Delayed release rasagiline formulation

Abstract

Disclosed are formulations of rasagiline base which are designed to delay release of rasagiline while maintaining specific pharmacokinetic properties. Also, disclosed are rasagiline citrate salt and the use and process of manufacture thereof.

1 - 6 . (canceled) 
     
     
         7 . A method of treating a human subject afflicted with Parkinson's disease comprising administering to the human subject while the human subject is in a fed state a stable oral dosage form comprising a core having at least one pharmaceutically acceptable excipient and rasagiline base, rasagiline citrate, or a mixture of rasagiline base and rasagiline citrate; and an acid resistant pharmaceutically acceptable coating. 
     
     
         8 . The method of  claim 7 , wherein the rasagiline base is crystalline rasagiline base. 
     
     
         9 . The method of  claim 7 , wherein the core of the dosage form consists essentially of at least one pharmaceutically acceptable excipient and rasagiline citrate. 
     
     
         10 . The method of  claim 7 , wherein in the dosage form the at least one pharmaceutically acceptable excipient in the core is at least one anti-oxidant. 
     
     
         11 . The method of  claim 10 , wherein in the core of the dosage form the anti-oxidant is citric acid. 
     
     
         12 . The method of  claim 7 , wherein in the core of the dosage form the at least one pharmaceutically acceptable excipient in the core is at least one disintegrant. 
     
     
         13 . The method of  claim 12 , wherein in the dosage form the disintegrant is present in the core at an amount between 0.5% and 20% by weight. 
     
     
         14 . The method of  claim 12 , wherein the disintegrant is pre-gelatinized starch. 
     
     
         15 . The method of  claim 7 , wherein the dosage form is less than 150 mg by weight. 
     
     
         16 . The method of  claim 9 , wherein the content of rasagiline citrate in the dosage form is 0.74 mg to 3.63 mg. 
     
     
         17 . The method of  claim 9 , wherein the dosage form, in addition to the rasagiline citrate, comprises mannitol, colloidal silicon dioxide, starch NF, pregelatinized starch, stearic acid, talc, hypromellose, methacrylic acid ethyl acrylate copolymer, talc extra fine, and triethyl citrate. 
     
     
         18 . The method of  claim 17 , wherein in the dosage form the content of rasagiline is 1.0 mg and the dosage form comprises 45.0 mg of mannitol, 0.4 mg of aerosil, 5.0 mg of starch NF, 20.0 mg of pregelatinized starch, 1.5 mg of stearic acid, 1.5 mg of talc, 3.5 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine. 
     
     
         19 . The method of  claim 17 , wherein in the dosage form the content of rasagiline is 0.5 mg and the dosage form comprises 45.5 mg of mannitol, 0.4 mg of aerosil, 5.0 mg of starch NF, 20.0 mg of pregelatinized starch, 1.5 mg of stearic acid, 1.5 mg of talc, 3.5 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine. 
     
     
         20 . The method of  claim 18 , wherein the dosage form further comprises 2.0 mg of a color coating agent. 
     
     
         21 . The method of  claim 7 , wherein the core of the dosage form is in the form of a tablet. 
     
     
         22 . The method of  claim 7 , wherein the acid resistant pharmaceutically acceptable coating of the dosage form comprises methacrylic acid-ethyl acrylate copolymer (1:1) and a plasticizer. 
     
     
         23 . The method of  claim 22 , wherein in the acid resistant pharmaceutically acceptable coating the ratio of methacrylic acid-ethyl acrylate copolymer (1:1) to plasticizer is between 10 to 1 and 2 to 1. 
     
     
         24 . The method of  claim 23 , wherein in the acid resistant pharmaceutically acceptable coating the ratio of methacrylic acid-ethyl acrylate copolymer (1:1) to plasticizer is about 5 to 1. 
     
     
         25 . The method of  claim 24 , wherein the plasticizer is triethyl citrate. 
     
     
         26 . The method of  claim 22 , wherein the acid resistant pharmaceutically acceptable coating of the dosage form further comprises talc. 
     
     
         27 . The method of  claim 7 , wherein the acid resistant pharmaceutically acceptable coating of the dosage form is between 3% and 12% by weight of the dosage form. 
     
     
         28 . The method of  claim 27 , wherein the acid resistant pharmaceutically acceptable coating of the dosage form is about 8% by weight of the dosage form. 
     
     
         29 . The method of  claim 7 , wherein the acid resistant pharmaceutically acceptable coating of the dosage form comprises two coating layers. 
     
     
         30 . The method of  claim 29 , wherein the inner one of the two coating layers comprises hypromellose. 
     
     
         31 . The method of  claim 7 , wherein the dosage form releases between 80 and 100% of rasagiline when placed in a basket apparatus in 500 mL of buffered aqueous media at a pH of 6.8 at 37° C. at 75 revolutions per minute for 20 minutes. 
     
     
         31 - 37 . (canceled) 
     
     
         38 . The method of  claim 7 , wherein the dosage form when ingested by a human subject in a fed state provides an AUC value of rasagiline which is greater than that of the corresponding amount of rasagiline ingested as an immediate release formulation. 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 7 , wherein the dosage form when ingested by a human subject in a fed state provides a C max  of rasagiline which is greater than that of the corresponding amount of rasagiline ingested as an immediate release formulation. 
     
     
         42 - 64 . (canceled) 
     
     
         65 . The method of  claim 7 , wherein the subject suffers from delayed gastric emptying. 
     
     
         66 - 68 . (canceled) 
     
     
         69 . The method of  claim 19 , wherein the dosage form further comprises 2.0 mg of a color coating agent.