A NEW POWDER COMPOSITION

Abstract

Disclosed are powder compositions with a pH of at least 6 for delivery of an active agent to the nasal cavity, wherein the active agent is selected from at least one of nicotine, tetrahydrocannabinol (THC) and ethanol. The compositions comprise a filling agent of water soluble and water insoluble microcrystalline cellulose and a matrix forming agent and have a defined brightness and particle size range. Also disclosed are products including the powder compositions and support particles inducing a desired property to the product.

Claims

1. A powder particle composition with a water content of less than 30 wt %, with an ISO brightness that is not less than about 60, preferably not less than about 70, and more preferably not less than about 80, as measured according to ISO 2470-1:2016, and with a pH of at least 6 for delivery of an active agent to the nasal cavity, wherein the active agent is selected from at least one of nicotine, tetrahydrocannabinol (THC) and ethanol, the composition comprises, a filling agent, and a matrix forming agent and wherein it has (i) a water content of 30 wt % or less, preferably from 1 to 20 wt % more preferably from 5 to 15 wt %; and wherein (ii) the filling agent comprises at least one water insoluble microcrystalline cellulose (MCC) and at least water-soluble microcrystalline cellulose (MCC).

2. The composition according to any claim 1, comprising at least 60 wt % filling agent, preferably 60 to 90 wt % filling agent.

3. The composition according to claim 1, wherein the filling agent comprises 5 to 90 wt % of water insoluble MCC and 5 to 90 wt % of water soluble MCC, preferably 10 to 90 wt % of water insoluble MCC and 10 to 90 wt % of water soluble MCC and more preferably 45 to 55 wt % of water insoluble MCC and 45 to 55 wt % of water soluble MCC.

4. The composition according to claim 1, comprising at least one additional a natural or synthetic fiber material, preferably the fiber material is a biopolymer or a plant fiber.

5. The composition according to claim 4, wherein the filling agent comprises tobacco fibers in amount of 0.05 to 20 wt %, preferably the tobacco fibers are obtained from a bleached and/or washed tobacco raw material or microencapsulated tobacco.

6. The composition according to claim 1, wherein the filling agent comprises a food or pharmaceutical grade polyol selected from at least one of mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, preferably the polyol is mannitol.

7. The composition according to claim 6, wherein up to 50 wt % of the filling agent is a polyol, most preferably the polyol is mannitol.

8. The composition according to claim 1, wherein the filling agent comprises a mucoadhesive agent selected from at least one of a cellulose derivative, a starch derivative and polyvinylpyrrolidone, preferably the mucoadhesive agent is selected from at least one of sodium starch glycolate and crosslinked polyvinylpyrrolidone.

9. The composition according to claim 1, wherein the powder particles have an average size of 0.01 to 3 mm, preferably from 0.01 to 0.1 mm.

10. The composition according to claim 1, wherein the matrix forming agent is a gelling agent, preferably a gelling polysaccharide, preferably selected from at least one of alginate and salts thereof, -glucan, xanthan, carrageenan, methyl cellulose, cudlan and pullulan.

11. The composition according to claim 1, comprising 0.5 to 95 wt % of the matrix forming agent.

12. The composition according to claim 1, comprising 0.5 to 10 wt % of the matrix forming agent, preferably 0.5 to 10 wt % of the matrix forming agent and at least 60 wt % filling agent.

13. The composition according to claim 11, wherein the matrix forming agent is a salt of alginate, preferably sodium alginate.

14. The composition according to claim 1, further comprising a lubricating agent, preferably the lubricating agent is at least one of glycerol and propylene glycol, more preferably the lubricating agent is present in an amount of 1 to 5 wt %.

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

16. The composition according to claim 1, comprising 0.1 to 5 wt % of nicotine, the nicotine is selected from at least of one of nicotine base, and/or salts of nicotine, including nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulphate, nicotine polyacrylex, nicotine zinc chloride (monohydrate) or nicotine salicylate.

17. The composition according to claim 1, further comprising an antioxidant effective at a pH of at least 6, preferably the antioxidant is a complex binding antioxidant, preferably selected from at least one of alkali and/or alkaline earth metal salts of ascorbate, calcium citrates, calcium lactates, calcium maleates, calcium tartrates, Ca-diNa-EDTA, calcium phosphates and ammonium citrates, more preferably the antioxidant is calcium ascorbate.

18. A product for nasal use, comprising the powder particle composition according to claim 1 and 1 to 5 wt % of support particles free from active agent.

19. The product according to claim 18, wherein the support particles add at least one characteristic to the product selected from visual appearance, a rheologic characteristic, capacity to lubricate the nasal cavity and/or to regulate the uptake of active agent.

20. The product according to claim 18, wherein the particles of the powder particle composition and the support have the same average size and comprises the same filling agent.

21. The product according to claim 20, wherein the support particles are microcapsules having an average size of 10 to 1000 m, preferably the microcapsules are insoluble and comprise a colouring agent.

22. The product according to claim 18, comprising support particles derived from to tobacco fiber.

Description

[0076] The following experimental section demonstrates non-limiting examples of how to manufacture powder compositions according to the invention.

EXAMPLE 1

[0077] In Example 1 a batch of 250 g powder composition according to the invention with about 7% (wt) water content was produced with the components and amounts in Table 1.

TABLE-US-00001 A MCC (soluble or unsoluble) 85.0% ALGINATE 1.0% Sodium chloride 3.0% Glycerol 1.0% B Sodium Bicarbonate 0.3% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint 2.0% Optionally Ammonium Chloride 0.0% Nicotine Liquid Form 0.6%

Table 1

[0078] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture. The components C were weighed, mixed and slowly added to the blender with A and B to obtain a homogenous mixture of A, B and C. The resulting mixture was carefully sieved to avoid aggregations and the powder composition was collected and packaged in batches of 5-10 gram.

EXAMPLE 2

[0079] In Example 2 a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 2.

TABLE-US-00002 A MCC 85.00% Sodium choride 3.0% Glycelrol 1.0% B Sodium bicarbonate 0.3% Water 3.5% C Water 3.5% Acesulfame K. 0.2% Optionally Ammonium Chloride 0.0% D Nicotine Liquid Form 0.60% ALGINATE 1.0% Mint 2.0%

Table 2

[0080] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture. The components C were weighed, mixed and slowly added to the blender with A and B to obtain a homogenous mixture of A, B and C. The components D were weighed, mixed and slowly added to the blender to obtain a homogenous mixture of A, B, C and D.

[0081] The resulting mixture was carefully sieved to avoid aggregations and the powder composition was collected and packaged in batches of 5-10 gram.

EXAMPLE 3

[0082] In Example 3, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 3. In contrast to Example 1 and 2, a slurry or paste is formed that dried and processed to the powder composition with about 7% (wt) water content. The filling agent in Example 3 was a water soluble colloid MCC with the trade name FEIYUN XW591.

TABLE-US-00003 A MCC soluble/Gel forming 61.8% Sodium chloride 3.0% Glycelrol 1.0% B Sodium Bicarbonate 0.3% Water 10.0% C Water 20.0% Acesulfame K 0.2% Optionally Ammonium Chloride 0.0% Potassium sorbate 0.2% D Nicotine Liquid Form 0.6% ALGINATE 1.0% Mint 2.0%

Table 3

[0083] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture. The components C were weighed, mixed and slowly added to the blender with A and B to obtain a homogenous mixture of A, B and C. The components D were weighed, mixed and slowly added to the blender to obtain a homogenous mixture of A, B, C and D. The resulting paste is collected carefully sieved to avoid aggregations, dried overnight and milled to suitable particle size in the range of 0.01-0.1 mm. The resulting powder composition was collected and packaged in batches of 5-10 gram.

EXAMPLE 4

[0084] In Example 4, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 4 in a dry mixing process.

TABLE-US-00004 A MCC 91.4% Natrium Klorid 3.0% Glycerol 1.0% Sodium bicarbonate 0.3% Acesulfame K 0.2% OptionallyAmmonium Choride 0.0% Nicotine Salt 1.2% B ALGINATE 1.0% Mint 2.0% Optionally water 0.0%

Table 4

[0085] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture, optionally with water added. The resulting mixture was collected and carefully sieved to avoid aggregations and packaged 5-10 g batches.

EXAMPLE 5

[0086] In Example 5, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 5 in a dry mixing process

TABLE-US-00005 A MCC 91.4% Sodium chloride 3.0% Sodium Bicarbonate 0.3% Acesulfame K 0.2% Optionally ammonium chloride 0.0% B ALGINATE 1.0% Nicotine Salt 1.2% Mint 2.0% Optionally water 0.0% Glycelrol 1.0%

Table 5

[0087] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture, optionally with water added. The resulting mixture was collected and carefully sieved to avoid aggregations and packaged in 5-10 g batches.

EXAMPLE 6

[0088] In Example 6, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 6 in a dry mixing process

TABLE-US-00006 A MCC 91.4% Sodium chloride 3.0% Sodium Bicarbonate 0.3% Acesulfame K 0.2% Optionally ammonium chloride 0.0% Alginate 1.0% Nicotine Salt 1.2% B Mint 2.0% Optionally water 0.0% Glycerol 1.0%

Table 6

[0089] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture, optionally with water added. The resulting mixture was collected and carefully sieved to avoid aggregations and packaged in 5-10 g batches.

EXAMPLE 7

[0090] In Example 7, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 7 in a dry mixing process.

TABLE-US-00007 A MCC 90.2% Sodium chloride 3.0% Sodium carbonate free 0.3% Sodium carbonate. microencasulated 0.15% Acesulfame K 0.2% Optionally ammonium chloride 0.0% ALGINATE 1.0% Mint powder 1.0% Nicotine Salt 1.2% B Mint 2.0% Glycerol 1.0%

Table 7

[0091] The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture, optionally with water added. The resulting mixture was collected and carefully sieved to avoid aggregations and packaged in 5-10 g batches.

EXAMPLE 8

[0092] In Example 8, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 8 in a dry mixing process The components A were weighed and mixed in a blender during a suitable period. The components B were weighed, mixed and slowly added to the blender to obtain a homogenous mixture, optionally with water added. The resulting mixture was collected and carefully sieved to avoid aggregations and packaged in 5-10 g batches.

TABLE-US-00008 A Sodium starch glycolate 91.4% Sodium chloride 3.0% Glycerol 1.0% Sodium carbonate 0.3% Acesulfame K 0.2% Optionally Ammonium chloride 0.0% Nicotine Salt 1.2% B ALGINAT 1.0% Mint 2.0% optionally water 0.0%

Table 8

EXAMPLE 9

[0093] In Example 9, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 9

TABLE-US-00009 Alginate 61.8% Sodium chloride 3.0% Glycerol 1.0% Sodium bicarbonate 0.3% Water 10.0% Water 20.0% Acesulfame K 0.2% Optionally Ammonium chloride 0.0% Potassium sorbate 0.2% Nicotine Liquid Form 0.6% ALGINATE 1.0% Mint 2.0%

Table 9

[0094] The first three components were weighed and mixed in a blender during a suitable period. Water and bicarbonate were added to the blender to homogeneity Water, acesulfame K, potassium sorbate and optionally ammonium chloride were weighed and added to the blender to homogeneity. Nicotine, alginate and mint were weighed and added to the blender to homogeneity. The resulting mixture was collected and carefully sieved to avoid aggregations and dried overnight to a desired water level.

EXAMPLE 10

[0095] In Example 10, a batch of 250 g powder composition according to the invention was produced with the components and amounts in Table 10.

TABLE-US-00010 Sodium starch gluconate 85.0% ALGINATE 1.0% Sodium chloride 3.0% Glycelrol 1.0% Sodium bicarbonate 0.3% Water 3.5% Water 3.5% Acesulfame K 0.2% Mint 2.0% Optionally ammonium chloride 0.0% Nicotine Liquid Form 0.6%

Table 10

[0096] As previously, the three batches of components were individually weighed and blended before successively added to blender and mixed to homogeneity. The resulting mixture was sieved and packaged according to procedure in previous Examples.

EXAMPLE 11

[0097] In order to study the nicotine release from powder particle compositions according to the invention compositions 11.1 to 11.9 was prepared as above. Three commercially available references were used: Gawith, Ozona and McChrystal's. All were tobacco based and intended for nasal use.

[0098] In formulations 11.1 to 11.9, the alginate used was Satialgine S900 NS, the water insoluble MCC is HiCel 90M. and the water soluble MCC was XW-591 from Huzhou City Linghu Xinwang Chemical. Generally, the water content of the formulations was about 7 wt %. Liquid nicotine (base form) or the nicotine alt nicotine polyacrylex were alternatively used for comparison.

[0099] Formulations 11.1 to 11.9 were made according to process with steps A to E: [0100] A: filling agent(s), alginate, sodium chloride and nicotine when present as a salt were combined in a dry mixer and suitably mixed; [0101] B: Sodium bicarbonate, propylene glycol (PG) and water was mixed and put in the mixer and mixed to homogeneity; [0102] C: sweetener, taste or flavor enhancer, water in an amount to reach the target of 7 wt %, and nicotine when present in liquid base form were mixed slowly put into the mixer and mixed to homogeneity; [0103] D: the resulting mixture was sieved to avoid lumps or aggregates; and [0104] E: the obtained powders were packages in batches of 5-10 g.

TABLE-US-00011 11.1 A MCC 100% soluble 82.2% Alginate 2.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

TABLE-US-00012 11.2 A MCC 100% soluble 78.8% Alginate 2.0% Sodium chloride 3.0% Nicotine salt 20% 4.2% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5%

TABLE-US-00013 11.3 A MCC 100% soluble 84.2% Alginate 0.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

TABLE-US-00014 11.4 A MCC non-soluble 82.2% Alginate 2.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

TABLE-US-00015 11.5 A MCC non soluble 78.8% Alginate 2.0% Sodium chloride 3.0% Nicotine salt 20% 4.15% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5%

TABLE-US-00016 11.6 A MCC non soluble 84.2% Alginate 0.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

TABLE-US-00017 11.7 A MCC soluble 41.1% MCC non soluble 41.1% Alginate 2.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

TABLE-US-00018 11.8 A MCC soluble 39.4% MCC non soluble 39.4% Alginate 2.0% Sodium chloride 3.0% Nicotine salt 20% 4.15% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5%

TABLE-US-00019 11.9 A MCC soluble 42.1% MCC non soluble 42.1% Alginate 0.0% Sodium chloride 3.0% B Sodium bi-carbonate 0.3% PG 2.0% Water 3.5% C Water 3.5% Acesulfame K 0.2% Mint Flavour, Taiga 2.5% Nicotine liquid form 0.83%

Tables 11.1 to 11.9

[0105] For the tests, Petri dishes (Roth EL49.1) with 14.5 diameter were used. In each Petri dish a filter paper 110 mm diameter (Roth AP29.1) was saturated and continued with water for 15 minutes. The dishes were controlled to avoid air bubbles.

[0106] 1.00 g of samples of each of compositions 11.1 to 11.9 were weighed centrifuge tubes and 47 mm filters (VWR SARTFT-3-01304-47) were put over and sealed with rubber bands over each tube. The tubes were turned upside down and put in the middle of the prepared wet Petri dishes and the filters and their powder contents were carefully loosened from the tubes.

[0107] The filters were removed at 5, 10, 15, 20, 35, 55 and 70 minutes. The filters were put in 50 ml centrifuge tubes with 25 ml 80% methanol in water and shaken for 30 minutes, centrifuged as for nicotine analysis and the liquid phases were analyzed on HPLC. The results are demonstrated in Table 12.

TABLE-US-00020 t = 5 min t = 10 min t = 15 min t = 20 min t = 30 min t = 55 min t = 70 min Soluble Soluble Soluble Soluble Soluble Soluble Soluble Composition t = 0 % % % % % % % 11.1 0 10 15 16 19 16 15 13 11.2 0 1 12 12 12 6 8 10 11.3 0 4 16 16 15 14 14 11 11.4 0 15 15 16 12 14 17 16 11.5 0 1 11 8 11 11 9 5 11.6 0 16 18 20 18 22 18 16 11.7 0 24 21 20 23 25 21 22 11.8 0 3 7 6 7 6 5 8 11.9 0 8 10 11 15 16 15 20 Gawith 0 14 16 16 15 15 17 20 Ozona 0 8 11 9 15 21 20 20 McC Yellow 0 17 16 26 17 19 18 20

Table 12

[0108] The results of Table 12 show that composition 11.7 with a mixture water insoluble and water soluble MCC and 2% sodium alginate provided a surprisingly fast nicotine delivery and released 24% of the nicotine in 5 minutes. In comparison, the formulation without sodium alginate released 8% of the nicotine. In further comparison, the tobacco based comparison products, released 8 to 17% of the nicotine in 5 minutes. It is also notable in that fluid nicotine resulted in better nicotine release than the salt nicotine polyacrylex in all formulations tested. It can be concluded that the matrix forming agent (sodium alginate) contributed to improve an early release in all formulations. It is also noted that formulations only based on water soluble MCC had a tendency form a gel lump with comparatively poor release. In further conclusion, the results show that the powder particle compositions of the invention meet requirements of admitting fast release of nicotine for user satisfaction and that matrix forming agent, here exemplified by alginate, is useful to modulate the release of nicotine.

[0109] In stability tests for 9 weeks at 40 C. 75% RH, compositions made according to the protocols above were compared with the snus products Lyft Liq (about 45 wt % water) and Zyn Spearmint (about 30 wt % water). The tests demonstrated a 15 wt % loss of nicotine and 2% pH loss, whereas the commercial snus products lost about 25 wt % of their nicotine contents and lost 4-6% in pH. These tests conclude that the inventive powder particle compositions also have a surprisingly high stability in addition the favorable release characteristics.