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. 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, gastric motility, and volume and viscosity of gastric fluid. 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 extended release of a drug, the composition comprising a capsule shaped multilayer core comprising a first narrow end and a second narrow end; wherein
 the multilayer core comprises a placebo layer positioned at the first narrow end, a push layer positioned at the second narrow end, and an active layer positioned between and in contact with the placebo layer and the active layer; wherein   the active layer comprises at least one drug selected from the group consisting of CNS-acting drugs, cardiovascular drugs, anti-infectives, analgesics, anesthetics, antiarthritics, anticholinergics, anti-asthmatics, antidepressants, antimigraine drugs, antiparkinson drugs, anticonvulsants, armodafinil, modafinil, calcium channel blockers, beta blockers, decongestant, sedatives, antihypertensives, ACE inhibitors, antidiabetics, and tranquilizers: wherein   the placebo layer, the active layer, and the push layer, each comprise at least one polyethylene oxide polymer; wherein   molecular weight of the polyethylene oxide polymer in the push layer is higher than molecular weight of the polyethylene oxide polymer in the placebo layer; and the molecular weight of the polyethylene oxide polymer in the placebo layer is higher than molecular weight of the polyethylene oxide polymer in the active layer.   
     
     
         2 . The composition of  claim 1 , wherein the composition further comprises a semipermeable membrane comprising at least one orifice and surrounding the core. 
     
     
         3 . The composition of  claim 2 , wherein the semipermeable membrane comprises a water-insoluble polymer and a water-soluble pore former. 
     
     
         4 . The composition of  claim 3 , wherein the water-insoluble polymer in the semipermeable membrane is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose triacetate, and combinations thereof. 
     
     
         5 . The composition of  claim 2 , wherein the water-soluble pore former is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl acetate, mannitol, and methyl cellulose, poloxamer, triethyl citrate, triacetin, hydroxypropyl methylcellulose, glycerol, and combinations thereof. 
     
     
         6 . The composition of  claim 2 , 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. 
     
     
         7 . The composition of  claim 1 , wherein the molecular weight of the polyethylene oxide polymer in the placebo layer is between 300,000 Da and 1,000,000 Da. 
     
     
         8 . The composition of  claim 1 , wherein the molecular weight of the polyethylene oxide polymer in the active layer is less than or equal to 300,000 Da. 
     
     
         9 . The composition of  claim 1 , wherein the molecular weight of the polyethylene oxide polymer in the push layer is greater than or equal to 1,000,000 Da. 
     
     
         10 . 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 
     
     
         11 . The composition of  claim 10 , wherein the composition releases no more than 10% of the drug during the lag time. 
     
     
         12 . 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, and combinations thereof. 
     
     
         13 . The composition of  claim 12 , wherein the osmogen is present in an amount of from about 5 wt % to about 40 wt % of the push layer. 
     
     
         14 . The composition of  claim 1 , wherein the placebo layer is present in an amount of from about 10 wt % to about 60 wt %, based on the total weight of the multilayer core. 
     
     
         15 . The composition of  claim 1 , wherein the active layer further comprises a surfactant selected from the group consisting of esters of fatty acids; sorbitan fatty acid esters; polyethylene glycol fatty acid esters; polyethylene glycol esters and polyethylene glycol ethers; and polyethoxylated carboxylic acids, PEG-7 hydrogenated castor oil, and PEG-30 dipolyhydroxystearate; block copolymers based on ethylene oxide and propylene oxide; dioctyl sodium sulfosuccinate (docusate sodium); sodium lauryl sulfate; PEG-32 glyceryl laurate; PEG-32 glyceryl palmitostearate; PEG-8 glyceryl caprylate/caprate; PEG-6 glyceryl caprylate/caprate; macrogol 15 hydroxystearate; polyoxyethylene 20 sorbitan monolaurate (polysorbate 20); polyoxyethylene 20 sorbitan monooleate (polysorbate 80); sorbitan monolaurate; sorbitan monooleate; polyoxyl 40 stearate, and any combinations thereof. 
     
     
         16 . The composition of  claim 15 , wherein the composition further comprises an immediate release drug layer containing a drug for immediate release and surrounding the multilayer core. 
     
     
         17 . The composition of  claim 16 , wherein the composition provides a pulsatile release comprising a first pulse comprising an immediate release of the drug present in the immediate release drug layer, and a second pulse comprising a delayed extended release of the drug from the active layer. 
     
     
         18 . An osmotic-controlled oral pharmaceutical composition providing delayed chrono release of a drug, the composition comprising a capsule shaped multilayer core comprising a first narrow end and a second narrow end; wherein
 the multilayer core comprises a placebo layer, an active layer 1, an active layer 2, and a push layer; wherein   the placebo layer is positioned at the first narrow end; the push layer is positioned at the second narrow end; the active layer 1 is positioned between and in contact with the placebo layer and the active layer 2; and the active layer 2 is positioned between and in contact with the active layer 1 and the push layer; wherein   the active layer 1 and the active layer 2, each comprise at least one drug for delayed chrono release; wherein   the at least one drug is selected from the group consisting of CNS-acting drugs, cardiovascular drugs, anti-infectives, analgesics, anesthetics, antiarthritics, anticholinergics, anti-asthmatics, antidepressants, antimigraine drugs, antiparkinson drugs, anticonvulsants, armodafinil, modafinil, calcium channel blockers, beta blockers, decongestant, sedatives, antihypertensives, ACE inhibitors, antidiabetics, and tranquilizers: wherein   the placebo layer, the active layer 1, the active layer 2, and the push layer, each comprise at least one polyethylene oxide polymer; wherein   molecular weight of the polyethylene oxide polymer in the push layer is higher than molecular weight of the polyethylene oxide polymer in the placebo layer; and the molecular weight of the polyethylene oxide polymer in the placebo layer is higher than molecular weight of the polyethylene oxide polymer in the active layer 1 and the active layer 2; and   wherein the active layer 1 and the active layer 2 release the drug over a period of at least two successive intervals, wherein more drug is released in the second interval compared to the first interval.   
     
     
         19 . The composition of  claim 18 , wherein a ratio of the drug to the polyethylene oxide polymer in the active layer 1 is less than a ratio of the drug to the polyethylene oxide polymer present in the active layer 2. 
     
     
         20 . The composition of  claim 18 , wherein the molecular weights of the polyethylene oxide polymer in the drug layer 1 and the drug layer 2 are same. 
     
     
         21 . A pulsatile release oral pharmaceutical composition comprising a capsule shaped multilayer core comprising a first narrow end and a second narrow end; wherein the multilayer core comprises an active layer 1 comprising a first drug, a first placebo layer, an active layer 2 comprising a second drug, and a push layer; wherein
 the active layer 1 is positioned at the first narrow end; the push layer is positioned at the second narrow end; the placebo layer is positioned between and in contact with the active layer 1 and the active layer 2; and the active layer 2 is positioned between and in contact with the placebo layer and the push layer; wherein   the active layer 1 and the active layer 2, each comprise at least one drug selected from the group consisting of CNS-acting drugs, cardiovascular drugs, anti-infectives, analgesics, anesthetics, antiarthritics, anticholinergics, anti-asthmatics, antidepressants, antimigraine drugs, antiparkinson drugs, anticonvulsants, armodafinil, modafinil, calcium channel blockers, beta blockers, decongestant, sedatives, antihypertensives, ACE inhibitors, antidiabetics, and tranquilizers: wherein   the active layer 1, the placebo layer, the active layer 2, and the push layer, each comprise at least one polyethylene oxide polymer; wherein   molecular weight of the polyethylene oxide polymer present in the push layer is higher than molecular weight of the polyethylene oxide polymer present in the placebo layer; and the molecular weight of the polyethylene oxide polymer present in the placebo layer is higher than molecular weight of the polyethylene oxide polymer present in each of the active layer 1 and the active layer 2; wherein   the molecular weight of the polyethylene oxide polymer present in the active layer 1 is equal to the molecular weight of the polyethylene oxide polymer present in active layer 2;   wherein the pulsatile release comprises release of a first pulse containing the drug present in the active layer 1 and a second pulse containing the drug present in the active layer 2.   
     
     
         22 . The composition of  claim 21 , wherein there is a lag time between release of the drug from the first pulse and the drug from the second pulse. 
     
     
         23 . The composition of  claim 21 , wherein the active layer 1 and the active layer 2 comprise the same drug.