Oral antagonist composition for reducing nicotine burning sensation

Abstract

The present invention relates to an oral analgesic composition for alleviating the perceived nicotine stimulus by inhibiting or blocking nicotinic-activated receptors or ion channels in the gastrointestinal tract, including the oral cavity. The composition comprises one or more nicotine sources, one or more buffering agents, and at least two antagonists in amounts effective to inhibit or block nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels, wherein the at least two antagonists are selected from the group consisting of a first antagonist comprising camphor or one or more camphor-like compounds, a second antagonist comprising eucalyptol, and a third antagonist comprising (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-12).

Description

[Technical Field]

[0001] The present invention relates to the field of analgesic compositions useful for alleviating nicotine stimulation during or after oral ingestion. More specifically, the present invention relates to the inhibition or blockade of nicotine-activated receptors or ion channels in the gastrointestinal tract. [Background technology]

[0002] Nicotine is a well-known, highly characteristic alkaloid that can be isolated from the dried leaves of tobacco (Nicotiana tabacum). Its many commercial uses include incorporation into fumigants and insecticides. The compound is therapeutically useful in the treatment of smoking withdrawal syndrome. This treatment is based on the administration of nicotine under controlled conditions, with a gradual decrease in nicotine strength.

[0003] However, various short-term drawbacks are related to the oral ingestion of nicotine due to the chemical properties of the compound. Nicotine irritation upon oral ingestion, such as nicotine burning or hiccups, is a well-known discomfort associated with nicotine withdrawal therapy.

[0004] The main receptors and ion channels involved in nicotine uptake in the gastrointestinal tract have been reported to include nicotinic acetylcholine receptors (nAChRs) and transient receptor potential (TRP) ion channels. More specifically, receptors and channels reported to be activated by nicotine include nicotinic acetylcholine receptors (nAChRs), transient receptor potential vanilloid type 1 (TRPV1) ion channels, transient receptor potential ankyrin 1 (TRPA1) ion channels, and transient receptor potential melastatin 8 (TRPM8) ion channels.

[0005] Various attempts have been made to avoid the unpleasant sensations associated with nicotine in oral compositions. Some of these attempts involve flavor masking, which involves adding relatively large amounts of sugar or sugar alcohol to achieve a pleasant flavor that can mask the nicotine stimulus. Other attempts include the nonspecific addition of flavorings to obtain a flavor profile that masks the drawbacks of nicotine. Yet another attempt involves the inclusion of nonspecific cooling agents in oral compositions that help to divert the perception of the nicotine stimulus.

[0006] What these nicotine masking efforts have in common is that they do not target the specific nicotine-activating receptors involved in nicotine intake, and therefore do not optimize the targets involved in nicotine stimulation. As a result, attempts at non-specific flavor masking are typically less effective in reducing nicotine stimulation and often do not address problems caused by nicotine interaction with nicotine-activating receptors, such as burning or hiccups.

[0007] In addition, side effects may be related to nicotine masking. For example, the use of excessive amounts of sugar alcohol to mask nicotine stimulation may include diarrheal side effects.

[0008] Furthermore, the use of nonspecific flavorings can lead to unpleasant sensations in the perception of fragrances, such as unpleasant sensations originating from the fragrance itself, which may be more detrimental than nicotine stimulation. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] International Journal of Pharmaceutics 1995, 116: pp. 131-146, especially p. 136. [Non-Patent Document 2] HP Fiedler, Lexikon der Hilfstoffe fur Pharmacie, Kosmetik und Angrenzende Gebiete, pp. 63-64 (1981) [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] While prior art solutions are suitable for masking the overall undesirable nicotine stimulus, there remains a need in the art for more specific, targeted oral compositions that can significantly reduce nicotine stimulus without the drawbacks of the prior art.

[0011] In particular, there is a need for oral compositions that can reduce nicotine stimulation without increasing harmful side effects resulting from the presence of nonspecific flavorings. [Means for solving the problem]

[0012] In a first aspect, the present invention relates to an oral analgesic composition for the relief of perceived nicotine stimulation by inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity, comprising one or more nicotine sources, one or more buffering agents, and at least two antagonists in an amount effective to inhibit or blockade nicotine agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels. In this first aspect, the at least two antagonists are selected from the group comprising a first antagonist comprising camphor or one or more compounds similar to camphor, a second antagonist comprising eucalyptol, and a third antagonist comprising (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide, also known as WS-12.

[0013] In a second aspect, the present invention relates to an oral analgesic composition for the mitigation of perceived nicotine stimulation by inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity. In this second aspect, the composition comprises one or more nicotine sources, one or more buffering agents, and at least two antagonists in an amount effective to inhibit or block nicotine agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels. In the second aspect, the at least two antagonists may be selected from a first antagonist, a second antagonist, and a third antagonist.

[0014] In a third aspect, the present invention relates to an oral analgesic composition for the mitigation of perceived nicotine stimulation by inhibiting or blocking nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity. In this third aspect, the composition comprises at least three antagonists in an amount effective to inhibit or block nicotine agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels. In the third aspect, the at least three antagonists can be selected from a first antagonist, a second antagonist, and a third antagonist.

[0015] Overall, the present invention aims to provide a specific oral analgesic composition that can alleviate perceived irritation associated with pharmaceutical active ingredients such as nicotine by inhibiting or blocking nicotine-activated receptors or ion channels in the gastrointestinal tract. The solution comprises the incorporation of at least two antagonists, e.g., three antagonists, in effective amounts. While the provision of only one antagonist is known in the prior art, the present invention aims to provide a synergistic effect in alleviating irritation from pharmaceutical compounds such as nicotine by providing at least two antagonists in effective amounts without the drawbacks of the prior art.

[0016] Specifically, the antagonists provided in the present invention can act on targeted receptors or ion channels, typically comprising different receptors or ion channels for individual antagonists applied to more effectively mitigate perceived stimuli. Compared to prior art solutions, the present invention can mitigate irritation from pharmaceutical compounds such as nicotine while simultaneously mitigating one or more side effects of known compositions. These side effects may include the unpleasant perception of the antagonist itself, which in some cases may be more pronounced than the irritation from the pharmaceutical compound, particularly when high concentrations of the antagonist are required to mitigate the irritation from the pharmaceutical compound.

[0017] One of the advantages related to the present invention is the significant reduction of nicotine irritation, such as burning and hiccups, associated with the oral administration of nicotine compositions, for example, during nicotine withdrawal therapy. Nicotine withdrawal therapy (thearapy) may include the administration of nicotine chewing gum, fast-disintegrating tablets (FDTs) containing nicotine, pouches containing an effective amount of a nicotine compound such as free nicotine, or nicotine oral sprays.

[0018] The nicotine stimulation reduction according to the present invention also provides an oral analgesic composition targeting specific nicotine-activating receptors involved in nicotine intake, thereby addressing one or more of the shortcomings of prior art solutions for masking the flavor of nicotine by providing a solution that is more optimized for gastrointestinal targets such as the oral mucosa.

[0019] The prior art side effects addressed by the present invention may include the mitigation of diarrheal side effects caused by the excessive use of sugars or sugar alcohols to mask nicotine stimulation. In addition, the present invention can address the use of nonspecific flavorings that may cause discomfort in the perception of flavors, such as discomfort derived from the flavor itself which may be more undesirable than nicotine stimulation, especially when higher concentrations of flavorings are required to mitigate nicotine stimulation.

[0020] More specifically, the present invention can address the discomfort resulting from nicotine irritation such as a burning sensation or a hiccup without increasing the harmful side effects resulting from the presence of a non-specific flavoring agent. Even more specifically, the present invention can reduce nicotine irritation such as a burning sensation or a hiccup without increasing the harmful side effects resulting from the presence of a non-specific flavoring agent. Further, the present invention can reduce nicotine irritation such as a burning sensation or a hiccup without causing the perception of a stronger antagonist.

[0021] Since most antagonists have their own flavors that can cause the perception of antagonists with strong discomfort at high concentrations, including eucalyptus and camphor, it was most surprising to the inventors that a combination of at least two antagonists according to the present invention can reduce nicotine irritation without causing the perception of a stronger antagonist. This advantage can also appear even when the total amount of the antagonist is higher than that of a composition in which only a single antagonist is present.

[0022] The prediction of the inventors was that by adding a larger amount of the antagonist, the perception of the antagonist would become significantly stronger compared to the situation where only a single antagonist was applied. It was even more surprising that the nicotine irritation level decreased significantly at the same time.

[0023] According to the present invention, a combination of at least two antagonists is considered to act synergistically with nicotine to reduce nicotine irritation such as a burning sensation.

[0024] Even more remarkable is the combination of three antagonists for reducing nicotine irritation. It has been found that a combination of at least three antagonists according to the present invention provides the best results in reducing nicotine irritation.

[0025] Therefore, it is clear that a combination of three antagonists also acts synergistically with nicotine to reduce nicotine irritation such as a burning sensation.

[0026] Furthermore, the inventors predicted that by adding an antagonist at a balanced level, the perception of the antagonist would be comparable to that of using only a single antagonist. However, it was surprising that even with an antagonist at a balanced level, the level of nicotine stimulation (burning sensation) decreased significantly.

[0027] Therefore, it is clear that in this setting as well, the combination of the three antagonists works synergistically with nicotine to reduce the burning sensation caused by nicotine.

[0028] According to the present invention, at least two antagonists are present in the oral analgesic composition.

[0029] In some embodiments, at least two antagonists include a first antagonist and a second antagonist.

[0030] In some embodiments, at least two antagonists comprise a first antagonist and a second antagonist in a mass ratio of 1:20 to 1:1. In some further embodiments, at least two antagonists comprise a first antagonist and a second antagonist in a mass ratio of 1:10 to 1:2. In some even further embodiments, at least two antagonists comprise a first antagonist and a second antagonist in a mass ratio of 1:8 to 1:3.

[0031] In some embodiments, at least two antagonists include a first antagonist and a third antagonist. In some embodiments, at least two antagonists include a first antagonist and a third antagonist in a mass ratio of 1:20 to 1:1. In some further embodiments, at least two antagonists include a first antagonist and a third antagonist in a mass ratio of 1:10 to 1:2. In some even further embodiments, at least two antagonists include a first antagonist and a third antagonist in a mass ratio of 1:8 to 1:3.

[0032] In some embodiments, at least two antagonists include a second antagonist and a third antagonist. In some embodiments, at least two antagonists include a second antagonist and a third antagonist in a mass ratio of 1:4 to 4:1. In some further embodiments, at least two antagonists include a second antagonist and a third antagonist in a mass ratio of 1:3 to 3:1. In some even further embodiments, at least two antagonists include a second antagonist and a third antagonist in a mass ratio of 1:2 to 2:1.

[0033] According to the present invention, at least two antagonists, such as at least three antagonists, are present in the oral analgesic composition. The combination of at least three antagonists according to the present invention has been found to yield the best results in reducing nicotine stimulation. Therefore, it is clear that the combination of three antagonists works synergistically with nicotine to reduce nicotine stimulation such as burning sensation.

[0034] Furthermore, the inventors predicted that by adding a balanced level of antagonists, the perception of the antagonist would be comparable to that of using a single antagonist. However, it was surprising that even with a balanced level of antagonists, the level of nicotine stimulation (burning sensation) was significantly reduced. Therefore, it is clear that, even in this setting, the combination of three antagonists works synergistically with nicotine to reduce nicotine stimulation such as burning sensation.

[0035] In some embodiments, the at least two antagonists include a first antagonist, a second antagonist, and a third antagonist. In some embodiments, the at least two antagonists include a first antagonist, a second antagonist, and a third antagonist in a mass ratio of 1:20:20 to 1:1:1. In some further embodiments, the at least two antagonists include a first antagonist, a second antagonist, and a third antagonist in a mass ratio of 1:10:10 to 1:2:2. In some even further embodiments, the at least two antagonists include a first antagonist, a second antagonist, and a third antagonist in a mass ratio of 1:8:8 to 1:3:3.

[0036] In some further embodiments, at least two antagonists are present in a total amount greater than 0.5 mg, for example, greater than 1.0 mg, for example, greater than 1.5 mg. In some further embodiments, at least two antagonists are present in a total amount greater than 1.5 mg, for example, greater than 2.0 mg, for example, greater than 2.5 mg.

[0037] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the oral cavity by more than 20% compared to the presence of only one of the same at least two antagonists in the same total amount.

[0038] In this context, "total amount" refers to the combined amount of antagonists when at least two antagonists are present, or the amount of just one of the same at least two antagonists. In either case, the total amount in comparison is the same; that is, the total amount of two antagonists is the same as the amount of just one of the two antagonists.

[0039] In this context, the phrase "perceived peak nicotine stimulation" refers to any peak point after oral administration that corresponds to the strongest perceived nicotine stimulation.

[0040] The inventors predicted that by adding a balanced level of antagonist, the perception of the antagonist would be comparable to that of using a single antagonist. However, it was surprising that even with a balanced level of antagonist, the level of nicotine stimulation (burning sensation) was significantly reduced in some embodiments of the present invention.

[0041] In other words, even when the total amount of at least two antagonists was the same as the amount of only one of the same at least two antagonists, the level of nicotine stimulation (burning sensation) was significantly reduced in some embodiments of the present invention.

[0042] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the oral cavity by more than 30% compared to the presence of only one of the same at least two antagonists in the same total amount.

[0043] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived nicotine stimulation of the peak during sublingual administration by more than 30% compared to the presence of only one of the same at least two antagonists in the same total amount.

[0044] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived nicotine stimulation of the peak during sublingual administration by more than 50% compared to the presence of only one of the same at least two antagonists in the same total amount.

[0045] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the throat by more than 30% compared to the presence of just one of the same at least two antagonists in the same total amount.

[0046] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the throat by more than 50% compared to the presence of just one of the same at least two antagonists in the same total amount.

[0047] In some embodiments, at least two antagonists are present in a total amount of less than 3.0 mg. In some further embodiments, at least two antagonists are present in a total amount of less than 2.5 mg. In some even further embodiments, at least two antagonists are present in a total amount of less than 2.0 mg.

[0048] In some embodiments, at least two antagonists are present in a total amount of less than 6.0 mg. In some further embodiments, at least two antagonists are present in a total amount of less than 5.0 mg. In some even further embodiments, at least two antagonists are present in a total amount of less than 4.0 mg.

[0049] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the oral cavity and lowering the perception of the peak antagonist, by more than 30% compared to the presence of just one of the same at least two antagonists in the same total amount.

[0050] In this context, "total amount" refers to the combined amount of antagonists when at least two antagonists are present, or the amount of just one of the same at least two antagonists. In either case, the total amount in comparison is the same; that is, the total amount of two antagonists is the same as the amount of just one of the two antagonists.

[0051] In this context, the phrase "perceived peak nicotine stimulation" refers to any peak point after oral administration that corresponds to the strongest perceived nicotine stimulation.

[0052] In this context, the phrase "decreased perception of the antagonist at its peak" refers to any peak point after oral administration that is associated with the strongest perception of the antagonist.

[0053] The inventors predicted that by adding a balanced level of antagonist, the perception of the antagonist would be comparable to that of using a single antagonist. However, it was surprising that even with a balanced level of antagonist, the perception level of the antagonist decreased significantly in some embodiments of the present invention.

[0054] In other words, even when the total amount of at least two antagonists is the same as the presence of only one of the same at least two antagonists, the perceived level of the antagonists was significantly reduced in some embodiments of the present invention.

[0055] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation during sublingual administration and reducing the perception of the peak antagonist, by more than 30% compared to the presence of only one of the same at least two antagonists in the same total amount.

[0056] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the throat and the perception of the peak antagonist, by more than 30% compared to the presence of just one of the same at least two antagonists in the same total amount.

[0057] In some embodiments, the first antagonist comprises an oily carrier. In some embodiments, the second antagonist comprises an oily carrier. In some embodiments, the first antagonist is camphor. In some embodiments, the first antagonist is a compound similar to camphor. In some embodiments, one or more compounds similar to camphor are selected from the group consisting of eight borneols, isoborneols, bornyl acetate, isobornyl acetate, monobornyl succinate, monoisobornyl succinate, monobornyl formate, and monoisobornyl formate. In some embodiments, the second antagonist is eucalyptol. In some embodiments, the third antagonist is WS-12.

[0058] In some embodiments, at least two antagonists inhibit or block nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential vanilloid type 1 (TRPV1) ion channels and / or transient receptor potential ankyrin 1 (TRPA1) ion channels and / or transient receptor potential melastatin 8 (TRPM8) ion channels.

[0059] In some embodiments, at least two antagonists inhibit or block nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and transient receptor potential vanilloid type 1 (TRPV1) ion channels, and transient receptor potential ankyrin 1 (TRPA1) ion channels, and transient receptor potential melastatin 8 (TRPM8) ion channels.

[0060] In some embodiments, at least two antagonists inhibit more than 20% of nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential vanilloid type 1 (TRPV1) ion channels and / or transient receptor potential ankyrin 1 (TRPA1) ion channels and / or transient receptor potential melastatin 8 (TRPM8) ion channels.

[0061] In some embodiments, at least two antagonists block more than 20% of nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential vanilloid type 1 (TRPV1) ion channels and / or transient receptor potential ankyrin 1 (TRPA1) ion channels and / or transient receptor potential melastatin 8 (TRPM8) ion channels.

[0062] While not bound by theory, it is believed that various receptors work in conjunction with nicotine activation, allowing nicotine to act as a complete or partial agonist to some or all of the receptors and ion channels. Furthermore, while not bound by theory, it is believed that various receptors work in conjunction with the antagonists according to the present invention, allowing the antagonists to inhibit or block some or all of the receptors and ion channels to the extent of complete blockade or inhibition of the receptors, or incomplete blockade or inhibition of the receptors.

[0063] In this context, the meaning of "more than 20%" is that nicotine activation decreases by a percentage greater than this, which can directly correlate with a decrease in nicotine intake that is greater than this percentage.

[0064] In some embodiments, inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract includes the oral cavity, and the perceived nicotine stimulus includes a burning sensation.

[0065] In some embodiments, inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract includes the position of the tongue, i.e., sublingually, and the perceived nicotine stimulus includes a burning sensation.

[0066] In some embodiments, inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract includes the pharynx, and the perceived nicotine stimulation includes a burning sensation.

[0067] In this context, "nicotine irritation" is intended to mean discomfort associated with nicotine interactions on the surface of the gastrointestinal tract. Discomfort typically occurs when nicotine interacts with receptors or ion channels that can be activated by nicotine. Specifically, "nicotine irritation" includes various subcategories such as "burning sensation" or "hiccups." Typically, "burning sensation" in this context is intended to mean the perception of a burning sensation when nicotine comes into contact with the mucous membrane of the oral cavity or pharynx. Typically, "hiccups" in this context is intended to relate to the physical interaction when nicotine comes into contact with receptors in the mucous membrane of the stomach.

[0068] In some embodiments, inhibition or blockade of nicotine-activating receptors or ion channels in the gastrointestinal tract includes the stomach, and perceived nicotine stimulation includes hiccups.

[0069] In some embodiments, one or more nicotine sources contain nicotine. In some embodiments, one or more nicotine sources contain nicotine bicarbonate. In some embodiments, one or more nicotine sources contain nicotine polarilex resin. In some embodiments, one or more nicotine sources contain free base nicotine. In some embodiments, one or more nicotine sources contain a premix containing free base nicotine and an ion exchange resin. In some embodiments, one or more nicotine sources contain a premix containing free base nicotine and polarilex resin. In some embodiments, one or more nicotine sources contain tobacco.

[0070] In some embodiments, nicotine is present in an amount of 0.5 to 8.0 mg. In some embodiments, nicotine is present in an amount of 1.0 to 4.0 mg. In some embodiments, nicotine is present in an amount of 1.0 to 6.0 mg. In some embodiments, nicotine is present in an amount of 2.0 to 4.0 mg.

[0071] In some embodiments, the composition comprises at least two antagonists and nicotine in a mass ratio of 1:4 to 4:1. In some embodiments, the composition comprises at least two antagonists and nicotine in a mass ratio of 1:3 to 3:1. In some embodiments, the composition comprises at least two antagonists and nicotine in a mass ratio of 1:2 to 2:1.

[0072] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the oral cavity by more than 20% without causing a higher peak perception of the antagonist compared to the presence of only one of the same single antagonists in the same individual amounts.

[0073] Since the vast majority of antagonists, including eucalyptus and camphor, have their own flavors that can trigger antagonist perceptions, including strong unpleasantness at high concentrations, it was most surprising to the inventors that the combination of at least two antagonists according to the present invention can reduce nicotine stimulation without triggering a stronger antagonist perception. This advantage can even appear when the total amount of antagonists is higher than in compositions containing only a single antagonist.

[0074] The inventors predicted that adding a higher total amount of antagonist would significantly increase the perception of the antagonist compared to the situation where only a single antagonist was applied. Even more surprising was the simultaneous significant decrease in nicotine stimulation levels.

[0075] In other words, even when the total amount of at least two antagonists was higher, the perceived level of the antagonist was significantly reduced in some embodiments of the present invention.

[0076] In this context, "total amount" refers to the combined amount of antagonists when at least two antagonists are present, as opposed to "individual amounts," which refer to the amount of any one of at least two antagonists. Our current understanding is that when two antagonists are present, the sum of the individual antagonist amounts for each "individual amount" becomes the "total amount" used.

[0077] In this context, "perceived nicotine stimulation at the peak" refers to any peak point after oral administration that is associated with the strongest perception of nicotine stimulation. In this context, "perceived antagonist at the peak" refers to any peak point after oral administration that is associated with the strongest perception of the antagonist.

[0078] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the oral cavity by more than 30% without causing a higher peak perception of the antagonist compared to the presence of only one of the same single antagonists in the same individual amounts.

[0079] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation during sublingual administration by more than 20% without causing a higher peak antagonist perception compared to the presence of only one of the same single antagonists in the same individual amounts.

[0080] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation during sublingual administration by more than 30% without causing a higher peak antagonist perception compared to the presence of only one of the same single antagonists in the same individual amounts.

[0081] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the pharynx by more than 20% without causing a higher peak perception of the antagonist compared to the presence of only one of the same single antagonists in the same individual amounts.

[0082] In some embodiments, at least two antagonists are present in a total amount effective in reducing the perceived peak nicotine stimulation in the pharynx by more than 30% without causing a higher peak perception of the antagonist compared to the presence of only one of the same single antagonists in the same individual amounts.

[0083] In some embodiments, one or more buffering agents are selected from the group consisting of tri(hydroxymethyl)aminomethane buffering agents, phosphate buffering agents, carbonate buffering agents, and combinations thereof. In some embodiments, the buffering agent is present in an amount of 1.0 to 5.0% by mass of the composition.

[0084] In some embodiments, the composition contains one or more sugar alcohol particles in an amount of at least 40% by mass of the composition. In some embodiments, the composition contains one or more sugar alcohol particles in an amount of at least 60% by mass of the composition.

[0085] In some embodiments, the composition comprises one or more sugar alcohol particles selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof.

[0086] In some embodiments, the composition comprises one or more sugar alcohol particles, including directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles.

[0087] In some embodiments, the composition comprises one or more sugar alcohol particles, each comprising non-DC sugar alcohol particles in an amount of at least 30% by mass of the composition. In some embodiments, the composition comprises one or more sugar alcohol particles, each comprising non-DC sugar alcohol particles selected from non-DC particles of erythritol, maltitol, xylitol, isomalt, and combinations thereof.

[0088] In some embodiments, the composition comprises one or more sugar alcohol particles, each containing DC sugar alcohol particles in an amount of at least 30% by mass of the composition.

[0089] In some embodiments, the composition comprises one or more sugar alcohol particles, including directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, in a mass ratio of 0.2 to 1.2 between the non-DC sugar alcohol particles and the DC sugar alcohol particles.

[0090] In some embodiments, the composition further comprises a disintegrant. In some embodiments, the composition further comprises a disintegrant in an amount of 1 to 10% by mass of the composition. In some embodiments, the composition further comprises a crosslinked polyvinylpyrrolidone disintegrant.

[0091] In some embodiments, the composition further comprises one or more high-intensity sweeteners. In some embodiments, the composition further comprises fillers, such as calcium carbonate and / or talc and / or cellulose fibers and / or microcrystalline cellulose. In some embodiments, the composition further comprises a foaming system.

[0092] In some embodiments, the composition is contained in tablets. In some embodiments, the composition is a tablet. In some embodiments, the composition is contained in tablets in a unit mass of 50 to 2000 mg. In some embodiments, the composition is contained in tablets in a unit mass of 50 to 200 mg. In some embodiments, the composition is contained in tablets in a unit mass of 200 to 1500 mg.

[0093] In some embodiments, the composition is contained in a tablet that disintegrates in no more than 2 minutes upon contact with saliva. In some embodiments, the composition is contained in a tablet that disintegrates in no more than 1 minute upon contact with saliva. In some embodiments, the composition is contained in a tablet that disintegrates in no more than 30 seconds upon contact with saliva.

[0094] In some embodiments, the composition is an orally disintegrating tablet. In some embodiments, the composition is a chewable tablet. In some embodiments, the composition is a lozenge. In some embodiments, the composition is contained in a sachet. In some embodiments, the composition is contained in a film strip. In some embodiments, the composition is contained in a liquid formulation. In some embodiments, the composition is contained in an oral spray.

[0095] In some embodiments, the composition is contained in a pouch. In some embodiments, nicotine is present in an amount of 5.0 to 20.0 mg, for example, 5 to 15 mg, for example, 5 to 10 mg.

[0096] In some embodiments, the composition comprises particles having an average particle size of at least 400 μm, for example, between 400 μm and 1400 μm, comprising a gum base. In some embodiments, the composition comprises at least 20% by mass of gum base. In some embodiments, the composition comprises at least 5% by mass of natural resin. In some embodiments, the composition comprises at least 5% by mass of elastomer. In some embodiments, the composition comprises an elastomer selected from styrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (PIB), and combinations thereof. In some embodiments, the composition is chewing gum. In some embodiments, the composition is compressed chewing gum.

[0097] In some embodiments, at least two antagonists are castor oil and its derivatives, allicin, borneol, bornyl acetate, carvacrol, carveol, capsaicin, capsiate, carlic, cinnamaldehyde, curcumin, CoolAct P, camphor, Cooling Agent 10, 1,4-cineole, 1,8-cineole, camphorquinone, dihydrocarbeol, etodolac, eugenol, evodiamine, eucalyptol (1,8-cineole), Frescolat ML, Frescolat Selected from the group consisting of MGA, (-)-fencone, fenquil alcohol, gingerol, geraniol, hydroxycitronellal, ishirin, isofran, (±)-isobornyl methyl ether, (±)-isobornol, (-)-limonene oxide, linalool, menthol, 2-methylisobornol, 3-methylene-2-norbornanone, norcamphor, probeneside, α-pinene oxide, PMD-38, shogaol, α,β-thujone, thymol, WS-3, WS-23, wintergreen, 8-borneol, isobornol, bornyl acetate, isobornyl acetate, monobornyl succinate, monoisobornyl succinate, monobornyl formate, and monoisobornyl formate.

[0098] In some embodiments, at least two antagonists are allicin, borneol, bornyl acetate, carvacrol, carveol, capsaicin, capsiate, carlic, cinnamaldehyde, curcumin, CoolAct P, camphor, Cooling Agent 10, 1,4-cineole, 1,8-cineole, camphorquinone, dihydrocarbeol, etodolac, eugenol, evodiamine, eucalyptol (1,8-cineole), Frescolat ML, Frescolat Selected from the group consisting of MGA, (-)-fencone, fenquil alcohol, gingerol, geraniol, hydroxycitronellal, ishirin, isofran, (±)-isobornyl methyl ether, (±)-isobornol, (-)-limonene oxide, linalool, menthol, 2-methylisobornol, 3-methylene-2-norbornanone, norcamphor, probeneside, α-pinene oxide, PMD-38, shogaol, α,β-thujone, thymol, WS-3, WS-23, wintergreen, 8-borneol, isobornol, bornyl acetate, isobornyl acetate, monobornyl succinate, monoisobornyl succinate, monobornyl formate, and monoisobornyl formate.

[0099] In some embodiments, at least two antagonists are selected from the group consisting of borneol, carvacrol, carveol, eugenol, menthol, thymol, WS-3, WS-23, and wintergreen.

[0100] In some embodiments, the composition is intended for use in smoking cessation therapy.

[0101] In some embodiments, the first and second antagonists are combined with a solubilizer.

[0102] In some embodiments, the first and third antagonists are combined with a solubilizer.

[0103] In some embodiments, the second and third antagonists are combined with a solubilizer.

[0104] In some embodiments, the first, second, and third antagonists are combined with a solubilizer.

[0105] In some embodiments, the first antagonist is combined with a solubilizer.

[0106] In some embodiments, the first antagonist is combined with a number of solubilizers.

[0107] In some embodiments, the first antagonist is combined with castor oil or a derivative thereof.

[0108] In some embodiments, the first antagonist is combined with polyethoxylated hydrogenated castor oil.

[0109] In some embodiments, the first antagonist is combined with ricinoleic acid.

[0110] In some embodiments, the first antagonist is combined with citric acid.

[0111] In a fourth aspect of the present invention, the composition is for use in smoking cessation therapy.

[0112] A fifth aspect of the present invention provides a method for alleviating perceived nicotine stimulation by inhibiting or blocking nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity, the method comprising the step of administering an oral analgesic composition according to the present invention. [Brief explanation of the drawing]

[0113] [Figure 1a] This graph shows 1 mg nicotine rapidly disintegrating tablets (FDTs) that do not contain an antagonist. [Figure 1b]This graph shows 2mg nicotine rapidly disintegrating tablets (FDTs) that do not contain an antagonist. [Figure 1c] This graph shows commercially available 2mg sublingual tablets. [Figure 1d] This graph shows commercially available 2mg lozenges. [Figure 2a] Figure 1a is a graph showing a 1 mg nicotine tablet, which contains 10% eucalyptus but no nicotine. [Figure 2b] Figure 1a is a graph showing a 1 mg nicotine tablet, which contains 10% camphor but no nicotine. [Figure 2c] This graph shows a 1 mg nicotine tablet, as disclosed in Figure 1a, which contains 50% WS-12 but no nicotine. [Figure 2d] Figure 1a is a graph showing a 1 mg nicotine tablet, which contains 50% oleic acid but no nicotine. [Figure 3a] This graph shows a 1 mg nicotine tablet disclosed in Figure 1a, which contains 50% WS-12, 10% camphor, and 10% eucalyptus, but no nicotine. [Figure 3b] This graph shows a 2 mg nicotine tablet disclosed in Figure 1b, which contains 50% WS-12, 10% camphor, and 10% eucalyptus, but no nicotine. [Figure 4a] This graph shows a 1 mg nicotine tablet disclosed in Figure 1a, which contains 50% WS-12 and 10% camphor, but no nicotine. [Modes for carrying out the invention]

[0114] Accordingly, the present invention provides an oral analgesic composition for the mitigation of perceived nicotine stimulation by inhibiting or blocking nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity. The composition may comprise one or more pharmaceutically active ingredients, such as one or more nicotine sources. The composition may also comprise one or more buffering agents, and the composition may comprise at least two antagonists in amounts effective to inhibit or block nicotine agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels.

[0115] More specifically, the present invention provides at least two antagonists that can be selected from the group consisting of a first antagonist comprising camphor or one or more compounds similar to camphor, a second antagonist comprising eucalyptol, and a third antagonist comprising (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide, also known as WS-12.

[0116] More specifically, the present invention provides, in some examples, at least three antagonists in an amount effective to inhibit or block nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels.

[0117] As used herein, the terms “oral analgesic composition,” or simply “oral composition,” “oral preparation,” or “oral formulation,” or simply “composition,” “preparation,” or “formulation,” or “powder” are considered to be compositions for oral use. Typically, oral compositions are formed into rapidly disintegrating tablets. In other embodiments, compositions may be in the form of pouches, sachets, film strips, chewing gum, chewable tablets, lozenges, or other dispersed forms, such as liquid formulations, e.g., oral sprays or liquid formulations in evaporators.

[0118] In this context, the terms “mass of oral composition” or “relative to the mass of oral composition” or similar phrases meaning the same thing are defined as the mass of the oral composition, excluding the mass of any outer coatings, etc.

[0119] As used herein, the terms "%" and "percent" refer to mass percentages unless otherwise specified.

[0120] As used herein and in the claims, the verb “includes” and its inflections are used in their non-restrictive sense to mean that the items following the word are included, but not excluded from items not specifically mentioned. In addition, the reference of an element in the indefinite article “a” or “an” does not exclude the possibility of more than one element unless otherwise explicitly required that the content be one and only one element. Thus, the indefinite article “a” or “an” usually means “at least one.” In addition, the words “a” and “an” indicate “one or more” when used herein in relation to the word including or containing. The expression “one or more” is intended to mean one, two, three, or more.

[0121] As used herein, the terms “orally disintegrating tablet” or “ODT” are intended to mean a tablet as understood by those skilled in the art in the field of ODT tablets, i.e., a solid dosage form that disintegrates rapidly (within a few seconds) without water when placed on the tongue.

[0122] As used herein, the terms “rapidly disintegrating tablet,” “rapidly dissolving tablet,” or “FDT” are intended to mean a tablet as understood by those skilled in the art in the field of FDT tablets, i.e., a solid dosage form that disintegrates rapidly (within a few seconds) without water when placed on the tongue.

[0123] As used herein, the term “pouch” is intended to mean a container typically formed of a woven fabric of a fibrous material surrounding a cavity. Since pouches are designed for oral administration of active ingredients, they are adapted for oral use, non-toxic, and non-water-soluble. The fibrous material may, for example, form a woven or non-woven web or fabric. A pouch can be sealed, for example, by tying two corresponding pieces of the woven fabric or fabric together along their ends to form a cavity for the oral composition. To release the active ingredients, the pouch is permeable to water, allowing saliva from the oral cavity to penetrate the pouch and enter the cavity, where the saliva can come into contact with one or more active ingredients, thereby releasing one or more active ingredients from the oral pouch.

[0124] As used herein, the term “disintegrate” refers to the reduction of the substance into components, fragments, or particles. Disintegration time is measured in vitro. In vitro measurements are performed in accordance with European Pharmacopoeia 9.0, Section 2.9.1, Disintegration of Tablets and Capsules.

[0125] As used herein, the term “dissolve” refers to the process by which a solid substance enters a solvent (oral saliva) to obtain a solution. Unless otherwise specified, dissolution refers to the complete dissolution of the compound of interest.

[0126] As used herein, the term “disintegrant” refers to a component that promotes the disintegration of an orally disintegrating tablet when it comes into contact with saliva. Disintegrants that can be used within the scope of the present invention may include starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), cellulose, microcrystalline cellulose, alginates, and superdisintegrants, such as cross-linked cellulose (e.g., sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural superdisintegrants, and calcium silicate. Disintegrants can often be considered means that promote the disintegration of a dosage form into smaller fragments upon administration, thereby enabling the initiation of drug dissolution and final absorption.

[0127] The term "non-DC sugar alcohol particles" refers to particles of non-directly compressible (non-DC) sugar alcohols. Note that the terms "non-DC sugar alcohol particles" and "non-DC particles" are used interchangeably. In this context, non-DC sugar alcohol particles refer to particles that have not been pre-treated, for example, by granulation with other sugar alcohols or binders, for the purpose of obtaining so-called directly compressible particles (DC). In this context, non-DC sugar alcohol particles include particles obtained by crystallization and subsequent grinding that do not contain other sugar alcohols or binders. Therefore, non-DC sugar alcohol particles are considered to be particles consisting of non-DC sugar alcohols.

[0128] The term "DC sugar alcohol particles" refers to particles of directly compressible (DC) sugar alcohols. Note that the terms "DC sugar alcohol particles" and "DC particles" are used interchangeably. DC sugar alcohol particles can be obtained, for example, as particles of a sugar alcohol that is essentially DC grade, such as sorbitol, or by granulating a non-DC sugar alcohol with another sugar alcohol or binder, for example, for the purpose of obtaining so-called directly compressible (DC) particles. Furthermore, granules of a non-DC sugar alcohol with water as a binder are considered to result in "DC sugar alcohol particles" in this context.

[0129] The terms “sustained release” or “long-term release” are intended herein to mean release over a long period of time. The terms “rapid release” or “rapid release” or “fast release” are intended herein to mean release at a higher content over a given period of time. The term “controlled release” is intended to mean the release of a substance from an oral composition in the oral cavity of a subject, thereby assisting the actual use of the oral composition in which the actual use controls the amount of substance released.

[0130] As used herein, the term "pH adjuster" refers to an agent that actively adjusts and regulates the pH value of a solution to which it is added or to which it is intended to be added. Therefore, pH adjusters may be acids and bases, including acidic buffers and alkaline buffers. On the other hand, pH adjusters do not contain substances and compositions that can affect the pH through dilution. Furthermore, pH adjusters do not contain, for example, fillers.

[0131] As used herein, the term “buffering agent” is used interchangeably with “buffering agent” and refers to an agent for obtaining a buffered solution. Buffering agents include acidic buffering agents for obtaining a buffered solution with an acidic pH, and alkaline buffering agents for obtaining a buffered solution with an alkaline pH.

[0132] As used herein, the term "particle size" means the average particle size determined when using the particle size distribution estimation method 2.9.38 sieving analysis in accordance with European Pharmacopoeia 9.1, unless otherwise specifically stated.

[0133] As used herein, the term “nicotine source” refers to a substance that contains nicotine and has a physiological effect on the human body that is beneficial to the human body or a part thereof, such as tobacco, free nicotine base, or nicotine ion exchange resin.

[0134] As used herein, the terms “pharmaceutical active ingredient” or “active ingredient” refer to a substance that has a physiological effect in the human body that is beneficial to the human body or a part thereof, and which enables the activation of nicotine receptors or ion channels.

[0135] As used herein, the terms “nicotinic receptor,” “nicotinic ion channel,” or “nicotinic channel” include, but are not limited to, nicotinic acetylcholine receptors (nAChRs), transient receptor potential vanilloid type 1 (TRPV1) ion channels, transient receptor potential ankyrin 1 (TRPA1) ion channels, and transient receptor potential melastatin 8 (TRPM8) ion channels.

[0136] In this context, the term "antagonist" is intended to mean a compound that interacts with "nicotine receptors," "nicotine ion channels," or "nicotine channels" (activated / deactivated) and works to overwhelm nicotine stimulation, as opposed to flavorings that mask flavors, resulting in a reduction of nicotine stimulation.

[0137] The terms “water-insoluble gum base,” “gum base,” “gum base matrix,” or similar phrases primarily refer to water-insoluble and hydrophobic gum base components. “Gum base” may contain gum base polymers, as well as plasticizers, waxes, emulsifiers, fats, and / or fillers.

[0138] As used herein, the term “nicotine” refers to nicotine in any form, including free base nicotine, nicotine salts, nicotine bound to ion-exchange resins, nicotine bound to zeolites; nicotine bound to cellulose, e.g., microcrystalline cellulose, e.g., of microbial origin, or starch microspheres; nicotine bound to CaCO3; and mixtures thereof. Therefore, when referring to the amount of nicotine, the amount refers to the amount of pure nicotine. Thus, when measuring the concentration of nicotine added as a nicotine salt, this is the mass equivalent to pure nicotine, not the mass of the salt, and this is appropriate.

[0139] As used herein, the term "nicotine salt" refers to nicotine in an ionized form, electrostatically bound to a counterion.

[0140] In one embodiment of the present invention, the nicotine salt is selected from nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine hydrogen tartrate, nicotine chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine gensitate, nicotine lactate, nicotine mucoate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotine tosylate, and their hydrates (e.g., nicotine zinc chloride monohydrate).

[0141] In one embodiment of the present invention, the nicotine salt comprises nicotine bitartrate. In this context, nicotine bitartrate comprises its hydrate. According to one embodiment of the present invention, the nicotine salt comprises a water-soluble nicotine salt. In this context, the term “water-soluble salt” is understood as a salt having a solubility in water of at least 10 g per 100 mL of water under standard laboratory conditions including a temperature of 25°C, atmospheric pressure, and pH 7. It should also be understood that if nicotine comprises a nicotine salt in combination with other forms of nicotine, if possible, the nicotine salt may consist of only one nicotine salt or a combination of two or more nicotine salts. In one embodiment of the present invention, the nicotine salt is provided as a free nicotine base.

[0142] As used herein, the term “nicotine release” refers to nicotine that becomes bioavailable, for example, through absorption across the oral mucosa. Some forms of nicotine require dissolution for bioavailability, while others can be readily absorbed into the body without dissolution.

[0143] Nicotine (NCT) is the main alkaloid found in tobacco and is associated with its potential for addiction. NCT can be found both as a liquid and as an ionic complex in the form of a salt with a counterion, such as a chloride ion (Cl-) or a sulfate ion (HSO4-), and in its free base form.

[0144] In one embodiment, a buffer can be added to the oral composition to adjust the pH. The buffer can help promote nicotine absorption. The buffer may be selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate, potassium citrate and dipotassium phosphate, or mixtures thereof.

[0145] In one embodiment of the present invention, the composition further comprises a disintegrant.

[0146] In one embodiment of the present invention, the disintegrant is selected from starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), cellulose, microcrystalline cellulose, alginate, and superdisintegrants such as cross-linked cellulose (e.g., sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural superdisintegrants, and calcium silicate, as well as combinations thereof.

[0147] One advantage of the above embodiment is that the disintegrant may achieve the release of nicotine and pH control agents by promoting the disintegration and dissolution of the formulation.

[0148] Some embodiments of the present invention relate to rapidly dissolving tablet formulations that can be formed by compressing them into rapidly dissolving tablets as orally distributable delivery vehicles. The rapidly dissolving tablets have at least one compound (or "component") that partially or completely melts or softens below body temperature, and a water-soluble additive. For example, the use of a component that partially or completely melts below body temperature in an amount of about 0.01% to about 2.5% by mass in the rapidly dissolving tablets provides a rapidly dissolving tablet composition that conveniently brings established tablet manufacturing processes and apparatus, as well as established packaging methods. The rapidly dissolving tablets of the present invention may also contain one or more colorants, sweeteners, acidulants, flow enhancers, or lubricants.

[0149] The hardness of rapidly dissolving tablets is relatively low, approximately 2 kP or less. Rapidly dissolving tablets have an excellent mouthfeel, resulting from low-melting-point components that melt or soften in the mouth, creating a smooth sensation and masking the grittiness of insoluble components. In some embodiments, the disintegration of rapidly dissolving tablets can occur through a combination of factors, such as melting, disintegration of the tablet matrix, and dissolution of water-soluble additives. Rapidly dissolving tablets can remain relatively stable at high temperatures even if they contain low-melting-point components. Heating rapidly dissolving tablets with a melting point higher than that of their low-melting-point components does not significantly reduce their physical stability.

[0150] The crushability of conventional tablets is measured by the percentage of mass loss after a typical crushability test (rotating 10 tablets in a crushing device for every 100 revolutions). This test is extremely harsh on some rapidly dissolving tablets and therefore cannot be used to measure their crushability.

[0151] The rapidly dissolving tablets produced by the method of the present invention can withstand 20 to 50 rotations in a crushing device before the rapidly dissolving tablets break apart, in some embodiments. In some embodiments, after 20 rotations, the crushability (mass loss %) is typically less than 1%.

[0152] The term "low melting point compound" may include any edible compound that melts or softens at 37°C or below, which is suitable for inclusion in the rapidly dissolving tablets of the present invention. Materials commonly used to manufacture suppositories typically have a melting point at or just below body temperature and can be used in the rapidly dissolving tablets of the present invention. Low melting point compounds may be hydrophilic or hydrophobic.

[0153] Examples of hydrophilic low-melting-point compounds include, but are not limited to, polyethylene glycol, and the average molecular weight range of polyethylene glycol for use in the rapidly dissolving tablets of the present invention may be, for example, about 900 to about 1000.

[0154] Examples of hydrophobic low-melting-point compounds include, but are not limited to, low-melting-point triglycerides, monoglycerides and diglycerides, semi-synthetic glycerides (e.g., EUTECOL®, GELUCIRE® (Gattefosse)), hydrogenated oils, hydrogenated oil derivatives or partially hydrogenated oils (e.g., partially hydrogenated palm kernel oil and partially hydrogenated cottonseed oil), fatty acid esters, such as myristyl lactate, stearic acid and palmitate esters, cocoa butter or its artificial substitutes, palm oil / palm oil butter, and waxes or wax mixtures, which melt at 37°C or below. In some embodiments, the hydrogenated oil is Wecobec M. For effectiveness in rapidly dissolving tablet compositions, the low-melting-point compounds should be edible.

[0155] Monoglycerides, diglycerides, and triglycerides can be used as pure components in some embodiments. Hydrogenated vegetable oils and solid or semi-solid fats are typically mixtures of monoglycerides, diglycerides, and triglycerides. The melting point of fats or hydrogenated vegetable oils is a property of the mixture and does not depend on a single component. Witepsol® (trade name of Condea), Supocire (trade name of Gattefosse), and Novata (trade name of Henkel) are commonly used to manufacture suppositories because they melt at body temperature. All are mixtures of triglycerides, monoglycerides, and diglycerides.

[0156] The rapidly dissolving tablets of the present invention may also contain water-soluble additives. As used herein, the term “water-soluble additive” refers to a solid material or mixture of materials that is orally ingestible and readily soluble in water. Examples of water-soluble additives include, but are not limited to, sugars and amino acids. Sugars are one very suitable water-soluble additive. For example, sugars can be monosaccharides, disaccharides, or polysaccharides. Examples of sugars that can be added to the rapidly dissolving tablets of the present invention may include glucose, dextrose, fructose, maltose, and xylose (all monosaccharides); sucrose, lactose, and galactose (all disaccharides). In one embodiment, the sugar is lactose, as illustrated below. Other suitable sugars are oligosaccharides. Examples of oligosaccharides include dextrose and maltodextrin. Artificial sweeteners such as sucralose, acesulfame potassium, saccharin, or aspartame can also be used. For example, sugar alcohols such as sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrolyzed starch, and isomaltitol can also be used. Other water-soluble additives may include amino acids such as alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Glycine and lysine are examples of very suitable amino acids.

[0157] In some embodiments, the water-soluble additive comprises a rapidly dissolving tablet composition in an amount of about 25 to about 97.5 mass percent. This range can be, for example, about 40 to about 80 mass percent. For example, rapidly dissolving tablet compositions containing additives in an amount of about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 97.5 mass percent, such as monosaccharides, disaccharides, polysaccharides, modified sugars, artificial sweeteners, sugar alcohols, or mixtures thereof, are within the scope of the present invention.

[0158] For the purposes of embodiments relating to rapidly dissolving tablets, “binder” means one or more components added before or during granulation to form granules and / or to promote a sticky molded body during compression. “Binder compound” or “binder component” is a compound or substance contained in the binder. The binder of the present invention comprises at least a low-melting-point compound.

[0159] Rapidly dissolving tablets may also contain one or more flow-promoting materials that can improve the flow of powder blends and minimize mass deviation of the rapid-dissolving tablets. Flow-promoting materials such as silicone dioxide can be used in the rapid-dissolving tablets of the present invention.

[0160] In addition, the rapidly dissolving tablets of the present invention may contain a lubricant (e.g., magnesium stearate or sodium stearyl fumarate) that facilitates the removal of the final rapidly dissolving tablet from the die after compression and prevents the rapidly dissolving tablets from adhering to the punch surface and to each other.

[0161] In some embodiments, a method for forming a rapidly dissolving tablet composition includes the step of preparing rapidly dissolving granules by mixing a low-melting-point compound (e.g., a hardened oil, a partially hardened oil, or a hardened oil derivative) and a water-soluble additive (e.g., a sugar or a modified sugar). The term “rapidly dissolving granules” refers to a composition of a low-melting-point compound and a water-soluble additive prepared for use as granules in the manufacture of the rapidly dissolving tablets of the present invention. A portion of the rapidly dissolving granules may then be added to the remaining components. However, the method for forming the rapidly dissolving tablets of the present invention is within the scope of the invention, and all rapidly dissolving tablet components may be combined simultaneously, or any combination of rapidly dissolving tablet components may be combined separately with other components.

[0162] The granulation endpoint can be determined visually (by visual inspection) or by using a load cell to measure power consumption. Both techniques are routinely used in tablet manufacturing and granulation.

[0163] The rapidly dissolving tablet composition of the present invention can be formed by a preferred method, which is melt granulation. In particular, melt granulation can be performed using a high-shear mixer (e.g., high-shear granulation method), a low-shear mixer, or a fluidized bed granulator. An example of a high-shear mixer is Diosna (trade name of Diosna Dierks & Sohne GmbH). Examples of low-shear mixers are various rotary mixers (e.g., twin-shell blenders or V-blenders). Examples of fluidized bed granulators are those of Glatt and Aeromatic.

[0164] Examples of granule production, but not limited to, include: melting a low-melting-point component and then combining it with a water-soluble component (including water-soluble additives) in a granulator (e.g., by spraying) and mixing until granules are formed; filling a granulator with water-soluble additives and spraying the molten low-melting-point compound to it while mixing; or combining the two (water-soluble component (including water-soluble additives) and the low-melting-point component) with other components if possible and mixing while heating to around the melting point of the low-melting-point component until granules are formed. After the granules have set, they can be crushed and / or screened. Examples of mills that can be used are Co Mill and Stokes Oscillator (these are trade names). Any mill commonly used for crushing tablet granules can be used.

[0165] Melt extrusion can be used to form rapidly dissolving granules. An example of an extruder that can be used is the Nica (trade name of Niro-Aeromatic). Low-melting-point compounds and water-soluble sugars (or other additives) are mixed and heated in the bowl (low-shear mixer) of a planetary mixer, which is usually part of the extruder. The soft mass is then fed into the extrusion chamber and pressure is applied through a small hole or orifice to form a thin rod or cylinder. After the extruded material has set, it can be crushed or spheroidized using standard equipment. In the spheroidizing process, the extruded material is placed on a spinning plate of a spheroidizer, divided into small cylinders equal in length to its diameter, and then rolled by friction (see International Journal of Pharmaceutics 1995, pp. 116:131-146, especially p. 136).

[0166] Spray prying or prilling can also be used to form the rapidly dissolving tablet compositions of the present invention. Spray prying involves atomizing molten droplets of a composition that may contain a low-melting-point compound, a low-melting-point compound, and selected rapidly dissolving tablet components, or the entire rapidly dissolving tablet composition, onto a surface. The surface may be an inert mechanical support, a carrier surface, or, in embodiments where the prying contains droplets that are only a portion of the rapidly dissolving tablet components, a second portion of the rapidly dissolving tablet composition. Apparatus that can be used for spray prying includes spray dryers (e.g., Nero spray dryers) and fluid-bed coating / granulators with top spraying (e.g., Glatt fluid-bed coating / granulators). In some embodiments, rapidly dissolving granules are formed by suspending a water-soluble additive, such as sugar, in the molten low-melting-point component and the prying prying. After spray prying, the resulting composition can be cooled and agglomerated. Following the agglomeration of the mixture, it is screened or sieved and mixed with the remaining rapidly dissolving tablet components. A spray-coating method in which a rapidly dissolving granule containing any combination of a low-melting-point compound and other rapidly dissolving tablet components is melted and spray-coated onto other rapidly dissolving tablet components is within the scope of the present invention. A spray-coating method in which all rapidly dissolving tablet components, including the low-melting-point compound, are mixed, the low-melting-point compound is melted, and the mixture is spray-coated onto the surface is also within the scope of the present invention.

[0167] After spraying and setting, the mixture can be crushed and then combined with other fast-dissolving tablet components. Following the formation of the final fast-dissolving tablet composition, the composition can be further processed to form fast-dissolving tablets.

[0168] The mixing and grinding of the rapid-dissolving tablet components during the preparation of a rapid-dissolving tablet composition can be achieved by any method that mixes the composition to be essentially homogeneous. In some embodiments, the mixer is a high-shear mixer such as a Diosna, CoMill, or V-blender (VB lender).

[0169] Some embodiments of the present invention relate to lozenges. The lozenges comprise the oral composition of the present invention together with further components. In some embodiments, such further components may include combinations of water-soluble synthetic or semi-synthetic nonionic polymers having varying viscosities. As used herein, water-soluble synthetic or semi-synthetic nonionic polymers may include, but are not limited to, alkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, polyalkylene oxides, carboxyalkylcellulose ester methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and copolymers of ethylene oxide and propylene oxide. Examples of alkylcellulose may include methylcellulose. Examples of hydroxyalkylcellulose may include hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose. Examples of hydroxyalkylalkylcellulose may include hydroxyethylmethylcellulose and hydroxypropylmethylcellulose. Examples of polyalkylene oxides may include polyethylene oxide and polypropylene oxide. Water-soluble synthetic or semi-synthetic nonionic polymers may also include dextrin, semi-synthetic starch, polyhydroxyethyl methacrylate (PHEMA), water-soluble nonionic polymethacrylate and its copolymers, modified cellulose, modified polysaccharides, nonionic semi-synthetic gum, nonionic polysaccharides, and / or mixtures thereof.

[0170] In certain embodiments, the polymer is a cellulose ether derivative such as hydroxypropyl methylcellulose and hydroxypropyl cellulose (HPC). In another embodiment, the polymer is hydroxypropyl methylcellulose. In yet another embodiment, the polymer is hydroxypropyl methylcellulose (HPMC).

[0171] The lozenges of the present invention may contain, for example, a high-viscosity polymer and a low-viscosity polymer. In certain embodiments, the high-viscosity polymer has a viscosity of about 2,000 cps to about 6,000 cps, or about 3,000 cps to about 5,000 cps, or about 3,500 cps to about 5,500 cps. In one embodiment, the high-viscosity polymer has a viscosity of about 4,000 cps. The viscosity of the high-viscosity polymer was determined using the Brookfield LV model or an equivalent.

[0172] In certain embodiments, the low-viscosity polymer has a viscosity of about 50 cps to about 150 cps, or about 80 cps to about 100 cps, or about 90 cps to about 110 cps. In one embodiment, the low-viscosity polymer has a viscosity of about 100 cps. The viscosity of the low-viscosity polymer was determined using capillary viscometer methods911.

[0173] The amount of high-viscosity polymer may be approximately 1% to 20% by mass, or approximately 2% to 10% by mass, or approximately 3% to 7% by mass. The amount of low-viscosity polymer may be approximately 1% to 20% by mass, or approximately 2% to 10% by mass, or approximately 3% to 7% by mass.

[0174] The ratio of high-viscosity polymer to low-viscosity polymer in a lozenge can vary depending on the desired solubility characteristics of the lozenge. For example, if a lozenge that dissolves slowly is desired, a higher ratio of high-viscosity polymer to low-viscosity polymer is desirable. However, if a lozenge that dissolves rapidly is desired, a lower ratio of high-viscosity polymer to low-viscosity polymer is desirable. In certain embodiments, the ratio of high-viscosity polymer to low-viscosity polymer can be between about 1:50 and about 50:1, or between about 1:30 and about 30:1, or between about 1:20 and about 20:1, or between about 1:10 and about 10:1, or between about 1:2 and about 2:1.

[0175] In some embodiments, optimizing the ratio of high-viscosity polymers to low-viscosity polymers can result in lozenges with improved solubility. For example, very high-viscosity polymers can result in lozenges with very varied solubility profiles relative to the lozenge base. In addition, the amount of high-viscosity polymer may not be uniform within the base of the lozenge; that is, the high-viscosity polymer may not be evenly distributed throughout the lozenge. When only low-viscosity polymers are used in the lozenge, the active ingredient may be released from the lozenge very rapidly. To obtain adequate release using only low-viscosity polymers, a large amount of polymer may be required, resulting in larger lozenge tablets, which can be considered to have undesirable texture characteristics, for example, the lozenge tablets may have a sticky mouthfeel.

[0176] According to some embodiments of the present invention, a combination of a high-viscosity polymer and a low-viscosity polymer is used in the lozenge. In some embodiments, this can result in well-controlled dissolution changes in the lozenge.

[0177] In some embodiments, the lozenge agent of the present invention may also include at least one additive selected from the group consisting of at least one excipient, a flavor masking agent, an antioxidant, a flow enhancer, and a colorant, or any combination thereof.

[0178] Suitable excipients for the lozenges of the present invention or its embodiments may include, for example, maltitol, maltose, fructose, glucose, trehalose, sorbitol, sucrose, sugars, mannitol, xylitol, isomalt, dextrose, maltodextrin, dextrose, dextrin, erythritol, lactitol, polydextrose, and mixtures thereof. In one embodiment, the excipient is mannitol. In one embodiment, the excipient is present in an amount of about 500 mg to about 1100 mg per lozenge, and in another embodiment, it is present in an amount of about 750 mg to about 1000 mg per lozenge.

[0179] The lozenges of the present invention or its embodiments may have a total mass per lozenge between approximately 100 mg and approximately 2000 mg, between approximately 500 mg and approximately 1500 mg, or between approximately 1000 mg and approximately 1300 mg. In one embodiment, the total mass per lozenge is approximately 1200 mg.

[0180] The lozenges of the present invention or its embodiments can be compressed by conventional compression tableting techniques. In certain embodiments, the lozenges can be compressed to a hardness of about 20N to about 200N, or about 30N to about 150N, or about 50N to about 100N.

[0181] Certain embodiments of the present invention relate to lozenges containing granular and extragranular components. The use of granular components for formulations is common in solid dosage forms such as tablets and compressed lozenges. Typically, granular components (or “main granules”) are formulated to improve the processability of the solid dosage form and reduce shattering during transport and handling. In the absence of granular components, tablets or lozenges using high levels of indirect compressible excipients may be difficult to process or may result in highly shatterable products. Active ingredients and other optional additives may, for example, be blended with the granular components before compression to constitute the “extragranular” components of these conventional lozenge formulations. Alternatively, the active ingredients may be contained within the granular components.

[0182] In some embodiments, the granular components can be formed by preferred means, such as slugging, aqueous or non-aqueous wet granulation, fluidized bed granulation, spray drying, or roller compression. In one embodiment, the granular material is formed by wet granulation, and the granular components are mixed in a suitable granulator to form a powder blend. Water or a suitable solvent or solvent mixture can be added and thoroughly mixed with the powder blend. This process allows the powder blend to become wet and aggregate, forming granules. The wet granular material can then be dried, for example, in a conventional tray dryer, then pulverized and screened to obtain granules having a desired particle size distribution. In another exemplary embodiment, the granular material is formed by fluidized bed granulation, in which the granular components are fluidized in a fluidized bed dryer and then sprayed with water or a suitable solvent. The wet granules thus formed are dried, then pulverized and screened to obtain granules having a desired particle size distribution. In another exemplary embodiment, spray granulation is used as a method for granulating powder to obtain spherical, free-flowing granules. In spray granulation, the desired granular components can be suspended in water or a suitable solvent. This suspension is sprayed into a spray dryer using an atomizer. The atomizer then dries the resulting droplets to form granules, which are then ground and screened to obtain granules having the desired particle size distribution. In yet another exemplary embodiment, roller compression can be used as a method for producing granules, in which a dry blend of other desired granular components is subjected to force through a pair of rollers held under high pressure, thereby compressing the powder body to form a wafer-like sheet, which is then ground and screened to obtain granules having the desired particle size distribution. A small amount of water may be sprayed onto the powder blend before supplying it to the rollers to improve the binding properties of the components in this process. The granules thus obtained by any of the granulation methods described can be further processed to obtain tablets or lozenges.

[0183] The presence of polymers in the intragranular and extragranular components can serve two distinct functions. Polymers in the intragranular components can serve as binders that form the main granules. In some embodiments, the intragranular components include high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers, low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers, or both. In one embodiment, the intragranular components include both high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers and low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers. The amount of high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers can be between about 1% by mass and about 20% by mass, or between about 2% by mass and about 10% by mass, or between about 3% by mass and about 7% by mass. In some embodiments, the amount of low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers can be between about 1% by mass and about 20% by mass, or between about 2% by mass and about 10% by mass, or between about 3% by mass and about 7% by mass. In one embodiment, the granular components include about 5% of a high-viscosity water-soluble synthetic or semi-synthetic nonionic polymer and about 5% of a low-viscosity water-soluble synthetic or semi-synthetic nonionic polymer.

[0184] In some embodiments, the ratio of high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers to low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers in the granular components may be between about 1:50 and about 50:1, or between about 1:30 and about 30:1, or between about 1:20 and about 20:1, or between about 1:10 and about 1:10, or between about 1:2 and about 2:1.

[0185] The presence of polymers in the extragranular components can, in some embodiments, act as dissolution modifiers. Various dissolution profiles can be achieved by changing the amount and ratio of high-viscosity and low-viscosity polymers. In some embodiments, the extragranular components may include high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers, low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers, or both. In one embodiment, the extragranular components include low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers.

[0186] The amount of high-viscosity water-soluble synthetic or semi-synthetic nonionic polymer may, in some embodiments, be between about 1% by mass and about 20% by mass, or between about 2% by mass and about 10% by mass, or between about 3% by mass and about 7% by mass. The amount of low-viscosity water-soluble synthetic or semi-synthetic nonionic polymer may, in some embodiments, be between about 1% by mass and about 20% by mass, or between about 2% by mass and about 10% by mass, or between about 3% by mass and about 7% by mass.

[0187] In one embodiment, the non-granular component contains about 2% of a low-viscosity water-soluble synthetic or semi-synthetic nonionic polymer, or about 5% of a low-viscosity water-soluble synthetic or semi-synthetic nonionic polymer, or about 18% of a low-viscosity water-soluble synthetic or semi-synthetic nonionic polymer.

[0188] The ratio of high-viscosity water-soluble synthetic or semi-synthetic nonionic polymers to low-viscosity water-soluble synthetic or semi-synthetic nonionic polymers in the granular components may, in some embodiments, be between about 1:50 and about 50:1, or between about 1:30 and about 30:1, or between about 1:20 and about 20:1, or between about 1:10 and about 10:1, or between about 1:2 and about 2:1.

[0189] The active ingredient may be present in the granular components, the extragranular components, or both, depending on the various embodiments. In one embodiment, the active ingredient is present in the extragranular components. The pH-controlling acid may also be present in the granular components, the extragranular components, or both. In one embodiment, the pH-controlling acid is present in the extragranular components. In another embodiment, the pH-controlling acid is present in both the granular and extragranular components.

[0190] The lozenges of the present invention may have in vitro solubility profiles of 25% to 50% after 1 hour; 50% to 99% after 3 hours; and 75% to 100% after 6 hours (determined using a USP II type apparatus with a rotating paddle at pH 7.4, 37°C, and 900 ml of phosphate buffer, with the rotation speed set to 75 rpm).

[0191] In other embodiments, the lozenges of the present invention may have in vitro solubility profiles of 30% to 40% in 1 hour; 50% to 70% in 3 hours; and 90% to 100% in 6 hours (determined using a USP II apparatus with a rotating paddle at pH 7.4, 37°C, and 900 ml of phosphate buffer; rotation speed set to 75 rpm).

[0192] In further embodiments, the lozenges of the present invention may have in vitro solubility profiles of 33% to 37% after 1 hour; 65% to 70% after 3 hours; and 97% to 100% after 6 hours (determined in a USP Type I apparatus, basket, and phosphate buffer at pH 7.4 and 37°C, with a rotation speed set to 100 rpm).

[0193] In certain embodiments, the lozenge formulation of the present invention may have the following dissolution profiles in the oral cavity: 45% to 60% in 15 minutes; 70% to 85% in 30 minutes; and 90% to 100% in 60 minutes.

[0194] In another embodiment, the lozenge formulation of the present invention may have the following dissolution profiles in the oral cavity: 50% to 55% in 15 minutes; 75% to 80% in 30 minutes; and 95% to 100% in 60 minutes.

[0195] In one embodiment, 100% of the lozenge formulation of the present invention dissolves in the oral cavity in less than about 60 minutes, less than about 50 minutes, or less than about 45 minutes.

[0196] In another embodiment, at least about 50% of the lozenge dissolves in the mouth in less than about 30 minutes or less than about 15 minutes.

[0197] Some embodiments of the present invention relate to chewing gum, such as compressed chewing gum, as an orally distributable delivery vehicle. The chewing gum in these embodiments comprises the oral composition of the present invention.

[0198] The phrase "compressed chewing gum" refers to chewing gum containing granules or powder that have been exposed to a punching mechanism in a tablet forming machine, which presses granules or powder into a cohesive mass of material.

[0199] In some embodiments of the present invention, the gum base is, for example, - Elastomer in the range of 5-40% by mass of gum base, - Natural resins in the range of 8-45% by mass of the gum base, and - Synthetic resin in the range of 5-95% by mass of gum base Includes.

[0200] In some embodiments of the present invention, the chewing gum tablet contains a natural resin in an amount of 0.1 to 40%, for example 1 to 30%, for example 3 to 25%, or 5 to 20%, relative to the mass of the chewing gum tablet.

[0201] In embodiments of the present invention, the chewing gum tablet contains a synthetic resin in an amount of 0.1 to 40%, for example 1 to 30%, for example 3 to 25%, or 5 to 20%, relative to the mass of the chewing gum tablet.

[0202] In embodiments of the present invention, the chewing gum tablet contains an elastomer in an amount of at least 2% by mass of the chewing gum formulation, for example, at least 4% by mass of the chewing gum tablet. In embodiments of the present invention, the chewing gum tablet contains an elastomer in an amount of less than 35% by mass of the chewing gum formulation, for example, less than about 25% by mass of the chewing gum formulation, for example, less than 20% by mass, 15% by mass, or 10% by mass of the chewing gum tablet.

[0203] In embodiments of the present invention, the chewing gum tablet contains a water-retaining agent such as propylene glycol or glycerol.

[0204] In embodiments of the present invention, the chewing gum tablet is coated.

[0205] In embodiments of the present invention, the chewing gum tablet has a mass in the range of 0.1 to 10 grams, for example, in the range of 0.5 to 4 grams.

[0206] According to one embodiment of the present invention, a chewing gum tablet may contain a filler. In the embodiment of the present invention, the chewing gum tablet contains a filler in an amount of 0.1 to 50% by mass of the chewing gum. In the embodiment of the present invention, the chewing gum tablet contains a filler in an amount of 0.1 to 50% by mass of the chewing gum, the filler is hydrophobic, and at least 90% of the filler is contained in the chewing gum tablet while the user is chewing for at least 10 minutes.

[0207] Elastomers impart a rubbery tackiness to gum, which varies depending on the chemical structure of the component and how it can combine with other components. Suitable elastomers for use in gum bases and gums according to the present invention may include natural or synthetic types. Elastomer plasticizers alter the hardness of the gum base. Their specificity in the intramolecular chains of the elastomer that breaks (plasticizes), along with their altered softening point, changes the degree of hardness and suitability of the final gum when used in the base. This can be important if you want to provide more exposure of elastomer chains to the alkane chains of the wax.

[0208] The elastomer (rubber) used in a gum base can vary depending on various factors, such as the desired type of gum base, the desired texture of the gum formulation, and other components used in the formulation to produce the final chewing gum product. The elastomer can be any water-insoluble polymer known in the art, including these gum polymers used in chewing gum and bubble gum. Specific examples of polymers suitable for gum bases include both natural and synthetic elastomers. For example, these polymers suitable for gum base formulations include, but are not limited to, natural substances (of plant origin), such as chicle gum, natural rubber, crown gum, nispero, rosidingha, jelton, perillo, nigagutta, tunu, balata, gata-percha, lechi capsi, solva, gutta kay, etc., and mixtures thereof. Examples of synthetic elastomers include, but are not limited to, styrene-butadiene copolymer (SBR), polyisobutylene, isobutylene-isoprene copolymer, polyethylene, polyvinyl acetate, and mixtures thereof.

[0209] Natural resins can be used in accordance with the present invention and may be natural rosin esters, also commonly referred to as ester gums, and include, for example, glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of tally oil rosin, pentaerythritol esters of partially cured rosin, methyl esters of rosin, partially cured methyl esters of rosin, pentaerythritol esters of rosin, synthetic resins, such as terpene resins derived from alpha-pinene, beta-pinene, and / or d-limonene, and natural terpene resins.

[0210] In one embodiment of the invention, the resin includes, for example, terpene resins derived from alpha-pinene, beta-pinene, and / or d-limonene, natural terpene resins, glycerol esters of gum rosin, tall oil rosin, wood rosin, or other derivatives thereof, such as glycerol esters of partially cured rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, pentaerythritol esters of partially cured rosin, methyl esters of rosin, partially cured methyl esters of rosin, or pentaerythritol esters of rosin, and combinations thereof.

[0211] In one embodiment of the present invention, the powdered chewing gum tablet base material includes a sweetener, such as a bulk sweetener, a carbohydrate sweetener, a sugar substitute sweetener, an artificial sweetener, a high-intensity sweetener, or any combination thereof.

[0212] Suitable bulk sweeteners contain both carbohydrate and non-carbohydrate sweetening components. The bulk sweetener typically constitutes about 5 to about 95% by mass of a chewing gum tablet, more typically about 20 to about 80% by mass, for example, 30 to 70% by mass or 30 to 60% by mass of a chewing gum tablet.

[0213] Useful carbohydrate sweeteners are sugar-containing components commonly known in the field of tablets and chewing gum tablets, and include, but are not limited to, sucrose, dextrose, maltose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levrose, galactose, corn syrup solids, etc., either alone or in combination.

[0214] For example, sorbitol can be used as a non-carbohydrate sweetener. Other useful non-carbohydrate sweeteners include, but are not limited to, other sugar alcohols, such as mannitol, xylitol, hydrolyzed starch, maltitol, isomalt, erythritol, lactitol, etc., either alone or in combination.

[0215] High-intensity artificial sweeteners can also be used by using the above-mentioned sweeteners alone or in combination. For example, high-intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, stevioside (a naturally strong sweetener), etc., alone or in combination. To provide a longer-lasting sweetness, encapsulation of at least a portion of the artificial sweetener, or otherwise control of its release, is desirable. Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, preservation, encapsulation into yeast cells, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of sweeteners can also be provided using other chewing gum tablet components such as resinous compounds.

[0216] The level of artificial sweetener use varies considerably and depends on factors such as the strength of the sweetener, release rate, desired sweetness of the product, and cost considerations. Therefore, the effective concentration of artificial sweeteners can vary from approximately 0.001% to approximately 8% by mass (e.g., approximately 0.02% to approximately 8% by mass). If a carrier is used for encapsulation, the level of encapsulated sweetener use increases proportionally. Combinations of carbohydrate and / or non-carbohydrate sweeteners can be used in chewing gum formulations.

[0217] The chewing gum tablets according to the present invention may optionally contain one or more fillers / texturizers, including, for example, magnesium carbonate and calcium carbonate, sodium sulfate, crushed limestone, silicate compounds such as magnesium silicate and aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate, cellulose polymers such as wood, and combinations thereof.

[0218] Several chewing gum tablet base materials known in the art can be applied within the scope of the present invention. Such components include, but are not limited to, waxes, fats, softeners, fillers, antioxidants, emulsifiers, colorants, binders, and acidulants.

[0219] The gum-based granules according to the present invention can be produced, for example, by extrusion and water pelletization.

[0220] The size of the gum-based granules according to the present invention is controlled by several factors, such as the opening size, gum composition, gum temperature, and pressure drop, when the die plate is used in an extruder. Due to the interaction between the pressurized gum composition, temperature, and friction at the opening of the die device, the average diameter of the granules produced is usually larger than the diameter of the opening of the die device. The relationship between the diameter of the die device opening and the average diameter of the granules produced from a specific gum composition can be determined by those skilled in the art based on routine experiments.

[0221] According to the present invention, it is also possible to produce granules of different average diameters by creating granules of one diameter, and then mix the granules of different average diameters in a desired proportion.

[0222] The openings of the die device may have any desired cross-section, such as circular, elliptical, or square, but in some embodiments, it is preferable that the die device includes openings having a substantially circular cross-section and a diameter in the range of 0.1 to 1.3 mm. The first set of openings may have a first diameter in the range of 0.07 to 0.7 mm, for example, 0.15 to 0.6 mm, preferably in the range of 0.2 to 0.5 mm. The second set of openings may have a second diameter larger than the first diameter. The second diameter is conveniently in the range of 0.4 to 1.3 mm, for example, 0.7 to 1.2 mm.

[0223] In some embodiments, the chewing gum granulation system further includes a drying device. Powdered sweetener or talk may be added to the granules in the final drying step. The drying device may be a conventional centrifugal dryer or another suitable dryer, such as a fluid bed dryer. The drying device may include, for example, a mixer. In one embodiment, the powdered sweetener may be sorbitol, which is mixed with the dried or partially dried granules. A small amount of residual moisture on the surface of the granules, for example 2% wt. relative to the total mass of the granules, may contribute to the adhesion of the sorbitol powder to the granule surface. Conventional anti-flocculants can be used, for example, as talcum, but sorbitol powder can function as an anti-flocculant and simultaneously serve as a sweetener. Sorbitol is found to be the most preferred, but other polyol-based bulk sweeteners may also be preferred, such as mannitol, xylitol, maltitol, isomaltitol, erythriol, and lactitol.

[0224] In one embodiment, the chewing gum granulation system according to the present invention further includes one or more sieves adjusted to remove granules with an average diameter greater than 1.3 mm. Removal of larger granules improves the subsequent compounding process.

[0225] According to one embodiment of the present invention, at least the extruder and / or die device includes means for controlling the temperature of the chewing gum composition. The means for controlling the temperature may be a cooling or heating device which may help to facilitate the flow of the gum composition through the extruder and die device. In one embodiment, the extruder includes delivering means for delivering sweeteners and / or flavorings to the gum composition in the extruder.

[0226] During the extrusion of the gum composition, the differential pressure between the gum composition in the extruder and the gum composition in the liquid filling chamber, i.e., across the die device, is preferably greater than 10 bar, for example greater than 18 bar, for example in the range of 25 to 90 bar. The temperature of the gum composition in the extruder may be, for example, in the range of 40 to 125°C, preferably in the range of 50 to 115°C. The temperature of the die device may be, for example, in the range of 60 to 250°C, preferably in the range of 80 to 180°C. The temperature of the liquid in the liquid filling chamber is conveniently in the range of 8 to 40°C. However, the optimal values ​​for pressure and temperature in the method according to the present invention can be determined by those skilled in the art as a matter of routine practice. The optimal values ​​for a specific gum composition will, of course, vary depending on the composition.

[0227] Rapid cooling in an air-filled or water-filled chamber can help preserve fragile components in the gum composition, thus maintaining their quality better and transferring them to the granules in the final gum product. This improved quality of the gum composition in the granules improves the overall composition of the chewing gum product.

[0228] Granule fractions with different average masses can be produced in two different settings, each producing one batch of granules with a specific average mass, followed by blending the fractions. To obtain granules with different average diameters simultaneously, it is also possible to design a die mechanism with at least two different sized die openings. Thus, it is possible to obtain granules with different masses. More than two different average masses can be obtained by designing the die mechanism used. For example, it is possible to obtain granules with three, four, or more different average masses.

[0229] The granules can be cut in a very large liquid-filled chamber, and the granules are also cooled. In some embodiments, cooling is combined with the transfer of the granules from the chamber. This can be done, for example, by cooling the cut granules in water during the transfer from the liquid-filled chamber to the dewatering device. The transfer time from cutting to dewatering can be less than 6 seconds. The advantage of this is that water-soluble components in the gum composition are not unnecessarily washed away from the granules. Optionally, the total contact time between the granules and the cooling water can be further limited to less than 4 seconds.

[0230] In some embodiments, the chewing gum composition supplied to the extruder is a gum base, i.e., it contains at least one or more flavorings when extruded through a die. The flavorings within the granules cause a prolonged release of flavor during chewing.

[0231] The powdered chewing gum tablet base material according to the present invention may include, for example, so-called primary particles or aggregated primary particles, also called granules. When these are compressed, bonds are established between the particles or granules, thereby imparting a certain mechanical strength to the compressed chewing gum tablet.

[0232] It should be noted that the terms introduced above—powder, primary particles, and granules—can be somewhat misleading in that the difference between primary particles and granules can very often be perceived differently depending on the user's context. For example, despite the fact that sorbitol, when delivered to consumers after typical pretreatment performed on sorbitol, should rather be considered a type of granule, some people may consider sweeteners such as sorbitol to be primary particles. The definition adopted in this specification is that granules refer to larger particles that include primary particles that have undergone some pretreatment.

[0233] When pressure is applied to powdered raw materials, the bulk volume decreases and the amount of air decreases. Energy is consumed during this process. As the particles become closer to each other during the volume reduction process, bonds are established between the particles or granules. The formation of these bonds is related to the energy reduction of the system, which releases energy.

[0234] Volume reduction occurs through various mechanisms, and different types of bonding are established between particles or granules depending on the applied pressure and the properties of the particles or granules.

[0235] The composition of a chewing gum base formulation is a mixture of chewing gum components as defined below, but can vary substantially depending on the specific product being prepared and the desired chewing and other sensory characteristics of the final product. However, a typical range (mass%) of the above-mentioned gum base components is 5-50% by mass of elastomer compounds, 5-55% by mass of elastomer plasticizers, 0-50% by mass of fillers / texturizers, 5-35% by mass of softeners, and 0-1% by mass of miscellaneous components, such as antioxidants and colorants.

[0236] Suitable bulk sweeteners include, for example, both carbohydrate and non-carbohydrate components. Bulk sweeteners typically constitute about 5-95% by mass of chewing gum tablets, more typically about 20-80% by mass, for example, 30-60% by mass of chewing gum tablets. Useful carbohydrate sweeteners are sugar-containing components commonly known in the field of tablets and chewing gum tablets, and include, but are not limited to, sucrose, dextrose, maltose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levose, galactose, corn syrup solids, etc., either alone or in combination.

[0237] If a low-calorie gum is desired, a low-calorie filler may be used. Examples of low-calorie fillers include polydextrose, raftilose, raftilin, inulin, fructooligosaccharides (NutraFlora®, oligosaccharide-modified palatinose; guar gum hydrolysate (e.g., Sun Fiber®), or indigestible dextrin (e.g., Fibersol®)). However, other low-calorie fillers may be used.

[0238] Further chewing gum tablet base components that may be included in the chewing gum tablet mixture processed in this process include surfactants and / or solubilizers. Examples of types of surfactants used as solubilizers in chewing gum compositions are, according to the present invention, HP Fiedler, Lexikon der Hilfstoffe fur Pharmacie, Kosmetik und Angrenzende Gebiete, pp. 63-64 (1981), and the list of approved food emulsifiers in various countries. Anionic, cationic, amphoteric, or nonionic solubilizers may be used. Suitable solubilizers include lecithin, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty acid salts, monoacetyl tartrate and diacetyl tartrate esters of monoglycerides and diglycerides of edible fatty acids, citrate esters of monoglycerides and diglycerides of edible fatty acids, saccharose esters of fatty acids, polyglycerol esters of fatty acids, polyglycerol esters of transesterified castor oil (E476), sodium stearoyl lactylate, sodium laureth sulfate, and sorbitan esters of fatty acids, as well as polyoxyethylated hydrogenated castor oil (e.g., products sold under the trademark name CREMOPHOR), block copolymers of ethylene oxide and propylene oxide (e.g., products sold under the trademark names PLURONIC® and POLOXAMER), polyoxyethylene aliphatic alcohol ethers, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids, and polyoxyethylene stearic acid (steraric acid Contains acid esters.

[0239] Particularly preferred solubilizers include polyoxyethylene stearate, such as polyoxyethylene (8) stearate and polyoxyethylene (40) stearate; polyoxyethylene sorbitan fatty acid esters sold under the trademark name TWEEN®, such as TWEEN® 20 (monolaurate), TWEEN® 80 (monoleate), TWEEN® 40 (monopalmitate), TWEEN® 60 (monostearate) or TWEEN® 65 (tristearate); monoacetyl tartrate and diacetyl tartrate esters of monoglycerides and diglycerides of edible fatty acids; citrate esters of monoglycerides and diglycerides of edible fatty acids; sodium stearoyl lactylate; sodium lauryl sulfate; polyoxyethylated hydrogenated castor oil; block copolymers of ethylene oxide and propylene oxide; and polyoxyethylene aliphatic alcohol ethers. Solubilizers can be either a single compound or a combination of several compounds. The expression “solubilizer” is used in this text to describe both possibilities, and the solubilizers used may be suitable for use in food and / or medicine.

[0240] Gum-based formulations applicable within the scope of the present invention include synthetic elastomers selected from polyisobutylene (e.g., having a gas pressure chromatography (GPC) average molecular weight in the range of about 10,000 to 1,000,000, including a range of 50,000 to 80,000), isobutylene-isoprene copolymer (butyl elastomer), styrene-butadiene copolymer (e.g., having a styrene-butadiene ratio of about 1:3 to 3:1), and polyvinyl acetate (PVA), wherein higher molecular weight polyvinyl acetates are typically used in bubble gum bases, polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymers (e.g., having a vinyl laurate content of about 5 to 50% by mass of the copolymer, e.g., 10 to 45% by mass), and combinations thereof. It is common in this industry to combine synthetic elastomers having high and low molecular weight elastomers in the gum base. Current preferred combinations of synthetic elastomers include, but are not limited to, polyisobutylene and styrene-butadiene, polyisobutylene and polyisoprene, polyisobutylene and isobutylene-isoprene copolymer (butyl rubber), and combinations of polyisobutylene, styrene-butadiene copolymer and isobutylene-isoprene copolymer, as well as all of the above individual synthetic polymers mixed with polyvinyl acetate and vinyl acetate-vinyl laurate copolymer, respectively, and combinations thereof. Particularly interesting elastomer or resin polymer compounds that can be advantageously used in the processes of the present invention include polymers that, in contrast to currently used elastomers and resins, can be physically, chemically, or enzymatically degraded in the environment after chewing gum use, thereby allowing the used, degradable chewing gum residue to be more easily removed by physical or chemical means from the site where it eventually disintegrates and / or is discarded, thus resulting in less environmental pollution than chewing gum based on non-degradable polymers.

[0241] In this context, useful elastomer plasticizers include, but are not limited to, natural rosin esters, also commonly referred to as ester gums, such as glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of tally oil rosin, pentaerythritol ester of partially cured rosin, methyl ester of rosin, partially cured methyl ester of rosin, and pentaerythritol ester of rosin. Other useful resinous compounds include synthetic resins, e.g., terpene resins derived from alpha-pinene, beta-pinene, and / or d-limonene, natural terpene resins, and any preferred combinations thereof. The choice of elastomer plasticizer depends on the specific application and the type of elastomer used.

[0242] In some embodiments of the present invention, the composition can also be used as a powder in various application forms. Note that additional components may be present in the powder.

[0243] One application of the powder according to the present invention is a flow pack formulation. In this application, the composition optionally contains additional components and can be administered directly for oral use. In some embodiments, the flow pack formulation is designed to allow only specific doses for oral use. A particular advantage of these embodiments may be that saliva is generated instantaneously upon oral administration.

[0244] In some embodiments of the present invention, the oral composition may also be present in the pouch formulation as a powder. Therefore, this aspect of the present invention includes oral compositions in pouch formulations that are not tabletized but contain other powders or powder components, or are part of a powder formulation. Directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles of the present invention may be included in the pouch formulation according to the present invention. Additional embodiments relating to the oral composition of the present invention are also applicable when included in the pouch formulation. Note that additional components may be present in the pouch formulation, such as water-soluble or water-insoluble fibers containing microcrystalline cellulose.

[0245] According to an advantageous embodiment of the present invention, the pouch agent comprises a water-permeable membrane such as a woven or nonwoven fabric.

[0246] The pouch formulation according to the present invention includes an opening, the dimensions of which are characteristic of the oral composition, and are adjusted to the characteristic dimensions of the opening to hold the matrix composition inside the pouch formulation before use and / or hold a portion of the contents inside the pouch formulation during use.

[0247] In other words, according to various embodiments, the pouch forms a membrane that allows saliva to pass through and prevents or inhibits the passage of at least some of its contents. The membrane of the pouch can be of any suitable material, such as woven or nonwoven fabrics (e.g., cotton, fleece, etc.), heat-sealable nonwoven cellulose, or other polymer materials such as synthetic, semi-synthetic, or natural polymer materials. Examples of suitable pouch materials are pulp paper and small amounts of wet-strength enhancers. Suitable materials for use must form a semi-permeable membrane layer that prevents the powder or composition from leaking out of the bag or pouch during use. Suitable materials also do not significantly affect the release of the active ingredients from the pouch.

[0248] The powder is filled into a pouch and retained in the pouch by sealing. An ideal pouch is chemically and physically stable, pharmaceutically acceptable, insoluble in water, easy to fill with powder and seal, and provides a semipermeable membrane layer that prevents the powder from leaking out of the bag but allows saliva and dissolved or sufficiently small suspended components from the powder in the pouch to pass through the pouch.

[0249] The pouch can be placed in the mouth by the user. Saliva then enters the pouch, and the active ingredients and other components, which are soluble in saliva, begin to dissolve and are transported from the pouch to the mouth along with the saliva. In some embodiments of the present invention, the pouch can be chewed in a manner similar to gum. This is particularly advantageous when the oral composition contains a gum base. Thus, the pouch can be chewed to form a cohesive residue containing water-insoluble components.

[0250] Typically, the pouch includes an opening, and the characteristic dimensions of the opening are adjusted to the characteristic dimensions of the matrix composition to hold the matrix composition inside the pouch before use and / or to hold a portion of the matrix composition, such as an insoluble composition, inside the pouch during use.

[0251] To obtain a pouch having a suitable opening size in terms of the matrix composition used, the material for the pouch can therefore be selected and may include, for example, woven or non-woven materials.

[0252] In other words, according to various embodiments, the pouch forms a membrane that allows saliva to pass through and prevents or inhibits the passage of the water-insoluble composition. The membrane of the pouch may be any suitable material, such as woven or nonwoven fabrics (e.g., cotton, fleece, etc.), heat-sealable nonwoven cellulose, or other polymer materials such as synthetic, semi-synthetic, or natural polymer materials. Examples of suitable pouch materials are pulp paper and a small amount of wet strength enhancer. Suitable materials for use must form a semipermeable membrane layer that prevents the powder or composition from leaking out of the bag or pouch during use. Suitable materials also should not significantly affect the release of the active ingredient from the pouch.

[0253] The powder is filled into a pouch and retained in the pouch by sealing. An ideal pouch is chemically and physically stable, pharmaceutically acceptable, insoluble in water, easy to fill with powder and seal, prevents the powder from leaking out of the bag, but provides a semipermeable membrane layer that allows saliva and dissolved or sufficiently small suspended components from the powder in the pouch, such as the active ingredient, to pass through the pouch.

[0254] The pouch can be placed in the mouth by the user. Saliva then enters the pouch, and one or more active ingredients and other ingredients, which are soluble in saliva, begin to dissolve and are transported from the pouch to the mouth along with the saliva, allowing for absorption of the active ingredients.

[0255] According to one embodiment of the present invention, the matrix composition may further comprise one or more accelerators.

[0256] In one embodiment of the present invention, the accelerator is selected from the group consisting of bile salts, cetomacrogol, chelating agents, citrates, cyclodextrins, detergents, enamine derivatives, fatty acids, labrasols, lecithin, phospholipids, synthetic and natural surfactants, nonionic surfactants, compounds that impair the cell envelope, solvents, steroidal detergents, chelating agents, solubilizers, charge regulators, pH regulators, degrading enzyme inhibitors, mucolytic or mucocleansing agents, membrane permeability enhancers, epithelial junction physiology modifiers, vasodilators, selective transport enhancers, or any combination thereof. The pH regulator includes buffers.

[0257] According to one embodiment of the present invention, the accelerator includes one or more pH control agents, such as buffering agents.

[0258] In one embodiment of the present invention, the pH control agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, or any combination thereof.

[0259] According to one embodiment of the present invention, the water-insoluble composition includes, for example, cellulose as a carrier. In one embodiment of the present invention, the cellulose is microcrystalline cellulose, or comprises microcrystalline cellulose. One advantage of the above embodiment is that the microcrystalline cellulose can absorb a relatively large amount of active ingredients, while also allowing one or more active ingredients to be effectively released from the pouch during use.

[0260] Cellulose may be synthetic or semi-synthetic cellulose, or may be derived from natural cellulose. It is usually crystalline, such as microcrystalline. Certain specific embodiments may also utilize other forms of carriers, such as fibrous materials or carbohydrates, in addition to or including mcc, including cellulose (including naturally occurring cellulose, such as cellulose from algae of the genus Cladophora sp., etc., hemicellulose, cellulose with different crystallineities and structures (e.g., including solid fibers, in addition to or including different structures including fibers, etc. in various structures such as woven-like structures and / or other structures), dextran, agarose, agar, pectin, alginate, xanthan gum, chitosan, starch (including potato starch, shoti starch), etc., or mixtures thereof.

[0261] Microcrystalline cellulose can be selected from the group consisting of AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20, and EMOCEL® grades 50M and 90M, as well as mixtures thereof.

[0262] In one embodiment of the present invention, the cellulose is provided in the form of particles having an average particle size between 1 and 1000 micrometers, for example between 10 and 250 micrometers, for example between 15 and 200 micrometers, for example between 20 and 150 micrometers, for example between 50 and 100 micrometers, for example about 75 micrometers.

[0263] In one embodiment of the present invention, the cellulose is 0.65 to 1.5 m 2 Between / g, for example, 0.75~1.25m 2 Between / g, for example, 0.85~1.15m 2 Between / g, for example, 0.9~1.1m 2 Between / g, for example, about 0.95m 2 / g, about 1.00 m 2 / g, or for example about 1.05 m 2 / g has a specific surface area of

[0264] In one embodiment of the present invention, the cellulose is 0.1 to 1.0 grams per cubic centimeter (g / cm 3 ), for example 0.25 to 0.5 grams per cubic centimeter, for example 0.26 to 0.31 grams per cubic centimeter, or for example 0.28 to 0.33 grams per cubic centimeter has a bulk density of

[0265] In the context of the above embodiment, it should preferably be understood that the bulk density of the cellulose is the bulk density at about 25 °C.

[0266] In one embodiment of the present invention, the cellulose is 0.003 cm 3 / g to 0.60 cm 3 / g, for example between 0.01 and 0.3 cm 3 / g has a porosity characterized by an average pore volume between

[0267] In one embodiment of the present invention, the cellulose has a water content of less than about 5% by mass, for example between 2 and 5% by mass, for example between 3 and 5% by mass, for example about 4% by mass.

[0268] Examples of various types of cellulose that can be used include microcrystalline cellulose (MCC); carboxymethyl cellulose (CMC), such as sodium carboxymethyl cellulose; hydroxypropyl methyl cellulose (HPMC); methyl cellulose; ethyl cellulose (EC); methyl ethyl cellulose (MEC); hydroxyethyl cellulose (HEC); hydroxyethyl methyl cellulose (HEMC); and any combination thereof.

[0269] In one embodiment of the present invention, the cellulose has an average fiber size of less than 200 micrometers, for example between 75 and 125 micrometers, or for example less than 75 micrometers. In one embodiment of the present invention, the cellulose contains pores, and the pores have an average pore diameter between about 3 nanometers and about 300 nanometers, for example between 10 nanometers and 200 nanometers, or for example between 20 nanometers and 100 nanometers.

[0270] In one embodiment of the present invention, the cellulose is derived from a natural source, such as wood pulp. Other examples of natural sources of cellulose include sugar beet fiber, cotton fiber, rice bran fiber, citrus pulp fiber, grass fiber, willow fiber, poplar fiber, bamboo fiber, and combinations thereof, or combinations thereof, including wood pulp. In some embodiments, the cellulose can be chemically treated, for example, by CMC, MPMC, HPC, MCC, and / or other methods. Alternatively, the cellulose may be semi-synthetic or synthetic cellulose.

[0271] According to various embodiments of the present invention, sugar alcohols may be included in the pouch formulation as a matrix composition or as part thereof, as a water-retaining agent, or as a sweetener. Suitable sugar alcohols include those selected from the group consisting of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrolyzed starch, isomalt, or any combination thereof.

[0272] In one embodiment of the present invention, the pouch formulation contains a high-intensity sweetener. Preferred high-intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, stevioside, etc., either alone or in combination. In one embodiment of the present invention, the pouch formulation contains a bulk sweetener containing carbohydrates and / or sugar-free components.

[0273] In one embodiment of the present invention, the pouch contains a bulk sweetener in an amount of 5 to about 95% by mass of the pouch, more typically constituting 20 to about 80% by mass of the pouch, and more generally 30 to 60% by mass of the pouch. The bulk sweetener can also function as both a sweetener and a water-retaining agent.

[0274] Carbohydrate sweeteners generally include, but are not limited to, sugar-containing components commonly known in the field of pouch formulations, such as sucrose, dextrose, maltose, saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, glucose syrup, hydrogenated glucose syrup, etc., either alone or in combination. These carbohydrate sweeteners may also be included as water-retaining agents.

[0275] Sweeteners can be used in combination with sugar-free sweeteners. Generally, sugar-free sweeteners contain components that have sweet properties but do not contain commonly known sugars, and include, but are not limited to, sugar alcohols such as sorbitol, mannitol, xylitol, hydrolyzed starch, maltitol, isomalt, erythritol, lactitol, etc., either alone or in combination. These sugar-free sweeteners may also be included as water-retaining agents.

[0276] In various embodiments of the present invention, the matrix composition includes a release control composition for controlling the release of the matrix composition and / or a portion thereof, particularly one or more active ingredients.

[0277] The release-controlled composition may be selected from the group consisting of metal stearates, modified calcium carbonate, hydrogenated vegetable oils, partially hydrogenated vegetable oils, polyethylene glycol, polyoxyethylene monostearate, animal fats, silicates, silicon dioxide, talc, magnesium stearate, calcium stearate, fumed silica, powdered hydrogenated cottonseed oil, hydrogenated vegetable oils, hydrogenated soybean oil, and mixtures thereof, according to various embodiments. In particular, metal stearates such as magnesium stearate may be advantageous.

[0278] The release-controlled composition can be added to the matrix composition in various ways. For example, the release-controlled composition can be added by the complete powder mixture during the last few minutes of final mixing. Alternatively, the release-controlled composition can be added after the granulation step in the granulation premix. Furthermore, since the release-controlled composition can be added only as a fraction of the matrix composition, two different release profiles of the active ingredient can be achieved. Two or more further fractions of the matrix composition may contain different amounts of the release-controlled composition, if any, to provide a more complex and controlled release profile of the active ingredient.

[0279] Release-controlled compositions, such as magnesium stearate, may have a sealing effect and can be used to control the release of one or more active ingredients and the solubility of the matrix composition. According to one embodiment of the present invention, the pouch comprises polyvinylpyrrolidone (PVP). One advantage of the above embodiment may be that a more uniform composition can be obtained. In some embodiments of the present invention, the oral composition comprises non-direct compressible (non-DC) sugar alcohol particles. In this context, non-DC sugar alcohol particles are understood and defined by those skilled in the art with reference to their typical commercially available grades. In one embodiment of the present invention, the non-DC sugar alcohol particles are not granulated. Thus, the non-DC sugar alcohol particles are provided as ungranulated particles.

[0280] These are typically available in a non-DC form of a suitable sugar alcohol as particles that have not been pretreated by granulation with other sugar alcohols or binders for the purpose of obtaining so-called direct compressible particles (DC) based on sugar alcohol particles that are not themselves suitable for direct compression. Such non-DC particles of sugar alcohol typically consist of sugar alcohol. Thus, non-DC sugar alcohol particles can typically be particles consisting of sugar alcohol that are non-direct compressible in their pure form. Examples of sugar alcohols that are non-direct compressible when provided as particles consisting of the desired sugar alcohol include erythritol, xylitol, maltitol, mannitol, lactitol, isomalt, etc. Thus, preferred non-DC grades of sugar alcohol can include pure sugar alcohol particles.

[0281] In one embodiment of the present invention, an oral composition comprises at least two modules, one or more sugar alcohol particles are tableted in a first module and combined with a second oral composition tableted in a second module, and the second module has a different composition from the first module.

[0282] In one embodiment of the present invention, an oral composition comprises at least two modules, one or more sugar alcohol particles are tableted in a first module and combined with a second oral composition tableted in a second module, and the first module comprises the ion exchange composition.

[0283] In this context, it should also be understood that "being tableted in" allows for other components that are part of the tableted module. Thus, the module can include additional components other than one or more sugar alcohol particles.

[0284] In one embodiment of the present invention, the oral composition comprises at least two modules, one or more sugar alcohol particles comprising directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, which are tabletized in the first module and combined in the second module with a tabletized second oral composition, the second module having a different composition from the first module.

[0285] In one embodiment of the present invention, the oral composition comprises at least two modules, one or more sugar alcohol particles comprising directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, which are tabletized in the first module and combined with a tabletized second oral composition in the second module, the first module comprising the ion exchange composition.

[0286] One advantage of the above embodiment is that the second module may have higher mechanical strength due to a different composition containing, for example, a very large amount of directly compressible components, such as DC sugar alcohols.

[0287] A further advantage of the above embodiment is that the second module may have a higher packing capacity for the active ingredient, for example, by partly due to a higher mechanical strength that can be achieved with a large amount of directly compressible components, such as DC sugar alcohols.

[0288] Accordingly, in the above embodiments, the oral composition is tableted into a first module, and the tablet further comprises a second oral composition tableted into a second module. The first module may be tableted before the second module, or vice versa. In some embodiments, the tablet may comprise one or more further modules.

[0289] In one embodiment of the present invention, the oral composition comprises at least two modules. A tablet comprising two or more modules has a module size in which each module is comparable to the volume of a complete tablet. In this context, "comparable" means that the modules are not understood as small particles, and the modules are at least 1 / 20 of the volume of a complete tablet, preferably larger than 1 / 10 of the volume of a complete tablet.

[0290] In this context, the term "module" is intended to mean multiple particles that, when compressed together, form a module of collected particles.

[0291] In one embodiment of the present invention, the oral composition comprises a plurality of oral composition modules. In this context, the application of, for example, two modules is particularly advantageous because the use of non-DC sugar alcohols can result in a more brittle tablet or at least module that is essentially a non-DC sugar alcohol. In other words, the non-DC sugar alcohol may be primarily present in one module, thereby optimizing the desired salivary secretion and sensory experience from the module and the tablet itself, while another module may serve as a support to ensure that the desired stability and crushability of the complete tablet are obtained.

[0292] According to one embodiment of the present invention, the tablet has two modules. Optionally, a coating can be applied around the two modules to form the final tablet.

[0293] While the advantages of the two modules used are described above, it should also be noted that this effect can also be obtained when applying layers with very different properties. Such applications may include, for example, the use of a gum module and a non-gum module, where the non-gum module contains non-DC sugar alcohol particles. In this way, the non-gum layer can release beneficial non-DC sugar alcohols, and the gum layer stabilizes both tablets as described above, but can also interact with the non-DC sugar alcohols, especially during the initial release, to establish a very pleasant and favorable initial chewing phase. This includes experiencing an increase in saliva and moisture.

[0294] In one embodiment of the present invention, the oral composition comprises at least two modules, wherein one or more sugar alcohol particles are tableted in the first module and combined with a second oral composition tableted in the second module, the second module comprising a gum base.

[0295] In one embodiment of the present invention, the oral composition comprises at least two modules, one or more sugar alcohol particles comprising directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, which are tableted in the first module and combined with a tableted second oral composition in the second module, the second module comprising a gum base.

[0296] In one embodiment of the present invention, the oral composition is tabletized into a first module and combined with a second oral composition tabletized into a second module, the second module not containing non-DC sugar alcohol particles.

[0297] In one embodiment, the second oral composition contains a large amount of DC sugar alcohol, for example, a larger amount than that of the first oral composition. For example, the second oral composition may contain at least 30% by mass of DC sugar alcohol, for example, at least 50% by mass of DC sugar alcohol, or for example, at least 70% by mass of sugar alcohol. In an exemplary embodiment, the second oral composition may contain sugar alcohol between 50% and 99.9% by mass, for example, sugar alcohol between 70% and 99% by mass. The amount of DC sugar alcohol may depend on the type and amount of active ingredient applied to the tablet.

[0298] In one embodiment of the present invention, the oral composition is tabletized into a first module and combined with a second oral composition tabletized into a second module, the second module being an orally disintegrating tablet (ODT).

[0299] In one embodiment of the present invention, the tablet contains the non-DC sugar alcohol particles in an amount of at least 10% by mass of the tablet. In one embodiment of the present invention, the tablet contains the non-DC sugar alcohol particles in an amount of at least 20% by mass of the tablet. In one embodiment of the present invention, the tablet contains the non-DC sugar alcohol particles in an amount of at least 30% by mass of the tablet. In one embodiment of the present invention, the first module contains the non-DC sugar alcohol particles in an amount of at least 30% by mass of the first module. In one embodiment of the present invention, the first module contains the non-DC sugar alcohol particles in an amount of at least 40% by mass of the first module.

[0300] In one embodiment of the present invention, the DC sugar alcohol particles include sugar alcohols selected from DC particles of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof. Sorbitol is an example of a sugar alcohol and is considered DC grade when provided as particles consisting of sorbitol, i.e., in its pure form. On the other hand, some other sugar alcohols are considered non-DC grade when provided as particles consisting of specific sugar alcohols. Therefore, for example, such non-DC sugar alcohols are conventionally processed into DC grade sugar alcohols, for example, by granulation with a binder. Examples of commercially grade DC sugar alcohols include, for example, sorbitol particles provided as Neosorb® P 300 DC by Roquette, for example, mannitol particles provided as Pearlitol® 300 DC or Pearlitol 200 SD by Roquette, for example, maltitol provided as SweetPearl® P 300 DC, for example, and xylitol provided as Xylisorb® 200 DC or Xylitab 200 by Dupont.

[0301] In one embodiment of the present invention, the tablet contains the DC sugar alcohol particles in an amount of at least 10% by mass of the tablet. In one embodiment of the present invention, the tablet contains the DC sugar alcohol particles in an amount of at least 20% by mass of the tablet. In one embodiment of the present invention, the tablet contains the DC sugar alcohol particles in an amount of at least 30% by mass of the tablet. According to one embodiment of the present invention, the oral composition contains the DC sugar alcohol particles in an amount of at least 10% by mass. According to one embodiment of the present invention, the first module contains the DC sugar alcohol particles in an amount of at least 10% by mass of the first module. According to one embodiment of the present invention, the first module contains the DC sugar alcohol particles in an amount of at least 10% by mass of the first module. According to one embodiment of the present invention, the first module contains the DC sugar alcohol particles in an amount of at least 30% by mass of the first module. In one embodiment of the present invention, the second module contains the DC sugar alcohol particles in an amount of at least 30% by mass of the second module. In one embodiment of the present invention, the second module contains the DC sugar alcohol particles in an amount of at least 50% by mass of the second module. In one embodiment of the present invention, the second module contains DC sugar alcohol particles in an amount of at least 70% by mass of the second module. In another embodiment of the present invention, the second module contains DC sugar alcohol particles in an amount of at least 90% by mass of the second module. In another embodiment of the present invention, the DC sugar alcohol particles in the second module are selected from DC particles of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof.

[0302] In one embodiment of the present invention, the tablet contains one or more binders other than the binder that forms part of the DC sugar alcohol particles, in an amount of 0.1 to 6% by mass of the tablet.

[0303] Suitable binders include gum arabic, methylcellulose, liquid glucose, tragacanth, ethylcellulose, gelatin, hydroxypropylmethylcellulose (HPMC), starch, hydroxypropylcellulose (HPC), pregelatinized starch, sodium carboxymethylcellulose (NaCMC), alginic acid, polyvinylpyrrolidone (PVP), maltodextrin (MD); cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polymethacrylate, copovidone, or microcrystalline cellulose (MCC), either alone or in combination.

[0304] According to one embodiment of the present invention, the one or more binders include one or more cellulose binders. In one embodiment of the present invention, the one or more binders include microcrystalline cellulose (MCC), hydroxypropylcellulose (HPC), or hydroxypropylmethylcellulose (HPMC), or any combination thereof. In one embodiment of the present invention, the oral composition contains hydroxypropylcellulose (HPC) binder in an amount of 0.1 to 6% by mass of the tablet, such as 0.1 to 5% by mass of the tablet, such as 0.1 to 4% by mass, such as 0.1 to 3% by mass, such as 0.1 to 2% by mass. HPC can be applied as a particularly attractive binder. Therefore, when this binder is used together with a non-DC sugar alcohol such as erythritol, it exhibits an advantageous sensory experience when compared with other well-known binders. In particular, users of HPC less than 4% by mass of the tablet, such as 0.1 to 3% by mass of the tablet, such as 0.1 to 2% by mass, are advantageous.

[0305] In one embodiment of the present invention, the non-DC sugar alcohol particles are ungranulated particles, and the one or more binders are present as separate components in the tablet.

[0306] In one embodiment of the present invention, the tablet has a mass ratio between the non-DC sugar alcohol particles and the DC sugar alcohol particles that is between 0.2 and 1.2. In one embodiment of the present invention, the tablet has a mass ratio between the non-DC sugar alcohol particles and the DC sugar alcohol particles that is between 0.3 and 1.0. In one embodiment of the present invention, the tablet has a mass ratio between the non-DC sugar alcohol particles and the DC sugar alcohol particles that is between 0.3 and 0.7.

[0307] The mass ratio between non-DC sugar alcohol particles and DC sugar alcohol particles is important according to one embodiment of the present invention, in that a relatively large amount of non-DC sugar alcohol particles must be present to obtain the mouthfeel and flavor obtained through this invention. However, this flavor and mouthfeel are also present in the DC sugar alcohol particles. An example of such DC sugar alcohol particles is DC-grade xylitol, which, together with non-DC sugar alcohol particles, can provide a mouthfeel that is unique and highly appealing to test panels.

[0308] In one embodiment of the present invention, a tablet comprises particles containing a gum base and is designed to be chewed to form a cohesive residue containing a water-insoluble component. In another embodiment of the present invention, an oral composition comprises particles containing a gum base, the gum base comprising at least 5% by mass of an elastomer.

[0309] As described below, unless otherwise stated, the raw materials refer to the mixed particles that are compressed into tablets according to embodiments of the present invention.

[0310] The following description is an overview of how the tablets of the present invention are manufactured, and further details may be added to the composition of the present invention.

[0311] Typically, the tablet manufacturing process of the present invention can be carried out in a single tablet press, such as a rotary tablet press. However, this may be advantageous in some situations where separate tablet presses are applied. Preferably, the upper punch is a convex body that produces a concave shape on the upper surface of the pressed tablet. Naturally, it should be noted that the shape of the punch may vary depending on the desired tablet shape. In some embodiments of the present invention, the tablets are pressed with a force of 20 to 50 kN.

[0312] In further embodiments, sucrose fatty acid esters can also be used to enhance the release of sweeteners, such as so-called very strong sweeteners, including saccharin, cyclamate, aspartame, thaumatin, dihydrochalcone, stevioside, glycyrrhizin, or salts or compounds thereof.

[0313] When a gum base is included in the formulation, sugar alcohols typically constitute about 5 to about 95% by mass of the tablet, more typically about 20 to about 80% by mass of the tablet, for example, 30 to 70% by mass or 30 to 60% by mass.

[0314] In such embodiments of the present invention, the tablets further include, in addition to the sugar alcohols already described, materials selected from the group consisting of bulk sweeteners, drying binders, tableting aids, anti-caking agents, emulsifiers, antioxidants, accelerators, absorption enhancers, buffers, high-intensity sweeteners, softeners, pigments, or any combination thereof.

[0315] High-intensity artificial sweeteners can also be used by using the above sweeteners alone or in combination. Preferred high-intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, stevioside (a naturally strong sweetener), etc., alone or in combination. To provide a longer-lasting sweetness, encapsulation of at least a portion of the artificial sweetener, or otherwise control of its release, is desirable. Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, preservation, encapsulation into yeast cells, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of sweeteners can also be provided using other tablet components such as resinous compounds.

[0316] The level of artificial sweetener use varies considerably and depends on factors such as the strength of the sweetener, release rate, desired sweetness of the product, and cost considerations. Therefore, the effective concentration of the artificial sweetener can vary from about 0.001% to about 8% by mass (preferably about 0.02% to about 8% by mass). If a carrier is used for encapsulation, the level of encapsulated sweetener use increases proportionally. Combinations of carbohydrate and / or non-carbohydrate sweeteners can be used in tablet formulations.

[0317] The tablets according to the present invention may optionally contain one or more fillers / texturizers, including, for example, magnesium carbonate and calcium carbonate, sodium sulfate, crushed limestone, silicate compounds such as magnesium silicate and aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate, cellulose polymers, and combinations thereof.

[0318] In some embodiments of the present invention, the oral composition is contained in a liquid, such as a carrier liquid, such as an oral spray.

[0319] As used herein, the term “carrier liquid” is intended to refer to a carrier liquid suitable for use in oral sprays. One important limitation in embodiments of the present invention is that the carrier liquid can typically consist of one or more pharmaceutically acceptable additives, since they are pharmaceutically acceptable.

[0320] According to an advantageous embodiment of the present invention, the carrier liquid is selected from the group consisting of water, alcohols such as ethanol, propylene glycol, polyethylene glycol such as PEG 400, glycerol, and other similar alcohols; and mixtures or combinations thereof.

[0321] According to one embodiment of the present invention, if the carrier liquid contains water, it contains at least one component selected from the group consisting of alcohols, such as ethanol, propylene glycol, polyethylene glycol, such as PEG 400, glycerol, and other similar alcohols, as well as mixtures or combinations thereof.

[0322] According to an advantageous embodiment of the present invention, the carrier liquid comprises a substance selected from the group consisting of alcohols, such as ethanol, propylene glycol, polyethylene glycol, such as PEG 400, glycerol, and other similar alcohols, as well as mixtures or combinations thereof.

[0323] According to one embodiment of the present invention, the carrier liquid includes water. The water may be present, for example, in an amount of 0.1 to 99.9 mass percent of the liquid active ingredient composition.

[0324] According to one embodiment of the present invention, the carrier liquid contains ethanol. Ethanol may be present, for example, in an amount of 0.1 to 99.9 mass percent of the liquid active ingredient composition.

[0325] According to one embodiment of the present invention, the carrier liquid contains propylene glycol. The propylene glycol may be present, for example, in an amount of 0.1 to 99.9 mass percent of the liquid active ingredient composition.

[0326] According to one embodiment of the present invention, the carrier liquid contains glycerol. Glycerol may be present, for example, in an amount of 0.1 to 99.9 mass percent of the liquid active ingredient composition.

[0327] According to one embodiment of the present invention, the carrier liquid contains polyethylene glycol such as PEG-400. The polyethylene glycol such as PEG-400 may be present, for example, in an amount of 0.1 to 99.9 mass percent of the liquid active ingredient composition.

[0328] According to an advantageous embodiment of the present invention, the liquid composition is for oral mucosal administration.

[0329] According to one embodiment of the present invention, the desired dosage can be influenced by controlling the particle size distribution of the generated aerosol, for example, the average diameter of the aerosol.

[0330] According to an advantageous embodiment of the present invention, the liquid composition further comprises a sweetener, such as an artificial sweetener, such as sucralose.

[0331] According to one embodiment of the present invention, the sweetener is included in an amount of a liquid active ingredient composition between 0.1 and 5 mass percent, for example, a liquid active ingredient composition between 0.2 and 3 mass percent, for example, a liquid active ingredient composition between 0.5 and 2 mass percent. [Examples]

[0332] The following non-limiting examples illustrate different variations of the present invention.

[0333] (Example 1) Oral analgesic compositions containing or not containing nicotine

[0334] [Table 1]

[0335] Examples of specific ingredients used in the table are as follows: Nicotine can be, for example, nicotine bicarbonate dihydrate (NBT). Oicariptor can be, for example, Oicariptor Nat, which is available from Symrise. Oleic acid can be, for example, NF-LQ-(MH), which is available from Croda Inc. The camphor could be, for example, Camphor USP, which is available from Rochem International Inc. WS-12 could be, for example, Symcool WS-12, which is available from Symrise. Mannitol can be, for example, Pearlitol 200 SD, which is available from Roquette. Crospovidone can be, for example, Kollidon CL-F, which is available from BASF. The thyroid can be, for example, thyroid 244 FP or thyroid XDP 3050, which are available from Grace GmbH. Microcrystalline cellulose can be, for example, Avicel PH-102.

[0336] (Example 1A) Oral analgesic composition containing nicotine

[0337] [Table 2]

[0338] Examples of specific ingredients used in the table are as follows: Nicotine can be, for example, nicotine bicarbonate dihydrate (NBT). Carvacrol is available, for example, from Sigma Aldrich. Poloxamer can be, for example, Kolliphor P407, which is available from BASF. Mannitol can be, for example, Pearlitol 200 SD, which is available from Roquette. Crospovidone can be, for example, Kollidon CL-F, which is available from BASF. The thyroid can be, for example, thyroid 244 FP or thyroid XDP 3050, which are available from Grace GmbH.

[0339] (Example 1B) Nicotine-free oral analgesic composition

[0340] [Table 3]

[0341] Examples of specific ingredients used in the table are as follows: Carvacrol is available, for example, from Sigma Aldrich. Poloxamer can be, for example, Kolliphor P407, which is available from BASF. Mannitol can be, for example, Pearlitol 200 SD, which is available from Roquette. Crospovidone can be, for example, Kollidon CL-F, which is available from BASF. The thyroid can be, for example, thyroid 244 FP or thyroid XDP 3050, which are available from Grace GmbH.

[0342] (Example 1C) Oral analgesic composition containing nicotine

[0343] [Table 4]

[0344] Examples of specific ingredients used in the table are as follows: Cremophor® RH 40 is a polyethoxylated hydrogenated castor oil available from BASF. Nicotine can be, for example, nicotine bicarbonate dihydrate (NBT). The camphor could be, for example, Camphor USP, which is available from Rochem International Inc. Mannitol can be, for example, Pearlitol 200 SD, which is available from Roquette. Crospovidone can be, for example, Kollidon CL-F, which is available from BASF. The thyroid can be, for example, thyroid 244 FP or thyroid XDP 3050, which are available from Grace GmbH.

[0345] (Example 1D) Nicotine-free oral analgesic composition

[0346] [Table 5]

[0347] Examples of specific ingredients used in the table are as follows: Cremophor® RH 40 is a polyethoxylated hydrogenated castor oil available from BASF. The camphor could be, for example, Camphor USP, which is available from Rochem International Inc. Mannitol can be, for example, Pearlitol 200 SD, which is available from Roquette. Crospovidone can be, for example, Kollidon CL-F, which is available from BASF. The thyroid can be, for example, thyroid 244 FP or thyroid XDP 3050, which are available from Grace GmbH.

[0348] (Example 2) Fast-dissolving tablets (FDT) containing or not containing nicotine Fast-dissolving tablets (FDT) were prepared based on the compositions of Example 1 and Examples 1A to 1D. The tablets were prepared as follows: The raw materials are weighed from the bag or bucket into a separate weighing container. To formulate using thyroid, premixes are prepared by mixing eucalyptus and thyroid XDP 3050, camphor and thyroid 244 FP, or oleic acid and thyroid 244 FP, respectively, based on the specific formulation. A low-solubility antagonist is first dissolved / suspended in a surfactant or oil to obtain a solution / dispersion to be added to the thyroid.

[0349] Transfer all additives to stainless steel or plastic bottles in the following order, passing them through an 800-micron sieve: • Half the amount of filler / bulk sweetener • All other additives, including the premix, except for nicotine (if present) and magnesium stearate and sodium stearyl fumarate. • Remaining half of filler / bulk sweetener

[0350] These are mixed in a Turbula mixer at 25 RPM for 4-10 minutes. Then, a lubricant, such as magnesium stearate, is transferred to the mixing bottle through an 800-micron sieve, and lubrication is performed by further mixing at 25 RPM for 1-2 minutes. The filling level of the mixing bottle is maintained between 40% and 70% according to standardized practice. The lubricated powder blend is transferred to the hopper of the tablet forming machine.

[0351] Rapidly disintegrating tablets were manufactured using a laboratory-scale machine, specifically a RIVA Piccola double-layer tablet press. Punch used: 7.00 mm, circular, shallow concave, D-tool. Tablet mass: 100.0 mg.

[0352] The tablet forming machine was operated by adjusting the filling depth and compression force so that the mass and hardness of the tablets met the acceptable standards. Pre-compression force could be included to avoid capping.

[0353] [Table 6]

[0354] The in vivo dissolution time of the rapidly disintegrating tablets was less than 30 seconds. The rapidly disintegrating tablets according to the present invention may contain coloring agents. According to the present invention, one or more antagonists are not considered flavoring agents that mask flavors and work in a different manner than flavoring agents that mask flavors by interacting with specific receptors and / or ion channels. According to one embodiment of the present invention, the rapidly disintegrating tablets may contain FD&C type dyes and coloring agents and bleaching agents such as leiks, fruit and vegetable extracts, titanium dioxide, and combinations thereof.

[0355] (Example 3) Preparation of test samples The sample was prepared based on the tablets from Example 2.

[0356] Tablets with nicotine content as in (25-01) and (25-02) were evaluated by a sensory panel and used as a standard for sublingual, oral, and pharyngeal nicotine stimulation. These samples were applied under test conditions with a mass of 100 mg, equivalent to the mass of the tablets in Example 2.

[0357] In addition, nicotine-free tablets such as (34-06), (34-04), (34-02), and (25-07) were combined with nicotine tablets such as (25-01) and (25-02) in various configurations.

[0358] In some configurations, one of each of these nicotine-free tablets was combined with one of the nicotine tablets to obtain samples of nicotine tablets and single antagonist tablets for evaluation by sensory panels of nicotine stimulation sublingually, orally, and pharynx.

[0359] In several other configurations, two of each of these nicotine-free tablets were combined with one nicotine tablet to obtain samples of nicotine tablets and two antagonist tablets for evaluation by sensory panels of nicotine stimulation sublingually, orally, and pharynx.

[0360] In some further configurations, three of each of these nicotine-free tablets were combined with one nicotine tablet to obtain samples of nicotine tablets and three antagonist tablets for evaluation by sensory panels of nicotine stimulation sublingually, orally, and pharynx.

[0361] Various fractions of the antagonist tablets were applied in combination with one of the nicotine tablets in the various configurations outlined above for evaluation by sensory panels of nicotine stimulation sublingually, orally, and pharynx.

[0362] For example, in one sample, one nicotine tablet (25-01) was combined with a fraction of an antagonist tablet (25-07) at a 0.5x ratio to obtain a total sample of 150 mg.

[0363] In another sample, one nicotine tablet (25-01) was combined with a fraction of an antagonist tablet (34-06) at a 0.1x dilution to obtain a total sample of 110 mg.

[0364] In yet another sample, one nicotine tablet (25-01) was combined with both a fraction of a 0.5x antagonist tablet (25-07) and a fraction of a 0.1x antagonist tablet (34-06) to obtain a total sample of 160 mg.

[0365] Furthermore, one nicotine tablet (25-01) was combined with, for example, the fractions of a 0.5x antagonist tablet (25-07), a 0.1x antagonist tablet (34-06), and a 0.1x antagonist tablet (34-02) to obtain a total sample of 170 mg.

[0366] (Example 4) Test sample The sample was prepared according to the procedure of Example 3.

[0367] [Table 7]

[0368] (Example 5) Test samples containing one antagonist at different levels The sample was prepared according to the procedure of Example 3.

[0369] [Table 8]

[0370] (Example 6) Test sample containing two antagonists at different levels The sample was prepared according to the procedure of Example 3.

[0371] [Table 9]

[0372] (Example 7) Test sample containing three antagonists at different levels The sample was prepared according to the procedure of Example 3.

[0373] [Table 10]

[0374] (Example 8) Test samples containing one antagonist and three antagonists in the same total amount. Samples 7 and 8 were prepared in the same manner as in Example 3, except that the total antagonist content in these samples was adjusted to match the content of each sample containing only one single antagonist (Samples 3, 5, and 6). Samples 3, 5, and 6 had total antagonist masses of 1.0 mg, 0.2 mg, and 1.0 mg, respectively. The three antagonists were applied at the same balanced levels as in Samples 7 and 8. A total of four samples were provided with the total level of three antagonists compared to the level of a single antagonist. These samples were numbered Samples 41 to 44.

[0375] [Table 11]

[0376] (Example 8A) Test sample containing tablets of the same size Samples 3-44 were prepared in the same manner as in Example 3. However, instead of using a 100 mg nicotine tablet in combination with the antagonist tablet fraction to obtain a total amount of more than 100 mg for each sample, each sample 3-44 was contained in a single 100 mg tablet with the same antagonist ratio and amount, as well as the same amount of nicotine as samples 3-44. These samples were numbered samples 45-78.

[0377] (Example 9) Test Procedure The samples prepared in the above-described examples were tested according to a specific procedure for the purpose of standardization.

[0378] The sample was moistened by placing it under the tongue and gently moving the tongue from side to side (60 movements / minute) until the sample dissolved. Before placing the sample under the tongue, the mouth was moistened by swallowing excess saliva and then gently moving the tongue throughout the mouth. Saliva was not swallowed for 60 seconds while the sample was placed under the tongue. Nicotine-derived irritation (e.g., nicotine burning sensation in the mouth or gastric hiccups) and the perception of the antagonist were evaluated every 30 seconds on a quantified scale ranging from 0 to 5.

[0379] The study setup consisted of a panel of eight subjects. Each subject was a healthy individual who met objective criteria according to specified requirements. Sensory analysis was performed according to ISO 4121-2003 under test conditions in accordance with ISO 8589. The results are the average of the results of the eight individuals. Each sample was subjected to a triple rating for each of the eight subjects, yielding a total of 24 measurements for each sample.

[0380] (Example 10) Setting up sensory evaluation tests Participants rated their responses on a scale of 0 to 5, where "0" represented "no recognition of the parameter" and "5" represented "highest level of recognition of the parameter."

[0381] The scale was applied as follows: 0 = No stimulation 1 = Very weak stimulus 2 = weak stimulus 3 = Moderate stimulation 4 = Strong stimulation 5 = The worst possible stimulation imaginable

[0382] Four different parameters were tested on the test panel:

[0383] [Table 12]

[0384] "Antagonist Perception" - The overall impression of the sample under test regarding the antagonist. For example, a very weak antagonist perception would result in a very low rating, while a highly unpleasant antagonist perception would result in a very high rating.

[0385] "Burning Sensation" - The overall impression of nicotine-derived irritation from the composition being tested. For example, if no burning sensation was experienced under the tongue, it received a low rating, while if a significant irritation (burning sensation) was experienced, it received a high rating.

[0386] (Example 11) Sensory evaluation test results Overall, the studies revealed that combinations of two or more antagonists produced a favorable effect on nicotine stimulation (burning sensation). Referring to the figures, some reduction in nicotine stimulation was experienced with the use of a single antagonist (e.g., Figures 2a and 2b), while a more significant effect was observed with two antagonists (e.g., Figure 4a), and an even more significant effect with three antagonists (e.g., Figure 3a).

[0387] Since the vast majority of antagonists have their own flavors, including eucalyptol and camphor, which can trigger the perception of an antagonist, including strong unpleasantness at high concentrations, it was most surprising to the inventors that combinations of antagonists could reduce nicotine stimulation to a degree that was observed without triggering a stronger perception of the antagonist. In some cases, the perception of the antagonist was even more significantly reduced compared to samples with reduced nicotine stimulation. This was observed even when the total amount of antagonists was higher than in tests using only a single antagonist.

[0388] The inventors predicted that adding a larger amount of antagonist (samples 7-8 and 17-40) would significantly increase the perception of the antagonist compared to samples with only a single antagonist. This was observed with two antagonists, but surprisingly, it was even more pronounced with three antagonists. Even more surprising was the simultaneous and significant decrease in nicotine stimulation (burning sensation) levels. While not bound by theory, it is clear that the combination of three antagonists works synergistically with nicotine to reduce nicotine stimulation (burning sensation).

[0389] Specifically, it was found that combinations of at least three antagonists (Figure 3a) yielded the best results in reducing nicotine stimulation. However, even with two antagonists, nicotine stimulation was reduced according to the present invention, although to a lower degree than with three antagonists (Figure 4a). While not bound by theory, it is clear that the combination of two antagonists according to the present invention also works synergistically with nicotine to reduce nicotine stimulation (burning sensation).

[0390] Furthermore, the inventors predicted that by adding balanced levels of antagonists as in Example 8 (samples 41-44), the perception of the antagonist would be comparable to that of samples containing only a single antagonist. However, it was surprising that even with balanced levels of antagonists, the level of nicotine stimulation (burning sensation) decreased significantly. While not bound by theory, it is clear that even in this setting, the combination of antagonists works synergistically with nicotine to reduce nicotine stimulation (burning sensation).

[0391] Specifically, the combination of at least three antagonists used in Example 8 (samples 41-44) was found to yield the best results in reducing nicotine stimulation. However, even with two antagonists, nicotine stimulation was reduced according to the present invention, although to a lower degree than with three antagonists.

[0392] The same results were observed in samples 45-78 prepared according to Example 8A.

Claims

1. An oral analgesic composition suitable for alleviating perceived nicotine stimulation by inhibiting or blocking nicotine-activating receptors or ion channels in the gastrointestinal tract, including the oral cavity, One or more nicotine sources selected from the group consisting of nicotine bicarbonate, nicotine polarilex resin, and free base nicotine; One or more buffering agents selected from the group consisting of tris(hydroxymethyl)aminomethane buffering agents, phosphate buffering agents, and carbon dioxide buffering agents; and An amount effective in inhibiting or blocking nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential (TRP) ion channels, A first antagonist comprising camphor or one or more camphor-like compounds, wherein one or more camphor-like compounds are selected from the group consisting of borneol, isoborneol, bornyl acetate, isobornyl acetate, monobornyl succinate, monoisobornyl succinate, monobornyl formate, and monoisobornyl formate. The second antagonist, including Oikariptor, and A third antagonist containing (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-12) It includes three antagonists selected from the group consisting of, An oral analgesic composition comprising three antagonists and one or more nicotine sources in a mass ratio of 1:4 to 4:

1.

2. The oral analgesic composition according to claim 1, wherein the three antagonists comprise a first antagonist and a second antagonist in a mass ratio of 1:20 to 1:1, or the three antagonists comprise a first antagonist and a third antagonist in a mass ratio of 1:20 to 1:1, or the three antagonists comprise a second antagonist and a third antagonist in a mass ratio of 1:4 to 4:

1.

3. The oral analgesic composition according to claim 1 or 2, wherein the three antagonists comprise a first antagonist, a second antagonist, and a third antagonist in a mass ratio of 1:20:20 to 1:1:

1.

4. The oral analgesic composition according to any one of claims 1 to 3, wherein the three antagonists are present in a total amount effective to reduce the perceived peak nicotine stimulation in the pharynx by more than 30% compared to the presence of just one of the same three antagonists in the same total amount.

5. The oral analgesic composition according to any one of claims 1 to 4, wherein the three antagonists are present in a total amount effective to reduce the peak perceived nicotine stimulation in the oral cavity and the peak perception of the antagonist by more than 30% compared to the presence of just one of the same three antagonists in the same total amount; and / or present in a total amount effective to reduce the peak perceived nicotine stimulation during sublingual administration and the peak perception of the antagonist by more than 30% compared to the presence of just one of the same three antagonists in the same total amount; and / or present in a total amount effective to reduce the peak perceived nicotine stimulation in the pharynx and the peak perception of the antagonist by more than 30% compared to the presence of just one of the same three antagonists in the same total amount.

6. The oral analgesic composition according to any one of claims 1 to 5, wherein three antagonists inhibit or block nicotinic agonist activation of nicotinic acetylcholine receptors (nAChRs) and / or transient receptor potential vanilloid type 1 (TRPV1) ion channels and / or transient receptor potential ankyrin 1 (TRPA1) ion channels and / or transient receptor potential melastatin 8 (TRPM8) ion channels.

7. An oral analgesic composition according to any one of claims 1 to 6, wherein nicotine is present in an amount of 0.5 to 8.0 mg.

8. An oral analgesic composition according to any one of claims 1 to 7, comprising three antagonists and nicotine in a mass ratio of 1:3 to 3:

1.

9. The oral analgesic composition according to any one of claims 1 to 8, wherein three antagonists are present in a total amount effective to reduce the perceived peak nicotine stimulation in the oral cavity by more than 20% without causing a higher peak perception of the antagonist compared to the presence of just one of the same single antagonists in the same individual amounts.

10. The oral analgesic composition according to any one of claims 1 to 9, wherein three antagonists are present in a total amount effective to reduce the perceived peak nicotine stimulation in the pharynx by more than 20% without causing a higher peak antagonist sensation compared to the presence of just one of the same single antagonists in the same individual amounts.

11. The oral analgesic composition according to any one of claims 1 to 10, wherein a buffering agent is present in an amount of 1.0 to 5.0% by mass of the composition.

12. An oral analgesic composition according to any one of claims 1 to 11, comprising one or more sugar alcohol particles in an amount of at least 40% by mass of the composition.

13. An oral analgesic composition according to any one of claims 1 to 12, further comprising a disintegrant in an amount of 1 to 10% by mass of the composition.

14. An oral analgesic composition according to any one of claims 1 to 13, contained in a tablet.

15. An oral analgesic composition according to any one of claims 1 to 14, which is an orally disintegrating tablet, a chewable tablet, or a lozenge, or contained in a sachet, film strip, liquid formulation, oral spray, or pouch.

16. An oral analgesic composition according to any one of claims 1 to 15, wherein the composition is chewing gum.

17. The oral analgesic composition according to any one of claims 1 to 16, wherein the composition is compressed chewing gum.

18. The oral analgesic composition according to any one of claims 1 to 17, wherein the first, second, and third antagonists are combined with a solubilizing agent.

19. An oral analgesic composition according to claims 1 to 18 for use in smoking cessation therapy.

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