IMPLANTABLE DEVICES FOR THE SUSTAINED DELIVERY OF AN OPIOID ANTAGONIST AND METHODS FOR TREATING INFLAMMATORY, NEUROINFLAMMATORY AND METABOLIC DISORDERS
Diffusion-based, implantable devices for the delivery of an opioid antagonist, such as naltrexone, are described. The devices are cylindrical or discoidal in shape and fitted with a biocompatible membrane. These are filled with a compressed formulation of the opioid antagonist, and optionally, a binder. Upon introduction of an aqueous fluid into the device, the compressed formulation erodes at a constant rate along one axis to release the opioid antagonist from the device at a constant rate. The rate is selected to range from approximately 0.02-2.00 mg/day for the treatment of inflammatory, neuroinflammatory, or metabolic disorders.
1 . A device for delivery of an opioid antagonist, comprising:
a device comprising an interior reservoir with an inner diameter, a first end, a second end, and a porous partition, the device dimensioned for subcutaneous implantation into a subject;
a solid formulation comprising an opioid antagonist and one or more of a binder, a stabilizing excipient, and a lubricant, the solid formulation in the form of a compressed shape with a diameter equal to or greater than 80% of the inner diameter of the interior reservoir,
wherein the compressed shape when hydrated forms an aqueous phase in the interior reservoir of the device, the aqueous phase comprising dissolved opioid antagonist that is released from the device by diffusion across the porous partition for a period of at least about one month.
2 - 4 . (canceled)
5 . The device of claim 1 , wherein the compressed shape is selected from a tablet, a pellet and a rod.
6 . The device of claim 5 , wherein the compressed shape has a diameter equal to or greater than 90% of the inner diameter of the interior reservoir.
7 . The device of claim 1 , wherein the solid formulation comprises a binder.
8 . The device of claim 7 , where the binder is selected from the group consisting of lactose, maltose, mannitol, trehalose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethyleneglycol, a fatty acid or alcohol containing a minimum of 12 carbon atoms, and a dicarboxylic acid containing a minimum of 8 carbon atoms.
9 . (canceled)
10 . The device of claim 9 , wherein the solid formulation comprises a stabilizing excipient selected from a metal chelating agent, a buffering agent, and an antioxidant.
11 . The device of claim 1 , wherein the solid formulation has a melting point greater or equal to about 40° C.
12 - 20 . (canceled)
21 . The device of claim 1 , wherein the opioid antagonist is naltrexone base or a pharmaceutically acceptable salt of naltrexone.
22 - 25 . (canceled)
26 . The device of claim 1 , wherein the opioid antagonist is in amount to maintain a therapeutically effective plasma level of the opioid antagonist and/or a metabolite thereof for the period.
27 - 28 . (canceled)
29 . A method for in vivo delivery of an opioid antagonist, comprising:
providing a device according to claim 1 , and
implanting the device into a subcutaneous space of a human subject, whereby said implanting results in an aqueous fluid in the subcutaneous space entering the device to hydrate the formulation, or
prior to implanting the device into a subcutaneous space of a human subject, contacting the device with an aqueous fluid to wet the device membranes and formulation.
30 - 32 . (canceled)
33 . A method for the treatment of an inflammatory, neuroinflammatory, or metabolic disorder, comprising:
providing a device according to claim 1 ,
administering the device to a human subject by subcutaneous implantation, whereby said administering provides delivery of the opioid antagonist in an amount that provides a therapeutic blood level for a period of between about 1-36 months.
34 - 38 . (canceled)
39 . The device of claim 10 , wherein the metal chelating agent is ethylenediaminetetraacetic acid.
40 . The device of claim 10 , wherein the buffering agent is selected from the group consisting of a phosphate salt, a carboxylate salt, and an amino acid.
41 . The device of claim 10 , wherein the antioxidant is selected from ascorbic acid, an ascorbic acid ester, tocopherol, a tocopherol ester, cysteine, a cysteine ester or amide, methionine, a methionine ester or amide, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
42 . The device of claim 1 , wherein the solid formulation comprises a lubricant selected from the group consisting of stearic acid, magnesium stearate, stearin, calcium stearate, sodium lauryl sulfate, glyceryl behenate, sodium benzoate, and talc.