SELF-REGULATING OSMOTIC GASTRORETENTIVE DRUG DELIVERY SYSTEMS
Self-regulating, osmotic, floating gastroretentive compositions that provide extended release, delayed release, and/or delayed extended release of active pharmaceutical agents, as well as, optionally, immediate release of the same or a different active pharmaceutical agent, are provided here. The gastroretentive compositions of the disclosure comprise a swellable, extended release, multilayer core comprising a push layer and a pull layer; a water-insoluble permeable elastic membrane surrounding the multilayer core; and an orifice (e.g., a laser-drilled orifice, a manually drilled orifice) on the pull-layer side of the dosage form. The gastric retention of the composition is controlled by rapid floating of the composition and expansion of the membrane. The rapid swelling of the composition to a size greater than the size of the pyloric sphincter is due to the presence of an osmogen, adequate membrane permeability that provides for fast generation of CO 2 from a gas-generating agent(s), and adequate membrane elasticity that provides for rapid expansion of the membrane. The hydrated core, especially the polyethylene oxide in the push layer, and the permeable elastic membrane with an orifice (1) provide extended release of the active pharmaceutical agent, and (2) maintain the dosage form at a size suitable for gastric retention. The self-regulating composition collapses, or breaks into pieces, after releasing at least about 80% of the drug from the composition.
1 . A gastroretentive dosage form suitable for once-a-day administration, the dosage form comprising:
a) a multilayer core comprising:
(i) a pull layer comprising an active pharmaceutical agent, and a gas generating agent; and
(ii) a push layer, and
b) a functional coat surrounding the multilayer core,
wherein the functional coat is a permeable elastic membrane comprising at least one orifice,
wherein the orifice in the permeable elastic membrane is in fluid communication with the pull layer, and
wherein the dosage form exhibits a floating lag time of about 30 minutes or less and exhibits at least about 50% volume gain at about 30 minutes, measured in about 200 ml to about 250 ml dissolution medium comprising pH 4.5 acetate buffer, using Rotating Bottle method at 15 rpm and 37° C.
2 . The dosage form of claim 1 , wherein the dosage form exhibits a floating lag time of about 60 minutes or less, measured in about 250 ml dissolution medium comprising pH 4.5 acetate buffer, using USP Dissolution Apparatus III, at 25 dpm and 37° C.
3 . The dosage form of claim 1 , wherein the dosage form exhibits a floating lag time of about 60 minutes or less, measured in a about 250 ml dissolution medium comprising 10 mM of NaCl and 0.001N HCl, using Rotating Bottle method at 15 rpm and 37° C.
4 . The dosage form of claim 1 , wherein the dosage form exhibits a volume gain of at least about 100% in about 60 minutes or less, measured in about 250 ml dissolution medium comprising pH 4.5 acetate buffer, measured using Rotating Bottle Method at 15 rpm and 37° C.
5 . The dosage form of claim 1 , wherein the permeable elastic membrane comprises at least one copolymer of ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride.
6 . The dosage form of claim 5 , wherein the copolymer is present in an amount of greater than 60 wt %, based on the total weight of the permeable elastic membrane.
7 . The dosage form of claim 1 , wherein the permeable elastic membrane comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, polyethylene glycol, propylene glycol, dibutyl sebacate, and mixtures thereof.
8 . The dosage form of claim 1 , wherein the gas generating agent is sodium bicarbonate, calcium carbonate, or a mixture thereof.
9 . The dosage form of claim 1 , wherein the gas generating agent is present in an amount of from about 5 wt % to about 50 wt % of the pull layer.
10 . The dosage form of claim 1 , wherein the pull layer further comprises an acid selected from the group consisting of succinic acid, citric acid, acetic acid, malic acid, tartaric acid, boric acid, and mixtures thereof.
11 . The dosage form of claim 1 , wherein both the pull layer and the push layer further comprise at least one swellable water-soluble hydrophilic polymer.
12 . The dosage form of claim 1 , wherein the dosage form is an oval, modified oval, or capsule shaped, multilayer, gastroretentive tablet comprising a long axis and a short axis, wherein the long axis is from about 12 mm and to about 22 mm, and the short axis is from about 8 mm to about 11 mm.
13 . The dosage form of claim 1 , wherein the dosage form is made by a method comprising:
a) making a pull layer blend comprising at least one active pharmaceutical agent, an acid, a gas generating agent, and a swellable water-soluble hydrophilic polymer, b) making a push layer blend comprising a water-soluble hydrophilic polymer and an osmogen,
c) compressing the pull layer blend and the push layer blend into a bilayer tablet core, d) coating the bilayer tablet core with a functional coat, and
e) drilling an orifice into the functional coat, wherein
the functional coat is a permeable elastic membrane comprising at least one copolymer of ethyl acrylate, methyl methacrylate, and trimethylamminoethyl methacrylate chloride; and at least one plasticizer,
wherein the orifice in the permeable elastic membrane is in fluid communication with the pull layer,
14 . The dosage form of claim 14 , wherein the pull layer blend and the push layer blend are compressed horizontally into the bilayer tablet core.