Single-layer oral dose of neuro-attenuating ketamine
The present invention is directed to oral neuro-attenuating ketamine (NAKET) tablet formulations, and methods of administration, which ensure the steady release of a therapeutically effective concentration of ketamine from an oral tablet without neurologically toxic spikes in ketamine concentration. In particular, the present invention provides single layer oral tablet formulation of NAKET. In a specific embodiment, the NAKET tablet formulation, and methods of administration provide steady administration of NAKET to a subject for 24 hours or greater, for example, up to 36 hours, after a single administration event.
1 . A single-layer orally administered tablet composition comprising: neuro-attenuating ketamine (NAKET) and;
a polymer carrying one or more negatively charged groups selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylates, hyaluronic acid, salts thereof, and mixtures thereof; and
a water-insoluble neutrally charged non-ionic matrix selected from the group consisting of cellulose-based polymers, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVP blends; and mixtures thereof;
wherein the tablet is formulated without another active therapeutic agent;
wherein the tablet composition does not contain an anionic gum;
wherein the tablet composition has a release period of the NAKET of greater than 12 hours after oral administration and achieves a combined concentration of ketamine and its metabolite norketamine in plasma in the range of 10-500 ng/ml; and maintains this concentration for duration of the release period.
2 . The tablet composition of claim 1 , wherein the composition is adapted for maximum sustained release polymer carrying one or more negatively charged groups is polyacrylic acid.
3 . The tablet composition of claim 1 , wherein the tablet composition comprises NAKET comprises a combination of (i) a water-insoluble neutrally charged non-ionic matrix; (ii) a polymer carrying one or more negatively charged groups; and (iii) ketamine.
4 . The tablet composition of claim 3 , wherein the non-ionic matrix is selected from cellulose-based polymers, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVP blends; and mixtures thereof.
5 . The tablet composition of claim 4 claim 2 , wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).
6 . The tablet composition of claim 1 , wherein the polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylates, cation-exchange resins, clays, zeolites, hyaluronic acid, anionic gums, salts thereof, and mixtures thereof.
7 . The tablet composition of claim 6 , wherein the anionic gum is selected from the group consisting of naturally occurring materials and semi-synthetic materials.
8 . The tablet composition of claim 7 , wherein the naturally occurring material is selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth.
9 . The tablet composition of claim 7 , wherein the semi-synthetic material is selected from the group consisting of carboxymethyl-chitin and cellulose gum.
10 . The tablet composition of claim 1 , comprising an amount of ketamine therapeutically effective for the treatment of pain.
11 . The tablet composition of claim 1 , comprising an amount of ketamine therapeutically effective for use in the treatment of brain injury.
12 . The tablet composition of claim 1 , comprising an amount of ketamine therapeutically effective for the treatment of depression.
13 . The tablet composition of claim 1 , wherein the neuro-attenuating ketamine achieves a combined concentration of ketamine and its metabolite norketamine in plasma in the range of 10-500 ng/ml, and maintains this concentration for duration of the release period.
14 . The tablet composition of claim 1 , wherein the polymer comprises one or more negatively charged groups.
15 . A tablet composition formulated for oral administration comprising: ketamine and:
a polymer carrying one or more negatively charged groups selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylates, hyaluronic acid, salts thereof, and mixtures thereof; and
a water-insoluble neutrally charged non-ionic matrix selected from the group consisting of cellulose-based polymers, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVP blends; and mixtures thereof;
wherein the tablet is formulated without another active therapeutic agent;
wherein the tablet composition does not contain an anionic gum;
wherein the tablet composition has a release period of the ketamine of greater than 12 hours after oral administration and achieves a combined concentration of ketamine and its metabolite norketamine in plasma in the range of 10-500 ng/ml, and maintains this concentration for duration of the release period.
16 . The tablet of claim 15 wherein the polymer comprises one or more negatively charged groups.
17 . The tablet of claim 15 wherein the polymer comprises one or more acid groups.
18 . The tablet of claim 17 wherein the polymer comprises a water-insoluble neutrally charged non-ionic matrix.
19 . The table of claim 18 wherein the non-ionic matrix is selected from cellulose-based polymers, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVP blends; and mixtures thereof.
20 . The tablet composition of claim 19 claim 15 , wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).
21 . A kit for the treatment of a subject with ketamine comprising 1) a single-layer orally administered tablet composition of claim 1 and 2) and instructions for use in the treatment of pain.
22 . A kit for the treatment of a subject with ketamine comprising 1) a single-layer orally administered tablet composition of claim 1 and 2) instructions for use in the treatment of brain injury.
23 . A kit for the treatment of a subject with ketamine comprising 1) a single-layer orally administered tablet composition of claim 1 and 2) instructions for use in the treatment of depression.
24 . The kit of claim 21 , wherein the polymer comprises one or more negatively charged groups.
25 . The kit of claim 22 , wherein the polymer comprises one or more negatively charged groups.
26 . The kit of claim 23 , wherein the polymer comprises one or more negatively charged groups.
27. The tablet composition of claim 1 , wherein the NAKET achieves a combined concentration of ketamine and its metabolite norketamine in plasma in the range of 10-300 ng/ml, and maintains this concentration for duration of the release period.
28. The tablet composition of claim 1 , wherein the NAKET achieves a combined concentration of ketamine and its metabolite norketamine in plasma in the range of 10-100 ng/ml, and maintains this concentration for duration of the release period.