Programmable pharmaceutical compositions for chrono drug release

An osmotic-controlled oral pharmaceutical composition comprising a multilayer core comprising a drug for delayed extended release;

• a semipermeable membrane containing at least one orifice and surrounding the multilayer core;
• and an immediate release drug layer containing a drug for immediate release and surrounding the semipermeable membrane,
• wherein the multilayer core comprises a placebo layer, an active layer, and a push layer, wherein:
• (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da,
• (ii) the active layer comprises a drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da,
• (iii) the push layer comprises an osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M Da;
• wherein the layers in the multilayer core are placed in the following order:
• the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane;
• the active layer;
• and the push layer facing away from the at least one orifice,
• wherein the composition provides an immediate release of the drug present in the immediate release drug layer, and a delayed extended release of the drug present in the multilayer core, and
• 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% of the drug present in the multilayer core.

An osmotic-controlled oral pharmaceutical composition providing pulsatile release of a first drug and a second drug, the composition comprising:

• a) a multilayer core comprising layers in the following order:
• (i) a first placebo layer comprising at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da,
• (ii) a first active layer comprising a first drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da,
• (iii) a second placebo layer comprising at least one polyethylene oxide polymer having an average molecular weight from about 300K Da to about 900K Da,
• (iv) a second active layer comprising a second drug and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da,
• (v) a push layer comprising an osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M;
• and
• b) a semipermeable membrane, containing at least one orifice and surrounding the multilayer core,
• wherein the layers in the multilayer core are placed in the following order:
• the first placebo layer in fluid communication with the at least one orifice in the semipermeable membrane;
• the first active layer;
• the second placebo layer, the second active layer, and the push layer facing away from the at least one orifice,
• wherein the pulsatile release comprises release of a first pulse containing the first drug and a second pulse containing the second drug,
• wherein the release of the first pulse containing the first drug is delayed by at least 4 hours.

A method for making an osmotic controlled pharmaceutical composition, the method comprising:

• (i) preparing a placebo layer blend comprising granules containing at least one polyethylene oxide polymer with an average molecular weight of from about 600K Da to about 900K Da,
• (ii) preparing an active layer blend comprising granules containing at least one drug and at least one polyethylene oxide polymer with an average molecular weight of less than or equal to about 300K Da,
• (iii) preparing a push layer blend comprising at least one osmogen and at least one polyethylene oxide polymer with an average molecular weight of greater than or equal to 1M Da,
• (iv) compressing the placebo layer blend, the active layer blend, and the push layer blend into a trilayer tablet core,
• (v) coating the trilayer tablet core from step (iv) with a coating solution comprising a water-insoluble polymer and a water-soluble pore former to obtain a coated trilayer core, and
• (vi) drilling at least one orifice into the coated trilayer from step (v),
• wherein the layers in the multilayer core are placed in the following order:
• the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane;
• the active layer;
• and the push layer facing away from the at least one orifice, and
• 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% of the drug.

A method for treating a condition that requires release of a drug following circadian rhythm of the condition, the method comprising administering to a subject in need thereof an osmotic controlled oral pharmaceutical composition providing delayed release of a therapeutically effective amount of the drug, the composition comprising:

• a) a multilayer core comprising a placebo layer, an active layer, and a push layer, wherein:
• (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600K Da to about 900K Da, or intermediate values thereof,
• (ii) the active layer comprises the drug, and at least one polyethylene oxide polymer having an average molecular weight of less than or equal to 300K Da,
• (iii) the push layer comprises at least one osmogen and at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1M Da;
• and
• b) a semipermeable membrane, containing at least one orifice and surrounding the core,
• wherein the layers in the multilayer core are placed in the following order:
• the placebo layer in fluid communication with the at least one orifice in the semipermeable membrane;
• the active layer;
• and the push layer facing away from the at least one orifice,
• 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% of the drug.