RU2782830C2 - Tablet for oral administration for induced saliva formation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to a tablet for oral administration, suitable for active pharmaceutical ingredients, including a set of particles. In this case, the set of particles includes directly compressed (hereinafter – DC) and non-directly compressed (hereinafter – non-DC) particles of sugar alcohol, where non-DC particles provide the tablet with a set of discrete non-DC areas, and where non-DC areas lead to induced saliva formation, when chewing the tablet.

EFFECT: obtaining a tablet for saliva formation.

20 cl, 13 dwg, 17 tbl, 75 ex

Description

The field to which the invention relates

The present invention relates to an oral tablet for induced salivation. In particular, the oral tablet is suitable for the delivery of active pharmaceutical ingredients.

Prerequisites for the creation of the invention

Chewable and lozenges are well known in the art in which a substantial portion of the delivery carrier consists of a sugar alcohol. It is also well known that such delivery vehicles can be used to deliver active ingredients.

The problem with such delivery media is that the user is more and more focused on convenience and enhanced functionality. Such requirements very often contradict what is technically possible.

European Patent Application 0 922 464 A1 discloses a rapidly disintegrating injection molded material such as tablets obtained by conventional tabletting processes. The tablets contain granular erythritol and rapidly disintegrate and dissolve when placed in the mouth or water.

EP 0 922 464 is thus a typical example of one of many reference documents describing the use of granular polyols such as erythritol for compressed tablets.

The aim of the invention is to provide a tablet for oral administration, which is able to stimulate the formation of saliva.

The essence of the invention

The present invention relates to an oral tablet suitable for active pharmaceutical ingredients comprising a particle population wherein the particle population comprises directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, where the non-DC particles provide the tablet with a plurality of discrete non-DC regions, and where the non-DC regions result in induced saliva production upon tablet chewing.

One of the advantages of the invention is the surprisingly strong production of saliva compared to conventional chewable and lozenges. In particular, the plurality of non-DC regions provided in the tablet unexpectedly causes salivary production to be noticeable. Having a combination of non-DC particles and DC particles in the particle population can further contribute to sufficient mechanical strength in combination with tablet stability, tablet disintegration upon chewing, and induced saliva production upon chewing.

One unexpected advantage over the prior art is that saliva production surprisingly persists even after the user has swallowed the majority of the non-DC sugar alcohols. Such maintenance of salivation can be beneficial in relation to many uses of an oral tablet, ranging from mouthfeel, taste, smell, and so on.

In addition, a delivery platform suitable for the active ingredients is provided. Oral tablets may be very suitable as a delivery platform, eg because of the superior saliva production induced by non-DC regions. Alternatively, an oral tablet may be used, for example, as a confectionery tablet without the inclusion of active pharmaceutical ingredients.

It should be noted that in this context, an oral tablet includes a particle population, while a particle population includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles.

In the context of the present invention, non-DC sugar alcohol particles are understood and defined by those skilled in the art with reference to their typical commercial grade.

In an embodiment of the invention, the non-DC sugar alcohol particles were not granulated prior to tabletting.

Thus, the non-DC sugar alcohol particles are in the form of non-granular particles.

They are generally available in the non-DC form of the respective sugar alcohol in particulate form which has not been pre-granulated with other sugar alcohols or binders to form so-called directly compressible particles (DC) based on sugar alcohol particles which are themselves not suitable for direct pressing. Such non-DC sugar alcohol particles can typically be composed of sugar alcohol. Therefore, non-DC sugar alcohol particles can generally be particles composed of sugar alcohol, which in its pure form cannot be directly compressed. Examples of sugar alcohols that cannot be directly compressed when presented as particles composed of the sugar alcohol in question include erythritol, xylitol, maltitol, mannitol, lactitol, isomalt, and the like.

Therefore, preferred non-DC sugar alcohol grades may include pure sugar alcohol particles.

In an embodiment of the invention, the plurality of particles is tableted into the first module and combined with the second plurality of particles, which is tableted into the second module.

Thus, a synergy is provided between the use of non-DC sugar alcohol particles as a disintegration promoter due to lower mechanical strength, and also as a saliva activator in combination with a second module that can provide additional mechanical strength, thereby acting as a module. -carrier. This is particularly advantageous when the second particle population contributes to a pleasant mouthfeel due to the high content of DC sugar alcohols, which also provides mechanical strength to the tablet.

One of the advantages of the above embodiment may be that the second module may have a higher mechanical strength, for example by using a different composition including, for example, a very large amount of directly compressible ingredients such as DC sugar alcohols.

An additional advantage of the above embodiment may be that the second module may have a higher degree of loading, eg active ingredients, due in part to the higher mechanical strength achieved by higher amounts of direct compression ingredients such as DC sugar alcohols.

Thus, in the embodiment described above, said plurality of particles is tableted into a first module, and wherein the tablet further comprises a second plurality of particles which is tabletted into a second module. The first module may be tableted before the second module or vice versa. In some embodiments, the implementation of the tablet may include one or more additional modules.

In an embodiment of the invention, an oral tablet comprises at least two modules. A tablet containing two or more modules will have module dimensions that are each comparable to the volume of the entire tablet. Comparable, in the context of the present invention, means that the modules are not understood as fine particles, and the module must be at least more than 1/20 of the total volume of the tablet, preferably more than 1/10 of the total volume of the tablet.

A module can typically be assembled from a plurality of compressed particles and have a mass that is greater than 0.2 grams and less than 10 grams.

In an embodiment of the invention, a module is defined as a plurality of particles pressed together to form an assembled module of particles.

In an embodiment of the invention, an oral tablet includes a plurality of oral tablet modules. In the context of the present application, for example, two modules are particularly preferred because the use of non-DC sugar alcohols by nature can result in a more brittle tablet, or at least a module containing non-DC sugar alcohols. In other words, non-DC sugar alcohols can be present primarily in one module, thereby optimizing the desired salivation and sensory experience of the module and tablet itself, while the other module can serve as a support to provide the desired stability and abrasion resistance of the entire resulting tablet. .

In an embodiment of the invention, the plurality of modules are plate-like layers. The term “lamellar” layer is a simple but very accurate definition for one skilled in the art of how a module can be represented, since such a layer is a standard structure produced by conventional tabletting procedures.

According to an embodiment of the invention, the tablet has two modules. Optionally, a coating may be applied around the two modules to form the final tablet.

The advantage of using two modules is described above, but it should also be noted that this effect can also be obtained by applying layers of a very different nature. Such use may, for example, include the use of a gum-containing module and a gum-free module, where the gum-free modules contain non-DC sugar alcohol particles. Thus, the gum-free layer can release beneficial non-DC sugar alcohols, and the gum-containing layer can not only stabilize the tablet as described above, but also interact with non-DC sugar alcohols during, in particular, initial release to establish a very pleasant and impressive initial phase of chewing. This includes an increased sensation of saliva and moisture.

In an embodiment of the invention, said population of particles is tableted into a first module and combined with a second population of particles which is tableted into a second module, wherein the second population of particles is different from the first population of particles.

In an embodiment of the invention, said plurality of particles is tableted into a first module and combined with a second plurality of particles which is tableted into a second module, wherein the second module differs in composition from the first module.

In an embodiment of the invention, said population of particles is tableted into a first module and combined with a second population of particles that is tableted into a second module, where the second population of particles is different from the first population of particles, where the second population of particles does not contain non-DC sugar alcohols.

In an embodiment of the invention, said population of particles is tableted into a first module and combined with a second population of particles that is tableted into a second module, wherein the second module does not include non-DC sugar alcohol particles.

In one embodiment, the second population of particles includes a large number of DC sugar alcohols, for example more than the first population of particles. For example, the second population of particles may include at least 30% by weight of DC sugar alcohols, such as at least 50% by weight of DC sugar alcohols, such as at least 70% by weight of sugar alcohols. In an exemplary embodiment, the second population of particles may include from 50 to 99.9% by weight of sugar alcohols, for example from 70 and 99% by weight of sugar alcohols.

The amount of sugar alcohol DC may depend on the type and amount of active ingredient used in the tablet.

In an embodiment of the invention, the second module is tableted before the first module.

In an embodiment, said plurality of particles is tableted into a first module and combined with a second plurality of particles which is tableted into a second module, wherein the second module is an orally disintegrating tablet (ODT).

In an embodiment of the invention, the non-DC regions are evenly distributed in the tablet or in at least one module of the tablet.

One of the advantages of the above embodiment may be that a uniform distribution of the non-DC regions contributes to the effective disintegration of the module during chewing, for example, due to the smaller contribution of non-DC particles to mechanical strength, thereby facilitating effective contact of the resulting chewing fragments with chewing. saliva, again increasing the dissolution of the tablet. In addition, the uniform distribution of the non-DC regions promotes more chews with non-DC sugar alcohols, which again effectively promotes salivation. Thus, a synergy is provided between the use of non-DC sugar alcohol particles as a disintegration promoter due to lower mechanical strength, and also as a saliva activator in combination with uniform distribution to facilitate the effect of dispersing chewing fragments in the oral cavity during chewing.

In an embodiment of the invention, a series of at least 10 of said tablets comprises said non-DC particles in an amount varying with a relative standard deviation (RSD) below 10%.

One advantage of the above embodiment may be that a uniform product can be obtained with little variation in the amount of non-DC sugar alcohol between tablets. Therefore, the functionality provided by the non-DC regions in a tablet may provide slight differences between tablets.

It should be noted that reference to the RSD and tablet sequence usually refers to a series of production line tablets.

In addition, the RSD of non-DC sugar alcohol between tablets is a measure of the degree of even distribution of non-DC regions. Therefore, the presence of RSD below 10% in a series of at least 10 tablets indicates a uniform distribution of non-DC areas. Evenly distributed non-DC areas contribute to strong salivation, since non-DC areas are effectively distributed in the mouth during chewing, and, as a result, disintegration of the tablet.

According to an embodiment of the invention, the number of non-DC particles between runs of at least 10 tablets has a relative standard deviation (RSD) of less than 5%.

A preferred method for dosing non-DC sugar alcohols into a multi-tablet formulation has been developed that facilitates accurate dosing of non-DC sugar alcohols in a series of tablets. This means that large-scale production of tablets comprising non-DC sugar alcohols is made possible by improved results regarding the distribution of non-DC regions in tablets, and thus an improved RSD between series tablets.

The term RSD as used herein is an abbreviation for relative standard deviation, which is used in the art to refer to the uniformity of non-DC sugar alcohol content in a series of tablets. The assay can be performed on a group of 10 tablets of a series in which the content of the non-DC sugar alcohols in question is measured. From these values, RSD can be calculated using the standard formula RSD = (set X standard deviation) × 100% / (set X mean).

In some cases, it may be most convenient to measure the RSD of non-DC sugar alcohol particles indirectly. For example, the RSD of another ingredient can be used as an indicator of the amount of non-DC sugar alcohol particles, since segregation affects the entire formulation of the tablet or module in question.

When attempting to achieve a high degree of uniform distribution of non-DC regions, insufficient agitation can lead to uneven distribution, such as undesirable particle agglomeration in certain portions of the tablet. In addition, even with very thorough mixing of the ingredients, undesirable processing of the mixture from the mixing stage to the tablet machine can lead to segregation. For example, smaller particles can typically separate to the bottom of the container, resulting in different particle distributions for different tablets. In particular, when different ingredients have different particle sizes, for example, if the non-DC particles are larger than the other ingredients, layering can result in different levels of non-DC sugar alcohols in different tablets. However, another aspect is that even storing a thoroughly mixed composition for a long time can lead to delamination.

On the other hand, an indication of achieving a uniform distribution of non-DC regions in at least one tablet module may be that a batch of at least 10 tablets has a relative standard deviation (RSD) of less than 10% in terms of non-DC sugar alcohol content. .

It should be noted that the term stratification in the context of the present application will be understood by the skilled person as meaning the separation of the mixture according to similarity, usually size. In the context of the present invention, this can be a problem when processing a mixture that includes particles of very different sizes, for example in a storage bin and feeding the composition through a feed mechanism into the die cavity.

In particular, when an active ingredient is included in a tablet, it is highly desirable to have a low RSD content of such active ingredients.

In an embodiment of the invention, the non-DC regions are evenly distributed in the tablet or in at least one module of the tablet.

One of the advantages of the above embodiment may be that a uniform distribution of the non-DC regions contributes to the effective disintegration of the module during chewing, for example, due to the smaller contribution of non-DC particles to mechanical strength, thereby facilitating effective contact of the resulting chewing fragments with saliva, again increasing the dissolution of the tablet. In addition, the uniform distribution of the non-DC regions promotes more chews with non-DC sugar alcohols, again effectively promoting salivation. Thus, a synergy is provided between the use of non-DC sugar alcohol particles as a disintegration promoter due to lower mechanical strength, and also as a saliva activator in combination with a uniform distribution to facilitate the effect of dispersing chewing fragments in the oral cavity during chewing.

In an embodiment of the invention, the tablet is a chewable tablet.

In an embodiment of the invention, at least 20% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 microns.

In an embodiment of the invention, at least 30% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 microns.

In an embodiment of the invention, at least 40% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 microns.

To the inventor's surprise, it was found that the larger non-DC sugar alcohol particles were particularly useful in accordance with the invention. In particular, it has been observed that larger non-DC sugar alcohol particles result in induced saliva production, eg, a higher total mass of saliva produced compared to smaller non-DC particles. In addition, the perceived wetting effect can be increased compared to smaller non-DC particles. The inventor did not expect these results.

In an embodiment of the invention, at least 10% by weight of said population of particles have a particle size of less than 250 microns, and at least 30% by weight of said population of particles have a particle size of more than 500 microns.

According to an embodiment of the invention, the population of particles has a particle size distribution with a full width at half maximum (FWHM) of at least 100 microns.

In an embodiment of the invention, at least 10% by weight of the non-DC sugar alcohol particles have a particle size of less than 250 microns.

In an embodiment of the invention, at least 5% by weight of the non-DC sugar alcohol particles have a particle size of less than 250 microns.

In particular, given a wide particle size distribution in a population of particles, it was surprising to the inventor that a uniform distribution of non-DC regions could be achieved. Typically, when the particle size distribution is broad, for example, when the width is from 10% quantile to 90% quantile, greater than 30% of the average value, the respective compositions are considered vulnerable to delamination. However, according to an embodiment of the invention, the non-DC regions are evenly distributed in at least one tablet module and may have non-DC particle counts between tablets in a series of at least 10 tablets with a relative standard deviation (RSD) maintained below 10%.

According to an embodiment of the invention, the non-DC particles have an average non-DC particle size of at least 50 µm larger than the average DC particle size of the DC particles.

In an embodiment of the invention, the non-DC sugar alcohol particles are selected from non-DC particles of erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof.

One of the advantages of the above embodiment may be to obtain the desired induced saliva production.

According to an embodiment of the invention, the non-DC sugar alcohol particles are composed of sugar alcohols selected from erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof.

In an embodiment of the invention, the non-DC sugar alcohol particles are selected from non-DC particles of erythritol, maltitol, xylitol, isomalt, and combinations thereof.

One of the advantages of the above embodiment may be to obtain the desired induced saliva production.

In an embodiment of the invention, the non-DC sugar alcohol particles are selected from non-DC particles of erythritol, maltitol, xylitol, and combinations thereof.

One of the advantages of the above embodiment may be to obtain the desired induced saliva production. In addition, when a cooling effect is desired, it is advantageous to have non-DC sugar alcohol particles comprising or consisting of erythritol, xylitol, or combinations thereof.

In an embodiment, the non-DC sugar alcohol particles are non-DC erythritol particles.

One of the advantages of the above embodiment may be to obtain the desired induced salivation along with a cooling effect.

In an embodiment, the non-DC sugar alcohol particles are non-DC xylitol particles.

One of the advantages of the above embodiment may be to obtain the desired induced salivation along with a cooling effect.

In an embodiment, the non-DC sugar alcohol particles are non-DC isomalt particles.

One of the advantages of the above embodiment may be to obtain the desired induced saliva production.

In an embodiment, the tablet comprises said non-DC sugar alcohol particles in an amount of at least 10% by weight of the tablet.

In an embodiment, the tablet comprises said non-DC sugar alcohol particles in an amount of at least 20% by weight of the tablet.

In an embodiment, the tablet comprises said non-DC sugar alcohol particles in an amount of at least 30% by weight of the tablet.

In an embodiment, the first module comprises said non-DC sugar alcohol particles in an amount of at least 30% by weight of the first module.

In an embodiment of the invention, the first module comprises said non-DC sugar alcohol particles in an amount of at least 40% by weight of the first module.

In an embodiment of the invention, said 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 that is considered a DC category if it is presented as particles composed of sorbitol, that is, in its pure form. On the other hand, several other sugar alcohols are considered non-DC category alcohols if they are presented as particulates composed of the specified sugar alcohol. Therefore, such non-DC sugar alcohols are usually processed into the DC category of sugar alcohols, for example, by granulating them, for example, with a binder.

Examples of trademarked DC sugar alcohols include sorbitol particles represented, for example, as Neosorb® P 300 DC from Roquette, mannitol particles, represented, for example, as Pearlitol® 300DC or Pearlitol 200 SD from Roquette, maltitol, represented, for example, as SweetPearl® P 300 DC, xylitol, represented for example as Xylisorb® 200 DC or Xylitab 200 from Dupont.

In an embodiment, the tablet comprises said DC sugar alcohol particles in an amount of at least 10% by weight of the tablet.

In an embodiment, the tablet comprises said DC sugar alcohol particles in an amount of at least 20% by weight of the tablet.

In an embodiment, the tablet comprises said DC sugar alcohol particles in an amount of at least 30% by weight of the tablet.

According to an embodiment of the invention, said population of particles comprises DC sugar alcohol particles in an amount of at least 10% by weight.

According to an embodiment of the invention, the first module comprises DC sugar alcohol particles in an amount of at least 10% by weight.

According to an embodiment of the invention, the first module comprises said DC sugar alcohol particles in an amount of at least 10% by weight of the first module.

According to an embodiment of the invention, the first module comprises said DC sugar alcohol particles in an amount of at least 30% by weight of the first module.

In an embodiment of the invention, the second module includes DC sugar alcohol particles in an amount of at least 30% by weight of the second module.

In an embodiment of the invention, the second module comprises DC sugar alcohol particles in an amount of at least 50% by weight of the second module.

In an embodiment of the invention, the second module comprises DC sugar alcohol particles in an amount of at least 70% by weight of the second module.

In an embodiment of the invention, the second module comprises DC sugar alcohol particles in an amount of at least 90% by weight of the second module.

In an embodiment, the sugar alcohol DC particles in the second module are selected from the DC particles of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof.

In an embodiment of the invention the tablet friability is less than 3%, for example less than 2%, for example less than 1.5%, where the friability is measured in accordance with the European Pharmacopoeia 9.1, test method 2.9.7., using the PTF 10E pharmaceutical tablet friability tester from Pharma test.

One of the advantages of the above embodiment may be that a tablet is obtained with a relatively high mechanical stability, while at the same time having the desired mouthfeel according to the invention.

According to an embodiment of the invention, the tablet friability is 0.2% to 3%, for example 0.2% to 2%, where the friability is measured in accordance with the European Pharmacopoeia 9.1, test method 2.9.7., using a pharmaceutical tablet friability tester PTF 10E from Pharma Test.

In an embodiment of the invention, the tablet comprises one or more binders, other than those forming part of the sugar alcohol DC particles, in an amount of 0.1 to 6% by weight of the tablet.

Suitable binders include gum arabic, methyl cellulose, liquid glucose, tragacanth, ethyl cellulose, gelatin, hydroxypropyl methyl cellulose (HPMC), starches, hydroxypropyl cellulose (HPC), pregelatinized starch, sodium carboxymethyl cellulose (NaCMC), alginic acid, polyvinylpyrrolidone (PVP), maltodextrin (MD ); cellulose, polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylates, copovidone or microcrystalline cellulose (MCC), alone or in combination.

According to an embodiment of the invention, the one or more binders comprise one or more cellulosic binders.

In an embodiment of the invention, one or more binders include microcrystalline cellulose (MCC), hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC), or any combination thereof.

In an embodiment, the oral tablet comprises a hydroxypropyl cellulose (HPC) binder in an amount of 0.1 to 6% by weight of the tablet, such as 0.1 to 5%, such as 0.1 to 4%, such as 0 .1 to 3%, for example 0.1 to 2% by weight of the tablet.

HPC can be used as a particularly attractive binder. Thus, this binder, when used with non-DC sugar alcohols such as erythritol, exhibits a favorable sensory experience compared to other well known binders. In particular, it is preferred to use an HPC of less than 4% by weight of the tablet, eg 0.1 to 3%, eg 0.1 to 2% by weight of the tablet.

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

In an embodiment of the invention, the non-DC sugar alcohol particles are particles composed of sugar alcohol and the particles are not previously granulated together with one or more binders that are present as separate components in the tablet.

It should be noted that the use of binders as particles separate from the non-DC sugar alcohol particles does not compromise beneficial sensory properties even under high tabletting pressure, whereas granulation with a sugar alcohol binder clearly reduces desirable sensory properties.

In an embodiment of the invention, the tablet crush strength is greater than 60 N, such as greater than 70 N, such as greater than 80 N, such as greater than 90 N, such as greater than 100 N, such as greater than 110, such as greater than 130 N, such as greater than 150 N, wherein the tablet strength is crushing strength is less than 300 N, for example less than 250 N, for example less than 200 N, where the crushing strength is determined in accordance with the European Pharmacopoeia 9.1, test method 2.9.8., using a pharmaceutical crushing strength tester model Pharma Test type PTB 311 .

According to an embodiment of the invention, the tablet comprises at least one module, wherein the module comprises greater than 10% by weight of compressed non-DC sugar alcohol particles, wherein the module crush strength is greater than 60 N, such as greater than 70 N, such as greater than 80 N, such as more than 90 N e.g. more than 100 N, where the crush strength is determined according to the European Pharmacopoeia 9.1, test method 2.9.8., using a pharmaceutical crush strength tester model Pharma Test type PTB 311.

High intensity artificial sweeteners can also be used alone or in combination with the above sweeteners. Preferred high intensity sweeteners include, but are not limited to, sucralose, aspartame, acesulfame salts, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (a natural intense sweetener) and the like, singly or in combination. To provide a longer lasting sensation of sweetness and flavor, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweeteners. Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, canning, yeast cell encapsulation, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of sweeteners can also be achieved using another tablet component, such as a resinous compound.

The level of artificial sweetener use will vary greatly and will depend on factors such as the effectiveness of the sweetener, the rate of release, the desired sweetness of the product, the level and type of flavoring used, and the cost factor. Thus, the active level of the artificial sweetener may range from about 0.001 to about 8% by weight (preferably from about 0.02 to about 8% by weight). When carriers used for encapsulation are included, the level of use of the encapsulated sweetener will be proportionately higher. Combinations of sugar and/or non-sugar sweeteners can be used in the composition.

In an embodiment, the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is between 0.2 and 1.2.

In an embodiment, the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is between 0.3 and 1.0.

In an embodiment, the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is between 0.3 and 0.7.

The weight ratio between non-DC sugar alcohol particles and DC sugar alcohol particles is found to be significant in accordance with an embodiment of the invention in that a relatively high amount of non-DC sugar alcohol particles must be present to obtain the mouthfeel and taste achieved in accordance with the present invention. However, this taste and mouthfeel is also inherent in 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 a group of test subjects.

The weight ratio between the non-DC sugar alcohol particles and the DC sugar alcohol particles proved to be significant, as mentioned above, in terms of the immediate sensation and mouthfeel experienced by the user, but in addition, it solves the problem associated with the taste sensation when the DC sugar alcohol particles alcohol crumble at the beginning of chewing. The mechanical stability of the tablet is highly desirable when the tablet is in its non-chewed form, but rapid disintegration and dissolution is desirable when the tablet is chewed, due to the fact that the tablet user does not like the gritty feeling caused by small, highly compressed sugar alcohol DC crumbs. The use of a very large amount of non-DC sugar alcohol particles will promote rapid dissolution and disintegration of the tablet once it has been chewed.

According to an embodiment of the invention, the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is greater than 0.3, such as greater than 0.4, such as greater than 0.5.

According to an embodiment of the invention, the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is less than 0.7, such as less than 0.6, such as less than 0.55.

The weight ratio between non-DC sugar alcohol particles and DC sugar alcohol particles is important to obtain the preferred taste and mouthfeel. By having an upper limit to this mass ratio, the chewer will also experience the desired crunchy sensation when chewing the tablet, the crunch being obtained by using significant amounts of DC sugar alcohol particles rather than non-DC sugar alcohol particles.

According to an embodiment of the invention, the tablet comprises non-DC sugar alcohol particles in an amount greater than 0.3 grams.

According to an embodiment of the invention, the weight of the non-DC sugar alcohol particles contained in the tablet is greater than 0.4 grams, such as greater than 0.5 grams, such as greater than 0.6 grams, such as greater than 0.7 grams, such as greater than 0.8 gram, eg more than 0.9 gram, eg more than 1.0 gram.

According to a further embodiment of the invention, the amount of non-DC sugar alcohol particles is relatively high. It is particularly high considering that non-DC sugar alcohol is not generally considered attractive for pressing, but the mouthfeel and salivation experienced by the user is greatly improved when compared to small amounts or the same amounts of DC sugar alcohol.

According to an embodiment of the invention, the tablet comprises non-DC sugar alcohol particles in an amount of less than 3.0 grams, such as less than 2.0 grams, such as less than 1.5 grams.

In one embodiment of the invention, the weight of the tablet is from 0.5 to 4.0 grams.

In an embodiment of the invention, saliva is induced when the tablet is chewed compared to a tablet without non-DC sugar alcohol particles.

In an embodiment of the invention, saliva is induced when the tablet is chewed, compared to a tablet in which the discrete regions are based on DC sugar alcohol particles.

In an embodiment of the invention, the tablet generates more than 1.5 ml of saliva within 30 seconds from the start of chewing.

According to an embodiment of the invention, discrete non-DC regions induce the formation of more than 2.0 ml of saliva within 30 seconds from the start of chewing.

According to an embodiment of the invention, discrete non-DC regions induce the formation of more than 3.0 ml of saliva within 30 seconds from the start of chewing.

In an embodiment of the invention, the tablet generates more than 1.5 ml of saliva over a period of 30 to 90 seconds from the start of chewing.

According to an embodiment of the invention, discrete non-DC regions induce the formation of more than 2.0 ml of saliva within 30 to 90 seconds from the start of chewing.

In an embodiment of the invention, the tablet generates more than 1.5 ml of saliva over a period of 90 to 180 seconds from the start of chewing.

In an embodiment of the invention, the tablet generates more than 1.5 ml of saliva over a period of 180 to 300 seconds from the start of chewing.

In an embodiment of the invention, the tablet further comprises at least one viscosity modifier.

In an embodiment of the invention, at least one viscosity modifier is selected from the group consisting of sodium alginate, pectin, carrageenan, xanthan gum, gum arabic, and mixtures thereof.

In an embodiment of the invention, the tablet further comprises at least one viscosity regulator which, when hydrated, forms a gel having a positive surface electrical charge, and at least one viscosity regulator which, when hydrated, forms a gel with a negative surface electric charge.

In an embodiment of the invention, the tablet includes a flavoring agent.

The amount of flavor may, for example, be from 0.1% to about 10% by weight of the tablet, for example from 0.1% to about 6% by weight of the tablet.

Usable flavors include almond, almond amaretto, apple, Bavarian cream, black cherry, black sesame seeds, blueberry, brown sugar, chewing gum, toffee cream flavor, cappuccino, caramel, caramel cappuccino, cheesecake (wholemeal coating) , chili, hot cinnamon, cotton candy, fluffy cotton candy, cloves, coconut, coffee, pure coffee, double chocolate, energy milk flavor, ginger, glutamate, wholemeal cracker, grape juice, green apple, Hawaiian punch, honey , Jamaican Rum, Kentucky Bourbon, Kiwi, Colada, Lemon, Lemon Lime, Tobacco, Maple Syrup, Maraschino Cherry, Marshmallow, Menthol, Milk Chocolate, Mocha, Mountain Dew, Peanut Butter, Pecan, Peppermint, Raspberry, Banana, Ripe banana, root beer, RY 4, mint, strawberry, sweet cream, sweet-tart flavor, sweetener, roasted almonds, tobacco, tobacco blend, vanilla ice cream, vanilla cake, vanilla swirl , vanillin, waffles, Belgian waffles, watermelon, whipped cream, white chocolate, wintergreen, amaretto, banana cream, black walnut, blackberry, butter, creamy rum, cherry, chocolate hazelnut, cinnamon roll, cola, mint liqueur, eggnog -mogul, English toffee, guava, lemonade, licorice, maple, mint chocolate chips, orange cream, peach, pina colada, pineapple, plum, pomegranate, praline and cream, red licorice, salt water toffee, strawberry-banana, strawberry -kiwi, tropical punch, tutti frutti, vanilla, or any combination thereof.

In an embodiment of the invention, the tablet comprises an active ingredient.

According to an embodiment of the invention, the active ingredient is included in a set of particles.

According to an embodiment of the invention, the active ingredient is included in a second set of particles.

In an embodiment of the invention, the tablet comprises a lipophilic association between the active ingredient and a fatty acid such as oleic acid.

In an embodiment of the invention, the tablet comprises an active pharmaceutical ingredient.

According to an embodiment of the invention, the active pharmaceutical ingredient is included in a set of particles.

According to an embodiment of the invention, the active pharmaceutical ingredient is included in a second set of particles.

In an embodiment of the invention, the tablet comprises a self-emulsifying system which, when hydrated by saliva upon oral administration, forms an emulsion.

Because of the poor solubility of certain active ingredients in body fluids, there is an unmet need for a high dose of certain active ingredients in a form that solubilizes the active ingredient when mixed with body fluids to facilitate bioabsorption. To overcome low oral bioavailability, various lipid-based drug delivery systems and self-emulsifying systems have been developed. Lipid-based delivery systems, and in particular self-emulsifying drug delivery systems (SEDDS), have been shown to increase the solubility, dissolution, and bioavailability of many insoluble active ingredients. However, lipid-based delivery systems and SEDDS are very limited in the amount of loaded active ingredient that must be dissolved in the carrier composition. Higher concentrations of active ingredients are achieved by using co-solvents, which in certain cases allow loading up to 30%.

It is believed that particular problems arise when formulating oral tablets with SEDDS. For example, problems may arise in obtaining a homogeneous mixture in which variations are avoided and safe and convenient delivery can be obtained. In addition, the general composition of tablets for oral administration, providing convenience to the user, should not be compromised, which is often the case if precautions are not taken, for example, in cases where a high loading of active ingredients is required.

Particularly with regard to SEDDS, the composition of the present invention may provide some distinct advantages in allowing higher loading of active ingredients and at the same time offering improved sensory properties of the composition during use. There are other benefits as well.

It is important to note that the presence of SEDDS, or at least a self-emulsifying agent, acts synergistically with increased saliva production. Although increased saliva production has been observed to distribute some active ingredients and place a higher load of active ingredients on, for example, mucosal surfaces, it has been observed that the presence of SEDDS, or at least a self-emulsifying agent, further enhances absorption of these active ingredients across surfaces. oral cavity. Accordingly, the synergy between the presence of SEDDS, or at least a self-emulsifying agent, and increased saliva production, according to the invention, was a surprise to the inventors. In some embodiments, increased saliva production may result in greater exposure of the active ingredients to the mucosal surface. The presence of SEDDS may increase the affinity of the active ingredients from this saliva for the mucosa. In particular, the ability of SEDDS to have a high load of active ingredients further contributes to the synergism of the tablet according to the invention in combination with improved saliva production.

In the context of the present invention, SEDDS is a solid or liquid dosage form comprising an oil phase, a surfactant and, optionally, an additional surfactant, characterized primarily in that said dosage form can spontaneously form an oil-in- water in the mouth at ambient temperature (usually refers to body temperature, namely 37°C). When SEDDS enters the oral cavity, it initially self-emulsifies as emulsion droplets and quickly disperses throughout the oral cavity, thereby reducing the irritation caused by direct contact of the active ingredient with the oral mucosa and therefore helps to mask the taste of the active ingredients. In the oral cavity, the structure of the microparticles of the emulsion will change or break down. The obtained microparticles of micrometer or nanometer level can penetrate into the mucous membrane, such as the oral cavity, and the absorbed oil droplets enter the bloodstream, thereby significantly improving the bioavailability of the active ingredient.

In an embodiment of the invention, the self-emulsifying system includes one or more emulsifiers and one or more oil carriers.

In an embodiment, the self-emulsifying system includes one or more emulsifiers, one or more oil carriers, and one or more solubilizers.

In an embodiment, the self-emulsifying system includes one or more emulsifiers, one or more oil carriers, one or more solubilizers, and one or more solvents.

In an embodiment, the self-emulsifying system includes one or more emulsifiers and one or more solvents.

In an embodiment of the invention, the self-emulsifying system includes one or more emulsifiers that have both emulsifying and solubilizing properties.

In an embodiment of the invention, the self-emulsifying system includes one or more emulsifiers that act as both an emulsifier and a carrier.

In an embodiment, the self-emulsifying system includes one or more emulsifiers that act as an emulsifier, as a carrier, and as a solubilizer.

In an embodiment, the self-emulsifying system comprises one or more fatty acids, one or more glycerols, one or more waxes, one or more flavonoids, and one or more terpenes.

In an embodiment, the self-emulsifying system comprises one or more emulsifiers that have an HLB value greater than 6, preferably 8-18.

In an embodiment of the invention, one or more emulsifiers are selected from the group consisting of PEG-35 castor oil, PEG-6 oleoylglycerides, PEG-6 linoleoylglycerides, PEG-8 PEG-8 Caprylic/capric triglycerides, sorbitan monolaurate, sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate , polyoxyethylene (60) sorbitan monostearate, polyoxyethylene (80) sorbitan monooleate, lauroylpolyoxyl-32 glycerides, stearoylpolyoxyl-32 glycerides, polyoxyl-32 stearate, propylene glycol monolaurate, propylene glycol dilaurate, and mixtures and combinations thereof.

In an embodiment of the invention, one or more emulsifiers include PEG-35 castor oil.

In an embodiment of the invention, the carrier oil is selected from the group consisting of naturally occurring fatty acids; medium chain triglycerides of caprylic (C8) and capric (C10) acids; esters of propylene glycol and caprylic (C8) and capric (C10) acids; mono-, di- and triglycerides, mainly linoleic (C18:2) and oleic (C18:1) acids; fatty acid 18:1 cis-9; natural fatty acids; mono-, di- and triglycerides of oleic (C18:1) acid; and mixtures and combinations thereof.

In an embodiment of the invention, one or more solvents are selected from the group consisting of polyglyceryl-3-dioleate, 1,2-propanediol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and mixtures and combinations thereof.

In an embodiment, the carrier oil is selected from the group consisting of corn oil, Labrafac WL1349 lipophile, Labrafac PG, Maisine CC, oleic acid, olive oil, Peceol, and mixtures and combinations thereof.

In an embodiment of the invention, one or more solvents are selected from the group consisting of polyglyceryl-3-dioleate, 1,2-propanediol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and mixtures and combinations thereof.

In an embodiment of the invention, one or more solubilizers are selected from the group consisting of lauroylpolyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; Polyoxyl-32 stearate; synthetic copolymer of ethylene oxide (80) and propylene oxide (27); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; alpha, beta or gamma cyclodextrins and their derivatives; pea proteins (globulins, albumins, glutelins); and their mixtures and combinations.

In an embodiment of the invention, the tablet comprises an active pharmaceutical ingredient and a self-emulsifying system which, when hydrated by saliva upon oral administration, forms an emulsion.

In an embodiment of the invention, the tablet comprises nicotine and a self-emulsifying system which, when hydrated by saliva upon oral administration, forms an emulsion.

In an embodiment of the invention, the population of particles includes particles comprising a gum base, and the tablet is designed to be chewed to a coherent residue containing water-insoluble components.

The use of gum in the context of the present invention may cause a delay in the release of the active ingredients, and this may again promote the absorption of the active pharmaceutical ingredient through the cheek and upper throat when it is released from the oral tablet during chewing.

In an embodiment, the oral tablet contains particles comprising a gum base, wherein the gum base comprises at least 5% by weight of an elastomer.

The specific use of a relatively high proportion of elastomer in the gum base can be used effectively to modify the release of active ingredients in terms of time and amount, and the elastomer can also provide a strong tablet structure that facilitates chewing to a coherent residue containing water insoluble components. Some active ingredient may cause the risk of disintegration of the residue, while the elastomer may increase coherence and balance the action of aggressive active ingredients.

In an embodiment of the invention, the gum base comprises at least 10% by weight of an elastomer.

In an embodiment of the invention, the gum base comprises at least 15% by weight of an elastomer.

In an embodiment of the invention, the gum base comprises from 15% to 25% by weight of an elastomer.

In an embodiment of the invention, the gum base comprises from 17% to 23% by weight of an elastomer.

In an embodiment of the invention, the tablet does not contain a gum base.

In an embodiment of the invention, the tablet dosage form is intended for buccal absorption of the active ingredients.

In an embodiment, the oral tablet comprises toothpaste in an amount of at least 0.1% by weight of the oral tablet.

In an embodiment, the oral tablet comprises a dentifrice in an amount of at least 0.1% by weight of the oral tablet.

In an embodiment, the oral tablet comprises a dentifrice in an amount of at least 0.1% by weight of the oral tablet, and the particle population comprises particles comprising a gum base.

In an embodiment, the oral tablet comprises a dentifrice in an amount of at least 0.1% to 25% by weight of the oral tablet, excluding the abrasive.

In an embodiment, the oral tablet comprises toothpaste in an amount of at least 0.1% to 25% by weight of the oral tablet, excluding the abrasive.

The dentifrice or toothpaste typically includes at least one of the following active ingredients.

In an embodiment of the invention, the active ingredient comprises one or more oral care products.

In an embodiment of the invention, the active ingredient comprises one or more antiplaque agents.

Anti-plaque agents include sources of fluoride ions. Antiplaque agents are any substance that by itself prevents the accumulation of bacterial deposits on the surface of the oral cavity. Examples include xylitol and other antimicrobial agents. The inhibitory effects of xylitol on oral microbes may be best when used in combination with an extract, as the extract also acts to inactivate microbes.

Typical examples of active ingredients that are particularly desirable in terms of efficacy, safety and composition of antiplaque agents are:

Nafcillin, oxacillin, vancomycin, clindamycin, erythromycin, trimethoprim-sulfamethoxazole, rifampin, ciprofloxacin, broad-spectrum penicillin, amoxicillin, gentamicin, ceftriazoxone, cefotaxime, chloramphenicol, clavunate, sulbactam, probenecid, doxycycline, spectinomycin, cefixime, penicillin G β-lactamase inhibitors; mesiocillin, piperacillin, aztreonam, norfloxacin, trimethoprim, ceftazidime, dapsone. Halogenated diphenyl ethers, for example 2',4,4'-trichloro-2-hydroxydiphenyl ether (Triclosan), 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether. Halogenated salicylanilides, e.g. ,3',5-tetrachlorosalicylanilide, 3,5-dibromo-3'-trifluoromethyl salicylanilide, 5-n-octanoyl-3'-trifluoromethyl salicylanilide, 3,5-dibromo-4'-trifluoromethyl salicylanilide, 3 ,5-dibromo-3'-trifluoromethyl salicylanilide (Flurofen). Benzoic ethers, for example, methyl p-hydroxybenzoic ether, ethyl p-hydroxybenzoic ether, propyl p-hydroxybenzoic ether, butyl p-hydroxybenzoic ether. Halogenated carbanilides, for example 3,4,4'-trichlorocarbanilide, 3-trifluoromethyl-4,4'-dichlorocarbanilide or 3,3,4'-trichlorocarbanilide. Phenolic compounds (including phenol and its homologues, mono- and polyalkyl and aromatic halophenol and their homologues), for example, phenol, 2-methyl-phenol, 3-methyl-phenol, 4-methyl-phenol, 4-ethyl-phenol, 2 ,4-dimethyl-phenol, 2,5-dimethyl-phenol, 3,4-dimethyl-phenol, 2,6-dimethyl-phenol, 4-n-propyl-phenol, 4-n-butyl-phenol, 4-n -amyl-phenol, 4-tert-amyl-phenol, 4-n-hexyl-phenol, 4-n-heptyl-phenol, 2-methoxy-4-(2-propenyl)-phenol (Eugenol), 2-isopropyl- 5-methyl-phenol (Thymol), mono- and polyalkyl- and aralkyl-halophenols, methyl-p-chlorophenol, ethyl-p-chlorophenol, n-propyl-p-chlorophenol, n-butyl-p-chlorophenol, n-amyl -p-chlorophenol, sec-amyl-p-chlorophenol, n-hexyl-p-chlorophenol, cyclohexyl-p-chlorophenol, n-heptyl-p-chlorophenol, n-octyl-p-chlorophenol, o-chlorophenol, methyl-o -chlorophenol, ethyl-o-chlorophenol, n-propyl-o-chlorophenol, n-butyl-o-chlorophenol, n-amyl-o-chlorophenol, tert-amyl-o-chlorophenol, n-hexyl-o-chlorophenol, n -heptyl-o-chlorophenol, p-chlorophenol, o-benzyl-p-chlorophenol, o-benzyl-m-methyl-p-chlorophenol, o-benzyl-m, m-dimethyl-p-chlorophenol, o-phenylethyl-p -chlorophenol, o-phenylethyl-m-methyl-p-chlorophenol, 3-methyl-p-chlorophenol, 3,5-dimethyl-p-chlorophenol, 6-ethyl-3-methyl-p-chlorophenol, 6-n-propyl -3-methyl-p-chlorophenol, 6-iso-propyl-3-methyl-p-chlorophenol, 2-ethyl-3,5-dimethyl-p-chlorophenol, 6-sec-butyl-3-methyl-p-chlorophenol , 2-iso-propyl-3,5-dimethyl-p-chlorophenol, 6-diethylmethyl-3-methyl-p-chlorophenol, 6-iso-propyl-2-ethyl-3-methyl-p-chlorophenol, 2-sec -amyl-3,5-dimethyl-p-chlorophenol, 2-diethylmethyl-3,5-dimethyl-p-chlorophenol, 6-sec-octyl-3-methyl-p-chlorophenol, p-bromophenol, methyl-p-bromophenol , ethyl-p-bromophenol, n-propyl-p-bromophenol, n-butyl-p-bromophenol, n-amyl-p-bromophenol, sec-amyl-p-bromophenol, n-hexyl-p-bromophenol, cyclohexyl-p -bromophenol, o-bromophenol, tert-amyl-o-bromophenol, n-hexyl-o-bromophenol, n-propyl-m, m-dimethyl-o-bromophenol, 2-phenyl-phenol, 4-chloro-2-methyl -phenol, 4-chloro-3-methyl-phenol, 4-chloro-3,5-dimethyl-phenol, 2,4-dichloro-3,5-dimethyl-phenol, 3,4,5,6-tetrabromo-2 -methylphenol, 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenylmethane. Resorcinol and its derivatives e.g. -resorcinol, n-nonyl-resorcinol, phenyl-resorcinol, benzyl-resorcinol, phenylethyl-resorcinol, phenylpropyl-resorcinol, p-chlorobenzyl-resorcinol, 5-chloro-2,4-dihydroxydiphenyl-methane, 4'-chloro-2, 4-dihydroxydiphenylmethane, 5-bromo-2,4-dihydroxydiphenylmethane, 4"-bromo-2,4-dihydroxydiphenylmethane. Bisphenolic compounds, such as bisphenol A, 2,2'-methylene-bis-(4- chlorophenol), 2,2'-methylene-bis-(3,4,6-trichlorophenol) (hexachlorophene), 2,2'-methylene-bis-(4-chloro-6-bromophenol), bis-(2-hydroxy -3,5-dichlorophenyl)-sulfide, bis-(2-hydroxy-5-chlorobenzyl)-sulfide.

Exemplary polyphosphate compounds with plaque inhibiting properties are di-alkali metal and tetra-alkali metal pyrophosphate and mixtures thereof in hydrated or non-hydrated form. Examples of pyrophosphate salts are Na ₂ H ₂ P ₂ O ₇ , Na ₄ P ₂ O ₇ and K ₄ P ₂ O ₇ . Other suitable polyphosphates include hydrated or non-hydrated alkali metal tripolyphosphates such as Na ₅ P ₃ O ₁₀ and K ₅ P ₃ O ₁₀ .

In an embodiment of the invention, the active ingredient comprises one or more anti-gingivitis agents.

Anti-gingivitis agents may include anti-inflammatory agents such as salicylic acid derivatives (eg, aspirin), paraminophenol derivatives (eg, acetaminophen), indole- and indene-acetic acids (indolmethacin, sulindac, and etodalac), heteroarylacetic acids (tolmetin, diclofenac, and ketorolac ), arylpropionic acid derivatives (ibuprofen, naproxen, phenoprenophen, oxaprozin), anthranilic acids (mefenamic acid, meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone and oxyphentatrazone), lactic acid bacteria (LAB), osteopontin (ONP), IG- Lyt, hexefine, aloe vera, chlorhexedine, myrrh, or sage.

Anti-gingivitis agents also include psychotherapeutic agents such as Thorazine, Serentil, Mellaril, Millazine, Tindal, Permitil, Prolixin, Trilafon, Stelazine, Suprazine, Taractan, Navan, Closaril, Haldol, Halperon, Locitan, Moban, Orap, Risperdal, Alprazolam, chlordiazepoxide, clonezepam, clorezepat, diazepam, galazepam, lorazepam, oxazepam, prazepam, buspirone, elvavil, anafranil, adapine, sinequan, tofranil, surmontil, azendine, norpramine, pertofran, ludiomil, pamelor, vivactil, prozac, luvox, paxil, zoloft, effexor, velibutrin, serzon, desirel, nardil, parnate, or eldepril.

In an embodiment of the invention, the active ingredient comprises one or more dental cosmetic ingredients.

The dental cosmetic ingredient includes a whitening agent. They are conveniently selected from tooth color modifying agents which may be considered among the oral care actives used in the tablet according to the invention. These substances are suitable for discoloring teeth to satisfy the consumer, such as those listed in the CTFA Cosmetic Ingredient Handbook, 3.sup.rd Edition, Cosmetic and Fragrances Association Inc., Washington D.C. (1982), incorporated herein by reference. Specific examples include talc, mica, magnesium carbonate, calcium carbonate, calcium pyrophosphate, baking soda, Iceland moss, bamboo, sodium hexa-metaphosphate, magnesium silicate, magnesium aluminum carbonate, silicon dioxide, titanium dioxide, zinc oxide, iron oxide red, brown iron oxide, iron oxide yellow, iron oxide black, iron ammonium ferrocyanide, manganese violet, ultramarine, nylon powder, polyethylene powder, methacrylate powder, polystyrene powder, silk powder, crystalline cellulose, starch, titanized mica, titanized iron oxide mica, oxychloride bismuth and mixtures thereof. Typical levels are from about 0.05% to about 20%, preferably from about 0.1% to about 15%, and most preferably from about 0.25% to about 10% by weight of the composition.

Whitening agents for use in the present invention may also include materials that remove or whiten intrinsic or extrinsic stains on or in teeth surfaces. Such substances are selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, persulfates, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof. Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite and potassium chlorite. Additional bleaching agents can be hypochlorite and chlorine dioxide. The preferred percarbonate is sodium percarbonate. Preferred persulfates are oxones. The content of these substances depends on the available oxygen or chlorine.

In an embodiment of the invention, the active ingredient includes one or more abrasives.

Within the scope of the present invention, the oral tablet may include an abrasive. Typical materials include silica gels and precipitates, aluminas, phosphates, and mixtures thereof. Specific examples include dicalcium orthophosphate dihydrate, calcium pyrophosphate, bamboo, tricalcium phosphate, hydrated alumina, calcium beta pyrophosphate, calcium carbonate, sodium polymetaphosphate, sodium hexametaphosphate, Calgen, Giltex, Quadrafos, Hagan phosphate, micromet, dibasic calcium phosphate, calcium monohydrogen phosphate, dicalcium orthophosphate dicalcium phosphate, calcium carbonate, cacti, calcichui, calcidium, citric, aragonite, calcite, valerite, alumina, alumina, silica, silica, silicic anhydride, and resinous abrasives such as urea condensation products and fine particle formaldehyde, and others such as those disclosed in US Pat. No. 3,070,510. Mixtures of polishing agents may also be used.

Silica polishing materials typically have an average particle size in the range of about 0.1 to about 30 microns; and preferably from about 5 to about 15 microns. The polishing agent may be precipitated silica or silica gels such as the silica xerogels described in US Pat. Also preferred are precipitated silica materials such as those marketed by the J. M. Huber Corporation under the trademark "Zeodent", especially the silica having the name "Zeodent 119". The types of silica-based tooth polishes that can be used in the tablets of the present invention are described in more detail in US Pat. No. 4,340,583. from about 10% to about 50% by weight of the tablet.

In an embodiment, the oral tablet comprises one or more of the following active ingredients: an antiplaque agent, an antigingivitis agent, a dental cosmetic ingredient, and/or an abrasive in an amount of from 0.1% to 35%, for example, from 1% to 25% or, for example, from about 5% to about 10% by weight of an oral tablet.

The content of these oral care ingredients in an oral tablet according to the invention will typically range from about 0.1% to about 35%, preferably from about 1% to about 25%, and most preferably from about 5% to about 10% by weight of the tablet. In an embodiment of the invention, the oral tablet essentially consists of ingredients that are naturally present.

In an embodiment, the oral tablet comprises natural high intensity sweeteners such as stevioside. In an embodiment, the oral tablet comprises stevioside and xylitol.

In addition, the present invention relates to an oral tablet suitable for active pharmaceutical ingredients, comprising a set of particles, while the set of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, the tablet is designed to turns into liquid within 20 seconds of chewing.

In addition, the present invention relates to an oral tablet suitable for active pharmaceutical ingredients, comprising a population of particles, while the population of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, while the tablet is designed to dissolution within 20 seconds of chewing.

In addition, the present invention relates to a medical device in the form of a tablet comprising a particle population, where the particle population includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, and the medical device is intended to alleviate or treat xerostomia.

In addition, the present invention relates to a medical device in the form of a tablet, comprising a collection of particles, where the population of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, and the medical device is intended to alleviate or treat dysphagia.

In addition, the present invention relates to a method for providing induced saliva production in the oral cavity, the method comprising the steps of:

i) providing an oral tablet comprising a population of particles, wherein the population of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, and

ii) chewing the tablet and thus producing saliva in the mouth induced by a plurality of discrete non-DC regions in the tablet.

In addition, the present invention relates to a method for alleviating or treating xerostomia, the method comprising the steps of:

i) providing an oral tablet comprising a population of particles, wherein the population of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, and

ii) chewing the tablet and thereby alleviating or treating xerostomia.

In addition, the present invention relates to a method for alleviating or treating dysphagia, the method comprising the steps of:

i) providing an oral tablet comprising a population of particles, wherein the population of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, and

ii) chewing the tablet and thus producing saliva in the mouth,

iii) swallowing one or more pills along with induced saliva.

Thus, in a preferred embodiment, the oral tablet of the present invention can be used with a conventional swallowable tablet by first using the saliva producing tablet of the present invention and then swallowing the conventional oral tablet. Thus, the tablet of the present invention can compensate for or counteract the difficulty of swallowing conventional oral tablets by a user.

In an embodiment, step ii) of chewing the tablet comprises chewing the tablet, thereby accelerating the release of the active ingredients induced by a plurality of discrete non-DC regions in the tablet.

In an embodiment, step ii) of chewing the tablet comprises chewing the tablet to release water soluble ingredients into saliva induced by a plurality of discrete non-DC regions in the tablet.

In an embodiment of the invention, step ii) of chewing the tablet comprises releasing at least 50% by weight of the active ingredient within 20 seconds of chewing.

BLUEPRINTS

The present invention will be described with reference to the drawings, where

Fig. 1a and 1b show an embodiment of the invention,

Fig. 2a and 2b show a two-module version of an embodiment of the invention,

Fig. 3a and 3b show a three-module version of an embodiment of the invention,

Fig. 4 and 5 illustrate embodiments of the invention.

Fig. 6 illustrates a two-module version of an embodiment of the invention, and where

Fig. 7 illustrates the short and long term salivation effects obtained with various types of non-DC sugar alcohols.

Fig. 8 illustrates a light microscope image of a cross section of a two-module version of an embodiment of the invention. The right side of the tablet, shown in slightly darker color, constitutes the first tablet module, and the left side of the tablet, shown in lighter color, constitutes the second tablet module. In the first non-DC module, the sugar alcohol particles can be seen as dark discrete areas evenly distributed in the tablet.

Fig. 9 illustrates a light microscope image of a cross-sectional view of a two-module version of the tablet shown in FIG. 8, but without non-DC sugar alcohol particles in the tablet.

Fig. 10 illustrates a light microscope image of a cross section of a single module version of an embodiment of the invention. Non-DC sugar alcohol particles can be seen as dark discrete areas evenly distributed throughout the tablet.

Fig. 11 illustrates a light microscope image of a cross section of a single module version of the tablet shown in FIG. 10, but no non-DC sugar alcohol particles in the tablet.

Fig. 12 illustrates a scanning electron microscope (SEM) close-up of a cross section of the first tablet module in FIG. 8. The morphology of non-DC sugar alcohol particles larger than 500 µm can be viewed in detail along with other particles as large irregularly shaped particles.

Fig. 13 illustrates a scanning electron microscope (SEM) close-up of a cross section of the second tablet module in FIG. 8 where non-DC sugar alcohol particles are not present.

Detailed description of the invention

In the context of this application, the term "tablet for oral administration" is considered as a tablet for oral administration. In particular, a tablet for oral administration is considered to be formed by tableting, ie compressing, a composition of particles comprising said plurality of particles. Thus, a tablet is considered a compressed multiparticulate tablet. Generally, an oral tablet may also be referred to as a tablet.

The term "weigh of a tablet for oral administration" or a similar wording meaning the same is defined in the context of the present invention as the weight of a tablet for oral administration, not including the weight of an outer coating such as a hard coating, a soft coating, and the like.

By "texture" is meant a qualitative measure of the properties of an oral tablet and the overall mouthfeel experienced by the user during use. Thus, the term "texture" covers measurable quantities such as hardness, as well as more subjective parameters related to the sensations experienced by the user.

The term "delayed release" or "extended release" in this application is intended to mean prolonged release over time. The term "accelerated release" or "quick release" or "intense release" in this application is intended to mean a higher amount of content released over a given period of time. The term "controlled release" is intended to mean the release of a substance from an oral tablet upon active use of the oral tablet in the oral cavity of a subject, whereby the active use regulates the amount of substance released.

The verb "include" as used herein and in the claims, and its conjugations, is used in a non-limiting sense to mean that elements following this word are included, but elements not specifically mentioned are not excluded. Also, referring to an element with the indefinite article "a" or "an" does not exclude the possibility of more than one of the elements, unless the context clearly requires one and only one of the elements. Thus, the indefinite article "a" or "an" usually means "at least one". In addition, the words "a" and "an" when used herein in conjunction with the word including or containing, mean "one or more". The expression "one or more" is intended to mean one, two, three or more.

In the context of this application, the term "about" or "about" in relation to a number generally includes numbers that fall within the range of 5%, 10%, 15%, or 20% in any direction (greater than or less than) of the specified value, unless otherwise specified or not obvious from the context (unless such a number would be less than 0% or greater than 100% of the possible value).

In the context of the present invention, the phrase “particle population” refers to a statistical population of particles. The population of particles can be characterized by a number of different parameters, such as statistical parameters such as particle distribution, average particle size, breadth of particle size distribution, and so on. The population of particles may contain subpopulations such as DC sugar alcohol particles, non-DC sugar alcohol particles, or, in some embodiments, particles comprising a gum base. The phrase "particle population" in an embodiment of the invention may be represented as a plurality of particle pellets, and where the population of particles is tableted into one module, or it may refer to a population of particles, where some of the particles are tableted into one module, and other particles are tableted into another module. .

In the context of the present invention, the term “non-DC regions” refers to small volumes or spaces formed during tableting from non-DC particles of non-DC sugar alcohol. In addition, each of the non-DC regions may consist of a single non-DC sugar alcohol particle or may include multiple non-DC sugar alcohol particles. When non-DC regions are well-defined, i.e. non-blurred, non-DC regions may be uniformly distributed within a tablet, or at least one module thereof, when the tablet includes two or more modules. In such embodiments, where the non-DC regions are evenly distributed throughout the tablet, or at least one module thereof, the non-DC regions can thus promote uniform saliva production in the mouth during chewing.

The term “non-DC sugar alcohol particles” refers to non-directly compressible (non-DC) sugar alcohol particles. It should be noted that the terms "non-DC sugar alcohol particles" and "non-DC particles" are used interchangeably. In the context of the present invention, non-DC sugar alcohol particles refer to particles that have not been previously granulated, for example with other sugar alcohols or binders, to obtain so-called directly compressible particles (DC). In the context of the present invention, non-DC sugar alcohol particles include particles obtained by crystallization followed by grinding that does not include other sugar alcohols or binders. Thus, non-DC sugar alcohol particles are considered to be non-DC sugar alcohol particles.

The term “DC sugar alcohol particles” refers to directly compressible (DC) sugar alcohol particles. It should be noted that the terms "DC sugar alcohol particles" and "DC particles" are used interchangeably. DC sugar alcohol particles can be obtained, for example, in the form of particles of sugar alcohols having the category DC in nature, for example, sorbitol, or by granulating non-DC sugar alcohol, for example, with other sugar alcohols or binders in order to obtain so-called direct compressible particles (DC). In addition, granulation of non-DC sugar alcohol with water as a binder results in "DC sugar alcohol particles" in the context of the present invention.

In the context of the present invention, when non-DC regions are referred to as "discrete", this means that non-DC sugar alcohols are not continuously distributed, but are present in discrete regions corresponding to the discrete nature of the non-DC sugar alcohol particles.

In the context of the present invention, the term "suitable for active pharmaceutical ingredients" refers to a tablet as a suitable carrier, for example, for the inclusion and delivery of active pharmaceutical ingredients. However, it should be noted that a tablet may or may not include active pharmaceutical ingredients or active ingredients.

With regard to induced saliva production, it should be noted that this induced saliva production exceeds any saliva production without using the tablet of the invention. In particular, in an embodiment, induced saliva production exceeds saliva production using conventional tablets without non-DC regions. Thus, induced saliva production is increased compared to any saliva production associated with conventional products, for example when compared to a tablet without non-DC sugar alcohol particles, or a tablet where the discrete regions are based on DC sugar alcohol particles.

With regard to induced saliva production, saliva production is tested using the following method, unless otherwise indicated.

The subject of the study refrains from eating and drinking at least 30 minutes before the start of any study. Immediately before the introduction of the tablet into the oral cavity, the subject swallows. The subject refrains from swallowing during the test. Immediately after inserting the tablet into the oral cavity, the subject begins chewing the tablet at a frequency of 1 chew per second for 20 seconds. The saliva and any residue of the tablet is then held in the mouth while chewing for 10 seconds. 30 seconds after the start of the test, the subject spits saliva, including any tablet fragments, into a plastic cup, which is weighed. Saliva is also spit out 90 seconds after the start of chewing, 180 seconds after the start of chewing, 300 seconds after the start of chewing, 420 seconds after the start of chewing, and 600 seconds after the start of chewing. All the time the subject makes as few movements as possible and refrains from swallowing.

In the context of this application, the term "orally disintegrating tablet" or "ODT" is intended to mean a tablet as understood by a person skilled in the art of ODT tablets, i.e. a solid dosage form that rapidly (within seconds) disintegrates without water when placed on the tongue.

In the context of this application, the term "particle size" refers to the average particle size determined in accordance with the European Pharmacopoeia 9.1 using test method 2.9.38, evaluation of particle size distribution by analytical sieving, unless specifically stated otherwise.

The term "particle" or similar wording is intended to refer to a single discrete composition of a solid, such as a granule or individual elements in a powder, having a certain size, which can vary significantly.

In the context of this application, the term "active ingredient" refers to a substance that is biologically active and has a physiological effect on the human body for the benefit of the human body or part thereof. Active ingredients include active pharmaceutical ingredients as well as other active substances such as nutraceuticals.

A "self-emulsifying agent" is an agent that will form an emulsion when presented with an alternative phase with minimal energy consumption. In contrast, an emulsifying agent, unlike a self-emulsifying agent, requires additional energy to form an emulsion.

In the context of the present invention, the term "release" refers to the released substance released from the water-soluble matrix. In some embodiments, the release process of the substance corresponds to the dissolution of the substance in saliva. The term “release” in the context of the present invention means that it has been tested under “in vivo” conditions, unless otherwise indicated. In the context of the present invention, when a tablet is chewed, "in vivo" means that in a group of 8 subjects, the sample is chewed at a chewing frequency of 60 times per minute for a certain period of time, unless otherwise indicated. These subjects abstain from food and drink for at least 30 minutes prior to the start of any study. The test subjects are healthy subjects, objectively assigned in accordance with established requirements.

In the context of the present invention, the term “liquid” is intended to mean that the tablet disintegrates and the tablet fragments or particles are either suspended or dissolved in saliva, which is perceived as a liquid by the test subject, in accordance with the test procedure for induced saliva production.

In the context of the present invention, "crunchiness", "crunchiness", "crunchiness" or similar expressions, when used in connection with the maximum tablet resistance test, have the same meaning.

By "water-insoluble gum base" or "gum base" or "gum base matrix" or similar expressions are meant essentially water-insoluble gum base ingredients and hydrophobic gum base ingredients. The “gum base” may contain gum base polymers and plasticizers, waxes, emulsifiers, fats and/or fillers.

In the following, starting materials will refer to mixed particles to be compressed into a tablet according to embodiments of the invention, unless otherwise indicated.

The following description explains how the tablet of the present invention can be made and describes in more detail what can be added to the composition of the present invention.

Typically, the tablet manufacturing process of the present invention can be carried out in a single tablet press, such as a rotary tablet press. But in some circumstances it may be useful to use a separate tablet press.

Preferably, the top punch is convex, which gives the top surface of the compressed tablet a concave shape.

Of course, it should be noted that the shape of the punches may vary depending on the desired tablet shape.

In some embodiments of the invention, the tablets are compressed with a force of 20 to 50 kN.

Important tablet starting materials of the present invention are non-DC sugar alcohol particles in combination with DC sugar alcohol particles.

DC sugar alcohol particles refer to sugar alcohols known in the art as directly compressible (DC).

Non-DC sugar alcohol particles refer to sugar alcohols known in the art as indirectly compressible (DC).

According to a further embodiment of the invention, the non-DC sugar alcohol particles used are best characterized as non-directly compressible (non-DC). The use of non-DC sugar alcohols compared to conventional directly compressible sugar alcohols (DCs) has shown remarkable effects on the user's chewing delivery device experience. This may in part be due to the somewhat larger size of non-DC sugar alcohol compared to DC sugar alcohol, but it may also be the result of the high sugar alcohol content of the individual particles used for compression. DC sugar alcohols, which for obvious reasons are sold and used for compression, do not lead to such an improvement in the effect of salivation and mouthfeel.

It should be noted that non-DC terminology is readily understood in the art. Sugar alcohol suppliers provide clear guidance to the user regarding suitability for use in connection with tablet compression. The non-DC particle is referred to in this connection as a particle that is expressly not recommended for compression by the supplier. Examples of non-DC grade erythritol include Zerose (TM) 16952F erythritol available from Cargill. Further examples of non-DC sugar alcohol particles include non-DC xylitol as Xivia C from Dupont, non-DC isomalt as Isomalt GS from Beneo Paltinit, non-DC mannitol as Pearlitol from Roquette, non-DC maltitol as Maltisorb. P200 by Roquette. Examples of the Direct Compressible (DC) grade of erythritol include Zerose™ DC 16966, also available from Cargill. Additional examples of DC sugar alcohols include sorbitol particles represented, for example, as Neosorb® P 300 DC from Roquette, mannitol particles, represented, for example, as Pearlitol® 300DC or Pearlitol 200 SD from Roquette, maltitol, represented, for example, as SweetPearl® P 300 DC, xylitol, such as Xylisorb® 200 DC or Xylitab from Dupont.

Non-directly compressible (non-DC) sugar alcohols may include non-DC xylitol categories, non-DC erythritol categories, non-DC mannitol categories, non-DC maltitol categories, non-DC lactitol categories, non-DC isomalt categories, or other suitable categories of non-DC sugar alcohols.

Directly compressible (DC) sugar alcohols may include sorbitol, which is DC in nature, xylitol DC, erythritol DC, mannitol DC, maltitol DC, lactitol DC, isomalt, or other suitable DC sugar alcohols.

The present invention takes advantage of the synergy between non-DC sugar alcohol particles and DC sugar alcohol particles. DC sugar alcohols may be, for example, sorbitol, which is directly compressible in nature, or they may be other sugar alcohols that have been pre-treated, such as granulated with a suitable binder, to form particles that, when compressed, can encapsulate non-DC sugar particles. alcohol into a mechanically stable tablet. At the same time, the non-DC sugar alcohol particles serve as a salivation agent, which is attractive to the user, and also serve to dissolve the DC sugar alcohol particles while chewing the tablet as quickly as possible.

According to embodiments of the invention, encapsulated flavors or active ingredients may be added to the final mixture of starting materials prior to compression.

Various methods for encapsulating flavors or active ingredients, which can refer to both flavors and active ingredients mixed with the starting materials for compression into an oral tablet, for example, include spray drying, spray cooling, film coating, coacervation, double emulsions (extrusion technology) or prilling.

Materials that can be used for the encapsulation methods listed above may include, for example, gelatin, wheat protein, soy protein, sodium caseinate, casein, gum arabic, modified starch, hydrolyzed starches (maltodextrins), alginates, pectin, carrageenan, xanthan gum, gum carob, chitosan, beeswax, candelilla wax, carnauba wax, hydrogenated vegetable oils, zein and/or sucrose.

Preferably, these ingredients should be added after any significant heating or mixing. In other words, the active ingredients should preferably be added immediately prior to compression of the final tablet.

When the present invention is applied to chewing gum, the added active ingredients can be carefully mixed with the premixed gum base granulates and other ingredients, such as the ingredients mentioned in the present claims, just prior to the final compression of the tablet.

In one embodiment, the tablet according to the invention comprises a pharmaceutically, cosmetically or biologically active substance. Examples of such active substances, a complete listing of which can be found, for example, in WO 00/25598, which is incorporated herein by reference, include drugs, nutritional supplements, antiseptic agents, pH adjusting agents, anti-smoking agents, and substances for care or treatment. oral and dental cavities such as hydrogen peroxide and compounds capable of releasing urea when chewed. Examples of useful active substances in the form of antiseptics include salts and derivatives of guanidine and biguanidine (for example, chlorhexidine diacetate) and the following types of substances with limited water solubility: Quaternary ammonium compounds (for example, ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (for example, paraformaldehyde ), dequalin derivatives, polyoxylin, phenols (e.g. thymol, p-chlorophenol, cresol), hexachlorophene, salicylic anilide compounds, triclosan, halogens (iodine, iodophors, chloramine, dichlorocyanuric acid salts), alcohols (3,4-dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), see also Martindale, The Extra Pharmacopoeia, 28th edition, pages 547-578; metal salts, complexes and compounds with limited solubility in water, such as aluminum salts (for example, aluminum-potassium sulfate AlK(SO ₄ ) ₂ , 12H ₂ O), and salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulfate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium; other compositions for caring for the oral cavity and teeth: for example; salts, complexes and compounds containing fluorine (such as sodium fluoride, sodium monofluorophosphate, aminofluorides, stannous fluoride), phosphates, carbonates and selenium. Other active substances can be found in J. Dent. Res. Vol. 28 no. 2, pages 160-171, 1949.

Examples of active substances in the form of oral pH regulators include: acids such as adipic acid, succinic acid, fumaric acid or salts thereof, or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases such as carbonates, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.

The active ingredients may include, but are not limited to, the following compounds or derivatives thereof: Acetaminophen, Acetylsalicylic Acid, Buprenorphine, Bromhexine, Celcoxib, Codeine, Diphenhydramine, Diclofenac, Etoricoxib, Ibuprofen, Indomethacin, Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodone, Parecoxib , Piroxicam, Pseudoephedrine, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib, Calcium Carbonate, Magaldrate, Disulfiram, Bupropion, Nicotine, Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline, Granisetron, Ondansetron, Promethazine, Tropisetron, Brompheniramine, Ceterizine, Leko-Ceterizine, Chlorcyclizine, Chlorpheniramine, Chlorpheniramine, Diphenhydramine, Doxylamine, Phenofenadine, Guaifenesin, Loratidine, Des-Loratidine, Phenyltoloxamine, Promethazine, Pyridamine, Terfenadine, Troxerutin, Methyldopa, Methylphenidate, Benzalkonium Chloride, Benzethonium Chloride, Cetylpyridinium Chloride, Chlorhexidine, Ecooperidol, Halopexidine, Allopurinol, Colquinine, Theophylline, Propanolol, Prednisolone, Prednisone, Fluoride, Urea, Actot, Glibenclamide, Glipizide, Metformin, Miglitol, Repaglinide, Rosiglitazone, Apomorphine, Cialis, Sildenafil, Vardenafil, Diphenoxylate, Simethicone, Cimetidine, Famotidine, Ranitidine, Ratinidine, Cetrizine, Loratadine, Aspirin, Benzocaine, Dextromethorphan, Phenylpropanolamine, Pseudoephedrine, Cisapride, Domperidone, Metoclopramide, Aciclovir, Dioctylsulfosuccinates, Phenolphthalein, Almotriptan, Eletriptan, Ergotamine, Migea, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan, Aluminum salts, Calcium salts, Iron salts, Ag salts, Zinc salts, Amphotericin B, Chlorhexidine, Miconazole, Triamcinoloneacetonide, Melatonin, Phenobarbitol, Caffeine, Benzodiazepine, Hydroxyzine, Meprobamate, Phenothiazine, Buclizine, Bromethazine, Cinnarizine, Cyclizine, Diphenhydramine, Dimenhydrinate, Buflomedil, Amphetamine, Caffeine, Ephedrine, Orlistat, Phenylephedrine, Phenylpropanolamine, Pseudoephedrine, Pseudoephedrine, Ketoconazole, Nitroglycerin, Nystatin, Progesterone, Testosterone, Vitamin B12, Vitamin C, Vitamin A, Vitamin D, B vitamin E, pilocarpine, aluminum aminoacetate, cimetidine, esomeprazole, famotidine, lansoprazole, magnesium oxide, nizatide and/or ratinidin.

The present invention is suitable for increased or accelerated release of active substances selected from the group of nutritional supplements, oral and dental compositions, antiseptics, pH adjusting agents, anti-smoking agents, sweeteners, flavoring agents, flavoring agents or drugs. Some of them will be described below.

The active substances used in connection with the present invention may be any substance that is desired to be released from the tablet. Actives for which a controlled and/or accelerated release rate is desired are primarily those with limited water solubility, typically below 10 g/100 ml, including those that are completely water insoluble. Examples are drugs, nutritional supplements, oral compositions, anti-smoking agents, strong sweeteners, pH adjusting agents, flavorings, and the like.

Other active ingredients are, for example, paracetamol, benzocaine, cinnarizine, menthol, carvone, caffeine, chlorhexidine diacetate, cyclizine hydrochloride, 1,8-cineol, nandrolone, miconazole, mystatin, sodium fluoride, nicotine, cetylpyridinium chloride, other quaternary ammonium compounds , vitamin E, vitamin A, vitamin D, glibenclamide or its derivatives, progesterone, acetylsalicylic acid, dimenhydrinate, cyclizine, metronidazole, sodium bicarbonate, ginkgo active ingredients, propolis active ingredients, ginseng active ingredients, methadone, peppermint oil, salicylamide, hydrocortisone or astemizole.

Examples of active substances in the form of food supplements are, for example, salts and compounds with a nutritional effect of vitamin B2 (riboflavin), B12, folinic acid, folic acid, niacin, biotin, sparingly soluble glycerophosphates, amino acids, vitamins A, D, E and K , complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chromium, selenium, molybdenum, potassium, sodium or cobalt.

In addition, reference is made to lists of nutritionists adopted by authorities in various countries, such as, for example, the US Code of Federal Regulations, title 21, section 182.5013.182 5997 and 182.8013-182.8997.

Examples of active substances in the form of antiseptics are, for example, salts and compounds of guanidine and biguanidine (for example, chlorhexidine diacetate) and the following types of substances with limited solubility in water: quaternary ammonium compounds (for example, ceramine, chloroxylenol, crystal violet, chloramine), aldehydes ( e.g. paraformaldehyde), dequalin compounds, polyoxylin, phenols (e.g. thymol, p-chlorophenol, cresol), hexachlorophene, salicylic anilide compounds, triclosan, halogens (iodine, iodophors, chloramine, dichlorocyanuric acid salts), alcohols (3,4- dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), see also Martindale, The Extra Pharmacopoeia, 28th edition, pages 547-578; metal salts, complexes and compounds with limited solubility in water, such as aluminum salts (for example, aluminum-potassium sulfate AlK (SO ₄ ) ₂ , 12H ₂ O) and in addition, salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulfate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium; other compositions for caring for the oral cavity and teeth: for example; salts, complexes and compounds containing fluorine (such as sodium fluoride, sodium monofluorophosphate, aminofluorides, phosphates, carbonates and selenium.

See also J. Dent. Res. Vol. 28 no. 2, pages 160-171, 1949, which presents a wide range of tested compounds.

Examples of active substances in the form of oral pH regulators include, for example: acceptable acids such as adipic acid, succinic acid, fumaric acid or salts thereof, or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases such as carbonates, bicarbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.

Examples of active substances in the form of anti-smoking agents include, for example: nicotine, tobacco powder or silver salts such as silver acetate, silver carbonate and silver nitrate.

Other examples of active substances are drugs of any kind.

Examples of active substances in drug form include caffeine, salicylic acid, salicylamide and related substances (acetylsalicylic acid, choline salicylate, magnesium salicylate, sodium salicylate), paracetamol, pentazocine salts (pentazocine hydrochloride and pentazocine lactate), buprenorphine hydrochloride, codeine hydrochloride and codeine phosphate. , morphine and morphine salts (hydrochloride, sulfate, tartrate), methadone hydrochloride, ketobemidone and ketobemidone salts (hydrochloride), beta-blockers (propranolol), calcium antagonists, verapamil hydrochloride, nifedinpine, as well as suitable substances and their salts listed in Pharm . Int., Nov.85, pages 267-271, Barney H. Hunter and Robert L. Talbert, nitroglycerin, erythrityl tetranitrate, strychnine and its salts, lidocaine, tetracaine hydrochloride, etorphine hydrochloride, atropine, insulin, enzymes (eg papain, trypsin , amyloglucosidase, glucose oxidase, streptokinase, streptodornase, dextranase, alpha-amylase), polypeptides (oxytocin, gonadorelin, (LH.RH), desmopressin acetate (DDAVP), isoxsuprine hydrochloride, ergotamine compounds, chloroquine (phosphate, sulfate), isosorbide, demoxytocin , heparin.

Other active ingredients include beta-lupeol, Letigen®, sildenafil citrate and derivatives thereof.

Additional examples of active ingredients include dental products including urea, casein phospho-peptide CPP; chlorhexidine, chlorhexidine diacetate, chlorhexidine chloride, chlorhexidine digluconate, hexetedine, strontium chloride, potassium chloride, sodium bicarbonate, sodium carbonate, fluorine-containing ingredients, fluorides, sodium fluoride, aluminum fluoride.

Additional examples of active ingredients include ammonium fluoride, calcium fluoride, tin fluoride, other fluorine-containing ingredients Ammonium fluorosilicate, potassium fluorosilicate, sodium fluorosilicate, ammonium monofluorophosphate, calcium monofluorophosphate, potassium monofluorophosphate, sodium monofluorophosphate, ammonium octadecentyl fluoride, stearyltrihydroxyethyl propylenediamine dihydrofluoride.

Additional examples of active ingredients include vitamins. Vitamins include A, B1, B2, B6, B12, folinic acid, folic acid, niacin, pantothenic acid, biotin, C, D, E, K. Minerals include calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese , chromium, selenium, molybdenum. Other active ingredients include:

Q10®, enzymes. Natural remedies including ginkgo biloba, ginger and fish oil.

Additional examples of active ingredients include migraine drugs such as serotonin antagonists: Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Eletriptan; nausea medicines such as cyclizine, cinnarizine, dimenhydramine, diphenhydrinate; hay fever medicines such as Cetrizine, Loratidine, pain medicines such as Buprenorphine, Tramadol, oral medicines such as Miconazole, Amphotericin B, Triamcinoloneacetone; and medicines Cisapride, Domperidone, Metoclopramide. In a preferred embodiment, the invention relates to the release of nicotine and its salts.

In a preferred embodiment, the active ingredient is selected from throat active ingredients selected from acetylcysteine, ambroxol, amylmethacresol, benzocaine, bisacodyl, bismuth subsalicylate, bromhexine, cetirizine, cetylpyridinium, chlorhexidine, dextromethorphan hydrobromide, 2,4-dichlorobenzyl alcohol, doxylamine succinate, eucalyptus oil, flurbiprofen, glycerin, hexylresorcinol, lidocaine, menthol, myrrh, paracetamol, pectin, peppermint oil, phenol, phenylephrine, povidone-iodine, pseudoephedrine, ranitidine, simethicone, sodium docusate, peppermint, zinc, or any combination thereof; active ingredients of gastrointestinal active ingredients selected from alginate, atenolol, aspirin (acetylsalicylic acid), ampicillin, amino salicylates, anhydrous citric acid, aspirin, bisacodyl, bismuth subsalicylate, bupropion, caffeine, calcium, calcium carbonate, cetirizine, cimetidine, cisapride, clarithromycin, desloratadine, dexlansoprazole, diphenhydramine HCl, diphenhydramine citrate, dimenhydrinate, docusate sodium, erythromycin, dopamine, esomeprazole, famotidine, fexofenadine HCl, guaifenesin, hydrotalcite, ibuprofen, ketoprofen, lactase enzyme, lansoprazole, lorcaloramidine HCl, magnesium, magnesium carbonate, magnesium hydroxide, melatonin, methamphetamine HCl, metoclopramide, metronidazole, montelukast, mycostatin, naltrexone, naproxen, naproxen sodium, nizatidine, omeprazole, ondansetron, orlistat, pantoprazole, paracetamol (acetaminophen), pectin, phentermine HCl, polypodium leucotomos, prednisolo Na, Prednisone, Progesterone, Propranolol, Propantheline Bromide, Pseudoephedrine HCl, Phentermine, Rabeprazole, Ranitidine, Roflumilast, Scopolamine Butyl Hydroxide, Simethicone, Sodium, Sodium Bicarbonate, Sodium Docusate, Sumatriptan, Testosterone, Tetracycline, Topiramate, Vitamin A, Vitamin B, Vitamin B12, vitamin C (ascorbic acid), vitamin D and vitamin E, vitamin K, or any combination thereof, and active ingredients for buccal absorption selected from atenolol, baclofen, caffeine, carvedilol, chlorpheniramine, chlorpheniramine maleate, fluticasone propionate, maleate, desmopressin, diltiazem hydrochloride, doxylamine succinate, mycostatin, nicotine, nifedipine, nitroglycerin, omeprazole, ondansetron, oxymetazoline HCl, oxytocin, phenylephrine, piroxicam, prednisone, propranolol, salbutamol sulfate, scopolamine butyl hydroxide, sumatriptan, triamcinolone, and any combination thereof.

In another embodiment, sucrose fatty acid esters can also be used to increase the release of sweeteners, including, for example, so-called high-potency sweeteners such as, for example, saccharin, cyclamate, aspartame, thaumatin, dihydrocalcones, stevioside, glycyrrhizin, or salts or compounds thereof. . For increased sweetener release, the sucrose fatty acids preferably have a palmitate content of at least 40%, such as at least 50%.

When a gum base is included in the composition, sugar alcohols typically comprise from about 5% to about 95% by weight of the tablet, more typically from about 20% to about 80%, such as 30 to 70% or 30 to 60% by weight of the tablet.

In such an embodiment, the tablet further comprises, in addition to the sugar alcohols already described, substances selected from the group consisting of dry sweeteners, flavors, dry binders, tabletting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers , high intensity sweeteners, softeners, colors, or any combination thereof.

Suitable sugar alcohols typically comprise from about 40% to about 99.9% by weight of the tablet, for example, from about 80% to about 99% by weight of the tablet.

High intensity artificial sweeteners can also be used alone or in combination with the above sweeteners. Preferred high intensity sweeteners include, but are not limited to, sucralose, aspartame, acesulfame salts, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (a natural intense sweetener) and the like, singly or in combination. To provide a longer lasting sensation of sweetness and flavor, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweeteners. Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, canning, yeast cell encapsulation, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of sweeteners can also be achieved using another tablet component, such as a resinous compound.

The level of artificial sweetener use will vary greatly and will depend on factors such as the effectiveness of the sweetener, the rate of release, the desired sweetness of the product, the level and type of flavoring used, and the cost factor. Thus, the active level of the artificial sweetener may range from about 0.001 to about 8% by weight (preferably from about 0.02 to about 8% by weight). When carriers used for encapsulation are included, the level of use of the encapsulated sweetener will be proportionately higher. Combinations of sugar and/or non-sugar sweeteners can be used in the tablet composition.

The tablet according to the invention may, if desired, include one or more fillers/texturizers including, for example, magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, alumina, silicon oxide, talc, titanium oxide, mono-, di- and tricalcium phosphates, cellulose polymers, and combinations thereof.

Fig. 1a and 1b illustrate an embodiment of an oral tablet 10 according to an embodiment of the invention. Fig. 1a shows an oral tablet from the side and FIG. 1b shows the tablet from above.

The composition and method by which the tablet is made or can be made is described elsewhere in the application, and details regarding the structure and operation of this tablet 10 are also indicated and explained further with reference to FIG. 4 and FIG. 5.

Fig. 2a and 2b illustrate a two-module version of an oral tablet according to an embodiment of the invention. Fig. 2a shows an oral tablet from the side and FIG. 2b shows the tablet from above.

The composition and method by which the tablet is prepared are described elsewhere in the application.

Details regarding the structure and action of this tablet 10 are also indicated and explained below with reference to FIG. 4, 5 and 6.

This illustration is intended to provide an example of a physical form that may be applicable within the scope of the invention. The purpose is also to illustrate how the term "module" is understood and applied in the description, i.e. that a module refers to a collection of a plurality of particles, and the particles have been pelletized together to form a module. The term module is used to mean that one module includes one set of pelletized particles and another module includes a different set of tableted particles. Thus, a set of particles in the present context should be understood as a plurality of particles. Thus, a single particle, of course, is not understood as a module.

The modules are usually, but not necessarily, recognizable to the human eye, in particular if the compounds used in the various modules are formed by differently colored assemblies of particles or mixtures of particles.

Oral tablet 20 includes an upper module 21 and a lower module 22. Thus, the modules herein in the form of layers are physically distinct and each includes a population of particles that has been tableted. The collection of different modules 21 and 22 can typically be different for many purposes. Examples include use for visual presentation, for mechanical purposes such as strength, for medical purposes, and of course also for maximizing the desired effect of the non-DC sugar alcohol contained in the tablet.

In a preferred embodiment, most of the non-DC sugar alcohol(s) used are included in the upper module 21 and the lower module 22 is primarily composed of DC components, i.e., components such as sugar alcohols, fillers, flavors, colors etc. commonly used for direct pressing. In embodiments of the invention, the first module, here the lower module 22, can be considered and used as a carrier module supporting another module, here the upper module 21. The advantage of this separation in the development of properties is that the module containing non-DC sugar alcohol particles, may include significant amounts of non-DC sugar alcohol particles even though the intrinsic mechanical strength of the modules is significantly reduced, as the structural strength of the support modules can be calculated such that the overall structural strength of the tablet is sufficient to obtain the desired tablet friability and appearance. This multi-module design approach is of even greater interest as tablets designed according to this principle benefit from the disintegration and dissolution of the tablet matrix during tablet chewing due to the increased salivation effect resulting from the high content of applied non- DC of sugar alcohol particles in a relatively weak modulus.

Fig. 3a and 3b illustrate a three-module version of an oral tablet 30 according to an embodiment of the invention. Fig. 3a shows an oral tablet 30 from the side, and FIG. 3b shows the tablet from above.

The illustrated tablet 30 includes an upper module 31 and an intermediate module 33 and a lower module 32.

The top module 31 may, as explained in relation to the top module in FIG. 2a and 2b be formed by a collection of particles comprising an effective amount of non-DC sugar alcohol particles. The intermediate layer may include other non-DC sugar alcohol particles and/or the desired active ingredient.

The bottom module 32 may include significant amounts of DC particles such as sugar alcohol(s), fillers, some binder, and other appropriate ingredients to allow the bottom module 32 to form a structural support for at least the top module 31.

Fig. 4 illustrates a cross-sectional portion 40 of one of the oral tablets in FIG. 1-3. The oral tablet portion shown in FIG. 4 may thus correspond to the appearance of a part of the top layers 21 or 31 or a part of a tablet 1.

Such tablet portion 40 within the scope of the present invention may include at least two different types of particles, namely non-DC sugar alcohol particles 41 and DC particles 42. Preferred, but not limited, non-DC sugar alcohols are non-DC erythritol. and non-DC xylitol, as these non-DC sugar alcohols have been shown to be effective in producing the desired effect. The depicted non-DC particles 41, although they are represented graphically in the drawings, can of course include non-DC sugar alcohol particles of the same type, but also include a mixture of two or more non-DC sugar alcohol particles.

The particles are evenly distributed among the many DC particles 42 in the specified module. DC particles 42, although shown in the figure as particles of the same type, may include various types of DC particles of sugar alcohol, flavor particles, binders, and so on. The purpose of the drawing is to illustrate that the non-DC sugar alcohol particles 41 should in practice be uniformly distributed among the DC particles 42 in the final oral tablet 40. It may not be sufficient for the non-DC particles and DC particles to be homogeneously mixed at some manufacturing stage during the tableting process. A homogeneous mixture should preferably be maintained in the final oral tablet 40 in order to promote the desired effect and so that a mechanically stable tablet can be obtained. An additional beneficial effect of evenly distributed non-DC sugar alcohol particles can be obtained due to the preferential and increased salivation during tablet chewing.

The understanding and concept of a uniform distribution of non-DC sugar alcohol particles in the respective tablet module, from a practical point of view, can be very difficult to determine, since such definitions are very difficult to monitor and control during tablet processing, but it was possible to establish an industrial scale process where a mixture containing significant amounts of non-DC sugar alcohol(s) can be set throughout the process to the final tablet. Such a process can, for example, be confirmed by test production of a number of tablets, where deviations in the content of non-DC sugar alcohol in the manufactured tablets are determined.

It should be noted that the non-DC particles 41 form small subregions or subspaces in the final oral tablet or corresponding module of the final tablet, such as upper modules 21 and 31. These subregions are referred to elsewhere in this application as discrete non-DC regions and may be formed by individual non-DC particles or very small groups of these non-DC particles. Thus, these discrete non-DC regions are believed to be contained within a matrix formed by DC sugar alcohol particles or other DC particles.

Non-DC regions, in the present embodiment, the non-DC sugar alcohol particles 41 are thus included in the tablet in significant amounts and are mechanically supported and retained by the DC particles 42 and together form a matrix that, when chewed, can result in non- DC particles of sugar alcohol 42 in contact with the oral cavity and promote salivation. Increased salivation, together with the relatively weak mechanical structure of the module or tablet incorporating non-DC sugar alcohol particles, causes the tablet to rapidly break down and thus push the non-DC particles into contact with the oral cavity in a way that is completely different from compressed tablets. made from DC sugar alcohol particles such as granular erythritol or xylitol.

Thus, non-DC regions can lead to induced saliva production when the tablet is chewed and also induce and promote very fast and pleasant dissolution of the tablet matrix compared to conventional compressed tablets.

The active ingredients may be present as both DC and non-DC particles, provided that the active ingredient as such does not significantly interfere with other compounds. If the active ingredients are non-DC particles, the amount should be low enough to ensure mechanical stability of the tablet or modules, or alternatively compensated by appropriate DC particles or binders. It should be noted that such compensation should be carefully considered as this compensation may reduce both the salivation effect and the texture/feel in the mouth during chewing.

Fig. 5 illustrates a partial cross section of one of the oral tablets in FIG. 1-3. The oral tablet portion shown in FIG. 5 can thus correspond to the appearance of a part of the upper modules 21 or 31 or of the tablet 1.

With regard to the components used, the part of the tablet shown in FIG. 5 may largely correspond to the embodiment of FIG. 4, but the tablet portion now includes larger non-DC particles 51 containing DC particles 52 when compressed.

This Fig. 5 is presented simply to show that, in particular, non-DC sugar alcohol particles can be larger than DC particles, and in this context it is also noted that using larger non-DC sugar alcohol particles can indeed increase the salivation to be achieved or the desired effect.

Fig. 6 illustrates a particular transition in tablet 60 with two adjacent modules according to an embodiment of the invention. The illustrated portion of such a tablet may, for example, refer to the transition between modules 21 and 22 of tablet 20 as shown in FIG. 2a. Tablet 60 includes non-DC sugar alcohol particles 61 and DC particles 62 in one module, and another module includes DC particles 63. The concept of a module is easy to imagine here, since the combination of non-DC sugar alcohol particles 61 and DC particles 62 forms one module, and the collection of DC particles 63 forms another module. Often, the compositions of the DC sugar alcohol particles 62 and the DC sugar alcohol particles 63 may differ depending on the specific circumstances.

Also, with regard to FIG. 5 and FIG. 6, the active ingredients may be present as both DC and non-DC particles, provided that the active ingredient as such does not significantly interfere with other compounds. If the active ingredients are non-DC particles, the amount should be low enough to ensure mechanical stability of the tablet or modules, or alternatively compensated by appropriate DC particles or binders. It should be noted that such compensation should be carefully considered as this compensation may reduce both the salivation effect and the texture/feel in the mouth during chewing.

Particles comprising a gum base may also be present as both non-DC and DC particles, although DC particles comprising a gum base are highly preferred over non-DC particles containing a gum base. When using particles comprising a gum base, these particles are preferably, but not necessarily, included in the maintenance module as DC particles 63, for example mixed with sugar alcohol particles 63, as shown in FIG. 6.

All modules illustrated above are provided as layers. It is emphasized that other forms of modules may be applicable within the scope of the invention. Non-limiting examples are modules having a ball shape, a diamond shape, an oval shape, a cone shape, and so on. All appropriate forms must, of course, be adapted to suit the tabletting process according to criteria known in the art.

EXAMPLES

Examples 1-38. Obtaining bilayer tablets

Table 1A
Oral tablet compositions for the first layer of bilayer tablets containing non-DC sugar alcohol variants. Amounts are given in wt % based on the weight of the respective tablet layer. *Method limitation means maximum crush strength that can be measured up to 350 N. **Ungranulated sorbitol. starting material
(wt%) First layer Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Non-DC Xylitol fifty - - - - - Sorbitol** - fifty - - - - Non-DC Isomalt - - fifty - - - Non-DC Erythritol - - - fifty - - Non-DC Mannitol - - - - fifty - non-DC
Maltite - - - - - fifty DC Isomalt 43.75 43.75 43.75 43.75 43.75 43.75 flavoring four four four four four four HIS 0.25 0.25 0.25 0.25 0.25 0.25 magnesium stearate one one one one one one Binder HPC one one one one one one Crushing strength [N]* 160 >350 190 142 90 174 Abrasion 0.74 0.25 0.63 1.30 1.45 1.00 Table 1B
Oral tablet compositions for the first layer of bilayer tablets containing non-DC sugar alcohol variants. Amounts are given in wt % based on the weight of the respective tablet layer. *Method limitation means maximum crush strength that can be measured up to 350 N. **Ungranulated sorbitol. starting material
(wt%) First layer Ex 7 Ex 8 Ex 9 Ex 10 Ex 11 Ex 12 Non-DC Xylitol fifty - - - - - Sorbitol** - fifty - - - - Non-DC Isomalt - - fifty - - - Non-DC Erythritol - - - fifty - - Non-DC Mannitol - - - - fifty - non-DC
Maltite - - - - - fifty Sorbitol 44.25 44.25 44.25 44.25 44.25 44.25 flavoring four four four four four four HIS 0.25 0.25 0.25 0.25 0.25 0.25 magnesium stearate one one one one one one Binder HPC 0.5 0.5 0.5 0.5 0.5 0.5 Crushing strength [N]* 190 >350 270 170 120 210 Abrasion 0.65 0.12 0.87 1.13 1.25 0.88 table 2
Oral tablet compositions for the second layer of bilayer tablets. Amounts are given in wt % based on the weight of the respective tablet layer. starting material
(wt%) Second layer Ex 1-12 Ex 13-24 Project 25-36 DC Maltite 94.75 - - DC Xylitol - 94.75 - DC Isomalt - - 94.75 flavoring four four four HIS 0.25 0.25 0.25 magnesium stearate one one one Table 3
Oral tablet compositions for bilayer tablets containing DC-sugar alcohol variants. Amounts are given in wt % based on the weight of the respective tablet layer. *Method limitation means the maximum crushing strength that can be measured up to 350 N. starting material
(wt%)
First layer Project 37 Project 38 Non-DC Erythritol fifty fifty DC Isomalt 43.75 43.75 flavoring four four HIS 0.25 0.25 magnesium stearate one one Binder HPC one one starting material
(wt%) Second layer Project 37 Project 38 DC Erythritol 94.75 - DC Mannitol - 94.75 flavoring four four HIS 0.25 0.25 Magnesium
Stearate one one Crushing strength [N]* 140 182 Abrasion 1.25 1.68

Process flow diagram

Each of the compositions shown in Tables 1A and 1B and 2 was processed into bilayer tablets with the compositions shown in examples 1-12, 13-24 and 25-36. In other words, examples 1-12 are bilayer tablets with the first layer according to Tables 1A and 1B and the second layer based primarily on DC maltitol. In examples 13-24, the second layer is based primarily on DC Xylitol. In examples 25-36, the second layer is based primarily on DC isomalt, as shown in Table 2.

The composition of Table 3 was similarly processed into the corresponding bilayer tablets with each of the compositions, as indicated in examples 37 and 38.

For each example 1-38, the starting materials were sieved through a 1600 micron sieve and then weighed in the required amount in accordance with the exemplary compositions of Tables 1A - 3.

The weighed amounts were then added to the Turbula mixer in a stainless steel container and mixed at 50 rpm for 5 minutes. MgSt was added after 4 minutes of stirring.

The mixtures were then tabletted using Piccola RIVA DC-SC-041-2 or Fette 3090i.

The dies used had circular cross sections with 16 mm diameters and had a recess to produce concave and/or curved tablets. Obviously, other mold sizes and shapes can be used within the scope of the present invention.

The resulting tablets according to Examples 1-38 were then prepared by tableting with a suitable pressure force.

For each tablet of Examples 1-38, the second layer, as shown in Table 2 and referred to as the second layer in Table 3, was first compressed at a first relatively low pressure. The mixed composition of the so-called first layer, i.e. the compositions of Tables 1A and 1B and the first layer of Table 3, was then fed into a mold, and the final bilayer tablet was then compressed at a higher pressure than the pressure applied to the first layers, thus obtaining the final bilayer tablets in accordance with Examples 1-38. It should be noted that the final bilayer tablets of Examples 1-38 are tablets with a weight of 1.8 grams, and that the first layer of tablets has a weight of 0.9 and the second layer of tablets has a weight of 0.9 grams.

The specification of the respective compounds used in the examples explained above is given below.

HPC: Hydroxypropylcellulose. Ashland Klucel Nutra D

Non-DC Xylitol: Xivia C by Dupont

PharmSorbidex Raw Sorbitol by Cargill

Non-DC Isomalt: Isomalt GS by Beneo Paltinit

Non-DC Mannitol: Pearlitol by Roquette

Non-DC Maltitol: Maltisorb. P200 by Roquette

Non-DC Erythritol: Zerose 16952 by Cargill

DC Erythritol -Zerose 16966 by Cargill

DC Xylitol - Xylitab 200 by Dupont

DC Isomalt - Isomalt DC 101 by Beneo Paltinit

DC Mannitol - Pearlitol SD200 by Roquette

DC Maltite - Sweetpearl 300 DC by Roquette

Examples 39-41

Table 3B
Compositions for tablets for oral administration weighing 1.8 grams. Amounts are given in wt % based on the weight of the tablet. starting material
(wt%) l layer Project 39 Ex 40 Project 41 DC Isomalt 45 35 - Non-DC Erythritol 48.75 43.75 48.75 DC _CaCO3 - fifteen 45 flavoring four four four HIS 0.25 0.25 0.25 magnesium stearate one one one Binder HPC one one one

All ingredients were obtained in the form of a powder.

DC Isomalt - Isomalt DC 101 by Beneo Paltinit

Non-DC Erythritol: Zerose 16952 by Cargill

HPC: Hydroxypropylcellulose. Ashland Klucel Nutra D

DC CaCO3: Scoralite 97 PVP by Scora

Process flow diagram

For each of Examples 39-41, the starting materials were sieved through a 1600 micron sieve and then weighed in the required amount in accordance with the composition examples of Table 3B.

For each example, the weighed amounts were then added to a Turbula mixer in a stainless steel container and mixed at 50 rpm for 4 minutes and then magnesium stearate was added and mixed for another minute.

The resulting tablets according to Examples 39-41 were then prepared by tableting the mixtures with Piccola RIVA DC-SC-041-2. It is also possible to use Fette 3090i.

Grade

Table 3C
Sensory Evaluation Examples 13-18. Etc. General sensory perception
Good/
Acceptable (acceptable)/Poor Suitable fast dissolving chewable tablet Elementary
wetting effect 1-5
1 low
5 high 13 Accept. Slightly hard initial chew, crumbles with a crunchy feeling, many large particles for a long time four fourteen Badly Unacceptable hard chewing - not chewed or completely dissolved within the first 30 seconds. 2 fifteen Badly Very hard and hard to break. Saliva increases, but in the first 30 seconds there are many large undissolved particles. 3 16 Good Pleasantly crunchy, fast-dissolving tablet 5 17 Badly Soft initial chewing, change in mouthfeel.
Feeling sticky. Doesn't dissolve fast enough and doesn't give a nice wetting effect 2 eighteen Badly Hard initial chewing. Very crumbly and feeling of sand. Saliva formation, but feeling of liquid with grains of sand four

The above-described bilayer tablets of examples 13-18 were evaluated in accordance with three parameters using a group of subjects.

Two of the parameters were chewability and one parameter was considered the wetting effect. Due to the more complex nature of the bilayer tablet, two additional parameters were evaluated, namely crush strength and friability.

First of all, it was noted that the wetting effect was considered relatively high for examples 13, 15, 16 and 18, ie examples based on non-DC Xylitol, non-DC Isomalt, non-DC Erythritol and non-DC Maltitol. The wetting effect was considered representative or equal to the salivation effect described in another section.

The test group clearly showed that the overall chewing process and mouth feel were at least impressive compared to Example 16 based on non-DC Erythritol. It was also noted that the test panel identified non-DC Xylitol Example 13 and non-DC Maltitol Example 18 as having an impressive wetting effect compared to, for example, a sorbitol-based example.

In addition to sensory evaluation, crush strength and friability were measured and reported in Examples 13-24, i.e. for a bilayer tablet with a first layer as listed in Table 1A and Table 1B and a second layer based primarily on DC xylitol. as indicated in Table 2.

The crushing strength was determined according to the European Pharmacopoeia 9.1, test method 2.9.8., using a pharmaceutical crushing strength tester model Pharma Test type PTB 311.

The friability was measured according to the European Pharmacopoeia 9.1, test method 2.9.7, using the PTF 10E pharmaceutical tablet friability tester from Pharma Test.

Fig. 7 illustrates the measurement of the effect of salivation in relation to the above Examples 13-18, where various non-DC sugar alcohols were used. Sorbitol was used as a reference as a representative DC sugar alcohol.

ISX1 refers to the non-DC xylitol of Example 13,

ISX2 refers to Example 14 sorbitol,

ISX3 refers to the non-DC isomalt of Example 15,

ISX4 refers to non-DC erythritol Example 16,

ISX5 refers to non-DC mannitol example 17 and

ISX6 refers to the non-DC maltitol of Example 18.

Saliva production measured with reference to FIG. 7 and the corresponding examples, is defined in the description as the definition with reference to the measurement method.

The results of measuring saliva production are shown in FIG. 7 where saliva production was measured in grams as a function of time (minutes).

It should be noted that saliva production from all non-DC sugar alcohols is initially impressive, but it should also be noted that saliva production over time is at least astonishing for ISX4, i.e. non-DC erythritol Example 16. Thus, it is noted that the salivation effect is enhanced for a very long time after most of the non-DC erythritol tablet has been swallowed or collected at the time of measurement. It was also observed that the relatively low initial effect of the perceived salivation of Example 14, i.e. the sorbitol-based example, confirms the sensory score above.

Examples 42-43. Preparation of bilayer tablets with ODT tablet

Table 4
Oral tablet compositions for bilayer tablets, wherein the layer comprising Pearlitol Flash is an ODT layer. The ratio of layer 1 to layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. Pearlitol Flash** is a trademark of Roquette and is a combination of strength with fast disintegration, composed of mannitol and starch, specially formulated for disintegrating properties, instant melt in the mouth with a creamy slightly sweet texture. starting material
(wt%)
First layer Project 42 Project 43 Non-DC Erythritol fifty fifty DC Isomalt - 44.75 Pearlitol Flash** 44.75 - flavoring 2 2 HIS 0.25 0.25 magnesium stearate 2 2 Binder HPC one one starting material
(wt%) Second layer Project 42 Project 43 Pearlitol Flash** - 98.8 DC Xylitol 98.8 - flavoring one one HIS 0.2 0.2 magnesium stearate one one Table 4B
An oral tablet formulation for bilayer tablets wherein layer 2 is an ODT layer. The ratio of layer 1 to layer 2 is 75:25. The weight of the tablet is 1.2 g. Therefore, the weight of layer 1 is 0.90 g, while the weight of layer 2 is 0.30 g. The amounts are given in wt.% of the weight of the respective tablet layer. It was observed that the ODT layer disintegrated within 60 seconds. starting material
(wt%)
First layer Project 43B Non-DC Erythritol 55 DC Isomalt 34.75 flavoring four HIS 0.25 magnesium stearate one Binder HPC 5 starting material
(wt%) Second layer Project 43B DC Mannitol 85 Microcrystalline cellulose (MCC) 5 Binder Crospovidone eight flavoring one HIS one

Examples 44-46 Preparation with different levels of non-DC sugar alcohol

Table 5
Oral tablet compositions for bilayer tablets. The ratio of layer 1 to layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. *Method limitation means maximum crush strength that can be measured up to 350 N starting material
(wt%) l layer Project 44 Project 45 Project 46 Non-DC Erythritol 5 fifty 82 DC Isomalt 90.8 43.8 9.8 flavoring 3 3 3 HIS 0.2 0.2 0.2 Binder HPC one 3 5 starting material
(wt%) Second layer Project 44 Project 45 Project 46 DC Xylitol 91.9 91.9 91.9 DC _CaCO3 5 5 5 flavoring 3 3 3 HIS 0.1 0.1 0.1 Crushing strength [N]* 140 100 55 Abrasion 0.70 1.98 5.8

Examples 47-50 Preparation with different levels of non-DC sugar alcohol

Table 6
Oral tablet compositions for bilayer tablets. The ratio of layer 1 to layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. *Method limitation means the maximum crushing strength that can be measured up to 350 N. starting material
(wt%) l layer Project 47 Project 48 Project 49 Project 50 DC Erythritol 0 twenty thirty fifty Non-DC Erythritol fifty thirty twenty 0 DC Isomalt 43.8 43.8 43.8 43.8 flavoring 3 3 3 3 HIS 0.2 0.2 0.2 0.2 Binder HPC 3 3 3 3 starting material
(wt%) Second layer Project 47 Project 48 Project 49 Project 50 DC Xylitol 91.9 91.9 91.9 91.9 DC _CaCO3 5 5 5 5 flavoring 3 3 3 3 HIS 0.1 0.1 0.1 0.1 Crushing strength [N]* 77 97 109 133 Abrasion 2.01 0.73 0.53 0.45

Process flow diagram

Each of the compositions shown in Tables 4, 4B, 5 and 6 was processed into bilayer tablets with the compositions shown in examples 42-50 and 43B.

For each example 42-50 and 43B, the starting materials were sieved through a 1600 micron sieve and then weighed in the required amount in accordance with the exemplary compositions.

The weighed amounts were then added to the Turbula mixer in a stainless steel container and mixed at 50 rpm for 5 minutes. If necessary, magnesium stearate was added after 4 minutes of mixing.

The mixtures were then tabletted using Piccola RIVA DC-SC-041-2 or Fette 3090i.

The dies used had circular cross sections with 16 mm diameters and had a recess to produce concave and/or curved tablets. Obviously, other mold sizes and shapes can be used within the scope of the present invention.

The resulting tablets according to Examples 42-50 and 43B were then prepared by tableting with a suitable pressure force.

For each tablet of Examples 44-50, the second layer was first compressed at a first relatively low pressure. The mixed composition of the so-called first layer was then fed into a mold, and the final bilayer tablet was then compressed at a higher pressure than the pressure applied to the first layers, thus obtaining the final bilayer tablets according to Examples 44-50. For examples 42-43 and 43B, the first layer was first compressed at a first relatively low pressure. The mixed composition of the so-called second layer was then fed into a mold, and the final bilayer tablet was then compressed at a higher pressure than the pressure applied to the first layers, thus obtaining the final bilayer tablets according to Examples 42-43 and 43B.

It should be noted that the final bilayer tablets of Examples 42-43 are 1.5 gram tablets and the ratio of layer 1 to layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g.

It should be noted that the final bilayer tablets of Example 43B are 1.2 gram tablets and the ratio of layer 1 to layer 2 is 75:25. The weight of the tablet is 1.2 g. Therefore, the weight of layer 1 is 0.90 g, while the weight of layer 2 is 0.30 g.

It should be noted that the final bilayer tablets of Examples 44-50 are 1.5 gram tablets and the ratio of layer 1 to layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g.

The specification of the respective compounds used in the examples described above is given below.

HPC: Hydroxypropylcellulose. Ashland Klucel Nutra D

Non-DC Xylitol: Xivia C by Dupont

PharmSorbidex Raw Sorbitol by Cargill

Non-DC Isomalt: Isomalt GS by Beneo Paltinit

Non-DC Mannitol: Pearlitol by Roquette

Non-DC Maltitol: Maltisorb. P200 by Roquette

Non-DC Erythritol: Zerose 16952 by Cargill

DC Erythritol -Zerose 16966 by Cargill

DC Xylitol - Xylitab 200 by Dupont

DC Isomalt - Isomalt DC 101 by Beneo Paltinit

DC Mannitol - Pearlitol SD200 by Roquette

DC Maltite - Sweetpearl 300 DC by Roquette

DC CaCO3: Scoralite 97 PVP by Scora

Pearlitol Flash is a trademark Roquette

Microcrystalline cellulose (MCC): Avicel PH-105 from FMC

Crospovidone: Kollidon CL-SF from BASF

Test scheme

The bilayer tablets of Examples 42-50 and 43B described above were evaluated for wetting effect by a group of subjects in an intensity versus time evaluation model. The wetting effect is the wetting effect felt by the test group, that is, the overall impression of the wetting effect when administered orally and at the start of the test.

The test design consisted of 8 subjects in a test panel with 2 repetitions of each option. Each of the subjects was a healthy person assigned on an objective basis in accordance with established requirements. Sensory analysis was performed in accordance with ISO 4121-2003 under test conditions in accordance with ISO 8589. The result is the average of the results of 8 individuals for 2 repetitions, which gives a total of 16 measurements for each option.

8 Subjects were instructed to swallow saliva prior to the test and were not allowed to swallow during the test. The subjects chewed the samples at a frequency of about 60 chewing movements per minute. After 30 seconds, the saliva formed was collected and its weight was recorded. Before conducting a new test, the oral cavity was rinsed with water and kept for a period of 4 minutes before the next test. Each sample was tested twice by each participant. Thus, 16 test results were obtained for each sample. Each subject was allowed to test 6 samples in a series of tests. There was a break of at least 30 minutes between each series of tests.

Subjects reported the intensity of the wetting effect on a scale of 0 to 10, with 10 being the highest wetting effect. The wetting effect was measured as a function of time in seconds.

It was seen that the ODT layers of Examples 42, 43 and 43B disintegrate in seconds, for example within 90 seconds or less.

Due to the more complex nature of the bilayer tablet, two additional parameters were evaluated, namely crush strength and friability. Crush strength and abrasion were measured and reported in Examples 44-50.

The crushing strength was determined according to the European Pharmacopoeia 9.1, test method 2.9.8., using a pharmaceutical crushing strength tester model Pharma Test type PTB 311.

The friability was measured according to the European Pharmacopoeia 9.1, test method 2.9.7, using the PTF 10E pharmaceutical tablet friability tester from Pharma Test.

wetting effect

Table 7
Wetting effect results based on the data of Examples 44-46. The values indicate the intensity of the wetting effect on a scale of 0 to 10, where 10 is the highest rating for the wetting effect. The wetting effect was measured as a function of time in seconds. Samples were chewed for 30 seconds without swallowing. wetting effect Project 44 Project 45 Project 46 15 sec. 6.33 7.36 7.66 20 sec. 7.38 8.37 8.53 25 sec. 8.36 8.93 9.38

The results clearly show that a high amount of non-DC erythritol (Ex 46) favorably affects the wetting effect. A low value of non-DC erythritol (Ex 44) is less useful in terms of wetting effect. It should be noted that even a small difference in these values is noticeable. The result also clearly shows that the wetting effect for all samples was higher as a function of time. The value of 9.38, obtained in just 25 seconds for Ex 46, was close to the highest perceptible level.

Table 8
Wetting effect results based on the data of Examples 47-50. The values indicate the intensity of the wetting effect on a scale of 0 to 10, where 10 is the highest rating for the wetting effect. The wetting effect was measured as a function of time in seconds. Samples were chewed for 30 seconds without swallowing. wetting effect Project 47 Project 48 Project 49 Project 50 5 sec. 1.85 1.98 1.95 1.82 10 sec. 3.67 3.99 3.52 3.43 20 sec. 6.74 6.16 6.18 5.73 25 sec. 8.03 7.42 7.61 7.64

The results show that a high amount of non-DC erythritol (Ex 47) favorably affects the wetting effect. A low non-DC erythritol value (Ex. 50) is less beneficial for the wetting effect, but still acceptable. It should be noted that even a small difference in these values is noticeable. The result also clearly shows that the wetting effect for all samples was higher as a function of time. It was surprising that these values increased as much over time.

Examples 51-59 Preparation of powders with different particle size distributions

Table 9
Test comparing different particle size distributions of selected non-DC sugar alcohols. The particles were sifted through a sieve with a mesh size allowing particles smaller than 500 microns to pass and particles larger than 500 microns to be collected. Two fractions were used for further analysis. "Non-DC" with no particle size specification was the starting material that was not screened. Initial powder Project 51 Isomalt non-DC < 500 microns Project 52 Isomalt non-DC > 500 microns Project 53 Isomalt non-DC Project 54 Xylitol non-DC < 500 microns Project 55 Xylitol non-DC > 500 microns Project 56 Xylitol non-DC Project 57 Erythritol non-DC < 500 microns Project 58 Erythritol non-DC > 500 microns Project 59 Erythritol non-DC

In this example, the powders were tested by evaluating the total mass of saliva formed upon oral administration.

Non-DC Xylitol: Xivia C by Dupont

Non-DC Isomalt: Isomalt GS by Beneo Paltinit

Non-DC Erythritol: Zerose 16952 by Cargill

The particles were sifted through a sieve with a mesh size allowing particles smaller than 500 microns to pass and particles larger than 500 microns to be collected. Two fractions were used for further analysis. "Non -DC" with no particle size specification was the starting material as above which was not sieved.

Test scheme

The above powders of Examples 51-59 were tested by evaluating the total mass of saliva formed by oral administration, using a group of subjects.

The test scheme consisted of 8 subjects with 2 repetitions. The subjects were healthy individuals assigned on an objective basis in accordance with established requirements. Sensory analysis was performed according to ISO 4121-2003 under test conditions according to ISO 8589.

Different fractions were tested for the total mass of saliva produced, according to the following procedure:

Fractions were tested in a continuous procedure, without stopping, to obtain reproducible values. A powder fraction of 1.0 g was weighed into a container. In this test, subjects were instructed to swallow saliva prior to the start of the test and were not allowed to swallow it during the test. The powder was placed on the first 1/3 of the tongue, the head was pushed forward and not allowed to be swallowed during the test. The subjects chewed the powder at a frequency of about 60 chews per minute. After 60 seconds, the saliva formed was collected and its weight was recorded. Before conducting a new test, the oral cavity was rinsed with water and kept for a period of 4 minutes before the next test. For each subject, a series of 2 tests was performed.

Table 10
The results of determining the total mass of the allocated saliva when using the preparations of examples 51-59. Mass of saliva, grams Project 51 Project 52 Project 53 Project 54 Project 55 Project 56 Project 57 Project 58 Project 59 Mean 3.9 4.0 3.9 4.1 4.5 4.3 4.4 5.1 4.5

The results can be divided into two main conclusions:

First, the results clearly show that non-DC erythritol provided better saliva production (Ex. 59) than non-DC xylitol (Ex. 56), and even better than non-DC isomalt (Ex. 53). It should be noted that although non-DC erythritol showed the best result in total saliva production during the test period, the result of both xylitol and isomalt was at a very favorable level.

Secondly, the results also show very favorably that for all three non-DC sugar alcohols, particle sizes greater than 500 microns were particularly favorable for saliva formation compared to less than 500 microns. The best results were obtained for non-DC erythritol (Ex. 58) with a particle size distribution greater than 500 microns, with xylitol at the lowest value (Ex. 55) and isomalt at the lowest value (Ex. 52), but still very favorable meaning.

Examples 60-62 Preparation of powders with various sugar alcohols

Table 11
Test comparing selected non-DC sugar alcohols. Initial powder Project 60 Isomalt non-DC Project 61 Xylitol non-DC Project 62 Erythritol non-DC

In this example, various sugar alcohol powders were tested for the total weight of saliva produced by oral administration.

Non-DC Xylitol: Xivia C by Dupont

Non-DC Isomalt: Isomalt GS by Beneo Paltinit

Non-DC Erythritol: Zerose 16952 by Cargill

Test scheme

The above powders of Examples 60-62 were evaluated on the total weight of saliva formed by oral administration, using a group of subjects.

The test design consisted of 8 subjects in a test panel with 2 repetitions of each option. Each of the subjects was a healthy person assigned on an objective basis in accordance with established requirements. Sensory analysis was performed in accordance with ISO 4121-2003 under test conditions according to ISO 8589. The result is the average of the results in 8 individuals for 2 repetitions, which gives a total of 16 measurements for each option.

Various samples were tested for the total mass of saliva produced according to the following procedure:

A powder fraction of 1.0 g was weighed into a container. In this test, 8 subjects were instructed to swallow their saliva before starting the test. The powder was placed on the first 1/3 of the tongue, the head was pushed forward and not allowed to be swallowed during the test. The subjects chewed the powder at a frequency of about 60 chews per minute. After 60 seconds, the saliva formed was collected and its weight was recorded. Before conducting a new test, the oral cavity was rinsed with water and kept for a period of 4 minutes before the next test. For each subject, a series of 2 tests was performed. Thus, a total of 16 test pieces were obtained for each starting powder. Each subject was allowed to test 6 samples in a series of tests. A break of at least 30 minutes was required between each series of tests.

Table 12
The results of determining the total mass of the allocated saliva when using the preparations of examples 60-62. Mass of saliva, grams Project 60 Project 61 Project 62 Mean 4.1 4.2 4.4

The results clearly showed that non-DC erythritol provided better results (Ex 62) than non-DC xylitol (Ex 61), and even better than non-DC isomalt (Ex 60). It should be noted that although non-DC erythritol showed the best result in terms of total saliva production during the test period, the result for xylitol and isomalt was at a very favorable level.

Table 13
Test comparing different particle size distributions of selected non-DC sugar alcohols. Commercial grade non-DC sugar alcohol particles were sieved through a sieve with a mesh size allowing particles smaller than 500 microns to pass and particles larger than 500 microns to be collected. Two fractions were used for further analysis. Initial powder Project 63 Isomalt non-DC < 500 microns Project 64 Isomalt non-DC > 500 microns Project 65 Erythritol non-DC < 500 microns Project 66 Erythritol non-DC > 500 microns

In this example, the powders were tested for total oral saliva weight using different particle sizes of sugar alcohols.

Non-DC Isomalt: Isomalt GS by Beneo Paltinit

Non-DC Erythritol: Zerose 16952 by Cargill

The particles were sifted through a sieve with a mesh size allowing particles smaller than 500 microns to pass and particles larger than 500 microns to be collected. Two fractions were used for further analysis. "Non -DC" with no particle size specification was the starting material as above which was not sieved.

Test scheme

The above powders of Examples 63-66 were evaluated on the total weight of saliva formed by oral administration, using a group of subjects.

The test design consisted of 8 subjects in a test panel with 2 repetitions of each option. Each of the subjects was a healthy person assigned on an objective basis in accordance with established requirements. Sensory analysis was performed in accordance with ISO 4121-2003 under test conditions according to ISO 8589. The result is the average of the results in 8 individuals in 2 repetitions, which gives a total of 16 measurements for each option.

Various samples were tested for the total mass of saliva produced according to the following procedure:

A powder fraction of 1.0 g was weighed into a container. In this test, 8 subjects were instructed to swallow their saliva before starting the test. The powder was placed on the first 1/3 of the tongue, the head was pushed forward and not allowed to be swallowed during the test. The subjects chewed the powder at a frequency of about 60 chews per minute. After 60 seconds, the saliva formed was collected and its weight was recorded. Before conducting a new test, the oral cavity was rinsed with water and kept for a period of 4 minutes before the next test. For each subject, a series of 2 tests was performed. Thus, a total of 16 test specimens were obtained for each starting powder. Each subject was allowed to test 6 samples in a series of tests. A break of at least 30 minutes was required between each series of tests.

Table 14
The results of determining the total mass of the allocated saliva when using the preparations of examples 63-66. Mass of saliva, grams Project 63 Project 64 Project 65 Project 66 Mean 4.0 4.3 4.2 4.6

The results can be divided into two main conclusions:

First, the results showed very advantageously that for the two non-DC sugar alcohols, a particle size greater than 500 microns was particularly preferred over a particle size less than 500 microns. The best results were obtained for non-DC erythritol (Ex66) with a particle size distribution greater than 500 microns and isomalt with the lowest value (Ex64), but still an acceptable value.

Second, the result showed that saliva production was highest for non-DC erythritol compared to non-DC isomalt.

Examples 67-69. Getting bilayer tablets with CaCO ₃

Table 15
Oral tablet formulations for bilayer tablets with different levels of CaCO ₃ . The ratio of layer 1 and layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. *Method limitation means maximum crush strength that can be measured up to 350 N. **Ungranulated sorbitol. starting material
(wt%) l layer Project 67 Project 68 Project 69 Non-DC Erythritol fifty fifty fifty Sorbitol** 37.4 32.4 27.4 flavoring 2.5 2.5 2.5 HIS 0.1 0.1 0.1 Binder gum arabic 5 5 5 DC _CaCO3 5 ten fifteen starting material
(wt%) Second layer Project 67 Project 68 Project 69 DC Xylitol fifty fifty fifty Sorbitol** 42.9 37.9 32.9 flavoring 2 2 2 HIS 0.1 0.1 0.1 DC _CaCO3 5 ten fifteen Crushing strength [N]* 145 115 107 Abrasion 1.08 1.45 1.87

Each of the compositions shown in Table 15 above was processed into bilayer tablets with the compositions shown in Examples 67-69 and processed according to the flow chart of Examples 42-50. The compositions of Examples 67-69 were further evaluated for wetting effect by a panel of subjects in an intensity versus time scoring model according to the test design of Examples 42-50. The compositions are particularly suitable for whitening effects.

Examples 70-72. Preparation of bilayer tablets with dentifrice

Table 16
Oral tablet compositions for bilayer tablets with dentifrice. The ratio of layer 1 and layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. *Method limitation means maximum crush strength that can be measured up to 350 N. **Ungranulated sorbitol. starting material
(wt%) l layer Project 70
Whitening Project 71
Cavity Project 72
Sensitivity Non-DC Erythritol fifty fifty fifty DC Isomalt 20.4 30.9 39.4 flavoring 2.5 2.5 2.5 HIS 0.1 0.1 0.1 Binder gum arabic 5 5 0 Binder HPC 0 0 one Sodium lauryl sulfate 2 1.5 2 DC _CaCO3 twenty ten 5 starting material
(wt%) Second layer Project 70 Project 71 Project 72 DC Xylitol fifty fifty fifty Sorbitol** 27.9 35.35 28.35 flavoring 2 2 2 HIS 0.1 0.1 0.1 DC _CaCO3 ten ten ten Sodium lauryl sulfate 2 1.5 2 zinc acetate 0 1.0 0 sodium fluoride 0 0.05 0.05 Bicarbonate of soda 0.5 0 0 calcium pyrophosphate 7.5 0 0 Potassium gluconate 0 0 7.5 Crushing strength [N]* 145 115 107 Abrasion 3.08 2.45 1.87

Each of the compositions shown in Table 16 above was processed into bilayer tablets with the compositions shown in Examples 70-72 and processed according to the flow chart of Examples 42-50. The compositions of Examples 70-72 were further evaluated for wetting effect by a panel of subjects in an intensity versus time scoring model according to the test design of Examples 42-50. The compositions are particularly suitable for dentifrice related effects such as whitening or for sensitive teeth.

Examples 73-75. Obtaining bilayer tablets with a clean label / natural ingredients

Table 17
Oral tablet formulations for bilayer tablets with natural ingredients. The ratio of layer 1 and layer 2 is 55:45. The weight of the tablet is 1.5 g. Therefore, the weight of layer 1 is 0.825 g, while the weight of layer 2 is 0.675 g. The amounts are given in wt.% of the weight of the respective tablet layer. starting material
(wt%) l layer Project 73 Project 74 Project 75 Non-DC Erythritol fifty 0 0 DC Erythritol 37.35 0 0 Non-DC Xylitol 0 fifty 0 DC Xylitol 0 37.35 0 Non-DC Organic Cane Sugar 0 0 fifty DC Organic Tapioca Dextrose 0 0 37.35 natural flavors 2.5 2.5 2.5 Stevia glycoside 0.15 0.15 0.15 Binder gum arabic 5 5 0 DC _CaCO3 5 5 5 starting material
(wt%) Second layer Project 73 Project 74 Project 75 DC Erythritol 92.5 0 0 DC Xylitol 0 92.5 0 DC Organic Tapioca Dextrose 0 0 92.5 natural flavors 2.5 2.5 2.5 DC _CaCO3 5 5 5

Each of the compositions shown in Table 17 above was processed into bilayer tablets with the compositions shown in Examples 73-75 and processed according to the flow chart of Examples 42-50. The compositions of Examples 73-75 were further evaluated for wetting effect on a group of subjects in an intensity versus time scoring model according to the test design of Examples 42-50.

Claims (20)

1. An oral tablet suitable for induced saliva production, wherein the tablet contains the active ingredients included in a particle population, the particle population comprising directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, where non -DC sugar alcohol particles are not granulated prior to tabletting and provide the tablet with a plurality of discrete non-DC regions uniformly distributed in the tablet or at least one tablet module, and where the non-DC regions result in induced saliva production upon tablet chewing, where the non- DC sugar alcohol particles are selected from the group consisting of non-DC particles of erythritol, maltitol, xylitol, isomalt, lactitol, and combinations thereof. 2. An oral tablet according to claim 1, wherein said plurality of particles is tableted in a first module and combined with a second plurality of particles which is tableted in a second module. 3. Tablet for oral administration according to any one of paragraphs. 1 or 2, wherein said plurality of particles is tableted into a first module and combined with a second plurality of particles which is tableted into a second module, wherein the second module does not include non-DC sugar alcohol particles. 4. An oral tablet according to any one of the preceding claims, wherein said plurality of particles is tableted in a first module and combined with a second plurality of particles which is tableted in a second module, wherein the second module is different in composition from the first module. 5. An oral tablet according to any one of the preceding claims, wherein said plurality of particles is tableted in a first module and combined with a second plurality of particles which is tableted in a second module, wherein the second module is an orally disintegrating tablet (ODT). 6. An oral tablet according to any one of the preceding claims, wherein the particle population comprises particles comprising a gum base, and wherein the tablet is intended to be chewed to a coherent residue containing water-insoluble components. 7. An oral tablet according to any one of the preceding claims, wherein the non-DC particles have an average non-DC particle size of at least 50 microns greater than the average DC particle size of the DC particles. 8. An oral tablet according to any one of the preceding claims, wherein at least 20% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 microns. 9. An oral tablet according to any one of the preceding claims, wherein the non-DC sugar alcohol particles are selected from the group consisting of non-DC particles of erythritol, maltitol, xylitol, isomalt, and combinations thereof. 10. An oral tablet according to any one of the preceding claims, wherein the non-DC sugar alcohol particles are non-DC xylitol particles. 11. An oral tablet according to any one of the preceding claims, wherein the non-DC sugar alcohol particles are non-DC isomalt particles. 12. An oral tablet according to any one of the preceding claims, wherein the tablet comprises said non-DC sugar alcohol particles in an amount of at least 10% by weight of the tablet, for example, in an amount of at least 20% by weight of the tablet, for example, in an amount of at least 30% by weight of the tablet. 13. An oral tablet according to any one of the preceding claims, wherein the tablet comprises said DC sugar alcohol particles in an amount of at least 10% by weight of the tablet, for example, in an amount of at least 20% by weight of the tablet, for example, in an amount of at least 30% by weight of the tablet. 14. An oral tablet according to any one of the preceding claims, wherein the tablet comprises one or more binders, other than the binders forming part of the sugar alcohol DC particles, in an amount of 0.1 to 6% by weight of the tablet. 15. An oral tablet according to any one of the preceding claims, wherein the tablet has a weight ratio between said non-DC sugar alcohol particles and said DC sugar alcohol particles that is between 0.2 and 1.2, such as between 0.3 and 0.7. 16. An oral tablet according to any one of the preceding claims, further comprising at least one viscosity modifier. 17. An oral tablet according to any one of the preceding claims, wherein the active ingredient is an active pharmaceutical ingredient. 18. The oral tablet according to any one of the preceding claims, wherein the oral tablet comprises toothpaste and/or dentifrice in an amount of at least 0.1% by weight of the oral tablet. 19. A tablet for oral administration, comprising a set of particles, while the set of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, as defined in any of the preceding paragraphs. 1-18, wherein the oral tablet is for use in alleviating or treating xerostomia. 20. A tablet for oral administration, comprising a set of particles, while the set of particles includes directly compressible (DC) and indirectly compressible (non-DC) sugar alcohol particles, as defined in any of the preceding paragraphs. 1-18, wherein the oral tablet is for use in the alleviation or treatment of dysphagia.

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