Programmable pharmaceutical compositions for chrono drug release

Abstract

The present disclosure provides programmable osmotic-controlled oral compositions providing delayed release of a therapeutically acceptable amount of a drug. In certain embodiments, the programmable osmotic-controlled compositions of the disclosure provide a lag time that is independent of the presence or absence of food, type of food, pH, gastric emptying, and volume of gastric fluid. The programmable osmotic-controlled oral compositions of the disclosure comprise a multilayer core comprising a drug for controlled release, wherein the core is coated with a semipermeable membrane comprising an orifice and, optionally, an immediate release coating, comprising a drug for immediate release, over the semipermeable membrane. The multilayered core comprises a pull layer containing the drug and a push layer. The pull layer comprises at least two layers: a placebo layer for providing a desired lag time for the drug release; and an active layer containing the drug and providing a delayed controlled release of the drug. The compositions of the disclosure can be programmed to provide a desired and precise lag time, and release drug, after the lag time, at a rhythm, e.g., that matches the human circadian rhythm of a condition's symptoms and/or of the individual being treated in the application of the therapy to optimize therapeutic outcome and minimize side effects.

What is claimed is: 
     
         1 . An osmotic-controlled oral pharmaceutical composition providing delayed release of a drug, the composition comprising a multilayer core comprising a placebo layer, an active layer, and a push layer; wherein
 the active layer comprises at least one drug for delayed release; wherein the placebo layer, the active layer, and the push layer, each comprise at least one polyethylene oxide polymer; wherein   an average molecular weight of the polyethylene oxide polymer in the push layer is higher than an average molecular weight of the polyethylene oxide polymer in the placebo layer; and the average molecular weight of the polyethylene oxide polymer in the placebo layer is higher than an average molecular weight of the polyethylene oxide polymer in the active layer; and   wherein the active layer is positioned between and in contact with the placebo layer and the push layer.   
     
     
         2 . The composition of  claim 1 , wherein the average molecular weight of the polyethylene oxide polymer in the placebo layer is between 300,000 Da and 1,000,000 Da. 
     
     
         3 . The composition of  claim 1 , wherein the average molecular weight of the polyethylene oxide polymer in the active layer is less than or equal to 300,000 Da. 
     
     
         4 . The composition of  claim 1 , wherein the average molecular weight of the polyethylene oxide polymer in the push layer is greater than or equal to 1,000,000 Da. 
     
     
         5 . The composition of  claim 1 , wherein the composition further comprises a semipermeable membrane comprising at least one orifice and surrounding the core. 
     
     
         6 . The composition of  claim 1 , wherein the placebo layer is in fluid communication with the at least one orifice in the semipermeable membrane and the push layer is facing away from the at least one orifice. 
     
     
         7 . The composition of  claim 1 , wherein the composition when tested for dissolution in about 900 ml of a dissolution medium comprising about 0.01N HCl, using USP Apparatus II (sinkers) at about 50 rpm and about 37° C., provides a lag time of at least 4 hours during which the composition releases no more than 10 wt % of the drug. 
     
     
         8 . The composition of  claim 1 , wherein the drug is selected from the group consisting of amphetamines, methylphenidate, diltiazem, carbamazepine, metoprolol, oxprenolol, nifedipine, albuterol, phenylpropanolamine, pseudoephedrine, chlorpheniramine maleate, prazosin, doxazosin, verapamil, oxybutynin chloride, isradipine, hydromorphone, paliperidone, modafinil, armodafinil, liothyronine, oseltamivir (Tamiflu), rifamycin, and glipizide. 
     
     
         9 . The composition of  claim 5 , wherein the semipermeable membrane comprises a pH-independent water-insoluble polymer and a water-soluble pore former. 
     
     
         10 . The composition of  claim 9 , wherein the pH-independent water-insoluble polymer in the semipermeable membrane is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose triacetate, and combinations thereof. 
     
     
         11 . The composition of  claim 9 , wherein the water-soluble pore former is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, polyvinyl pyrolidone, polyvinyl acetate, mannitol, and methyl cellulose, poloxamer, triethyl citrate, triacetin, hydroxypropyl methylcellulose, glycerol, and combinations thereof. 
     
     
         12 . The composition of  claim 9 , wherein the water-soluble pore former is a plasticizer selected from the group consisting of polyethylene glycol, triethyl citrate, triacetin, diethyl tartrate, and combinations thereof. 
     
     
         13 . The composition of  claim 9 , wherein the pH-independent water-insoluble polymer and the water-soluble pore former are present in a weight ratio of from about 80:20 to about 99.5:0.5. 
     
     
         14 . The composition of  claim 1 , wherein the push layer further comprises an osmogen selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, lithium sulfate, sodium sulfate, lactose and sucrose combination, lactose and dextrose combination, sucrose, dextrose, mannitol, dibasic sodium phosphate, or combinations thereof. 
     
     
         15 . An osmotic-controlled oral pharmaceutical composition comprising a multilayer core comprising a placebo layer, an active layer, and a push layer; and an immediate release drug layer containing a drug for immediate release and surrounding the multilayer core; wherein
 the active layer comprises at least one drug for delayed release; wherein the placebo layer, the active layer, and the push layer, each comprise at least one polyethylene oxide polymer; wherein   an average molecular weight of the polyethylene oxide polymer in the push layer is higher than an average molecular weight of the polyethylene oxide polymer in the placebo layer; and the average molecular weight of the polyethylene oxide polymer in the placebo layer is higher than an average molecular weight of the polyethylene oxide polymer in the active layer; wherein   the active layer is positioned between and in contact with the placebo layer and the push layer; and   wherein the composition provides an immediate release of the drug present in the immediate release drug layer, and a delayed release of the drug present in the active layer.   
     
     
         16 . The composition of  claim 15 , wherein the release of the drug from the multilayer core is delayed by at least 4 hours, during which the composition releases no more than 10 wt % of the drug present in the multilayer core. 
     
     
         17 . The composition of  claim 15 , wherein the average molecular weight of the polyethylene oxide polymer in the placebo layer is between 300,000 Da and 1,000,000 Da; the average molecular weight of the polyethylene oxide polymer in the active layer is less than or equal to 300,000 Da; and the average molecular weight of the polyethylene oxide polymer in the push layer is greater than or equal to 1,000,000 Da. 
     
     
         18 . The composition of  claim 15 , wherein the composition further comprises a semipermeable membrane comprising at least one orifice, wherein the semipermeable membrane is surrounding the core and is placed between the immediate release drug layer and the core. 
     
     
         19 . The composition of  claim 18 , wherein the placebo layer is in fluid communication with the at least one orifice in the semipermeable membrane and the push layer is facing away from the at least one orifice. 
     
     
         20 . An osmotic-controlled oral pharmaceutical composition providing delayed release of a drug, the composition comprising a multilayer core comprising a first placebo layer, a first active layer, a second placebo layer, a second active layer, and a push layer; wherein
 the first active layer and the second active layer, each comprise at least one drug for delayed pulsatile release; wherein   the first placebo layer, the first active layer, the second placebo layer, the second active layer, and the push layer, each comprise at least one polyethylene oxide polymer;   wherein an average molecular weight of the polyethylene oxide polymer present in the push layer is higher than an average molecular weight of the polyethylene oxide polymer present in each of the first and the second placebo layers; and the average molecular weight of the polyethylene oxide polymer present in each of the first and the second placebo layers is higher than an average molecular weight of the polyethylene oxide polymer present in each of the first and the second active layers; wherein the average molecular weight of the polyethylene oxide polymer present in each of the first and the second placebo layers are the same; and the average molecular weight of the polyethylene oxide polymer present in each of the first and the second active layers are the same;   wherein the first active layer is positioned between and in contact with the first placebo layer and the second placebo layer; and the second active layer is positioned between the second placebo layer and the push layer; and   wherein the pulsatile release comprises release of a first pulse containing the drug in the first active layer and a second pulse containing the drug in the second active layer.   
     
     
         21 . The composition of  claim 20 , wherein each of the first and the second placebo layers comprise at least one polyethylene oxide polymer having an average molecular weight of between 300,000 Da and 1,000,000 Da; each of the first and the second active layers comprise at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300,000 Da, and the push layer comprises at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1,000,000 Da. 
     
     
         22 . The composition of  claim 21 , wherein the composition further comprises a semipermeable membrane comprising at least one orifice and surrounding the core.