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Details for Patent: 7,387,788

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Details for Patent: 7,387,788

Title:Pharmaceutical compositions of nicotine and methods of use thereof
Abstract: The present invention comprises non occlusive compositions for transdermal delivery of nicotine, and more particularly pharmaceutically acceptable salts thereof, and methods of making same. The composition may, for example, be a gel suitable for transdermal or transmucosal applications. The compositions of the present invention typically comprise a mixture of water and alcohol, and a solvent system having a mono alkyl ether of diethylene glycol and a glycol present in specified ratios and in specific amounts, wherein the pH of the gel is usually between a pH of 5.5 and 7. The compositions may include further components, for example, the hydroalcoholic vehicle may further comprise additional penetration enhancer(s), buffering agent(s), antioxidant(s), stabilizer(s) and/or gelling agent(s). The invention also relates to a method for the sustained delivery of nicotine pharmaceutically acceptable salts to treat a variety of conditions and disorders.
Inventor(s): Carrara; R. Dario Norberto (Oberwil, CH), Grenier; Arnaud (Steinbrunn le Haut, FR), Besse; Celine (Saint Louis, FR)
Assignee: Antares Pharma IPL AG (Zug, CH)
Filing Date:Jul 24, 2006
Application Number:11/492,568
Claims:1. A transdermal or transmucosal non occlusive pharmaceutical gel formulation comprising: a nicotine compound; a gelling agent; and a solvent system present in an amount sufficient to solubilize the nicotine and characterized in that it includes: (i) a pharmaceutically acceptable monoalkyl ether of diethylene glycol present in an amount of between about 1% and 30% by weight of the solvent system; (ii) a pharmaceutically acceptable glycol present in an amount of between about 1% and 30% by weight of the solvent system, with the monoalkyl ether of diethylene glycol and glycol being present in a weight ratio of 10:1 to 2:1 or 1:2 to 1:10; and wherein the monoalkyl ether of diethylene glycol and the glycol in combination are present in an amount of at least 15% and no more than 60% of the formulation; and (iii) a mixture of a C.sub.2 to C.sub.4 alcohol and water which mixture is present in an amount of between about 40% and 98% of the solvent system, wherein the C.sub.2 to C.sub.4 alcohol is present in an amount of about 5% to 80% of the mixture, and the water is present in an amount of about 20% to 95% of the mixture, so that, compared to formulations containing the same (i) and (ii) components but in different amounts and ratios, the present solvent system (a) inhibits crystallization of the at least one active ingredient on a skin or mucosal surface of a mammal, (b) reduces or prevents transfer of the formulation to clothing or to another being, (c) modulates biodistribution of the at least one active agent within different layers of skin, (d) facilitates absorption of the at least one active agent by a skin or a mucosal surface of a mammal, or (e) provides a combination of one or more of (a) through (d).

2. The non occlusive pharmaceutical formulation of claim 1, wherein the nicotine compound is nicotine, nicotine free base, a pharmaceutically acceptable complex of nicotine, a pharmaceutically acceptable salt of nicotine, or a mixture thereof.

3. The non occlusive pharmaceutical formulation of claim 2, wherein the pharmaceutically acceptable salt of nicotine is nicotine hydrogen tartrate or nicotine bitartrate dihydrate.

4. The non occlusive pharmaceutical formulation of claim 1, wherein the nicotine compound is presented at a concentration of about 0.5 to about 5 weight percent of nicotine free base equivalents and wherein the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 1:2 to 1:10.

5. The non occlusive pharmaceutical formulation of claim 1, wherein the nicotine compound is presented at a concentration of about 1 to about 2 weight percent of nicotine free base equivalents wherein the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 1:2 to 1:10.

6. The non occlusive pharmaceutical formulation of claim 1, wherein the monoalkyl ether of diethylene glycol is selected from the group consisting of diethylene glycol mono methyl ether, and diethylene glycol mono ethyl ether or mixtures thereof, the glycol is selected from the group consisting of propylene glycol, dipropylene glycol or mixtures thereof, and the C.sub.2 to C.sub.4 alcohol is elected from the group consisting of ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or mixtures thereof.

7. The non occlusive pharmaceutical formulation of claim 1, wherein the glycol modulates the capacity of diethylene glycol mono ethyl ether to build a skin depot, and the gel provides a surface area of 50 to 1000 cm.sup.2 when applied to skin.

8. The non occlusive pharmaceutical formulation of claim 1, further including a permeation enhancer present in an amount sufficient to increase permeability of the active agent across a dermal or mucosal surface of a mammal.

9. The non occlusive pharmaceutical formulation of claim 1, further comprising an agent selected from the group consisting of permeation enhancers, preservatives, antioxidants, buffers, humectants, sequestering agents, moisturizers, surfactants, emollients, and any combination thereof.

10. The non occlusive pharmaceutical formulation of claim 9, wherein the permeation enhancer is a fatty alcohol present between 0.1% and 2% by weight of the formulation.

11. A method of delaying or inhibiting crystallization of a nicotine compound in a transdermal or transmucosal non occlusive pharmaceutical formulation, which comprises providing the formulation according to claim 1.

12. The method of claim 11, wherein the nicotine compound is nicotine free base, a pharmaceutically acceptable complex of nicotine, a pharmaceutically acceptable salt of nicotine, and mixtures thereof.

13. The method of claim 12, wherein the pharmaceutically acceptable salt of nicotine is nicotine hydrogen tartrate or nicotine bitartrate dihydrate.

14. The method of claim 11, wherein the nicotine compound is presented at a concentration of about 0.5 to about 5 weight percent of nicotine free base equivalents and the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 1:2 to 1:10.

15. The method of claim 11, wherein the nicotine is presented at a concentration of about 1 to about 2 weight percent of nicotine free base equivalents and the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 1:2 to 1:10.

16. The method of claim 11, wherein the monoalkyl ether of diethylene glycol is selected from the group consisting of diethylene glycol mono methyl ether, and diethylene glycol mono ethyl ether or mixtures thereof, the glycol is selected from the group consisting of propylene glycol, dipropylene glycol or mixtures thereof, and the C.sub.2 to C.sub.4 alcohol is elected from the group consisting of ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or mixtures thereof.

17. The method of claim 11, wherein the glycol modulates the capacity of diethylene glycol mono ethyl ether to build a skin depot and the pH of the formulation is between about pH 4.5 and about pH 8.5.

18. The method of claim 11, further including a permeation enhancer present in an amount sufficient to increase permeability of the active agent across a dermal or mucosal surface of a mammal.

19. The method of claim 11, wherein the permeation enhancer is a fatty alcohol present in an amount of between 0.1% and 2% by weight of the formulation.

20. The method of claim 11, further comprising an agent selected from the group consisting of gelling agents; permeation enhancers, preservatives, antioxidants, buffers, humectants, sequestering agents, moisturizers, surfactants, emollients, and any combination thereof.

21. The pharmaceutical composition of claim 1 provided in a unit dose container.

22. The pharmaceutical composition of claim 21, wherein the container is a packet or a vial, wherein the inner surface of the container optionally comprises a liner.

23. The pharmaceutical composition of claim 22, wherein the packet is a flexible, foil packet and the liner is a polyethylene liner.

24. The pharmaceutical composition of claim 1 provided in a multiple dose container.

25. The pharmaceutical composition of claim 24, wherein the multiple dose container dispenses fixed or variable metered doses and optionally includes a stored-energy metered dose pump or a manual metered dose pump.

26. A method for administering an active agent to a human subject in need thereof, the method comprising: providing a gel for pharmaceutical drug delivery, comprising: a therapeutically effective amount of a nicotine compound, or a pharmaceutically acceptable salt thereof; a solvent system present in an amount sufficient to solubilize the nicotine and characterized in that it includes: (i) a pharmaceutically acceptable monoalkyl ether of diethylene glycol present in an amount of between about 1% and 30% by weight of the solvent system; (ii) a pharmaceutically acceptable glycol present in an amount of between about 1% and 30% by weight of the solvent system, with the monoalkyl ether of diethylene glycol and glycol being present in a weight ratio of 10:1 to 2:1 or 1:2 to 1:10; and (iii) a mixture of a C.sub.2 to C.sub.4 alcohol and water which mixture is present in an amount of between about 40% and 98% of the solvent system, wherein the C2 to C4 alcohol is present in an amount of about 5% to 80% of the mixture, and the water is present in an amount of about 20% to 95% of the mixture, applying one or more daily dose of the gel to a skin surface of the subject in an amount sufficient for the nicotine to achieve therapeutic concentration in the bloodstream of the subject.

27. The method of claim 26, wherein the human subject is in need of nicotine therapy to treat smoking cessation.

28. The method of claim 26, wherein the human subject is in need of nicotine therapy to treat irritable bowel syndrome.

29. The method of claim 26, wherein the human subject is in need of nicotine therapy to treat neurological disorders, selected from the group consisting of anxiety, depression, schizophrenia, Alzheimer's Disease, Parkinson's Disease, Restless Legs Syndrome, Tourette's Syndrome, Chronic Tic Disorder, Essential Tremor, and Attention Deficit Hyperactivity Disorder.

30. The method of claim 26, wherein the gel has an amount of nicotine free base equivalents between about 0.5 and about 5 weight percent and up to about 10 grams of the gel is applied daily to a skin surface area of between about 50 to about 1000 cm.sup.2 in single or divided doses.

31. The pharmaceutical composition of claim 1 provided in a dosage form for delivery of nicotine to a subject, wherein said dosage form is configured to provide steady-state delivery of nicotine with once-a-day dosing.

32. The pharmaceutical composition of claim 31, wherein said once-a-day dosing is performed for at least about 2 successive days.

33. The pharmaceutical composition of claim 31, wherein said dosage form comprises a dose of nicotine between about 0.5 to about 5 weight percent of nicotine free base equivalents.
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