NEW COMPOSITIONS FOR ORAL OR NASAL USE

Abstract

Compositions for use in the oral or nasal cavity are disclosed. The compositions include a biologically active agent, a matrix forming agent comprising β-glucan and a filling agent. The compositions can further include additional excipients such as antioxidants, preservatives, taste or flavour enhancers, pH adjusters, plasticizers and sweeteners. Methods of producing the compositions are also disclosed.

Claims

1.-24. (canceled)

25. A composition for use in the oral or nasal cavity, the composition comprising: a biologically active agent; a matrix forming agent comprising β-glucan; and a filling agent.

26. The composition according to claim 25, having a pH of at least 6.5, wherein the biologically active agent is nicotine or a cannabinoid.

27. The composition according to claim 25, wherein the β-glucan comprises at least 30% β(1-3) β(1-4) glucan.

28. The composition according to claim 25, wherein the matrix forming agent comprises at least one additional pharmaceutically acceptable gum.

29. The composition according to 26, wherein the matrix forming agent comprises at least 50% by weight of cereal β-glucan.

30. The composition according to claim 25, further comprising an antioxidant effective at a pH of at least 6.5.

31. The composition according to claim 25, wherein the filling agent comprises a fiber material.

32. The composition according to claim 25, wherein the filling agent comprises a polyol.

33. The composition according to claim 32, in which the filling agent comprises a plant fiber material and 5 to 70% by weight of a polyol.

34. The composition according to claim 25, further comprising at least one excipient, the at least one expedient being selected from the group including preservatives, taste or flavor enhancers, pH adjusters, plasticizers and sweeteners.

35. The composition according to claim 25, further comprising less than 50% by weight of the matrix forming agent.

36. The composition according to claim 25, in which the composition is a powder adapted for delivery to the nasal cavity, and comprising less than 20% water by weight.

37. The composition according to claim 36, wherein the powder is made up of particles having a size of 0.01 to 2 mm.

38. The composition according to claim 36, wherein the filling agent comprises a water soluble cellulose.

39. The composition according to claim 25, in which the composition is adapted to contact with a mucous membrane of the oral cavity, comprising at least 30% of water by weight and the filling agent comprising microcrystalline cellulose.

40. The composition according to claim 39, comprising 40 to 60% water by weight.

41. The composition according to claim 25, wherein the composition is adapted to be used in the oral cavity as a lozenge or tablet, comprising 1 to 30% of water by weight and the filling agent comprising least one of microcrystalline cellulose, plant fibers and a polyol.

42. The composition according to claim 25, wherein the composition is configured as a film suitable for transmucosal delivery of the biologically active agent having a thickness 0.01 to 7 mm, further comprising at least 50% of the matrix forming agent by weight and optionally a plasticizer.

43. The composition according to claim 42, comprising 0.1 to 20% of the filling agent by weight.

44. A method of manufacturing a composition according to claim 25, the method comprising: (i) dry mixing the filling agent and at least one of the matrix forming agent and an antioxidant; (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 flavor enhancer and a sweetener; and (iv) adding a third aqueous solution comprising one or more biologically active agents and mixing all added components to a mixture with a suitable amount of water.

45. The method according to claim 44, wherein the filling agent is dry mixed with the matrix forming agent and the antioxidant.

46. The method according to claim 44, further comprising dry mixing the filling agent and the antioxidant and wherein the third aqueous solution comprises the matrix forming agent and the one or more biologically active agents.

47. The method according to claim 44, further comprising producing 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).

48. The method according to claim 44, further comprising producing a composition for use in the oral cavity by one or more further processing methods of the resulting mixture with at least one of filling in pouches, tablet or lozenge forming, extrusion, punching, casting, molding, injection molding, kneading spinning, film forming and admixing with a chewing gum base.

Description

DETAILED AND EXEMPLIFYING DESCRIPTION OF THE INVENTION

[0057] Table 1 below further illustrates examples of oral or nasal compositions including suitable excipients.

TABLE-US-00001 TABLE 1 Amount Ingredient Use (wt %) Water Humidification 2-70%.sup.  Sodium Chloride Taste <15%  Microcrystalline cellulose Filling agent 5-95%.sup.  Sodium bicarbonate/carbonate pH adjuster <2% Beta-glucan >70% purity Matrix forming agent <5% Ammonium chloride Flavour <2% Potassium sorbate Preservative <0.2%.sup.  Xylitol Sweetener <5% Acesulfame K/Stevia Sweetener <0.5%.sup.  Menthol/Spearmint/Lemon/Others Flavour <5% Calcium ascorbate Antioxidant <5% Nicotine Active agent <20% 

EXAMPLE 1

[0058] A specific example of a composition product made with the outlined methods is demonstrated in Table 2.

TABLE-US-00002 TABLE 2 Amount Ingredient Use (wt %) Water Humidification 45.93 Microcrystalline cellulose Filling agent 42.10 Sodium Chloride Taste 5.22 Flavour Smell and taste 1.86 Xylitol Sweetener/Filling agent 1.74 Nicotine Active agent 0.89 Beta-glucan of oat 98% Matrix forming agent 0.70 purity from Xi'an Retalin Biotechnology, Xi'an, China Calcium ascorbate Antioxidant 0.70 Ammonium chloride Taste 0.35 Sodium bicarbonate pH adjuster 0.26 Potassium sorbate Preservative 0.2 Acesulfame K Sweetener 0.07
A composition of Table 2 without flavor, which may have a pH of about 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. without adjusted relative humidity).

TABLE-US-00003 TABLE 3 Composition of Commercial Table 2 product Water content % (wt) 45.93 41.9 Initial amount nicotine (mg) 1.1 1.0 Amount nicotine after 9 1.1 0.74 weeks (mg)
Table 3 demonstrates that the beta-glucan and the antioxidant of the inventive compositions results in a significant increase in nicotine stability. A previous test with a composition similar to that of Table 2, but without any antioxidant demonstrates a comparable stability of nicotine to the commercial tobacco based product. This result indicates that a matrix forming agent comprising β-glucan according to the inventive compositions has a comparable capacity of preserving nicotine as the natural tobacco fibers. In conclusion, the combination of a matrix forming agent comprising β-glucan and a chelate binding antioxidant provides an effective long term stability of nicotine.

EXAMPLE 2

[0059]

TABLE-US-00004 TABLE 4 Amount Ingredient Use (wt %) Xylitol Filling agent 31.0 Guar gum/Gum arabicum Matrix forming agent 31.0 Maltodextrin Matrix forming agent 31.0 Magnesium stearate Lubricator 1.0 Nicotine Active agent 0.4 Beta-glucan of oat 98% Matrix forming agent 0.7 purity from Xi'an Retalin Biotechnology, Xi'an, China Acesulfam K Sweetener 0.3 Sodium bicarbonate pH adjuster 0.4 Anise oil Aroma 0.2 Honey aroma/menthol/mint Aroma 4

[0060] Table 4 shows an example of a lozenge or water soluble tablet comprising beta-glucan as a matrix forming agent.

[0061] The lozenge or tablet is made by dry mixing all components in Table 4, the resulting product is transferred to a conventional tablet forming machine and subjected to a high pressured and formed to tablets/lozenges. The tablets are spray coated and dries in coating pan to obtain a desirably tasting coating, comprising sweeteners, aroma and similar agents. The coating may optionally include nicotine to provide an initial dose.

EXAMPLE 3

[0062] Products according to the invention and Table 1 with 0.89% (wt) nicotine, about 41% (wt) water, 1 or 2% of the beta-glucan as the matrix forming agent. The product was made with the two alternative methods outlined above. In Process 1, beta-glucan is dry mixed with the filling in the first step and a solution of nicotine is added in the third step. The product from Process 1 comprises 1% (wt) of beta-glucan. In Process 2, 1 or 2% (wt) of beta-glucan is added in the solution comprising nicotine in the third step. The product from Process 2 comprises 1 or 2% (wt) beta-glucan. The products were packaged in conventional snus pouches and benchmarked with two commercial tobacco free nicotine products, CP1 and CP2, respectively, comprising a microcrystalline cellulose as a filler, but not including any beta-glucan as a matrix forming agent. The product according to the invention, CP1 and CP2 were studied for stability and nicotine release. For the stability test, the products were all put in a heating cabinet at 40C and 75% humidity for 9 weeks (representing 7 months in room temperature.

TABLE-US-00005 TABLE 5 Initial Amount Amount nicotine nicotine % after 7 (wt) months % Nicotine loss Product from Process 0.89 0.75 20 1 CP1 1 0.74 26 CP2 0.61 0.46 25

TABLE-US-00006 TABLE 6 pH after 7 Initial pH months % pH reduction Product from Process 7.6 7.4 3 1 CP1 8.4 7.9 6 CP2 8.3 8 4

TABLE-US-00007 TABLE 7 Water Initial water content % content % (wt) after 7 (wt) months % change Product from Process 41.2 43.9 +7 1 CP1 41.9 39.8 −5 CP2 45.3 47.9 +6

[0063] The results of Tables 5 to 7 indicate that the product according to the invention comprising matrix forming agent with beta glucan stabilizes both nicotine and pH value during storage significantly better than either CP1 or CP2. The variations in water content between the product may result from different filling agents.

[0064] 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 5 ml with Milli-Q water for 5 minutes. Thereafter, 100 ml of 0.05M 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 8, below.

TABLE-US-00008 TABLE 8 Nicotine Initial Nicotine bound nicotine content Release of to matrix content after 38 min nicotine forming (mg/g) (mg/g) (mg/g) agent Product from process 1, 8.1 2.8 5.3 (65%) 44% 1%(wt) beta-glucan Product from Process 2, 8.1 4.4 3.7 (45%) 55% 1%(wt) beta-glucan Product from Process 2, 8.1 5.1 3.0 (37%) 63% 2%(wt) beta-glucan CP1 8.9 5.7 3.2 (36%) N/A

[0065] Table 8 demonstrates that the amount of matrix forming agent of the inventive compositions can be used to control the release rate of nicotine. For example, doubling the amount of beta glucan from 1 to 2% (wt) generates 18% more nicotine bound to the matrix forming agent during a time period of 38 minutes. Also, the methods of manufacturing the compositions can be used to control the amount of bound nicotine to the beta-glucan 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.