TRANSMUCOSAL KETAMINE DELIVERY COMPOSITION

• US 20160256415A1
• Filed: 05/06/2016
• Published: 09/08/2016
• Est. Priority Date: 02/24/2003
• Status: Active Grant

• Current Assignee: Pharmaceutical Productions, Inc.
• Original Assignee: Pharmaceutical Productions, Inc.
• Inventors: McCarty, John A.
• Granted Patent: US 10,172,810 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

Disclosed are preparations and formulations of high thermodynamic activity lipophilic associations (LA), in which there is pairing between an ionizable pharmaceutical agent and a lipophilic species having ionic characteristics opposite to that of the pharmaceutical agent. Such lipophilic associations manifest high thermodynamic activity, as evidenced by their being predominantly in a liquid phase at room temperature or solvated in a lower-than-water dielectric solvent. Further the pharmaceutical agent being solubilized means that dissolution is not rate limiting to transmucosal absorption. This LA or LA-solvate is formulated into a low dielectric dosage form, from when, upon the dosage form'"'"'s hydration, the pharmaceutical agent is driven through the mucosal tissue and into systemic circulation. The invention therefore provides an enhanced transmucosal drug delivery system for ionizable pharmaceutical agents at or near physiological pH.

Claims

1. A pharmaceutical composition in a solid dosage form for buccal or sublingual delivery, comprising:

ketamine;

a fatty acid in which the ketamine is solvated; and

a solid adsorbent to which solvated ketamine is adsorbed, the adsorbent being a silica or silicified microcrystalline cellulose,

wherein the ketamine in the solid dosage form of the composition is in solution.

2. The pharmaceutical composition of claim 1, wherein the fatty acid is caproic acid, oleic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, gadoleic acid, erucic acid, ricinoleic acid, linoleic acid, linoleic acid, licanic acid, arachidonic acid, clupanodonic acid, or mixtures thereof.

3. The pharmaceutical composition of claim 2, wherein the fatty acid comprises oleic acid.

4. The pharmaceutical composition of claim 1, further including a co-solvent.

5. The pharmaceutical composition of claim 4, wherein the co-solvent comprises polyethylene glycol (PEG), ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate, tributyl citrate, substituted polyethylene glycols, bisabolol, glycerin, mineral oil, ethyl oleate, squalane, animal oils, vegetable oils, propylene glycol, hydrogenated vegetable oils, isopropyl myristate, isopropyl palmitate, glycofurol, terpenes, essential oils, alcohols, polyols, silicone fluids, or mixtures thereof.

6. The pharmaceutical composition of claim 5, wherein the co-solvent comprises ethanol.

7. The pharmaceutical composition of claim 1, further comprising a solid, water-soluble excipient, a disintegrant, a lubricant, or mixtures thereof.

8. The pharmaceutical composition of claim 7, further comprising a co-solvent.

9. The pharmaceutical composition of claim 7, wherein the solid water-soluble excipient is selected from the group consisting of a sugar, a polyol, a saccharide, a polysaccharide, a dextrate, a dextrin, dextrose, fructose, lactitol, lactose, erythritol, maltose, maltitol, a maltodextrin, a polydextrose, trehalose, mannitol, a polyethylene glycol, sorbitol, sucrose, xylitol and mixtures thereof.

10. The pharmaceutical composition of claim 9, wherein the water-soluble excipient, comprises mannitol.

11. The pharmaceutical composition of claim 9, wherein the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, microcrystalline cellulose and mixtures thereof.

12. The pharmaceutical composition of claim 11, wherein the disintegrant comprises low-substituted hydroxypropyl cellulose.

13. The pharmaceutical composition of claim 7, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stearate and mixtures thereof.

14. The pharmaceutical composition of claim 13, wherein the lubricant comprises sodium stearyl fumarate.

15. The pharmaceutical composition of claim 1, comprising:

about 0.1 mg to about 20 mg ketamine

about 0.4 mg to about 80 mg fatty acid; and

up to about 200 mg adsorbent.

16. The pharmaceutical composition of claim 15, further comprising a co-solvent in an amount up to about 50 mg.

17. The pharmaceutical composition of claim 15, further comprising:

about 25 mg to about 500 mg solid water-soluble excipient;

about 0.5 mg to about 150 mg disintegrant; and

/or

about 0.1 mg to about 20 mg lubricant.

18. The pharmaceutical composition of claim 1, which is in the form of a tablet.

19. A process for the preparation of the pharmaceutical composition of claim 1, comprising:

solvating ketamine in the pharmaceutically acceptable fatty acid to form a solvated drug solution; and

adsorbing the solvated drug solution to the adsorbent,

the solvated drug solution being in liquid form in the adsorbent.

20. A process for the preparation of the pharmaceutical composition of claim 7, comprising:

solvating ketamine in the pharmaceutically acceptable fatty acid and co-solvent to form a solvated drug solution;

adsorbing the solvated drug solution to the adsorbent;

mixing the solvated drug solution/adsorbent with a water-soluble excipient, a disintegrant, and/or a lubricant; and

compressing the solvated drug solution, adsorbent, disintegrant, excipient, and/or lubricant into the tablet form,

the solvated drug solution being in liquid form in the adsorbent.

21. A method for treating depression, suicidal ideation, pain, anesthesia, analgesia post traumatic shock disorder, and other central nervous systems disease states for which ketamine is an effective therapeutic, in a patient in need thereof, comprising:

administering the pharmaceutical composition of claim 1 to the buccal or sublingual cavity of the patient,

whereby a therapeutically effective amount of ketamine is released and is systemically administered to the patient within 5 minutes to 15 minutes.

22. A method for treating depression, suicidal ideation, pain, anesthesia, analgesia post traumatic shock disorder, and other central nervous systems disease states for which ketamine is an effective therapeutic, in a patient in need thereof, comprising:

administering the pharmaceutical composition of claim 7 to the buccal or sublingual cavity of the patient,

whereby a therapeutically effective amount of ketamine is released and is systemically administered to the patient within 5 minutes to 15 minutes.

23. The pharmaceutical composition of claim 1, wherein ketamine is an R enantiomer, an S enantiomer, or a mixture thereof.

24. The pharmaceutical composition of claim 7, wherein ketamine is an R enantiomer, an S enantiomer, or a mixture thereof.

25. A method for treating depression, suicidal ideation, pain, anesthesia, analgesia post traumatic shock disorder, and other central nervous systems disease states for which ketamine is an effective therapeutic, in a patient in need thereof, comprising:

administering the pharmaceutical composition of claim 23 to the buccal or sublingual cavity of the patient,

whereby a therapeutically effective amount of ketamine is released and is systemically administered to the patient within 5 minutes to 15 minutes.

26. A method for treating depression, suicidal ideation, pain, anesthesia, analgesia post traumatic shock disorder, and other central nervous systems disease states for which ketamine is an effective therapeutic, in a patient in need thereof, comprising:

administering the pharmaceutical composition of claim 24 to the buccal or sublingual cavity of the patient,

whereby a therapeutically effective amount of ketamine is released and is systemically administered to the patient within 5 minutes to 15 minutes.