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Title:
NICOTINE POWDER COMPOSITION
Document Type and Number:
WIPO Patent Application WO/2015/090337
Kind Code:
A1
Abstract:
The present invention relates to unexpected and improved powder compositions for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.

Inventors:
NIELSEN BRUNO PROVSTGAARD (DK)
BØJE NIELS RAMSKOV (DK)
Application Number:
PCT/DK2014/050444
Publication Date:
June 25, 2015
Filing Date:
December 18, 2014
Export Citation:
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Assignee:
FERTIN PHARMA AS (DK)
International Classes:
A61K9/00; A61K9/51; A61K31/465
Domestic Patent References:
WO2014135630A12014-09-12
WO2012134380A12012-10-04
WO2007113665A22007-10-11
WO2007118653A22007-10-25
WO1999015171A11999-04-01
Attorney, Agent or Firm:
PATENTGRUPPEN A/S (4th floor, Aarhus C, DK)
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Claims:
CLAIMS

1. A powder composition for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.

2. The powder composition according to claim 1, wherein the content of water is below 5% by weight of the powder composition, such as below 3% by weight of the powder composition.

3. The powder composition according to claim 1 or 2, wherein the content of water is between 0.2 and 5.0% by weight of the powder composition, such as between 0.2 and 3.0% by weight of the powder composition.

4. The powder composition according to any of the preceding claims, wherein the average size of the plurality of solid lipid particles is between 20 nm and 100 μπι, such as between 20 nm and 20 μιη.

5. The powder composition according to any of the preceding claims, wherein lipid is present in an amount of between 20 and 95% by weight of the powder composition, such as between 30 and 80% by weight of the powder composition. 6. The powder composition according to any of the preceding claims, wherein the at least one surfactant is present in an amount of between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.

7. The powder composition according to any of the preceding claims, wherein nicotine is present in an amount of between 0.1 and 20% by weight of the powder composition, such as between 0.5 and 10% by weight of the powder composition. 8. The powder composition according to any of the preceding claims, wherein the solid lipid particles having a content of nicotine and at least one surfactant imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins. 9. The powder composition according to any of the preceding claims, wherein nicotine is selected from the group consisting of a nicotine base and a salt of nicotine, such as nicotine bitartrate.

10. The powder composition according to any of the preceding claims, wherein nicotine and the at least one surfactant is distributed within and onto the surface of the solid lipid particles.

11. The powder composition according to any of the preceding claims, wherein the solid lipid particles imply an increased stability of nicotine compared to adsorption or absorption of nicotine onto delivery vehicles.

12. The powder composition according to any of the preceding claims, wherein the powder composition contains no more than 6% of trans nicotine-N-oxide and no more than 4% of cis nicotine-N-oxide when placed in a sealed plastic bottle and stored for four weeks at 50° C. and 75% relative humidity.

13. The powder composition according to any of the preceding claims, wherein the solid lipid particles imply a faster delivery of nicotine compared to nicotine polacrilex resins.

14. The powder composition according to any of the preceding claims, wherein the solid lipid particles imply an increased taste masking of nicotine compared to nicotine polacrilex resins.

15. The powder composition according to any of the preceding claims, further comprising at least one mucoadhesive.

16. The powder composition according to any of the preceding claims, wherein the content of the at least one mucoadhesive is between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.

17. The powder composition according to any of the preceding claims, wherein the solid lipid particles having a content of nicotine, at least one surfactant and at least one mucoadhesive imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins.

18. The powder composition according to any of the preceding claims, wherein the solid lipid particles essentially consist of lipid, nicotine, at least one surfactant and at least one mucoadhesive.

19. The powder composition according to any of the preceding claims, wherein the solid lipid particles essentially do not contain any content of water.

20. The powder composition according to any of the preceding claims, wherein water is present on the outside of the solid lipid particles within the powder composition.

21. The powder composition according to any of the preceding claims, wherein the solid lipid particles comprise 20 to 95% lipid, 1 to 15% surfactant, 0.1 to 20% nicotine and 1 to 15% mucoadhesive by weight of the powder composition.

22. The powder composition according to any of the preceding claims, wherein the solid lipid particles comprise 30 to 80% lipid, 1 to 10%> surfactant, 0.5 to 10%> nicotine and 1 to 10%> mucoadhesive by weight of the powder composition.

23. The powder composition according to any of the preceding claims, wherein a cryoprotectant is added and the cryoprotectant being located in the powder composition outside the solid lipid particles. 24. The powder composition according to claim 23, wherein retention of nicotine is above 70% by adding a cryoprotectant.

25. The powder composition according to any of claims 23 to 24, wherein the cryoprotectant is present in an amount of between 4 and 95% by weight of the powder composition, such as between 15 and 65% by weight of the powder composition, such as between 30 and 60% by weight of the powder composition.

26. The powder composition according to any of claims 23 to 25, wherein the cryoprotectant is lactose or trehalose.

27. The powder composition according to any of claims 23 to 26, wherein the solid lipid particles comprise 4 to 95% lipid, 0.1 to 15% surfactant, 0.1 to 20% nicotine and 0.1 to 15% mucoadhesive, and 4 to 95% cryoprotectant by weight of the powder composition.

28. The powder composition according to any of claims 23 to 26, wherein the solid lipid particles comprise 30 to 80% lipid, 1 to 10% surfactant, 0.5 to 10% nicotine, 1 to 10%) mucoadhesive, and 15 to 65% cryoprotectant by weight of the powder composition.

29. The powder composition according to any of claims 1 to 22, wherein no cryoprotectant is added.

30. The powder composition according claim 29, wherein the average size of the plurality of solid lipid particles when no cryoprotectant is added is between 20 nm and 1000 nm, such as between 50 nm and 500 nm.

31. The powder composition according to any of the preceding claims, wherein the average size of the plurality of solid lipid particles without cryoprotectant is less than 5 times the average size when cryoprotectant is added, such as less than 10 times the average size.

32. The powder composition according to any of claims 23 to 31, wherein the cryoprotectant is instead an excipient.

33. The powder composition according to any of the preceding claims, wherein lipid is present in an amount of between 50 and 95% by weight of the solid lipid particles, such as between 50 and 80% by weight of the solid lipid particles. 34. The powder composition according to any of the preceding claims, wherein the lipid is selected from the group consisting of fatty acids, fatty esters and fatty mono-, di-, and triglycerides thereof, partial glycerides, fatty alcohols and their esters and ethers, natural and synthetic waxes such as bees wax and carnauba wax, wax alcohols and their esters, hydrogenated vegetable oils, hard paraffin's, phospholipids, sterols and sterol derivatives, and mixtures of any of the above lipids.

35. The powder composition according to any of the preceding claims, wherein the lipid is selected from the group consisting of C8-24 fatty acids and C8-24 fatty mono-, di-, or triglycerides, such as CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, such as saturated CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, preferably wherein said at least one lipid is selected from the group consisting of capric, lauric, myristic, palmitic, stearic, and arachidic acids and mono-, di- and triglycerides thereof, preferably trimyristin, tripalmitin, tristearin, tricaprin, myristic acid, palmitic acid, stearic acid, and behenic acid.

36. The powder composition according to any of the preceding claims, wherein the surfactant is selected from the group consisting of ionic, non-ionic, and amphoteric surfactants, preferably selected from the group consisting of non-ionic surfactants such as polyvinyl alcohol (PVA), polyoxyethylene esters and ethers, lecithin, sodium docecyl sulfate (SDS), copolymers of polyoxyethylene oxide and polyoxypropylene oxide.

37. The powder composition according to any of claims 15 to 36, wherein the mucoadhesive is selected from the group consisting of pectin, chitosan, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), methyl cellulose (MC), sodium carboxy methylcellulose (SCMC), hydroxy propyl cellulose (HPC), preferably selected from the group consisting of pectin, PVA and PAA.

38. A method of producing a powder composition for oromucosal delivery of nicotine comprising the steps of i) providing a liquid suspension of a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and ii) subjecting the liquid suspension to a drying step and thereby obtaining a powder composition having a content of water below 10.0% by weight of the powder composition.

39. The method according to claim 36 obtaining a powder composition according to any of claims 1 to 37.

40. The method according to any of claim 38 to 39, wherein the drying step comprises freeze drying in presence of a cryoprotectant. 41. The method according to any of claim 38 to 39, wherein the drying step comprises spray drying in presence of an excipient.

42. An oromucosal delivery system comprising a powder composition according to any of claims 1 to 37.

43. The oromucosal delivery system according to claim 42, wherein the powder composition is added in an amount of 1 to 70% by weight of the oromucosal delivery system, such as in an amount of 10 to 50% by weight of the oromucosal delivery system

44. The oromucosal delivery system according to any of claims 42 to 43, wherein the powder composition is compressed and constitutes the oromucosal delivery system.

45. The oromucosal delivery system according to any of claims 42 to 44, wherein the content of water is between 0.2 and 2.0% by weight of the oromucosal delivery system.

46. The oromucosal delivery system according to any of claims 42 to 45 in form of a lozenge.

47. The oromucosal delivery system according to any of claims 42 to 45 in form of a chewing gum.

48. The oromucosal delivery system according to claim 47, wherein the powder composition is added as part of a bulk portion after mixing of a gum base matrix.

49. The oromucosal delivery system according to any of claims 47 to 48, wherein the gum base matrix constitutes 30 to 80% by weight of the chewing gum. 50. The oromucosal delivery system according to any of claims 47 to 49, further comprising a buffering agent.

51. The oromucosal delivery system according to any of claims 47 to 50, wherein the powder composition is compressed together with chewing gum base particles to obtain a compressed chewing gum.

52. The oromucosal delivery system according to any of claims 42 to 43 in form of a mouth spray. 53. The oromucosal delivery system according to any of claims 42 to 43 in form of a pouch.

54. The oromucosal delivery system according to any of claims 42 to 53, wherein the powder composition is being produced by the method of claims 38 to 41.

Description:
NICOTINE POWDER COMPOSITION FIELD OF THE INVENTION

The present invention pertains to the field of powder compositions for oromucosal delivery of nicotine. In particular, the present invention pertains to solid lipid powder compositions with a content of nicotine and low water content.

BACKGROUND

Nicotine has been the subject of various attempts to optimize delivery and uptake in the oral cavity. One of the critical issues when nicotine enters the oral cavity is to avoid that most of the nicotine is swallowed and degraded in the gastrointestinal tract. While this may be an advantage for the vast majority of medical active ingredients, the effect of nicotine in oral formulations is mainly obtained by uptake of nicotine in the oral mucosa. Uptake in the oral mucosa and subsequent absorption in the blood stream is critical to deliver nicotine to its receptor target sites in the human brain. This way of uptake will ensure that nicotine will pass directly to the target receptors in the human brain.

Due to these circumstances, nicotine has traditionally been formulated for the purpose of sustained delivery in the oral cavity. By securing a sustained release, it has been the expectation in the prior art that a higher ratio of nicotine would be delivered into the blood stream and a lower ratio of nicotine would be swallowed and degraded in the gastrointestinal tract. One such oral delivery vehicle used for sustained delivery of nicotine is nicotine polacrilex resins. The mechanism in these kinds of systems is that ion-bonding of nicotine provides a stable nicotine complex during storage which after entering the oral cavity will slowly deliver nicotine to the oral cavity. It has been the conventional wisdom that the mechanism involves a number of limiting factors, such as concentration limits in the saliva and concentration limits in the oral mucosa, as well as barrier properties through the oral mucosa. By keeping the release rate of nicotine low, it has been conventional thinking that such limiting factors may be optimized.

However, although degradation in the gastrointestinal tract may be avoided, previously known systems for oromucosal delivery do not fulfil the desire for users expecting a fast effect of nicotine. Some of the expected problems with a faster release of nicotine include a burning sensation and unpleasant taste of nicotine because of the inherently bitter taste of nicotine. Also, it has always been expected to give rise to stability problems when nicotine is to be delivered fast.

SUMMARY OF THE INVENTION

Accordingly, there has been provided an unexpected and improved powder composition for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.

Additionally, the present invention provides a method of producing a powder composition for oromucosal delivery of nicotine comprising the steps of providing a liquid suspension of a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and subjecting the liquid suspension to a drying step and thereby obtaining a powder composition having a content of water below 10.0% by weight of the powder composition. Furthermore, the present invention provides an oromucosal delivery system, such as a lozenge or compressed chewing gum, comprising a powder composition according to the invention.

FIGURES Figure 1 shows the particle size distribution of a suspension of solid lipid particles. The particle concentrations in this figure is 1,3 % of the total weight of the suspension. Figure 2 shows the particle size distribution of a suspension containing solid lipid particles and 2 % trehalose that has been freeze dried to a powder. The suspension measured in Figure 1 and Figure 2 is the same, and the two figures are thus directly comparable. It is thus a comparison of the suspension before and after the freeze drying process.

DEFINITIONS

In the present context the term "oromucosal delivery" refers to delivery to the oral cavity.

In the present context the term "solid lipid" is a lipid that is solid at room

temperature and also at physiological body temperature.

In the present context the terms "mucoadhesive" and "mucoadhesion" refers to the concept of a composition adhering to a mucous membrane. Mucoadhesive compounds may facilitate mucoadhesion by their specific properties.

Unless otherwise stated, when nicotine is mentioned to be released from a chewing gum after a chewing process this chewing process refers to the procedure set forth in the Ph. Eur. 6 th ed. 2.9.25, at pH = 7.4, a chewing rate of 60 chew per minute, and with the temperature of the medium at 37°C for about 10 minutes.

By the terms "gum base" and "gum base matrix" we mean the mainly water insoluble and hydrophobic gum base ingredients that are mixed together before the bulk portion of the chewing gum formulation is added. The term "bulk portion" intends to mean the mainly water soluble chewing and hydrophilic gum ingredients that are mixed into the gum base matrix after it has been mixed.

DETAILED DESCRIPTION

It has surprisingly been found by the present inventors that an unexpected system may be obtained by a powder composition for oromucosal delivery of nicotine comprising a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and the powder composition having a content of water below 10.0% by weight of the powder composition.

In general, the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may also or alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected by the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs. By incorporating nicotine into solid lipid particles, nicotine may also be stabilized to a high degree. The surfactant of the present invention may facilitate stabilizing nicotine in the solid lipid particles. Accordingly, the concept may be seen as a way to stabilize nicotine and at the same time offer the best conditions for delivery of nicotine to the target site. In addition, the solid lipid particles according to the present invention may be an advantage in terms of less burning and unpleasant taste compared to conventional systems for delivery of nicotine since nicotine may provide a burning sensation to target receptors in the oral cavity. Hence, burning may be less pronounced according to the present invention. As an example, nicotine is released directly into the oral cavity when using nicotine polacrilex resins and bitterness receptors may be triggered. This direct exposure may be avoided according to the present invention. This would in turn also be the case for systems where nicotine is adsorbed into or onto carriers such as cellulose particles where nicotine is also delivered directly in the oral cavity.

It is believed by the present inventors that bitterness receptors may be less triggered by the present invention and that taste masking is improved. The reason may in part be that the solid lipid particles of the present invention are targeted to the site of action, and in part the solid lipid particles protect nicotine from exposure to bitterness receptors.

Another advantage of the present invention is that nicotine may be stabilized by using a relatively low amount of water, i.e. an amount of water of less than 10.0% by weight of the powder composition or even lower. Compared to conventional systems this offers improved conditions for the powder composition according to the present invention. That it was in fact possible to provide a system with such a relative low amount of water was a surprise to the present inventions and completely unexpected. It was in fact expected by the present inventors that such relative low water content would compromise the quality of nicotine and impart problems with evaporation of nicotine either during the process of lowering the amount of water or during storage. However, contrary to expectations, the exact opposite was seen. In an embodiment of the invention, the content of water of the powder composition is below 5% by weight of the powder composition, such as below 3% by weight of the powder composition. In one embodiment of the invention, the content of water of the powder composition is below 2.5% by weight of the powder composition, such as below 2% by weight of the powder composition, such as below 1.5% by weight of the powder composition.

In another embodiment of the invention, the content of water of the powder composition is between 0.2 and 5.0% by weight of the powder composition, such as between 0.2 and 3.0% by weight of the powder composition.

In another embodiment of the invention, the content of water of the powder composition is between 0.3 and 4.0% by weight of the powder composition, such as between 0.5 and 3.0% by weight of the powder composition, such as between 0.7 and 2.5%) by weight of the powder composition, such as between 0.8 and 2.0% by weight of the powder composition.

A particularly preferred embodiment of the present invention may be a powder composition, wherein the average size of the plurality of solid lipid particles is between 20 nm and 100 μιτι, such as between 20 nm and 20 μιη.

Such an average size of the particles, such as nano-sized particles, may provide for improved taste-masking properties of the present invention because less sized particles may be less susceptible for bitterness receptors. In addition, less sized particles have been shown to be an advantage in order for the particles to enter the barrier of epithelium. Hence, such less sized particles may provide for an improved uptake or absorption of nicotine into the blood stream and higher effect of nicotine. However, the size of the particles will have a lower limit. This is partly due to restrictions in the manufacturing process.

In another embodiment, the average size of the plurality of solid lipid particles is between 50 nm and 20 μιτι, such as between 70 nm and 15 μιτι, such as between 100 nm and 15 μιτι, such as between 200 nm and 15 μιτι, such as between 300 nm and 15 μπι, such as between 400 nm and 12 μιτι, such as between 500 nm and 10 μιη.

In another embodiment, the average size of the plurality of solid lipid particles is between 50 nm and 15 μιτι, such as between 70 nm and 12 μιτι, such as between 100 nm and 10 μιτι, such as between 200 nm and 5 μιτι, such as between 300 nm and 3 μπι, such as between 400 nm and 2 μιτι, such as between 500 nm and 1 μιη.

The solid lipid particles according to the invention may contain additional ingredients, such as a cryoprotectant or an excipient for further handling. In this respect, the size of the particles above may include such additional ingredient.

In essence, it was not expected by the present inventors that it may be possible to obtain relatively low particles sizes while at the same time providing for a desired absorption of nicotine and stability of nicotine. Indeed, it was also a surprise to the inventors that an increased uptake of nicotine may be seen by lowering the size of the particles according to the present invention.

According to the present invention it is believed that solid lipid particles with a relatively large size may be adsorbed to the epithelium and that the oral mucosa will somehow be of less importance to penetrate. On the other hand, it is believed that solid lipid particles with a relatively small size may be absorbed into the oral mucosa and thereby reaching the epithelium via uptake in the oral mucosa. In other circumstances, it may be that both mechanisms would be present. This may be the case for intermediate sizes particles dependent on the thickness of the oral mucosa. This may depend of the affinity of the lipid particle according to the invention to the lipid structures in the oral mucosa and/or the epithelium or the like.

In one embodiment of the invention, lipid is present in an amount of between 20 and 95% by weight of the powder composition, such as between 30 and 80% by weight of the powder composition.

In another embodiment of the invention, lipid is present in an amount of between 25 and 90% by weight of the powder composition, such as between 30 and 75% by weight of the powder composition.

The solid lipid particles according to the invention are considered lipid particles. While the amount of lipid is not always 100%, lipid contributes to a major part of the properties of the particles. Hence, lipid will be the major contributor to the properties of the particles. For instance, nicotine may be protected by nearly 100%) lipid, but according to the invention may also be protected by a less amount of lipid because the characteristics of the lipid according to the invention are overwhelming.

For instance when a cryoprotectant or a further excipient is present according to the invention, the amount of lipid may be even lower, such as 15 and 60%> by weight of the powder composition, such as between 20 and 55% by weight of the powder composition, such as between 25 and 50% by weight of the powder composition, such as between 30 and 45% by weight of the powder composition. In one embodiment of the invention, the at least one surfactant is present in the powder composition in an amount of between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.

In another embodiment of the invention, the at least one surfactant is present in the powder composition in an amount of between 2 and 10% by weight of the powder composition, such as between 2 and 8% by weight of the powder composition, such as between 2 and 7% by weight of the powder composition, such as between 1 and 8% by weight of the powder composition, such as between 2 and 7% by weight of the powder composition.

The surfactant according to the invention may be used to stabilize the composition with nicotine. While nicotine both contains lipophilic and hydrophilic properties, the surfactant according to the invention may secure an adequate balance in order to provide for a stable and desired amount of nicotine present.

For instance when a cryoprotectant or a further excipient is present according to the composition, the at least one surfactant may be present in the powder composition in an amount of between 1 and 7% by weight of the powder composition, such as between 1 and 6% by weight of the powder composition, such as between 1 and 5% by weight of the powder composition, such as between 1 and 4% by weight of the powder composition.

In one embodiment of the invention, nicotine is present in an amount of between 0.1 and 20% by weight of the powder composition, such as between 0.5 and 10% by weight of the powder composition.

In another embodiment of the invention, nicotine is present in an amount of between 1 and 20%) by weight of the powder composition, such as between 3 and 15%> by weight of the powder composition, such as between 3 and 10%> by weight of the powder composition.

In another embodiment of the invention, nicotine is present in an amount of between 8 and 20% by weight of the powder composition, such as between 10 and 20% by weight of the powder composition, such as between 15 and 20% by weight of the powder composition. In another embodiment of the invention, nicotine is present in an amount of between 5 and 15% by weight of the powder composition, such as between 6 and 14% by weight of the powder composition, such as between 7 and 13% by weight of the powder composition.

As the case may for instance be for lipid and surfactant, the amount of nicotine may be influenced by the presence of cryoprotectant and/or additional excipient in the process.

According to the invention, the solid lipid particles having a content of nicotine and at least one surfactant may imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins. In particular, the lower amount of nicotine may be obtained as nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs. The type of nicotine used according to the present invention may be selected from the group consisting of a nicotine base and a salt of nicotine, such as nicotine bitartrate. In particular, nicotine base is preferred.

In an embodiment of the invention, said nicotine salts are selected from the group comprising nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride, nicotine salicylate, or any combination thereof.

The use of a salt of nicotine, such as nicotine bitartrate, may be beneficial in order to change the mechanism of absorption through the cell layers.

In one embodiment of the invention, nicotine and the at least one surfactant is distributed within and onto the surface of the solid lipid particles. In another embodiment, nicotine and the at least one surfactant is distributed evenly in the solid lipid particles. In another embodiment, more than 70% nicotine and the at least one surfactant is distributed within the outermost 80% of the solid lipid particles.

In one embodiment of the invention, the solid lipid particles imply an increased stability of nicotine compared to adsorption or absorption of nicotine onto delivery vehicles.

By incorporating nicotine into solid lipid particles, nicotine may also be stabilized to a high degree. Accordingly, the concept may be seen as a way to stabilize nicotine and at the same time offer the best conditions for delivery of nicotine to the target site.

In one embodiment of the invention, the powder composition contains no more than 6% of trans nicotine-N-oxide and no more than 4% of cis nicotine-N-oxide when placed in a sealed plastic bottle and stored for four weeks at 50° C. and 75% relative humidity.

In one embodiment of the invention, the solid lipid particles imply a faster delivery of nicotine compared to nicotine polacrilex resins. In particular, the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs.

In one embodiment of the invention, the solid lipid particles imply an increased taste masking of nicotine compared to nicotine polacrilex resins.

In one embodiment of the invention, the solid lipid particles imply an increased taste masking of nicotine compared to nicotine bitartrate.

In particular, the solid lipid particles according to the present invention may be an advantage in terms of less burning and unpleasant taste compared to conventional systems for delivery of nicotine since nicotine may provide a burning sensation to target receptors in the oral cavity. Hence, burning may be less pronounced according to the present invention. As an example, nicotine is released directly into the oral cavity when using nicotine polacrilex resins and this direct exposure may be avoided according to the present invention. As another example, nicotine is released directly into the oral cavity when nicotine is adsorbed into or onto carriers such as cellulose particles.

In one embodiment of the invention, the powder composition may further comprise at least one mucoadhesive. The advantage of at least one mucoadhesive is that an increased amount of nicotine is targeted to the sites of absorption. In one embodiment of the invention, the content of the at least one mucoadhesive is between 1 and 15% by weight of the powder composition, such as between 1 and 10% by weight of the powder composition.

In another embodiment of the invention, the content of the at least one mucoadhesive is between 2 and 12% by weight of the powder composition, such as between 3 and 1 1%) by weight of the powder composition, such as between 5 and 10% by weight of the powder composition.

In another embodiment of the invention, the content of the at least one mucoadhesive is between 5 and 15% by weight of the powder composition, such as between 7 and 15%) by weight of the powder composition.

In another embodiment of the invention, the content of the at least one mucoadhesive is between 1 and 9% by weight of the powder composition, such as between 2 and 8%) by weight of the powder composition.

In one embodiment of the invention the solid lipid particles having a content of nicotine, at least one surfactant and at least one mucoadhesive imply that a lower amount of nicotine is necessary for oromucosal delivery of nicotine compared to nicotine polacrilex resins.

In particular, the present invention may offer a fast effect of nicotine compared to conventional systems. Contrary to conventional systems where nicotine is delivered to saliva in the oral cavity, nicotine may be delivered directly into the oral mucosa by the present invention. In turn, nicotine may alternatively be delivered directly to the epithelium in the oral cavity by the present invention. Without being bound by theory, it is believed that nicotine is protected in the solid lipid particles of the present invention and that this protection offers improved conditions for targeting nicotine to the sites of absorption. Hence, while obtaining conditions that allows for less nicotine being swallowed into the gastrointestinal tract, the present invention may utilize a higher amount of nicotine compared to conventional systems and thereby reduced costs.

In one embodiment of the invention, the solid lipid particles essentially consist of lipid, nicotine, at least one surfactant and at least one mucoadhesive.

This embodiments is particularly preferred when the size of the particles are to be low, e.g. in nano size. In one embodiment of the invention, the solid lipid particles essentially do not contain any content of water.

In one embodiment of the invention, water is substantially present on the outside of the solid lipid particles within the powder composition.

In one embodiment of the invention, the solid lipid particles comprise 20 to 95% lipid, 1 to 15%) surfactant, 0.1 to 20% nicotine and 1 to 15%> mucoadhesive by weight of the powder composition. In one embodiment of the invention, the solid lipid particles comprise 30 to 80%> lipid, 1 to 10%) surfactant, 0.5 to 10%> nicotine and 1 to 10%> mucoadhesive by weight of the powder composition.

In one embodiment of the invention, a cryoprotectant is added and the cryoprotectant being located in the powder composition outside the solid lipid particles. In one embodiment of the invention, retention of nicotine is above 70% by adding a cryoprotectant, such as above 75% by adding a cryoprotectant, such as above 80% by adding a cryoprotectant. This means that nicotine is not lost by adding a

cryoprotectant. Retention in this respect means the percentage of nicotine retained during the process.

In one embodiment of the invention, the cryoprotectant is present in an amount of between 4 and 95% by weight of the powder composition, such as between 15 and 65% by weight of the powder composition, such as between 30 and 60% by weight of the powder composition.

In one embodiment of the invention, the cryoprotectant is lactose or trehalose. According to the invention, lactose and trehalose have shown to give particularly good results.

In another embodiment of the invention, the cryoprotectant is selected from members known to those skilled in the art to work within the present invention.

In one embodiment of the invention, the solid lipid particles comprise 4 to 95% lipid, 0.1 to 15%) surfactant, 0.1 to 20% nicotine and 0.1 to 15% mucoadhesive, and 4 to 95%) cryoprotectant by weight of the powder composition. In one embodiment of the invention, the solid lipid particles comprise 30 to 80% lipid, 1 to 10%) surfactant, 0.5 to 10% nicotine, 1 to 10% mucoadhesive, and 15 to 65%) cryoprotectant by weight of the powder composition.

In one embodiment of the invention, no cryoprotectant is added. This may be an advantage in case less sized particles are preferred, such as nano-sized particles. In one embodiment of the invention, the average size of the plurality of solid lipid particles when no cryoprotectant is added is between 20 nm and 1000 nm, such as between 50 nm and 500 nm, such as between 50 nm and 400 nm.

In another embodiment of the invention, the average size of the plurality of solid lipid particles when no cryoprotectant is added is between 50 nm and 300 nm, such as between 75 nm and 250 nm, such as between 75 nm and 200 nm, such as between 75 nm and 150 nm.

In one embodiment of the invention, the average size of the plurality of solid lipid particles without cryoprotectant is less than 5 times the average size when cryoprotectant is added, such as less than 10 times the average size. In another embodiment of the invention, the average size of the plurality of solid lipid particles without cryoprotectant is less than 11 times the average size when cryoprotectant is added, such as less than 15 times the average size.

In another embodiment of the invention, the average size of the plurality of solid lipid particles without cryoprotectant is more than 2 times the average size when cryoprotectant is added, such as more than 3 times the average size, such as more than 4 times the average size

According to the invention, the size of the solid lipid particles in part depend of the amount of cryoprotectant added during manufacture.

In one embodiment of the invention, cryoprotectant is added after formation of the solid lipid particles and before drying. In another embodiment of the invention, the cryoprotectant is instead an excipient. This excipient may be selected from any excipient known to be useful to those skilled in the art, for instance when the particles undergo spray drying. In another embodiment of the invention, lipid is present in an amount of between 50 and 95% by weight of the solid lipid particles, such as between 50 and 80% by weight of the solid lipid particles.

In another embodiment of the invention, the lipid is selected from the group consisting of fatty acids, fatty esters and fatty mono-, di-, and triglycerides thereof, partial glycerides, fatty alcohols and their esters and ethers, natural and synthetic waxes such as bees wax and carnauba wax, wax alcohols and their esters,

hydrogenated vegetable oils, hard paraffin's, phospholipids, sterols and sterol derivatives, and mixtures of any of the above lipids.

In another embodiment of the invention, the lipid is selected from the group consisting of C8-24 fatty acids and C8-24 fatty mono-, di-, or triglycerides, such as CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, such as saturated CI 0-22 fatty acids and CI 0-22 fatty mono-, di-, or triglycerides, preferably wherein said at least one lipid is selected from the group consisting of capric, lauric, myristic, palmitic, stearic, and arachidic acids and mono-, di- and triglycerides thereof, preferably trimyristin, tripalmitin, tristearin, tricaprin, myristic acid, palmitic acid, stearic acid, and behenic acid. In an embodiment of the invention said at least one lipid is selected from the group consisting of capric, lauric, myristic, palmitic, stearic, and arachidic acids and mono-, di- and triglycerides thereof, preferably selected from trimyristin, tripalmitin, tristearin, tricaprin, myristic acid, palmitic acid, stearic acid, and behenic acid. In an embodiment of the invention the lipid is a phospholipid preferably selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA), DPG (bisphosphatidyl glycerol), PEOH (phosphatidyl alcohol), cholesterol, ergosterol and lanosterol, preferably phosphatidylcholine (PC).

In another embodiment of the invention, the surfactant is selected from the group consisting of ionic, non-ionic, and amphoteric surfactants, preferably selected from the group consisting of non-ionic surfactants such as polyvinyl alcohol (PVA), polyoxy ethylene esters and ethers, lecithin, sodium docecyl sulfate (SDS), copolymers of polyoxy ethylene oxide and polyoxypropylene oxide.

The use of a surfactant may stabilize the particles according to the invention and prevent agglomeration of the individual particles. The use of a surfactant may also control the morphology of the particles produced.

In an embodiment of the invention at least one porogen is present. Porogen leaching from the particles can be used to control the particles and porosity by selecting suitable amounts of the added porogens, thus further controlling the release over time of nicotine. Modification of porogen surface to volume ratio can be used to optimize the permeability of the particles and thus control the release of nicotine.

In an embodiment of the invention the composition further comprises a compound having mucoadhesive properties in order to further control the delivery of the nicotine and/or flavour component to the desired place of delivery.

In another embodiment of the invention, the mucoadhesive is selected from the group consisting of pectin, chitosan, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), methyl cellulose (MC), sodium carboxy methylcellulose (SCMC), hydroxy propyl cellulose (HPC), preferably selected from the group consisting of pectin, PVA and PAA.

In an embodiment of the invention the composition comprises nicotine and a flavour component, wherein the nicotine component is immobilized in separate lipid particles from the particles immobilizing the flavour component. By incorporating nicotine in separate lipid particles from the flavour component the release of both the nicotine component and the flavour component may be controlled to obtain e.g. a fast release of nicotine to satisfy the nicotine craving and a longer lasting flavour release to obtain a pleasant taste in the mouth.

In an embodiment of the invention the composition further comprises at least one ingredient, preferably wherein said ingredient is a hydrophilic polymer and/or amphiphilic polymer, preferably selected from the group consisting of pectin, chitosan, dextran, pullulan, carrageenan, starch, cellulose acetate, sodium alginate, polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyethylene oxide (PEO), methyl cellulose (MC), sodium carboxy methylcellulose (SCMC), hydroxy propyl cellulose (HPC), preferably selected from the group consisting of pectin, PEO, PVA and PAA. Such an excipient may further impart a desired hydrophilicity to the composition and may further control the dissolution rate and may thereby control the release of nicotine and to result in swelling and/or erosion of particles.

In an embodiment of the invention the solid lipid particles are prepared by hot homogenization, such as in the following order:

1. One or more lipids in a melted state are provided, optionally by heating to above the phase transition temperature thereof. Thus heating may not be necessary when the lipid(s) in question is/are in a liquid state at room temperature. However, in other embodiments heating will be applied in order to provide the lipid(s) in a melted state. 2. nicotine is dissolved or dispersed therein.

3. any optional ingredients, such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) are added to the lipid dispersion either neat or as a solution, preferably an aqueous solution thereof, and mixed.

4. thereafter the mixture obtained is subjected to high pressure homogenization in a manner known per se, at an elevated temperature, 5. thereafter the mixture obtained is cooled, to obtain the solid lipid particles.

In another embodiment of the invention the solid lipid particles are prepared by hot high shear homogenization and/or ultrasoni cation techniques, such as in the following order:

1. one or more lipids and nicotine is mixed in the melted state, optionally by heating to above the phase transition temperature of the lipid(s). Thus, heating may not be necessary when the lipid(s) in question is/are in a liquid state at room temperature. However, in other embodiments heating will be applied in order to provide the lipid(s) in a melted state

2. any optional ingredients, such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) in aqueous solution or dispersion are heated and added to the above lipid-active ingredient mixture

3. the above solution or dispersion is emulsified in the melted state by probe sonication or using high speed stirring

4. the above solution or dispersion is cooled to below the phase transition temperature or below the melting point. In another embodiment of the invention the solid lipid particles are prepared by cold homogenization, such as in the following order: 1. one or more lipids in a melted state are provided, optionally by heating to above the phase transition temperature thereof. Thus heating may not be necessary when the lipid in question is/are in a liquid state at room temperature. However, in other embodiments heating will be applied in order to provide the lipid(s) in a melted state 2. the at least one active ingredient is dissolved or dispersed therein and rapidly cooled afterwards

3. the above solid lipid mixture is milled to nano-micron size 4. optionally, the above mixture is mixed with any optional ingredients, such as surfactant(s), excipient(s) and/or mucoadhesive compound(s) and/or porogen(s) that are added to the mixture either neat or as a solution, preferably as an aqueous solution thereof, 5. thereafter the mixture obtained is subjected to high pressure homogenisation below the melting temperature of the lipid(s), to obtain the solid lipid particles.

In one embodiment of the invention, the shape of the solid lipid particles is not spherical. The shape may be somehow elongate compared to spherical particles.

Another aspect of the present invention is a method of producing a powder composition for oromucosal delivery of nicotine comprising the steps of providing a liquid suspension of a plurality of solid lipid particles, the solid lipid particles having a content of nicotine and at least one surfactant, and subjecting the liquid suspension to a drying step and thereby obtaining a powder composition having a content of water below 10.0% by weight of the powder composition.

This method may provide a powder composition according to the invention.

In one embodiment of the invention, the drying step comprises freeze drying in presence of a cryoprotectant.

Freeze drying according to the invention includes a number of steps. Thus, the material to be dehydrated is frozen at a temperature and speed depending upon the type of material. The frozen material is then placed in a chamber which is evacuated to a degree which also depends upon the nature of the material which is to be freeze dried. During the second dehydrating phase, which is to say after the greatest part of the free water has been eliminated by sublimation, the remainder of the water (compositional water) is eliminated by evaporation. The water which is freed during dehydration is fixed in a condenser which possesses a chilled surface having a temperature of less than 40 (degree) C and dimensions which are determined by the quantity of water to be fixed. The material which has been dehydrated is then enclosed within a sealed package in which there prevails an evacuated or inert atmosphere.

Various proposals for carrying out the freeze drying have already been made in order to eliminate drawbacks such as excessive lengths of time and high cost of equipment as well as possible dangers in the operation. Thus it has already been proposed and described by Copson and his collaborators in 1957 to apply heat to the product which is to be freeze dried exclusively by radio frequency in order to obtain a freeze drying method of extremely short duration. However a practical realization of this latter technique has always presented great difficulties because of the requirement of extremely large sources of power in order to heat several hundred kilos of the material to be freeze dried. The use of these high sources of power necessitates the use of extremely high voltages which in combination with the low pressure in the evacuated atmosphere gives the risk of electrical discharge between the electrodes with the result that the material to be freeze dried is frequently scorched or burned. In one embodiment of the invention, the drying step comprises spray drying in presence of an excipient.

Spray drying according to the invention is a rapid, one-step process to obtain the solid lipid particles. Usually the drying gas is air, but nitrogen can also be used for special products needing oxygen-free conditions. The most common feed materials are aqueous-based solutions, emulsions and suspensions, where water is evaporated in the dryer. The liquid feed is fed to an atomizer, which is a device that breaks up the liquid stream into tiny droplets. This atomization takes place within the drying chamber so that the droplets are immediately exposed to hot air that initiates rapid moisture evaporation. The droplets become small particles of powder as the moisture is evaporated and they fall to the bottom of the drying chamber. Pressure nozzles, rotary disks, two-fluid nozzles, and the like are used as the atomizing unit. In many cases, the drying time is as short as 5 to 30 seconds (see, Handbook of Chemistry and Engineering (1999) revised sixth edition, Maruzen Corporation, p. 770, p. 780). A four-fluid nozzle has also been developed, which has enabled mass-scale spray drying with a liquid droplet having a mean particle size of several micrometers.

The spray drying method according to the invention is used in many cases of mass scale production. In general, to produce a large volume of powder in a short period of time, a solution or slurry is fed at a fast feed rate into a spray dryer, while the inlet temperature of the spray dryer and the outlet temperature thereof are elevated as high as possible, to dry the slurry at a high speed. For example, milk is dried at an inlet temperature of the spray dryer of 150 to 250.deg.C and yeast is dried at the inlet temperature of 300 to 350.deg.C. Drying at such high temperatures may negatively impact the flavor of the raw material itself and produce a dry powder with a burned odor. However, spray drying at a low temperature to avoid these disadvantages can increase process times and costs. See US 2005/0031769 and US Patent No.

6,482,433.

Commercially available spray dryers can be used as in the practice of the present invention. For example, a spray dryer with a vertical parallel flow function can be used. The spray dryer should be a system with a dehumidifying and drying function. For example, a spray dryer capable of blowing a high volume of desiccated air with a dew point of less than 5.deg.C is particularly preferable. For a spray dryer with no dehumidifying and drying function, the spray dryer is inevitably arranged with a dry dehumidifier, e.g., a honeycomb-type rotary dehumidifier (e.g., Nichias Corporation or Sweden PROFLUTE Corporation). Suitable spray dryers include the micromist spray dryer and the hybrid granulator series manufactured by Fujisaki Electric Co., Ltd.; the fluidized spray dryer FSD with internal fluid bed as manufactured by Niro Corporation; the fluid granulation spray dryer and L-8 type spray dryer manufactured by Ogawara (Japan); the type spray dryers manufactured by Yamato Scientific Co., Ltd., and Anhydro Spray Bed Dryer manufactured by SPX Corporation.

Among the operation conditions of the spray drying apparatus according to the invention, in certain embodiments the outlet temperature of the spray drying apparatus is between 20.deg.C and 60.deg.C, preferably 30 to 60.deg.C, and more preferably 40 to 60.deg.C. For the purposes of this invention, the outlet temperature of the spray dryer means the product temperature of the dry powder in the vicinity of the powder collection part of the spray dryer. For the spray dryer of the vertical parallel flow type, the outlet temperature means the temperature (exhaust gas temperature) at the exhaust part thereof.

In other embodiments of this invention, the average inlet air temperature of the spray drying apparatus is less than 100 .deg.C. In certain embodiments, the average inlet air temperature of the spray drying apparatus is in the range of 40. deg.C to 99. deg.C, more preferably 60. deg.C to 99. deg.C and most preferably 80. deg.C to 99. deg.C. For the purposes herein, the average inlet air temperature is a sum total of all inlet air streams, e.g., main chamber inlet air and the inlet air to the fluid bed(s).

In some embodiments, the solid lipid particles are obtained by spray-drying the mixture or drying the mixture in a fluidized bed (e.g. fluid bed-drying). This method of obtaining the solid formulation poses additional challenge compared to freeze- drying, since the components of the mixture remain in the liquid state during the process with potential for loss of nicotine during the drying process. However, it has been found that, according to methods disclosed herein, substantially none of the nicotine is lost.

In one embodiment of the invention, nicotine is substantially not degraded during the step of freeze drying or spray drying. In another embodiment of the nicotine is degraded less than 1 % during the step of freeze drying or spray drying, such as less than 2% during the step of freeze drying or spray drying, such as less than 5% during the step of freeze drying or spray drying, such as less than 10% during the step of freeze drying or spray drying.

Another aspect of the invention provides for an oromucosal delivery system comprising a powder composition according to the invention.

In one embodiment of the invention, the powder composition is added in an amount of 1 to 70%) by weight of the oromucosal delivery system, such as in an amount of 10 to 50%) by weight of the oromucosal delivery system.

In one embodiment of the invention, the powder composition is added in an amount of 5 to 65%) by weight of the oromucosal delivery system, such as in an amount of 7 to 60%o by weight of the oromucosal delivery system, such as in an amount of 10 to 55%) by weight of the oromucosal delivery system, such as in an amount of 15 to 50%o by weight of the oromucosal delivery system, In another embodiment of the invention, the powder composition is added in an amount of 2 to 50% by weight of the oromucosal delivery system, such as in an amount of 5 to 40% by weight of the oromucosal delivery system, such as in an amount of 7 to 30% by weight of the oromucosal delivery system, such as in an amount of 10 to 25% by weight of the oromucosal delivery system,

In another embodiment of the invention, the powder composition is added in an amount of 10 to 70% by weight of the oromucosal delivery system, such as in an amount of 20 to 65% by weight of the oromucosal delivery system, such as in an amount of 25 to 60% by weight of the oromucosal delivery system, such as in an amount of 30 to 50% by weight of the oromucosal delivery system,

In one embodiment of the invention, the powder composition is compressed and constitutes the oromucosal delivery system. This embodiment is particularly useful if a whole tablet is to be produced in one step. This saves additional processes and it is believed by the inventors that such a one step process may result in even more stable products. In one embodiment of the invention, the content of water is between 0.2 and 2.0% by weight of the oromucosal delivery system.

In one embodiment of the invention, the oromucosal delivery system is in form of a lozenge, such as a fast disintegrating oral tablet, or the like.

In one embodiment of the invention, the oromucosal delivery system is in form of a chewing gum.

In the embodiment of a chewing gum, the gum base matrix may comprise two or more ingredients selected from the group consisting of elastomers, elastomer plasticizers, resins, polyvinyl acetate, hydrogenated resins, polyterpene, fillers, fats and waxes, or any combination thereof.

It should be noted that various concentrations of gum base in the chewing gum may be applied within the scope of the invention.

According to the invention a preferred amount of gum base matrix in the chewing gum is above 30 percent by weight of the chewing gum, such as above 35 percent by weight of the chewing gum, such as above 40 percent by weight of the chewing gum, such as above 45 percent by weight of the chewing gum, such as about 40 percent by weight of the chewing gum, such as about 47 percent by weight of the chewing gum.

The composition of gum base formulations can vary substantially depending on the particular product to be prepared and on the desired masticatory and other sensory characteristics of the final product. However, typical ranges (% by weight) of the above gum base components are: 5 to 80% by weight elastomeric compounds, 5 to 80%) by weight elastomer plasticizers, 0 to 40% by weight of waxes, 5 to 35% by weight softener, 0 to 50% by weight filler, and 0 to 5% by weight of miscellaneous ingredients such as antioxidants, colourants, etc. The gum base may comprise about 5 to about 95 percent, by weight, of the chewing gum, more commonly the gum base comprises 10 to about 60 percent, by weight, of the gum.

Elastomers provide the rubbery, cohesive nature to the gum, which varies depending on this ingredient's chemical structure and how it may be compounded with other ingredients. Elastomers suitable for use in the gum base and gum of the present invention may include natural or synthetic types.

Elastomer plasticizers vary the firmness of the gum base. Their specificity on elastomer inter-molecular chain breaking (plasticizing) along with their varying softening points cause varying degrees of finished gum firmness and compatibility when used in base. This may be important when one wants to provide more elastomeric chain exposure to the alkane chains of the waxes.

The elastomer compounds may be of natural origin but are preferably of synthetic origin, preferably synthetic polyesters.

The elastomers (rubbers) employed in the gum base may vary depending upon various factors such as the type of gum base desired, the texture of gum composition desired and the other components used in the composition to make the final chewing gum product. The elastomer may be any water-insoluble polymer known in the art, and includes those gum polymers utilized for chewing gums and bubble gums. Illustrative examples of suitable polymers in gum bases include both natural and synthetic elastomers. For example, those polymers which are suitable in gum base compositions include, without limitation, natural substances (of vegetable origin) such as chicle gum, natural rubber, crown gum, nispero, rosidinha, jelutong, perillo, niger gutta, tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and the like, and mixtures thereof. Examples of synthetic elastomers include, without limitation, styrene-butadiene copolymers (SBR), polyisobutylene, isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate and the like, and mixtures thereof.

According to the invention, the preferred molecular weight of the elastomers is below 500.000 (MW) to give a homogeneous product which is easiler to manufacture and which provides an optimized release profile of pH, and/or active ingredients. Natural resins may be used according to the invention and may be natural rosin esters, often referred to as ester gums including as examples glycerol esters of partially hydrogenated rosins, glycerol esters of polymerised rosins, glycerol esters of partially dimerized rosins, glycerol esters of tally oil rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins, pentaerythritol esters of rosins, synthetic resins such as terpene resins derived from alpha-pinene, beta-pinene, and/or d-limonene, and natural terpene resins.

In an embodiment of the invention, the resin comprises terpene resins, e.g. derived from alpha-pinene, beta-pinene, and/or d-limonene, natural terpene resins, glycerol esters of gum rosins, tall oil rosins, wood rosins or other derivatives thereof such as glycerol esters of partially hydrogenated rosins, glycerol esters of polymerized rosins, glycerol esters of partially dimerised rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins or pentaerythritol esters of rosins and combinations thereof.

However, in a preferred embodiment of the invention polyterpene resins may be avoided in order to give a homogeneous product which is easiler to manufacture and which provides an optimized release profile of pH, and/or active ingredients.

Mixing, rolling and scoring may be done by a conventional procedure. Double sigma blade mixers are used for mixing the gum base with the other components of the formulation. The gum base may be softened in the mixer. By heat (from the heating jacket) and mixing, the gum base becomes plastic. So, the softened base is mixed with the liquid components, e g flavours, liquid, sorbitol and glycerol, optionally an active ingredient, such as nicotine in base form, and the solid materials, optionally active ingredients, such as nicotine in any form other than in liquid form, buffer, bulk sweetener, color as a powder mixture. The warm mass is discharged from the mixer in form of loaves stacked on trays on a truck and stored in a conditioned area until the next step starts. This is to cool the gum.

After this, the rolling and scoring takes place. The gum is extruded into a thick sheet, which is rolled by multiple sets of calender rolls to the correct thickness. The scoring rolls, usually two sets, cut the gum into the correct size. The sheets are then transferred to a conditioned area on trays, where the sheets are cooled to make them brittle enough to be broken. The conditioned gum sheets are then 20 passed through a breaker, which is a rotating drum that parts the sheets into separate pieces of gum along the scores.

In an embodiment of the invention, said chewing gum formulation comprises said gum base matrix and one or more chewing gum ingredients.

In an embodiment of the invention, said chewing gum ingredients are selected from the group consisting of bulk sweeteners, flavors, dry-binders, tabletting aids, anti- caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, high intensity sweeteners, colors, or any combination thereof.

In an embodiment of the invention, the chewing gum formulation comprise one or more chewing gum ingredients selected from the group consisting of bulk sweeteners, flavors, dry-binders, tabletting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, or any combination thereof.

Further useful chewing gum base components include antioxidants, e.g. butylated hydroxytoluene (BHT), butyl hydroxyanisol (BHA), propylgallate and tocopherols, and preservatives.

In an embodiment of the invention, chewing gum granules are produced and mixed with chewing gum powder obtained through the following steps:

a) cooling of a gum base to a temperature of between about 0 and -273 deg.C, b) grinding of the cooled gum base,

c) optional mixing of the powder thus obtained with at least one free-flowing agent, to obtain a chewing gum blend. In an embodiment of the invention, chewing gum granules are produced and mixed with chewing gum powder obtained through the following steps:

a) mixing of a gum base with at least one sweetener and, optionally, at least one other typical chewing-gum ingredient,

b) cooling of the mixture thus obtained to a temperature of between about 0 and -273 deg.C,

c) grinding of the cooled gum base,

d) mixing of the powder thus obtained with at least one free-flowing agent, e) optional mixing of the powder thus obtained with one or more of sweeteners, flavorings, colorings, food acids or other active ingredients, to obtain a chewing gum blend.

In an embodiment of the invention, said chewing gum blend is compressed.

Several different processes for manufacturing of chewing gum are known within the art. The different processes may be overall categorized in basically two different processes; that is chewing gum mechanically mixed on the basis of a gum base compounds or chewing gum compressed on the basis of more or less discrete gum base particles. The first type of chewing gum generally benefits from a very comfortable texture, among several different parameters, most likely due to the mechanically mixing of the polymers and for example the flavors. One disadvantage of such type of process and chewing gum is, however, that the different ingredients, such as encapsulated flavor, active ingredients, etc. may be more or less destroyed or degraded by the mixing process. The second type of chewing gum generally benefits from a relatively gentle handling of vulnerable additives, such as the above-mentioned flavors or active ingredients. One disadvantage of such type of chewing gum is, however, that the resulting chewing gum tablet may typically disintegrate too easy, especially during the initial chew of the gum. Different proposals in order to obtain compressed chewing gum have been made in the prior art. Typically, such techniques are directed to adaptation of the

manufacturing process. WO 03/011045 discloses a technique where the sticking or adhering of the chewing gum mixture to the tableting process equipment is dealt with by controlling the size of the mixture granules.

Chewing gum tablets are typically manufactured by applying pressure to an amount of powder by suitable compression means. Suitable compression means will be disclosed and explained below. The powder is then compressed into a compact coherent tablet.

The powder may for example comprise so-called primary particles or aggregated primary particles, also referred to as granules. When these are compressed, bonds are established between the particles or granules, thereby conferring a certain mechanical strength to the compressed tablet.

It should be noted that the above-introduced terms: powder, primary particles and granules may be somewhat misleading in the sense that the difference between primary particles and granules may very often be looked upon differently depending on the background of the user. Some may for instance regard a sweetener, such as sorbitol, as a primary particle in spite of the fact that sorbitol due to the typically preprocessing performed on sorbitol when delivered to the customer should rather be regarded as some sort of granule. The definition adopted in the description of this invention is that granules refer to macro-particles comprising more or less preprocessed primary particles. It should, however, be noted that this adoption of terms only relates to the description of background prior art and is not mandatory for defining the scope of the invention.

When pressure is applied to the powder raw material, the bulk volume is reduced and the amount of air is decreased. During this process energy is consumed. As the particles come into closer proximity to each other during the volume reduction process, bonds may be established between the particles or granules. The formation of bonds is associated with a reduction in the energy of the system as energy is released. Volume reduction takes place by various mechanisms and different types of bonds may be established between the particles or granules depending on the pressure applied and the properties of the particles or granules.

The first thing that happens when a powder is compressed is that the particles are rearranged under low compaction pressures to form a closer packing structure.

Particles with a regular shape appear to undergo rearrangement more easily than those of irregular shape. As the pressure increases, further rearrangement is prevented and subsequent volume reduction is obtained by plastic and elastic deformation and/or fragmentation of the tablet particles. Brittle particles are likely to undergo fragmentation, i.e. breakage of the original particles into smaller units. Plastic deformation is an irreversible process resulting in a permanent change of particle shape, whereas the particles resume their original shape after elastic deformation. Evidently, both plastic and elastic deformation may occur, when compressing a chewing gum tablet.

Several studies of the bond types in compressed tablets have been made over the years, typically in the context of pharmaceuticals and several techniques of obtaining compressed tablets on the basis of available powders has been provided. Such studies have been quite focused on what happens when the volume reduction is performed and how the end-product may be optimized for the given purpose. Several refinements with respect to compressed tablets has for instance been made in the addition of for example binders in the tablet raw materials for the purpose of obtaining a sufficient strength to the final compressed tablet while maintaining acceptable properties, e.g. with respect to release. Over the years, especially the pharmaceutical industry has gradually introduced chewing gum as a mean for obtaining release of active ingredients in the oral cavity.

Traditionally, the compression technique has been preferred by the pharmaceutical industry for the manufacturing of chewing gum. As indicated above, a problem related to the compression technique is that the nature of chewing gum granules is quite different to that of pure pharmaceutical conventional tablet powder. A further, and even more significant problem is that the required texture is basically completely different from that of a tablet intended for completely dissolving within the mouth of the user. Hence, this compression technique has been regarded as inferior with respect to the basic texture properties of therewith obtained chewing gum.

In one embodiment of the invention, the powder composition is added as part of a bulk portion after mixing of a gum base matrix.

In one embodiment of the invention, the gum base matrix constitutes 30 to 80% by weight of the chewing gum.

In one embodiment of the invention, the oromucosal delivery system further comprises a buffering agent, such as a pH controlling agent.

In one embodiment of the invention, the powder composition is compressed together with chewing gum base particles to obtain a compressed chewing gum. In one embodiment of the invention, the oromucosal delivery system is in form of a mouth spray.

In one embodiment of the invention, the oromucosal delivery system is in form of a pouch. In one embodiment of the invention, the powder composition is being produced by the method according to the invention.

The following non-limiting examples illustrate different variations of the present invention. The examples are meant for indicating the inventive concept; hence the mentioned examples should not be understood as exhaustive for the present invention.

EXAMPLES

In the following, examples 1-8 (except 3) are normalized to 100 ml for easier comparison. The batch size can be increased within the scope of this invention. Example 1

Producing a suspension of solid lipid particles using high shear homogenization with the following composition.

About 400 mg of hydrogenated sunflower oil provided from ADM/Sio with a melting point of 65-73 °C and 800 mg of stearic acid/palmitic acid provided from BASF with a melting point of 53-56 °C are melted together in a water bath at 10 °C above their melting point. About 50 mg of polysorbate 60 provided from Seppic is dissolved in 2 ml warm water at about 80 °C, and poured into the mixture of the melted lipid of hydrogenated sunflower oil and stearic/palmitic acid. This solution is shaken shortly. About 40 μΐ of liquid nicotine base provided from Siegfred is added to this solution. This solution containing polysorbate, hydrogenated sunflower oil, stearic/palmitic acid and water is transferred either by a syringe or by pouring immediately to the solution described below. In another beaker 50 mg of poly-vinyl-alcohol (PVA) provided by Nippon Gohsei is dissolved in 98 ml of water by heating to above the melting temperature of the lipid solution containing nicotine, e.g. 80 °C. After about 10 minutes, when the PVA is dissolved in the beaker, the lipid solution containing nicotine is added to obtain an emulsion.

This emulsion is homogenized using an Ultra Turrex or similar high shear mixer. The rpm of the mixer is set to the desired value, e.g. 8000 rpm. During the homogenization the emulsion is warmed by a hotplate, to avoid premature solidification of lipids caused by lowered temperatures. The duration of the homogenization is about 30-60 minutes. After homogenization the high shear mixer is removed and the emulsion is allowed to cool at room temperature for 30 minutes, before being transferred to 5 °C for further cooling. As the emulsion cools, the lipid crystallizes and forms small particles resulting in a suspension of solid lipid particles.

Example 2

Producing a suspension of solid lipid particles using high pressure homogenization with the following composition.

About 400 mg of hydrogenated sunflower oil provided from ADM/Sio with a melting point of 65-73 °C and 800 mg of stearic acid/palmitic acid provided from BASF with a melting point of 53-56 °C are melted together in a water bath at 10 °C above their melting point. About 50 mg of polysorbate 60 provided from Seppic is dissolved in 2 ml warm water at about 80 °C, and poured into the mixture of the melted lipid of hydrogenated sunflower oil and stearic/palmitic acid. 40 μΐ liquid nicotine is added to the solution. This solution is poured immediately to the solution described below. In another beaker 50 mg of poly-vinyl-alcohol (PVA) provided by Nippon Gohsei is dissolved in 98 ml of water by heating to above the melting temperature of the lipid solution containing nicotine, e.g. 80 °C. After about 10 minutes, when the PVA is dissolved in the beaker, the lipid solution containing nicotine is added to obtain an emulsion.

To form a crude pre-emulsion the emulsion is homogenized for 1 minute with an Ultra Turrex or other similar instrument. Upon creation of the pre-emulsion the liquid changes to a milky white color, this indicates the presence of small particles. The high pressure homogenizer should be pre-warmed to above the melting point of the lipid solution to avoid clogging by solidifying lipids. The crude pre-emulsion is connected to the inlet tube of the homogenizer and the outlet tube is either connected to the same beaker to establish a continuous flow or to another beaker to ensure that the emulsion is homogenized equally. When the flow is established, the pressure is adjusted to the desired level, e.g. 500-1500 bar. The homogenization process runs for 1-20 cycles or 5-120 minutes. After homogenization the homogenizer is emptied by removing the inlet tube from the emulsion. As the emulsion cools, the lipid crystallizes and forms small particles resulting in a suspension of solid lipid particles.

Example 3

Producing a suspension of solid lipid particles using high pressure homogenization with the following composition, where the relative water content is lowered.

Ingredient Amount

Hydrogenated sunflower oil 3.32 u

Stearic/palmitic acid (e.g. Kolliwax® S) 6,68 g

Poly-vinyl alcohol 1, 15 g

Polysorbate 60 0,42 g

Nicotine base 0,416 ml

Water 40 ml The production process is as described in example 2. Upon cooling this results in a cream.

Example 4

Producing a suspension of solid lipid particles using high pressure homogenization with the following composition, where the relative water content is lowered.

The production process is as described in example 2. Example 5

Producing a suspension of solid lipid particles using high pressure homogenization with the following composition, where the relative water content is lowered and lipid with low melting point is added.

Ingredient A in on nl

Hydrogenated sunflower oil 2.S3 u

Stearic/palmitic acid (e.g. Kolliwax® S) 6, 17 g

Miglyol 812 i g

Poly-vinyl alcohol 1, 15 g

Polysorbate 60 0,42 g

Nicotine base 0,416 ml

Water 100 ml Miglyol 812 supplied by Sasol is added to hydrogenated sunflower oil and Kolliwax S before melting. Following this, the production process is as described in example 2. Miglyol 812 has a melting point below 0 °C and is thus a liquid at room temperature. In the cooled solid lipid particles, the Miglyol will as such still be a liquid. The particles in this example have a main body of solidified lipid, with a small amount of liquid lipid interdispersed between the solidified parts.

Example 6

Producing a suspension of solid lipid particles using high pressure homogenization with following composition, where an alternative emulsifier is used.

The mono-/diglyceride emulsifier supplied by Kerry Ingredients & Flavours is mixed with the lipids before melting and the mix is heated to a temperature 10 °C above the melting temperature of the lipids. Following this, the production process is as described in example 2.

Example 7

Producing a suspension of solid lipid particles using high pressure homogenization with following composition, where an alternative emulsifier is used.

Ingredient Amount

Hydrogenated sunflower oil

Stearic/palmitic acid (e.g. Kolliwax® S) 6,68 g

SDS 0,5 g Polysorbate 60 0,4 g

Nicotine base 0,416 ml

Water 100 ml

The SDS is dissolved in water followed by heating of the solution to 10 °C above the melting point of the lipids, e.g. 80°C. Following this, the production process is as described in example 2, where the lipid/nicotine solution is poured into the SDS solution.

Example 8

Producing a suspension of solid lipid particles using high pressure homogenization with the following composition, where the nicotine content is higher.

The production process is as described in example 2. Example 9

Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles. A suspension with the following composition and production process described in example 2 is freeze dried to obtain a powder.

Ingredient Amount

Hydrogenated sunflower oil 400 mg

Stearic/palmitic acid (e.g. Kolliwax® S) 800 mg Poly-vinyl alcohol 50 mg

Polysorbate 60 50 mg

Nicotine base 0,040 ml

Water 100 ml

The primary drying step of the freeze drying is performed below -35 °C, to ensure that freeze drying is performed below the collapse temperature of the suspension. The suspension is freeze dried to a low water content and the resulting product is a white powder. The freeze drying cycle may include an annealing step prior to the drying step, to optimize the drying process. Below is an example of the freeze drying cycle.

The composition of the freeze dried powder is shown in the table below. I ngredient A mount | « | « iii ireilient/« pow der

Water 0,03 0,0089

Poly-vinyl-alcohol 0,05 0,0148

Polysorbate 60 0,05 0,0148

Nicotine 0,04 0,0119

Hydr. Sunfloweroil 0,4 0, 1187

Kolliwax S 0,8 0,2374

Cryoprotectant 2 0,5935

In the following table, the effect of the annealing step is evident.

The product is a non-free flowing white powder. Example 10

Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles. A suspension with the composition and production process shown in examples 3-8 is freeze dried. The freeze drying is performed at described in example 9.

Example 11

Producing a powder of solid lipid particles by freeze drying a suspension of solid lipid particles with a cryoprotectant e.g. lactose, trehalose or mannitol. A suspension with the following composition and production process described in example 2 is freeze dried to obtain a powder.

Ingredient Amount

Hydrogenated sunflower oil 400 mg

Stearic/palmitic acid (e.g. Kolliwax® S) 800 mg

Poly-vinyl alcohol 50 mg Polysorbate 60 50 mg

Nicotine base 40 mg

Water 100 ml

Lactose (cryoprotectant) 2 g

The cryoprotectant is dissolved in the suspension and the suspension is freeze dried in bulk trays. The freeze drying cycle is as described in example 9. The result is a non-free flowing white powder. The effect of adding a cryoprotectant is shown in the table below.

Table 1 Effect on nicotine retention of different cryoprotectants

The average size of the particles is increased from approximately 400 nm in suspension to 10 μιη in the final powder. The degradation of nicotine is not affected by the freeze drying process.

Example 12 Producing a powder of solid lipid particles by spray drying a suspension of solid lipid particles. A suspension with the compositions and production process described in examples 1-8 is spray dried to obtain a powder. The suspension of solid lipid particles is fed at a high rate and temperature through a nozzle, which atomizes the suspension. The atomized suspension is subjected to drying by contact with hot air e.g. 100 °C that evaporates the water in the suspension, resulting in a dry powder. To increase particle stability drying protectants, e.g. lactose or trehalose can be added to the suspension avoid agglomeration of particles.

Example 13

The powder obtained from examples 9-12 can be used in a formulation intended for oral use. This formulation could be a lozenge where the powder is mixed with flavors, sweeteners and buffer systems. The final composition of such a lozenge is shown in the following table.

I ngredient A mount | in« Ιοζοιι«ο|

Water 1,780

Poly- vinyl-alcohol 2,967

g Polysorbate 60 2,967

'■ g Nicotine 2,374

-a Hydrogenated sunflow ¾r oil 23,739

'B i

^ Kolliwax S 47,478

j¾ Cryoprotectant 1 19

Sucralose 0,4

Acesulfame 0,2

Sodium carbonate 2

Menthol 0,4

∞ Peppermint 4

j^ Bulk sweetener (mann itol) 202,7

Alginate 60 Xanthan gum 30

Total 500

All raw materials are weighed before the mixing process begins. A batch size could be e.g. 1-10 kg equivalent to 2000-20000 tablets. First approximately half of the mannitol is added to a mixing bin. The remaining ingredients, including the active pharmaceutical ingredient, are sieved and added to the mixing bin. Finally the last half of mannitol is sieved in to the mixing bin. The powder blend is mixed in by the Turbula for 5 minutes.

Before the tableting, magnesium stearate is added to the tablet machine. The magnesium stearate will be sprayed onto the pistons while tableting. The raw material mixture is filled into the tablet press feed hopper. Tablets are compressed with a speed of 8-12 rpm and a pressure of 25 kN (acceptance criteria 20-30 kN) and the weight is adjusted by means of the filling depth, until the weight of 10 tablets is 5,00 g+/- 0, 12g. The feed hopper continuously filled to ensure that it does not run empty during the compression process.

The nicotine contained in the lozenge is released in the oral cavity upon sucking and chewing it.

Example 14

The powder obtained from examples 9-12 can be used in a formulation intended for oral use. This formulation could be a compressed gum, where one layer contains the gum base and the second layer contains flavor and sweetener. The solid lipid particles can be placed in either layer. The tables below show two examples of a composition, with the solid lipid particles in layer 1 and layer 2 respectively. Table 2 Composition of compressed gum with solid lipid particles in layer 1 Polysorbate 60 3,0

Nicotine 2,4

Hydr. Sunfloweroil 23,7

Kolliwax S 47,5

Cryoprotectant 1 18,7

Gum base 500,0

Isomalt 362,8

Acesulfame potassium 3,0 o 4,2

X Sucralose

Peppermint 30,0

Layer 2

Isomalt 286,4

Acesulfame potassium 3,30 o Sucr 3,30

X alose

Peppermint 6,95 Total 1400

Table 3 Composition of compressed gum with solid lipid particles in layer 2

All raw materials are weighed before the mixing process begins. A batch size could be e.g. 1-10 kg equivalent to 700-7000 tablets. The two layers are dry mixed separately. First approximately half of the isomalt is added to a mixing bin. The remaining ingredients, including the active pharmaceutical ingredient, are sieved and added to the mixing bin. Finally the last half of isomalt is sieved in to the mixing bin. The powder blend is mixed in by the Turbula for 5 minutes.

Before the tableting, magnesium stearate is added to the tablet machine. The magnesium stearate will be sprayed onto the pistons while tableting. The raw material mixtures are filled into the tablet press feed hoppers. Tablets are compressed with a speed of 8-12 rpm and a precompression pressure of 2-3 kN and a main compression pressure of 25 kN (acceptance criteria 20-30 kN). The weight is adjusted by means of the filling depth of chamber 2, until the weight of 10 tablets is 14,00 g+/- 0,35g. The feed hoppers continuously filled to ensure that it does not run empty during the compression process. The tableting procedure is stopped when the powder is just above the hopper product censor.