MICROENCAPSULATION OF NICOTINE FOR TOBACCOLESS ORAL ADMINISTRATION

Abstract

This disclosure provides nicotine-loaded microcapsules for use in treating or preventing nicotine dependence, or a withdrawal symptom thereof, in a subject in need thereof. The disclosure also provides pharmaceutical compositions and pharmaceutical formulations comprising nicotine-loaded microcapsules. The disclosure also provides methods of making nicotine-loaded microcapsules.

Claims

1. A microcapsule comprising: (a) an agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein: (i) the inner core comprises nicotine and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell comprises one or more food grade wall materials.

2. The microcapsule of claim 1, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.

3. (canceled)

4. The microcapsule of claim 1, wherein the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg protein, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, canola protein, albumin, poly-lysine, dilutan gum, locus bean gum, or Welan gum, or a combination thereof.

5. (canceled)

6. The microcapsule of claim 1, wherein the inner core, the primary shell, and/or the outer shell further comprise one or more processing aids.

7. The microcapsule of claim 6, wherein the one or more processing aids comprise an antioxidant, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof.

8. (canceled)

9. The microcapsule of claim 1, wherein the primary shell and/or the outer shell comprises cross-linked food grade wall materials.

10. The microcapsule of claim 1, wherein the primary shell and/or the outer shell comprises a complex coacervate of the food grade wall materials.

11. The microcapsule of claim 1, wherein the diameter of the microcapsule is from about 1 μm to about 500 μm.

12. The microcapsule of claim 1, wherein the microcapsule comprises from about 1 wt % to about 25 wt % of nicotine.

13. A pharmaceutical composition comprising the microcapsule of claim 1 and one or more pharmaceutically acceptable excipients.

14. A pharmaceutical formulation comprising the microcapsule of claim 1, for oral administration to a subject, wherein said formulation is administered to the subject as a softgel, a tablet, a capsule, a gummie, a lozenge, a chewing gum, a taffy, a film, or an edible product.

15. (canceled)

16. An emulsion comprising nicotine, one or more food grade oils, one or more food grade wall materials, and water.

17. The emulsion of claim 16, wherein the emulsion droplet size is about 5 μm or less.

18. The emulsion of claim 16, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.

19. (canceled)

20. The emulsion of claim 16, wherein the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg proteins, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, canola protein, albumin, poly-lysine, dilutan gum, locus bean gum, or Welan gum, or a combination thereof.

21. (canceled)

22. The emulsion of claim 16, further comprising one or more processing aids.

23. The emulsion of claim 22, wherein the one or more processing aids comprise an antioxidant, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof.

24. (canceled)

25. A method of preparing the microcapsule of claim 1, the method comprising: (i) providing an emulsion comprising nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; and (ii) spray drying the emulsion to provide a powder comprising the microcapsule.

26. A method of preparing the microcapsule of claim 1, the method comprising: (i) providing an emulsion comprising nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; (ii) adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, of the emulsion to form a coacervate slurry; and (iii) spray drying the coacervate slurry to provide a powder comprising the microcapsule.

27. The method of claim 25, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.

28. (canceled)

29. The method of claim 25, wherein the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg proteins, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, canola protein, albumin, poly-lysine, dilutan gum, locus bean gum, or Welan gum, or a combination thereof.

30. (canceled)

31. The method of claim 25, wherein the emulsion comprises one or more processing aids.

32. The method of claim 31, wherein the one or more processing aids comprise an antioxidant, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, tocopherols, or a mixture thereof.

33. (canceled)

34. The method of claim 25, wherein the one or more processing aids comprise a transglutaminase enzyme.

35. A method of treating or preventing nicotine dependence, or a withdrawal symptom thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of the microcapsule of claim 1.

36. The method of claim 35, wherein the nicotine dependence comprises smoking tobacco.

37.-38. (canceled)

39. The method of claim 35, wherein the withdrawal symptom is craving, anxiety, irritability, restlessness, difficulty concentrating, depressed mood, frustration, anger, increased hunger, insomnia, constipation or diarrhea, or a combination thereof.

40. A kit comprising a therapeutically effective amount of the microcapsule of claim 1, and instructions for administering the microcapsule to a subject having a nicotine dependence.

41. A microcapsule comprising: (a) an agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein: (i) the inner core comprises nicotine and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell comprises one or more food grade wall materials, produced by: (A) providing an emulsion comprising nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; and (B) spray drying the emulsion to provide a dry powder comprising the microcapsule.

42. A microcapsule comprising: (a) an agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein: (i) the inner core comprises nicotine and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell comprises one or more food grade wall materials, produced by: (A) providing an emulsion comprising nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; (B) adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, of the emulsion to form a coacervate slurry; and (C) spray drying the coacervate slurry to provide a powder comprising the microcapsule.

43.-50. (canceled)

Description

EXAMPLES

Example 1

Microencapsulated Nicotine in Palm Oil by Complex Coacervation

[0208] 1. Dissolved 11.2 g of gelatin (250 bloom) in 63.5 g of distilled water at 250 RPM between 45-55° C.

[0209] 2. 294.5 g of distilled water was added to a 500 mL reactor with the temperature maintained at 45° C.

[0210] 3. 1.875 g ascorbic acid was added to the reactor at 45° C.

[0211] 4. 18.0 g of liquid palm oil solution (15.3 g palm oil and 2.7 g nicotine with 1000 ppm vitamin E) was added to the gelatin solution.

[0212] 4. The resulting suspension was emulsified at 15 K RPM for 4 minutes until the emulsion size was 1-5 μm in diameter, and uniform in size and shape. Emulsification was accomplished using a Pro Scientific D-Series Benchtop homogenizer.

[0213] 5. The emulsion was added to the distilled water in the reactor and the pH of the mixture was measured.

[0214] 6. 0.8 g polyphosphate (PP) was dissolved in 7.5 g of distilled water. The freshly made PP solution was then added to the diluted emulsion in the reactor.

[0215] 7. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0216] 8. The slurry was cooled to 15° C. with controlled cooling, then the pH was raised to 7.0 with 10% NaOH solution.

[0217] 9. 0.775 g of transglutaminase was dissolved in 2.5 g of distilled water, and then added to the microcapsules at 15° C.

[0218] 10. Temperature was held at 15° C. for 30 minutes, then increased to 25° C. and held overnight for crosslinking.

[0219] 11. The finished suspension of microcapsules was then ready for spray drying (under nitrogen) to produce its powder.

[0220] 12. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 2

Microencapsulated Nicotine in Coconut Oil by Complex Coacervation

[0221] 1. Dissolved 11.2 g of gelatin (250 bloom) in 63.4 g of distilled water at 250 RPM between 50-60° C.

[0222] 2. Set up a separate reactor with 294 g water, heated to 45° C. and stirred at 320 RPM; and add 1.875 g ascorbic acid into the mix.

[0223] 3. Weighed 15.3 g coconut oil and 2.7 g of pure nicotine with 1000 ppm vitamin E to mix with the above gelatin solution.

[0224] 4. Emulsified the mixture at 14 K RPM for more than 4 minutes until the emulsion droplet diameter was about 1 μm, using a Pro Scientific D-Series Benchtop homogenizer.

[0225] 5. The emulsion was added to distilled water/ascorbic acid in the reactor and pH of the mixture was measured.

[0226] 6. 1.15 g of polyphosphate (PP) was dissolved in 15 g of distilled water. This freshly made PP solution was then added to the diluted emulsion in the reactor.

[0227] 7. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0228] 8. The slurry was cooled to 11° C. with controlled cooling, then raised the pH to 7.0 with 10% NaOH solution.

[0229] 9. 0.775 g of transglutaminase was dissolved in 5 g of distilled water and added to the microcapsules at 4° C.

[0230] 10. Raised temperature to 25° C. in 30 minutes for crosslinking overnight (12 hours).

[0231] 11. The finished suspension of microcapsules is then ready for spray drying (under nitrogen) to produce its powder.

[0232] 12. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 3

Microencapsulated Nicotine in Hempseed Oil by Complex Coacervation

[0233] 1. Dissolved 11.2 g of gelatin (250 bloom) in 63.4 g of distilled water at 250 RPM between 50-60° C.

[0234] 2. Set up a separate reactor with 294 g water, heated to 45° C. and stirred at 320 RPM; and add 1.875 g ascorbic acid into the mix.

[0235] 3. Weighed 15.3 g hempseed oil and 2.7 g of pure nicotine with 1000 ppm vitamin. E to mix with the above gelatin solution.

[0236] 4. Emulsified the mixture at 14 K RPM for more than 4 minutes until the emulsion droplet diameter was about 1 μm, using a Pro Scientific D-Series Benchtop homogenizer.

[0237] 5. The emulsion was added to distilled water/ascorbic acid in the reactor and measure pH of the mixture.

[0238] 6. 1.15 g of polyphosphate (PP) was dissolved in 15 g of distilled water. This freshly made PP solution was then added to the diluted emulsion in the reactor

[0239] 7. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0240] 8. The slurry was cooled to 11° C. with controlled cooling, then raise the pH to 7.0 with 10% NaOH solution.

[0241] 9. 0.775 g of transglutaminase was dissolved in 5 g of distilled water and added to the microcapsules at 4° C.

[0242] 10. Raised temperature to 25° C. in 30 minutes for crosslinking overnight (12 hours).

[0243] 11. The finished suspension of microcapsules was then ready for spray drying (under nitrogen) to produce its powder.

[0244] 12. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 4

Microencapsulated Nicotine in MCT Oil by Complex Coacervation

[0245] 1. Dissolved 11.2 g of gelatin (250 bloom) in 63.4 g of distilled water at 250 RPM between 50-60° C.

[0246] 2. Set up a separate reactor with 294 g water, heated to 45° C. and stirred at 320 RPM; and add 1.875 g ascorbic acid into the mix.

[0247] 3. Weighed 15.3 g MCT oil and 2.7 g of pure nicotine with 1000 ppm vitamin E to mix with the above gelatin solution.

[0248] 4. Emulsified the mixture at 14 K RPM for more than 4 minutes until the emulsion droplet diameter was about 1 μm, using a Pro Scientific D-Series Benchtop homogenizer.

[0249] 5. The emulsion was added to distilled water/ascorbic acid in the reactor and measure pH of the mixture.

[0250] 6. 1.15 g of polyphosphate (PP) was dissolved in 15 g of distilled water. This freshly made PP solution was then added to the diluted emulsion in the reactor.

[0251] 7. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0252] 8. The slurry was cooled to 11° C. with controlled cooling, then raise the pH to 7.0 with 10% NaOH solution.

[0253] 9. 0.775 g of transglutaminase was dissolved in 5 g of distilled water and added to the microcapsules at 4° C.

[0254] 10. Raised temperature to 25° C. in 30 minutes for crosslinking overnight (12 hours).

[0255] 11. The finished suspension of microcapsules was then ready for spray drying (under nitrogen) to produce its powder.

[0256] 12. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 5

Microencapsulated Nicotine in Canola Oil by Complex Coacervation

[0257] 1. Dissolved 22.4 g of gelatin (250 bloom) in 127 g of distilled water at 250 RPM between 50-60° C.

[0258] 2. Set up a separate reactor with 600 g water, heat to 45° C. and stirred at 320 RPM; and add 3.75 g ascorbic acid into the mix.

[0259] 3. Weighed 30.6 g canola oil and 5.4 g of pure nicotine with 1000 ppm vitamin

[0260] E to mix with the above gelatin solution.

[0261] 4. Emulsified the mixture at 14 K RPM for more than 4 minutes until the emulsion droplet diameter is about 1 μm, using a Pro Scientific D-Series Benchtop homogenizer.

[0262] 5. The emulsion was added to distilled water/ascorbic acid in the reactor and measure pH of the mixture.

[0263] 6. 2.3 g of polyphosphate (PP) was dissolved in 15 g of distilled water. This freshly made PP solution was then added to the diluted emulsion in the reactor.

[0264] 7. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0265] 8. The slurry was cooled to 11° C. with controlled cooling, then raise the pH to 7.0 with 10% NaOH solution.

[0266] 9. 1.55 g of transglutaminase was dissolved in 5 g of distilled water and added to the microcapsules at 4° C.

[0267] 10. Raised temperature to 25° C. in 30 minutes for crosslinking overnight (12 hours).

[0268] 11. The finished suspension of microcapsules was then ready for spray drying (under nitrogen) to produce its powder.

[0269] 12. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 6

Microencapsulated Nicotine in Sunflower Oil by Complex Coacervation

[0270] 1. Dissolved 44.8 g of gelatin (250 bloom) in 254 g of distilled water at 250 RPM between 45-55° C.

[0271] 2. 1179 g of distilled water as added to a 2 L reactor with the temperature maintained at 45° C.

[0272] 3. 7.5 g ascorbic acid was added to the 45° C. reactor.

[0273] 4. 72.0 g of liquid palm oil solution (61.2 g palm oil and 10.8 g nicotine w/1000 ppm Vit. E) is added to the gelatin solution

[0274] 5. The resulting suspension was then emulsified at 15 K RPM for 4 minutes until the emulsion size is 1-5 μm in diameter, and uniform in size and shape. Emulsion was done using a Pro Scientific D-Series Benchtop homogenizer.

[0275] 6. The emulsion was added to the distilled water in the reactor and the pH of the mixture was measured.

[0276] 7. 3.2 g polyphosphate (PP) was dissolved in 30 g of distilled water. The freshly made PP solution was then added to the diluted emulsion in the reactor.

[0277] 8. Suspension pH was then lowered with 10% citric acid to form agglomerations of primary microcapsules.

[0278] 9. The slurry was cooled to 15° C. with controlled cooling, then the pH was raised to 7.0 with 10% NaOH solution.

[0279] 10. 3.1 g of transglutaminase was dissolved in 10 g of distilled water, and then added to the microcapsules at 15° C.

[0280] 11. Temperature was held at 15° C. for 30 minutes, then increased to 25° C. and held overnight for crosslinking.

[0281] 12. The finished suspension of microcapsules was then ready for spray drying (under nitrogen) to produce its powder.

[0282] 13. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 7

Microencapsulated Nicotine in Palm Oil by Spray Drying

[0283] 1. Dissolved 100 g of gum Arabic in 500 mL of distilled water at 400 RPM (overhead stirrer) between 45-50° C.

[0284] 2. 1.5 g of ascorbic acid was added to the solution.

[0285] 3. 50 g of liquid palm oil solution (40 g palm oil and 10 g nicotine with 1000 ppm vitamin E) was added to the gum Arabic solution.

[0286] 4. The resulting suspension was then emulsified at 15 K to 17 K RPM for 20 minutes until the emulsion size was about 1 to 10 μm in diameter, and uniform in size and shape. Emulsification was accomplished using a Pro Scientific D-Series Benchtop homogenizer.

[0287] 5. The emulsion was then ready for spray drying (under nitrogen) to produce its powder.

[0288] 6. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

Example 8

Microencapsulated Nicotine in Sunflower Oil by Spray Drying

[0289] 1. Dissolved 100 g of gum Arabic in 500 mL of distilled water at 400 RPM (overhead stirrer) between 45-50° C.

[0290] 2. 1.5 g of ascorbic acid was added to the solution.

[0291] 3. 50 g of sunflower oil solution (40 g Sunflower oil and 10 g nicotine with 1000 ppm vitamin E) was added to the gum Arabic solution.

[0292] 4. The resulting suspension was then emulsified at 17 K RPM for 10 minutes until the emulsion size was about 1 to 10 μm in diameter, and uniform in size and shape. Emulsification was accomplished using a Pro Scientific D-Series Benchtop homogenizer.

[0293] 5. The emulsion was then ready for spray drying (under nitrogen) to produce its powder.

[0294] 6. Pack the powder under vacuum or nitrogen for quantitative analysis and oral formulation preparation.

[0295] Having now fully described the methods, microcapsules, and compositions herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety.