NEW COMPOSITIONS FOR ORAL OR NASAL USE

Abstract

The specification discloses compositions for use in the oral or nasal cavity comprising a biologically active agent, a matrix forming agent comprising alginate and suitable salts thereof, a filling agent and at least one antioxidant that is an effective complex binder. The compositions can further comprise additional excipients such as preservatives, taste or flavour enhancers, pH adjusters, plasticizers and sweeteners. The specification also discloses methods of producing the compositions.

Claims

1. A composition for use in the oral or nasal cavity having a pH of at least 6.5, comprising an active agent selected from nicotine and a cannabinoid, a matrix forming agent comprising alginate and suitable salts thereof, a filling agent and an antioxidant that is an effective complex binder at a pH of at least 6.5, comprising at least one ammonium citrate or a salt thereof.

2. The composition according to claim 1, wherein the matrix forming agent comprises an at least one additional pharmaceutically acceptable gum, preferably selected from β-glucan, xanthan, carrageenan, methyl cellulose, cudlan and pullulan.

3. The composition according to claim 1, wherein the matrix forming agent comprises at least 50% (weight) of alginate and suitable salts thereof.

4. The composition according to claim 1, comprising 5 to 95% (wt) of filling agent, comprising at least one plant fiber, more preferably the filling agent comprises natural or modified cellulose fibers and most preferably at least one microcrystalline cellulose.

5. The composition according to claim 4, wherein the filling agent further comprises a polyol, preferably a polyol selected from one or more mannitol, xylitol, sorbitol, maltitol and/or isomaltitol, lactitol and erythritol.

6. The composition according to claim 1, comprising at least one excipient selected from preservatives, taste or flavour enhancers, pH adjusters, plasticizers and sweeteners.

7. The composition according to claim 1, comprising less than 50% (wt) of the matrix forming agent, preferably less than 40% (wt).

8. The composition according to claim 1, adapted to delivery to the nasal cavity, comprising less than 20% (wt) water, preferably 1 to 15 % (wt) of water.

9. The composition according to claim 8, wherein the powder particles have a size range of 0.01 to 2 mm.

10. The composition according to claim 8, wherein the filling agent comprises a water soluble cellulose, preferably water soluble microcrystalline cellulose, more preferably a combination of water soluble and water insoluble microcrystalline cellulose.

11. The composition according to claim 1, adapted to contact with a mucous membrane of the oral cavity, comprising at least 30% (wt), preferably at least 40% (wt) of water and a filling agent comprising at least one of microcrystalline cellulose and other plant fibers.

12. The composition according to claim 1, comprising 40 to 60% (wt) water.

13. The composition according to claim 1, adapted to contact with a mucous membrane of the oral cavity, comprising less than 40% (wt) of water and filling agent selected from at least one of microcrystalline cellulose and other plant fibers, preferably the composition comprises 1 to 40% (wt) of water.

14. The composition according to claim 1, configured as a film suitable for transmucosal delivery of active agent having a thickness 0.01 to 7 mm, comprising at least 50% (wt) of the matrix forming agent and optionally a plasticizer.

15. The composition according to claim 14, comprising 0.1 to 20% (wt), preferably 5 to 10% (wt) of filling agent, preferably the filling agent is a microcrystalline cellulose and a plasticizer, preferably the plasticizer is selected from at least one of sorbitol and glycerol.

16. The composition according to claim 1, wherein the alginate is sodium alginate.

17. A method of manufacturing a composition according to claim 1, comprising: (i) dry mixing filling agent and at least one of the matrix forming agent, an antioxidant and optionally at least one taste or flavour enhancer; (ii) mixing the dry mixture with a first aqueous solution comprising a pH adjuster; (iii) adding a second aqueous solution comprising at least one of a preservative, a taste or flavour enhancer and a sweetener; (iv) adding a third aqueous solution comprising active agent and mixing all added components to a mixture with a suitable amount of water.

18. The method according to claim 17, wherein the filling agent is dry mixed with the matrix forming agent, the antioxidant and optionally at least one taste or flavour enhancer.

19. The method according to claim 17, comprising dry mixing the filling agent, the antioxidant and optionally at least one taste or flavour enhancer, and wherein the third aqueous solution comprises the matrix forming agent and active agent.

20. The method according to claim 17, configured to produce a powder composition for nasal use by one or more further processing steps of the resulting mixture, comprising drying to a powder of a particle size of less than 2 mm with less than 15% water (wt).

21. The method according to claim 17, configured to produce a composition for use in the oral cavity by one or more further processing method of the resulting mixture with at least one of filling in pouches, tablet or lozenge forming, extrusion, punching, casting, moulding, injection moulding, kneading spinning, film forming and admixing with chewing gum base.

Description

DETAILED AND EXEMPLIFYING DESCRIPTION OF THE INVENTION

[0060] As used herein in both general and exemplifying contexts, weight percent (wt) % means percent weight of the total composition.

[0061] Table 1 below further illustrates examples of oral or nasal compositions including suitable excipients.

TABLE-US-00001 Ingredient Use Amount (wt %) Water Humidification 2-70% Sodium Chloride Taste <15% Microcrystalline cellulose Filling agent 5-95% Sodium bicarbonate/ carbonate pH adjuster <2% Sodium alginate Matrix forming agent <5% Ammonium chloride Flavour <2% Potassium sorbate Preservative <0.2% Xylitol Sweetener <5% Acesulfame K/Stevia Sweetener <0.5% Menthol/Spearm int/Lemon/Others Flavour <8% tri-Ammonium citrate, CAS No. 3458-72-8. Antioxidant <5% Nicotine Active agent <20%

[0062] A specific example of a composition product made with the outlined methods is demonstrated in Table 2

TABLE-US-00002 Ingredient Use Amount (wt %) Water Humidification 45.93 Microcrystalline cellulose Filling agent 42.10 Sodium Chloride Taste 5.22 Flavour Smell and taste 1.86 Xylitol Sweetener 1.74 Nicotine Active agent 0.89 Sodium alginate from Carl Roth GmbH Karlsruhe, Germany Matrix forming agent 0.70 tri-Ammonium citrate, CAS No. 3458-72-8 Antioxidant 0.70 Ammonium chloride Taste 0.35 Sodium bicarbonate pH adjuster 0.26 Potassium sorbate Preservative 0.2 Acesulfame K Sweetener 0.07

Example 1

[0063] A composition in accordance with Table 2 without flavor with about 1 % nicotine, having a pH of 8.5, suitable to be packaged in pouches as a snus type of product for use in the oral cavity was tested for stability of nicotine. Samples of 80 g of the composition of Table 2 and a commercial snus product based on tobacco were compared during 9 weeks at 40° C. and 75% relative humidity (comparable to 10 months at 25° C. see Table 3. For the compositions demonstrated in Table 3 equal amounts of different chelate forming antioxidants and a non-complex forming antioxidant were compared with the commercial product.

TABLE-US-00003 omposition of Table 2 with ammonium citrate Composition of Table 2 with calcium ascorbate Composition of Table 2 with BHT Commercial product Water content % (wt) 41.2 42.3 43.8 41.5 Initial pH 8.6 7.9 8.8 8.5 pH after 9 weeks 8.3 7.9 8.1 8.2 Initial amount nicotine (mg) 1 1.5 1.4 1.0 Amount nicotine after 9 weeks (mg) 0.85 0.99 0.58 0.76 % loss of nicotine 15% 34 % 59 % 24 %

[0064] Table 3 demonstrates that the sodium alginate and an antioxidant of the inventive compositions results in a significant increase in nicotine stability This result indicates that a matrix forming agent comprising sodium alginate according to the inventive compositions has a comparable capacity of preserving nicotine as the natural tobacco fibers. A positive effect of ammonium citrate compared to calcium ascorbate can also been seen in this example. The negative effect of the non-complex forming antioxidant BHT (butylhydroxytoluene) can also be seen in Table 3. In conclusion, the combination of a matrix forming agent comprising an alginate salt and a complex binding antioxidant provides an effective long term stability of nicotine.

Example 2

[0065] The product with about 1% (wt) nicotine was made in accordance with Table 2 with the two embodied methods generally outlined above. In Process 1, sodium alginate is dry mixed with the MCC filling agent in a first step and a solution of nicotine is added in a third step. The product from Process 1 comprises 0.7% (wt) of sodium alginate. In Process 2, sodium alginate is added in a solution comprising nicotine as a third step. The product from Process 2 comprises 0.7% sodium alginate. The products were packaged in conventional snus pouches and benchmarked with a commercial tobacco free nicotine product, CP1, comprising a microcrystalline cellulose as a filling agent, but not including any sodium alginate as a matrix forming agent. The products made according to the invention and CP1 were studied for stability and nicotine release.

[0066] For testing the nicotine release capacity of compositions according to the invention, pouches with products were made as outlined above with Process 1 and Process 2 and compared with CP1. The products were orally tested by respondents, taken out after a defined time period and processed for remaining nicotine. A consumed pouch was chopped into a 100 ml glass bottle and exposed to ultrasound together with 5ml with Milli-Q water for 5 minutes. Thereafter, 100ml of 0.05 M potassium hydroxide solution was added, and the sample is shaken and then exposed to ultrasound for 60 minutes. The sample is shaken overnight on a vibrating table and is exposed to ultrasound an additional 30 minutes on the day after. Thereafter the sample is centrifuged and diluted to the desired level, the internal standard was added, and the sample was then analyzed by LC / MS / MS. The averaged results of three tests are demonstrated in Table 4, below.

TABLE-US-00004 Initial nicotine content (mg/g) Nicotine content after 38 min (mg/g) Release of nicotine (mg/g) Product from Process 1 6.13 2.57 3.56 (26%) Product from Process 2 6.43 3.52 2.91 (45%) CP1 8.9 5.7 3.2 (36%)

[0067] Table 4 demonstrates that the amount of matrix forming agent of the inventive compositions can be used to control the release rate of nicotine. The alternate methods of manufacturing the compositions can be used to control the amount of bound nicotine to the alginate of the matrix forming agent. The results of Table 8 demonstrate a higher amount of bound nicotine is obtained when nicotine is added together with the matrix forming agent as a third, final step in the manufacturing process.

Example 3

[0068] In order to further asses the stabilizing effect of the antioxidant according to the invention, products with about 1% (wt) nicotine were made in accordance with the recipe of Table 2 and with process 1 according to Example 2. These products were made with and without an ammonium citrate antioxidant and compared with same commercial product (CP1) as I Example 2. For the stability tests, the products were all put in a heating cabinet at 40C and 75% humidity for 9 weeks (representing 7 months in room temperature). The results of tested losses of nicotine, pH and water content are presented in Tables 5-7 below.

TABLE-US-00005 Initial Amount nicotine % (wt) Amount nicotine after 9 weeks % Nicotine loss Product with antioxidant 1 0.85 15 Product without antioxidant 1.1 0.81 26 CP1 1 0.74 26

TABLE-US-00006 Initial pH pH after 9 weeks % pH reduction Product with antioxidant 8.6 8.3 3 Product without antioxidant 8.9 8.3 7 CP1 8.4 7.9 6

TABLE-US-00007 Initial water content % (wt) Water content % (wt) after 7 months % change Product with antioxidant 41.2 42.7 +4 Product without antioxidant 46.9 43.1 -8 CP1 41.9 39.8 -5

[0069] The results of Table 5-7 demonstrate the stabilizing capacity of the inventive composition comprising an ammonium citrate antioxidant.