizer.  
     
     
         33 . The composition of  claim 27  wherein said BTSI is GW1843.  
     
     
         34 . The composition of  claim 28  wherein said BTSI is GW1843.  
     
     
         35 . The composition of  claim 29  wherein said BTSI is GW1843.  
     
     
         36 . The composition of  claim 30  wherein said BTSI is GW1843.  
     
     
         37 . The composition of  claim 31  wherein said BTSI is GW1843.  
     
     
         38 . The composition of  claim 27  wherein the hydrogenated soy phosphatidylcholine to cholesterol molar ratio is from about 5:1 to 2:1.5.  
     
     
         39 . The composition of  claim 38  wherein said molar ratio is about 2:1.  
     
     
         40 . The composition of  claim 38  wherein said molar ratio is about 4:1.  
     
     
         41 . The composition of  claim 39  wherein said liposome is unilamellar and less than 100 nm.  
     
     
         42 . The composition of  claim 41  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 5:1 to 75:1.  
     
     
         43 . The composition of  claim 42  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 8:1 to 20:1.  
     
     
         44 . The composition of  claim 25  wherein said BTSI is GW1843 and wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine (HSPC), and wherein said HSPC:cholesterol are in a molar ratio of about 2:1, and wherein the HSPC:BTSI molar ratio is from 8:1 to 20:1.  
     
     
         45 . A process for making liposomes comprising a benzoquinazoline thymidylate synthase inhibitor (BTSI), said method comprising: 
 a) forming a lipid film or powder comprised of phosphatidylcholine and cholesterol;    b) hydrating said lipid film or powder with an aqueous solution containing BTSI;    c) applying energy whereby liposomes that are unilamellar and less than 100 nm are obtained;    d) cross-filtering against an aqueous solution to remove unencapsulated BTSI, whereby liposomes containing BTSI are obtained.    
     
     
         46 . The method of  claim 45  wherein said phosphatidylcholine is selected from the group consisting of distearoylphosphatidylcholine, hydrogenated soy phosphatidylcholine, soy phosphatidylcholine, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, and dimyristoylphosphatidylcholine.  
     
     
         47 . The method of  claim 46  wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine.  
     
     
         48 . The method of  claim 46  wherein said phosphatidylcholine is soy phosphatidylcholine.  
     
     
         49 . The method of  claim 46  wherein said phosphatidylcholine is dioleoylphosphatidylcholine.  
     
     
         50 . The method of  claim 46  wherein said phosphatidylcholine is dielaidoylphosphatidylcholine.  
     
     
         51 . The method of  claim 46  wherein said liposome further comprises phosphatidylglycerol.  
     
     
         52 . The method of  claim 45  wherein said energy is applied by a homogenizer.  
     
     
         53 . The method of  claim 47  wherein said BTSI is GW1843.  
     
     
         54 . The method of  claim 48  wherein said BTSI is GW1843.  
     
     
         55 . The method of  claim 49  wherein said BTSI is GW1843.  
     
     
         56 . The method of  claim 50  wherein said BTSI is GW1843.  
     
     
         57 . The method of  claim 51  wherein said BTSI is GW1843.  
     
     
         58 . The method of  claim 47  wherein the hydrogenated soy phosphatidylcholine to cholesterol molar ratio is from about 5:1 to 2:1.5.  
     
     
         59 . The method of  claim 58  wherein said molar ratio is about 2:1.  
     
     
         60 . The method of  claim 58  wherein said molar ratio is about 4:1.  
     
     
         61 . The method of  claim 59  wherein said liposome is unilamellar and less than 100 nm.  
     
     
         62 . The method of  claim 61  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 5:1 to 75:1.  
     
     
         63 . The method of  claim 62  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 8:1 to 20:1.  
     
     
         64 . The method of  claim 45  wherein said BTSI is GW1843 and wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine (HSPC), and wherein said HSPC:cholesterol are in a molar ratio of about 2:1, and wherein the HSPC:BTSI molar ratio is from 8:1 to 20:1.  
     
     
         65 . A method of inhibiting the growth of a tumor comprising the administration of a therapeutic or effective amount of the composition of  claim 1  to a tumor.  
     
     
         66 . The method of  claim 65  wherein said tumor is drug resistant or drug sensitive.  
     
     
         67 . The method of  claim 65  wherein said tumor is from a cancer selected from the group consisting of ovarian, lung, colorectal breast, head and neck, prostate, uteran, glioblastoma, and sarcoma.  
     
     
         68 . The method of  claim 67  wherein said phosphatidylcholine is selected from the group consisting of distearoylphosphatidylcholine, hydrogenated soy phosphatidylcholine, soy phosphatidylcholine, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dielaidoylphosphatidylcholine, and dimyristoylphosphatidylchoiline.  
     
     
         69 . The method of  claim 68  wherein said phosphatidylcholine is hydrogenated soy phosphatidylcholine.  
     
     
         70 . The method of  claim 68  wherein said phosphatidylcholine is soy phosphatidylcholine.  
     
     
         71 . The method of  claim 68  wherein said phosphatidylcholine is dioleoylphosphatidylcholine.  
     
     
         72 . The method of  claim 68  wherein said phosphatidylcholine is dielaidoylphosphatidylcholine.  
     
     
         73 . The method of  claim 68  wherein said liposome further comprises phosphatidylglycerol.  
     
     
         74 . The method of  claim 69  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         75 . The method of  claim 70  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         76 . The method of  claim 71  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         77 . The method of  claim 72  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         78 . The method of  claim 73  wherein said benzoquinazoline thymidylate synthase inhibitor is GW1843.  
     
     
         79 . The method of  claim 78  wherein said hydrogenated soy phosphatidylcholine, cholesterol and phosphatidylglycerol are in a molar ratio of about 2:1:0.1.  
     
     
         80 . The method of  claim 74  wherein the hydrogenated soy phosphatidylcholine to cholesterol molar ratio is from about 5:1 to 2:1.5.  
     
     
         81 . The method of  claim 80  wherein said molar ratio is about 2:1.  
     
     
         82 . The method of  claim 80  wherein said molar ratio is about 4:1.  
     
     
         83 . The method of  claim 81  wherein said liposome is unilamellar and less than 100 nm.  
     
     
         84 . The method of  claim 83  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 5:1 to 75:1.  
     
     
         85 . The method of  claim 75  wherein said molar ratio is about 2:1.  
     
     
         86 . The method of  claim 76  wherein said molar ratio is about 2:1.  
     
     
         87 . The method of  claim 77  wherein said molar ratio is about 2:1.  
     
     
         88 . The method of  claim 83  wherein said hydrogenated soy phosphatidylcholine to GW1843 molar ratio is from about 8:1 to 20:1.